TW201006791A - Oxime carbamoyl derivatives as modulators of fatty acid amide hydrolase - Google Patents

Abstract

The present invention relates to new oxime carbamoyl derivatives of formula I, processes for their preparation, and to pharmaceutical compositions containing them for the treatment of neurological disorders, such as neuropathic pain and anxiety.

Description

201006791 VI. INSTRUCTIONS OF THE INVENTION [Technical Fields of the Invention] The present invention relates to novel indolemethine derivatives, methods for their preparation, and pharmaceuticals containing the same for treating neurological diseases such as neuropathic pain and anxiety Composition. [Prior Art] φ It is known that endogenous cannabinoids (Anandamide) and other fatty acid guanamines are chemical transmitters that regulate many physiological processes (Hanus L.O., Chem. Biodivers., 2, 7, 4, 1828). Endogenous cannabinoids are activated by binding to both central (CB1) and peripheral (CB2) cannabinoid receptors (Devane W. Α· et al., Science, 1 992, 25 8, 1 946-1 949 ). The report states that endocannabinoids are associated with pain receptor acceptance, feeding, vomiting, anxiety, cell growth, inflammation, and memory (Labar G. et al., Chem. Biodivers., 2007, 4, 1 882). The pharmacological action of φ endogenous cannabinoids is terminated by the fatty acid indoleamine hydrolase (FAAH), an enzyme that is distributed in the central nervous system and degrades fatty acid guanamine at its site of action (Cravatt BF et al., Nature, 1 996, 3 84, 83; Patricelli MP et al., B iochemistry, 1 9 9 9, 3 8, 9804; WO 98/20 1 1 9 and U.S. Patent No. 6,271,01 5). The crystal structure of the complex of FAAH and the ligand has been clarified, and it is confirmed that it is catalyzed by the triplet Ser-Ser-Lys (Bracey MH et al., Science, 2002, 298, 29, 1 793 ° FAAH is also responsible for the catabolism of many other lipid-fat fatty acid guanamines (ie, oleic acid 201006791 guanamine, N-oil 醯 ethanolamine 'arachidonic acid glycerol and palm lanthanum ethanolamine amide). As has recently been observed cautiously, the results of modulating the endocannabinoid system activity by reverting to the level of endogenous signaling lipids have therapeutic hopes for a wide range of different conditions and pathological conditions, such as pathological conditions such as Energy metabolism diseases (cachexia and anorexia), pain and inflammation, central nervous system diseases (stroke, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, epilepsy, schizophrenia) Disease, anxiety, depression and insomnia), cardiovascular and respiratory diseases (hypertension, circulatory shock, myocardial reperfusion injury, atherosclerosis and asthma), retinopathy, cancer, gastrointestinal and liver diseases (inflammatory bowel disease) And hepatitis), musculoskeletal diseases (arthritis and osteoporosis) (Pasher P. et al., Pharmacol. Rev., 2006, 58, 3 89 and references therein). FAAH-/-KO mice are unable to metabolize endocannabinoids, and although they are fertile and generally normal, show enhanced endogenous cannabinoid signaling and related fatty acid guanamine activity at cannabinoid receptors, Such as reducing pain (Cravatt BF et al., Proc. Natl. Acad. Sci., 2001, 98, 937 1). This suggests that FAAH target drugs may increase the likelihood of excitatory effects of endogenous cannabinoids, while avoiding the multiple and often undesirable effects of A9-THC and other direct-acting cannabinoid agonists (Hall W. Etc., Lancet, 1 998, 3 5 2, 1611; Chaperon, F. et al., Crit. Rev. Neurobiol., 1 999, 1 3, 243). In particular, URB-5 97 (a urethane-based inhibitor) has been reported to be effective for the zero-maze labyrinth model of anxiety, and has analgesic effect on the large -6-201006791 rat hot plate and the fumarin test. (Kathuria S., et al, Nat. Med., 2003, 9, 1,76) ° W003007955 describes endonuclease inhibitors as useful agents for the treatment of cancer. In this application, the only description of the aminocarbonyl hydrazine derivative 1- 1-propion-1-(2'-fluoro[1,1'-biphenyl]-4-yl)-0-[[(3,5) -Dichlorophenyl)amino]carbonyl]indole has been reported to have an anti-Hapl IC5G of 2.4 μM. 1-acetone-1-(2'-fluoro[1,1'-biphenyl]-4-yl)-indole-[(phenylamino)carbonyl] hydrazine with 1-acetone-1-(2'-fluoro [1, plant-biphenyl]-4-yl)-indole-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl] oxime is a conventional compound, but the activity cannot be regained in the literature. Or reference. In a virtual screen targeting a novel non-nucleoside inhibitor of HI V-1 reverse transcriptase, two commercially available compounds, 1-keto-1-(6-benzofuranyl)-0-[[(2), were identified. -methylamino)amino] ruthenium] with acetamidine-1-(6-benzofuranyl)-fluorene-[[(3-methylphenyl)amino]carbonyl] hydrazine, but when reported It loses activity at concentrations up to 100 μΜ in HIV replication assays in MT-2 cells (Barreiro G. et al., J Chem. Inf. Model., 2007, 47, 6, 2416) ° US5438056 indicates Formula 1 Amino formates (wherein Ri and R2 may not be alkyl groups, and R3 and R4 may be hydrazine, C4-C2Q hydrocarbon chains) are effective agents for reducing excess cholesterol in humans.

Ri R3 丫n, r' ο Formula 1 201006791 W0200305 1 842 A compound of the formula 其中^Ι^ΝερΧ)!^ (where X can be 〇, and L can be of the formula -ON = CRalRa2) as a steroid sensitive lipid Enzymes are effective agents that modulate plasma levels of free fatty acids. Eight hydrazine derivatives are specifically described in this patent application. These eight indole derivatives are also presented in W0200305 1 841. Such defects are not part of the invention. US6949574 proposes a hydrazine-based mercapto fatty acid guanamine hydrolase inhibitor of formula 2, wherein A can be dibenzofuranyl, dibenzothiophenyl, naphthyl, anthracenyl, fluorenyl, oxazolyl or Substituted alkoxyphenylalkyl, and further B may be a group -N = CR2R3, wherein R2 is methyl or hydrazine, and R3 may be optionally substituted by halogen, hydrazine: -4 haloalkyl and nitro One of the phenyl groups.

B"°T^A 22 Forty years ago, an amine-mercaptopurine derivative of the formula 3 having an analgesic property (wherein Y may be an alkyl group and R'R2 and R3 may be an alkyl group or an aryl group) will be described. And X is a lower dialkylamino residue (GB 1 2 1 4077). X, Y / R2 R1 human Ν · 〇丫 N, R3 Ο Formula 3 almost 30 years ago, the report proposed morphine and 0-(4-methoxyphenylamine carbaryl)-3-diethylamine hydrochloride The relative analgesic, behavioral, and dependent properties of acetaminophen. This compound shows analgesic efficacy similar to morphine and is considered to be slightly more dependent on the latter (Watzman N. et al., Journal of -8-201006791)

Pharmaceutical Sciences, 1 980, 69, 2, 225). Recently, virtual screening results using a comparative model of human monoglycerolase (MGL) have been disclosed (Saario S. M. et al. 'J. Med. Chem. 2006, 49, 4650). When tested against the MGL enzyme, the compounds found were not productive. When tested against the FAAH enzyme, an indole derivative (MWP00348) showed inhibition of the enzyme at a lower than micromolar IC5Q. The possible therapeutic relevance of inhibition of FAAH has spurred interest in developing selectivity and potent inhibitors. Such a strategy may represent an alternative to using an exogenous cannabinoid agonist that has been found to provide a variable effect. Inhibition of FAAH appears to be an ideal way to increase the level of endogenous amidated lipids that activate the CB 1 receptor. Therefore, the expectation of a possible and selective FAAH inhibitor remains a concern and a promising goal. DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel compounds for inhibiting fatty acid indoleamine hydrolase (FAAH), compositions comprising such compounds, and for treating energy metabolic diseases by administering a FAAH inhibitor to a patient, Pain and inflammation, central nervous system diseases, cardiovascular and respiratory diseases, retinopathy, cancer, gastrointestinal and liver diseases, musculoskeletal diseases. The present invention comprises a compound of the formula I A'VN, a 〇 〆 I R2

Formula I -9- 201006791 wherein: R 1 and R 2 are independently hydrazine, alkyl, aryl, aralkyl, alkoxyaryl or haloaryl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring G is a phenyl or thienyl group; hydrazine is a phenyl group, a thienyl group, a cyclohexyl group, a pyrrolyl group or a pyridyl group, which are optionally substituted once or twice with an aminocarbonyl group or an alkyl group; , geometric isomers thereof, optically active forms thereof (such as mirror image isomers, non-image isomers and their racemate forms), and pharmaceutically acceptable salts thereof; the prerequisites are when A is cyclohexyl If R2 is hydrazine, R1 may not be 4-chlorophenyl or 3,4-dichlorophenyl. A particular embodiment of the invention is a compound of formula I for use as a medicament. In another embodiment, the agent is for the treatment of neurological disorders, energy metabolism disorders, cardiovascular and respiratory diseases, gastrointestinal and liver disorders, retinopathy, cancer and musculoskeletal disorders. In a preferred embodiment, the agent is for treating a neurological condition. In a more preferred embodiment, the agent is used to treat anxiety and pain. The term "alkyl" refers to a straight or branched alkyl group preferably having from 1 to about 12 carbon atoms. Examples of lower alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isoprene-10-201006791, neomethyl, A group such as n-hexyl. The term "alkoxy" refers to the group -〇R ' wherein R includes lower alkyl, "<: 3-(:1()cycloalkyl" and "heterocycloalkyl". "" and/or heterocyclic ring means a saturated five or six membered ring containing one or two nitrogen, oxygen or sulfur atoms. Preferred heterocycloalkyl groups include pyrrolidine, piperidine, piperazine, morpholine, sulfur? Porphyrin, etc. The term "aryl" means an aromatic carbocyclic group having from 6 to 14 carbon atoms which has a single ring (for example, phenyl) or a polycyclic ring which may be attached in a side chain manner or may be fused. Preferred aryl groups include phenyl, naphthyl, biphenyl, hydroquinone, etc. The term "aralkyl" refers to an alkyl group as defined above having one or more aryl substituents, including benzoyl. The term "heteroaryl" refers to a monocyclic heteroaromatic or bicyclic fused ring heteroaromatic radical. Specific examples of heteroaromatic radicals include optionally substituted pyridyl groups. , pyrrolyl, furyl, thienyl or benzothiophene. The term "aminocarbonyl" refers to the group -C(0)NRR', wherein each R, . independently includes H, "alkyl", Aryl" "Arylaminocarbonyl". "Pharmaceutically acceptable salt" means a compound of formula (I) identified below which retains the desired biological activity. Examples of such salts include, but are not limited to, inorganic An acid addition salt formed by an acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and an organic acid (such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, Maleic acid, anti--11 - 201006791 Ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polybasic acid, naphthalenesulfonic acid, toluenesulfonic acid, naphthalene disulfonic acid, methanesulfonic acid a salt formed with polygalacturonic acid. When the salt is a salt of a monovalent acid (for example, a hydrochloride, a hydrobromide, a p-toluenesulfonate or an acetate), a hydrogen form of a dibasic acid (for example) , hydrogen sulphate, or succinate), or a dihydrogen form of a trivalent acid (eg, dihydrogen phosphate or citric acid), using at least one molar equivalent and usually molar excess of the acid. When a salt such as a sulfate, a hemisuccinate, a hydrogen phosphate or a phosphate is used, Suitable and precise acid equivalents. Suitable pharmaceutical acceptable pharmaceutically acceptable salts of the compounds of the invention include the metal salts prepared from the following: aluminum, calcium, lithium, magnesium, potassium, sodium and zinc; or from the following Organic salts: lysine, N, N'-diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucose) Amine) and procaine. Particularly preferred as sodium salt. "Spiegelmer" means asymmetric synthesis (ie, synthesis of non-racemic starting materials and/or reactants or at least one mirror selectivity) The product obtained, thus forming an excess of about 52% of one of the image isomers. The compounds of the present invention can be prepared by conventional synthetic methods and described below. It will be understood that given a representative or In the case of preferred experimental conditions (|卩, reaction temperature, time, moles of reactants, solvent, etc.), other experimental conditions may be used unless otherwise stated. The invention further provides a process for the preparation of a compound of formula I by reacting a compound of formula II in a non-aprotic solvent such as toluene or benzene at a temperature of from 2 〇 to ==c to the reflux of the solvent of the 201006791 solvent. Made with a compound of formula III

Formula II where A and G are as previously described

ΛΛν-1 R2

Formula III wherein R1 and R2 are as described above. Alternatively, a compound of formula I (wherein R 2 is hydrogen) can be reacted in an aprotic solvent such as toluene or benzene at 2 (TC to the temperature at which the solvent is refluxed to react a compound of formula II with formula IVCC^ONR1) Made with the compound. In all such variations, any interfering reactive groups may be according to well-known processes well known in the art of organic chemistry and well known to those skilled in the art (see, for example, Greene TW, Wuts PGM, (Protective Groups in Organic Synthesis), J. Wiley & Sons, Inc., 3rd Ed., 1999) Protected and then protected. All such modifications are merely examples of well-defined processes described in organic chemistry and well known to those skilled in the art (see, for example, March J., (Advanced Organic Chemistry), J. Wiley & Sons, Inc., 4th Ed., 1992). The present inventors have found that the derivative (I) prepared according to the present invention and the pharmaceutically acceptable salt thereof, in the treatment of the disease state, disease and pathological state, which are mediated by fatty acid indoleamine hydrolase, are particularly useful. It can be used to treat anxiety and pain. Accordingly, another object of the present invention is a method of treating a mammal suffering from a condition, a disease, and a pathological condition (especially treating anxiety and pain) mediated by a fatty acid indoleamine hydrolase, the method comprising administering a therapeutically effective amount of the above formula ( Compound of I). The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent required to treat, ameliorate, or otherwise detect a target condition or condition. For any compound, the therapeutically effective dose can be initially estimated by cell culture assay or by animal model (usually mouse, rat, guinea pig, rabbit, dog or pig). This animal model can also be used to determine the appropriate concentration range and route of administration. This information can then be used to assess the available dosage and route of administration for use in humans. In calculating human isodose (HED), it is recommended to use the conversion table provided in the Guidance for Industry and Reviewers document (2002, U. S. Food and Drug Administration, Rockville, Maryland, USA). The pharmaceutical composition contains at least one compound of the formula (I) as an active ingredient in an amount sufficient to produce a significant therapeutic effect. The composition encompassed by the present invention is entirely a conventional composition and is prepared by a general practice in the pharmaceutical industry, such as, for example, the method exemplified in the latest edition of Remington's Pharmaceutical Science Handbook, Mack Pub. N.Y. Depending on the route of administration selected, the compositions may be in solid or liquid form suitable for oral, parenteral or topical administration. The composition of the present invention - 14 - 201006791 contains at least one pharmaceutically acceptable carrier or excipient and the active ingredient. These may be particularly useful formulations, such as solubilizers, dispersing agents, suspending agents, and emulsifying agents. The amount of the compound actually administered is usually determined by the physician based on the relevant circumstances. 'These conditions include the state to be treated, the route of administration selected, the actual compound administered, the combination of drugs, age, body weight, and individual patients. Reaction, severity of symptoms of the patient, etc. Generally, an effective dose is from 0.01 mg/kg to 100 mg/kg, preferably from 0.05 mg/kg to 50 mg/kg. For any compound, the therapeutically effective dose can be initially estimated by cell culture analysis or by animal model (usually mouse, rat, guinea pig, rabbit, dog or pig). The precise and effective dose for a human subject will depend on the severity of the condition, the general health of the subject, age, weight, and the sex of the subject, diet, time and frequency of administration, drug combination, response sensitivity, and tolerance to treatment/ It depends on the reaction. This amount can be determined by routine experimentation and within the discretion of the clinician. The composition may be administered to a patient alone or may be administered in combination with other agents, drugs or hormones. The medicament may also contain a pharmaceutically acceptable carrier for administration of the therapeutic agent. Such carriers include antibodies and other polypeptides, genes and other therapeutic agents, such as liposomes, provided that the carrier itself does not induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Suitable carriers can be macromolecules that are large and slow to metabolize, such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polyamino acids, amino acid copolymers, and deactivated virions. -15- 201006791 A complete discussion of pharmaceutically acceptable carriers can be found in Pharmaceutical Sciences (Mack Pub. Co., NJ therapeutic composition of pharmaceutically acceptable carriers can be used in water, saline, glycerol and ethanol, etc. Substances such as wetting or emulsifying agents, PH may be present in such compositions. These carriers make the pharmaceutical composition tablets, nine doses, dragees, capsules, liquids, gels, suspensions and the like for administration to a patient. After formulation, the composition of the present invention can be directly administered to a subject, and can be an animal, in particular, a human subject can be administered by a plurality of routes, including oral, intravenous 'intramuscular, intra-arterial' Internal, spinal endothelium or transdermal administration, subcutaneous, intraperitoneal, intranasal, enteral, intravaginal or rectal. The composition for oral administration can be in the form of bulk liquid powder in bulk. However, more commonly, The composition dosage form is for precise administration. The term "unit dosage form does not contain a predetermined amount per unit of the unit dose of the human subject and other mammals. It is calculated to produce the desired therapeutic effect with the appropriate pharmaceutical excipients. Refills, pre-measured ampoules or syringes of representative unit dosage forms, or nine doses, lozenges, capsules, and the like in the solid form. In such compositions, the materials are usually in small amounts (about 0.1 to about 50% by weight, or to about 40% by weight), with the balance being various carriers or carriers.

Remington's 1991) ° Contains substances such as buffer substances, etc., syrup, pulp. The composition of the present invention is not limited to, indoor, transparent, topical, lingual, suspending or by means of a unit, and the active ingredient comprises the liquid composition. It helps to form 201006791 as a processing aid in the desired form of administration. Dosage therapy can be a single dose or multiple doses. The object of the present invention is a pharmaceutical composition comprising one or more compounds of the above formula (I) and excipients and/or pharmaceutical composition diluents. The composition in question may contain a compound of formula (I) in combination with conventional active ingredients. Another object of the invention is a process for the preparation of a pharmaceutical composition characterized by mixing one or more compounds of formula (I) with a suitable excipient, stabilizer and/or pharmaceutical composition diluent. Specific examples of the invention are the compounds of the above formula (I), wherein R1 is aryl, alkoxyaryl or haloaryl, and R2 is deuterium. A preferred embodiment of the invention is a compound of the above formula (I), wherein R1 is an optionally substituted aromatic group, R2 is fluorene and G is a phenyl group, and hydrazine is a heteroaryl group. A more preferred embodiment of the invention is a compound of the above formula (I), wherein R1 is an optionally substituted aromatic group, R2 is fluorene and G is a phenyl group, and hydrazine is a 2-thienyl group. Specific examples of the invention are represented by the following compounds: 1-phenylaminocarbonyloxyimino-1-(4-biphenylyl)ethane (ST3 715); 1-dimethylaminocarbonyloxyl Imino-1-(4-biphenylyl)ethane (ST374 1 ); 1-phenylaminocarbonyloxyimino-1-(3-biphenylyl)ethane (ST3 9 86); 1-(1-naphthylaminocarbonylimino)-1-(3-diphenyl)ethane (ST3 987); 1-(4-fluorophenylaminocarbonyloxyimino)- 1-(3-biphenylyl)ethane (ST3 988); 1-(4-methoxyphenylaminocarbonyloxyimino)-1-(3- -17- 201006791 biphenyl) Alkane (ST3989); 1-(1-piperidinylcarbonyloxyimino)-1-(3-biphenylyl)ethane (ST4017); 1-(diphenylaminocarbonyloxyimino) )-1-(3-biphenylyl)ethane (8 butyl 4 018); 1-(phenylaminocarbonyloxyimino)-1-(3-(2-thienyl)phenyl) Alkane (8 butyl 4 0 0 0); 1-(phenylaminocarbonyloxyimino)-1-(3-(3'-aminocarbonyl)biphenyl)ethane (8 butyl 4 055); 1-[3'-(1-(Phenylaminocarbonyloxyimino)-ethyl)-biphenyl-3-carbonyl]-3-phenylurea (ST4056); 1-(1-piperidine Alkyloxyimino)-1-(3-(2-thienyl) Phenyl)ethane (ST4 163); 1-(1-dodecylaminocarbonyloxyimino)-1-(3-(2-thienyl)phenyl)ethane (814164); -(phenylaminocarbonyloxyimino)-1-(4-(2-thienyl)phenyl)ethane (ST4 165); 1-(phenylaminocarbonyloxyimino)- 1-(4-cyclohexylphenyl)ethane; 1-(4-fluorophenylaminocarbonyloxyimino)-1-(4-cyclohexylphenyl)ethane; 1-(4-A Oxyphenylaminocarbonylcarbonylimino)-1-(4-cyclohexylphenyl)ethane; 1-(1-piperidinylcarbonyloxyimino)-1-(4-cyclohexyl) Phenyl)ethane; 1-(phenylaminocarbonyloxyimino)-1-[4-(2,5-dimethylpyrrol-1-yl)-phenyl]ethane; 1-( 4-fluorophenylaminocarbonyloxyimino)-1-[4-(2,5-dimethylpyrrol-1-yl)-phenyl]ethane; 1-naphthylaminocarbonyloxy Amino-l-[4-(2,5-dimethylpyrrol-1-yl)-phenyl]ethane (8 butyl 7 2 62); 1-(4-methoxyphenylaminocarbonyloxyl -i[4-(2,5-dimethylpyrrol-1-yl)phenyl]ethane; 1-(1-piperidinylcarbonyloxyimino)-1- [4-(2,5-dimethylpyrrol-1-yl)-phenyl]ethane; 1-(phenylaminocarbonyloxyimine )-1-([2,2']bithiophen-5-yl])ethane; 1-(4-fluorophenylaminocarbonyloxyimino)-1-([2,2'] Thiophen-5-yl])ethane; 1·(1·naphthylaminocarbonylimino)-1-([2,2′]bithiophen-5-yl])ethane; 1-(4 -methoxyphenylaminocarbonyloxyimino)-1-([2,2'] 201006791 thiophene-5-yl]) ethane; 1-(1-piperidinylcarbonyloxyimine -l-([2,2']bithiophen-5-yl])ethane; 1-(phenylaminocarbonyloxyimino)-1-(5-phenyl-thiophene-2 - Ethyl; 1-(4-fluorophenylaminocarbonyloxyimino)-1-(5-phenyl-thiophen-2-yl)ethane; 1-(1-naphthylaminocarbonyloxy) (imino)-1-(5-phenyl-thiophen-2-yl)ethane; 1-(4-methoxyphenylaminocarbonyloxyimino)-1-(5-phenyl - sanidin-2-yl) phenylene; 1-(1-indole-based oxyimino)-1-(5-phenyl-thiophen-2-yl)ethane; 1-(phenylamine Carboxyoxyimino)-1-(4-pyridin-4-yl-phenyl)ethane; 1-(4-fluorophenylaminocarbonyloxyimino)-1-(4-pyridine 4-yl-phenyl)ethane; 1-(1-naphthylaminocarbonylimino)-1-(4-pyridin-4-yl-phenyl)ethane; 1-(4·A Oxyphenylamine Carboxyoxyamino)-1-(4-pyridin-4-yl-phenyl)ethane; 1-(1-piperidinylcarbonyloxyimino)-1-(4-pyridine-4- Ethyl-phenyl)ethane; 1-(phenylaminocarbonyloxyimino)-1-(4-pyridin-2-yl-phenyl)ethane; 1-(4-fluorophenylamino group Carboxyoxyimino)-1-(4-pyridin-2-ylphenyl)ethane; fluorenyl-naphthylaminocarbonylimino)-1-(4-pyridin-2-yl-benzene Ethyl; 1-(4-methoxyphenylaminocarbonyloxyimino)-1-(4-pyridin-2-yl-phenyl)ethane; 1-(1-piperidinyl Carboxyoxyimino)-1-(4-pyridin-2-yl-phenyl)ethane; 1-(benzothiophen-5-yl-aminocarbonyloxyimido-1-biphenyl- 3-yl-ethane (ST5742); 1-(1-naphthylaminocarbonyloxyimino)-1-(4-biphenylyl)ethane (ST738 0); 5-phenylpentylaminocarbonyl Oxyimido-1-biphenyl-3-yl-ethane (ST7378); 1-(1-naphthylaminocarbonylimino)-1-(4-cyclohexyl-phenyl)-B Alkane (ST726 1 ). A particularly preferred compound is: phenylaminocarbonyloxyimino-1-(4-biphenylyl)ethane-19- 201006791 (ST3 7 1 5); 1-phenylaminocarbonyloxyimido group 1-(3-biphenylyl)ethane (ST3 9 86); 1-(1-naphthylaminocarbonylimino)-1-(4-biphenylyl)ethane (ST3 9 87) ; 1-(4-fluorophenylaminocarbonyloxyimino)-1-(3-biphenylyl)ethane (ST3 988); 1-(4-methoxyphenylaminocarbonyloxyl Imino)-1-(3-biphenylyl)ethane (ST398 9); 1-(1-piperidinylcarbonyloxyimino)-1-(3-biphenyl)ethane (ST4 017); 1-(phenylaminocarbonyloxyimino)-1-(3-(2-thienyl)phenyl)ethane (ST402 0); 1-(phenylaminocarbonyloxy) Amino)-1-(3-(3'-aminocarbonyl)-biphenyl)ethane (8 butyl 405 5); 1-(1-piperidinylcarbonyloxyimino)-1-( 3-(2-thienyl)phenyl)ethane (ST4 163); ΙΟ-dodecylaminocarbonyloxyimino)-1-(3-(2-thienyl)phenyl)ethane (ST4 164); 1-(phenylaminocarbonyloxyimino)-1-(4-(2-thienyl)phenyl)ethane (ST4 165); 1-(1-naphthylaminocarbonyl) Oxyimido)-1-[4-(2,5-dimethylpyrryl) [rho-1-yl)-phenyl]ethane (3 butyl 7 2 62); 1-(benzothiophene-5-yl-amino methoxyoxyimino-1-biphenyl-3-yl-B Institute (ST5742); 1_(1-naphthylaminocarbonyloxyimino)-1-(4-biphenylyl)ethane (ST73 80); 5-phenylpentylaminocarbonylimido- 1-biphenyl-3-yl-ethane (ST7378) and 1-(1-naphthylaminocarbonylimino)-1-(4-cyclohexylphenyl)-ethane (ST7261). Mode] Example Abbreviation: AA: Arachidonic Acid AcOEt: Ethyl Acetate-20- 201006791

AnNH: arachidonic acid decylamine (endogenous cannabinoid) DCM: dichloromethane; DMSO: dimethyl hydrazine Et20: diethyl ether MeOH: methanol Na2S04: sodium sulfate NaH: sodium hydride

RP-HPLC: Reverse Phase High Performance Liquid Chromatography RT: Room Temperature General Description: Record the 1 Η spectrum in CDC 13 at 300 MHz using a Bruker instrument as indicated. The chemical shift enthalpy is in ppm. Flash column chromatography was performed using silicone (Merck 230-400 mesh). Unless otherwise specified, all reactions were carried out using a dry solvent under a nitrogen atmosphere.

Example 1 Phenylaminocarbonyloxyimino-1-(4-biphenylyl)ethane (ST 3715)

A suspension of 4-ethenylbiphenyl (200 mg, 0.95 mmol) and phenyl isocyanate (340 mg, 2.85 mmol) in 8.5 ml of toluene was stirred at 50 °C for 2 hours. Then, the reaction mixture was washed with aqueous ammonia and extracted with AcOEt at -21 - 201006791. The mixed organic phase was washed with water and dried over Na 2 SO 4 . After purification by gelatin chromatography (hexane/AcOEt = 4:1), the solvent is removed in vacuo to afford 1-phenylaminocarbonyloxyimino 4-(4-biphenyl)ethane; (280 mg, 89%). lU NMR (CDCb) δ : 2.53 (s,3H), 7.12 (t,lH), 7.35- 7.68 (m,9H), 7.62 (d,2H), 7.79 (d,2H), 8.40 (br.s, lH) Example 2 φ

1-Dimethylaminocarbonyloxyimino-1-(4-biphenylyl)ethane (ST 3 74 1 )

4-O-branched biphenyl (200 mg '0.95 mmol) was applied at 501 with hydrazine, dimethyl-dimethylaminomethyl hydrazino chloride (3 06 mg, 2 · 85 mmol) at 8 · 5 ml The suspension in dichloromethane was stirred for 2 hours. After cooling to 0 ° C, ice was added to the reaction mixture. The organic phase was separated, washed with water and dried over Na.sub.2.sub.4. After purification by gelatin chromatography (DCM), the solvent is removed in vacuo to afford 1-dimethylaminocarbonyloxyimino-1-(4-biphenyl)ethane; (180 mg' 67 %). *H NMR (CDC13) δ : 1.80 (br. s, 6 Η), 2.52 (s, 3H), 7.3-7.5 (m, 3 H), 7.6-7.78 (m, 4H), 7.82 (m, 2H) . Example 3 -22- 201006791 1-Phenylaminocarbonyloxyimino-1-(3-biphenylyl)ethane (ST3986)

A solution of 1-biphenyl-3-yl-ethanone (100 mg, 0.47 mmol) and phenyl isocyanate (85 mg, 0.71 mmol) in toluene (45 ml) was refluxed for 1.5 h. After cooling to RT, the reaction mixture was washed with aqueous ammonia and extracted with AcOEt. The mixed organic phase was washed with water and dried over Na 2 SO 4 . After purification by gelatin chromatography (DCM/Et20 = 98/2), the solvent was removed in vacuo to afford 1-phenylaminocarbonyloxyimino-1-(3-biphenyl). It was a white solid (140 mg, 9.0%). *H NMR (CDC13) δ : 2.51 (s, 3H), 7.15 (t, lH), 7.2-7.9 (m, l 3H), 8.38 (s, lH). Example 4 1-(1-Naphthylaminocarbonylimino)-1-(3-biphenylyl)ethane (ST3987)

A solution of 1_ hydrazin-3-yl-acetonitrile (80 mg, 0.38 mmol) and isophthalic acid naphthyl ester (8 3 μΐ, 0.57 mmol) in toluene (8 ml) was refluxed for 1 hour. The solvent was then removed under reduced pressure. The crude reaction mixture was washed with EtOAc (EtOAc) (EtOAc) , 16H), 9.83 (s, lH) Example 5 1-(4-Fluorophenylaminocarbonyloxyimino)-1-(3-biphenylyl)ethane (ST3988)

A solution of 1-biphenyl-3-yl-ethanone (80 mg, 0.38 mmol) and 4-fluorophenyl isocyanate (66 μM, 0·57 mmol) in toluene (7 ml) was refluxed 1 hour. After removing the solvent under reduced pressure, the crude reaction mixture was washed with Et20 and MeOH to give 1-(4-fluorophenylaminocarbonyloxyimino)-1-(3-biphenyl)ethane. It is a white solid (60 mg, 45%). *H NMR (DMSO-d6) δ : 2.49 (s, 3H), 7.21 (t, 2H), 7.30-7.65 (m, 6H), 7.65-7.90 (m, 4H), 8.03 (s, lH), 9.90 (s, lH). Example 6 1-(4-Methoxyphenylaminocarbonyloxyimino)-1-(3-biphenyl)ethane (ST3989)

-24- 201006791 1_ _ _ _ _ _ _ 嗣 ( (80 mg, 0.38 mmol) and isotine 4-methoxy benzene vinegar (74 μΐ, 0. 57 mmol) in toluene (8 ml) The mixture was refluxed for 1 hour. After removing the solvent under reduced pressure, the crude reaction mixture was washed with Et20 and MeOH to give 1-(4-methoxyphenylaminocarbonyloxyimino)-1-(3-biphenyl) Ethane·, which was a white solid (114 mg, 84%). !H NMR (DMSO-d6) δ : 2.51 (s, 3H), 3.76 (s, 3H), 6.92 (d, 2H), 7.35-7.65 (m, 6H), 7.70-7.85 (m, 4H), 8.03 (s, lH), 9.63 (s, 1 H). Example 7 1-(1-Piperidinylcarbonyloxyimino)-1-(3-biphenylyl)ethane (ST401 7)

To a solution of 1-biphenyl-3-yl-ethanone (70 mg, 0.33 mmol) in 5 ml of THF was added 26 mg (0.66 mmol) of NaH, and the reaction mixture was stirred for 15 min. Piperidine-1-carbonyl chloride (130 μM, 1.04 mmol) was added and the mixture was refluxed for 30 min. After cooling to RT, the reaction mixture was poured into ice. The mixture was acidified with HC1 2N (until pH = 3) and then extracted with AcOEt. The mixed organic phase was washed with brine and dried over Na2SO4. After purification by gelatin chromatography (hexane/AcOEt = 9/1), the solvent was removed in vacuo to afford 1-(piperidinylcarbonyloxyimino)-1-(3-biphenyl) Ethane; it was a white solid (100 mg, 94%). -25- 201006791 *H NMR (CDC13) δ: 1.60 (m,6H), 2.41 (s,3H), 3.55 (m,4H), 7.28-7.50 (m,4H), 7.60 (m,3H), 7.72 (d, lH); 7.93 (s, lH). Example 8 1-(Diphenylaminocarbonyloxyimino)-1-(3-biphenylyl)ethane (ST4018)

To a solution of 1-biphenyl-3-yl-ethylidene (70 mg, 0.33 mmol) in 5 mL of THF was added 26 mg (0.66 mmol) of NaH and the reaction mixture was stirred for 15 min. Diphenylaminolamamidine chloride (230 mg, 1 mmol) was added and the mixture was refluxed for 30 min. After cooling to RT, the reaction mixture was poured into ice. The mixture was acidified with HC1 2N (until pH = 3) and then extracted with AcOEt. The mixed organic phase was washed with brine and dried over Na 2 SO 4 . After purification by gelatin chromatography (DCM/hexane = 8/2), solvent was removed in vacuo to afford 1-(diphenylaminocarbonyloxyimino)-1-(3-biphenyl) Ethane; white solid (90 mg, 67%) 〇*H NMR (CDC13) δ: 2.02 (s,3H), 7.21 (m,2H), 7.30-7.50 (m,llH), 7.55-7.75 (m, 5H), 8.90 (s, lH) Example 9 -26- 201006791 1-(phenylaminocarbonyloxyimino)-bu(3-(2.thienyl)phenyl)ethane ( ST4020)

Mixture of 1-(3-thiophen-2-yl-phenyl)-ethanone oxime (8 〇 mg '0.37 mmol) with phenyl isocyanate (61 μM, 0.56 mmol) in toluene (8 ml) φ Reflux for 30 minutes. After removing the solvent under reduced pressure, the crude reaction mixture was washed with Et.sub.2 to afford s((phenylaminocarbonyloxyimino)-1-(3-(2-thiophenyl)benzene) as a white solid. Ethyl) ethane (11 〇 mg, 89%). </ RTI> <RTIgt; (s, lH), 8.40 (s, lH). Example 1 Φ Φ 1-(Phenylaminocarbonyloxyimido)-1·(3-(3'-aminocarbonyl)biphenyl)ethane (ST4055)

3'-(Hydroxyiminoethyl)-biphenyl-3-carboxylic acid decylamine (1 mg, 0.39 mmol) with phenyl isocyanate (64 μM, 0.59 mmol) in toluene (5.7 ml The mixture was refluxed for 1 hour. After removing the solvent under reduced pressure, the crude reaction mixture was purified by silica gel chromatography (DCM/MeOH = 95/5) to afford 1-(phenylaminocarbonyloxyimine). 4-(3-(3^Aminocarbonyl)-biphenyl)ethane; white solid (65 mg </RTI> 44%). lH NMR (DMSO-d6) δ: 2.50 (s, 3H), 7.02 (t, lH), 7.30 (t, 2H), 7.40-7.70 (m, 5H), 7.86 (m, 4H), 8.04 (s, lH), 7.12 (s, lH), 8.20 (s, lH), 9.81 (s, lH). Example 1 1

1-[3'-(1-(phenylaminocarbonyloxyimino-ethyl)biphenyl-3-carbonyl

The above compound was obtained in accordance with the procedure described in Example 1 . The title compound was obtained as a white solid (30 mg, 15%).

'Η NMR (DMSO-d6) δ : 2.50 (s, 3H), 7.00-7.13 (m, 2H), 7.33 (m, 4H), 7.50-7.70 (m, 6H), 7.83 (d, lH), 7.93 (d,lH), 8.01 (d,2H), 8.12 (s,lH), 8.36 (s,lH), 9.83 (s,lH), 10.83 (s,lH), 1 1.18 (s,lH). Example 1 2 1-(1-Piperidinylcarbonyloxyimino)-1-(3-(2-thienyl)phenyl)ethane (ST4163) -28-201006791

NaH (13 mg, 0.33 mmol) was added to a solution of 1-(3-thiophen-2-yl-phenyl)-ethanone oxime (80 mg, 0.37 mmol) in 3.5 ml of THF. minute. Piperidine-1-carbonyl chloride (140 μί, 1.12 mmol) was added and the mixture was refluxed for 2 h. After cooling to RT, the reaction mixture was poured into ice. The mixture was acidified with HC1 1N (until pH = 3) and then extracted with AcOEt. The mixed organic phase was washed with brine and dried over Na 2 SO 4 . The solvent was removed under vacuum and the obtained solid was triturated with Et20 to afford 1-(1-piperidinylcarbonyloxyimino)-1-(3-(2-thienyl)phenyl)ethane; It was a white solid (100 mg, 83%). *H NMR (CDC13) δ : 1.62 (m,6H), 2.40 (s,3H), 3.55 (m,4H), 7.20 (t,lH), 7.30 (d,lH), 7.39 (m,lH), 7.41 (d,lH), 7.66 (m,2H), 8.96 (s,lH).

1-(Phenylaminocarbonyloxyimino)-1-(4-(2-thienyl)phenyl)ethane (ST4165)

A mixture of 1-(4-thiophen-2-yl-phenyl)-ethanone (80 mg, 0.37 mmol) and phenylisocyanate (61 μM, 0.56 mmol) in toluene (3.5 ml) was refluxed 30 minute. After removing the solvent under reduced pressure, the crude reaction mixture was triturated with Et.sub.20-29-201006791 to afford &lt;RTI ID=0.0&gt; Phenyl) ethane; white solid (40 mg, 3 2%) °H NMR (CDC13) δ: 2.52 (s, 3H), 7.11 (m, 2H), 7.38 (m, 4H), 7· 53 (d, 2H), 7.85 (m, 4H), 8.39 (s, NH). Example 1 4 1-(1-Dodecylaminocarbonyloxyimino)-1-(3-(2-thiophenyl)phenyl)ethane (ST4164)

a mixture of 1_(3_thiophen-2-yl-phenyl)-ethanone oxime (80 mg, 0.37 mm 〇l) with dodecyl isocyanate (130 μM, 0.56 mmol) in toluene (3.5 ml) Reflux for 2 hours. The crude reaction mixture was purified by gradient elution (DCM/hexane = 9/1 then DCM/Et20 = 9/1) to afford 1-0 to ten after the solvent was removed under reduced pressure. The second amino group is a carbonyloxyimino)-1-(3-(2-thiophenyl)phenyl)ethane; it is a pale yellow oil (60 mg, 38%). !H NMR (CDCI3) δ : 0.85 (m, 3H), 1.29 (m, 18 Η), 1.58 (q, 2H), 2.48 (s, 3H), 3.35 (q, 2 H), 6.43 (s, NH ), 7.12 (t, lH), 7.36 (m, 2H), 7.46 (t, lH), 7.58 (d, lH), 7.71 (d, lH), 7·88 (s, lH). Example 1 5 -30- 201006791 1-(1-Naphthylaminocarbonyloxyimino)-1 _[2,2']thiophen-5-yl-ethane (ST5585)

A solution of 5-ethenyl-2,2, thiophene (200 mg, 0.93 mmol) and NH20H.HC1 (133 mg, 1.96 mol) in 13 ml of ethanol was refluxed for 1 hr. Removal of the solvent under reduced pressure afforded the desired intermediate product which was used in the next step without further purification. To the solution of the latter (6 〇 mg) in warm toluene (2.6 ml) was added 1-naphthyl isocyanate (59 μM) and the resulting mixture was refluxed for 1 hour. The crude reaction mixture was purified by gradient elution (DCM / hexane = 9 / 1 then DCM / Et20 = 9 / 1) to afford white solids. -(1-Naphthylaminocarbonyloxyimino)-1-[2,2,] succin-5-yl group (30 mg). W 'Η NMR : δ 2.52 (s,3H), 7.05 (t,lH), 7.18 (d,lH), 7.31 (m,2H), 7.40 (d,lH), 7.58 (m,3H), 7.75 ( d, lH), 7.93 (d, lH), 8.08 (dd, 2H), 9.08 (s, lH). Example 1 6 1-(Benzothiophen-5-yl-aminocarbonyloxyimino)-1-biphenyl-3-yl-ethane (ST5742) -31 - 201006791

a mixture of 1-biphenyl-3-yl-ethanone oxime (120 mg, 0.57 mmol) and 5-benzothiophene isocyanate (162 mg, 0.93 mol) in toluene (5.6 ml) under nitrogen atmosphere Reflux for 5 hours. After the solvent was removed under reduced pressure, the crude reaction mixture was purified by chromatography eluting eluting eluting eluting eluting eluting eluting The title compound. *H NMR : δ 2.59 (s,3 Η ),7 · 3 3 (d,1 Η), 7.4 2 (t,2 Η ), 7.46-7.61 (m,4H), 7.62 (m,2H), 7.73 (m, 2H), 7.84 (d, lH), 7.93 (s, lH), 8.15 (s, lH), 8.51 (d, lH). Example 1 7

1-(1-Naphthylaminocarbonyloxyimino)-1-(4-cyclohexylphenyl)-ethane (ST7261)

1-(4-Cyclohexylphenyl)-ethanone oxime (80 mg' 〇_37 mmo'l) and 1-naphthyl isocyanate (84 μΐ, 0.59 mmol) in toluene under nitrogen atmosphere (3· The mixture in 7 ml) was refluxed for 1 hour. The crude reaction mixture was purified by gradient elution (DCM/hexane = 9/1 then DCM/Et2 〇 = -32 - 201006791 9/1) by gelatin chromatography after removal of the solvent under reduced pressure to provide 61 mg of the title compound. NMR: δ 1.17-1.50 (m, 5H), 1.72-1.97 (m, 5H), 2.57 (s, 3H and m, lH), 7.32 (d, 2H), 7.52 (m, 3H), 7.70 (d, 3H), 7,90 (t, 2H), 8.00 (d, lll), 9.00 (d, lH). Example 1 8 1-(1-Naphthylaminocarbonylimino)-1-(4-[2,5-dimethylpyrrol-1-yl]phenyl)ethane (ST7262)

1-[4-(2,5-Dimethylpyrrol-1-yl)-phenyl]-ethanone oxime (39 mg, 0.17 mmol) and 1-naphthyl isocyanate (41 μΐ) under a nitrogen atmosphere The mixture in toluene (18 ml) was refluxed for 1 hour. After removal of the solvent under reduced pressure, the crude reaction mixture was purified by chromatography eluting eluting eluting eluting eluting eluting ' NMR : δ 2.25 (s,6H), 2.60 (s,3H), 5.92 (s,2H), 7.31 (d,2H), 7.52 (m,3H), 7.72 (d,lH), 7.80-8.00 ( m, 5H), 8.82 (s, lH). Example 19 1-(5-Phenylpentylaminocarbonylimino)-1-biphenyl-3-yl-ethane -33- 201006791 (ST7378)

a mixture of 1-biphenyl-3-yl-ethanone oxime (60 mg, 0.29 mmol) and 5-phenylpentanyl isocyanate (79 mg, 0.86 mol) in toluene (2 ml) under nitrogen atmosphere Reflux for 1 hour. An additional 98 mg of this isocyanic acid was added in portions over a period of 3 hours. After cooling and removing the solvent under reduced pressure, the crude was purified by flash chromatography using hexane/AcOEt: 7/3 followed by hexane/AcOEt: 8/2. The reaction mixture was allowed to provide 50 mg of the title compound. NMR (CDC13): δ 7.84 (s, lH), 7.58-7.72 (m, 4H), 7.35-7.52 (m, 4H), 7.10-7.30 (m, 5H), 6.43 (m, lH), 3.30 (q , 2H), 2.60 (t, 2H), 2.47 (m, 3H), 1_62 (m, 4H), 1.40 (m, 2 H).

Example 20 1-(1-Naphthylaminocarbonyloxyimino)-1-(4-biphenylyl)ethane (ST73 80)

1-Biphenyl-4-yl-ethanone oxime (80 mg 0·38 mmol) and 1-naphthyl isocyanate (83 μΐ, 0.58 mol) in toluene (4 ml) under nitrogen atmosphere The mixture was refluxed for 4 hours. After removing the solvent under reduced pressure, the crude reaction mixture was purified by flash chromatography (DCM/hexanes from 9:1 to 95:5) to afford 6 5 mg (45%) Title compound. NMR (CDC13): δ 8.98 (s, l Η), 7.80-8.03 (m, 5 Η), 7.3 3 - 7.80 (m, llH), 2·55 (s, 3H). Biological Results FAAH Assay The compounds of the present invention show affinity and inhibit the enzymatic activity of fatty acid indoleamine hydrolase. The measurement of FAAH (EC 3.5.1.4) was carried out by measuring the release of [1 - 14C]AA from [l-14C]AnNH (52 mCi/inmol) using RP-HPLC. [3H]AnNH (205 Ci/mmol) was also used as a substrate, and the release of [3H]AA was measured under the same experimental conditions of [1-14C]AnNH described below. Various concentrations of the compound of the invention were added to a 200 μΐ hydrolase assay buffer (50 mM Tris-HCl, pH 9.0) in a 2-ml Eppendorf tube to a concentration of up to 10 μΜ prior to the addition of [l-14C]AnNH2. The reaction was started by adding mouse brain homogenate (40 pg), and after incubation at 37 ° C for 15 minutes, the reaction was stopped by vortexing with 800 μM ice methanol/chloroform (2:1, Wv). The mixture was allowed to stand at room temperature for 30 minutes, and then 240 μL of chloroform and 240 μM of water were added by vortexing. After 10 minutes at room temperature, the mixture was centrifuged at 3 000 g for 5 minutes, and the upper aqueous layer was removed by suction and passed at 1 mbar and 30 Torr. (: Rotate the samples in DNA MINI speedvac (Heto-Holten, Denmark) for 30 minutes to dry the lower organic phase. Dissolve the residue in 50 μM methanol for RP-HPLC analysis of AA quantification as follows -35- 201006791 The specific activity of FAAH is expressed by the AA/min/mg protein released by pmol. The dynamics is analyzed by Lineweaver-Burk using [l-14C]AnNH in the concentration range of 0-12 μΜ. [l-14C]ODNHEtOH or [l-14C]ODNH2. The linear regression equation (Kaleidagraph 3.0) was used to match the experimental points to generate a straight line of r値&gt;0.97.

EXAMPLE ST number IC50 (nM) Ki(nM) 1 ST3715 + ++ 2 ST3741 ΝΑ ND 3 ST3986 ND -Hl· 4 ST3987 ND +-H-+ 5 ST3988 ND 6 ST3989 ND +-H-+ 7 ST4017 ND - Hf 8 ST4018 NA NA 9 ST4020 +H++ ++++ 10 ST4055 -HH- +++ 11 ST4056 NA ND ❹ [+ + + + ] [IC50] &lt; ίο nM and / or [Ki] &lt; 10 nM [ + + + ] i〇nM &lt;[IC5〇] &lt; 100 nM and / or 10 nM &lt; [Ki] &lt; 100

nM

[ + + ] 100 &lt; [IC5〇] &lt; 500 nM and / or 100 &lt; [Ki] &lt; 500 nM [+ ] 500 &lt; [IC5〇] &lt; 5000 nM and / or 500 &lt; [Ki ] &lt; 5000 nM NA : Inactive ND : Not measured -36 - 201006791 The selectivity is also based on Maccarrone et al., J. Biol. Chem" 2000, 275, 1 3484; Fezza F. et al. Anal Biochem., 2005, 33 9, 113, Dinh Τ·Ρ· et al. 2002, Proc. Natl. Acad. Sci. 99, 10819; Bisogno T. et al., 2003, J. Cell Biol, 163 , 463; Maccarrone M. et al., j. Bi〇i. chem., 2000, 275, 3 1 93 8 ; Ross RA et al., Br. J. Pharmacol" 2001, 132, 63 1 The selectivity of the compounds of the invention was evaluated for the following targets: AMT, NAPE-PLD, MAGL, DAGL, CB1/CB2 and TRPV1. The results are shown in Table 2. Table 2

ST4020 ST3715 CB 1R a CB2R ·— a TRPV 1 a NAPE-PLD I·_ ...b AMT __ a DAGL .... ____ MAGL — aa: The maximum concentration tested is equivalent to 10 times the concentration of IC5G on FAAH b: The maximum concentration tested is equivalent to 1〇〇 times [---·] 1 00 times [1C 5〇] of the IC5Q concentration on FAAH, and the inhibitory activity against the target is &lt;60% [---] 100 times [ IC5Q], the inhibitory activity against the target &lt;60% [--]1〇[IC5Q], the inhibitory activity against the target &lt;60% -37- 201006791 [-]5 times [IC5〇], inhibition of the target Activity &lt; 60% ST4020 showed selectivity for the above targets. Reversibility Reversibility is determined by developing FAAH for 20 minutes (e.g., enzyme assay conditions) in excess (i.e., concentrations well above 1 〇 5{|値) of the compounds of the invention. Then, the FAAH/compound mixture (1 ml volume) was dialyzed against 2 liters of 1 mM Tris-HCl buffer (pH 7.4) overnight. The FAAH/compound mixture was assayed for activity as described above before and after dialysis. The results confirmed that all of the compounds of the present invention are reversible, as opposed to URB597 which has been found to be irreversible. Anxiety Animal Models Many animal models of anxiety are based on the principle of innate general avoidance behavior. These include the elevated plus maze (EPM) (Hogg S., Pharmacol. Biochem. Behav., 1 9 96, 54, 2 1 ; Masse F. et al., Behav. Brain Res., 2007, 177, 2, 214) It is based on the natural dislike of open space using the contradiction between exploration and disgusting open space; the irritated behavior in the EPM shows elements of fear, exploration and proximity/avoidance of new things. EPM can confirm the anti-aware effect of the drug. The purpose of this study was to establish an animal model of anxiety EP using the anxiolytic effect of benzodiazepine diazepam in mice and to evaluate the effect of FAAH inhibition [f URB597 and ST4020]. Twelve male CD 1 mice of approximately 30 g were used in each group (Charles -38- 201006791)

River) (February age). The elevated cross maze device is made of grey piexigias and consists of two open and two closed arms connected by a common central platform. The labyrinth is 40 cm above the ground and shines brightly. The animals are placed in a central platform of the labyrinth facing an open arm. Use the standard 5 minute test. The time taken by each animal to open or close the arm and the number of times each animal entered each arm was recorded. Experiment: URB597 and ST4020 at a dose of 10 mg/io mL/kg and diazogen at a dose of mg.5 mg/5 mL/kg. URB 5 9 7 and ST4020 dispersed in a solution of 5% Tween 80 and 0.5% carboxymethylcellulose were orally administered 60 minutes before the test; dinitrogen system in a solution of 3% Tween 80 was tested. The first 3 minutes were administered intraperitoneally. Table 3 Group dose level (mg/kg) Time spent on open arm (S) Number of times to enter open arm Number of times to enter closed arm Total number of entry controls 3_08 ± 1.24 0.75 ± 0.30 12.67 ± 1.00 13.42 ± 1.12 0.5 36.00 ± 3.47 * 7.75 ± 0.74 11.75 ± 1.32 19.50 ± 1.84 § URB597 10 24.67 ± 3.59 * 4.25 + 0.88 10.75 ± 1.17 15.00 ± 1.23 ST4020 10 25.92 ± 2.27 * 3.83 ± 0.45 9.92 ± 1.34 13.75 + 1.31

Kruskal-Wallis analysis of single factor variances for sorting · Time spent on open arms * = P &lt; 0.05 vs. control analysis of single factor variance: total number of entries -39- 201006791

Variance source DF F P group 4.5 5 4.04 8 0.006

Dunnett's trial: § = Ρ&lt;〇·〇5 reduced anxiety relative to the control group ST4〇20 and did not affect the assessed behavioral activity in the elevated plus maze. Analgesic animal model The analgesic effect of the selective FAAH inhibitor ST4020 was evaluated in a rat model of neuropathic pain induced by intraperitoneal administration of vincristine. The FAAH inhibitor or vehicle (control group) is administered orally. The former was administered at doses of 10 and 50 mg/kg, and the analgesic effect was measured using a paw withdrawal test as a model of mechanical hyperesthesia. The treated rats were divided into two groups: vehicle (9 animals) and vincristine (54 animals). Neuropathy was induced by intraperitoneal injection of 0.15 mg/kg vinpoxin three times a week. Two weeks later, the rats were divided into six groups of 9 animals: vehicle, vincristine + carrier, vinorelbine + URB5 97 (10 mg/kg), Changchun new test + URB597 (50 mg/kg), Vincristine + ST4020 (1 0 mg/kg) and Changchun New Test + ST4020 (50 mg/kg). The animals were subjected to a paw withdrawal test after oral administration of the test compound for 60, 120 and 240 minutes. The acute systemic administration of the selective FAAH inhibitor ST4020 significantly reduces the mechanical hyperesthesia associated with the chemotherapeutic model of neuropathic pain. -40- 201006791 [Simplified Schematic] Figure 1 illustrates the selective FAAH inhibitor ST4020 and URB597 in two different doses in a rat model of neuropathic pain induced by intraperitoneal administration of vincristine. The pain relief effect at three time points. The animals were subjected to a paw withdrawal test after oral administration of the test compound for 60, 120 and 240 minutes.

-41 -

Claims (1)

201006791 VII. Patent application scope 1. A compound with formula I G Formula I R1 where: R1 and R2 are independently hydrazine, alkyl, aryl, aralkyl, alkoxy or haloaryl; or R1 and R2 and the nitrogen atom to which they are attached form a heterocyclic ring; G is a phenyl or thiophene A phenyl group, a thienyl group, a cyclohexyl group, a pyrrolyl group or a pyridyl group, which are optionally substituted once or twice with an aminocarbonyl group or an alkyl group; tautomers thereof, geometric isomers thereof, Optically active forms (such as mirror image isomers, non-image isomers and their racemate forms), and pharmaceutically acceptable salts thereof; The prerequisite is that when A is a cyclohexyl group, if R2 is hydrazine, W is not a 4-chlorophenyl group and a 3,4-dichlorophenyl group. 2. A compound according to claim 1 wherein R1 is aryl, alkoxyaryl or haloaryl' and R2 is deuterium. 3. A compound according to claim 1 or 2 wherein G is a phenyl group and hydrazine is a phenyl group, a thienyl group, a cyclohexyl group, a pyrrolyl group or a pyridyl group. ‘ 4. For a compound of the patent scope table 3, where α is 2-thiophenyl. The compound of any one of claims 1 to 3, which is selected from the group consisting of 1-phenylaminocarbonyloxyimido-1-( 4-biphenyl)ethane (ST3715); 1-dimethylaminocarbonyloxyimino-1-(4-biphenylyl)ethane (ST3 74 1); 1-phenylaminocarbonyl Oxyimido-1-(3-biphenylyl)ethane (813986); 1-(1-naphthylaminocarbonylimino)- 1-(4-biphenylyl)ethane (ST3 987); 1-(4-Fluorophenylaminocarbonyloxyimino)-1-(3-biphenylyl)ethane (ST3 988); 1-(4-methoxyphenylaminocarbonyl) Oxyimido)-1-(3-biphenylyl)ethane (ST398 9); 1-(1-piperidinylcarbonyloxyimino)-1-(3-biphenylyl)ethane (ST4 017); 1-(diphenylaminocarbonyloxyimino)-1-(3-biphenylyl)ethane (ST4018); 1 (phenylaminocarbonyloxyimino) 1-(3-(2-thienyl)phenyl)ethane (ST4 02 0); 1-(phenylaminocarbonyloxyimino)-1-(3-(3aminocarbonyl)- Biphenyl)ethane (ST40 5 5); 1-[3'-(1-(phenylaminocarbonyloxyimino)-ethyl)-biphenyl-3-carbonyl]-3-benzene Urea (ST4 056); 1-(1-piperidinylcarbonyloxyimino)-1-(3-(2-thinyl)phenyl)ethane (ST4 163); 1-(1-dodecylaminocarbonyl) Oxyimido)-1-(3-(2-thienyl)phenyl)ethane (ST4 164); 1-(phenylaminocarbonyloxyimino)-1-(4-(2) -thienyl)phenyl)ethane (ST4 165); 1-(phenylaminocarbonyloxyimino)-1-(4-cyclohexylphenyl)ethane; 1-(4-fluorophenyl) Aminocarbonyloxyimino)-1-(4-cyclohexylphenyl)ethane; 1-(4-methoxyphenylaminocarbonyloxyimino)-1-(4-cyclohexyl) Phenyl)ethane; 1-(1-piperidinylcarbonyloxyimino)-1-(4-cyclohexylphenyl)ethane; 1-(phenylaminocarbonyloxyimino)- 1-[4-(2,5·dimethylpyrrol-1-yl)-phenyl]ethane; 1-(4-fluorophenylaminocarbonyloxyimino)-1-[4-( 2,5-Dimethylpyrrol-1-yl)-phenyl]ethane; 1-(1-naphthylaminocarbonyloxy-43-201006791 amine)-l-[4-(2,5- Dimethylpyrrol-1-yl)-phenyl]ethane (ST7262); 1-(4-methoxyphenylaminocarbonyloxyimino)-1-[4-(2,5-di Methylpyrrol-1-yl)phenyl]ethane; 1-(1-piperidinylcarbonyloxyimino)-1-[4-(2,5- Dimethylpyrrol-1-yl)-phenyl]ethane; 1-(phenylaminocarbonyloxyimino)-1-([2,2']bithiophen-5-yl])ethane 1-(4-fluorophenylaminocarbonyloxyimino)-1-([2,2|]bithiophen-5-yl])ethane; 1-(1-naphthylaminocarbonyloxy) Imino)-1-([2,2·]bithiophen-5-yl])ethane; 1-(4-methoxyphenylaminocarbonyloxyimino)-1-([2 , 2']bithiophen-5-yl])ethane; 1-(1-piperidinylcarbonyloxyimino)-1-([2,2']bithiophen-5-yl])ethane ; 1-(phenylaminocarbonyloxyimino)-1-(5-phenyl-thiophen-2-yl)ethane; 1-(4-fluorophenylaminocarbonyloxyimino) 1-(5-phenyl-peptan-2-yl)ethane; 1-(1-naphthylaminocarbonylimino)-1-(5-phenyl-thiophen-2-yl)ethyl Alkane; 1-(4-methoxyphenylaminocarbonyloxyimino)-1-(5-phenyl-thiophen-2-yl)ethane; 1-(l-piperidinylcarbonyloxyl) Imino)-l-(5-phenyl-thiophen-2-yl)ethane; 1-(phenylaminocarbonyloxyimino)-1-(4-pyridin-4-yl-phenyl Ethyl; 1-(4-fluorophenylaminocarbonyloxyimino)-1-(4-pyridin-4-yl-phenyl)ethane; 1-(1-naphthylaminocarbonyloxy) Imino)- 1-(4-pyridin-4-yl-phenyl)ethane; 1-(4-methoxyphenylaminocarbonyloxyimino)-1-(4-pyridin-4-yl-phenyl Ethyl; 1-(1-piperidinylcarbonyloxyimino)-1-(4-pyridin-4-yl-phenyl)ethane; 1-(phenylaminocarbonyloxyimino) )-1-(4-pyridin-2-yl-phenyl)ethane; 1-(4-fluorophenylaminocarbonyloxyimino)-1-(4-pyridin-2-yl)phenyl Ethyl; 1-(1-naphthylaminocarbonyloxyimino)-1-(4-pyridin-2-yl-phenyl)ethane; 1-(4-methoxyphenylaminocarbonyl Oxyimido)-1-(4-pyridin-2-yl-phenyl)ethane; 1-naphthylaminocarbonyloxyimide 201006791 -1-(4-biphenylyl)ethane (8 738 0); 5-phenylpentylaminocarbonylimino-1-phenyl-3-yl-ethane (ST7 378) and 1-(1-piperidinylcarbonyloxyimino) 1-(4-pyridin-2-yl-phenyl)ethane. 6. A compound according to claim 5, which is selected from the group consisting of 1-phenylaminocarbonyloxyimino-1-(4-biphenyl)ethane (ST3715) 1-phenylaminocarbonyloxyimino-1-(3-biphenylyl)ethane (ST3 98 6); 1-(1-naphthylaminocarbonylimino)-1- (4-Bismyl)ethane (ST3 9 8 7); 1-(4-fluorophenylaminocarbonyloxyimino)-1-(3-biphenylyl)ethane (ST3 988); 1-(4-Methoxyphenylaminocarbonyloxyimino)-1-(3-biphenylyl)ethane (ST3989); 1-(1-piperidinylcarbonyloxyimino) 1-(3-biphenylyl)ethane (ST4 017); 1-(phenylaminocarbonyloxyimino)-1-(3-(2-thienyl)phenyl)ethane (ST4 020); 1-(phenylaminocarbonyloxyimino)-1-(3-(3.-aminocarbonyl)-biphenyl)ethane (ST4055); 1-(1-piperidinyl) Carboxyoxyimino)-1-(3-(2-thinyl)phenyl)ethane (ST4163); ΙΟ-dodecylaminocarbonyloxyimido)-1-(3- (2-Thienyl)phenyl)ethane (ST41 64); 1-(phenylaminocarbonyloxyimino) 4-(4-(2-thienyl)phenyl)ethane (ST4165); 1-(benzothiazide Pheno-5-yl-aminocarbonyloxyimino)-1-biphenyl-3-yl-ethane (ST5 74 2); 1-naphthylaminocarbonylimino-1-(4- Biphenyl)ethane (ST7380); 5-phenylpentylaminocarbonylimido-1-phenylbiphenyl-3-yl-ethane (^73 78) and naphthylaminocarbonyloxyimine Base)-1-(4-cyclohexyl-phenyl)-ethane (St7261). 7. The use of a compound as claimed in any one of claims 1 to 7 as a medicament. 8 • As used in the scope of patent application No. 7, the results of the preparation of the FAAH activity of -45-201006791 will improve the patient's health. 9. For the purposes of item 8 of the request, sexually transmitted diseases, energy metabolism diseases, cardiovascular and disease, retinopathy, cancer and musculoskeletal 10. For example, the sexually transmitted diseases of claim 9 of the scope of patent application. 1 1 . If you apply for patent coverage, item 1 of the anxiety. 1 2 . If the scope of patent application is 10th, neuropathic pain. 1 3 . A method for synthesizing, as claimed in the patent application, a compound comprising a compound of the formula 与 与 ag 、 、 、 oh oh oh oh oh oh 治疗 治疗 治疗 治疗 治疗 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中disease. Use, wherein the disease is a use of God, wherein the disease is used, wherein the disease is a compound of the compound of the first item: a step of the compound reaction of III, wherein A and G are as described above, CI human (R2 R1) ΠΙ wherein R1 and R2 are as described above. Step 1 of the reaction of the compound of the compound of the range 2; 4. A method for synthesizing as in the patent application, which comprises the compound of the formula 11 and 5 (0 = C =NR1) 201006791 where R1 is as described above. -47-