TW200914046A - Method - Google Patents

Abstract

The present invention relates to patient selection tools and methods (including personalised medicine). In particular, the present invention permits the improved selection of a patient in need of treatment with a cannabinoid receptor (CB1R) antagonist drug, based on the levels of circulating endogenous cannabinoid ligands (endocannabinoids). One of the aspects of the invention is a method of selecting a mammal in need of weight loss and/or weight maintenance and/or prevention of weight gain treatment with a CB1R antagonist drug which comprises determining the level of at least one circulating endogenous cannabinoid ligand in the mammal, whereby to predict an increased likelihood of response to the CB1R antagonist drug. Some of the benefits of this personalised medicine approach include the ability to identify patients that are more likely to respond favourably to CB1R antagonist drug treatment and to identify patients less likely to respond to the drug treatment thus avoiding unnecessary treatment and any side effects that may be associated with such ineffective treatment.

Description

200914046 IX. INSTRUCTIONS: TECHNICAL FIELD OF THE INVENTION The present invention relates to patient selection tools and methods (including individualized medications). In particular, the present invention can improve the selection of patients requiring cannabis test (cannabinoidcc receptor (CB 1R) antagonist drug therapy to determine the patients most likely to benefit from CB 1R antagonist drug therapy (including, for example, Predicting a higher likelihood of responding to a CB 1R antagonist drug and/or identifying a patient who is not responsive to the drug, thereby avoiding unnecessary treatment and any side effects that may be associated with this ineffective treatment. The content of circulating endogenous cannabinoid ligand (endogenous cannabinoid) isolated from the test subject/patient. These endogenous cannabinoids, either alone or in combination, can therefore be used as a CB ruler antagonist for therapeutic suitability. Biomarkers. [Prior Art] CB1 antagonist drugs have been proposed for use in a variety of indications and the present invention can be used to determine a patient to whom any CB 1R antagonist treatment is applied. However, the present invention is particularly useful for weight treatment (eg, Weight loss, weight maintenance, prevention of weight gain, obesity, and the like) and for use in the treatment of or preventing other diseases The treatment of diseases such as type 2 diabetes, lipid metabolism disorders, hypertension, sleep apnea, muscle and bone disease, southern uric acidemia and cancer. The prevalence of obesity worldwide The rate of alarm is increasing and is related to the main adverse consequences of human health and actual medical expenses (Wee et al.

Am J Public Health, 1:159-165, 2005). According to the World Health Organization (WHO), more than 100 million adults are overweight worldwide and 132387.doc 200914046 At least 300 million are obese (Bays, 〇besity Res., 12 η97_ι2ΐι 2004). The obesity epidemic can affect all demographic groups including children (Hedley et al., jAMA, 291: 2847_285〇, 2 。. Obesity can increase the risk of various related diseases, such as metabolic syndrome, type 2 diabetes, Lipid metabolism disorders, hypertension, coronary artery disease, stroke, gallbladder disease, osteoarthritis, obstructive sleep apnea, asthma, cancer, reproductive and psychological disorders (Park et al., Curr 〇pin Gastr〇em (10)!, 21: 228-233, 2005). Obesity is also associated with impairment of quality of life (1) (Fontaine et al, J Fam Pract, 43:265_27〇, 1996). Given the prevalence of obesity and the high risk of obesity-related conditions 'The discovery of effective treatment strategies is important. The currently available drugs are moderately effective, but they are costly and do not achieve optimal pancreatic and side-effect properties. Obesity treatment surgery is fast and long-term significant in most patients. The only treatment for weight loss (Sj〇^r〇m et al. N Engl J Med, 351: 2683-2693, 2004). Currently, surgical procedures are recommended for morbidly obese patients or at The only treatment for patients at high risk of life-threatening comorbid conditions. In addition, surgical complications may occur: non-surgical obesity treatments that are often life-threatening and may require more significant weight loss and weight maintenance (Buchwald et al., JAMa , , 24 173 7, 2004). According to anti-obesity drug research, some patients respond well when using anti-obesity drugs, and get good silk (weight loss β), some get moderate effect and Some will have very limited effects. S is the reason for this difference in anti-obesity drugs. It is extremely important that you can identify a responder who is resistant to obesity before starting treatment. Successful Individualized medications can not only help improve the efficacy of clinical practice but also greatly enhance the health benefits of health care and reduce safety issues, as fewer patients are partially exposed to treatment. However, it is well known to determine predictable anti-obesity The response to the treatment (in terms of efficacy or safety) is very difficult. It has been proven in the brain The endogenous cannabinoid ligand (endogenous cannabinoid) produced locally has an important role in the regulation of food intake and body weight (Fride E, Prostaglandins Leukot Essent Fatty Acids, 66(2-3): 221-233 (2002 review)). In addition, pharmacological treatments targeting CB1R (including the use of exogenous cannabinoid ligands in extracts derived from plant cannabis (Cannabis sativa)) have been shown to stimulate appetite (Williams and Kirkham, Psychopharmacology 143: 315-317, 2004) ° It is believed that these effects can be modulated by binding the cannabis test to the G protein-coupled CB1R located in the brain, including the hypothalamic region. The CB1R may also be present in the periphery, for example, adipose tissue and liver, wherein the CB 1R regulates fat formation and lipogenesis (Osei-Hyiaman et al, J Clin Invest, 1 15:1298-1305, 2005). Administration of CB1R antagonist drugs has been shown to reduce food intake and cause weight loss in humans and animals. The cannabinoid system has a right-dry endogenous ligand' including arachidonic acid decylamine (AEA) and 2-arachidonyl glycerol (2_AG) involved in animal and human feeding regulation (Cota et al., Int J) Obes, 27: 289-301, 2003). It has been reported that obese patients have high levels of circulating endogenous cannabinoids. For example, 'Bilibier et al. (Diabetes, 55: 3053-3060 2006) found that circulating AEA levels were comparable but 2-AG levels were higher in obese individuals than in lean individuals. Furthermore, they found that CB1 receptors were reduced in obese individuals in adipose tissue. Cote et al. (Int J. Obesity 31(4): 692-699, 2007) studied circulating levels of 2-AG and AEA and found that 2-AG levels were elevated in obese men with intra-abdominal obesity, whereas AEA does not rise. Engeli et al. (Diabetes, 54: 2838-2843, 2005) found that the concentrations of AEA and 1/2-AG were higher in obese people than in lean women. However, none of these documents teach circulating endogenous cannabinoids in different (stratified) levels in obese or overweight individuals. ° Endogenous cannabinoid ligands have also been reported to have different amounts in other diseases. For example, 'Hemp et al. (Pharmacopsychiatry 41: 48-53; 2008) found that female patients with clinical depression often have low circulating levels of 2_AG endogenous cannabinoids. However, none of the documents teaches that circulating endogenous cannabis can be used as a biomarker for susceptibility to CB 1R antagonist drug therapy. Since the amount of food consumed affects body weight, the local content of endogenous ligands in the brain is also related to weight management. Local production and destruction of endogenous ligands in the brain is a strictly controlled process (Di MaiX() and

Matias' Nature Neuroscience 8: 585-589, 2005). The strict control of the local production of endogenous ligands in the brain is important for food intake. There is no reason not to believe that the circulating (blood) content of endogenous ligands is at least related to food intake and weight control. Surprisingly, the inventors have found that the circulating content of the endogenous ligand measured prior to initiation of treatment with the CB 1R antagonist drug clearly predicts weight loss during treatment. At 132387.doc 200914046

The higher levels of endogenous ligands in the blood prior to the start of treatment are associated with greater weight loss during treatment with CB j R antagonists. The lower level of endogenous ligand in the gold solution prior to the start of treatment is associated with less weight loss or no weight loss during CB1IU# anti-drug therapy. However, it is beneficial to identify overweight or obese patients with low circulating levels of endogenous cannabinoids. This is due, for example, to the subsequent elimination of such patients at the time of treatment, which avoids patients being less likely to The therapeutic benefit suffers from any drug-related side effects. Ο Endogenous cannabinoids play a role in regulating food intake and body weight, and studies have shown that it can regulate a variety of physiological and pathological functions. Examples are given in the following references: Maccarrone et al., Prostaglandins Leukot Essent Fatty Acids, 66(2-3): 309-317, (2002 review);

Cainazzo MM, Eur J Pharmacol, 441(1-2): 91-97, (2002);

Parolaro D, prostagiandins Leukot Essent Fatty Acids 66 (2-3): 3 19-32, (2002 review). A more specific list of cbir_ mediated diseases and (_) conditions is given below. SUMMARY OF THE INVENTION The present invention is based on the discovery that the circulating content of endogenous cannabinoid is related to the susceptibility of CB1R antagonist drug treatment. Therefore, this finding is to select patients who are treated with CB 1R antagonist drugs (specifically, patients who need weight reduction of Ik, weight maintenance, and prevention of weight gain, for example, overweight and obese patients) while avoiding difficulty in treatment. Patients who should be treated are treated and thereby avoiding the opportunity, methods, and tools provided by such patients to experience or suffer from any adverse drug-related effects. 132387.doc -10· 200914046 [Embodiment] CB1R·mediated diseases and conditions CB 1 is taken as a body; the body is involved in various diseases and conditions and thus CB1R antagonist drugs have been suggested for the treatment of obesity or overweight (for example, Promote weight 2 light weight and maintain weight), prevent weight gain (for example, increased weight induced by drug therapy or increased weight after smoking cessation), regulate appetite and / or fullness, eating disorders (eg, greed, loss of appetite, appetite) Hyperthyroidism and obsessive-compulsive disorder), addiction (drugs, tobacco, alcohol, any large nutrients or non-essential foods that promote your diet), treatment of mental disorders such as the following: mental and / or mood disorders, schizophrenia and schizophrenia Bipolar disorder, anxiety disorder, anxiety and depression, depression, mania, obsessive-compulsive disorder, impulsive control disorder (eg, GiUes heart Tourette's syndrome), attention disorder (eg add /adhd), stress disorder and neurological disorders such as dementia and cognitive and/or memory dysfunction (eg, amnesia, ar Alzheimer's disease, pick's dementia, Alzheimer's disease, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild Alzheimer's disease, nerves and/or Neurodegenerative disorders (eg, multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntingt〇n, s chorea, and Alzheimer's disease), Demyelination-related disorders, neuroinflammatory disorders (eg 'Guin-Barre syndrome'). These CB丨R antagonist drugs are also recommended for the prevention or treatment of dependent and addictive conditions and behaviors (eg, alcohol and/or substance abuse, 132387.doc -11 - 200914046 Ο ι-〆 pathological gambling, theft癖), drug withdrawal disorders (eg, alcohol withdrawal disorders with or without sensory impairment; alcohol withdrawal; ampheneamine (amPhetamine) withdrawal disorder; decoctional de-cancer disorder; nicotine de-cancer disorder; Opioid withdrawal disorder; sedatives, sleeping pills or anxiolytics withdrawal disorders with or without sensory impairments; sedatives, hypnotics or anti-anxiety agents for detumescent sputum; and anaphylaxis caused by other drugs), alcohol and/or Drug-induced and mood disorders, anxiety disorders, and/or sleep disorders that occur during withdrawal and re-use of alcohol and/or drugs. It is also recommended that these cmR antagonist drugs are used to prevent or treat neurological dysfunction such as dystonia, dyskinesia, sedation, tremor and convulsions, and to treat spinal injury, neuropathy, migraine, alertness, and sleep disorder ( For example, 'sleep structure messy' sleep apnea, obstructive sleep apnea, sleep beer suspension syndrome), pain disorder, care trauma. These cmR antagonist drugs are also recommended for the treatment of immune and cardiovascular disorders (eg, atherosclerosis, arteriosclerosis, abnormal heart rhythm and arrhythmia, congestive heart failure, coronary artery disease, heart disease, high stress, Prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient lack of blond hair, peripheral vascular disease, systemic inflammation of vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischemia, brain thrombosis , cerebral embolism, cerebral hemorrhage), metabolic disorders (for example, showing reduced metabolic activity or energy at rest: reduction (expressed as a percentage of total defatting substances), diabetes, lipids: metabolic disorders, fatty liver, gout , hypercholesterolemia, hyperlipidemia, triacetemia, hyperuricemia, glucose intolerance, hunger _ sugar abnormalities, insulin resistance, sputum resistance syndrome, metabolic syndrome 132387.doc 12 200914046 , snoring syndrome, obesity - hypoventilation syndrome (Pickwickian syndrome), type 1 diabetes, type 2 diabetes, low HDL- And / or LDL - cholesterol content, low adiponectin content), reproductive and urinary disorders (for example, treatment of male gonads, inadequate treatment of infertility or as a contraceptive, menstrual abnormalities / menstrual disease, polycystic ovarian disease, female And male sexual desire and reproductive dysfunction (erectile dysfunction), GH_deficient individuals, female hirsutism, normal variant short stature) and respiratory related diseases (eg, asthma and chronic obstructive pulmonary disease) and Gastrointestinal system-related diseases (for example, gastrointestinal motility or intestinal propulsion dysfunction, abdomen " writing ° vomiting, ° nausea, gallbladder disease, gallstones, obesity-related gastroesophageal reflux, ulcers). It is also recommended that these CB1IU# anti-drugs are used as agents for the treatment of skin diseases, cancer (eg, colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, gallbladder cancer). , cholangiocarcinoma, craniopharyngioma, prader_wuii sydrome, Turner sydr〇me, Frohlich, s sydrome, glaucoma, infectivity Diseases, urinary tract disorders, and inflammatory conditions (eg, osteoarthritis, inflammation, viral brain sequelae, osteoarthritis) and wall-shaped surgical conditions. These CB 1R antagonist drugs are also recommended for the treatment of (esophageal) insufficiency. The various aspects of the invention are applicable to a suitable patient who is determined to be suffering from any of the above-mentioned diseases, disorders or conditions and which can be administered a CB1IU# anti-drug. In a particular embodiment, the invention is applied to weight loss treatment, including treating or preventing obesity or being overweight (eg, promoting weight loss and maintaining weight loss to prevent weight gain (eg, drug-induced weight gain or cessation of smoking) Weight 132387.doc -13- 200914046 increase), regulate appetite and / or fullness, eating disorders (eg, greed, loss of food, appetite and obsessive-compulsive disorder), and addiction (drugs 'tobacco ^ alcohol has any increase a large amount of nutrients or non-essential foods of appetite.) According to the first aspect of the present invention, it is necessary to use a large silk i receptor (cmR) antagonist drug for weight reduction and/or weight maintenance and/or A method of preventing weight gain, treating a mammal, comprising determining the amount of at least one circulating endogenous cannabinoid ligand in the mammal, thereby predicting a higher likelihood of responding to the CB1R antagonist drug.

According to another aspect of the present invention, there is provided a method of selecting a mammal in need of weight loss and/or weight maintenance and/or prevention of weight gain treatment with a cannabis test receptor (CB1R) antagonist drug, comprising determining the The amount of at least one circulating endogenous cannabinoid ligand in a mammal thereby predicting a lower likelihood of responding to a CB1R antagonist drug. The mammal can be any mammal including, but not limited to, humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, and rodents. In a particular embodiment, the mammal is a human.

The CB1R G protein-coupled stylistic (GPCR) effect typically requires the agonist to bind to the receptor to cause receptor activation. However, certain receptors exhibit spontaneous intrinsic activity and are not activated by ligands and this purine receptor is called "constitutively active receptor". This CB1 receptor appears to have constitutive activity (B〇uab〇ula et al, j Biol Chem, 272: 22330-339, (1997)). CB R system: • CB 1 receptor agonist and a partial agonist that activates the receptor; part 132387.doc • 14- 200914046 An agonist activates the receptor but is less effective than its full agonist. If the potency is low enough, some of the agonists will be characteristic of the antagonist. • A CB1 receptor inverse agonist that interacts with the receptor and produces an opposite effect to the agonist, thereby blocking the action of the agonist (or partial agonist) and impairing constitutive receptor activity. A partial inverse agonist can inactivate the receptor' but has a lower potency than a fully inverse agonist. As is well known and commonly used in the art, CB1 receptor inverse agonists are also known as cbi antagonists. • A CB1 receptor neutral antagonist that blocks the action of an agonist or inverse agonist but does not alter the constitutive receptor activity; it can also be a low potency partial agonist as a neutral antagonist. As used herein, "block" CB1R activity means inactivation of its underlying constitutive active state in a particular environment in which it can be found, ie, its cellular function is reduced below that at CB 1 receptor agonism. The degree of basal function measured in the presence and/or inability to achieve its cellular function even in the presence of an exogenous CB1R agonist or a natural binding ligand. The natural binding system functions as an endogenous molecule that acts as a receptor agonist and, therefore, is "endogenous cannabinoids" in the context of the present invention. Compounds useful in the present invention may be derived from CB 1R agonists (including In the presence or absence of a cannabis test, the natural signaling function of CB 1 r is inhibited or attenuated to block the CB 1R. Thus, the term "cannabinoid CB 丨 receptor antagonist" as used herein encompasses partial activation of the CB 1 receptor. Agent, CB 1 receptor inverse agonist, CB 1 receptor partial inverse agonist and cb 1 receptor neutral antagonist. 132387.doc -15- 200914046 This month, the person found one or more endogenous sources with high circulating content The mammal of the marijuana ligand has a higher responsiveness to the CB1R# drug, and the circulating content of the endogenous cannabinoid ligand can be used for the treatment of CB1R antagonist drugs. The present inventors have found that mammals with low circulating levels of one or more endogenous large woven ligands have a lower likelihood of weight loss in response to CB1R antagonist drugs. However, these mammals have more May be Adverse events associated with this treatment and therefore may be deselected for treatment. The relationship between the circulating content of endogenous keninine and the likelihood of responding to drug treatment may enable the possibility of pre-selecting patients eligible for CB 1R antagonist therapy This pre-selected example can be used to select patients who can participate in clinical trials involving putative CB 1R antagonist therapeutics. According to another aspect of the invention, there is provided a method of determining one or more agents most likely to benefit from a CB1R antagonist A method of treating a patient comprising measuring the amount of one or more endogenous cannabinoid ligands in a blood sample previously isolated from the patient and determining whether the patient is likely to benefit from treatment with a CB 1R antagonist based on the amount present. For heavy treatment, patients with high levels are more likely to benefit from weight loss and patients with low levels will benefit from the pain and risk of not having to undergo treatment and thus avoiding unnecessary adverse effects. To provide a means of identifying whether an obese or overweight patient can benefit from or respond to a CB 1R antagonist treatment. And comprising determining the amount of at least one circulating endogenous cannabinoid ligand in the patient, and determining whether the patient may benefit from or reacting based on the amount present. 132387.doc •16-200914046 CB1R antagonist drug therapy. The various aspects of the invention can be used in conjunction with any suitable CB1R antagonist. The following is a representative non-limiting list of disclosures of CB 1R antagonist compounds and their uses. Certain CB1R antagonists are known to be useful in the treatment of obesity, mental and Neurological disorders (WO 01/70700, EP 658, 546 and EP 656, 354). Pyrazoles having anti-inflammatory activity are disclosed in WO 95/15316, WO 96/38418, WO 97/11704, WO 99/64415, EP 418 845 and WO. In 2004050632. 1,5-Diarylpyrazole-3-carboxamide derivatives are disclosed in US 5,624,941, WO 01/29007, WO 2004/052864, WO 03/020217, US 2004/01 19 972, Journal of Medicinal Chemistry, 46 (4): 642-645 2003 'Bioorganic & Medicinal Chemistry Letters, 14(10): 2393-2396 2004, Biochemical Pharmacology, 60(9): 13 15-1323 2000 'Journal of Medicinal Chemistry, 42(4): 769-776 1999 and U.S. Patent Application Publication No. US 2003 199536. Certain 4,5-diarylimidazole-2-carboxamide CB1 receptor antagonists are disclosed in WO 03/007887 and WO 03/075660. Certain 1,2-diarylimidazole-4-carboxamide CB1 receptor antagonists are disclosed in WO 03/27076 and WO 03/63781. WO 03/40107 and WO 2006/067443 disclose certain 1,2-diarylimidazole-4-guanamines for the treatment of obesity and obesity-related disorders. A 1,5-diarylpyrazole-3-carboxamide derivative having a fluorinated alkylsulfonyloxyphenyl substituent is disclosed in WO 2005/080343 and WO 2006/067428. WO 2005/095354 and WO 2007/03 1720 disclose certain 1,2-diarylimidazole-4-carboxamides having a fluorinated alkylsulfonyloxyphenyl substituent. 132387.doc -17- 200914046 For the treatment of obesity and obesity related disorders. WO 200 Lan 74MPCT/GB2_/嶋95) reveals 4,5,6,7 tetraazaindolo[3,2-C] bites|ketones and 4,5_diox d ratio 2 and [3,2★ And the use of the compounds as a cbi antagonist in the treatment of obesity, psychosis and neurological disorders, methods of such therapeutic use, and pharmaceutical compositions containing the same. In one embodiment, the CB1R antagonist is a CB1R antagonist as described in the previously listed patent references. Specific (^(1) ulnar antagonist "rimonabant" (aka SR141716/AC〇mplia®; (5_(4. chlorobenyl)-l-(2,4-chlorophenyl)) _4_Methyl_N-(1-hexahydroindole. Dingerpyrazol-3-decylamine, CAS NO: 158681-13-1), which is described in European Patent No. EP 656,354. Other specific CB1R antagonism Agents include "taranabant" ((MK-0364), as described in J. Med. Chem. 2006, 49 7584 and references therein); CP945598 (l-[9-(4-gasbenzene) 8-)(2-Chlorophenyl)-9H-indol-6-yl]-4-ethylaminopyrohydropyridine_4_carboxylic acid decylamine HC1; disclosed in WO 2005 049615); SR147778 (SR147778 [5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(l-hexahydroacridinyl)-1Η-° ratio. - guanamine], "surinabant 1'; disclosed in J Pharmacol Exp Ther. 2004 Sep; 310(3): 905-914), AVE-1625 ((N-{1- [Bis-(4-chlorophenyl)-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide; disclosed in WO 2006 040464 And those in SLV319 (disclosed in J. Med. Chem 2004, 47, 627-643) CB1R other antagonists disclosed in Hertzog (Expert Opinion 132387.doc -18- 200914046

Therapeutic Patents 14(10): 1435-1452, 2004) 0 In one embodiment, the CB1R antagonist is a compound of formula (1)

Wherein R1 represents a C3 6 alkyl group optionally substituted by one or more fluorines; R2 represents Η and R3 represents cyclohexyl group optionally substituted by hydroxy or R2 together with the nitrogen atom to which it is attached, optionally substituted by hydroxy group a hexahydropyridine ring;

Or or c; wherein the bond of the mark * is linked to the benzene ring carrying the oxy group and the other bond of the tag # is connected to the nr2r3; the butyl---- is optionally between the 6-position and the 7-position Additional linkage; R4 and R5 independently represent H, bromo, chloro or fluoro; and R6 represents methyl or hydroxymethyl; 132387.doc -19· 200914046 η and m independently represent hydrazine or 1; or pharmaceutically acceptable Accept the salt. In another embodiment, the CB1R antagonist is selected from the group consisting of 1-propanesulfonic acid 3,3,3-trifluoro-4-[l-(2,4-dichlorophenyl)-3- [[(2-hydroxycyclohexyl)amino]carbonyl]4-(hydroxymethyl)_ih-°bazin-5-yl]phenyl ester; 1-propanesulfonic acid 3,3,3-trifluoro- 4-[3-[(cyclohexylamino)carbonyl(2,4-diphenyl)-4-(hydroxyindenyl)_1Η_σ-biazole-5-yl]phenyl ester; propanesulfonic acid 3,3,3 -Trifluoro-4-[l-(2,4-dichlorophenyl).4,5,6,7-tetrahydro-3-indolyl-4-oxo-5-(1-hexahydroacridine Base)_1H_D is more than [3,2_c] η than pyridine·2_yl] phenyl ester; 1-propanesulfonic acid 3,3,3-trifluoro·4-[1-(2,4-digas Phenyl)_4_mercapto-3-[(1·hexahydro D-pyridylamino)carbonylbiazole-5-yl]phenyl ester; s propanesulfonic acid 4-[1-(2,4-di Chlorophenyl)_4-mercapto-3-[(l-hexahydroacridinylamino)yl]_1H_pyrazol-5-yl]phenyl ester; 3,3,3-trifluoropropane-1 -sulfonic acid 4_ [2-(2,4-dichlorophenyl)-5-indolyl-4-(hexahydro.biter-1-ylaminoguanidino)imidazol-1-yl]phenyl ester Or 3,3,3-trifluoropropane-1-sulfonic acid 4-[1-(2-chloro-4-fluorophenyl)-3-methyl-4-oxo-5-hexahydropyridine-indole _ base_4,5,6,7_tetrahydro-1Η- Pirolo[3,2-c]pyridin-2-yl]phenyl ester or a pharmaceutically acceptable salt thereof. The present invention contemplates any suitable potent CB 1R antagonist having a Ki value of <10 μΜ in a GTPYS assay using CP-5594 as an agonist ligand (Ryberg et al., FEBS Letters, 579:259-264). (2005)) A predetermined individualized method of administration suitable for the present invention. Endogenous cannabinoids and endocanna-binoids are derived from unsaturated fatty acid derivatives of ligands for cannabinoid receptors. 132138.doc -20· 200914046 (DiMarzo Biochim Biophys Acta 1392: 153-157, 1998). It includes metabolites of metabolites such as: anandamide (aka arachidonic acid) Indoleamine; AEA), 2-Peanut Four Glycerin (2-AG) and Noladin Ether (see Cannabinoid physio-logy and pharmacology: 30 years 〇f progress (Howlett et al., Neuropharmacology 47:345) -358, 2004). Virod-hamine, palm-based ethanolamine and oil-based ethanolamine are a new addition to the increasing number of characterized endogenous cannabinoids. Long-chain fat for endogenous marijuana Acid (C16-C22) ethanolamine, which binds to the CB1 receptor. Examples of such compounds are, but are not limited to, di-iso-gamma-linolenic acid amine, peanut tetras-mercaptoethanolamine, Bis-γ-linolenic acid methyl ester, docosatetradecylethanol decylamine, leukotriene 醯 4 ethanol decylamine, prostaglandin D2 ethanol decylamine, prostaglandin Ε 1 ethanol guanamine, prostaglandin Ε 2 ethanol 醯Amine, R-1 Methanandamide, R-2 methyl amide, R-palmital-(2-methyl)ethanolamine, S-1 guanaamide, stearic acid Mercaptoethanolamine, docosahexaethanolethanolamine, linoleylethanolamine, hydrazine-linoleyl glycerol, alpha-linoleic ethanolamine, mead acid Ethanol-rich amine. The content of any such endogenous kenafine can be used to predict susceptibility to a CB1R antagonist of the invention. In a particular embodiment, the endogenous kenafine used in the present invention is selected from the group consisting of Group: anaminamide (Peanut four-smelling ethanolamine (AEA)), 2-arachidonyl glycerol (2-AG), Norramine (noladin 132387.doc 21· 200914046 ether), palmitoylethanolamine, vir〇dhamine and oleoresin. A particularly useful biomarker for the susceptibility of arachidonic acid decylamine (AEA) and 2-Peanut tetrasyl glycerol (2-AG) to CB 1R antagonists. DATA DESCRIPTION Various aspects of the invention rely on the determination of the content of at least one endogenous cannabinoid. In one embodiment, at least one endogenous cannabinoid system, AEA or 2-AG, is measured/detected. In another embodiment, AEA & 2_ € l AG is measured. The inventors have discovered that the predictive likelihood of the circulating amount of endogenous cannabis ligand in the blood can be used to determine the effect of CB1R antagonist therapy. They found that the patient selection method of the present invention operates based on the content of a single endogenous cannabinoid (e.g., AEA or 2-AG). See figure 本文 and Figure 2 of this article. However, in terms of more accurate prediction or patient stratification, the best Ο results can be obtained by mathematically combining data obtained from two or more endogenous cannabinoids. See, for example, Figures 3 and 4 herein. Such mathematical constructions herein specify A as a biomarker synthesis score or synthesis score. The composite score 彳 includes adjustments for other relevant covariates such as age or gender or normal weight gain. The biomarker synthesis score can be constructed in a number of ways. The linear combination of endogenous cannabis can be written as: 1 = 1 (1) where the Li system endogenous cannabis ligands i, & are the corresponding coefficients and are 132387.doc -22- 200914046 intercept. The model categories described by this equation include even one of them refers to endogenous cannabinoid ligands while others indicate a total of one variable such as age or gender. More complex biomarker synthesis scores can be constructed by adding cross terms and square terms. The following is the equation for the first and second term (square terms) but the cubic or higher term can be easily added. +Κ> * Α·) + Σ *L. +±Kii *L; Ο片+t (2) Two examples of different biomarker synthesis scores are shown in Figures 3 and 4. In Figure 3, a linear combination of AE^2_AG is used. In the figure, add the intersection (multiplier) of AEA and 2-AG. These additions enhance the effectiveness of this prediction. It is possible to hunt a person who is familiar with the technology; Dengli ^ Speakers I choose or determine which specific mathematical model to use for such endogenous cannabinoid data. The number of tested (four) cannabis tests can be compared to the control individual. This comparison can be performed simultaneously on the control individual and the test individual, or it can be historical versus daily recall data. Such comparative values (predetermined reference values) can be obtained from measurements of endogenous cannabinoids in comparable biological samples taken from a common population of mammalian individuals or selected populations (e.g., overweight or obese populations). This pre == can be the pole of the large sample data. For example, the difference between the number of individual samples (direct value or synthetic score) and the intended group. The bite, the second "competent responder group or non-sounding bed ... = patient group (for example, - group may participate in the sample of patients) compared with their other member groups per - endogenous large 1323S7.doc -23 - 200914046 The value or amount or amount of hemp base in a particular patient's circulatory system or the synthetic score generated therefrom. In a particular embodiment 'this group of patients is an overweight or obese individual. In a particular embodiment, if the patient has Endogenous cannabis ligands with high circulating levels' are more likely to benefit from CB 1R antagonist therapy than patients with low levels of endogenous cannabinoid ligand. In other embodiments, if endogenous cannabis Alkali content (or synthetic fraction) allows the patient/individual to be (incremental priority) up to 50°/., 40%, 30%, 20%, 15%, 1%% or 5%, then the patient/individual Identification or continued to be more beneficial to CB 1R antagonists and/or treatment with cb 1 r antagonist drugs. In one embodiment, if circulating endogenous cannabinoid ligands are up to 30 % (up to 30%), or synthetic scores for patients The patient may be treated with a CB1R antagonist in the range of up to 30%.These methods are particularly useful for assessing the likelihood of responding to a CB1R antagonist to treat a body mass disorder. In other embodiments, 'if endogenous cannabinoids are present (or synthetic score) to place the patient/individual (incremental priority) as low as 40%, 30%, 2%, 1 5°/〇, 10°/. or 5% of the position' then the patient/individual The bell is or is determined to be less susceptible to treatment by CB 1R antagonists. As used herein, 'overweight and obese individuals can be determined based on body mass index (BMI) values set by World Health 〇rganisati〇n (WHO). The overweight person has a BMI of 225 kg/m2 and the obese person has a BMI of 230 kg/m2. However, it is known that the overweight and obese BMI cutoff values may change in the future. In addition, 132387.doc -24- 200914046 BMI can also or preferably define people at risk of cardiovascular disease and who can benefit from weight loss based on the amount of visceral fat tissue and/or waist circumference and/or waist-to-hip ratio. Gender and ethnic groups cutoff Different methods of detecting such endogenous cannabinoid unsaturated fatty acid derivatives and any method capable of directly or indirectly detecting the amount of endogenous marijuana in a blood sample or a portion thereof (for example, blood or clarification) or Techniques can be used in the context of the present invention. Some of the well-known techniques that can be used in the methods of the invention include mass spectrometry, chromatographic separation, displacement methods, binding assays (eg, immunoassays), competitive inhibition assays, and the like. Any effective method for measuring the amount of lipid or low molecular weight marker is included in the present invention. A one of ordinary skill should be able to determine which method is most suitable for measuring a particular marker. Thus, for example, a strong ELISA assay may be best suited for use in a physician's office and an I-test that requires a more complex instrument may be best suited for an analytical laboratory. Not relevant to the chosen method. Importantly, these measurements should be reproducible. The endogenous cannabinoid marker of the present invention can be measured by directly measuring the mass spectrum of the analyte with high sensitivity and reproducibility. Many mass spectrometry methods are available and can be used to complete this measurement. Electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and photoionization (Αρρι) can be applied to endogenous cannabis. Same ionization technology. These techniques can be used with a single-stage _(MS) or a three-level quadrupole: and the absolute quantification of the endogenous cannabis test (by using appropriate sputum), which can quantify various substances in a test The relative concentration in the sample and in another sample. Matrix-assisted laser desorption ionization (MALDI) or related SELDI techniques can also be used to determine the presence or absence of endogenous 132387.doc •25- 200914046 Cannabis test and the relative or absolute content of this endogenous cannabis test. Moreover, the time-of-flight (TOF) mass spectrometer and the Fourier transform mass spectrometer (XFTMS) can operate at extremely high resolutions. This enables low-abundance materials to be measured with high accuracy and resolution. These endogenous cannabinoid markers can be combined using mass spectrometry such as liquid chromatography-mass spectrometry (LC/MS, LC/MS/MS, LC/MSn) or gas chromatography-mass spectrometry (GC/MS, GC/MS). Separation techniques such as /MS, GC/Msn) are used to measure, and: the analytes in the sample can be indicated by specific residence times and mass-to-charge ratios mb. As understood by one skilled in the art, many other separation techniques can be used in conjunction with mass spectrometry. For example, a wide variety of separation columns are commercially available. Alternatively, separation can be performed using conventional chromatographic surfaces (e.g., beads that immobilize marker-specific reagents). Next, the molecules retained on the substrate are eluted for analysis by mass spectrometry. Analysis by liquid chromatography-f spectrum produces a mass density spectrum, and each component of the sample of the line has a characteristic mass-to-charge ratio (2) off: peak: (10). The presence of the m/z and the residence time of the biomarker, for example, indicates the presence of the marker. The peak value indicating the marker can be compared with the corresponding peak value of the other 对照' control sample to obtain a relative measurement value. When quantitative measurements are required, any normalization technique of this technique can be used: (eg, internal standard). The residence time depends on the extent of the conditions of separation. I. Chromatography of the label of the present invention may also be used or detected by a method of detection or measurement using a number of chemically derivatized cores known in the art, using detectors other than mass spectrometry, 132387.doc -26-200914046 'For example, fluorescent detection of labeled molecules, nuclear magnetic resonance (NMR), capillary uv, evaporative light scattering or electrochemical detection. Other suitable methods that may be employed include radioimmunoassay, enzyme-linked immunosorbent assay (ELISA/EIA), and sandwich assays. See U.S. Patent Nos. 4,376,110 and 4,486,530. In other embodiments, standard immunoassays can be used (eg, sandwich enzyme-linked immunosorbent assay (ELISAd and, for example, chemiluminescence detection using matched antibody pairing) to determine the content of endogenous cannabis test markers. "A Practical Guide to ELISA" DM Kemeny, Pergamon Press, Oxford, England. Commercially available or customary single or multiple antibodies are used. However, this assay may be suitable for use with other agents that specifically bind to the label. Standard protocols and data analysis can be used to determine marker concentrations from analytical data. Many of the above assays use reagents that specifically bind to endogenous cannabinoid markers ("label-specific reagents"). Any of the molecules of the binding label is included in the invention. In certain embodiments, the label-specific reagent is an antibody or antibody fragment. In other embodiments, the label-specific reagent is a non-antibody Drugs include multiple antibodies, monoclonal antibodies, and various antibody constructs (eg, F(ab')2, Fab, and Chain Fv). The affinity of the binding can be determined using conventional techniques (for example, they are described by Scatchard et al. in Αηη ν γ,

Acad. Sci., (1949) 51:660) to determine. Multiple strains of antibodies can be readily produced from a variety of sources (e.g., horses, cows, goats, sheep, dogs, chickens, rabbits, mice, or rats) by means of well-known procedures in the art 132387.doc -27 - 200914046. In general, the host animal is usually administered an antigen by parenteral injection. The immunogenicity of the antigen can be enhanced by the use of an adjuvant (e.g., Freund's complete or incomplete adjuvant). After boosting the immunization, small serum samples were taken and tested for reactivity to the antigen. Monoclonal antibodies can be readily prepared using well-known procedures, see, for example, U.S. Patent No. RE 32,011; 4,902,614; 4,543,439 and

No. 4,41 1,993; Monoclonal Antibodies, Hybridomas: A

New Dimension in Biological Analyses, Plenum Press, Kennett, McKearn, and Bechtol (ed.) (1980). Label-specific reagents can be identified and produced by any method accepted in the art. Methods for identifying and producing antibodies and antibody fragments specific for an analyte are well known. Examples of other methods for identifying marker-specific reagents include design methods based on marker structure analysis and binding assays. According to one embodiment, the amount of circulating endocannabinic ligand is detected by immunoassay. Specific immunoassay techniques that can be employed include enzyme-linked immunosorbent assay (ELISA/EIA) and radioimmunoassay (ria). In certain embodiments of the invention, the endogenous cannabinoid content can be detected indirectly. For example, fatty acid indoleamine hydrolase (FAAH) degrades AEA's belief that low levels of faaH are associated with high levels of AEA. Therefore, the detection of FAAH content can be regarded as an indicator of aea content. Similarly, the detection of 'monodecylglycerol lipase (2-AG degrading enzyme) can be regarded as an indicator of 2-AG content. 132387.doc • 28· 200914046 The various aspects of the invention described herein can be applied to select patients who can participate in clinical testing (especially in clinical trials of CB 1R antagonist drugs). According to another aspect of the present invention, a method of providing a stratified-group of patients to identify one or more patients suitable for the treatment of a CDR antagonist drug, which is present in a previous patient-separated The amount or amount of endogenous cannabinoid ligand in the blood. In a particular embodiment, the population of patients is an overweight or obese individual. According to another aspect of the present invention, there is provided a method of causing a salty weight and/or weight maintenance and/or prevention of weight increase in a patient in need thereof, which comprises measuring a circulating or endogenous cannabinoid ligand The amount in the patient is selected and appropriate therapy is selected based on the amount of endogenous cannabinoid ligand determined. According to a particular embodiment, if the patient has a high level of circulating endogenous cannabinoid ligand, it can be treated with a CB1R antagonist drug. The aspect of the eclipse is also used for the method of endogenous cannabis test for assessing the likelihood of effective treatment of the Cb 1 r antagonist. According to another aspect of the present invention, a circulating amount of endogenous cannabinoid ligand is provided as a biomarker for effective weight loss of a CB1R antagonist drug or susceptibility to chyme inhibition treatment. According to another aspect of the present invention, a circulating amount of one or more endogenous cannabinoid ligands is provided in a patient selected for clinical trials of a CB1R antagonist drug or in a patient selected for (1) ulnar antagonist drug therapy Uses. In one embodiment, the circulating content of endogenous cannabinoid ligands in a patient participating in the trial or in a drug therapy suitable for a CB1R antagonist is such that the patient is in the initial group 132387.doc -29-200914046 (incremental priority) a position of up to 5〇%, 4〇%, 3G〇/〇, 2〇0/., 15%, 10% or 5%. In a particular embodiment, the initial group is an overweight or obese patient. Each aspect relies on the measurement of the amount of one or more endogenous cannabinoids in the circulating (blood) system. Those skilled in the art will appreciate that whole blood or part of the blood (eg, serum or mortar fraction) may be understood. Performing such measurements. A blood sample may be taken just prior to the above measurement, but the blood sample may also be a blood sample collected from an associated individual long ago and stored in an appropriate manner prior to the above measurements. Use appropriate standardization protocols to measure endogenous! cannabis ligand values. For example, v〇geser et al. (CHn and Lab Medicine 44(4): 488-491, 2006) have studied different sample processing conditions. The effect of the measured plasma anadine concentration and the discovery that anadine is released from the ex vivo blood cells at a very high rate. The blood from the test patient is stored for different periods of time and/or different from Storage under conditions of other samples may result in deviations from the actual circulating endocannatic cannabinoid data. To avoid doubt, the method of the present invention should not involve the diagnosis of human practice. Preferably, the sample previously removed from the individual is used. The method of the invention is practiced. However, the kit of the invention may comprise the extraction of the sample from an individual. The invention also provides for determining that a mammal (specifically, a human) will have a CB1R antagonist when administered a set of possible responses, the set including for detecting endogenous cannabinoids in a sample (specifically, a gray sample) 2 132387.doc -30· 200914046

The amount of reagent. The set of fines W, '' includes an instruction to use the reagents. Such agents may include endogenous cannabis antibodies or antibody fragments or any other binding member capable of binding endogenous cannabinoids. Moreover, the antibody or antibody, tablet & or binding member may be suitably labeled, with glory or radiation not wearing @ and, the kit may include means for collecting blood samples from an individual mammal; for example, a syringe, a wipe Sub, ethanol wipes, sterile test tubes and the like. According to still another aspect of the present invention, a method of treating a patient in need of treatment with a C-antibody agent, comprising measuring the amount of one or more endogenous cannabis tests in the circulatory system of the patient, comparing the amount with The predetermined reference value and if the measured amount is above the _ reference value, the patient can be administered a suitable amount of the CB1R antagonist. According to a further aspect of the invention, there is provided a CB1R antagonist for use in the treatment of obese or overweight patients, said patients being identified as having a high level of at least one circulating endogenous marijuana relative to the entire over-obese or overweight population Check the ligand. According to still another aspect of the present invention, there is provided a use of a CB1R antagonist for the manufacture of a medicament for treating an obese or overweight patient, and (4) a patient is determined to have at least one circulation having a high sputum relative to the entire over-obese or overweight population. Endogenous cannabinoid ligand. The CB1R antagonist compound of the present invention for treating a patient may generally comprise a pharmaceutical preparation in the form of a sexual ingredient or a pharmaceutically acceptable addition salt (in a pharmaceutically acceptable dosage form) by the following route: oral administration , parenterally, intravenously, intramuscularly, subcutaneously or by other injectable means, 132387.doc -31 - 200914046, transrectal, vaginal, transdermal and/or nasal route and/or by inhalation . Depending on the condition being treated and the patient and the route of administration, the compositions may be administered in different doses. A suitable daily dose of a CB1R antagonist compound for use in the treatment of human disease, as in the method of the present invention, is about 0.00 M0 mg/kg body weight, preferably 0.01 to 3 mg/kg body weight. Oral formulations are especially preferably tablets or capsules which can be formulated by methods known to those skilled in the art to provide between 〇5^^ and (10). The active compound dose between mg ', for example'; L mg, 2 mg, 4 mg, 6 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 1 及 and 3 〇〇 mg. The invention is further illustrated by the following non-limiting examples and figures, in which: Figure 1 shows weight loss as a function of pre-treatment AEA content in a CB1 receptor antagonist (rimonabant) treatment. The dashed line indicates the least square linear regression fit of the data (p = 〇.〇31; r2 = 0.15).

Figure 2 shows weight loss as a function of pre-treatment content of 2_AG in the treatment with a CB 1 receptor antagonist (rimonabant). The dashed line indicates the least squares linear regression fit of the data (p=0.0013; r2=〇.3i). Figure 3 is a graph showing the biomarker synthesis score (horizontal axis) of body weight loss (straight axis) treated with a CB1 receptor antagonist (rimonabant) and an equation for pre-treatment content of AEA and 2-AG (horizontal axis) a scatter plot. The dashed line indicates the least squares linear regression fit of the data (p = 8 2e_〇5; r2 = 〇 5〇). Note: Here, the X-value is equal to the fitted value fitted to the y-axis regression. Figure 4 shows the weight loss in the treatment of CB 1 receptor antagonist (rimonabant) 132387.doc • 32- 200914046 2 (vertical axis) and the equation by the combination of AEA and 2_AG pre-treatment content A scatter plot of the biomarker synthesis score (horizontal axis). The dotted line indicates the least squares linear regression fit of the data (p = 15e 〇 6; r2 = 〇 68). Note: Here, the X-value is equal to the fitted value of the regression fit to the y-axis. EXAMPLES: Example 1 This study was carried out in Sprague_Dawley strain male rats (Rheoscience, Led0je, Denmark). The rats were housed in a normal light cycle (in 6 AM-6 PM light) under controlled temperature conditions (1 rat/cage), and the rats were free to obtain water and a high-energy diet (4.41). Kcal/g-% energy: 514 kcal% carbohydrate, 31.8 kcal % fat, protein 16_8 kcal %; diet number 1226 dip; Research Diets, New jersey, USA). For this experiment, 15 + 15 individuals were used. Such individuals are selected from a group of rats that are selectively fed to show an increased likelihood of developing diet-induced obesity (Dl〇) or an increased likelihood of resistance to diet-induced obesity (DR). The animals used for the study were selected so that the weight of each group showed the greatest change (weight range at the start of the study: DIO 392-626 g and DR 395-459 g). At the start of the study, ie, the rats had been evaluated on a 15-week and 16-week high-energy diet (see above), the rats were 19 weeks and 20 weeks old, respectively. The animals received CB 1 receptor antagonist (/inverse agonist) rimonabant (5_(4_ chlorophenyl) at 1 pm Pmoles/kg at 2 pm daily (9 hours after entering the light phase) 1-(2,4-Dichlorophenyl)-4-indolyl-N-(l-hexahydropyridyl)_ΐΗ·pyridin-3-indolamine' CAS NO: 15868 1-13-1) Tube feeding and administration. The selected doses used to reduce the appetite and body weight of low obese rodents are within the scope of the literature (eg, Colombo et al, Life Sci.; 63: PLU 3-7, 1 998). The volume of the drug should be kept at 5 ml/kg during the study. Prior to the implementation of the experiment, the simulated tube feeding method was adapted for 3 days. 24-hour food intake and body weight were measured twice a week from day -1 and thereafter. Fasting blood samples were collected 2 days before the start of the dosing period (day -2) and on the 14th day after dosing, at 6 am, and after 8 hours (3 hours before the end of the light phase). Blood samples from each animal were collected by cutting the tail in a ml·2 ml EDTA tube, a 500 μΐ EDTA tube, and a 300 μΐ Heparin tube. All tubes were pre-chilled with ice and returned to ice-cold after sampling. Beginning at up to 5 minutes after sampling, the blood is centrifuged for 1 minute at a rate corresponding to 2000 RCF at the bottom of the tube to minimize endogenous cannabis release from blood cells (V〇geser et al., ciin Chem Lab Med. 44(4): 488-491 (2006)). The top y4 plasma was then aspirated into a new pre-chilled 0.5 ml polypropylene microtube (〇.5 ml, 30x8 mm 0, SARSTEDT, Germany) and immediately frozen at -80 °C (250 μl + 1 〇〇μΐ ' from 1.2 ml EDTA tube; 100 μl +1 〇〇μΐ from 5 μμΐ EDTA tube and 100 μl from 300 μl Heparin tube). Add 1 ng of AEA-D8 and 100 ng of 2-AG-D5 (Cayman Chemical, Ann Arbor, Mi, USA) to 100 μM of plasma as internal standard and 6 μM methyl tertiary-butyl ether/isohexyl Alkane (5 〇: 5 〇, volume ratio). After 1 min of extraction, the supernatant was transferred to a new tube, evaporated to dryness in nitrogen, and dissolved at 75 °/. A mixture of acetonitrile in water (5 〇 μ1) was placed in a refrigerated autosampler (1〇0). Then 2〇41 was injected into ^1}^111* (1:18 column (5〇*2 1 132387.doc •34- 200914046 mm, 3 μηι) (Thermo Electron). Gradient mobile phase system by a (63% water, 5 mM ammonium acetate, 0.02% formic acid and 37% acetonitrile) and B (1% water, 5 mM ammonium acetate, 0.02% formic acid, 50% acetonitrile, 49% 2-propanol) constitute '0.3 ml /'min is given. A linear gradient from 40 〇/〇B to 90% B is used in 5 min. The serial MS is desolvated in an electrospray positive multi-reaction detection mode at a heat source temperature of '45 CTC' at 120 °C. Work at temperature and cone voltage of 27 V. Set the cone and desolvation gas flow to 1 〇〇 and 90 〇 L/hr. The monitored conversion is m/z 348 to 62 (AEA), m/z 356 To 63 (person £8-D8), m/z 379 to 287 (2_8 (}), and 111/2 384 to 287 (2_ag_D5). The collision energy used for all analytes was 16 eV. Serial mass spectrometry (LC-MS/MS) analysis of arachidonic acid decylamine (AEA) and 2-arachidonyl glycerol (2_) in blood destruction

AG). The QUattro Premier XE mass spectrometer (Waters) is used in conjunction with the HP11® LC pump (Agilent Technologies) and the Waters 2777C Sample Manager. The same method was used to analyze other endogenous cannabis such as oil-based ethanolamine (OEA) and palmitoylethanolamine (PEA). When collecting blood samples (days -2 and 14), the atmospheres were weighed. To separate the therapeutic effects, body weight data was pre-treated by subtracting the natural weight gain of rats at approximately 19 weeks of age. DI0 and DR rats used a normal daily weight gain of 3 a § and 丨 8 g, respectively. The baseline levels of the two endogenous cannabis tests are closely related to the therapeutic response to weight loss during treatment. Both AEA (Figure 1) and 2-AG (Figure 2) are predictive of weight loss. Combining the levels of AEA and 2-AG into a biomarker synthesis score further improves the prediction of treatment outcome (Figure 3). In order to systematically determine all possible linear regression models for the biomarker synthesis scores involved or (in other words) how to arrange the various subset combinations of AEA, 2-AG, OEA and PEA, we use the branches 132387.doc -35- 200914046 Delimitation algorithm (FurniVal and wils〇n, Technometdcs, 42 (1): 69-79, 2000). The model or biomarker synthesis score is then selected using a model with the lowest Bayesian Information Base (BIC, Schwartz, Ann Stat, 6: 461_464, 19-8) values. This BIC value is the statistical basis for model selection. The BIC is an increasing function of the decreasing function of the sum of squared residuals (goodness of fit) and the number of variables involved. The resulting model is shown in Figure 4. In addition to the first model, the final composite score includes the intersection of AEA and 2-AG. In other cases, we can choose an alternative method that does not use BIC or all subset regression models. Linear regression modeling and branch and bound algorithms (in the leap package) were implemented using software R, version 2.4.1 (www_R_project 〇rg). As an example of responders and non-responders, rats with the highest quartile of final biomarker synthesis scores have an average body weight loss of 61.8 ± 4·2 g and biomarkers with low quartiles The synthetic fraction of rats had an average weight loss of 8.3 ± 3.1 g (mean SEM). Example L = a method of selecting a mammalian animal for treatment with a cannabinoid guanidine receptor (CB1R) antagonist drug for weight reduction and/or weight maintenance and/or prevention of weight gain, comprising determining at least one of the mammals Follow: The content of endogenous cannabinoid ligands, thereby predicting a higher likelihood of responding to CB1R antagonist drugs. 132387.doc • 36- 200914046 2. The method of embodiment 1, wherein the mammal is a human. 3. The method of embodiment 1, wherein the CB1R antagonist is an inverse agonist. 4. The method of embodiment 1, wherein the CB1R antagonist is a neutral antagonist. In the case of the mammalian ligand, it has a response. 5. The method of any one of embodiments 1 to 4, the high probability of endogenous cannabinoids having a high circulating content in the CB 1R antagonist music

6. A method of determining a patient most likely to benefit from (3) (10) (iv) drug therapy comprising measuring a content of one or more endogenous cannabis ligands in a blood sample previously isolated from the patient and determining the content based on the content Whether the patient can benefit from treatment with a CB1R antagonist. At least one of the endogenous properties wherein at least two of them are determined. 7. The method of any one of embodiments 1 to 6 wherein the cannabinoid system AEA or 2-AG. 8. A method according to any one of embodiments 1 to 7 wherein the content of the source cannabinoid ligand is. The method of any one of embodiments 1 to 8, wherein the cmiu# anti-drug is selected from the group consisting of: rimonabant, taranaban, sulinaban, CP945598 and SLV3 19. 10. The method of embodiment 9, wherein the drug is rimonabant. 11. The method of embodiment 6, wherein if the patient has a high circulating amount of endogenous cannabinoid ligand, it may benefit from treatment with a cmR antagonist. 12. The method of embodiment 6, wherein if the patient has a low circulating amount of endogenous cannabinoid ligand, it is less susceptible to treatment with a CB1R antagonist 132387.doc-37-200914046. 13. The method of Example 6 wherein the patient is treated with a CB1R antagonist if the endocannabinic ligand content of the circulating endogenous ligand is as high as 30%, or the synthetic fraction is such that the patient is in the range of up to 30%. 14. The method of embodiment 6, wherein the patient does not benefit from and/or is not susceptible to benefiting if the circulating endocannabinic ligand content is less than 30%, or the synthetic score is such that the patient is in the lowest 30% range CB1R antagonist treatment. 15. The method of embodiment, wherein the group of patients is an overweight or obese individual. The method of any of embodiments 1 to 15, wherein the amount of circulating endogenous cannabis ligand is detected using mass spectrometry. 17. The method of Example 16, which uses liquid chromatography mass spectrometry (lc/ms, LC/MS/MS, LC/MSn) or gas chromatography mass spectrometry (Gc/Ms, GC/MS/MS, GC/ MSn). The method of any one of embodiments 1 to 17, wherein the amount of circulating endogenous cannabinoid ligand is detected after derivatization by means of a fluorescent reagent for the chromatography system. 19. The method of any one of embodiments 18 to 18, wherein the amount of circulating endogenous cannabin ligand is detected by Luguang displacement analysis. The method of any of the embodiments wherein the amount of circulating endogenous cannabis ligand is detected by immunoassay. 21. The method of Example 2, wherein the immunoassay is an enzyme-linked immunosorbent assay (EUS), a radioimmunoassay (RIa), a fluorescent immunological fraction 132387.doc-38. 200914046, a luminescent immunoassay, Electrochemiluminescence immunoassay or a combination of SELDI-based immunoassay and mass spectrometry. The method of any one of the embodiments (1), wherein the endogenous cannabinoid is detected by using "A degrading enzyme, fatty acid guanamine hydrolase (FAAH) and /42_ag degrading enzyme, monomercaptoglycerol lipase) The amount of ligand. The method of any of the preceding clauses (1), wherein the method is for selecting a patient who can participate in a clinical trial. 24. A stratification-group of patients to determine one or more methods for a patient treated with (3) Han Boostin medications, which comprises determining one or more circulating endogenous properties in blood previously isolated from such patients The amount or amount of the cannabinoid ligand. 25. The method of embodiment 24, wherein the group of patients is an overweight or obese individual. 26. A method of reducing weight and/or weight maintenance and/or weight gain in a patient in need thereof, comprising determining the amount of one or more circulating endogenous cannabinoid ligands in the patient and detecting The content of the source cannabinoid ligand is chosen to select the appropriate therapy. 27. The method of embodiment 26, wherein the patient is treated with a CB 1R antagonist drug if the patient has a high level of circulating endogenous cannabinoid ligand. 28. Use of a circulating amount of endogenous cannabinoid ligand as a biomarker for effective weight loss or appetite suppression susceptibility to a CB1R antagonist drug. 132387.doc •39· 200914046 29. Use of a circulating content of one or more endogenous cannabinoid ligands to select patients who may participate in clinical trials of CB1 r antagonist drugs or to select a suitable CB1R antagonist drug The patient. 30. Use as in Example 29 wherein a patient who is involved in the test or is eligible for CB1R antagonist drug therapy has an endogenous kenafine ligand circulating content that allows the patient to be in the initial group up to 50%. 3. The use of embodiment 29, wherein the patient participating in the test or a drug therapy suitable for CB 1R antagonist has an endogenous cannabin ligand circulating content such that the patient is at a position of up to 40% of the initial group. 32. The use of embodiment 29, wherein the patient participating in the test or a drug therapy suitable for CB1R antagonist has an endocannabinic ligand ligand circulating level that allows the patient to be in the initial group up to 30%. The use of any of embodiments 29 to 32, wherein the initial group is an overweight or obese patient. 132387.doc -40-

Claims (1)

200914046 X. Patent application scope: 1. The use of an endogenous cannabinoid ligand as a biomarker for the suitability of a cannabinoid 1-fork (CB1R) antagonist drug. 2. The use of claim 1, wherein the endogenous cannabinoid ligand is used as a biomarker for effective weight loss or appetite suppression susceptibility to a CB1R antagonist drug. 3. The use of claim 1 or 2, wherein the amount of the endogenous cannabinoid ligand in the blood sample isolated from the patient is measured and the amount present indicates whether the patient is likely to benefit from the CB1R antagonist treatment. 4. The use of claim 3, wherein the patient is selected from a group of patients who are overweight or obese. 5. The use of claim 2, wherein if the patient has a high circulating amount of endogenous cannabinoid ligand, it may benefit from treatment with a CB丨R antagonist. 6. The use of any of the claims, wherein the endogenous cannabinoid system is AEA or 2-AG. 7. The use of any one of the claims, wherein the content of at least two endogenous cannabinoid ligands is determined. 8. The use of claim 7 wherein the at least two endogenous cannabis ligands 3 3: a biomarker synthesis score (C0nip0Site score) is produced. 9. The use of any of the preceding claims for the selection of a patient who is eligible for clinical trials of a cb1r antagonist drug or for a patient selected for treatment with a CB1R antagonist drug. The use according to any of the preceding claims, wherein the CB1R antagonist is selected from 132387.doc 200914046 from: rimonabant, taranabant, surinabant, CP945598 and SLV319. The use according to any one of claims 1 to 9, wherein the CB1R antagonist is selected from the group consisting of: 1-propanesulfonic acid 3,3,3-trifluoro-4-[l-(2,4 -dichlorophenyl)_3_[[(2-ylcyclohexyl)amino]carbonyl]-4-(hydroxymethyl)-imbazole-5-yl]phenyl]' 1-propylidene acid 3 , 3,3-Trifluoro-4-[3-[(cyclohexylamino))yl]_ι_(2,4-diphenyl)-4-(hydroxyindenyl)-1Η-. Biazo-5-yl]phenyl vinegar; l propane sulfonic acid 3,3,3-trifluorodichlorophenyl)_4,5,6,7-tetrahydro_3_methyl_4_oxo (οχο) -5-(1·hexahydropyridyl)_1H_pyrrolo[3,2_^pyridin-2-yl]phenyl ester; 1-propanesulfonic acid 3,3,3-trifluorodichlorophenyl)-4 -mercapto-3-[(l-hexahydro)pyridylamino)carbonyl]_1Η_βpyrazole-5-yl]phenyl ester; 1-propanesulfonic acid 4-[1-(2,4-dichloro Phenyl)_4_methyl...-[(丨^hydropyridylamino)carbonyl]-1Η-pyrazole-5-yl]phenyl ester; 3,3 3 trifluoropropan-1-pyrimidine 4-[2-(2,4-dioxaphenyl)_5-methyl, hexafluoroaminocarbamimidyl imidazol-1-yl]phenyl ester; and 3,3,3_ Sulfonic acid 4-[1-(2-chloro-4-fluoro-4-,-yl-4,5,6,7-tetrahydro-1H-0, its pharmaceutically acceptable salt. Where the mammal is a human. 12. The method of selecting a cannabinoid receptor (CBlR) to antagonize a milk animal, the endogenous cannabinoid with a j reaction is high. 13. The method of claim 12, 132387.doc 200914046 14. The method of claim 12, wherein the mammal requires weight loss and/or reset maintenance and/or prevention of weight gain treatment. 15. The method of claim 12, 13 or 14, wherein if the mammal has a high circulating content of endogenous cannabinoid ligand, it has an increased likelihood of a drug response to the cbir antagonist. The method of any one of claims 12 to 15, wherein the content of the endogenous cannabinoid ligand is detected by immunoassay. 17. The method of claim 16, wherein the immunoassay is selected from the group consisting of: enzyme-linked immunosorbent assay (ELISA/EIA), radioimmunoassay (RIA), fluorescent immunoassay, luminescence immunoassay, electrochemiluminescence immunoassay, and Combination of immunoassay and mass spectrometry based on SELDI. The method of any one of claims 12 to 17, wherein the detection is carried out by using an AEA degrading enzyme, a fatty acid indoleamine hydrolase (FAAH) and/or a 2-AG degrading enzyme, a monomercaptoglycerol lipase The amount of proven cannabis ligand. 19. A method of stratifying a population of patients to identify one or more patients treated with a CB1R antagonist drug comprising 'determining one or more circulating endocannabinic ligands present in blood previously isolated from such patients Quantity or content. 20. The method of claim 19, wherein the group of patients is an overweight or obese individual. 21. A method of inducing weight loss and/or weight maintenance and/or weight gain in a patient in need thereof, comprising determining the content of the patient-one or more circulating endogenous cannabinoid ligands and based on the detected endogenous source The amount of cannabinoid ligand is chosen to select the appropriate therapy. 22. The method of claim 21, wherein the patient is treated with a CB1R antagonist drug if the patient has a high content of circulating l323S7.doc 200914046 source cannabis ligand The method wherein the CB1R antagonist system, Surinameban, CP945598 and SLV319. A compound selected from the group consisting of 1-propenic acid 3,3,3-difluoro-4-[l-(2,4-dichlorophenyl)_3_[[(2-hydroxycyclohexyl)amino]carbonyl ]-4-(hydroxymethyl)_1Η_Π比唑_5_yl]phenyl ester; 1-propanesulfonic acid 3,3,3-trifluoro_4-[3-[(cyclohexylamino)carbonyl] 2,4-dichlorophenyl)-4-(hydroxymethyl)_ιΗ_π-biazole-5-yl]phenyl ester; ^propanone acid 3,3,3-trifluoro-4-[l-(2 ,4-dichlorophenyl)_4,5,6,7-tetrahydro-3-indolyl-4-oxo-5-(1-hexahydropyridyl)_ih-pyrolo[3,2-c Pyridin-2-yl]phenyl ester; 1-propanesulfonic acid 3,3,3-trifluoro-4-[l-(2,4-dichlorophenyl)-4-methyl-3-[( L-hexahydron-pyridylamino)carbonyl]-lH-nbiazol-5-yl]phenyl ester; 1-propanesulfonic acid 4-[1-(2,4-dichlorophenyl)-4- Methyl-3-[(l-hexahydropyridylamino)carbonyl]-1H-. Biazo-5-yl]phenyl ester; 3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(six Hydrogen n-pyridyl-l-ylaminoindenyl)imidazol-1-yl]phenyl ester; and 3,3,3-trifluoropropane-1-sulfonic acid 4-indole-(2-chloro-4- Phenyl)-3-mercapto-4-oxo-5-hexahydro 0-pyridyl-1-yl-4,5,6,7-tetrahydroindeno[3,2-c]n ratio bite -2-yl] styrene vinegar, or a pharmaceutically acceptable salt thereof. 132387.doc