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Definitions

• Example 2 General aspects of syntheses 14
• Example 3 Synthesis and spectral data of intermediates 18
• Example 7 Pharmacological test results 45
• Example 8 Pharmaceutical preparations 46
• This invention relates to the fields of pharmaceutical and organic chemistry, and provides 4,5- dihydro-(1 H)-pyrazole (pyrazoline) derivatives as cannabinoid CB 1 receptor modulators, and intermediates and formulations thereof, as well as methods to apply these compounds.
• 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).
• CB 2 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.
• CB 2 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; (2004), 2005; Ashton, 2006, Ofek, 2006).
• SR141716A now known as rimonabant, and other CB 1 receptor modulators, including CB 1 ZCB 2 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
• Diarylpyrazoline derivatives having cannabinoid CB 1 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 CB 1 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 CB 1 receptor agonistic activity.
• R represents a C 3- i 0 linear alkyl group, a C 4- io branched alkyl group, a C 4- i 0 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,
• R 2 represents an aryl or heteroaryl group, optionally substituted with 1-5 substituents Y, wherein Y has the abovementioned meaning
• R 3 represents a linear or branched C 3- i 0 alkyl group, a C 3-8 cycloalkyl group, C 5- io bicycloalkyl group, C 6 -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 R 3 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 R 3 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 fluor
• R 3 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 R 3 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 R 3 represents an aryl or heteroaryl group, optionally substituted with 1-5 substituents Y, wherein Y has the abovementioned
• R 5 represents a hydrogen atom or a Ci_ 2 alkyl group, optionally substituted with 1-3 fluoro atoms,
• R 6 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 R 2 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.
• R 2 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.
• FIG. 1 represents a phenyl, thienyl or pyridyl group, optionally substituted with 1 , 2 or 3 substituents Y, R 5 represents a hydrogen atom or a methyl group, Re represents a methyl group and the other symbols have the meanings as given above.
• FIG. 1 represents a C 4-8 branched or C 3-8 linear alkyl group, optionally substituted with 1-3 fluoro atoms
• R 2 represents a phenyl group, optionally substituted with 1 , 2 or 3 substituents Y
• R 5 represents a hydrogen atom or a methyl group
• Re represents a methyl group and the other symbols have the meanings as given above.
• R represents a C3-5 linear alkyl group
• R 2 represents a phenyl group, optionally substituted with a halogen atom
• R 5 represents a hydrogen atom or a methyl group
• R 6 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 CB 1 receptor modulating activity.
• the compounds of the invention also have affinity for CB 2 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.
• compositions for treating for example, a disorder or condition that may be treated by modulating cannabinoid CB 1 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 CB 1 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,
• 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 CB 1 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 CB 1 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.
• 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.
• 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.
• 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 [ 13 C]-, [ 14 C]-, [ 3 H]-, [ 18 F]-, [ 125 I]- 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.
• alkyl denotes a univalent saturated, branched or straight, hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms.
• 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.
• the alkyl group 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.
• 'alkyl(Ci -4 )' means 'methyl, ethyl, n- propyl, isopropyl, n-butyl, 2-butyl, isobutyl or tert-butyl'.
• '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.
• '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.
• 'alkenyl' and 'alkynyl' chains can contain from 1 to 18 carbon atoms.
• 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,
• '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.
• 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.
• unsubstituted means that the specified group bears no substituents.
• 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, noradaman
• the abbreviation 'C 8-H tetracycloalkyl group' refers to carbo- tetracyclic ring systems including cubyl, homocubyl and bishomocubyl groups.
• amino 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.
• sulfinyl and sulfonyl as used herein as part of another group respectively refer to an -SO- or an - SO 2 - group.
• 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.
• the term "leaving group” 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.
• 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.
• 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.
• 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.
• composition 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.
• 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.
• 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.
• the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
• 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 CB 1 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 CB 1 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.
• 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.
• 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.
• terapéuticaally effective amount 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.
• 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).
• treatment 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.
• the present method includes both medical therapeutic and/or prophylactic administration, as appropriate.
• 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.
• subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
• Sepacore chromatographic separations were carried out using Supelco equipment, VersaFLASHTM columns, VersaPakTM silica cartridges, B ⁇ chi UV monitor C-630, B ⁇ chi Pump module C-605, B ⁇ chi fraction collector C-660 and B ⁇ chi pump manager C-615. Melting points were recorded on a B ⁇ chi B-545 melting point apparatus or determined by DSC methods. Optical rotations ([ ⁇ ] 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 0 C.
• a Grignard reagent R 2 CH 2 MgCI or R 2 CH 2 MgBr 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 R 2 have the abovementioned meaning can be reacted with a halogenide derivative of general formula R 5 R 6 CHI in the presence of a base, such as sodium methoxide to give a compound of general formula (Na), wherein R, R 2 , R 5 and R 6 have the abovementioned meaning.
• the compound of general formula (Na) can be reacted with a brominating agent such as ⁇ /-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 R 1 R 2 , R 5 and Re have the abovementioned meaning.
• a brominating agent such as ⁇ /-bromosuccinimide (NBS)
• a radical initiator such as dibenzoyl peroxide
• an inert organic solvent such as carbon tetrachloride
• 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 R 1 R 2 , R 5 and Re have the abovementioned meaning.
• the enone derivative of general formula (III) can be reacted with hydra
• a reaction is preferably carried out in the presence of a base such as triethylamine or DIPEA (H ⁇ nig's base).
• 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 R 5 and R 6 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).
• 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 R 2 -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 R 1 R 2 , R 5 and R 6 have the abovementioned meaning.
• a transition metal- catalyzed cross-coupling reaction such as the so-called Suzuki-Miyaura reaction (Miyaura, 1995)
• a palladium-based catalyst such as Pd(OAc) 2
• a suitable ligand such as X-Phos, Ruphos or S-Phos and the like
• a compound of formula (IV), wherein R, R 2 , R 5 and R 6 have the abovementioned meaning can be reacted with phosgene, diphosgene or triphosgene to give a compound of formula (VIII) wherein R and R 2 have the abovementioned meaning (Scheme 2).
• a reaction is preferably carried out in the presence of a base such as triethylamine or DIPEA (H ⁇ nig's base).
• 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
• Part B To a magnetically stirred solution of pentanoic acid methoxy-methyl-amide (8.6 g, 59.3 mmol) at 0 0 C 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 0 C) aqueous hydrochloric acid (4 N solution) and extracted with MTBE. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give crude product.
• 3-phenyloctan-4-one (intermediate lla-2) was prepared from 1-phenylhexan-2-one (Intermediate 11-1 ), sodium methoxide and iodoethane in 60 % yield.
• in vitro affinity for cannabinoid-CB 2 receptors was determined using membrane preparations of CHO cells in which human cannabinoid CB 2 receptors were stably transfected in conjunction with [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]-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.
• CB 1 agonist stimulation lead to activation of PLA 2 followed by release of [ 3 H]-arachidonic acid into the medium.
• This CB 1 agonist-induced release was concentration-dependently antagonized by CB 1 receptor antagonists, such as rimonabant.
• cannabinoid-CB 2 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 K 1 cells expressing human CB 2 (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, 400 ⁇ g/ml Hygromycine B and 500 ⁇ g/ml G418 at 37 0 C in 93 % air / 5 % CO 2 .
• confluent cultures grown in 24 well plates were used.
• Reference compounds used to assess cannabinoid CB 2 receptor mediated adenylate cyclase activity were the full cannabinoid CB 2 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 "6 M. pEC 5 o and the pA 2 were calculated according to Cheng-Prusoff equation (Cheng and Prusoff, 1973). Two independent experiments were performed in triplicate.
• Cannabinoid CB 1 ZCB 2 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 CB 1 receptor agonist functional data of representative compounds of this invention are shown in the table below.
• 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.
• 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.
• 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.
• 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)
• 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.
• 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.
• 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.
• formulations of the present invention in the manufacture of medicaments for use in the treatment of a condition in which modulation of cannabinoid CB 1 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 CB 1 receptors is required or desired.
• compositions 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.
• 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.
• Bodanszky M. and A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, ISBN: 0-387-57505-7, 1994. Boyd, ST. and Fremming, B.A. Ann. Pharmacother. 2005, 39, 684-690 Carai, M.A.M. et al., Life Sc. 2005, 77, 2339-2350

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