WO2009109504A1 - Dérivés carbamates d'énol en tant que modulateurs de l'hydrolase d'amides d'acides gras - Google Patents

Dérivés carbamates d'énol en tant que modulateurs de l'hydrolase d'amides d'acides gras Download PDF

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WO2009109504A1
WO2009109504A1 PCT/EP2009/052258 EP2009052258W WO2009109504A1 WO 2009109504 A1 WO2009109504 A1 WO 2009109504A1 EP 2009052258 W EP2009052258 W EP 2009052258W WO 2009109504 A1 WO2009109504 A1 WO 2009109504A1
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aryl
alkyl
formula
disorder
acid
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Patrizia Minetti
Walter Cabri
Sabrina Dallavalle
Lucio Merlini
Sergio Penco
Franco Borsini
Antonio Caprioli
Mauro Maccarrone
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Sigma-Tau Industrie Farmaceutiche Riunite S.P.A.
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Publication of WO2009109504A1 publication Critical patent/WO2009109504A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • the present invention relates to enol carbamate derivatives, processes for their preparation, and to pharmaceutical compositions containing them for the treatment of neurological disorders, such as Parkinson, pain and anxiety.
  • Anandamide and other fatty acid amides are known to be chemical messengers that modulate a number of physiological processes (Hanus, L.O. Chem. Biodivers. 2007, 4, 1828-41). Anandamide activates through binding both the central-type (CBl) and peripheral type (CB2) cannabinoid receptors (Devane, W. A., et al. Science, 1992, 258, 1946-1949). Anandamide has been reported to be implicated in the modulation of nociception, feeding, emesis, anxiety, cell proliferation, inflammation, and memory (Labar, G., et al. C. Chem. Biodivers., 2007, 4, 1882-1902).
  • FAAH fatty-acid- amide-hydrolase
  • FAAH is also responsible of the catabolism of many other lipid signaling fatty acid amides (i.e. oleamide, ⁇ f-oleoylethanolamine, arachidonylglycerol and palmitoylethanolamide).
  • Modulating the activity of the endocannabinoid system by restoring the levels of endogenous signaling lipids turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions such as diseases of energy metabolism (cachexia and anorexia), pain and inflammation, central nervous system disorders (stroke, multiple sclerosis, Parkinson's disease, Huntington disease, Alzheimer disease, epilepsy, schizophrenia, anxiety, depression and insomnia), cardiovascular and respiratory disorders (hypertension, circulatory shock, myocardial reperfusion injury, atherosclerosis and asthma), retinopathy, cancer, gastrointestinal and liver disorders (inflammatory bowel disease and hepatitis), musculoskeletal disorders (arthritis and osteoporosis) as nicely reviewed lately (Pasher P.
  • diseases of energy metabolism cachexia and anorexia
  • central nervous system disorders stroke, multiple sclerosis, Parkinson's disease, Huntington disease, Alzheimer disease, epilepsy, schizophrenia, anxiety, depression and insomnia
  • cardiovascular and respiratory disorders hyperertension, circulatory shock, myocardial
  • FAAH-/- KO mice cannot metabolize anandamide and, though fertile and generally normal, show signs of enhanced anandamide and related fatty acid amides activity at cannabinoid receptors, such as reduced pain sensation (Cravatt, B. F., et al, Proc. Natl. Acad. ScL, 2001, 98, 9371).
  • the invention provides novel compounds for inhibiting Fatty Acid Amide Hydrolase (FAAH), compositions that include such compounds as well as methods of treating diseases of energy metabolism, pain and inflammation, central nervous system disorders, cardiovascular and respiratory disorders, retinopathy, cancer, gastrointestinal and liver disorders and musculoskeletal disorders by administering FAAH inhibitors to a patient.
  • Fatty Acid Amide Hydrolase FAAH
  • compositions that include such compounds as well as methods of treating diseases of energy metabolism, pain and inflammation, central nervous system disorders, cardiovascular and respiratory disorders, retinopathy, cancer, gastrointestinal and liver disorders and musculoskeletal disorders by administering FAAH inhibitors to a patient.
  • the invention comprises compounds of general formula (I)
  • R 1 is H, halogen or G 1 ;
  • G 1 is aryl, or heteroaryl, each being substituted with at least one radical chosen among halogen, hydroxy, lower alkoxy, cyano, aminocarbonyl, aryl or heteroaryl;
  • R 2 is H or halogen;
  • R 3 and R 4 are independently H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylkyl, alkylaryl, alkoxyaryl or haloaryl; or R 3 and R 4 taken together with the nitrogen atom to which they are attached form a heterocycle;
  • R 5 is the group [D-B-(A) n ]- wherein
  • An embodiment of this invention is that of compounds of formula (I), for use as medicaments.
  • said medicament is used for treating a neurological disorder, diseases of energy metabolism, cardiovascular and respiratory disorders, gastrointestinal and liver disorders, retinopathy, cancer and musculoskeletal disorders.
  • said medicament is used for treating a neurological disorder.
  • said medicament is used for treating anxiety and pain.
  • alkyl refers to linear or branched alkyl groups having from 1 to 20 carbon atoms, or preferably, 1 to 12 carbon atoms, or even more preferably 1 to about 6 carbon atoms. Lower alkyl group is exemplified by
  • Ci-C ⁇ -alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neo-butyl, tert-butyl, pentyl, iso-pentyl, n-hexyl and the like.
  • said alkyl can optionally be substituted with one or more alkyl, lower alkoxy, amino, aminocarbonyl, alkylcarbonyl or alkoxycarbonyl.
  • cycloalkyl refers to a saturated or unsaturated (but not aromatic) carbocyclic group of 3 to 10 carbon atoms having a single ring or multiple condensed rings.
  • C3-Cio-cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like. Where specified, said cycloalkyl can optionally be substituted with one or more alkyl, lower alkoxy, amino, aminocarbonyl, alkylcarbonyl or alkoxycarbonyl.
  • heterocycloalkyl and heterocycle refers to a saturated or unsaturated (but not aromatic) five-, six- or seven-membered ring containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings, where specified, may be substituted with amino, alkyl, heterocycloalkyl, alkoxycarbonyl, carboxy or aryl.
  • Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, ketopiperazine, 2,5-diketopiperazine, morpholine, thiomorpholine, dihydropyranyl, tetrahydropyranyl, tetrahydrofurane, dihydropyrrole, imidazolidine, dihydropyrazole, pyrazolidine and the like.
  • aryl refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e. g., phenyl) or multiple rings, which may be attached in a pendent manner or may be fused.
  • Preferred aryl include phenyl, naphthyl, phenantrenyl, biphenyl, indane and the like.
  • arylkyl refers to alkyl groups having one or more aryl substituent, including benzyl, phenethyl, diphenyl methyl and the like.
  • heteroaryl refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or pyrazolyl.
  • carboxy refers to the group -C(O)OH.
  • alkoxy or “lower alkoxy” refer to the group -OR where R includes “Ci-Ce-alkyl”.
  • alkylcarbonyloxy refers to the group -OC(O)R where R includes
  • heterocycloalkyl or “heteroaryl”.
  • amino refers to the group -NRR' where each R, R' is independently H, "alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl”,
  • heterocycloalkyl aryl, “heteroaryl” or where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3 to 8- membered heterocycloalkyl ring.
  • aminocarbonyl refers to the group -C(O)NRR' where each R, R' includes independently H, "Ci-Ce-alkyl", “(VCe-alkenyl”, “(VCe-alkynyl”,
  • Cs-Cio-cycloalkyl "heterocycloalkyl”, “aryl” or “heteroaryl”; or R and R' taken together with the nitrogen atom to which they are attached form a heterocycloalkyl.
  • aminocarbonyloxy refers to the group -OC(O)NRR' where each R, R' includes independently H, "Ci-Ce-alkyl”, “C 2 -C6-alkenyl”, “C 2 -C6-alkynyl”,
  • Cs-Cio-cycloalkyl "heterocycloalkyl”, “aryl” or “heteroaryl”; or R and R' taken together with the nitrogen atom to which they are attached form a heterocycloalkyl.
  • sulfonyloxy refers to a group -OSO2-R where R is selected from H, "Ci-C ⁇ -alkyl", substituted with halogens, e. g., an -OSO2-CF3 group,
  • alkoxycarbonyl refers to the group -C(O)OR where R includes
  • alkyl and cycloalkyl
  • alkylcarbonylamino refers to an amino group substituted by an alkylcarbonyl residue.
  • “Pharmaceutically acceptable salts” refers to salts of the below identified compounds of formula (I), that retain the desired biological activity. Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, toluene sulfonic acid, naphthalene disulfonic acid, methanesulfonic acid and poly-galacturonic acid.
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, toluene s
  • the salt is of a mono acid (for example, the hydrochloride, the hydrobromide, the p-toluenesulphonate, or the acetate)
  • the hydrogen form of a di-acid for example, the hydrogen sulphate, or the succinate
  • the dihydrogen form of a tri-acid for example, the dihydrogen phosphate, or the citrate
  • at least one molar equivalent and usually a molar excess of the acid is employed.
  • the appropriate and exact chemical equivalents of acid are generally used.
  • Suitable pharmaceutically acceptable base addition salts for the compound of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, ⁇ f,.ZV'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( ⁇ f-methylglucamine) and procaine.
  • Sodium salts are particularly preferred.
  • “Enantiomers” refers to the products that are obtained by an asymmetric synthesis, i.e.
  • the compounds of the present invention can be prepared by conventional synthetic methods and are described underneath.
  • R 5 has the meaning as described above, with a suitable base, usually NaH or LiH, to obtain the corresponding enolate, in an appropriate solvent, at a temperature ranging from -78°C to reflux of the solvent and by subsequently adding a suitable carbamoyl chloride.
  • the solvent should preferably be an aprotic polar solvent, such as tetrahydrofuran, dioxane, or dimethylsulfoxide and the reaction is preferentially conducted at room temperature, for example like as reported by Panella L., et al., Org. Lett.,
  • such compounds may also be prepared by reacting a ketone of formula (II) with a suitable carbamoyl chloride of formula (III)
  • such compounds may also be prepared by reacting an enol silylether of a ketone of Formula (II) with a carbamoyl fluoride or chloride, for example as reported by Olofson R.A., et al., Tetrahedron Lett., 1980, 21, 819.
  • a suitable base usually NaH or LiH
  • an appropriate solvent usually an aprotic polar solvent, such as tetrahydrofuran, dioxane, or dimethylsulf oxide
  • such compounds may also be prepared by reacting the enol silylether of a ketone of formula D-B-(A) n -CO-CHs with a carbamoyl fluoride or chloride, for example as reported by Olofson R.A., et al., Tetrahedron Lett., 1980, 21, 819.
  • such compounds can be prepared by reaction of an appropriate iodoaryl or iodoheteroaryl compound with a metallated (Li or BusSn) difluoroenolcarbamate, for example like as described by DeBoos G.A., et al. Synlett, 2000, 963.
  • Compounds of formula (I), where R 1 is G 1 , R 2 is H may be prepared by reacting an appropriate aryl or heteroaryl ethyne with CO2 and an appropriate amine, in the presence of a ruthenium catalyst, for example like as described by Bruneau C, et al., J. MoI. Catalysis, 1992, 74, 97, or by Hofer J., et al, Tetrahedron Lett., 1991, 32, 50, 7409.
  • any interfering reactive group can be protected and then deprotected according to well-established procedures described in organic chemistry (see for example: Greene T. W. and P. G. M. Wuts "Protective Groups in Organic Synthesis", J. Wiley & Sons, Inc., 3 rd Ed., 1999) and well known to those skilled in the art.
  • compositions covered by the present invention are entirely conventional and are obtained with methods which are common practice in the pharmaceutical industry, such as, for example, those illustrated in Remington's Pharmaceutical Science Handbook, Mack Pub. N. Y. — last edition. According to the administration route chosen, the compositions will be in solid or liquid form, suitable for oral, parenteral or topical administration.
  • the compositions according to the present invention contain, along with the active ingredient, at least one pharmaceutically acceptable vehicle or excipient. These may be particularly useful formulation coadjuvants, e.g. solubilising agents, dispersing agents, suspension agents, and emulsifying agents.
  • the compounds of this invention are administered in a "pharmaceutically effective amount".
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, drug combination, the age, body weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • an effective dose will be from 0.01 mg/kg to 100 mg/kg, preferably 0.05 mg/kg to 50 mg/kg.
  • the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually mice, rats, guinea pigs, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration.
  • compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • the medicament may also contain a pharmaceutically acceptable carrier, for administration of a therapeutic agent.
  • Such carriers include antibodies and other polypeptides, genes and other therapeutic agents such as liposomes, provided that the carrier does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • Suitable carriers may be large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactive virus particles.
  • compositions of the invention can be administered directly to the subject.
  • the subjects to be treated can be animals; in particular, human subjects can be treated.
  • the medicament of this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal or transcutaneous applications, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal or rectal means.
  • the compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include refilled, pre- measured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Dosage treatment may be a single dose schedule or a multiple dose schedule.
  • the compounds of the present invention are useful as medicaments due to their FAAH inhibiting properties for the treatment of disorders where such inhibition result in improving the health of the patient.
  • patients suffering from: cachexia, anorexia, pain, inflammation, stroke, multiple sclerosis, Parkinson's disease, Huntington disease, Alzheimer disease, epilepsy, schizophrenia, anxiety, depression, insomnia, hypertension, circulatory shock, myocardial reperfusion injury, atherosclerosis, asthma, retinopathy, cancer, inflammatory bowel disease, hepatitis, arthritis and osteoporosis can be treated.
  • An object of the present invention are pharmaceutical compositions containing one or more of the compounds of formula (I) described earlier, in combination with excipients and/or pharmacologically acceptable diluents.
  • compositions in question may, together with the compounds of formula
  • a further object of the invention is a process for the preparation of pharmaceutical compositions characterised by mixing one or more compounds of formula (I) with suitable excipients, stabilizers and/or pharmaceutically acceptable diluents.
  • An embodiment of this invention is that of compounds of formula (I), where
  • R 5 is a group [D-B-(A) n ].
  • a preferred embodiment of this invention is that of compounds of formula (I), where R 5 is a group [D-B-(A) n ] and R 1 and R 2 are H.
  • a more preferred embodiment of this invention is that of compounds of formula (I), where R 5 is a group [D-B-(A) n ], R 1 and R 2 are H and B and D are optionally substituted aryl.
  • An even more preferred embodiment of this invention is that of compounds of formula (I), where R 5 is a group [D-B-(A) n ], R 1 and R 2 are H, B and D are optionally substituted aryl and where R 3 and R 4 taken together form an optionally substituted heterocycle.
  • HMPT hexamethyl phosphorous triamide
  • N-methyl-N-phenylcarbamic acid l-biphenyl-3-yl- vinyl ester was obtained (100 mg, 40 %).
  • STEP 1 (3-biphenyl-4-yl-l-methylene-allyloxy)-trimethylsilane 0.32 ml of triethylamine was added dropwise to a solution of 4-biphenyl-4- yl-but-3-en-2-one (200 mg, 0.9 mmol) in THF (2.1 ml) at 0°C followed by dropwise addition of 0.18 ml of trimethylsilyl triflate. The mixture was stirred for 2 hrs at 0°C, then poured into a saturated solution of NH4CI, and extracted with Et2 ⁇ (3 x 15 ml). The resulting solution was dried over sodium sulfate and the solvent was removed under reduced pressure to afford 210 mg of the expected adduct which was used in the next step without any further purification.
  • reaction mixture was allowed to return to RT and 1.6 ml of dry HMPT were added together with 67 mg of N,N-dimethylcarbamoyl chloride. Stirring was maintained for 6 hrs.
  • the reaction mixture was poured into a solution of 10% citric acid at pH 4, and was extracted with AcOEt. The solvent were removed under reduced pressure and the crude reaction mixture was purified by flash chromatography (hexane / AcOEt) to afford the title product. Yield: 15%.
  • the compounds of the present invention show affinity and inhibit the enzymatic activity of the fatty acid amide hydrolase enzyme.
  • the assay of FAAH (EC 3.5.1.4) was performed by measuring the release of [1- 14 C]AA from [1- 14 C]AnNH (52 mCi/mmol), using RP-HPLC. Also [ 3 H]AnNH (205 Ci/mmol) could be used as substrate, measuring the release of [ 3 H]AA under the same experimental conditions described below for [1- 14 C]AnNH.
  • the compounds of the present invention were also evaluated with regard to their selectivity profile against the following targets: AMT, NAPE-PLD, MAGL, DAGL, CB1/CB2 and TRPVl according to the procedures described in Maccarrone M., et al., J. Biol. Chem., 2000, 275, 13484; Fezza F., et al., Anal Biochem., 2005, 339, 113; Dinh T.P., et al., 2002, Proc. Natl. Acad. ScL 99, 10819; Bisogno T., et al., 2003, J. Cell Biol, 163, 463; Maccarrone M., et al., J. Biol. Chem., 2000, 275, 31938; Ross R.A., et al., Br. J. Pharmacol, 2001, 132, 631. The results are shown in table 2. Table 2
  • the maximum concentration tested corresponds to 5 times those of the IC 50 on FAAH
  • ST3830, ST3851 and ST3899 were shown to be selective against the above targets. Among those targets, only ST3899 was interfering with AMT and CB2.
  • Reversibility Reversibility was ascertained by incubating FAAH with an excess (i.e., concentrations well above the IC50 values) of the compounds of the present invention for 20 min (as in the enzymatic assay conditions). Subsequently, the FAAH/compound mixtures (in 1 ml volume) were dialyzed overnight against 2 litres of 10 mM Tris-HCl buffer (pH 7.4). The FAAH/compound mixtures were subjected to activity assays as described above, both before and after dialysis.
  • EPM elevated plus maze
  • the purpose of the present study was to set up an animal model of anxiety EPM using the anxiolytic effects of benzodiazepine Diazepam in mice and evaluate the effect of FAAH inhibitors ST3108 (URB597) and ST4070. Twelve male CDl mice (Charles River) of about 30 g (2 months old) per group were used.
  • the Elevated Plus Maze apparatus was of grey Plexiglas and consisted of two open and two closed arms linked by a common central platform. The maze was elevated 40 cm above floor level and dimly lit. Animals were individually placed on the central platform of the maze facing an open arm. A standard five-min test was employed. The amount of time spent by each animal in either open or closed arm was recorded, as well as the number of entries by each animal into either arm.
  • ST3108 and ST4070 were tested at a dose of 10 mg/10 ml/kg and Diazepam at a dose of 0.5 mg/5 ml/kg.
  • ST3108 and ST4070 dispersed in a solution of 5% Tween 80 and 0.5% carboxymethylcellulose, were given orally 60 min before test;
  • Diazepam dispersed in a solution of 3% Tween 80, was given intraperitoneal ⁇ 30 min before test.
  • ST3108 and ST4070 reduced anxiety and did not affect the locomotor activity evaluated in elevated plus maze.
  • the paw withdrawal test was used to assess mechanical hyperalgesia.
  • the nociceptive threshold expressed in grams, was measured by applying increasing pressure to the left and right hind paws using an Randall- Selitto analgesimeter (Ugo Basile, Varese, Italy).
  • the parameter used to quantify the nociceptive threshold was defined as the pressure (grams) at which the rat withdrew its paw. Rats were habituated to the testing procedures and handling by the investigator in the week prior to the experiment.
  • Acute oral treatment with ST3108 (50 mg/kg) did not exert analgesic activity, while ST4070 (50 mg/kg) showed significant analgesic activity after one hour (P ⁇ 0.001) as demonstrated in figure 1.
  • a dose response experiment was also conducted with ST4070 at 25 and 50 mg/kg, demonstrating the increased activity at the higher dose with respect to the 25 mg/kg dose (figure 2).

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur de nouveaux dérivés carbamates d'énol de formule (I) pour inhiber l'hydrolase d'amides d'acides gras (FAAH), sur des compositions qui comprennent de tels composés ainsi que sur des procédés de traitement de maladies du métabolisme énergétique, de troubles du système nerveux central, de troubles cardiovasculaires et respiratoires, d'une rétinopathie, d'un cancer, de troubles gastro-intestinaux et hépatiques et/ou de troubles musculosquelettiques. Les composés de la présente invention se sont avérés particulièrement efficaces dans des modèles animaux de l'anxiété et de la douleur.
PCT/EP2009/052258 2008-03-07 2009-02-26 Dérivés carbamates d'énol en tant que modulateurs de l'hydrolase d'amides d'acides gras WO2009109504A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011085216A2 (fr) 2010-01-08 2011-07-14 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour traiter la maladie de parkinson et le syndrome des jambes sans repos
WO2011123719A2 (fr) 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes
CN103153946A (zh) * 2010-07-28 2013-06-12 加利福尼亚大学董事会 外周限制性 faah 抑制剂
US9745255B2 (en) 2011-08-19 2017-08-29 The Regents Of The University Of California Meta-substituted biphenyl peripherally restricted FAAH inhibitors
US9822068B2 (en) 2014-04-07 2017-11-21 The Regents Of The University Of California Inhibitors of fatty acid amide hydrolase (FAAH) enzyme with improved oral bioavailability and their use as medicaments

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2850377A1 (fr) * 2003-01-23 2004-07-30 Sanofi Synthelabo Derives d'arylalkylcarbamates, leur preparation et leur application en therapeutique
FR2866884A1 (fr) * 2004-02-26 2005-09-02 Sanofi Synthelabo Derives d'aryl-et d'heteroaryl-piperidinecarboxylates, leur preparation et leur application en therapeutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2850377A1 (fr) * 2003-01-23 2004-07-30 Sanofi Synthelabo Derives d'arylalkylcarbamates, leur preparation et leur application en therapeutique
FR2866884A1 (fr) * 2004-02-26 2005-09-02 Sanofi Synthelabo Derives d'aryl-et d'heteroaryl-piperidinecarboxylates, leur preparation et leur application en therapeutique

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011085216A2 (fr) 2010-01-08 2011-07-14 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour traiter la maladie de parkinson et le syndrome des jambes sans repos
WO2011123719A2 (fr) 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes
CN103153946A (zh) * 2010-07-28 2013-06-12 加利福尼亚大学董事会 外周限制性 faah 抑制剂
US9187413B2 (en) 2010-07-28 2015-11-17 The Regents Of The University Of California Peripherally restricted FAAH inhibitors
US9745255B2 (en) 2011-08-19 2017-08-29 The Regents Of The University Of California Meta-substituted biphenyl peripherally restricted FAAH inhibitors
US9822068B2 (en) 2014-04-07 2017-11-21 The Regents Of The University Of California Inhibitors of fatty acid amide hydrolase (FAAH) enzyme with improved oral bioavailability and their use as medicaments
US10435355B2 (en) 2014-04-07 2019-10-08 The Regents Of The University Of California Inhibitors of fatty acid amide hydrolase (FAAH) enzyme with improved oral bioavailability and their use as medicaments

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AR072346A1 (es) 2010-08-25
TW200948805A (en) 2009-12-01

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