EP2158184A2

EP2158184A2 - 4,5-dihydro-(1h)-pyrazole derivatives as cannabinoid cb1 receptor modulators

Info

Publication number: EP2158184A2
Application number: EP08774073A
Authority: EP
Inventors: Mahmut Yildirim; Hendrik C. Wals; Bernard J. Van Vliet; Josephus H.M. Lange
Original assignee: Solvay Pharmaceuticals BV
Current assignee: Abbott Healthcare Products BV
Priority date: 2007-06-15
Filing date: 2008-06-12
Publication date: 2010-03-03
Also published as: WO2008152086A3; CA2688208A1; EA201070019A1; IL202299A0; JP2010530367A; AU2008263915A1; KR20100020998A; WO2008152086A2

Abstract

This invention relates to 4,5-dihydro-(1 H)-pyrazole (pyrazoline) derivatives as cannabinoid CB1 receptor modulators, to pharmaceutical compositions containing these compounds, to methods for their syntheses, methods for preparing novel intermediates useful for their syntheses, and methods for preparing compositions. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in disorders in which CB1 receptors are involved, or that can be treated via manipulation of those receptors. The compounds have formula (I) wherein the symbols have the meanings given in the specification.

Description

4,5-DIHYDRO-(1 H)-PYRAZOLE DERIVATIVES AS CANNABINOID CB₁ RECEPTOR MODULATORS

INDEX page

Title of the invention 1

Index 1

Technical field 1

Background art 1 Disclosure 2

Definitions 7

Abbreviations and specialist terms 13

Example 1 : Materials and methods 14

Example 2: General aspects of syntheses 14 Example 3: Synthesis and spectral data of intermediates 18

Example 4: Syntheses of specific compounds of the invention 27

Example 5: Formulations used in animal studies 43

Example 6: Pharmacological methods 44

Example 7: Pharmacological test results 45 Example 8: Pharmaceutical preparations 46

Bibliography 48

Claims 50

Abstract 57

TECHNICAL FIELD

This invention relates to the fields of pharmaceutical and organic chemistry, and provides 4,5- dihydro-(1 H)-pyrazole (pyrazoline) derivatives as cannabinoid CB₁ receptor modulators, and intermediates and formulations thereof, as well as methods to apply these compounds.

BACKGROUND ART

Cannabinoid (CB) receptors are part of the endocannabinoid system which is involved in neurological-, psychiatric-, cardiovascular-, gastrointestinal-, reproductive- and eating disorders as well as in cancer (De Petrocellis, 2004; Di Marzo, 2004; Lambert, 2005; Vandevoorde, 2005).

CB₂ receptors occur predominantly in the immune system (spleen, tonsils, immune cells), but also in astrocytes, microglial cells, and to some extend in the central nervous system.

CB₂ receptor modulation has been linked to the perception of inflammatory and neuropathic pain, as well as allergies, asthma, multiple sclerosis, osteoporosis and (neuro)inflammatory conditions {Van Sickle, 2005; Giblin, 2007; Ibrahim, 2005; Ashton, 2006, Ofek, 2006).

SR141716A, now known as rimonabant, and other CB₁ receptor modulators, including CB₁ZCB₂ receptor subtype selective receptor antagonists, have several potential therapeutic applications including medicaments for treating psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea, sexual disorders, impulse control disorders and cardiovascular disorders (Boyd, 2005; Sorbera, 2005; Carai, 2005; Lange, 2004 & 2005; Hertzog, 2004; Smith, 2005; Thakυr, 2005; Padgett, 2005; Muccioli, 2005 & 2006; Reggio, 2003; Adam, 2006; Hόgenauer, 2007).

Diarylpyrazoline derivatives having cannabinoid CB₁ receptor antagonistic or inverse agonistic affinity have been claimed in WO 01/70700, WO 03/026647, WO 03/026648, WO 2005/074920, and were described by Lange (2004^{a b}, 2005 ^{a b}). Pyrazoline derivatives which act as agonists or partial agonists on the CB₁ receptor have not been reported yet, but certain pyrazoline derivatives have been claimed as vermin controlling agents (JP 61 189270) and as mitotic kinesin inhibitors (WO2006/068933, WO2003079973).

The objective of the present invention was to develop novel compounds with CB₁ receptor agonistic activity.

DISCLOSURE

Surprisingly, we have found that replacing the 3-aryl or 3-heteroaryl group in 4,5-dihydro- pyrazoles described in WO 01/70700, by a (substituted) alkyl moiety — in combination with (1 ) a different substitution pattern at the 1 -position of the pyrazoline moiety and (2) the presence of one or two alkyl substituents at the 5-position of the pyrazoline moiety — results in novel compounds with potent CB₁ receptor affinity. Some of these compounds were found to act as partial or full agonists at CB₁ receptors. The compounds of the invention also showed affinity for CB₂ receptors. The compounds may act as CB₂ receptor agonists, CB₂ receptor antagonists, or CB₂ receptor inverse agonists. This invention relates to a compound of formula (I):

or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein

- R represents a C_3-i₀ linear alkyl group, a C_4-io branched alkyl group, a C_4-i₀ alkynyl group, a C_3-io-heteroalkyl group or a Cs-s-cycloalkyl-Ci.s-alkyl group, which groups are optionally substituted with 1-3 fluoro, atoms or

R represents an aryl-Ci_-3-alkyl or heteroaryl-Ci_-3-alkyl group, optionally substituted with 1-3 substituents Y, which can be the same or different, chosen from methyl, ethyl, methoxy, ethoxy, halogen, trifluoromethyl, trifluoromethoxy and cyano, or,

R represents a cyclopropyl group, optionally substituted with a Ci_-5-alkyl, benzyl, aryl or heteroaryl group, which groups are optionally substituted with 1-3 substituents Y, wherein Y has the abovementioned meaning,

- R₂ represents an aryl or heteroaryl group, optionally substituted with 1-5 substituents Y, wherein Y has the abovementioned meaning,

- n is either 0 or 1 - R₃ represents a linear or branched C_3-i₀ alkyl group, a C_3-8 cycloalkyl group, C_5-io bicycloalkyl group, C₆-io tricycloalkyl group or C_8-n tetracycloalkyl group, which groups are optionally substituted with 1-5 substituents chosen from methyl, ethyl, hydroxy, amino, fluoro, or R₃ represents a C_3-8 cycloalkyl group substituted with an aryl or heteroaryl group, optionally substituted with 1-5 substituents Y, wherein Y has the meaning given above, or R₃ represents a C_5-8 heterocycloalkyl group, C_6-io bicycloheteroalkyl group, C_7-io tricycloheteroalkyl group, which groups are optionally substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluoro, or

R₃ represents a C_3-8 cycloalkyl-Ci_-3-alkyl group, C_5-io-bicycloalkyl-Ci_-3-alkyl group, C_6-io- tricycloalkyl-Ci-3— alkyl group, which groups are optionally substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluoro, or R₃ represents a branched or linear C_3-8 heterocycloalkyl-d-s-alkyl group, C_5-io bicycloheteroalkyl-d-s-alkyl group, C_6-io tricycloheteroalkyl-d-s-alkyl group, which groups are optionally substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluoro, or R₃ represents an aryl or heteroaryl group, optionally substituted with 1-5 substituents Y, wherein Y has the abovementioned meaning, or

R₃ represents an aryl-Ci_-5— alkyl group, a hetroaryl-Ci_-5-alkyl or a di(hetero)aryl-Ci_-5-alkyl group, in which groups the phenyl or heteroaromatic rings are optionally substituted with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R₃ represents a linear or branched C_4-8 alkenyl or C_4-8 alkynyl group which linear or branched C_4-8 alkenyl or C_4-8 alkynyl group, optionally substituted with 1-3 fluoro atoms, or, when n=1 , R₃ represents a branched or linear C_2-io heteroalkyl group, containing 1-2 heteroatoms selected from N, O or S,

- R₅ represents a hydrogen atom or a Ci_₂ alkyl group, optionally substituted with 1-3 fluoro atoms,

- R₆ represents a Ci_-2 alkyl group, optionally substituted with 1-3 fluoro atoms.

The invention also relates, in some embodiments, to a compound of formula (I) wherein R₂ represents a phenyl, thienyl or pyridyl group, optionally substituted with 1 , 2 or 3 substituents Y, and the other symbols have the meanings given above.

Other embodiments provide one or more compounds of formula (I) wherein n=1 , R₂ represents a phenyl, thienyl or pyridyl group, optionally substituted with 1 , 2 or 3 substituents Y, and the other symbols have the meanings given above.

Further embodiments provide one or more compounds of formula (I) wherein: n=1 , R₂ represents a phenyl, thienyl or pyridyl group, optionally substituted with 1 , 2 or 3 substituents Y, R₅ represents a hydrogen atom or a methyl group, Re represents a methyl group and the other symbols have the meanings as given above.

Further embodiments provide one or more compounds of formula (I) wherein: n=1 , R represents a C_4-8 branched or C_3-8 linear alkyl group, optionally substituted with 1-3 fluoro atoms, R₂ represents a phenyl group, optionally substituted with 1 , 2 or 3 substituents Y, R₅ represents a hydrogen atom or a methyl group, Re represents a methyl group and the other symbols have the meanings as given above. Most particularly the invention relates to compounds of the general formula (I) wherein n=1 , R represents a C3-5 linear alkyl group, R₂ represents a phenyl group, optionally substituted with a halogen atom, R₅ represents a hydrogen atom or a methyl group, R₆ represents a methyl group and the other symbols have the meanings as given above.

The compounds of the invention of the general formula (I), as well as the pharmacologically acceptable salts thereof, have cannabinoid CB₁ receptor modulating activity. The compounds of the invention also have affinity for CB₂ receptors. They are useful in the treatment of disorders in which cannabinoid receptors are involved, or that can be treated via manipulation of those receptors.

Other embodiments of the invention include:

pharmaceutical compositions for treating, for example, a disorder or condition that may be treated by modulating cannabinoid CB₁ receptors, the compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; methods of treatment of a disorder or condition that may be treated by modulating cannabinoid CB₁ receptors, the methods comprising administering to a mammal in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions for treating, for example, a disorder or condition selected from the group consisting of psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including chronic pain, neuropathic pain, acute pain and inflammatory pain, osteoporosis, septic shock, glaucoma, diabetes, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea, sexual disorders, impulse control disorders and cardiovascular disorders; methods of treatment of a disorder or condition selected from the group consisting of the disorders listed herein, the methods comprising administering to a mammal in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions for treatment of a disorder or condition selected from the group consisting of the disorders listed herein, the compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; methods of treatment of a disorder or condition that may be treated by modulating cannabinoid CB₁ receptors, the methods comprising administering to a patient in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof. methods of antagonizing a cannabinoid CB₁ receptor, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I);

The invention also provides the use of a compound or salt according to formula (I) for the manufacture of a medicament. The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed. Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the compounds of the invention.

The invention also provides compounds, pharmaceutical compositions, kits and methods for the treatment of a disorder or condition that may be treated by modulating cannabinoid CB₁ receptors, the method comprising administering to a patient in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of the invention possess cannabinoid CB₁ receptor modulating activity. The (ant)agonizing activities of the compounds of the invention are readily demonstrated, for example, using one or more of the assays described herein or known in the art.

The invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.

All compounds of the present invention do contain at least one chiral centre (at the 4- position of the 4,5-dihydropyrazole ring). Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base, such as for example (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Cis and trans isomers of the compound of formula (I) or a pharmaceutically acceptable salt thereof are also within the scope of the invention, and this also applies to tautomers of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

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

Isotopically-labeled compounds of formula (I) or pharmaceutically acceptable salts thereof, including compounds of formula (I) isotopically-labeled to be detectable by PET or SPECT, are also included within the scope of the invention, and same applies to compounds of formula (I) labeled with [¹³C]-, [¹⁴C]-, [³H]-, [¹⁸F]-, [¹²⁵I]- or other isotopically enriched atoms, suitable for receptor binding or metabolism studies.

The compounds of the invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction and disease.

DEFINITIONS

General terms used in the description of compounds herein disclosed bear their usual meanings. The term alkyl as used herein denotes a univalent saturated, branched or straight, hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te/f-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc. When qualified lower 'lower', the alkyl group will contain from 1 to 6 carbon atoms. The same carbon content applies to the parent term 'alkane', and to derivative terms such as 'alkoxy'. The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C_x-_y defines the number of carbon atoms present from the integer "x" to the integer "y" inclusive. for example, means methyl, ethyl, n-propyl or isopropyl, and 'alkyl(Ci_-4)' means 'methyl, ethyl, n- propyl, isopropyl, n-butyl, 2-butyl, isobutyl or tert-butyl'. The term 'alkenyl' denotes straight or branched hydrocarbon radicals having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, etc., and for example represents (C_2-4)alkenyl. In 'alkynyl' groups the straight or branched hydrocarbon radicals have one or more carbon-carbon triple bonds, such as ethynyl, propargyl, 1-butynyl, 2-butynyl, etc., and for example represent (C_2-4)alkynyl. Unless otherwise stated, 'alkenyl' and 'alkynyl' chains can contain from 1 to 18 carbon atoms.

The term 'acyl' means alkyl(d_-3) carbonyl, arylcarbonyl or aryl-alkyl(d_-3)carbonyl. 'Aryl' embraces mono- or polycyclic aromatic groups, including phenyl, naphthyl, 1 ,2,3,4-tetrahydro- naphtyl, indenyl, fluorenyl, anthracenyl, phenanthrenyl, naphthacenyl and azulenyl. 'Heteroaryl' embraces mono- or polycyclic hetero-aromatic, including furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1-b][1 ,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, 1 ,2,3,4-tetrahydroiso-quinolinyl, indanyl, indenyl, benzo[b]thienyl, 2,3-dihydro- 1 ,4-benzodioxin-5-yl, benzimidazolyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzothiazolyl, benzo[1 ,2,5]thia-diazolyl, purinyl, quinolinyl, isoquinolinyl, quinolizinyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl and pteridinyl.

'Halo' or 'Halogen' means chloro, fluoro, bromo or iodo; 'hetero' as in 'heteroalkyl, heteroaromatic' etc. means containing one or more N, O or S atoms, 'heteroalkyl' includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.

The term "substituted" means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. With reference to substituents, the term "independently" means that when more than one of such substituents are possible, they may be the same or different from each other.

'C_3-8-cycloalkyl' means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopheptyl or cyclooctyl; 'C_5-S heterocycloalkyl' refers to heteroatom containing rings including piperidinyl, morpholinyl, azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl; 'C_5-io bicycloalkyl group' refers to carbo-bicyclic ring systems including bicyclo[2.2.1]heptanyl, bicyclo[3.3.0]octanyl or the bicyclo[3.1.1] heptanyl group; 'C_6-io tricycloalkyl group' refers to carbo-tricyclic ring systems including 1-adamantyl, noradamantyl and 2-adamantyl groups. The abbreviation 'C_8-H tetracycloalkyl group' refers to carbo- tetracyclic ring systems including cubyl, homocubyl and bishomocubyl groups. The terms "oxy", "thio" and "carbo" as used herein as part of another group respectively refer to an oxygen atom, a sulphur atom and a carbonyl (C=O) group, serving as linker between two groups, such as for instance hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl, etc. The term "amino" as used herein alone, or as part of another group, refers to a nitrogen atom that may be either terminal, or a linker between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively) amine. The terms "sulfinyl" and "sulfonyl" as used herein as part of another group respectively refer to an -SO- or an - SO₂- group.

To provide a more concise description, the terms 'compound' or 'compounds' include tautomers, stereoisomers, N-oxides, isotopically-labelled analogues, or pharmacologically acceptable salts, hydrates or solvates, also when not explicitly mentioned.

As used herein, the term "leaving group" (L) shall mean a charged or uncharged atom or group that departs during a substitution or displacement reaction. The term refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples include N-hydroxysuccinimide, N- hydroxybenzotriazole, halides (Br, Cl, I), triflates, mesylates, tosylates, etc.

N-oxides of the compounds mentioned above belong to the invention. Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts to a near quantitative conversion. N-oxides may be more active than their corresponding tertiary amines, or less active. Whilst N-oxides can easily be reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases conversion is a mere trace reaction, or even completely absent (Bickel, 1969). 'Form' is a term encompassing all solids: polymorphs, solvates, amorphous forms.

'Crystal form' refers to various solid forms of the same compound, for example polymorphs, solvates and amorphous forms. 'Cocrystals' are multicomponent crystals with a unique lattice: new chemical species produced with neutral compounds. 'Amorphous forms' are noncrystalline materials with no long range order, and generally do not give a distinctive powder X- ray diffraction pattern. Crystal forms in general have been described by Byrn (1995) and Martin (1995). 'Polymorphs' are crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Polymorphism is a frequently occurring phenomenon, affected by several crystallization conditions such as temperature, level of supersaturation, the presence of impurities, polarity of solvent, rate of cooling. Different polymorphs usually have different X-ray diffraction patterns, solid state NMR spectra, infrared or Raman spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. 'Solvates' are generally a crystal form that contains either stoichiometric or non-stoichiometric amounts of a solvent. Often, during the process of crystallization some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. Common solvents in solvates include: DMF, DMSO, dioxane, p-xylene, benzene, THF, acetonitrile, acetic acid, carbon tetrachloride, toluene, dichloromethane, chloroform, methanol, acetone, 1-propanol, cyclohexamen, ethyl acetate, ethanol, diethyl ether and hexane. When the solvate is water, 'hydrates' may be formed. Such hydrates are also encompassed in the present invention. Examples include % hydrate, dihydrochloride dihydrate, etc. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to experimental or measurement conditions for such given value.

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

While it may be possible for the compounds of formula (I) to be administered as the raw chemical, it is preferable to present them as a 'pharmaceutical composition'. According to a further aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I), at least one pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, together with one or more pharmaceutically acceptable carriers thereof, and with or without one or more other therapeutic ingredients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "composition" as used herein encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. In relation to pharmaceutical compositions, this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The affinity of the compounds of the invention for cannabinoid CB₁ receptors was determined as described below. From the binding affinity measured for a given compound of formula (I), one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured K-value, nearly 100% of the cannabinoid CB₁ receptors likely will be occupied by the compound. Converting that concentration to mg of compound per kg of patient, yields a theoretical lowest effective dose, assuming ideal bioavailability.

Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, and may be determined by a physician. In general, total daily dose administration to a patient in single or individual doses, may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily, and more usually from 0.01 to 1 ,000 mg per day, of total active ingredients. Such dosages will be administered to a patient in need of treatment from one to three times each day, or as often as needed for efficacy, and for periods of at least two months, more typically for at least six months, or chronically.

The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating the conditions listed herein. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance. A "pharmaceutical salt' is an acid:base complex containing an active pharmaceutical ingredient (API) along with additional non-toxic molecular species in the same crystal structure. The term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids (Berge, 1977). Common anions used in pharmaceutically acceptable salts include: chloride, bromide, sulfate, nitrate, phosphate, bicarbonate, mesylate, esylate, isothianate, tosylate, napsylate, besylate, acetate, propionate, maleate, benzoate, salicylate, fumarate, citrate, lactate, maleate, tartrate, pamoate, succinate, glycolate, hexanoate, octanoate, decanoate, stearate, oleate, aspartate and glutamate. Common cations used as counterions in pharmaceutically acceptable salts include: sodium, potassium, calcium, magnesium, lithium, zinc, aluminum, arginine, lysine, histidine, triethylamine, ethanolamine, triethanolamine, ethilenediamine, meglumine, procaine and benzathine.

The 'free base' form may be regenerated by contacting the salt with a base or acid, and isolating the parent compound in the conventional matter. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. 'Complex' refers to a complex of the compound of the invention, e.g. formula (I), complexed with a metal ion, where at least one metal atom is chelated or sequestered. Complexes are prepared by methods well known in the art (Dwyer, 1964).

The term "treatment" as used herein refers to any treatment of a mammalian, for example human condition or disease, and includes: (1 ) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease. The term 'inhibit' includes its generally accepted meaning which includes prohibiting, preventing, restraining, alleviating, ameliorating, and slowing, stopping or reversing progression, severity, or a resultant symptom. As such, the present method includes both medical therapeutic and/or prophylactic administration, as appropriate. As used herein, the term "medical therapy" intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. 'Mammals' include animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred. The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. ABBREVIATIONS AND SPECIALIST TERMS

ACN acetonitrile

API active pharmaceutical ingredient API-ES atmospheric pressure ionization - electron spray

BOC te/f-butoxycarbonyl

BSA bovine serum albumin

CB₁ cannabinoid receptor subtype-1

CB₂ cannabinoid receptor subtype-2 CHO Chinese Hamster Ovary (cells)

CNS central nervous system

CUR curtain gas

DF deflector voltage

DIPEA Λ/,Λ/-diisopropylethylamine DMAP 4-dimethylaminopyridin

DMEM Dulbecco's Modified Eagle's Medium

DMF N,N'-dimethylformamide

DMSO dimethylsulfoxide

DSC differential scanning calorimetry EDCI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EP entrance potential

Et₃N triethylamine

FP focusing potential g gram(s) h hour(s)

HOBt N-hydroxybenzotriazole

HPLC high performance liquid chromatography

IBMX 3-isobutyl-1 -methylxanthine

IS ionspray voltage MeOH methanol mg milligram(s) min minute(s) ml milliliter(s) m.p. melting point e.g. melting range MTBE methyl te/f-butylether

NBS N-bromosuccinimide

NEB nebulizer gas

NMM N-methylmorpholine NMR-NOE nuclear magnetic resonance-nuclear Overhauser effect

PBS phosphate buffered saline

PET positron emission tomography

R_f retention factor (thin layer chromatography) R₁ retention time (LC/MS)

RT room temperature

SPECT single photon emission computed tomography

TEM temperature

THF tetrahydrofuran

EXAMPLES

EXAMPLE 1 : MATERIALS AND METHODS

¹H NMR spectra were recorded on either a Varian 300 MHz instrument, a Varian UN400 instrument (400 MHz) using DMSO-c/₆ or CDCI₃ as solvents with tetramethylsilane as an internal standard. ¹³C NMR spectra were recorded on a Varian UN400 instrument using CDCI₃ as solvent. Chemical shifts are given in ppm (δ scale) downfield from tetramethylsilane. Coupling constants (J) are expressed in Hz. Flash chromatography was performed using silica gel 60 (0.040-0.063 mm, Merck). Column chromatography was performed using silica gel 60 (0.063- 0.200 mm, Merck). Sepacore chromatographic separations were carried out using Supelco equipment, VersaFLASH™ columns, VersaPak™ silica cartridges, Bϋchi UV monitor C-630, Bϋchi Pump module C-605, Bϋchi fraction collector C-660 and Bϋchi pump manager C-615. Melting points were recorded on a Bϋchi B-545 melting point apparatus or determined by DSC methods. Optical rotations ([α]_D) were measured on an Optical Activity polarimeter. Specific rotations are given as deg/dm, the concentration values are reported as g/100 ml. of the specified solvent and were recorded at 23 ⁰C.

EXAMPLE 2: GENERAL ASPECTS OF SYNTHESES

Pyrazoline derivatives can be obtained by published methods (Barluenga, 1999 (and references cited therein); Wang, 2003). The synthesis of compounds having formula (I) is outlined in Scheme 1. Ketone derivatives of general formula (II) can be made by various methods known to those skilled in the art. Examples are the application of a Weinreb amide RC(=O)N(OCH₃)CH₃ which can be reacted with a Grignard reagent R₂CH₂MgCI or R₂CH₂MgBr or a reaction of RMgBr or RMgCI with a Weinreb amide of general formula R₂CH₂C(=O)N(OCH₃)CH₃. Alternatively, a Grignard reagent R₂CH₂MgCI or R₂CH₂MgBr can be reacted with HCN, followed by acidic hydrolysis, for example by using hydrochloric acid. A ketone derivative of general formula (II) wherein R and R₂ have the abovementioned meaning can be reacted with a halogenide derivative of general formula R₅R₆CHI in the presence of a base, such as sodium methoxide to give a compound of general formula (Na), wherein R, R₂, R₅ and R₆ have the abovementioned meaning. The compound of general formula (Na) can be reacted with a brominating agent such as Λ/-bromosuccinimide (NBS), preferably in the presence of a radical initiator such as dibenzoyl peroxide in an inert organic solvent such as carbon tetrachloride to give a compound of formula (lib), wherein R₁ R₂, R₅ and Re have the abovementioned meaning. The compound of general formula (lib) can be reacted in an elimination reaction with lithium chloride at elevated temperature in an organic solvent such as dimethylformamide to give a compound of formula (III), wherein R₁ R₂, R₅ and Re have the abovementioned meaning. The enone derivative of general formula (III) can be reacted with hydrazine, a hydrazine salt or hydrazine hydrate to give a 4,5-dihydropyrazole derivative of formula (IV).

A compound of formula (IV) can be reacted with a carboxylic acid R₃-CO₂H wherein R₃ has the abovementioned meaning in the presence of an 'activating reagent' or coupling reagent in an inert organic solvent such as dichloromethane to give a pyrazoline derivative of general formula (I), wherein n=0 and all other symbols have the meanings as given above. Additional information on activating and coupling methods of amines to carboxylic acids can be found in the literature {Bodanszky, 1994; Akaji, 1994; Albericio, 1997; Montalbetti, 2005).

Alternatively, a compound of formula (IV) wherein R, R₂, R₅ and R₆ have the abovementioned meaning can be reacted with an acid chloride R₃-COCI wherein R₃ has the abovementioned meaning to give a pyrazoline derivative of general formula (I), wherein n=0 and all other symbols have the meanings as given above. Such a reaction is preferably carried out in the presence of a base such as triethylamine or DIPEA (Hϋnig's base). A compound of formula (IV) wherein R, R₂, R₅ and R₆ have the abovementioned meaning can be reacted with an isocyanate derivative R₃-N=C=O (VII) wherein R₃ has the abovementioned meaning in the presence of an inert organic solvent such as diethyl ether to give a pyrazoline-1- carboxamide derivative of general formula (I), wherein n=1 and all other symbols have the meanings as given above, lsocyanates R₃-N=C=O can also be prepared in situ from the corresponding amine R₃-NH₂ and a carbonyl donor such as phosgene, diphosgene (trichloromethyl chloroformate) or triphosgene (bis(trichloromethyl) carbonate). Alternatively, isocyanates R₃-N=C=O can be prepared from the corresponding carboxylic acid R₃-COOH via the acylazide R₃-CON₃ in a Curtius rearrangement.

Alternatively, a Weinreb amide of general formula (Ilia) (which can be obtained from the corresponding acrylic acid derivatives according to methods well known to those skilled in the art) wherein R₅ and R₆ have the abovementioned meaning can be reacted with a Grignard reagent of formula RMgBr wherein R has the abovementioned meaning in the presence of an inert organic solvent such as tetrahydrofuran, to give a ketone derivative of formula (NIb). Compounds of formula (1Mb) can also be prepared from a Weinreb amide of general formula R- C^=O)-N(OCH₃)CH₃ and an olefinic Grignard reagent of general formula R₅R₆C=CHMgBr wherein R₅ and R₆ have the abovementioned meaning. The resulting ketone derivative of general formula (1Mb) can be brominated at its olefinic bond with bromine in the presence of an inert organic solvent such as dichloromethane, followed by reaction with a base such as triethylamine to afford a compound of general general formula (NIc) in a so-called one-pot reaction. The compound of general general formula (NIc) can be reacted in a transition metal- catalyzed cross-coupling reaction, such as the so-called Suzuki-Miyaura reaction (Miyaura, 1995) with a compound of general formula R₂-B(OH)₂ in the presence of a palladium-based catalyst such as Pd(OAc)₂ and a suitable ligand, such as X-Phos, Ruphos or S-Phos and the like to give a compound of general formula (III), wherein R₁ R₂, R₅ and R₆ have the abovementioned meaning.

(I) wherein n = O

(I) wherein n = 1

Scheme 1

Alternatively, a compound of formula (IV), wherein R, R₂, R₅ and R₆ have the abovementioned meaning can be reacted with phosgene, diphosgene or triphosgene to give a compound of formula (VIII) wherein R and R₂ have the abovementioned meaning (Scheme 2). Such a reaction is preferably carried out in the presence of a base such as triethylamine or DIPEA (Hϋnig's base). A compound of formula (VIII) can be reacted in an inert solvent such as dichloromethane with a compound NH₂R3 to give a pyrazoline-1-carboxamide derivative of formula (I), wherein n=1.

NH₂R ^V3

Scheme 2

The selection of the particular synthetic procedures depends on factors known to those skilled in the art such as the compatibility of functional groups with the reagents used, the possibility to use protecting groups, catalysts, activating and coupling reagents and the ultimate structural features present in the final compound being prepared.

Compounds of the general formula (III) wherein R is chosen from phenyl, pyridyl or thienyl, optionally substituted with 1-3 substituents Y1 wherein Y1 is chosen from halogen, methyl, CF₃, OCF₃ or OCH₃, and R₂ represents a n-propyl, n-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1 ,1- dimethylbutyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or 1 ,1-dimethyl-3,3,3-trifluoropropyl group are new. Such compounds are useful in the synthesis of compounds of the general formula (I). Compounds of formula (IV) wherein R, R₂, R₅ and R₆ have the same meanings as given above are new. Such compounds are useful in the synthesis of compounds of formula (I). Compounds of formula (VIII) wherein R, R₂, R₅ and R₆ have the same meanings as given above, are new. They are useful at synthesizing compounds of formula (I) wherein n = 1.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, e.g. by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid such as hydrochloric acid, or with an organic acid such as fumaric acid. According to these procedures the compounds described below have been prepared. They are intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is thus intended that the specification and examples be considered as exemplary only. EXAMPLE 3: SYNTHESIS AND SPECTRAL DATA OF INTERMEDIATES

Intermediate 11-1

/ Intermediate 11-1 °

Part A: To a magnetically stirred solution of valeric acid (10.9 ml, 0.1 mol) in dichloromethane (200 ml) was successively added: N-methyl-N-methoxy-amine. hydrochloride (10.14 gram, 0.104 mol), N-methylmorpholine (22.9 ml, 0.208 mol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide.HCI (EDCI) (19.92 gram, 0.104 mol) and HOBt (14.04 gram, 0.104 mol) and the resulting mixture was reacted for 20 hours at room temperature. The obtained suspension was successively washed with water, aqueous citric acid (a solution of 24 gram citric acid in 250 ml H₂O) and 5 % aqueous NaHCO₃. The organic layer was dried over Na₂SO₄, filtered and concentrated to give pentanoic acid methoxy-methyl-amide (12.31 gram, 85 % yield) as a colorless oil. ¹H-NMR (400 MHz, CDCI₃) δ 0.93 (t, J = 7, 3H), 1.31-1.43 (m, 2H), 1.57-1.66 (m, 2H), 2.42 (br t, J = 7, 2H), 3.18 (s, 3H), 3.69 (s, 3H).

Part B: To a magnetically stirred solution of pentanoic acid methoxy-methyl-amide (8.6 g, 59.3 mmol) at 0 ⁰C in anhydrous THF (100 ml) was slowly added benzylmagnesium chloride (2 M solution in THF, 45 ml, 90 mmol) and the resulting mixture was reacted for 20 hours in a nitrogen atmosphere at room temperature. The reaction mixture was poured in excess of a cold (0 ⁰C) aqueous hydrochloric acid (4 N solution) and extracted with MTBE. The organic layer was dried over Na₂SO₄, filtered and concentrated to give crude product. This crude product was further purified using Sepacore equipment: Gradient: (petroleum ether/diethyl ether = 98/2 (v/v)) => (petroleum ether/diethyl ether = 95/5 (v/v)) to give 1-phenylhexan-2-one (Intermediate 11-1 ) (7.38 gram, 71 % yield) as a colorless oil; ¹H-NMR (400 MHz, CDCI₃) δ 0.86 (t, J = 7, 3H), 1.21- 1.31 (m, 2H), 1.48-1.58 (m, 2H), 2.41-2.47 (m, 2H), 3.68 (s, 2H), 7.18-7.36 (m, 5H).

Intermediate lla-1

/ Intermediate lla-1 v ¹J \ — A \ / Intermediate lla-2

\ — o

To an ice-cold magnetically stirred mixture of 1-phenylhexan-2-one (Intermediate 11-1 ) (7.04 gram, 0.04 mol) and sodium methoxide (4.32 g, 0.08 mol) was added dropwise 2-iodopropane (15 ml) in a nitrogen atmosphere. The resulting mixture was heated for 1 hour at reflux temperature. The obtained mixture was allowed to attain room temperature and concentrated. The resulting residue was taken up in diethyl ether and water. The diethyl ether layer was separated and successively washed with an aqueous Na₂S₂θ3 solution and water. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was further purified using Sepacore equipment: (petroleum ether/diethyl ether = 19/1 (v/v)) to give 2-methyl-3-phenyl- octan-4-one (Intermediate lla-1 ) (3.52 gram) as a colorless oil; ¹H-NMR (400 MHz, CDCI₃) δ 0.66 (d, J = 7, 3H), 0.81 (t, J = 7, 3H), 0.96 (d, J = 7, 3H), 1.10-1.24 (m, 2H), 1.36-1.54 (m, 2H), 2.29-2.47 (m, 3H), 3.30 (d, J = 10 Hz, 1 H), 7.20-7.33 (m, 5H). R_f (petroleum ether/diethyl ether = 98/2 (v/v)) ~ 0.25.

Analogously, 3-phenyloctan-4-one (intermediate lla-2) was prepared from 1-phenylhexan-2-one (Intermediate 11-1 ), sodium methoxide and iodoethane in 60 % yield. ¹H-NMR (400 MHz, CDCI₃) δ 0.81 (d, J = 7, 3H), 0.83 (t, J = 7, 3H), 1.11-1.24 (m, 2H), 1.38-1.55 (m, 2H), 1.64-1.76 (m, 1 H), 2.00-2.1 1 (m, 1 H), 2.28-2.42 (m, 2H), 3.53 (t, J = 7 Hz, 1 H), 7.18-7.26 (m, 3H), 7.28-7.34 (m, 3H).

Intermediate llb-1

Intermediate llb-2

To a magnetically stirred solution of 2-methyl-3-phenyloctan-4-one (Intermediate lla-1 ) (4.31 gram, 0.02 mol) in CCI₄ (40 ml) was added a catalytic amount of dibenzoyl peroxide and NBS (6.56 gram). The resulting mixture was heated for 6 hours at reflux temperature. The obtained mixture was allowed to attain room temperature. The formed precipitate was removed by filtration. The filtrate was concentrated to give crude 2-methyl-3-bromo-3-phenyloctan-4-one (intermediate llb-1 ) - contaminated with some starting material - as a dark-colored oil (6.77 gram). ¹H-NMR (400 MHz, CDCI₃) Characteristic signals: δ 0.68 (d, J = 6, 3H), 0.78 (t, J = 7, 3H), 1.08 (d, J = 6, 3H).

Analogously, 3-bromo-3-phenyloctan-4-one (intermediate llb-2) was prepared in 74 % yield from 3-phenyloctan-4-one (Intermediate lla-2), dibenzoyl peroxide and NBS in CCI₄. R_f (petroleum ether/diethyl ether = 99/1 (v/v)) = 0.2. ¹H-NMR (400 MHz, CDCI₃) δ 0.81 (t, J = 7, 3H), 0.84 (t, J = 7, 3H), 1.14-1.24 (m, 2H), 1.41-1.62 (m, 2H), 2.20-2.47 (m, 3H), 2.65-2.75 (m, 1 H), 7.29-7.43 (m, 5H). Intermediate III-1

Intermediate I 11-1

Intermediate I II-2

The crude 2-methyl-3-bromo-3-phenyloctan-4-one (intermediate llb-1 ) was dissolved in magnetically stirred anhydrous DMF (35 ml) under a nitrogen atmosphere. Lithium chloride (3.2 gram, 0.075 mol) was added and the resulting mixture was heated at 130 ⁰C for 90 minutes. The resulting mixture was allowed to attain room temperature and was subsequently poured into water and extracted with diethyl ether. The organic layer was separated and washed with water (4 portions). The organic layer was dried over Na₂SC>₄, filtered and concentrated. The obtained residue was purified using Sepacore equipment: (petroleum ether/diethyl ether = 98/2 (v/v)) to give 2-methyl-3-phenyloct-2-en-4-one (Intermediate 111-1 ) (1.96 gram, 46 % yield) as a pale yellow oil; ¹H-NMR (400 MHz, CDCI₃) δ 0.81 (d, J = 7, 3H), 1.13-1.24 (m, 2H), 1.43-1.52 (m, 2H), 1.66 (s, 3H), 2.00 (s, 3H), 2.25 (t, J = 7, 2H), 7.15 (br d, J = 8, 2H), 7.20-7.39 (m, 3H). Analogously 3-phenyloct-2-en-4-one (Intermediate III-2; one stereoisomer) was prepared from 3-bromo-3-phenyloctan-4-one (intermediate llb-2) and LiCI in DMF in 57 % yield using Sepacore equipment: (petroleum ether/diethyl ether = 97/3 (v/v)). R_f (petroleum ether/diethyl ether = 95/5 (v/v)) ~ 0.15. ¹H-NMR (400 MHz, CDCI₃) δ 0.87 (d, J = 7, 3H), 1.23-1.34 (m, 2H), 1.52-1.61 (m, 2H), 1.72 (d, J = 7, 3H), 2.53 (t, J = 7, 2H), 6.97 (q, J = 7, 1 H), 7.10 (br d, J = 8, 2H), 7.29-7.41 (m, 3H).

Intermediate III-3

Intermediate III-3 Intermediate III-5

To a magnetically stirred solution of 3-bromo-2-methyl-oct-2-en-4-one (5 gram, 20.54 mmol) (Intermediate lllc-1 ) in nitrogen-degassed n-butanol (50 ml) was successively added thiophene- 3-boronic acid (3.94 gram, 30.80 mmol), palladium(ll)acetate (46.11 mg, 0.21 mmol), 2- dicyclohexylphosphino-2',6'-dimethoxy-1 ,1 '-biphenyl (S-Phos) (168.6 mg, 0.41 mmol) and K₃PO₄ (8.72 g, 41.07 mmol) and the resulting mixture was reacted at 100 ⁰C for 2 hours. The mixture was concentrated in vacuo and purified by sepacore chromatography (40x150 mm column), eluant: (Gradient: eluant 1 : petroleum ether (40-60); Eluant 2: petroleum ether (40- 60)/diethyl ether = 95/5 (v/v)) to give 3-(3-thienyl)-2-methyl-oct-2-en-4-one (2.80 gram, 55 %). ¹H-NMR (400 MHz, CDCI₃) δ 0.83 (t, J = 7, 3H), 1.17-1.27 (m, 2H), 1.45-1.54 (m, 2H), 1.72 (s, 3H), 1.97 (s, 3H), 2.30 (t, J = 7.4, 2H), 6.92 (br d, J = 5, 1 H), 7.04 (br d, J = 3, 1 H), 7.33 (dd, J = 5 and 3, 1 H).

Analogously, 3-(3-benzothienyl)-oct-2-en-4-one (Intermediate III-4) was prepared from 3-bromo- 2-methyl-oct-2-en-4-one. ¹H-NMR (400 MHz, CDCI₃) δ 0.75 (t, J = 7, 3H), 1.08-1.19 (m, 2H), 1.39-1.50 (m, 2H), 1.63 (s, 3H), 2.14 (s, 3H), 2.20 (t, J = 7.4, 2H), 7.21 (s, 1 H), 7.36-7.41 (m, 2H), 7.56-7.59 (m, 1 H), 7.88-7.92 (m, 1 H).

Analogously, 7,7,7-trifluoro-3-phenyl-2-methyl-hept-2-en-4-one (Intermediate III-5) was prepared from intermediate lllc-2 and phenylboronic acid (Ph-B(OH)₂). ¹H-NMR (400 MHz, CDCI₃) δ 1.66 (s, 3H), 2.07 (s, 3H), 2.28-2.49 (m, 4H), 7.14 (d, J = 8, 2H), 7.30-7.42 (m, 3H).

And using analogous methods also the intermediates III-6 - 111-1 1 were synthesized:

Intermediate III-6 Intermediate III-7 Intermediate III-8

Intermediate III-9 Intermediate 111-10 Intermediate 111-11

Intermediate III-6 (5-methyl-1 ,4-diphenyl-hex-4-en-3-one) was prepared from intermediate lllc-3 and Ph-B(OH)₂. ¹H-NMR (400 MHz, CDCI₃) δ 1.64 (s, 3H), 2.00 (s, 3H), 2.56 (t, J = 7, 2H), 2.81 (t, J = 7, 2H), 7.04 (d, J = 8, 2H),7.08-7.36 (m, 8H).

Intermediate III-7 (2-phenyl-3-methyl-1-(2-phenyl-trans-cyclopropyl)but-2-en-1-one) was from intermediate lllc-4 and Ph-B(OH)₂. ¹H-NMR (400 MHz, CDCI₃) δ 1.15-1.24 (m, 1 H), 1.66-1.72 (m, 4H), 2.02-2.08 (m, 4H), 2.47-2.54 (m, 1 H), 6.90 (br d, J = 8, 2H), 7.08-7.34 (m, 8H). Intermediate 111-8 (2-methyl-3-(4-chlorophenyl)oct-2-en-4-one) was prepared from 2-methyl-3- bromo-oct-2-en-4-one and 4-chlorophenylboronic acid. ¹H-NMR (400 MHz, CDCI₃) δ 0.82 (t, J = 7.4, 3H), 1.14-1.25 (m, 2H), 1.43-1.53 (m, 2H), 1.66 (s, 3H), 2.00 (s, 3H), 2.24 (t, J = 7.4, 2H), 7.09 (d, J = 8, 2H), 7.33 (d, J= 8, 2H).

Intermediate III-9 (2-methyl-3-(3-fluorophenyl)oct-2-en-4-one) was prepared from 2-methyl-3- bromo-oct-2-en-4-one and 3-fluorophenylboronic acid. ¹H-NMR (400 MHz, CDCI₃) δ 0.82 (t, J = 7.4, 3H), 1.13-1.24 (m, 2H), 1.43-1.53 (m, 2H), 1.66 (s, 3H), 2.01 (s, 3H), 2.26 (t, J = 7.4, 2H), 6.86-7.03 (m, 3H), 7.29-7.36 (m, 1 H).

Intermediate 111-10 (2-methyl-3-(2-methoxyphenyl)oct-2-en-4-one) was prepared from 2-methyl- 3-bromo-oct-2-en-4-one and 2-methoxyphenylboronic acid. ¹H-NMR (400 MHz, CDCI₃) δ 0.80 (t, J = 7.4, 3H), 1.12-1.23 (m, 2H), 1.41-1.50 (m, 2H), 1.64 (s, 3H), 2.09 (s, 3H), 2.17 (t, J = 7.2, 2H), 3.77 (s, 3H), 6.89 (d, J = 8, 1 H), 6.93-6.98 (m, 1 H), 7.09 (dd, J = 8 and 2, 1 H), 7.27-7.33 (m, 1 H).

Intermediate 111-1 1 (2-methyl-3-(2-fluorophenyl)oct-2-en-4-one) was prepared 2-methyl-3-bromo- oct-2-en-4-one and 2-fluorophenylboronic acid. ¹H-NMR (400 MHz, CDCI₃) δ 0.81 (t, J = 7.4, 3H), 1.14-1.24 (m, 2H), 1.43-1.53 (m, 2H), 1.64 (s, 3H), 2.10 (s, 3H), 2.23 (t, J = 7.4, 2H), 7.08- 7.18 (m, 3H), 7.28-7.36 (m, 1 H)..

Intermediate llla-1

To a magnetically stirred solution of 3,3-dimethylacrylic acid (25.0 gram, 250 mmol) in dichloromethane (400 ml) were successively added N, O-dimethylhydroxylamine. hydrochloride (26.79 gram, 275 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide. hydrochloride (52.66 gram, 275 mmol) and 1-hydroxybenzotriazole (16.87 gram, 124.8 mmol). The mixture was cooled with an ice-bath and N-methylmorpholine (82.36 ml, 749 mmol) was added and the resulting mixture was stirred at room temperature for 20 hours. Water (100 ml) was added and the organic layer was separated, and successively washed with citric acid (0.5 M aqueous solution), NaHCO₃ (5% aqueous solution) and brine, dried over MgSO₄, filtered and concentrated to give N-methoxy-N-methyl-acrylamide (29.53 gram, 78.5 % yield). ¹H-NMR (400 MHz, CDCI₃) δ 1.91 (d, J = 2 Hz, 3H), 2.14 (d, J = 2 Hz, 3H), 3.20 (s, 3H), 3.68 (s, 3H), 6.12 (br s, 1 H).

Intermediate lllb-1

To a magnetically stirred and ice-cooled solution of N-methoxy-N-methyl-acrylamide (20 gram, 132.7 mmol) in anhydrous tetrahydrofuran (200 ml) in a nitrogen atmosphere was slowly added n-butylmagnesium chloride (132.7 ml, 2 M solution in diethyl ether, 265 mmol) and the resulting mixture was stirred for 30 minutes. The resulting mixture was allowed to attain room temperature and stirred for 40 hours. An aqueous ammonium chloride solution (15 gram dissolved in 100 ml water) was slowly added, followed by addition of ethyl acetate (100 ml). The organic layer was separated, washed with brine, dried over MgSO₄, filtered and concentrated in vacuo to give crude 2-methyl-oct-2-en-4-one. Sepacore (80x150 mm column) separation (eluant: petroleum ether (40-60)/diethyl ether = 95/5 (v/v)) gave 2-methyl-oct-2-en-4-one (Intermediate lllb-1 ) as a colorless oil (9.30 gram, 47 % yield). ¹H-NMR (400 MHz, CDCI₃) δ 0.91 (t, J = 7.2 Hz, 3H), 1.27-1.38 (M, 2H), 1.52-1.62 (m, 2H), 1.89 (s, 3H), 2.14 (s, 3H), 2.39 (t, J = 7.4 Hz, 2H), 6.08 (br s, 1 H).

Intermediates lllb-2, lllb-3 and lllb-4

Intermediate lllb-2 Intermediate lllb-3 Intermediate lllb-4

To a solution of 4,4,4-trifluoro-N-methoxy-N-methyl-butyramide (6.17 g; 33.3 mmol) in anhydrous THF (100 ml) at 0 ⁰C was added dropwise 2-methyl-1-propenylmagnesium bromide (100 ml; 0.50 mol/l solution in THF; 50 mmol). The obtained mixture was stirred overnight at room temperature. The reaction mixture turned yellow and cloudy. 5 ml Water in 50 ml THF was added dropwise, followed by addition of 100 ml 5 M HCI. The resulting mixture was stirred for 15 minutes. 200 ml of brine was added and the resulting mixture was extracted three times with 200 ml dichloromethane. The organic layers were combined and successively dried and concentrated in vacuo to give 5.52 g of a dark red oil. Flash chromatographic purification (silica gel, gradient elution with petroleum ether (40-65)/ diethylether = 98/2→95/5 (v/v)) yielded (3.14 g) 7,7,7-trifluoro-2-methyl-hept-2-en-4-one. (Intermediate lllb-2). ¹H-NMR (400 MHz, CDCI₃) δ 1.91 (br s, 3H), 2.17 (br s, 3H), 2.36-2.48 (m, 2H), 2.68 (br t, J = 7 Hz, 2H), 6.08 (br t, J = 2, 1 H).

Using analogous methods, intermediates lllb-3 and lllb-4 were synthesized:

Intermediate lllb-3: 5-methyl-1-phenyl-hex-4-en-3-one: ¹H-NMR (400 MHz, CDCI₃) δ 1.85 (br s, 3H), 2.14 (br s, 3H), 2.70 (t, J = 7, 2H), 2.90 (t, J = 7 Hz, 2H), 6.04 (br t, J = 2, 1 H), 7.12-7.18 (m, 3H), 7.21-7.27 (m, 2H).

Intermediate lllb-4: 3-methyl-1-(2-phenyl-trans-cyclopropyl)but-2-en-1-one: ¹H-NMR (400 MHz, CDCI₃) δ 1.29-1.36 (m, 1 H), 1.66-1.72 (m, 1 H), 1.88 (br s, 3H), 2.13-2.18 (m, 4H), 2.47-2.54 (m, 1 H), 6.23 (br s, 1 H), 7.08 (d, J = 8, 2H), 7.14-7.19 (m, 1 H), 7.22-7.28 (m, 2H).

Intermediates lllc-1 , lllc-2, lllc-3 and lllc-4

Intermediate lllc-1 Intermediate lllc-2 Intermediate lllc-3 Intermediate lllc-4

To a magnetically stirred and ice-cooled solution of 2-methyl-oct-2-en-4-one (9.30 gram, 63 mmol) in dichloromethane (90 ml) was slowly added bromine (3.23 ml, 33 mmol; dissolved in 10 ml dichloromethane) and the resulting mixture was stirred for 10 minutes. To the obtained mixture was slowly added triethylamine (13.10 ml, 94.5 mmol: dissolved in 25 ml dichloromethane). The resulting mixture was allowed to attain room temperature and stirred for 1 hour and subsequently stirred for 16 hours at 40 ⁰C. The obtained mixture was washed with 1 N HCI (100 ml), dried over MgSO₄, filtered and concentrated in vacuo to give crude 3-bromo-2- methyl-oct-2-en-4-one. Sepacore (40x300 mm column) separation (Gradient: first eluant: petroleum ether (40-60); second eluant: petroleum ether (40-60)/diethyl ether = 98/2 (v/v)); third eluant: petroleum ether (40-60)/diethyl ether = 95/5 (v/v)) gave 3-bromo-2-methyl-oct-2-en-4- one (Intermediate lllc-1 ) pale-yellow oil (11.80 gram, 77 % yield). ¹H-NMR (400 MHz, CDCI₃) δ 0.92 (t, J = 7.2 Hz, 3H), 1.29-1.39 (m, 2H), 1.56-1.66 (m, 2H), 2.00 (br s, 6H), 2.78 (t, J = 7.4 Hz, 2H).

Using analogous methods, intermediates lllc-2, lllc-3 and lllc-4 were synthesized: Intermediate lllc-2: 7,7,7-trifluoro-3-bromo-2-methyl-hept-2-en-4-one: ¹H-NMR (400 MHz,

CDCI₃) δ 2.04 (s, 3H), 2.08 (s, 3H), 2.38-2.50 (m, 2H), 3.09 (t, J = 7 Hz, 2H).

Intermediate lllc-3: 4-bromo-5-methyl-1-phenyl-hex-4-en-3-one: ¹H-NMR (400 MHz, CDCI₃) δ 1.97 (s, 3H), 1.99 (s, 3H), 2.91-2.98 (m, 2H), 3.10-3.14 (m, 2H), 7.16-7.31 (m, 5H).

Intermediate lllc-4: 2-bromo-3-methyl-1-(2-phenyl-trans-cyclopropyl)but-2-en-1-one: ¹H-NMR (400 MHz, CDCI₃) δ 1.43-1.50 (m, 1 H), 1.75-1.81 (m, 1 H), 2.00 (s, 3H), 2.01 (s, 3H), 2.56-2.63 (m, 1 H), 2.66-2.73 (m, 1 H), 7.13-7.32 (m, 5H).

Intermediate IV-1

To a magnetically stirred solution of 2-methyl-3-phenyloct-2-en-4-one (Intermediate 111-1 ) (1.96 gram, 9.07 mmol) in absolute ethanol (15 ml) was added hydrazine. hydrate (0.88 ml, 18.14 mmol) and the resulting solution was heated at reflux temperature for 4 hours under a nitrogen atmosphere. The resulting solution was allowed to attain room temperature, concentrated and taken up in a mixture of MTBE and water. The organic layer was collected, dried over MgSO₄, filtered and concentrated to give crude 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1 ) (2.06 gram) as an oil. ¹H-NMR (400 MHz, CDCI₃) δ 0.80-0.89 (m, 6H), 1.23- 1.37 (m, 5H), 1.42-1.54 (m, 2H), 2.06-2.35 (m, 2H), 3.52 (s, 1 H), 4.90 (br s, 1 H), 7.07 (br d, J ~ 8 Hz, 2H), 7.19-7.38 (m, 3H).

Intermediates VIM and VII-2

Intermediate Vl I-2 To a magnetically stirred solution of diphosgene (4.26 ml, 0.0353 mol) in dichloromethane (90 ml) was slowly added a solution of endo-(1 R, 2S, 4R-)-1 ,7,7-trimethylbicyclo[2.2.1]hept-2- ylamine (CAS 3251 1-34-5) and N,N-dimethylaniline (15.2 ml, 0.12 mol)) in dichloromethane (90 ml) at 0 ⁰C. The resulting mixture was allowed to attain room temperature and stirred for 30 minutes. The mixture was concentrated and the residue taken up in dichloromethane, washed (3 x with 1 N HCI and 1x brine), dried (MgSO₄), filtered and concentrated in vacuo to give endo- 2-isocyanato-[(1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptane (10.43 g, 97 % yield. ¹H-NMR (400 MHz, CDCI₃) δ 0.85 (s, 3H), 0.86 (s, 3H), 0.89 (s, 3H), 1.11 (dd, J=13.2 and 4.2, 1 H), 1.21-1.28 (m, 1 H), 1.30-1.38 (m, 1 H), 1.67 (t, J=4, 1 H), 1.71-1.83 (m, 2H), 2.26-2.34 (m, 1 H), 3.75 (ddd, J = 10.5, 4.1 and 2.3, 1 H). Optical rotation ([α]_D) = + 40.2 (c = 1.07, dichloromethane).

Intermediate VII-2 was prepared from diphosgene, cumylamine and N,N-dimethylaniline in dichloromethane analogously to the procedure described for intermediate Vl 1-1. ¹H-NMR (400 MHz, CDCI₃) δ 1.71 (s, 6H), 7.22-7.29 (m, 1 H), 7.32-7.38 (m, 2H), 7.42-7.46 (m, 2H).

3-(n-Butyl)-5,5-dimetyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carbonyl chloride Intermediate VIIM

Intermediate VIII-1

To a magnetically stirred solution of 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole

(Intermediate (IV-1 ) (0.47 gram, 1.43 mmol) in dichloromethane (10 ml) was successively added DIPEA (0.35 ml, 2.07 mmol) and trichloromethyl chloroformate (0.25 ml, 2.07 mmol, dissolved in 10 ml dichloromethane) at O⁰C and the resulting solution was allowed to attain room temperature and subsequently reacted at room temperature for 1 hour in a nitrogen atmosphere. Subsequent Sepacore column chromatographic purification (eluant: petroleum ether / diethyl ether = 93/7 (v/v)) gave pure 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)- pyrazole-1 -carbonyl chloride (Intermediate VIII-1 ) (0.20 g, 43 % yield). (Intermediate VIII-1 ). ¹H- NMR (400 MHz, CDCI₃) δ 0.87 (t, J = 7, 3H), 1.1 1 (s, 3H), 1.27-1.39 (m, 2H), 1.45-1.59 (m, 5H), 2.10-2.20 (m, 1 H), 2.36-2.46 (m, 1 H), 3.91 (s, 1 H), 7.01 (br d, J ~ 8 Hz, 2H), 7.30-7.40 (m, 3H). EXAMPLE 4: SYNTHESIS OF SPECIFIC COMPOUNDS OF THE INVENTION

Compound 1

N-(1 -methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 - carboxamide

Crude 3-(n-Butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1 ) (1.03 gram, 4.48 mmol maximally) was dissolved in toluene (10 ml) and treated with 1 -methyl-1 -phenyl- ethylisocyanate (Intermediate VII-2) (0.72 g, 4.48 mmol) and 2 drops of triethylamine and the resulting solution was stirred at room temperature for 16 hours. The solution was concentrated and purified using Sepacore equipment: (petroleum ether/diethyl ether = 85/15 (v/v)) to give N- (1 -methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide as a colorless oil (0.97 gram, 55 % yield). R_f (petroleum ether/diethyl ether = 4/1 (v/v)) ~ 0.3. ¹H-NMR (400 MHz, CDCI₃) δ 0.88 (t, J = 7, 3H), 1.08 (s, 3H), 1.26-1.39 (m, 2H), 1.44 (s, 3H), 1.45-1.56 (m, 2H), 1.70 (s, 3H), 1.76 (s, 3H), 2.09-2.18 (m, 1 H), 2.25-2.35 (m, 1 H), 3.70 (s, 1 H), 6.59 (br s, 1 H), 7.03 (br d, J ~ 8 Hz, 2H), 7.20 (br t, J ~ 8 Hz, 1 H), 7.26-7.36 (m, 5H), 7.44 (br d, J ~ 8 Hz, 2H).

Compound 2

N-IEndo-ti R^S^RJ-I JJ-trimethylbicyclo^^.ilhept^-yll-S-tn-butylJ-S.S-dimethyl^- phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide (equimolar mixture of diastereoisomers) Compound 2 was obtained from 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1 ) and intermediate Vl 1-1 , analogously to the procedure described for compound 1. ¹H-NMR (400 MHz, CDCI₃) Characteristic signals: δ 0.97 (s, 3H) (bornyl-CH₃ group), 1.1 1/1.14 and 1.48/1.51 (diastereotopic pyrazoline C₅-CH₃ groups), 3.70 and 3.73 (pyrazoline C₄-H proton). R_f (petroleum ether 40-60/ diethyl ether = 4/1 (v/v)) = 0.3.

Compound 3

N-[Endo-(1 R,2S,4R)-1 JJ-trimethylbicyclo^^.ilhept^-yll-S-tn-butyO-S-methyl^-phenyl- 4,5-dihydro-3,4-trans-(1H)-pyrazole-1 -carboxamide (equimolar mixture of diastereoisomers) Compound 3 was obtained from 3-(n-butyl)-5-methyl-4-phenyl-4,5-dihydropyrazole and intermediate Vl 1-1. Sepacore chromatographic separation (petroleum ether/diethyl ether = 80/20 (v/v)) gave pure trans product (compound 3) and a fraction which consisted of a mixture of cis- and trans-product. ¹H-NMR (400 MHz, CDCI₃); Compound 3: Characteristic signals: δ 0.96 (s, 3H) (bornyl-CH₃ group), 3.60 (br d, J ~ 6, 1 H) (pyrazoline C₄-H proton), 4.22-4.29 (m, 1 H) (pyrazoline C₅-H proton). N. B.: This pyrazoline C₅-H proton is shifted to δ 4.39-4.48 in the corresponding cis compound. Com.3: R_f (petroleum ether 40-60/ diethyl ether = 4/1 (v/v)) = 0.3.

Compound 4

N-(1 -methyl-1 -phenyl-ethyl)-3-(n-butyl)-5-methyl-4-phenyl-4,5-cis-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide Prepared from 3-(n-butyl)-5-methyl-4-phenyl-4,5-dihydropyrazole and 1-methyl-1-phenyl- ethylisocyanate (Intermediate VII-2) analogously to the procedure described for compound 1. The obtained crude mixture of N-(1-methyl-1-phenyl-ethyl)-3-(n-butyl)-5-methyl-4-phenyl-4,5- cis-4,5-dihydro-(1 H)-pyrazole-1-carboxamide (compound 4) and N-(1-methyl-1-phenyl-ethyl)-3- (n-butyl)-5-methyl-4-phenyl-4,5-trans-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide (compound 5) was separated by Sepacore chromatographic purification: (petroleum ether/diethyl ether = 80/20 (v/v)) into pure compound 4 and pure compound 5. The 4,5-cis-trans assignment was based on NMR-NOE experiments, wherein the interaction between 4-phenyl ortho protons and the protons of the 5-methyl group was studied. Compound 4: ¹H-NMR (400 MHz, CDCI₃) δ 0.87 (t, J = 7, 3H), 0.97 (d, J = 7, 3H), 1.24-1.39 (m, 2H), 1.42-1.55 (m, 2H), 1.73 (s, 3H), 1.76 (s, 3H), 2.06-2.15 (m, 1 H), 2.23-2.32 (m, 1 H), 4.22 (d, J = 12, 1 H), 4.36-4.46 (m, 1 H), 6.46 (br s, 1 H), 7.05 (br d, J ~ 8 Hz, 2H), 7.18-7.37 (m, 6H), 7.46 (br d, J ~ 8 Hz, 2H).

Compound 5

N-(1 -methyl-1 -phenyl-ethyl)-3-(n-butyl)-5-methyl -4-phenyl -4,5-trans-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide. ¹H-NMR (400 MHz, CDCI₃) δ 0.87 (t, J = 7, 3H), 1.24-1.35 (m, 2H), 1.38 (d, J ~ 6 Hz, 3H), 1.42-1.55 (m, 2H), 1.76 (s, 6H), 2.02-2.12 (m, 1 H), 2.15-2.25 (m, 1 H), 3.59 (d, J = 6, 1 H), 4.23 (quintet, J = 6, 1 H), 6.39 (br s, 1 H), 7.10 (br d, J ~ 8 Hz, 2H), 7.19-7.29 (m, 2H), 7.30-7.37 (m, 4H), 7.47 (br d, J ~ 8 Hz, 2H).

Compound 6

N-Adamantyl-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1 -carboxamide

Compound 6 was obtained from 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole-1- carbonyl chloride (Intermediate VIII-1 ) and adamantylamine in dichloromethane (16 hours, room temperature). ¹H-NMR (400 MHz, CDCI₃) δ 0.87 (t, J=I .2 Hz, 3 H) 1.13 (s, 3 H) 1.24 - 1.36 (m, 2 H) 1.41 - 1.54 (m, 5 H) 1.63 - 1.76 (m, 6 H) 2.04 - 2.14 (m, 10 H) 2.21 - 2.31 (m, 1 H) 3.67 (s, 1 H) 6.00 (s, 1 H) 6.98 - 7.04 (m, 2 H) 7.25 - 7.35 (m, 3 H).

Compound 7

N-Benzyl-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1 -carboxamide

Compound 7 was obtained from 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1 ) and benzylisocyanate. ¹H-NMR (400 MHz, CDCI₃) δ 0.85 (t, J=7.4 Hz, 3 H) 1.17 (s, 3 H) 1.21 - 1.35 (m, 2 H) 1.38 - 1.51 (m, 2 H) 1.53 (s, 3 H) 2.05 - 2.14 (m, 1 H) 2.20 - 2.29 (m, 1 H) 3.73 (s, 1 H) 4.49 (d, J=6.0 Hz, 2 H) 6.42 (br t, J=5.7 Hz, 1 H) 7.01 (d, J=6.6 Hz, 2 H) 7.24 - 7.38 (m, 8 H).

Anologously the compounds 8 - 38 were prepared.

Compound 8

N-Naphtyl-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.94 (t, J=7.2 Hz, 3 H) 1.24 (s, 3 H) 1.35 - 1.48 (m, 2 H) 1.56 - 1.67 (m, 5 H) 2.18 - 2.27 (m, 1 H) 2.35 - 2.45 (m, 1 H) 3.84 (s, 1 H) 7.08 (d, J=6.9 Hz, 2 H) 7.29 - 7.41 (m, 3 H) 7.44 - 7.62 (m, 4 H) 7.86 (d, J=7.5 Hz, 1 H) 7.95 (d, J=8.4 Hz, 1 H) 8.14 (d, J=7.5 Hz, 1 H) 8.82 (s, 1 H). Compound 9

N-Phenyl-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.90 (t, J=7.4 Hz, 3 H) 1.20 (s, 3 H) 1.25 - 1.42 (m, 2 H) 1.46 - 1.58 (m, 2 H) 1.57 (s, 3 H) 2.10 - 2.21 (m, 1 H) 2.28 - 2.38 (m, 1 H) 3.78 (s, 1 H) 6.98 - 7.05 (m, 3 H) 7.25 - 7.38 (m, 5 H) 7.52 (d, J=7.5 Hz, 2 H) 8.18 (br s, 1 H).

Compound 10

N-(4-Methoxyphenyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 - carboxamide. ¹H-NMR (400 MHz, CDCI₃) δ 0.89 (t, J=7.4 Hz, 3 H) 1.19 (s, 3 H) 1.28 - 1.40 (m, 2 H) 1.48 - 1.59 (m, 5 H) 2.10 - 2.20 (m, 1 H) 2.27 - 2.37 (m, 1 H) 3.78 (s, 4 H) 6.83 - 6.87 (m, 2 H) 7.01 - 7.05 (m, 2 H) 7.27 - 7.37 (m, 3 H) 7.39 - 7.44 (m, 2 H) 8.02 (br s, 1 H).

Compound 11

N^-Phenyl-trans-cyclopropylJ-S-tn-butylJ-S.S-dimethyl^-phenyl^.S-dihydro-ti H)- pyrazole-1 -carboxamide. ¹H-NMR (400 MHz, CDCI₃) δ 0.87 (double t, J=I.2, Hz, 3 H) 1.16 (s, 3 H) 1.18 - 1.38 (m, 4 H) 1.40 - 1.56 (m, 5 H) 2.06 - 2.15 (m, 2 H) 2.22 - 2.31 (m, 1 H) 2.88 - 2.93 (m, 1 H) 3.71 (s, 1 H) 6.34 (br s, 1 H), 7.00 (d, J=6.6 Hz, 2 H) 7.12 - 7.20 (m, 3 H) 7.22 - 7.36 (m, 5 H).

Compound 12

N-((S)-1 -Phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 - carboxamide. ¹H-NMR (400 MHz, CDCI₃) δ 0.87 (double t, J=7.2 Hz, 3 H) 1.1 1/1.15 ( double s, 3 H) 1.22 - 1.38 (m, 2 H) 1.41 - 1.57 (m, 8 H) 2.06 - 2.15 (m, 1 H) 2.23 - 2.33 (m, 1 H) 3.70/3.72 (double s, 1 H) 5.00 - 5.10 (m, 1 H) 6.35-6.42 (m, 1 H) 6.98 - 7.05 (m, 2 H) 7.20 - 7.43 (m, 8 H).

Compound 13

N-(2-(Trifluoromethyl)phenyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole- 1 -carboxamide. ¹H-NMR (400 MHz, CDCI₃) δ 0.90 (t, J=7.4Hz, 3 H) 1.20 (s, 3 H) 1.28 - 1.45 (m, 2 H) 1.55 - 1.64 (m, 5 H) 2.12 - 2.21 (m, 1 H) 2.25 - 2.35 (m, 1 H) 3.81 (s, 1 H) 7.04 (d, J=6.6 Hz, 2 H) 7.08 (t, J=7.7 Hz, 1 H) 7.28 - 7.38 (m, 3 H) 7.50 (t, J=7.8 Hz, 1 H) 7.57 (d,

J=7.8 Hz, 1 H) 8.36 (d, J=8.4 Hz, 1 H) 8.90 (br s, 1 H). Compound 14

N-Cycloheptyl-S-tn-butylJ-S.S-dimethyl^-phenyl^.S-dihydro-tiHJ-pyrazole-i -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.87 (t, J=I .2 Hz, 3 H) 1.13 (s, 3 H) 1.23 - 1.37 (m, 2 H) 1.42 - 1.71 (m, 15 H) 1.94 - 2.03 (m, 2 H) 2.06 - 2.15 (m, 1 H) 2.22 - 2.32 (m, 1 H) 3.70 (s, 1 H) 3.80 - 3.90 (m, 1 H) 6.04 (br d, J=8 Hz, 1 H) 7.01 (d, J=6.3 Hz, 2 H) 7.25 - 7.36 (m, 3 H).

Compound 15

N-Cyclooctyl-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.87 (t, J=7.2 Hz, 3 H) 1.13 (s, 3 H) 1.23 - 1.38 (m, 2 H) 1.39 - 1.75 (m, 17 H) 1.84 - 1.96 (m, 2 H) 2.04 - 2.14 (m, 1 H) 2.22 - 2.32 (m, 1 H) 3.69 (s, 1 H) 3.84 - 3.95 (m, 1 H) 6.05 ( br d, J=8.1 Hz, 1 H) 7.01 (d, J=6.6 Hz, 2 H) 7.25 - 7.36 (m, 3 H).

Compound 16

N-(2,2-Diphenylethyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 - carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.84 (t, J=7.4Hz, 3 H) 1.11 (s, 3 H) 1.14 - 1.30 (m, 2 H) 1.31 - 1.44 (m, 2 H) 1.45 (S, 3 H) 1.97 - 2.05 (m, 1 H) 2.08 - 2.18 (m, 1 H) 3.64 (s, 1 H) 3.83 - 3.99 (m, 2 H) 4.26 (t, J=7.8 Hz, 1 H) 6.10 (br t, J=5.9Hz, 1 H) 6.95 (d, J=6.6 Hz, 2 H) 7.18 - 7.34 (m, 13 H).

Compound 17

N-(2-lndanyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.84 (t, J=7.2 Hz, 3 H) 1.15 (s, 3 H) 1.21 - 1.34 (m, 2 H) 1.37 - 1.50 (m, 2 H) 1.51 (s, 3 H) 2.03 - 2.12 (m, 1 H) 2.20 - 2.29 (m, 1 H) 2.85 - 2.94 (m, 2 H) 3.32 - 3.41 (m, 2 H) 3.70 (s, 1 H) 4.63 - 4.73 (m, 1 H) 6.26 (br d, J=7.8 Hz, 1 H) 7.00 (d, J=6.3 Hz, 2 H) 7.15 - 7.21 (m, 2 H) 7.21 - 7.27 (m, 2 H) 7.28 - 7.37 (m, 3 H).

Compound 18

N-(2-adamantyl)-3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 - carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.83 (t, J=7.3 Hz, 3 H) 1.22 (s, 6 H) 1.23 - 1.30 (m, 2 H) 1.38 - 1.98 (m, 16 H) 1.99 - 3.06 (m, 2 H) 3.92 - 3.99 (m, 1 H) 4.28 (br s, 1 H) 7.07 - 7.15 (m, 3 H) 7.27 - 7.37 (m, 3 H). Compound 19

N-trel-exo-bicyclo^^.ilhept^-ylJ-S-tn-butylJ-S.S-dimethyl^-phenyl^.S-dihydro-tiH)- pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.87 (t, J=7.4 Hz, 3 H) 1.13 (d, J=3.6 Hz, 3 H) 1.15 - 1.37 (m, 6 H) 1.38 - 1.58 (m, 8 H) 1.76 - 1.85 (m, 1 H) 2.04 - 2.15 (m, 1 H) 2.21 - 2.32 (m, 3 H) 3.62 - 3.69 (m, 1 H) 3.69 (s, 1 H) 5.92 (br d, J=6.0 Hz, 1 H) 6.98 - 7.03 (m, 2 H) 7.27 - 7.36 (m, 3 H).

Compound 20

N-(1 -phenyl -ethyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.84 - 0.91 (m, 3 H) 1.10/1.14 (double s, Signals together integrate for 3 H) 1.21 - 1.56 (m, 10 H) 2.06 - 2.15 (m, 1 H) 2.23 - 2.33 (m, 1 H) 3.71 (double s, Signals together integrate for 1 H) 4.99 - 5.09 (m, 1 H) 6.33-6.40 (m, 1 H) 6.97 - 7.05 (m, 2 H) 7.20 - 7.42 (m, 8 H).

Compound 21

N-(Quinolin-3-yl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.92 (t, J=7.4 Hz, 3 H) 1.24 (s, 3 H) 1.30 - 1.44 (m, 2 H) 1.49 - 1.63 (m, 5 H) 2.15 - 2.24 (m, 1 H) 2.34 - 2.44 (m, 1 H) 3.84 (s, 1 H) 7.05 (d, J=6.6 Hz, 2 H) 7.30 - 7.41 (m, 3 H) 7.46 - 7.53 (m, 1 H) 7.58 (dt, J=U, 1.5 Hz, 1 H) 7.76 - 7.80 (m, 1 H) 8.03 (d, J=8.4 Hz, 1 H) 8.42 (s, 1 H) 8.73 (q, J=2.6 Hz, 2 H).

Compound 22

N-(Naphtalen-1 -ylmethyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.81 (t, J=7.2 Hz, 3 H) 1.19 (s, 3 H) 1.21 - 1.32 (m, 2 H) 1.34 - 1.48 (m, 2 H) 1.55 (s, 3 H) 2.00 - 2.12 (m, 1 H) 2.15 - 2.24 (m, 1 H) 3.72 (s, 1 H) 4.95 (dd, J=5.6, 2.86 Hz, 2 H) 6.40 (br t, J=5.6 Hz, 1 H) 6.98 - 7.02 (m, 2 H) 7.27 - 7.36 (m, 3 H) 7.38 - 7.59 (m, 4 H) 7.81 (d, J=8.1 Hz, 1 H) 7.86 - 7.91 (m, 1 H) 8.16 (d, J=8.4 Hz, 1 H).

Compound 23

N-[1 -(ethyl)propyl]-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.87 (t, J=7.4 Hz, 3 H) 0.91 - 0.98 (m, 6 H) 1.14 (s, 3 H) 1.22 - 1.61 (m, 1 1 H) 2.06 - 2.15 (m, 1 H) 2.23 - 2.33 (m, 1 H) 3.59 - 3.69 (m, 1 H) 3.70 (s, 1 H) 5.88 (br d, J=9.0 Hz, 1 H) 7.00 - 7.04 (m, 2 H) 7.27 - 7.36 (m, 3 H). Compound 24

N-(1 -Methyl-1 -(4-fluorophenyl)-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(4-fluorophenyl)-4,5- dihydro-(1 H)-pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.88 (t, J = 7, 3H), 1.08 (s, 3H), 1.23-1.39 (m, 2H), 1.42 (s, 3H), 1.43-1.55 (m, 2H), 1.67 (s, 3H), 1.74 (s, 3H), 2.07-2.16 (m, 1 H), 2.25-2.35 (m, 1 H), 3.68 (s, 1 H), 6.56 (br s, 1 H), 6.95-7.05 (m, 6H), 7.36-7.41 (m, 2H).

Compound 25

N-(1 -Methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(4-fluorophenyl)-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.88 (t, J = 7, 3H), 1.09 (s, 3H), 1.23-1.39 (m, 2H), 1.41-1.55 (m, 5H), 1.70 (s, 3H), 1.77 (s, 3H), 2.07-2.15 (m, 1 H), 2.26-2.34 (m, 1 H), 3.67 (s, 1 H), 6.58 (br s, 1 H), 6.95-7.05 (m, 4H), 7.17-7.22 (m, 1 H), 7.29-7.34 (m, 2H), 7.41-7.46 (m, 2H).

Compound 26

N-(1 -Methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(3-thienyl)-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide. ¹H-NMR (400 MHz, DMSO-d₆) δ 0.84 (t, J = 7, 3H), 0.97 (s, 3H), 1.22-1.34 (m, 2H), 1.36 (s, 3H), 1.39-1.52 (m, 2H), 1.61 (s, 3H), 1.64 (s, 3H), 2.10-2.19 (m, 1 H), 2.23-2.33 (m, 1 H), 4.08 (s, 1 H), 6.60 (s, 1 H), 6.87 (d, J = 5 Hz, 1 H), 7.17-7.21 (m, 1 H), 7.27- 7.40 (m, 5H), 7.54 (dd, J = 5 and 3, 1 H).

Compound 27

N-(1 -Methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(3-benzothienyl)-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃): Some double peaks are present due to restricted amide bond rotations, δ 0.83-0.92 (m, 3H), 1.13 (s, 3H), 1.28-1.40 (m, 2H), 1.44-1.58 (m, 5H), 1.71 , 1.77 and 1.79 (3x s, 6H), 2.17-2.28 (m, 1 H), 2.34-2.44 (m, 1 H), 4.25 (s, 1 H), 6.58 and 6.63 (2x s, 1 H), 7.02 (s, 1 H), 7.18-7.23 (m, 2H), 7.30-7.50 (m, 5H), 7.62-7.72 (m, 1 H), 7.81-7.92 (m, 1 H).

Compound 28

N-(1 -Methyl-1 -(4-fluorophenyl)-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(3-benzothienyl)-4,5- dihydro-(1 H)-pyrazole-1 -carboxamide ¹H-NMR (400 MHz, DMSO-d₆) (140 ⁰C) δ 0.84 (t, J = 7, 3H), 1.10 (s, 3H), 1.29-1.40 (m, 2H), 1.48-1.59 (m, 5H), 1.70 (s, 3H), 1.71 (s, 3H), 2.15-2.36 (m, 2H), 4.42 (s, 1 H), 6.55 (s, 1 H), 7.04- 7.1 1 (m, 2H), 7.36-7.50 (m, 5H), 7.77-7.84 (m, 1 H), 7.97 (br d, J = 8, 1 H).

Compound 29

N-(1 -Methyl-1 -(4-fluorophenyl)-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(3-thienyl)-4,5-dihydro- (1 H)-pyrazole-1 -carboxamide 1H-NMR (400 MHz, DMSO-d₆) δ 0.83 (t, J = 7, 3H), 0.95 (s, 3H), 1.22-1.35 (m, 5H), 1.36-1.52 (m, 2H), 1.59 (s, 3H), 1.61 (s, 3H), 2.09-2.18 (m, 1 H), 2.22-2.32 (m, 1 H), 4.07 (s, 1 H), 6.60 (s, 1 H), 6.86 (dd, J = 5 and 1.5 Hz, 1 H), 7.06-7.14 (m, 2H), 7.31 (dd, J = 3 and 1.2 Hz, 1 H), 7.34- 7.40 (m, 2H), 7.54 (dd, J = 5 and 3, 1 H).

Compound 30

N-(1 -Methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(3-fluorophenyl)-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.90 (t, J = 7, 3H), 1.1 1 (s, 3H), 1.26-1.39 (m, 2H), 1.43 (s, 3H), 1.44-1.55 (m, 2H), 1.71 (s, 3H), 1.76 (s, 3H), 2.08-2.18 (m, 1 H), 2.26-2.36 (m, 1 H), 3.67 (s, 1 H), 6.57 (br s, 1 H), 6.74 (br d, J = 8, 1 H), 6.82 (d, J = 8, 1 H), 6.98 (td, J = 8 and 3, 1 H), 7.17-7.22 (m, 1 H), 7.27-7.36 (m, 3H), 7.43 (d, J = 8, 2H). Compound 31

N-(1 -Methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(2-fluorophenyl)-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide: ¹H-NMR (400 MHz, CDCI₃) δ 0.90 (t, J = 7, 3H), 1.15 (s, 3H), 1.29- 1.39 (m, 2H), 1.43-1.57 (m, 5H), 1.70 (s, 3H), 1.76 (s, 3H), 2.08-2.17 (m, 1 H), 2.27-2.37 (m, 1 H), 4.18 (br s, 1 H), 6.56 (br s, 1 H), 6.88-7.35 (m, 7H), 7.43 (d, J = 8, 2H).

Compound 32

N-(1 -Methyl-1 -phenyl -ethyl)-3-(n-butyl)-5,5-dimethyl-4-(2-methoxyphenyl)-4,5-dihydro- (1H)-pyrazole-1 -carboxamide: ¹H-NMR (400 MHz, CDCI₃) δ 0.90 (t, J = 7, 3H), 1.10 (s, 3H), 1.28-1.39 (m, 2H), 1.44 (s, 3H), 1.45-1.55 (m, 2H), 1.69 (s, 3H), 1.77 (s, 3H), 2.08-2.17 (m, 1 H), 2.25-2.35 (m, 1 H), 3.82 (s, 3H), 4.37 (s, 1 H), 6.56 (br s, 1 H), 6.78-6.82 (m, 1 H), 6.87-6.94 (m, 2H), 7.17-7.36 (m, 4H), 7.43 (d, J = 8, 2H).

Compound 33

N-(1 -Methyl-1 -phenyl-ethyl)-3-(n-butyl)-5,5-dimethyl-4-(4-chlorophenyl)-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 0.89 (t, J = 7, 3H), 1.09 (s, 3H), 1.25-1.38 (m, 2H), 1.42-1.57 (m, 5H), 1.70 (s, 3H), 1.76 (s, 3H), 2.04-2.15 (m, 1 H), 2.23-2.34 (m, 1 H), 3.66 (s, 1 H), 6.56 (br s, 1 H), 6.96 (d, J = 8, 2H), 7.17-7.23 (m, 1 H), 7.29-7.36 (m, 4H), 7.43 (d, J = 8, 2H).

Compound 34

N-(1 -Methyl-1 -phenyl -ethyl)-3 -(2 -phenyl-trans-cyclopropyl)-5,5-dimethyl-4-phenyl -4,5- dihydro-(1 H)-pyrazole-1 -carboxamide (equimolar diastereomeric mixture)

¹H-NMR (400 MHz, CDCI₃) δ 1.09 and 1.1 1 (2x s, 3H), 1.13-1.38 (m, 2H), 1.47 (s, 3H), 1.55- 1.62 and 2.1 1-2.18 (2x m, 1 H), 1.69-1.77 and 2.31-2.38 (2x m, 7H), 3.72 (br s, 1 H), 6.52 and 6.54 (2x br s, 1 H), 6.88-6.94 (m, 2H), 7.05-7.37 (m, 11 H), 7.43 (br d, J = 8, 2H).

Compound 35

N-(1 -Methyl-1 -phenyl-ethyl)-3-(2-phenyl-ethyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)- pyrazole-1 -carboxamide

¹H-NMR (400 MHz, CDCI₃) δ 1.05 (s, 3H), 1.38 (s, 3H), 1.70 (s, 3H), 1.76 (s, 3H), 2.40-2.50 (m, 1 H), 2.58-2.68 (m, 1 H), 2.82-2.96 (m, 2H), 3.63 (s, 1 H), 6.53 (br s, 1 H), 6.96 (br d, J = 8, 2H), 7.13-7.36 (m, 11 H), 7.41 (br d, J = 8, 2H). Compound 36

N-(1 -Methyl-1 -phenyl-ethyl)-3-(3,3,3-trifluoropropyl)-5,5-dimethyl-4-phenyl-4,5-dihydro- (1H)-pyrazole-1 -carboxamide: ¹H-NMR (400 MHz, CDCI₃) δ 1.10 (s, 3H), 1.47 (s, 3H), 1.71 (s, 3H), 1.76 (s, 3H), 2.37-2.55 (m, 4H), 3.71 (s, 1 H), 6.48 (br s, 1 H), 7.02 (br d, J = 8, 2H), 7.17- 7.23 (m, 1 H), 7.28-7.38 (m, 5H), 7.43 (br d, J = 8, 2H).

Compounds 37 and 38

rel 1 : relative configuration 1 rel 2: relative configuration 2

N-IEndo-ti R^S^RJ-I JJ-trimethylbicyclo^^.ilhept^-yll-S-tS.S.S-trifluoropropyO-S.S- dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide (diastereoisomer 1) and N-IEndo-ti R^S^RJ-I JJ-trimethylbicyclo^^.ilhept^-yll-S-tS.S.S-trifluoropropyO-S.S- dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole-1 -carboxamide (diastereoisomer 2)

Compounds 37 and 38 were separated by flash chromatography (silicagel, eluant gradient: petroleum ether (40-60)/ diethyl ether=9/1 (v/v) to petroleum ether (40-60)/diethyl ether=8/2 (v/v) Compound 37: Optical rotation ([α]_D) = +105 (c = 1 , MeOH, 25 ⁰C). ¹H-NMR (400 MHz, CDCI₃) δ 0.83-1.00 (m, 10H), 1.13 (s, 3H), 1.21-1.62 (m, 7H), 1.68 (t, J ~ 5, 1 H), 1.74-1.87 (m, 1 H), 2.35-2.60 (m, 4H), 3.76 (s, 1 H), 4.10-4.20 (m, 1 H), 6.14 (br d, J ~ 9, 1 H), 7.02 (br d, J ~ 8, 2H), 7.28-7.41 (m, 3H).

Compound 38: Optical rotation ([α]_D) = -89 (c = 1 , MeOH, 25 ⁰C). ¹H-NMR (400 MHz, CDCI₃) δ 0.83-0.98 (m, 10H), 1.15 (s, 3H), 1.21-1.60 (m, 7H), 1.68 (t, J ~ 5, 1 H), 1.74-1.87 (m, 1 H), 2.35- 2.60 (m, 4H), 3.72 (s, 1 H), 4.12-4.21 (m, 1 H), 6.13 (br d, J ~ 9, 1 H), 7.01 (br d, J ~ 8, 2H), 7.28- 7.41 (m, 3H). Compound 39

[3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazol-1 -yl]-3,5,5-trimethylhexan-1 - one (1 :1 mixture of diastereomers)

To a magnetically stirred solution of 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1 H)-pyrazole (1 ml: 0.25 M in anhydrous tetrahydrofuran, 0.25 mmol) was successively added 3,5,5- trimethylhexanoyl chloride (1.1 ml: 0.25 M in anhydrous tetrahydrofuran; 0.275 mmol) and DIPEA (1.1 ml: 0.285 M in anhydrous tetrahydrofuran; 0.313 mmol) and the resulting mixture was stirred for 21 hours at 30 ⁰C. An aqueous 5 % NaHCC>3 solution and dichloromethane were added to the mixture. The organic layer was separated, successively washed with brine and water, dried over MgSO₄, filtered and concentrated in vacuo to give [3-(n-butyl)-5,5-dimethyl-4- phenyl-4,5-dihydro-(1 H)-pyrazol-1-yl]-3,5,5-trimethylhexan-1-one as a mixture of diastereomers (55 mg, 57 % yield). ¹H-NMR (400 MHz, CDCI₃) δ 0.88 (t, J = 7, 3H), 0.94 (s, 9H), 1.00 and 1.01 (2x d, J = 7, 3H), 1.12-1.20 (m, 4H), 1.25-1.39 (m, 3H), 1.47-1.58 (m, 5H), 2.07-2.34 (m, 3H), 2.46-2.55 (m, 1 H), 2.63-2.73 (m, 1 H), 3.72 and 3.74 (2x s, 1 H), 6.98 (br d, J = 8 Hz, 2H), 7.28-7.37 (m, 3H).

EXAMPLE 5: FORMULATIONS USED IN ANIMAL STUDIES

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

For intraperitoneal (Lp.) administration: to the desired quantity (0.5-15 mg) of the solid compound 1 in a glass tube, some glass beads were added and the solid was milled by vortexing for 2 minutes. After addition of 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7. EXAMPLE 6: PHARMACOLOGICAL METHODS

In vitro affinity for cannabinoid-CE÷_H receptors was determined using membrane preparations of CHO cells in which human cannabinoid CB₁ receptors were stably transfected in conjunction with [³H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [³H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.

In vitro affinity for cannabinoid-CB₂ receptors: was determined using membrane preparations of CHO cells in which human cannabinoid CB₂ receptors were stably transfected in conjunction with [³H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [³H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.

In vitro cannabinoid-CB.| receptor (ant)agonism was assessed with human CB₁ receptors cloned in CHO cells. CHO cells were grown in a DMEM culture medium, supplemented with 10% heat-inactivated fetal calf serum. Medium was aspirated and replaced by DMEM, without fetal calf serum, but containing [³H]-arachidonic acid and incubated overnight in a cell culture stove (5% CO₂/95% air; 37 ⁰C; water-saturated atmosphere). During this period [³H]-arachidonic acid was incorporated in membrane phospholipids. On the test day, medium was aspirated and cells were washed three times using 0.5 ml DMEM, containing 0.2% BSA. CB₁ agonist stimulation lead to activation of PLA₂ followed by release of [³H]-arachidonic acid into the medium. This CB₁ agonist-induced release was concentration-dependently antagonized by CB₁ receptor antagonists, such as rimonabant.

In vitro cannabinoid-CB₂ receptor (ant)agonism was assessed using a forskolin-stimulated cAMP accumulation assay. The ability of compounds to stimulate and inhibit adenylate cyclase activity was assessed in CHO K₁ cells expressing human CB₂ (Euroscreen, Brussels) receptor. CHO cells were grown in a CHO-S-SFM-II culture medium, supplemented with 10 % heat- inactivated foetal calf serum, 2mM glutamine, 400μg/ml Hygromycine B and 500 μg/ml G418 at 37 ⁰C in 93 % air / 5 % CO₂. For incubation with test compounds, confluent cultures grown in 24 well plates were used. Each condition or substance was routinely tested in quadruplicate. Cells were loaded with I mCi [³H]-adenine in 0.5 ml medium per well. After 2 hours, cultures were washed with 0.5 ml PBS containing 1 mM IBMX and incubated for 20 minutes with 0.5 ml PBS containing 1 mM IBMX and 3x10^"7 M forskolin with or without the test compound. Antagonistic effects of test compounds were determined as inhibition of 0.1 μM JWH-133-decreased [³H]cAMP formation. After aspiration the reaction was stopped with 1 ml trichloroacetic acid (5% w/v). The [³H]-ATP and [³H]-CAMP formed in the cellular extract were assayed as follows: a volume of 0.8 ml of the extract was passed over Dowex (50WX-4200- 400 mesh) and aluminum oxide columns, eluted with water and 0.1 M imidazole (pH=7.5). Eluates were mixed with 7 ml Ultima-Flo [AP] and the β-radioactivity was counted with a liquid scintillation counter. The conversion of [³H]-ATP into [³H]-CAMP was expressed as the ratio in percentage radioactivity in the cAMP fraction as compared to the combined radioactivity in both cAMP and ATP fractions, and basal activity was subtracted to correct for spontaneous activity. Reference compounds used to assess cannabinoid CB₂ receptor mediated adenylate cyclase activity were the full cannabinoid CB₂ receptor agonists JWH-133 (Huffman, 1999^b) and WIN 55,212-2 (Huffman, 1999^a), and the inverse agonist or antagonist SR-144528 (Rinaldi-Carmona, 1998). Compounds were studied in a concentration range of 10^"10 M to 10^"6M. pEC₅o and the pA₂ were calculated according to Cheng-Prusoff equation (Cheng and Prusoff, 1973). Two independent experiments were performed in triplicate.

EXAMPLE 7: PHARMACOLOGICAL TESTRESULTS

Cannabinoid CB₁ZCB₂ receptor affinity data, expressed as pKj values (mean results of at least three independent experiments, performed according to the protocols given above) as well as CB₁ receptor agonist functional data of representative compounds of this invention are shown in the table below.

EXAMPLE 8: PHARMACEUTICAL PREPARATIONS

For clinical use, compounds of formula (I) are formulated into pharmaceutical compositions that are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds disclosed herein. Types of pharmaceutical compositions that may be used include: tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or are apparent to a person skilled in the art from the specification and general knowledge in the art. The active ingredient for instance, may also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer. The pharmaceutical formulation contains at least one compound of formula (I) in admixture with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier. The total amount of active ingredients suitably is in the range of from about 0.1 % (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w). In some embodiments, the amount of active ingredient is greater than about 95% (w/w) or less than about 0.1 % (w/w).

The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets. A tablet is prepared using the ingredients below: Ingredient Quantity (mg/tablet)

COMPOUND No. 1 10

Cellulose, microcrystalline 200

Silicon dioxide, fumed 10

Stearic acid 10 Total 230

The components are blended and compressed to form tablets each weighing 230 mg. The active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation. The active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.

Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.

Also provided according to the present invention are formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments for use in the treatment of a condition in which modulation of cannabinoid CB₁ receptors is required or desired, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one compound of formula (I), either as such or, in the case of prodrugs, after administration, to a patient suffering from, or susceptible to, a condition in which modulation of cannabinoid CB₁ receptors is required or desired.

By way of example and not of limitation, several pharmaceutical compositions are given, comprising preferred active compounds for systemic use or topical application. Other compounds of the invention or combinations thereof, may be used in place of (or in addition to) said compounds. The concentration of the active ingredient may be varied over a wide range as discussed herein. The amounts and types of ingredients that may be included are well known in the art.

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Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A compound of formula (I)

- n is either 0 or 1

- R₃ represents a linear or branched C_3-i₀ alkyl group, a C_3-8 cycloalkyl group, C_5-io bicycloalkyl group, C₆-io tricycloalkyl group or C_8-n tetracycloalkyl group, which groups are optionally substituted with 1-5 substituents chosen from methyl, ethyl, hydroxy, amino, fluoro, or R₃ represents a C_3-8 cycloalkyl group substituted with an aryl or heteroaryl group, optionally substituted with 1-5 substituents Y, wherein Y has the meaning given above, or R₃ represents a C_5-8 heterocycloalkyl group, C_6-io bicycloheteroalkyl group, C_7-io tricycloheteroalkyl group, which groups are optionally substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluoro, or R₃ represents a C_3-8 cycloalkyl-d-s-alkyl group, Cs-io-bicycloalkyl-d-s-alkyl group, C_6-io- tricycloalkyl-d-3-alkyl group, which groups are optionally substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluoro, or

R₃ represents a branched or linear C_3-S group, C_5-io bicycloheteroalkyl-d-s-alkyl group, C_6-io tricycloheteroalkyl-d-s-alkyl group, which groups are optionally substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluoro, or

R₃ represents an aryl or heteroaryl group, optionally substituted with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R₃ represents an aryl-d_-5-alkyl group, a hetroaryl-d_-5-alkyl or a di(hetero)aryl-d_-5-alkyl group, in which groups the phenyl or heteroaromatic rings are optionally substituted with 1-5 substituents Y, wherein Y has the abovementioned meaning, or

R₃ represents a linear or branched d-8 alkenyl or d-8 alkynyl group which linear or branched d-8 alkenyl or d-β alkynyl group, optionally substituted with 1-3 fluoro atoms, or, when n=1 , R₃ represents a branched or linear C₂-₁0 heteroalkyl group, containing 1-2 heteroatoms selected from N, O or S,

- R₅ represents a hydrogen atom or a Ci_-2 alkyl group, optionally substituted with 1-3 fluoro atoms,

2. A compound as claimed in claim 1 or a tautomer, stereoisomer, N-oxide, isotopically- labelled analogue, or pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein R₂ represents a phenyl, thienyl or pyridyl group, optionally substituted with 1 , 2 or 3 substituents Y, Y and the other symbols having the meanings given in claim 1.

3. A compound as claimed in claim 2, wherein n=1 and the other symbols have the meanings as given in claim 2.

4. A compound as claimed in claim 3, wherein R₅ represents a hydrogen atom or a methyl group, Re represents a methyl group and the other symbols have the meanings as given in claim 3.

5. A compound as claimed in claim 4, wherein R represents a C_4-8 branched or C_3-8 linear alkyl group, optionally substituted with 1-3 fluoro atoms, R₂ represents a phenyl group, optionally substituted with 1 , 2 or 3 substituents Y, Y and the other symbols having the same meanings as given in claim 4

6. A compound as claimed in claim 5, wherein R represents a C_3-5 linear alkyl group, R₂ represents a phenyl group, optionally substituted with a halogen atom, and the other symbols have the same meanings as given in claim 5.

7. A compound as claimed in any of the claims 1 -6, or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, said compound being an optically active enantiomer.

8. Compounds of formula (IV).

wherein R, R₅ and R₆ have the same meanings as given in claim 1 and R₂ represents a phenyl, thienyl or pyridyl group, which groups are optionally substituted with 1-3 substituents Y, which Y group has the meaning as given in claim 1 , such compounds being useful in the synthesis of compounds of the general formula (I).

9. Compounds of the general formula (III)

wherein R is chosen from phenyl, pyridyl or thienyl, optionally substituted with 1-3 substituents Y1 wherein Y1 is chosen from halogen, methyl, CF₃, OCF₃ or OCH₃, and R₂ represents a n-propyl, n-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1 ,1-dimethylbutyl, 3,3,3- trifluoropropyl, 4,4,4-trifluorobutyl or 1 ,1-dimethyl-3,3,3-trifluoropropyl group, such compounds being useful in the synthesis of compounds of the general formula (I).

10. Compounds of formula (VIII):

wherein R, R₂, R₅ and R₆ have the same meanings as given in claim 1 , such compounds being useful in the synthesis of compounds of the general formula (I) wherein n = 1.

1 1. A medicament, comprising a compound according to any one of the claims 1-7, or a pharmacologically acceptable salt, hydrate or solvate thereof.

12. A compound as claimed in any one of the claims 1-7, for use in treating multiple sclerosis, traumatic brain injury, pain, appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome, cerebral ischaemia or gastrointestinal disorders.

13. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of at least one compound of one of the claims 1-7, or a pharmacologically acceptable salt, hydrate or solvate thereof, as an active ingredient.

14. A pharmaceutical composition as claimed in claim 1 1 , for the prevention or the treatment of multiple sclerosis, traumatic brain injury, pain, appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome, cerebral ischaemia or gastrointestinal disorders.

15. The pharmaceutical composition according to claim 13, further comprising: at least one additional therapeutic agent.

16. Use of a compound as claimed in claims 1-7 for the preparation of a pharmaceutical composition for the treatment of multiple sclerosis, traumatic brain injury, pain including chronic pain, neuropathic pain, acute pain and inflammatory pain, osteoporosis, appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome, cerebral ischaemia, emesis, nausea and gastrointestinal disorders.

17. Process to prepare compounds as claimed in claim 1 , comprising the steps of:

(i) reacting ketone derivative of formula (II) with a halogenide derivative of formula R₅ReCHI in the presence of a base, to give a compound of formula (Na), which is reacted with a brominating agent, preferably in the presence of a radical initiator in an inert organic solvent, to give a compound of formula (lib), which is further reacted in an elimination reaction with lithium chloride at elevated temperature in an organic solvent to give a compound of formula (III):

or: by reacting an amide of formula (Ilia) with a Grignard reagent of formula RMgBr in the presence of an inert organic solvent to give a ketone derivative of formula (NIb), or by reacting an amide of formula R-C^=O)-N(OCH₃)CH₃ and an olefinic Grignard reagent of formula R₅R₆C=CHMgBr to give a ketone derivative of formula (NIb), which is subsequently brominated at its olefinic bond with bromine in the presence of an inert organic solvent, followed by reaction with a base to yield a compound of formula (NIc), which is reacted in a transition metal-catalyzed cross-coupling reaction, with a compound of general formula R₂-B(OH)₂ in the presence of a palladium-based catalyst resulting in a compound of formula (III):

(Ilia) (IMb) (NIc) cross coupling Pd cat, R₂(BOH)₂ (III) (ii) reacting an enone derivative of formula (III) with hydrazine, a hydrazine salt or hydrazine hydrate, to give a 4,5-dihydropyrazole derivative of formula (IV), which is subsequently reacted with a carboxylic acid R₃-CO₂H in the presence of a coupling reagent in an inert organic solvent to give a pyrazoline derivative of general formula (I), wherein n=0:

(IV)

(I) wherein n = O or: by reacting a compound of formula (IV) with an acid chloride R₃-COCI, preferably in the presence of a base to give a pyrazoline derivative of formula (I), wherein n=0,

(IV)

(I) wherein n = O or: by reacting a compound of formula (IV) with with an isocyanate derivative R₃-N=C=O (VII) in the presence of an inert organic solvent to give a pyrazoline-1-carboxamide derivative of general formula (I), wherein n=1 ,

(I) wherein n = 1 or: by reacting a compound of formula (IV) with phosgene, diphosgene or triphosgene, preferably carried out in the presence of a base, to give a compound of formula (VIII), which is further reacted reacted in an inert solvent such with a compound NH₂R3 to give a pyrazoline-1-carboxamide derivative of formula (I), wherein n=1 :

(l)wherein n = 1 in which all symbols, R, R₂, R_3, R₅ and Re, have the meanings as given in claim 1.