Use of 5-methoxy-2-aminoindan ("MEAI") in methods for treating metabolic syndrome

Abstract

The present invention relates to a method for treating a metabolic condition, comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan or a salt thereof. The present invention also relates to a method for treating a metabolic condition, comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 408,683, filed September 21, 2022, the contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates, inter alia, to methods of treating metabolic conditions and associated syndromes by administering a therapeutically effective amount of 5-methoxy-2-aminoindan ("MEAI"), hi certain embodiments, the treatment method comprises administering a combination of MEAI and one or more N-acylethanolamines, such as palmitoylethanolamide ("PEA"). [Background technology]

[0003] Background of the Invention Obesity is a chronic disease of epidemic proportions, with over one-third of US adults (34.9% or 78.6 million) considered obese. Obesity has been implicated as a catalyst for several conditions, most notably cardiovascular disease, type 2 diabetes mellitus (T2DM), and nonalcoholic fatty liver disease (NAFLD). Several metabolic factors have been associated with the development of obesity, but the precise molecular mechanisms involved are not fully understood.

[0004] Furthermore, despite the importance of obesity and its complications, only a few anti-obesity drugs are on the market. The etiology of obesity has been attributed to eating behavior or fast food, personality issues, depression, or genetic characteristics. Food addiction is one of the emerging hypotheses regarding the current growing obesity epidemic, which is often associated with both substance-related disorders and eating disorders (most notably overeating). There is evidence that excessive consumption of sugary, palatable foods increases extracellular dopamine in the striatum and has addictive potential. Furthermore, several biological and psychological similarities have been observed between food addiction and drug addiction, including craving and loss of control. Summary of the Invention [Problem to be solved by the invention]

[0005] Nevertheless, there remains a need for improved treatment options, as evidenced by the limited treatment options for obesity and other metabolic disorders. [Means for solving the problem]

[0006] Summary of the Invention In one embodiment, a method for treating a metabolic condition, e.g., one associated with one or more of metabolic syndrome, is provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically acceptable amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, thereby treating the metabolic condition. In one embodiment, the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 to about 520 mg. In another embodiment, the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 to about 40 mg.

[0007] In some embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg. In other embodiments, the dose is administered as a single dose or more than one divided dose. In other embodiments, the dose is administered daily in a single dose or more than one divided dose. In some embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice daily.

[0008] In certain embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is in the range of about 0.0084 to about 0.67 mg / kg body weight / day, about 0.33 to about 8.67 mg / kg body weight / day, about 0.33 to about 1.67 mg / kg body weight / day, about 0.42 to about 1.5 mg / kg body weight / day, about 0.5 to about 1.33 mg / kg body weight / day, about 0.67 to about 1.17 mg / kg body weight / day, or about 0.83 to about 1.0 mg / kg body weight / day.

[0009] In certain embodiments, the administered pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In certain embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, concentrate, suspension, or syrup. In certain embodiments, the pharmaceutical composition is a unit-dosage composition. In certain embodiments, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in the unit-dosage form is about 20 to about 520 mg, about 0.5 to about 40 mg, about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg. In certain embodiments, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

[0010] In some embodiments, administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation. In some embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous.

[0011] In some embodiments, the treatment of metabolic conditions, such as those associated with one or more of metabolic syndrome, comprises administering a pharmaceutical composition comprising a therapeutically acceptable amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and separately, simultaneously, or together administering an N-acylethanolamine or a pharmaceutically acceptable salt thereof, thereby treating the metabolic disorder.The N-acylethanolamine or a pharmaceutically acceptable salt thereof can be the same or a different pharmaceutical composition as the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 to about 1800 mg. In some embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg. In other embodiments, this dose is administered as a single dose or more than one divided dose. In other embodiments, this dose is administered as a single dose or more than one divided dose daily. In some embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered twice daily.

[0013] In certain embodiments, the 5-methoxy-2-aminoindan and the N-acylethanolamine can be administered in a molar ratio ranging from about 1:0.2 to about 1:2000.

[0014] In some embodiments, the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutyramide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), salts thereof, and any combination thereof. Each possibility represents a separate embodiment of the present invention. In some embodiments, the N-acylethanolamine is PEA or a salt thereof. In some embodiments, the N-acylethanolamine consists of PEA or a salt thereof. In some embodiments, the N-acylethanolamine consists of PEA.

[0015] In certain embodiments, the therapeutically effective amount of an N-acylethanolamine or a pharmaceutically acceptable salt thereof is in the range of about 2.5 to about 36.0 mg / kg body weight / day, about 3.12 to about 31.0 mg / kg body weight / day, about 3.75 to about 24.0 mg / kg body weight / day, about 4.38 to about 19.0 mg / kg body weight / day, about 5.0 to about 14.0 mg / kg body weight / day, about 5.62 to about 12.0 mg / kg body weight / day, or about 6.25 to about 11.0 mg / kg body weight / day.

[0016] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or additive.In certain embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, concentrated liquid, suspension or syrup.In some embodiments, the pharmaceutical composition is a unit-dosage composition.

[0017] In some embodiments, administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation. In some embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous.

[0018] In some embodiments, administration is oral, mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, or parenteral. In some embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous.

[0019] In some embodiments, the treatment of metabolic conditions comprises one or more of the following: alleviating one or more of metabolic syndrome, for example, reducing blood pressure, reducing blood sugar, reducing abdominal fat, normalizing abnormal cholesterol or triglyceride levels, reducing obesity, reducing overweight, reducing body weight, increasing lean body mass, reducing body fat mass, reducing adiposity, increasing energy expenditure, improving glycemic control, reducing fatty liver, reducing sugar intake, reducing food intake, maintaining glucose homeostasis, reducing dyslipidemia or maintaining liver function.In some embodiments, improving glycemic control comprises one or more of the following: improving glucose metabolism, reducing fasting blood glucose level or reducing insulin level.In some embodiments, increasing energy expenditure comprises one or more of the following: increasing oxygen consumption and carbon dioxide excretion, increasing fat oxidation or increasing locomotor activity.

[0020] In some embodiments, improving metabolic syndrome comprises reducing obesity. In some embodiments, treating metabolic syndrome comprises reducing overweight associated with obesity. In some embodiments, treating metabolic syndrome preserves lean body mass in a subject. In some embodiments, treating metabolic syndrome reduces body fat mass in a subject. In some embodiments, treating metabolic syndrome reduces adiposity in a subject.

[0021] In some embodiments, improving metabolic syndrome comprises increasing energy expenditure. In some embodiments, treating metabolic syndrome increases energy expenditure without altering food consumption. In some embodiments, treating metabolic syndrome increases energy expenditure and increases fat utilization. In some embodiments, treating metabolic syndrome increases energy expenditure and normalizes locomotor activity without overstimulatory effects.

[0022] In some embodiments, improving metabolic syndrome includes improving glycemic control. In some embodiments, treating metabolic syndrome includes ameliorating hyperglycemia, glucose intolerance, or hyperinsulinemia. In some embodiments, treating metabolic syndrome includes treating fatty liver. In some embodiments, treating fatty liver includes one or more of reducing liver lipid accumulation, liver triglyceride level, or liver cholesterol level. In some embodiments, treating metabolic syndrome includes maintaining glucose homeostasis. In some embodiments, maintaining glucose homeostasis includes one or more of increasing glucose tolerance, attenuating insulin resistance, reducing dyslipidemia, or reducing liver lipid accumulation.

[0023] In certain embodiments, a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is used for the treatment of metabolic syndrome according to any of the previous embodiments.

[0024] In certain embodiments, a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and palmitoylethanolamide or a pharmaceutically acceptable salt thereof is used for the treatment of metabolic syndrome according to any of the previous embodiments. [Brief explanation of the drawings]

[0025] The foregoing summary and the following detailed description of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, the accompanying drawings depict some, but not all, of alternative embodiments. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown. These drawings, which are incorporated in and constitute a part of this specification, help to explain the principles of the invention.

[0026] [Figure 1]The acute effects of MEAI administration on food intake patterns and energy utilization are shown. Shown are the experimental design (Figure 1A), cumulative food intake and summed food intake (Figure 1B, C), cumulative water intake and summed water intake (Figure 1D, E), respiratory exchange ratio (RER) (Figure 1F), oxygen consumption rate (Figure 1G), carbon dioxide excretion rate (Figure 1H), total energy expenditure (TEE) (Figure 1I, J), fat oxidation (Figure 1K), and carbohydrate oxidation (Figure 1L). Data represent the mean ± SEM from 6–8 mice per group. *P<0.05 vs. vehicle-treated group.

[0027] [Figure 2] Acute changes in activity profile after MEAI administration are shown. Shown are total ambulatory activity (Figure 2A), ambulatory movement (Figure 2B), walking speed (Figure 2C), wheel running distance (Figure 2D), and total step counts (Figure 2E). Data represent the mean ± SEM from 6–8 mice per group. *P<0.05 vs. vehicle-treated group.

[0028] [Figure 3]

[0033] Figure 1 shows the acute effect of MEAI on sweet taste preference. Shown is the percentage preference for sucrose compared to sterile water over the 48-hour test period. Data represent the mean ± SEM from 8 mice / group. *P<0.05 vs. vehicle-treated group.

[0029] [Figure 4] We demonstrate that chronic administration of MEAI attenuates obesity-associated weight gain and body composition changes. Shown are the experimental design for testing the efficacy of MEAI in the HFD-induced obesity model (Figure 4A), the change in body weight over time (Figure 4B), total body weight at the end of the experiment (Figure 4C), total body weight change at the end of the experiment (Figure 4D), lean body mass percentage of total body weight (Figure 4E), lean body mass in grams (Figure 4F), fat mass percentage of total body weight (Figure 4G), and fat mass in grams (Figure 4H). Data represent the mean ± SEM from 8–11 mice / group. *P<0.05 vs. STD vehicle; #P<0.05 vs. HFD vehicle.

[0030] [Figure 5] The effects of chronic MEAI administration on food consumption and energy metabolism are shown. Shown are hourly food consumption (Figure 5A), cumulative food consumption, total food consumption in grams / day, total food consumption in kcal / day (Figure 5B, C, D), cumulative water intake (Figure 5E), respiratory exchange ratio (RER) (Figure 5F), oxygen consumption rate (Figure 5G), carbon dioxide excretion rate (Figure 5H), total energy expenditure rate (Figure 5I, J), fat oxidation (Figure 5K), and carbohydrate oxidation (Figure 5L). Data represent the mean ± SEM from 8–11 mice / group. *P<0.05 vs. STD vehicle; #P<0.05 vs. HFD vehicle.

[0031] [Figure 6] Locomotor activity after chronic MEAI administration in HFD-induced obese mice is shown. Shown are the 24-hour time course of locomotor activity (Figure 6A), ambulatory movement (Figure 6B), ambulatory movement speed (Figure 6C), total distance traveled (Figure 6D), wheel running distance (Figure 6E), wheel speed (Figure 6F), and a chart showing the percentage of time mice spent engaged in various activities (Figure 6G). Data represent the mean ± SEM from 8–11 mice / group. *P<0.05 vs. STD vehicle; #P<0.05 vs. HFD vehicle.

[0032] [Figure 7] The effects of chronic MEAI administration on glucose tolerance and insulin sensitivity are shown. Shown are blood glucose levels in a glucose tolerance test (Figure 7A), area under the curve (AUC) values ​​in a glucose tolerance test (Figure 7B), blood glucose percentages in an insulin tolerance test (Figure 7C), AUC values ​​in an insulin tolerance test (Figure 7D), fasting blood glucose levels (Figure 7E), serum insulin levels (Figure 7F), homeostasis model assessment of insulin resistance (HOMA-IR) values ​​(Figure 7G), and insulin sensitivity index (ISI) values ​​(Figure 7H). Data represent the mean ± SEM from 8–11 mice / group. *P<0.05 vs. STD vehicle; #P<0.05 vs. HFD vehicle.

[0033] [Figure 8]Circulating lipid profiles after MEAI treatment are shown. Shown are HDL levels (Figure 8A), LDL levels (Figure 8B), HDL-to-LDL ratio (Figure 8C), cholesterol levels (Figure 8D), and triglyceride levels (Figure 8E). Data represent the mean ± SEM from 8–11 mice / group. *P<0.05 vs. STD vehicle; #P<0.05 vs. HFD vehicle.

[0034] [Figure 9] Effect of MEAI on kidney weight and function. Shown are kidney weight (Figure 9A), kidney-to-body weight ratio (Figure 9B), and BUN measured with a COBAS chemistry analyzer (Figure 9C). Data represent the mean ± SEM from 8–11 mice / group. *P<0.05 vs. STD vehicle; #P<0.05 vs. HFD vehicle.

[0035] [Figure 10] We demonstrate that MEAI ameliorates obesity-associated fatty liver. Shown are liver sample weights (Figure 10A), liver weight-to-body weight ratios (Figure 10B), ALT levels (Figure 10C), AST levels (Figure 10D), ALP levels (Figure 10E), liver triglyceride content (Figure 10F), liver cholesterol content (Figure 10G), Oil Red O-stained area percentage (Figure 10H), and Oil Red O-stained samples showing hepatocyte lipid vacuoles (Figure 10I) after chronic treatment with MEAI compared to vehicle. Data represent the mean ± SEM from 8–11 mice / group. *P<0.05 vs. STD vehicle; #P<0.05 vs. HFD vehicle. DETAILED DESCRIPTION OF THE INVENTION

[0036] Detailed Description of the Invention Compounds derived from 2-aminoindan may be used in the methods disclosed herein. Such compounds have been shown to selectively bind to dopamine D3 receptors. U.S. Patent 5,708,018 discloses several 2-aminoindan derivatives and hypothesizes that these 2-aminoindan derivatives may be useful in treating CNS disorders associated with dopamine D3 receptors. One such compound is 5-methoxy-2-aminoindan ("MEAI"), whose formula is: [ka] is.

[0037] Other 2-aminoindan derivatives that may be used in the present invention are those of formula I:

[0038] [ka] and the compound may be represented by

[0039] wherein each of R and R is independently selected from the group consisting of H, (C-C)alkyl, (C-C)alkenyl, (C-C)alkynyl, (C-C)cycloalkyl, aryl, heteroaryl, heteroalicyclic, —O(C-C)alkyl, OH, —OSOCF, —OSO—(C-C)alkyl, —SOR, —COR, —CONR, —COR, —CF, CN, —SR, —SONR, —SOR, —OCO—(C-C)alkyl, —NCO—(C-C)alkyl, —CHO—(C-C)alkyl, —(C-C)alkyl-OH, —NHSOR, and halogen; or R and R together with two or more of the phenyl carbon atoms form —X—(CRR) m -X2 ring, wherein each of X1 and X2 is independently selected from C, O, NH, or S, and m is 1, 2, 3, or 4;

[0040] Each of R3 and R4 is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, and -(CH2) p -thienyl, where p is 1, 2, 3, or 4, or R3 and R4 together form a heterocyclic ring (heteroalicyclic or heteroaryl) containing the nitrogen atom to which they are attached; and

[0041] Each of R5 and R6 is independently selected from the group consisting of H, (C1-C8) alkyl, (C2-C8) alkenyl, (C3-C8) cycloalkyl, and aryl.

[0042] In certain embodiments, the 2-aminoindan derivatives represented by Formula I presented herein are defined as follows:

[0043] Each of R1 and R2 is independently selected from the group consisting of H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, aryl, -OCH3, OH, -OSO2CF3, -OSO2CH3, -SOR5, -CO2R5, -CONR5R6-COR5, -CF3, -CN, -SR5, -SON2NR5R6, -S02R5, -CH2-OH, halogen, phthalimidyl, thiophenyl, pyrrolyl, pyrrolinyl, oxazolyl, or R1 and R2 together with two or more of the phenyl carbon atoms are -O(CH2) m forming an O ring, where m is 1 or 2;

[0044] R3 and R4 together with the nitrogen atom to which they are attached form a heterocyclic ring containing 4 to 8 carbon atoms; and

[0045] Each of R5 and R6 is independently selected from the group consisting of H, (C1-C8) alkyl, (C2-C8) alkenyl, and (C3-C8) cycloalkyl.

[0046] Non-limiting examples of 2-aminoindan derivatives include: (1) 5-Methoxy-2-aminoindan; (2) 5,6-dimethoxy-2-aminoindan: (3) 5-methoxy-2-(N-propylamino)indan; (4) 5,6-dimethoxy-2-(N-propylamino)indan; (5) 5,6-dimethoxy-2-(di-N-butylamino)indan; (6) 5-(trifluoromethylsulfonyloxy)-6-hydroxy-2-(di-N-propylamino)indan; (7) 5-(trifluoromethylsulfonyloxy)-2-(N-propylamino)indan; (8) 5,6-(di-trifluoromethylsulfonyloxy)-2-(N-propylamino)indan; (9) 5,6-dimethoxy-2(pyrrolidino)indan; (10) 5-(trifluoromethylsulfonyloxy)-6-acetoxy-2-(di-N-propylamino)indan; (11) 5-trifluoromethanesulfonyloxy-6-methoxy-2-(di-N-propylamino)indan; (12) 5,6-ethylenedioxy-2-(di-N-propylamino)indan; (13) 5,6-methylenedioxy-2-(di-N-propylamino)indan; (14) 5-hydroxy-2-(n-propylamino)indan; (15) 5,6-dihydroxy-2-(n-propylamino)indan; (16) 4-methyl-2-aminoindan; (17) 4,5-di-methyl-2-aminoindan; (18) 5,6-di-methyl-2-aminoindan; (19) 6-methyl-2-aminoindan; (20) 4-fluoro-2-aminoindan; (21) 5-(i-propyl)-2-aminoindan; (22) 4,6-dimethyl-2-aminoindan; (23) 4,7-dimethyl-2-aminoindan; (24) 5-(t-butyl)-2-aminoindan: (25) 5-propyl-2-aminoindan; (26) 5-fluoro-2-(di-N-propylamino)indan; (27) 6-methylenedioxy-2-(di-N-propylamino)indan: (28) 5,6-dimethoxy-2(pyrrolidino)indan; (29) 5,6-(di-carbomethoxy)-2-(di-N-propylamino)indan; (30) 5-(carbomethoxy)-6-hydroxy-2-(di-N-propylamino)indan; (31) 5-bromo-2-(dipropylamino)indan; (32) (6-Methylsulfanyl-indan-2-yl)-dipropyl-amine; (33) (6-Methylsulfonyl-indan-2-yl)-dipropyl-amine; (34) (6-Methylsulfinyl-indan-2-yl)-dipropyl-amine; (35) 2-Dipropylamino-indan-5-carbaldehyde; (36) (5-Iodo-indan-2-yl)-dipropyl-amine; (37) (4-Iodo-indan-2-yl)-dipropyl-amine; (38) Toluene-4-sulfonic acid 2-dipropylamino-indan-5-yl ester; (39) Toluene-4-sulfonic acid 2-dipropylamino-6-hydroxy-indan-5-yl ester; (40) N-[2-(benzyl-propylamino)-indan-5-yl]-4-methylbenzene-sulfonamide; (41) N-[2-(benzyl-propyl-amino)-indan-5-yI]methanesulfonamide; (42) 2-[2-(benzyl-propyl-amino)-indan-5-yl]-isoindole-1,3-dione; (43) Benzyl-propyl-(6-pyrrol-1-yl-indan-2-yl)-amine; (44) Propyl-(6-pyrrol-1-yl-indan-2-yl)-amine; (45) Propyl-(6-pyrrolidin-1-yl-indan-2-yl)-amine; (46) Dipropyl-(6-pyrrolidin-1-yl-indan-2-yl)-amine; (47) Cyclopropanecarboxylic acid-[2-(benzyl-propyl-amino)-indan-5-yl]acetamide; (48) N-[2-(benzyl-propyl-amino)-indan-5-yl]propionamide; (49) N-[2-(benzyl-propyl-amino)-indan-5-yl]-2,2-dimethylpropionamide; (50) 5-(2-propenyloxy)-2-(di-N-propylamino)-indan; (51) 5,6-di-toluenesulfonyloxy-2-(di-N-propylamino)indan; (52) 5-methanesulfonyloxy-2-(di-N-propylamino)indan; (53) 5-Carbomethoxy-2-(di-N-propylamino)indan; (54) 5-carboxamido-2-(di-N-propylamino)indan; (55) 5,6-di-trifluoromethanesulfonyloxy-2-(propylamino)indan; (56) 4-methyl-2-(di-N-propylamino)indan; (57) 4,5-Dimethyl-2-(di-N-propylamino)indan; (58) 5,6-Dimethyl-2-(di-N-propylamino)indan; (59) 5-methyl-2-(di-N-propylamino)indan; (60) 4-fluoro-2-(N-propyl)aminoindan; (61) 5-(i-propyl)-2-(di-N-propylamino)indan; (62) 5-(i-propyl)-2-(N-propylamino)indan; (63) 4,6-dimethyl-2-(di-N-propylamino)indan; (64) 4,7-dimethyl-2-(di-N-propylamino)indan; (65) 5-propyl-2-(di-N-propylamino)indan; (66) 5-(t-butyl)-2-(di-m-propylamino)indan; (67) 5-trifluoromethyl-2-(di-N-propylamino)indan; (68) 5-sulfoxamido-2-(di-N-propylamino)indan; (69) 5-(3-thiophene)-2-(di-N-propylamino)indan; (70) 5-ethynyl-2-(di-N-propylamino)indan; (71) 5-acetyl-2-(di-N-propylamino)indan; (72) 5-cyano-2-(di-N-propylamino)indan; (73) 5-Carbomethoxy-6-acetoxy-2-(di-N-propylamino)indan; (74) 5-Carbomethoxy-6-trifluoromethanesulfonyloxy-2-(di-N-propylamino)indan; (75) 5-Carbomethoxy-6-methoxy-2-(di-N-propylamino)indan; (76) 5-formyl-6-methoxy-2-(di-N-propylamino)indan: (77) 5-hydroxymethyl-6-methoxy-2-(di-N-propylamino)indan; (78) 5-carboxy-6-methoxy-2-(di-N-propylamino)indan; (79) 5-acetyl-6-methoxy-2-(di-N-propylamino)indan; (80) 5-Carboxamido-6-methoxy-2-(di-N-propylamino)indan; (81) 5-ethynyl-6-methoxy-2-(di-N-propylamino)indan: (82) 5-cyano-6-methoxy-2-(di-N-propylamino)indan; and (83) 5,6-Di-(hydroxymethyl-2-(di-N-propylamino)indan.

[0047] In certain embodiments described herein, the 2-aminoindan derivative represented by Formula I is any of compounds (1)-(13) above, wherein the phenyl moiety is substituted with one or two -OCH3 or -OSO2CF3 groups or has -O(CH2) fused thereto. m They retain the O ring, where m is 1 or 2. The structural formulas of compounds 1-13 are shown in Table A below.

[0048] [Table 1] [Table 2]

[0049] N-acylethanolamines (NAEs) are a type of fatty acid amide lipid-derived signaling molecule. They are formed when one of several types of acyl groups is attached to the nitrogen atom of ethanolamine. While these amides could conceptually be synthesized from fatty acids and ethanolamine with the removal of a water molecule, known biological synthesis uses specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamine. Examples of N-acylethanolamines include anandamide (an amide of arachidonic acid (20:4 omega-6) and ethanolamine), N-palmitoylethanolamine (an amide of palmitic acid (16:0) and ethanolamine), N-oleoylethanolamine (an amide of oleic acid (18:1) and ethanolamine), N-stearoylethanolamine (an amide of stearic acid (18:0) and ethanolamine), and N-docosahexaenoylethanolamine (an amide of docosahexaenoic acid (22:6) and ethanolamine).

[0050] Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl)hexadecanamide; hydroxyethylpalmitamide; palmidrol; N-palmitoylethanolamine; and palmitylethanolamide) is an example of an NAE, an endogenous fatty acid amide that belongs to the nuclear factor agonists. The chemical structure of PEA is: [ka] PEA binds to receptors in the cell nucleus (nuclear receptors) and is associated with chronic pain and inflammation. PEA has been shown to exert diverse biological functions. Studies have shown that it binds to distinct non-CB1 / CB2 receptors, suggesting that PEA utilizes a unique "parallel" endocannabinoid signaling system. This concept is further supported by growing evidence showing that PEA production and inactivation can occur independently of AEA and 2-AG production and inactivation. Most of PEA's biological effects on cells are attributed to its affinity for PPARs (particularly PPAR-alpha and PPAR-gamma). PEA has shown affinity for the cannabinoid-like G-coupled receptors GPR55 and GPR119 and the transient receptor potential vanilloid type 1 receptor (TRPV1). PEA has been shown to possess anti-inflammatory, antinociceptive, neuroprotective, and anticonvulsant properties.

[0051] In various embodiments, disclosed herein are methods for treating metabolic conditions, for example, by alleviating one or more symptoms of metabolic syndrome in general, and more specifically, but not exclusively, for treating obesity, comprising administering to a subject in need thereof a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further comprises administering an N-acylethanolamine or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the present invention also provides preclinical evidence for the effectiveness of MEAI in controlling energy metabolism and alleviating obesity and its related metabolic disorders.In some embodiments, MEAI shows remarkable effectiveness in preventing or alleviating various conditions associated with metabolic syndrome.In addition to reducing adiposity and reducing body weight, MEAI can also maintain glucose homeostasis, reduce dyslipidemia, preserve liver function, and possibly improve fat utilization and oxidation.In some embodiments, MEAI may have the potential as a new treatment option for obesity and its related metabolic disorders.

[0053] Definition: "Metabolic syndrome" refers to a group of symptoms (which may occur together) that increase a subject's risk of or are associated with a metabolic condition, such as obesity, heart disease, stroke, or type 2 diabetes. These symptoms, alone or in combination, include elevated blood pressure, hyperglycemia and / or insulin resistance (type 2 diabetes), excess abdominal body fat and abnormal cholesterol (low HDL and / or high LDL), triglyceride levels with or without fatty liver disease, obesity, overweight, excess body weight, excess body fat mass, excess adiposity, reduced energy expenditure, abnormal blood glucose control, increased fatty liver, excessive glucose intake, excessive food intake or consumption, abnormal glucose homeostasis, increased dyslipidemia, or abnormal liver function. In some situations, a person exhibiting metabolic syndrome may have excess abdominal body fat and / or be obese.

[0054] "Metabolic conditions" refers to a group of conditions associated with one or more of the metabolic syndrome. Examples of metabolic conditions include obesity, diabetes, diabetes-related obesity, cardiovascular disease, nonalcoholic steatohepatitis, fatty liver disease, or dyslipidemia. Examples of dyslipidemia may include subjects with high cholesterol levels, high triglyceride levels, and / or low HDL / LDL ratios.

[0055] "Overweight" and "obesity" refer to abnormal or excessive fat accumulation that threatens health. "Overweight" refers to a subject who weighs more than is considered healthy for their height and has a body mass index that exceeds a first threshold and is lower than a second threshold. It can be understood that the second threshold is greater than the first threshold. For a human subject, the first threshold body mass index can be 25.0 and the second threshold body mass index can be 30. "Obese" also refers to a subject who weighs more than is considered healthy for their height and has a body mass index that exceeds a second threshold.

[0056] "Type 2 diabetes" refers to a condition in which a subject is unable to process insulin to control blood glucose levels. "Type 2 diabetes" may be understood to develop from or be associated with overweight and / or obesity. Insulin resistance may be measured by known assays (e.g., homeostatic model assessment (HOMA), glucose / insulin ratio, insulin sensitivity test, insulin resistance test, hyperinsulinemic-euglycemic clamp, or any other known assay for determining insulin resistance).

[0057] "Isomers" refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with regard to the arrangement or configuration of the atoms in space.

[0058] "Stereoisomer" or "optical isomer" refers to a stable isomer that has at least one chiral atom or restricted rotation resulting in a perpendicular plane of asymmetry (e.g., certain biphenyl, allene, and spiro compounds) and is capable of rotating plane-polarized light. Due to asymmetric centers and other chemical structures that may be present in the compounds of the present invention that may give rise to stereoisomerism, the present invention contemplates stereoisomers and mixtures thereof. The compounds of the present invention and their salts contain asymmetric carbon atoms and therefore can exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds can be prepared as mixtures of enantiomers and diastereomers, e.g., racemic mixtures. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or stereoisomer-enriched mixtures. As described in more detail below, individual stereoisomers of the compounds are prepared by synthesis from optically active starting materials containing the desired chiral center, or by preparation of a mixture of enantiomeric products followed by separation or resolution, e.g., conversion to a diastereomeric mixture followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of enantiomers on a chiral chromatographic column. Starting compounds of particular stereochemistry are commercially available or may be prepared by the methods described below and resolved by techniques well known in the art.

[0059] It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often differ significantly in biological activity, including pharmacokinetic properties, including metabolism, protein binding, etc., and pharmacological properties, including the type and degree of activity, toxicity, etc. Thus, one skilled in the art will recognize that one enantiomer may be more active or exhibit beneficial effects when enriched relative to or separated from other enantiomers. Furthermore, one skilled in the art will know, from this specification and knowledge of the prior art, how to separate, enrich, or selectively prepare the enantiomers of the compounds of the present invention.

[0060] Thus, while a racemic form of a drug can be used, it is often less effective than administering an equal amount of the enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and merely act as a diluent. For example, ibuprofen was previously administered as a racemate, but only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent. (In the case of ibuprofen, however, the R-isomer is inactive but is converted to the S-isomer in vivo, and therefore the racemic form of the drug acts less rapidly than the pure S-isomer.) Furthermore, the pharmacological activity of enantiomers may have different biological activities. For example, S-penicillamine is a treatment for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over their racemates, such as the reported faster percutaneous penetration of purified individual isomers compared to the racemic mixture. See U.S. Patents 5,114,946 and 4,818,541.

[0061] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds in which the individual compounds of the mixture are present predominantly in the (S)- or (R)-isomeric configuration. For example, the (S)-enantiomeric excess of the compound mixture is greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In other embodiments, the (S)-enantiomeric excess of the compound mixture is from about 55% to greater than about 99.5%, from about 60% to greater than about 99.5%, from about 65% to greater than about 99.5%, from about 70% to greater than about 99.5%, from about 75% to greater than about 99.5%, from about 80% to greater than about 99.5%, from about 85% to greater than about 99.5%, from about 90% to greater than about 99.5%, from about 95% to greater than about 99.5%, from about 96% to greater than about 99.5%, from about 97% to greater than about 99.5%, from about 98% to greater than about 99.5%, from about 99% to greater than about 99.5% or more. In other embodiments, the (R)-enantiomer purity of the compound mixture is greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In certain other embodiments, the (R)-enantiomeric excess of the compound mixture is from about 55% to greater than about 99.5%, from about 60% to greater than about 99.5%, from about 65% to greater than about 99.5%, from about 70% to greater than about 99.5%, from about 75% to greater than about 99.5%, from about 80% to greater than about 99.5%, from about 85% to greater than about 99.5%, from about 90% to greater than about 99.5%, from about 95% to greater than about 99.5%, from about 96% to greater than about 99.5%, from about 97% to greater than about 99.5%, from about 98% to greater than about 99.5%, from about 99% to greater than about 99.5% or more.

[0062] Individual stereoisomers of the compounds of the present invention can be prepared by synthesis from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of racemic mixtures and resolution methods well known to those skilled in the art. Examples of these resolution methods include: (1) coupling the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and liberating the optically pure product from the auxiliary; (2) salt formation using an optically active resolving agent; or (3) direct separation of the optically enantiomeric mixture on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0063] Thus, if one enantiomer is more pharmacologically active, less toxic, or has more favorable properties in the body than the other enantiomer, preferential administration of that enantiomer may be therapeutically beneficial. In this way, the patient undergoing treatment is exposed to a lower total dose of drug and less to the enantiomer that may be toxic or an inhibitor of the other enantiomer.

[0064] As used herein, the naming of compounds, including organic compounds, may be presented using common names, IUPAC, IUBMB, or CAS recommended nomenclature. Those skilled in the art will recognize the naming conventions or CHEMDRAW TM The structure of a compound can be easily verified if the name is provided by systematic abbreviation of the compound structure using commercial software such as PerkinElmer CHEMDRAW (Cambridgesoft Corporation, USA). (登録商標) Created using Professional, version 17.

[0065] The compounds of the present invention may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. The term "stereoisomer," as used herein, consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbols "R" or "S," depending on the arrangement of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. While mixtures of enantiomers or diastereomers are designated by "(±)" in nomenclature, those skilled in the art will recognize that the structure may imply chiral centers. In certain embodiments, enantiomers or stereoisomers may be provided that are substantially free of the corresponding enantiomer.

[0066] In one embodiment, the present invention provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof.

[0067] In another aspect, the present invention provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between MEAI and the N-acylethanolamine is from about 1:0.2 to about 1:2000.

[0068] As used herein, "pharmaceutical composition" refers to a preparation of an active agent described herein and other chemical components, such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier, excipient, or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the compound being administered. Adjuvants are included under this term.

[0069] The term "additive" as used herein refers to an inactive substance added to a pharmaceutical composition to further facilitate the administration of an active ingredient. Examples of additives include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, oils such as vegetable oils or fish oils, and polyethylene glycols.

[0070] As used herein, the term "carrier" refers to a diluent, adjuvant, additive, or vehicle with which a compound is administered. Such pharmaceutical carriers can be sterile liquids such as water and oils. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 18th Edition.

[0071] As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and typically do not produce allergic or similar toxic effects when administered to an individual. Preferably, and particularly when the formulation is for human use, the term "pharmaceutically acceptable" can mean approved by a regulatory authority (e.g., the Food and Drug Administration) or listed in a generally recognized pharmacopoeia (e.g., the United States Pharmacopoeia) for animal use.

[0072] As used herein, the term "N-acylethanolamine" refers to a type of fatty acid amide, a lipid-derived signaling molecule generally formed when one of several types of acyl groups is attached to the nitrogen atom of ethanolamine. While these amides can conceptually be synthesized from fatty acids and ethanolamine with the removal of a water molecule, known biological syntheses use specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamine. The suffixes -amine and -amide in these names refer to the single nitrogen atom of ethanolamine that connects the compound: the "amine" in ethanolamine is so named because it is considered the free terminal nitrogen of the subunit, while the "amide" is called when it is considered to be attached to the adjacent carbonyl group of the acyl subunit. These compounds may be referred to as "amide" or "amine" in this application. The term "ethanolamine" is used in a generic sense and is meant to include mono-ethanolamine, di-ethanolamine, tri-ethanolamine, and mixtures thereof.

[0073] As used herein, the term "derivative" refers to a compound that has the same core structure as or closely mimics an N-acylethanolamine compound, but has chemical or physical modifications, such as different or additional side groups.

[0074] As used herein, the term "salt" refers to any form of an active ingredient in which the active ingredient is considered in ionic form and associated with a counterion (cation or anion) or in solution. It also includes complexes of the active ingredient with other molecules and ions, particularly complexes formed through ionic interactions. Pharmaceutically acceptable salts are known to those skilled in the art.

[0075] In some embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:0.2 to about 1:1000. In some embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:0.2 to about 1:900, about 1:0.2 to about 1:800, about 1:0.2 to about 1:700, about 1:0.2 to about 1:600, about 1:0.2 to about 1:500, about 1:0.2 to about 1:400, about 1:0.2 to about 1:300, about 1:0.2 to about 1:200, about 1:0.2 to about 1:100, about 1:0.2 to about 1:50, about 1:0.2 to about 1:40, about 1:0.2 to about 1:30, about 1:0.2 to about 1:20, or about 1:0.2 to about 1:10. Each possibility represents a separate embodiment of the present invention.

[0076] In some embodiments, the molar ratio of MEAI to N-acylethanolamine is from about 1:0.5 to about 1:2000. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:0.5 to about 1:1000, about 1:0.5 to about 1:900, about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:600, about 1:0.5 to about 1:500, about 1:0.5 to about 1:400, about 1:0.5 to about 1:300, about 1:0.5 to about 1:200, about 1:0.5 to about 1:100, about 1:0.5 to about 1:50, about 1:0.5 to about 1:40, about 1:0.5 to about 1:30, about 1:0.5 to about 1:20, or about 1:0.5 to about 1:10. Each possibility represents a separate embodiment of the present invention.

[0077] In some embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:1 to about 1:2000. In some embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:1 to about 1:1000, about 1:1 to about 1:900, about 1:1 to about 1:800, about 1:1 to about 1:700, about 1:1 to about 1:600, about 1:1 to about 1:500, about 1:1 to about 1:400, about 1:1 to about 1:300, about 1:1 to about 1:200, about 1:1 to about 1:100, about 1:1 to about 1:50, about 1:1 to about 1:40, about 1:1 to about 1:30, about 1:1 to about 1:20, or about 1:1 to about 1:10. Each possibility represents a separate embodiment of the present invention.

[0078] In some embodiments, the pharmaceutical composition contains about 0.5 to 10 mg of MEAI or a salt thereof. In some embodiments, the pharmaceutical composition contains about 1 to 9.5 mg, about 1.5 to 9 mg, about 2 to 8.5 mg, about 2.5 to 8 mg, about 3 to 7.5 mg, about 3.5 to 7 mg, about 4 to 6.5 mg, about 4.5 to 6 mg, or about 5 to 5.5 mg of MEAI or a salt thereof. In some embodiments, the pharmaceutical composition contains about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of MEAI or a salt thereof. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the pharmaceutical composition contains less than about 0.5 mg, less than about 1 mg, less than about 1.5 mg, less than about 2 mg, less than about 2.5 mg, less than about 3 mg, less than about 3.5 mg, less than about 4 mg, less than about 4.5 mg, less than about 5 mg, less than about 5.5 mg, less than about 6 mg, less than about 6.5 mg, less than about 7 mg, less than about 7.5 mg, less than about 8 mg, less than about 8.5 mg, less than about 9 mg, less than about 9.5 mg, or about 10 mg of MEAI or a salt thereof, each possibility representing a separate embodiment of the present invention. In certain embodiments, the pharmaceutical composition contains about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 6.5 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 8.5 mg, about 0.5 mg to about 9 mg, or about 0.5 mg to about 9.5 mg of MEAI or a salt thereof. Each possibility represents a separate embodiment of the present invention.

[0079] In some embodiments, the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a salt thereof. In some embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg, or about 500-550 mg of N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the pharmaceutical composition contains at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, In some embodiments, the composition comprises at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, or at least about 1800 mg of an N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg of an N-acylethanolamine or a salt thereof.Each possibility represents a separate embodiment of the present invention.

[0080] In some embodiments, a pharmaceutical composition comprising MEAI also comprises an N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide a patient with a dose of the N-acylethanolamine or salt thereof from about 2.5 mg / kg body weight / day to about 36 mg / kg body weight / day. In some embodiments, the pharmaceutical composition provides a patient with an N-acylethanolamine or a salt thereof from about 2.5 to about 5 mg / kg body weight / day, from about 5 mg / kg body weight / day to about 7.5 mg / kg body weight / day, from about 7.5 mg / kg body weight / day to about 10 mg / kg body weight / day, from about 10 mg / kg body weight / day to about 12.5 mg / kg body weight / day, from about 12.5 mg / kg body weight / day to about 15 mg / kg body weight / day, from about 15 mg / kg body weight / day to about 17.5 mg / kg body weight / day, from about 17.5 mg / kg body weight / day to about 20 mg / kg body weight / day, or from about 20 mg / kg body weight / day. The N-acylethanolamine or a pharmaceutically acceptable salt thereof is present in a concentration sufficient to provide a dose of about 22.5 mg / kg body weight / day to about 25 mg / kg body weight / day, about 25 mg / kg body weight / day to about 27.5 mg / kg body weight / day, about 27.5 mg / kg body weight / day to about 30 mg / kg body weight / day, about 30 mg / kg body weight / day to about 32.5 mg / kg body weight / day, or about 32.5 mg / kg body weight / day to about 36 mg / kg body weight / day. In certain embodiments, the pharmaceutical composition comprises an N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide a patient with a dose of about 2.5 mg / kg body weight / day, about 5 mg / kg body weight / day, about 7.5 mg / kg body weight / day, about 10 mg / kg body weight / day, about 12.5 mg / kg body weight / day, about 15 mg / kg body weight / day, about 17.5 mg / kg body weight / day, about 20 mg / kg body weight / day, about 22.5 mg / kg body weight / day, about 25 mg / kg body weight / day, about 27.5 mg / kg body weight / day, about 30 mg / kg body weight / day, about 32.5 mg / kg body weight / day, or about 36 mg / kg body weight / day of the N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present invention.In certain embodiments, the pharmaceutical composition comprises an N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide a patient with a dose of about 2.5 mg / kg body weight / day, less than about 2.5 mg / kg / day, less than about 5 mg / kg / day, less than about 7.5 mg / kg / day, less than about 10 mg / kg / day, less than about 12.5 mg / kg / day, less than about 15 mg / kg / day, less than about 17.5 mg / kg / day, less than about 20 mg / kg / day, less than about 22.5 mg / kg / day, less than about 25 mg / kg / day, less than about 27.5 mg / kg / day, less than about 30 mg / kg / day, less than about 32.5 mg / kg / day, or about 36 mg / kg body weight / day of the N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the pharmaceutical composition is administered to a patient in an amount of about 2.5 mg / kg body weight / day to about 5 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 7.5 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 10 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 12.5 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 15 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 17.5 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 20 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 25 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 30 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 35 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 40 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 45 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 50 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 55 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 60 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 65 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 70 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 75 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 80 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 8 and about 22.5 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 25 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 27.5 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 30 mg / kg body weight / day, about 2.5 mg / kg body weight / day to about 32.5 mg / kg body weight / day, or about 2.5 mg / kg body weight / day to about 36 mg / kg body weight / day of N-acylethanolamine or a pharmaceutically acceptable salt thereof, each possibility representing a separate embodiment of the present invention.

[0081] In some embodiments, the N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutyramide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), or a salt thereof, or any combination thereof. Each possibility represents a separate embodiment of the present invention. In some embodiments, the N-acylethanolamine is PEA or a salt thereof. In some embodiments, the N-acylethanolamine consists of PEA or a salt thereof. In some embodiments, the N-acylethanolamine consists of PEA.

[0082] In some embodiments, the administration of a pharmaceutical composition comprising an N-acylethanolamine or its pharmaceutically acceptable salt and the administration of a pharmaceutical composition comprising 5-methoxy-2-aminoindan separately, simultaneously, or together can improve the therapeutic effect of the separate, simultaneous, or combined administrations, compared with the administration of a pharmaceutical composition comprising 5-methoxy-2-aminoindan alone.In some embodiments, the required therapeutic dose of 5-methoxy-2-aminoindan can be reduced when administered together with an N-acylethanolamine, compared with the administration of 5-methoxy-2-aminoindan alone.

[0083] In some embodiments, the pharmaceutical composition is formulated for systemic administration. In some embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of the present invention. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In some embodiments, the pharmaceutical composition is formulated for nasal administration. In some embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0084] Techniques for formulation and administration of drugs are well known in the art and can be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa. The pharmaceutical compositions of the present invention can be prepared by methods well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or lyophilizing processes.

[0085] For oral administration, pharmaceutical compositions can be easily prepared by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers allow the pharmaceutical composition to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by patients. Oral pharmaceutical preparations can be prepared by using solid additives, optionally grinding the resulting mixture, and processing the resulting granular mixture, optionally with the addition of suitable additives, to obtain tablets or dragee cores. Suitable additives include, inter alia, fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, and sodium carbomethylcellulose; and / or physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0086] The term "oral administration" refers to any method of administration in which an active agent can be administered by swallowing, chewing, sucking, or drinking the oral dosage form. Examples of solid dosage forms include conventional tablets, multi-layer tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or oral cavity.

[0087] The sugar-coated core may be provided with a suitable coating.For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.Dyes or pigments may be added to the tablets or sugar-coated coatings for identification or to characterize different combinations of active compound doses.

[0088] Orally usable pharmaceutical compositions include hard or soft, sealed capsules made of gelatin and plasticizers, such as glycerol or sorbitol. The capsules contain the active ingredient mixed with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All formulations for oral administration should be in a dosage appropriate for the chosen route of administration. For buccal and sublingual administration, the compositions may be in the form of tablets or lozenges formulated in conventional manner or with an adhesive carrier. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, such as a sterile, pyrogen-free, water-based solution, before use.

[0089] A pharmaceutical composition suitable for use in the context of the present invention is one in which the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a "therapeutically effective amount" refers to an amount of active ingredients effective to prevent, reduce, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated. Determining a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed description provided herein. More specifically, a "therapeutically effective amount of a mixture" refers to an amount of at least two active ingredients, where each active ingredient may not be independently therapeutically effective, or both active ingredients may not be therapeutically effective, but the mixture is nevertheless effective to prevent, reduce, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated. As used herein, the term "mixture" refers to a non-covalent combination of two molecules.

[0090] For any preparation used in the methods of the present invention, the dosage or therapeutically effective amount can be estimated initially from in vitro, in vivo, and cell culture assays. For example, a dose can be formulated in an animal model to achieve a desired concentration or potency. Such information can be used to more accurately determine useful doses in humans. The dosage of each compound in the combination will depend on several factors, including the method of administration, the disease being treated, the severity of the disease, whether the disease is being treated or prevented, and the age, weight, and health of the person being treated. In addition, pharmacogenomic information (the influence of genotype on the pharmacokinetic, pharmacodynamic, or therapeutic efficacy profile) for a particular patient can influence the dosage used. Daily dosing may not be necessary; the treatment regimen may require drug-free cycles in between, or may provide treatment as needed during periods of acute disease exacerbation. Dose escalation may or may not be necessary; the treatment regimen may require dosage reductions. Toxicity and therapeutic efficacy of the active ingredients described herein may be determined in vitro, in cell culture, or in experimental animals using standard pharmaceutical procedures. The data obtained from these in vitro and cell culture assays and animal studies can be used to formulate a range of dosages for human use. The dosage may vary depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by various physicians in view of the patient's condition (see, for example, Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics," Ch. 1, p. 1). Depending on the severity and responsiveness of the condition to be treated, administration may be single or multiple administrations, with the course of treatment lasting from several days to several weeks, or until a cure is achieved or a desired level of reduction in the disease state is achieved.

[0091] The present invention further provides, in another aspect, a dosage unit comprising or consisting of the above pharmaceutical composition.

[0092] In some embodiments, the dosage unit comprises the pharmaceutical composition. In some embodiments, the dosage unit consists of the pharmaceutical composition. In some embodiments, the dosage unit is formulated as a gel, powder, or spray. In some embodiments, the dosage unit is formulated as a gel. In some embodiments, the dosage unit is formulated as a powder. In some embodiments, the dosage unit is formulated as a spray.

[0093] The present invention further provides, in another aspect, the above pharmaceutical composition or dosage unit for use in a method for the prevention or treatment of a condition that can be prevented or treated by at least one MEAI.

[0094] As used herein, the term "treatment" includes, but is not limited to, any one or more of the following: arresting, ameliorating, preventing, attenuating, reducing, blocking, suppressing, reducing, delaying, halting, alleviating, preventing or slowing the onset of one or more symptoms or side effects of the diseases or conditions of the invention.

[0095] The term "acute" refers to a condition or treatment of relatively short duration.

[0096] The term "chronic" as used herein means that the length of time of the disease or condition or treatment of the present invention may be weeks, months, or perhaps years. The intensity of the disease or condition may be differentiated by various factors such as patient age, temperature, season, disease type, etc.

[0097] As used herein, the term "about" in reference to a value, a plurality of values, or a range of values ​​defined by a minimum and maximum value, means a value that is 10% lower and / or higher than the corresponding value, plurality of values, or range of values. For example, the term "about 1" means "0.9 to 1.1," the term "about 1 or 2" means "0.9 to 1.1 or 1.8 to 2.2," and the term "about 1 to about 2" means "0.9 to 2.2."

[0098] As used herein, the singular includes plural referents unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" can include a plurality of compounds, including mixtures thereof.

[0099] Toxicity and therapeutic efficacy can be measured, for example, by LD 50 (50% lethal dose in the population) and ED 50 The LD50 dose (therapeutically effective dose in 50% of a population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD50 dose is the LD50 dose. 50 / ED 50 Compositions that exhibit large therapeutic indices are preferred.

[0100] Data from cell culture assays or animal studies can be used in formulating a range of dosages for use in humans. Therapeutically effective doses achieved in one animal model can be converted for use in other animals, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the equivalent surface area dosage factors below). [Table 3]

[0101] The dosage of such compounds is preferably ED with little or no toxicity. 50 The circulating concentration range includes the range of 100 to 200 mg / kg of steroids. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. Generally, the therapeutically effective amount may vary depending on the age, condition, and sex of the subject, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted as needed to meet the observed therapeutic effect.

[0102] Those skilled in the art will recognize that both in vivo and in vitro testing using appropriate, known and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0103] Those skilled in the art will further recognize that human clinical trials, including first-in-human, dose-ranging, and efficacy trials in healthy patients and / or those with a disorder, can be accomplished according to methods well known in the clinical and medical arts.

[0104] While the invention has been described with reference to particular embodiments, those skilled in the art will recognize that various changes can be made and equivalents substituted without departing from the scope of the invention. In addition, many modifications can be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is not intended that the invention be limited to the particular embodiments disclosed, but rather, the invention will include all embodiments falling within the scope of the appended claims.

[0105] The following examples are presented in order to more fully illustrate some embodiments of the invention, but should not be construed as limiting the broad scope of the disclosure.

[0106] Example 1: Anti-obesity effect of 5-methoxy-2-aminoindan (MEAI) method Mice. The experimental protocols used were approved by the Hebrew University Animal Care and Use Committee, an AAALAC internationally accredited laboratory. Female 6-week-old C57BL / 6 mice were obtained from Envigo. Animal studies were conducted in accordance with the ARRIVE guidelines, which aim to improve transparency and reproducibility in preclinical research. The number of animals used in this study was minimized by following the principles of utilizing alternative methods, reducing suffering, or reducing use. All animals were housed under specific pathogen-free (SPF) conditions in standard plastic cages, with no more than five animals of the same sex and dose group per cage, and provided with natural soft sawdust bedding.

[0107] Six-week-old female C57BL / 6 mice (Envigo, Israel) were maintained under a 12-hour light / dark cycle and allowed to feed ad libitum. A total of 32 animals were divided into four experimental groups (N = 8 mice / group) and administered a single dose of 40 mg / kg, 60 mg / kg, or 100 mg / kg MEAI or vehicle (sterile water), administered by gavage 2 hours before the dark phase. Animals were monitored for drug tolerability, food and water intake, and activity and metabolic parameters for 48 hours post-dose. At the end of the experiment, animals were sacrificed, and tissues (brain, liver, fat, and kidney) and blood were collected and frozen for further analysis. To produce diet-induced obesity, C57Bl6 / J mice were fed a high-fat diet (HFD) (60% of calories from fat, 20% from protein, and 20% from carbohydrate; Research Diet, D12492) or a standard laboratory chow (STD, 14% fat, 24% protein, 62% carbohydrate; NIH-31 rodent chow) for 18 weeks.

[0108] Effect of MEAI on obesity. Female C57BL / 6 mice were used to establish DIO by feeding a high-fat diet (HFD; 60% kcal fat, 20% kcal protein, and 20% kcal carbohydrate; Research Diet, D12492) for 18 weeks. After this period, mice were treated with vehicle (sterile water, N = 8) or MEAI (N = 11) by gavage daily for 28 days at a dose of 40 mg / kg body weight / day. Age-matched control mice (N = 10) fed a standard diet (STD; 14% kcal fat, 24% kcal protein, 62% kcal carbohydrate; NIH-31 rodent chow) received vehicle daily. Body weights of all mice were monitored daily, and total body fat and lean mass were measured using EchoMRI-100H. TM (Echo Medical Systems LLC, Houston, TX, USA). On day 29, at the end of the experimental period, mice were sacrificed by cervical dislocation under anesthesia. Kidneys, brains, livers, and fat pads were removed and weighed, and samples were either snap-frozen or fixed in buffered 4% formalin. Trunk blood was collected to determine biochemical parameters.

[0109] Sucrose preference test. Individually housed, 13-week-old female C57BL / 6 mice maintained in a standardized diet were acclimated to two water bottles in their home cages for 48 hours prior to testing. Baseline intake was measured by weighing the bottles. On the test day (Day 1), 2 hours before the onset of the dark period, fresh water and a 1.5% sucrose solution were added to the bottles, and mice were orally treated with MEAI (40 mg / kg, N = 8) or sterile water (N = 8). Mice were allowed to drink water ad libitum from either bottle for 24 hours, after which the bottles were weighed to measure consumption. The test was repeated another day (Day 2), with the bottles rotated (within cages) to account for left-right preference. Sucrose and water intakes were averaged over the two days, and a sucrose preference index was calculated by dividing the average sucrose solution consumed by the average volume of total liquid consumed (average water + average sucrose solution).

[0110] Multiparameter metabolic assessment. Mouse metabolic profiles and food and water intake were assessed using the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, NV, USA). Data acquisition and instrument control were performed using MetaScreen software version 2.2.18.0, and the resulting raw data were processed using ExpeData version 1.8.4, with analysis scripts detailing all aspects of data transformation. Mice, which had free access to food and water, were subjected to a standard 12-hour light / 12-hour dark cycle consisting of a 48-hour acclimation period followed by 24-hour sampling. Respiratory gases were measured using a GA-3 gas analyzer (Sable Systems, Inc., Las Vegas, NV, USA) in pull mode using a negative pressure system. Airflow was measured and controlled by an FR-8 (Sable Systems, Inc., Las Vegas, NV, USA) at a set flow rate of 2000 mL / min. Water vapor was measured continuously and mathematically corrected for its dilution effect on O2 and CO2. The respiratory exchange ratio (RER) was calculated using equation (1): RER = VCO2 / VO2(1) was calculated as the ratio of CO2 produced (VCO2) to O2 consumed (VO2) using

[0111] Total energy expenditure (TEE) is calculated using equation (2): TEE=VO2×(3.815+1.232×RER) (2) Calculations were made using VO2 and RER according to the following.

[0112] Fat oxidation (FO) and carbohydrate oxidation (CHO) are expressed as equations (3) and (4), respectively: FO = 1.69 × VO2 - 1.69 × VCO2 (3) CHO = 4.57 × VCO2 - 3.23 × VO2 (4) Calculations were made using VO2 and VCO2 based on the above.

[0113] Wheel running and locomotor activity. Wheel running and locomotor activity were assessed using the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, NV, USA). Wheel running activity was measured with a monitor that recorded spontaneous wheel running activity, and locomotor activity was quantified using an infrared XYZ beam array interruption with a beam spacing of 0.25 cm.

[0114] Glucose tolerance test (ipGTT) and insulin tolerance test (ipITT). On day 25 of the experiment, mice were fasted overnight, and then injected with glucose (1.5 g / kg ip) the next day (day 26). Blood glucose levels were measured using Contour (登録商標)Blood glucose levels were measured at 0, 15, 30, 45, 60, 90, and 120 minutes after injection using a blood glucose meter (Bayer, Pittsburgh, PA, USA). The mice were then fasted for 6 hours the following day (day 27), after which insulin (0.75 U / kg, i.p.; Actrapid vial, Novo Nordisk A / S, Bagsvaerd, Denmark) was administered. Blood glucose levels were determined at the same intervals as above. To assess insulin resistance, homeostatic model assessment insulin resistance (HOMA-IR) was calculated as fasting serum insulin ([μU / mL] × fasting plasma glucose [mmol / L] / 22.5). The relative insulin sensitivity index (ISI) was calculated as 1 / (glucose × insulin) × 1000, with glucose expressed as mg / dL and insulin expressed as mU / L.

[0115] Blood and urine biochemistry. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were determined using a Cobas C-111 chemistry analyzer (Roche, Switzerland). Blood urea nitrogen (BUN) was calculated based on serum urea levels as follows: BUN (mg / dL) = urea (mg / dL) / 2.1428. Fasting blood glucose was measured using the Contour (登録商標) Blood glucose levels were measured using a blood glucose meter (Bayer, Pittsburgh, PA). Serum insulin was determined using an Ultra-Sensitive Mouse Insulin ELISA kit (Crystal Chem, Inc., Elk Grove Village, IL, USA).

[0116] Liver triglyceride and cholesterol content. Liver tissue was extracted as described (Tam et al., 2012), and its cholesterol and triglyceride content was determined using a Cobas C-111 chemistry analyzer (Roche, Switzerland).

[0117] Histopathological diagnosis. First, 5 μm paraffin-embedded liver sections from 5 animals per group were stained with hematoxylin-eosin. Liver images were captured using a Zeiss AxioScope A1 light microscope (Carl Zeiss AG, Jena, Germany) equipped with a Zeiss AxioCam ICc5 color camera. Random 40x magnification fields were then taken from each animal to obtain representative images.

[0118] Oil Red O staining. Liver cryosections (8 μm) were stained with Oil Red O (Cat# ab150678; Abcam) according to the manufacturer's protocol. Images were acquired as described above. For quantitative analysis of Oil Red O staining, the lipid droplet area in liver cryosections was measured using ImageJ software.

[0119] Statistics. Data are presented as mean ± SEM. Statistical analysis was performed using GraphPad Prism 6.0 software (GraphPad Software, CA, USA). Differences between two groups were determined using an unpaired Student's t-test. For comparisons involving multiple groups and time-dependent variables, ANOVA followed by Tukey's multiple test was used. A p-value of less than 0.05 was considered statistically significant.

[0120] result To evaluate the immediate effects of MEAI on food intake patterns and respiratory parameters, a single dose of 40 mg / kg, 60 mg / kg, or 100 mg / kg was administered 2 hours before the onset of the dark period, as shown in Figure 1A. Results showed that the drug was well tolerated at the 40 mg / kg and 60 mg / kg doses, with no observable changes in behavior. However, two subjects in the 100 mg / kg group died within hours of drug administration, indicating reduced tolerance at this dose combined with stress caused by metabolic testing; therefore, they were excluded from the analysis. After MEAI administration, subtle changes in feeding patterns during the active (dark) and inactive (light) periods were observed, but these changes did not reach statistical significance (Figure 1B, C). Furthermore, there was no significant change in water consumption (Figure 1D, E). In contrast, acute MEAI administration resulted in significant changes in respiratory parameters. The increase in RER during the light phase for the 60 mg and 100 mg doses (Fig. 1F) was attributed to increased amounts of oxygen consumption (VO2) and carbon dioxide excretion (VCO2) (shown in Fig. 1G). During the 24-h period examined, a significant dose-dependent increase in TEE (Fig. 1I, J) and corresponding increases in FO and CHO rates (Fig. 1K, L) were evident, indicating an altered energy profile.

[0121] Next, we examined the acute effects of MEAI on activity patterns. Overall, there was no significant change in the total number of beam interruptions recorded, which represent a combination of ambulation and fine motor activity (Figure 2A). Notably, MEAI produced a significant, dose-dependent increase in directed spontaneous activity and speed, such as movement around the cage for eating, drinking, and grooming, at doses of 40 mg / kg and above (Figure 2B, C). While the increase in spontaneous wheel-running patterns at 40 mg / kg and 60 mg / kg was minimal, the 100 mg / kg dose group experienced a significant suppression of wheel-running (Figure 2D). Finally, MEAI increased total step counts at all doses tested (Figure 2E).

[0122] To evaluate the effect of MEAI on sweet taste preference, we used the sucrose preference test (SPT), a commonly used reward-based test for detecting anhedonia. After a single injection, MEAI at a dose of 40 mg / kg significantly reduced the acute preference of mice for sucrose solution without any associated reduction in water intake levels. This effect was prominent during the first 24 hours, with a slight reduction detected over the following 24 hours (Figure 3). These results indicate that MEAI has the potential to disrupt the rewarding stimuli, leading to a reduction in the hedonic effects typically associated with palatable foods.

[0123] The effects of MEAI on food-dependent behavior and its metabolic efficacy in controlling appetite and treating obesity and related disorders were evaluated in the DIO mouse model (Figure 4A). To evaluate the effects of chronic exposure, a suboptimal dose of 40 mg / kg body weight / day of MEAI was tested in this model. At baseline, before drug treatment, HFD-fed mice were significantly heavier than STD-fed controls. Over the 28-day treatment period, MEAI treatment significantly reduced body weight in HFD-fed mice (Figure 4B), with a reduction in total body weight of approximately 15% compared to the obese vehicle-treated group (Figure 4C, D). Thus, MEAI significantly reduced overweight in HFD-fed mice. Furthermore, MEAI treatment significantly reduced adiposity associated with obesity, as measured by lean body mass, lean body mass ratio, and net lean body mass in the DIO model (Figure 4E, F), while simultaneously reducing total body fat mass (Figure 4G, H).

[0124] Analysis of feeding behavior showed that mice on an HFD consumed less food, as indicated by reduced food intake per meal, in both the EAI and vehicle-treated groups (Fig. 5A). However, cumulative food intake over a 24-h period was similar in all groups (Fig. 5B, C), primarily due to the high caloric density of the HFD (Fig. 5D). Furthermore, as seen in the acute setting in lean animals (Fig. 1D, E), MEAI treatment had no effect on water intake in obese mice (Fig. 5E).

[0125] Metabolically, RER was slightly decreased in both the HFD vehicle- and MEAI-treated groups compared with the STD vehicle group (Fig. 5F). MEAI administration slightly increased oxygen consumption and carbon dioxide production compared with the HFD vehicle-treated group (Fig. 5G, H). Notably, the MEAI-treated group significantly increased energy expenditure compared with both the HFD and STD vehicle-treated groups, with clear increases observed during light and dark regimens (Fig. 5I). Regression analysis of TEE versus body mass revealed significant differences between groups independent of body mass (Fig. 5J). Furthermore, MEAI treatment increased the overall rate of FO compared with both the HFD and STD vehicle-treated groups (Fig. 5K). However, CHO was significantly decreased in the vehicle- and MEAI-treated groups, with no effect of the drug itself (Fig. 5L).

[0126] Analysis of locomotor activity showed that MEAI treatment increased spontaneous activities, such as ambulatory behavior and grooming, throughout the day, but more significantly during the dark phase of the day, consistent with their nocturnal nature (Figure 6A). Interestingly, although ambulatory activity, speed, and total distance traveled in the MEAI group increased compared to the HFD-vehicle-treated group, the drug did not exceed the levels of the STD-vehicle-treated group, suggesting that the drug did not induce an overstimulatory effect (Figure 6B-D). A similar behavioral pattern was observed for wheel running, a purely spontaneous activity parameter. MEAI-treated animals showed an increased ability to run spontaneously on the wheel, and their speed was similar to that of the STD-vehicle-treated group (Figure 6E, F). Furthermore, analysis of the time mice spent engaging in various activities in their cages showed that MEAI-treated mice preferred spontaneous activities, such as wheel running, ambulatory behavior, and spending more time at the food and water dispensers (Figure 6G).

[0127] MEAI improves glycemic control in DIO mice. Obesity is a well-known contributor to insulin resistance and hyperglycemia, ultimately leading to the development of diabetes. In the DIO model, substantial impairment in glucose tolerance and increased hyperinsulinemia were observed, as indicated by glucose and insulin resistance test results. However, after treatment with MEAI, significant improvements in glucose metabolism were observed (Figures 7A-D), and fasting blood glucose and insulin levels were also reduced (Figures 7E, F). These beneficial effects of MEAI were also reflected in HOMA-IR and ISI (Figures 7G, ​​H), indicating that MEAI has an impact on glucose metabolism. Furthermore, MEAI normalized insulin sensitivity (Figures 7C and D), demonstrating its beneficial effects on glucose metabolism.

[0128] Treatment with MEAI ameliorates HFD-induced dyslipidemia. To investigate whether MEAI can alleviate dyslipidemia commonly associated with obesity, blood lipid profiles were analyzed. Results showed that treatment with MEAI significantly reduced LDL levels compared with the HFD vehicle group without significantly altering HDL levels. This reduction in LDL levels was accompanied by an increase in the HDL-to-LDL ratio, indicating a beneficial effect on lipid metabolism (Figures 8A-C). Furthermore, although there was a trend toward lower cholesterol levels in the MEAI-treated group (Figure 8D), this change was not statistically significant. However, no significant changes in circulating triglyceride levels were observed in any of the test groups (Figure 8E). These findings suggest that MEAI may have a therapeutic effect on obesity-associated dyslipidemia.

[0129] Initial studies confirming the effect of MEAI on renal function show that after MEAI administration, the kidney-to-body weight ratio normalizes, accompanied by a slight improvement in blood urea nitrogen (BUN) levels (Figure 9A-C).

[0130] MEAI reverses obesity-induced liver dysfunction and hepatic steatosis. Obesity is a well-established factor in the development of NAFLD, characterized by hepatic steatosis due to an imbalance between hepatic fatty acid uptake, synthesis, oxidation, and excretion. Given MEAI's promising effects on body weight, fat oxidation, and circulating lipid levels, we investigated its effects on hepatic steatosis. Findings showed that MEAI treatment reduced liver weight (Figure 10A) and normalized its weight-to-body weight ratio (Figure 10B) in HFD-fed mice. Although MEAI administration did not significantly alter ALT or AST levels compared with the HFD-vehicle group, ALP levels were significantly reduced, suggesting an alleviation of liver injury (Figure 10C-E). Furthermore, treatment with MEAI had a beneficial effect on hepatic lipid accumulation, as evidenced by a significant decrease in hepatic triglycerides and a trend toward decreased hepatic cholesterol levels compared with HFD-vehicle controls (Figure 10F, G). These findings were further supported by the decreased Oil Red O staining and reduced number of lipid vacuoles in MEAI-treated livers compared with HFD vehicle-treated livers (Figures 10H, I). Overall, these findings suggest that MEAI may have beneficial effects on hepatic lipid accumulation and liver function in the setting of obesity-associated NAFLD.

[0131] The many features and advantages of the present invention will be apparent from the detailed description, and it is, therefore, intended by the appended claims to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Further, because numerous modifications and variations will readily occur to those skilled in the art, it is not intended to limit the invention to the exact construction and operation illustrated and described, and therefore, all suitable modifications and equivalents may be made that fall within the scope of the present invention.

[0132] Moreover, those skilled in the art will appreciate that the conception on which the present invention is based may readily be used as a basis for the design of other structures, methods and systems for carrying out the several purposes of the present invention. Accordingly, the claims should not be construed as limited to the foregoing description or examples.

Claims

1. 1. A method of treating a metabolic condition in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically acceptable amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, wherein the treatment reduces one or more symptoms of metabolic syndrome in the subject.

2. 10. The method of claim 1, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a dose of about 20 to about 520 mg.

3. 10. The method of claim 1, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.5 to about 40 mg.

4. 10. The method of claim 1, wherein 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a dose of about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

5. 3. The method of claim 2, wherein the dose is administered as a single dose or as more than one divided dose.

6. 3. The method of claim 2, wherein the dose is administered daily in a single dose or in more than one divided dose.

7. 3. The method of claim 2, wherein 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice daily.

8. 10. The method of claim 1, wherein the therapeutically effective amount is in the range of about 0.0084 to about 0.67 mg / kg body weight / day, about 0.33 to about 8.67 mg / kg body weight / day, about 0.33 to about 1.67 mg / kg body weight / day, about 0.42 to about 1.5 mg / kg body weight / day, about 0. to about 1.33 mg / kg body weight / day, about 0.67 to about 1.17 mg / kg body weight / day, or about 0.83 to about 1.0 mg / kg body weight / day.

9. The method of claim 1, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

10. 10. The method of claim 9, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, concentrate, suspension, or syrup.

11. 11. The method of claim 10, wherein the pharmaceutical composition is a unit dosage composition.

12. 12. The method of claim 11, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in the unit dosage form is from about 20 to about 520 mg, from about 0.5 to about 40 mg, from about 20 to about 100 mg, from about 25 to about 90 mg, from about 30 to about 80 mg, from about 40 to about 70 mg, or from about 50 to about 60 mg.

13. 13. The method of claim 12, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

14. 10. The method of claim 1, wherein administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation.

15. 15. The method of claim 14, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

16. 1. A method of treating a metabolic condition in a subject in need thereof, comprising administering to the subject therapeutically acceptable amounts of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising an N-acylethanolamine or a pharmaceutically acceptable salt thereof, wherein the treatment reduces one or more symptoms of metabolic syndrome in the subject.

17. 17. The method of claim 16, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a dose of about 20 to about 520 mg.

18. 17. The method of claim 16, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.5 to about 40 mg.

19. 17. The method of claim 16, wherein 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a dose of about 20 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

20. 18. The method of claim 17, wherein the dose is administered as a single dose or as more than one divided dose.

21. 18. The method of claim 17, wherein the dose is administered daily in a single dose or in more than one divided dose.

22. 20. The method of claim 19, wherein 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice daily.

23. 17. The method of claim 16, wherein the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is in the range of about 0.0084 to about 0.67 mg / kg body weight / day, about 0.33 to about 8.67 mg / kg body weight / day, about 0.33 to about 1.67 mg / kg body weight / day, about 0.42 to about 1.5 mg / kg body weight / day, about 0. to about 1.33 mg / kg body weight / day, about 0.67 to about 1.17 mg / kg body weight / day, or about 0.83 to about 1.0 mg / kg body weight / day.

24. 17. The method of claim 16, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

25. 25. The method of claim 24, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, concentrate, suspension, or syrup.

26. 26. The method of claim 25, wherein the pharmaceutical composition is a unit dosage form composition.

27. 27. The method of claim 26, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in the unit dosage form is from about 20 to about 520 mg, from about 0.5 to about 40 mg, from about 20 to about 100 mg, from about 25 to about 90 mg, from about 30 to about 80 mg, from about 40 to about 70 mg, or from about 50 to about 60 mg.

28. 28. The method of claim 27, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

29. 17. The method of claim 16, wherein administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation.

30. 30. The method of claim 29, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

31. 31. The method of any of claims 16 to 30, wherein the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutyramide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), salts thereof, and any combination thereof.

32. 32. The method of claim 31, wherein the N-acylethanolamine is palmitoylethanolamide or a pharmaceutically acceptable salt thereof.

33. 33. The method of any of claims 16 to 32, wherein the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 to about 1800 mg, about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg.

34. 34. The method of claim 33, wherein the dose is administered as a single dose or as more than one divided dose.

35. 34. The method of claim 33, wherein the dose is administered daily in a single dose or in more than one divided dose.

36. 36. The method of claim 35, wherein the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered twice daily.

37. 17. The method of claim 16, wherein the therapeutically effective amount of the N-acylethanolamine or a pharmaceutically acceptable salt thereof is in the range of about 2.5 to about 36.0 mg / kg body weight / day, about 3.12 to about 31.0 mg / kg body weight / day, about 3.75 to about 24.0 mg / kg body weight / day, about 4.38 to about 19.0 mg / kg body weight / day, about 5.0 to about 14.0 mg / kg body weight / day, about 5.62 to about 12.0 mg / kg body weight / day, or about 6.25 to about 11.0 mg / kg body weight / day.

38. 38. The method of any of claims 16 to 37, wherein the N-acylethanolamine is administered simultaneously with the 5-methoxy-2-aminoindan.

39. 39. The method of claim 38, wherein the N-acylethanolamine and 5-methoxy-2-aminoindan are administered as a single pharmaceutical composition.

40. 20. The method of claim 1 or 16, wherein administration is by oral, mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal or parenteral route.

41. 41. The method of claim 40, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

42. 42. The method of any of claims 1-41, wherein treating metabolic syndrome involves one or more of lowering blood pressure, lowering blood glucose, reducing abdominal body fat, normalizing abnormal cholesterol or triglyceride levels, reducing obesity, reducing overweight, reducing body weight, increasing lean body mass, reducing body fat mass, reducing adiposity, increasing energy expenditure, improving glycemic control, reducing hepatic steatosis, reducing glucose intake, reducing food intake, maintaining glucose homeostasis, reducing dyslipidemia, or preserving liver function.

43. 43. The method of claim 42, wherein the improved glycemic control comprises one or more of improved glucose metabolism, reduced fasting blood glucose levels, or reduced insulin levels.

44. 43. The method of claim 42, wherein the increased energy expenditure comprises one or more of increased oxygen consumption and carbon dioxide excretion, increased fat oxidation, or increased ambulatory activity.

45. 43. The method of claim 42, wherein treating metabolic syndrome reduces obesity.

46. 46. ​​The method of claim 45, wherein treating metabolic syndrome comprises reducing excess weight associated with obesity.

47. 47. The method of claim 45 or 46, wherein treating metabolic syndrome preserves lean body mass in the subject.

48. 47. The method of claim 45 or 46, wherein treating metabolic syndrome reduces body fat mass in the subject.

49. 47. The method of claim 45 or 46, wherein treating metabolic syndrome reduces adiposity in the subject.

50. 47. The method of claim 45 or claim 46, wherein treating metabolic syndrome increases energy expenditure.

51. 51. The method of claim 50, wherein food consumption remains unchanged.

52. 60. The method of claim 59, wherein fat utilization is increased.

53. 51. The method of claim 50, wherein locomotor activity is normalized without overstimulatory effects.

54. 47. The method of claim 45 or claim 46, wherein treating metabolic syndrome improves glycemic control.

55. 47. The method of claim 45 or claim 46, wherein treating metabolic syndrome ameliorates hyperglycemia, glucose intolerance or hyperinsulinemia.

56. 47. The method of claim 45 or claim 46, wherein treating metabolic syndrome ameliorates fatty liver.

57. 57. The method of claim 56, wherein the improvement in fatty liver comprises one or more of reducing liver lipid accumulation, liver triglyceride levels, or liver cholesterol levels.

58. 47. The method of claim 45 or claim 46, wherein treating metabolic syndrome preserves glucose homeostasis.

59. 59. The method of claim 58, wherein maintaining glucose homeostasis comprises one or more of increasing glucose tolerance, attenuating insulin resistance, reducing dyslipidemia, or decreasing hepatic lipid accumulation.

60. Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof for the treatment of a metabolic condition according to any one of claims 1 to 59.

61. 60. Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and an N-acylethanolamine (e.g., palmitoylethanolamide) or a pharmaceutically acceptable salt thereof for the treatment of a metabolic condition according to any one of claims 16 to 59.

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