TWI707677B - Treatment for obesity - Google Patents

Abstract

The present invention relates to a method for treating or preventing obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds. The invention further relates to methods for reducing body weight and/or reducing food intake in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds.

Description

Obesity treatment [Priority Statement]

This application claims the rights and interests of U.S. Provisional Application Serial No. 61/847,593 filed on July 18, 2013, and the entire contents of which are incorporated herein by reference.

The present invention relates to a method for treating or preventing obesity in a subject in need, including administering to the subject a therapeutically effective amount of certain carbamate compounds. The present invention further relates to a method of reducing weight and/or reducing food intake in a subject in need thereof, including administering to the subject a therapeutically effective amount of certain carbamate compounds.

Obesity is a worldwide health problem that has reached epidemic proportions. As of 2008, the World Health Organization estimates that at least 500 million adults are obese. The United States has the highest obesity rate in the developed world. According to reports, 35.7% of American adults in 2010 were obese. Overweight and obesity are the fifth highest risk of death worldwide.

Obesity is a complex disease affected by genes, diet, exercise and complex biology. Weight loss surgery to reduce the size of the stomach (gastric bypass surgery) is the only effective weight loss treatment for severely obese patients. Drugs used to treat obesity can be divided into three groups: drugs that reduce food intake or appetite suppressants; drugs that alter metabolism or block fat absorption; and drugs that increase thermogenesis. Currently, only two drugs have been approved by the FDA for the long-term treatment of obesity: the fat absorption blocker orlistat (XENICAL ^® ,ALLI ^® ) and the appetite suppressant sibutramine (MERIDIA ^® ) . These drugs cause severe side effects and only achieve a normal weight loss. Therefore, there is an urgent need to find novel obesity treatments.

或其藥學上可接受之鹽或酯；其中R為選自下列者所組成群組之成員：1至8個碳原子之烷基、鹵素、1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及1至3個碳原子之硫烷氧基(thioalkoxy)；x為0至3之整數，其條件為當x為2或3時R可相同或不同；R₁及R₂係獨立選自氫、1至8個碳原子之烷基、芳基、芳烷基、3至7個碳原子之環烷基所組成群組；或R₁及R₂可合起來形成未經取代或經一個或多個烷基或芳基取代之5至7員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不 直接彼此連接或不直接與氧原子連接；其中對象減輕體重，因而治療肥胖。 The present invention provides an effective and convenient method for treating or preventing obesity and helping people lose weight and/or reduce food intake. Therefore, one aspect of the present invention is to treat obesity in a subject in need, including administering to the subject a therapeutically effective amount of a compound of formula (I):

Or a pharmaceutically acceptable salt or ester thereof; wherein R is a member selected from the group consisting of: an alkyl group of 1 to 8 carbon atoms, a halogen, an alkoxy group of 1 to 3 carbon atoms, a nitro group , Hydroxyl, trifluoromethyl and thioalkoxy with 1 to 3 carbon atoms; x is an integer from 0 to 3, provided that when x is 2 or 3, R can be the same or different; R ₁ and R ₂ is independently selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, and cycloalkyl of 3 to 7 carbon atoms; or R ₁ and R ₂ can be combined to form A 5- to 7-membered heterocycle that is unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocycle may include 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms do not directly each other Connected or not directly connected to an oxygen atom; wherein the subject loses weight, thereby treating obesity.

或其藥學上可接受之鹽或酯；其中R為選自下列者所組成群組之成員：1至8個碳原子之烷基、鹵素、1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及1至3個碳原子之硫烷氧基；x為0至3之整數，其條件為當x為2或3時R可相同或不同；R₁及R₂係獨立選自氫、1至8個碳原子之烷基、芳基、芳烷基、3至7個碳原子之環烷基所組成群組；或R₁及R₂可合起來形成未經取代或經一個或多個烷基或芳基取代之5至7員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不直接彼此連接或不直接與氧原子連接；其中對象減輕體重。 Another aspect of the present invention is a method for weight reduction of a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

Or a pharmaceutically acceptable salt or ester thereof; wherein R is a member selected from the group consisting of: an alkyl group of 1 to 8 carbon atoms, a halogen, an alkoxy group of 1 to 3 carbon atoms, a nitro group , Hydroxyl, trifluoromethyl and thioalkoxy of 1 to 3 carbon atoms; x is an integer from 0 to 3, provided that when x is 2 or 3, R may be the same or different; R ₁ and R ₂ are Independently selected from the group consisting of hydrogen, alkyl groups of 1 to 8 carbon atoms, aryl groups, aralkyl groups, and cycloalkyl groups of 3 to 7 carbon atoms; or R ₁ and R ₂ can be combined to form unsubstituted Or a 5- to 7-membered heterocyclic ring substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may include 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected to each other or Directly connected to the oxygen atom; where the subject loses weight.

或其藥學上可接受之鹽或酯；其中R為選自下列者所組成 群組之成員：1至8個碳原子之烷基、鹵素、1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及1至3個碳原子之硫烷氧基；x為0至3之整數，其條件為當x為2或3時R可相同或不同；R₁及R₂係獨立選自氫、1至8個碳原子之烷基、芳基、芳烷基、3至7個碳原子之環烷基所組成群組；或R₁及R₂可合起來形成未經取代或經一個或多個烷基或芳基取代之5至7員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不直接彼此連接或不直接與氧原子連接；其中對象減少食物攝取。 Another aspect of the present invention is a method for reducing food intake for a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

Or a pharmaceutically acceptable salt or ester thereof; wherein R is a member selected from the group consisting of: an alkyl group of 1 to 8 carbon atoms, a halogen, an alkoxy group of 1 to 3 carbon atoms, a nitro group , Hydroxyl, trifluoromethyl and thioalkoxy of 1 to 3 carbon atoms; x is an integer from 0 to 3, provided that when x is 2 or 3, R may be the same or different; R ₁ and R ₂ are Independently selected from the group consisting of hydrogen, alkyl groups of 1 to 8 carbon atoms, aryl groups, aralkyl groups, and cycloalkyl groups of 3 to 7 carbon atoms; or R ₁ and R ₂ can be combined to form unsubstituted Or a 5- to 7-membered heterocyclic ring substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may include 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected to each other or Directly connected to oxygen atoms; where the subject reduces food intake.

In some embodiments of the present invention, the method includes administering to the subject Step of a therapeutically effective dose of the enantiomers of formula (I), and the enantiomers of formula (I) are substantially free of other enantiomers of formula (I), or one of the enantiomers of formula (I) ) A mixture of enantiomers in which the enantiomers account for the majority.

或其藥學上可接受之鹽或酯。 In some specific examples, the compound of formula (I) is a compound of formula (Ia):

Or a pharmaceutically acceptable salt or ester thereof.

或其藥學上可接受之鹽或酯。此化合物命名為胺甲酸(R)-(β-胺基-苯丙基)酯或O-胺甲醯基-(D)-苯丙胺醇及或者稱為ADX-N05、SKL-N05、SK-N05、YKP10A及R228060。 In some specific examples, the compound of formula (I) is a compound of formula (Ib):

Or a pharmaceutically acceptable salt or ester thereof. This compound is named carbamic acid (R)-(β-amino-phenylpropyl) ester or O-aminomethanyl-(D)-amphetamine and is also called ADX-N05, SKL-N05, SK-N05 , YKP10A and R228060.

Specific examples of the present invention include the use of compounds of formula (I) to treat obesity in subjects in need. Other specific examples of the present invention include the use of compounds of formula (I) to reduce body weight and/or food intake of subjects in need.

Specific examples of the present invention include the use of compounds of formula (I) to prepare drugs for treating obesity. Other specific examples of the present invention include the use of compounds of formula (I) to reduce body weight and/or food intake of subjects in need.

The present invention will be described below with reference to the drawings and embodiments, in which specific examples of the invention are shown. However, the present invention can be implemented in many different forms and should not be construed as being limited to the specific examples listed herein. To be more precise, these specific examples are provided to make this disclosure thorough and complete, and to fully convey the scope of the present invention to those with ordinary knowledge in the technical field.

Unless otherwise specified, all technical or scientific terms used herein have meanings commonly understood by those with ordinary knowledge in the field to which the present invention belongs. The terminology used in the present invention described herein is only for the purpose of describing specific examples and is not intended to limit the present invention.

Unless the context indicates otherwise, it should be specifically pointed out that the various features of the invention described herein can be used in any combination. Furthermore, The present invention also includes that in some specific examples of the invention, any feature or combination of features mentioned herein may be excluded or omitted. For example, if the specification states that the composition includes components A, B, and C, it specifically means that any A, B, and C or a combination thereof can be omitted or abandoned alone or in any combination.

definition

As used herein, "a", "an" or "the" can refer to one or more than one. For example, "a (a)" cell means a single cell or a plurality of cells.

Also as used herein, "and/or" means and includes any and all possible combinations of one or more related listed items, and no combination when interpreted as optional ("or").

The term "about", as used herein, when it means a measurable value such as a dose (eg, the amount of a compound), etc., it means to include ±20%, ±10%, ±5%, ±1% of the specified amount , ±0.5% or even ±0.1% change.

The terms "comprise", "comprises" and "comprising", as used herein, clearly state the existence of the features, integers, steps, operations, elements and/or components, but do not The existence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof is not excluded.

As used herein, the conjunction "mainly composed of the following" means that the scope of the claims is interpreted as including the specified substances or steps described in the patent application and that they will not materially affect the basic and novel characteristics of the claimed invention. . Please refer to In re Herz, 537 F.2d 549,551-52,190 USPQ461,463 (CCPA 1976) (the original text is emphasized); please also refer to MPEP § 2111.03. Therefore, when used in the scope of the patent application or the description of the present invention, the term "mainly composed of the following" does not mean to be interpreted as equal to "including".

As used herein, the terms "increase", "increases", "increased", "increasing" and similar terms indicate at least about 25%, 50%, 75%, 100 %, 150%, 200%, 300%, 400%, 500% or more.

As used herein, the terms "reduce", "reduces", "reduced", "reduction" and similar terms indicate at least about 5%, 10%, 15%, 20 %, 25%, 35%, 50%, 75%, 80%, 85%, 90%, 95%, 97% or more reduction. In particular embodiments, the reduction results in no or substantially no detectable activity or amount (ie, an insignificant amount, such as less than about 10% or even 5%).

"Effective amount" as used herein means the amount of a compound, composition, and/or formulation of the present invention, and the amount is sufficient to produce the desired benefit for therapeutic and/or beneficial effects. The effective amount depends on factors such as the age, the general condition of the subject, the severity of the symptoms to be treated, the special agent to be given, the duration of treatment, the nature of any simultaneous treatment, the pharmaceutically acceptable carrier used, and other factors that are generally in the technical field. The knowledge and expertise of the knowledgeable change within the scope. Depending on the circumstances, a person with ordinary knowledge in the relevant technical field can determine the "effective amount" in any case by referring to relevant texts and documents and/or using ordinary experiments.

The terms "treat", "treating" or "treatment of" (and their grammatical changes) mean the severity of the symptoms of the subject Severity reduction, at least partial improvement or improvement, and/or some alleviation, reduction or reduction of at least one clinical symptom, and/or delay in the progression of the disease or disorder. With regard to obesity, the term means, for example, reduced body mass index, weight loss, and/or body fat loss. In some embodiments, the treatment provides at least about 5% weight loss, such as about 10%, 15%, or 20%.

A "therapeutically effective" amount as used herein is an amount sufficient to treat (as defined herein) a subject. Those with general knowledge in the technical field should understand that the therapeutic effect does not need to be complete or cure, as long as it provides some benefits to the subject.

The terms "prevent", "preventing" and "prevention" (and their grammatical changes) mean the prevention and/or delay of the onset of the target disease, dysfunction and/or clinical symptoms and/ Or reduce the severity of the onset of diseases, dysfunctions and/or clinical symptoms that occur without the method of the present invention. Prevention can be complete, for example, there is no disease, dysfunction and/or clinical symptoms at all. Prevention may also be partial, so that the occurrence and/or severity of the occurrence and/or onset of the target's disease, dysfunction, and/or clinical symptoms are less than those occurring without the method of the present invention. As for obesity, the term means, for example, preventing the occurrence of obesity if treatment is given before the onset of obesity. In some specific examples, prevention means that the amount of weight gain is reduced compared to the lack of administration of the compound of the present invention.

As used herein, a "preventively effective" amount is sufficient to prevent and/or delay the onset of disease, dysfunction, and/or clinical symptoms of the subject and/or reduce the occurrence of diseases, dysfunctions, and/or clinical symptoms related to the absence of the method of the present invention The amount of severity of the attack. General knowledge in the technical field The reader should understand that the degree of prevention does not need to be complete, as long as it provides some benefits to the target.

The "subject" of the present invention includes any animal that has or is suspected of being obese or in need of weight loss, weight gain, and/or food intake. Such subjects are usually mammalian subjects (e.g., experimental animals such as rats, mice, guinea pigs, rabbits, primates, etc.), farm or commercial animals (e.g., cows, horses, goats, donkeys, sheep, etc.) Or domestic animals (eg, cats, dogs, ferrets, etc.). In a particular specific example, the object is a primate object, a non-human primate object (eg, chimpanzee, baboon, monkey, gorilla, etc.) or human. Subjects include males and/or females of any age, including newborns, infants, adolescents, adults, and elderly subjects.

The "object in need" of the method of the present invention can be a subject who is known, suspected, or at risk of developing overweight or obesity.

As used herein, the term "body mass index" or "BMI" means the ratio of weight in Kg divided by the square of height in meters.

The term "overweight" as used herein means that an adult's BMI is between 25 and 30. Those under the age of 20 are defined as being "overweight" as having a BMI between the 85th and 95th percentiles compared with those of the same age.

The term "obesity" as used herein means that the adult's BMI is between 30 and 40. "Obesity" for people under the age of 20 is defined as a BMI higher than the 95th percentile compared with people of the same age. As used herein, the term can include obesity and morbid obesity.

The term "morbidly obese" as used herein means that the adult's BMI is greater than 40.

The term "body weight" as used herein means the weight of a subject's body.

The term "weight gain" as used herein means an increase in the body weight of a subject over time.

The term "food intake" as used herein means the intake of calories in any form, including but not limited to food, beverages, intravenous or intestinal.

The term "pharmaceutically acceptable salts or esters" shall mean the non-toxic salts or esters of the compounds used in the present invention, usually through the reaction of a free acid with a suitable organic or inorganic base or the free base with a suitable organic or Prepared by reaction of inorganic acid. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate , D-camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, ethanedisulfonate, propionate lauryl sulfate, Ethylsulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate (hexvlresorcinate) ), Hybamine (hvdrabamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isthiosulfonate, lactate, lactobionate, laurate, malate, butine Alkenate, phenylglycolate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalenesulfonate, nitrate, oleate, oxalate, Pamoate, palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium salt, salicylate, sodium salt, stearate, hypoacetic acid Salt, succinate, tannate, tartrate, 8-chlorophylline, tosylate, triethyl iodide, and valerate.

The term "co-administration" or "combined administration" of a compound, a therapeutic agent or a known drug and the compound of the present invention as used herein means that the known drug or drug and another one or more compounds of the present invention are administered at this point in time. Drugs make known drugs and compounds have therapeutic effects. In some instances, this treatment effect is synergistic. Such co-administration related to the administration of the compound of the present invention may include simultaneous (ie, at the same time), prior or subsequent administration of a known drug. Those skilled in the art should not be difficult to determine the appropriate time point, sequence and dosage for the administration of the particular drug and the compound of the present invention.

In addition, in some specific examples, the compounds of the present invention or their salts or esters can be used alone or in combination with each other or in combination with one or more other therapeutic drugs as described above and used in manufacturing to provide patients or subjects in need for treatment of obesity Drugs for the purpose.

The present invention is based in part on the discovery that the phenylalkylamino carbamate of formula (I) has novel and unique pharmacological properties. Without being limited by mechanism, it is generally believed that the compound of formula (I) acts partly by increasing the concentration of dopamine. The neurotransmitter dopamine mediates food reward value and obese people have been found to have reduced dopamine receptor D2 availability. Dopamine regulates motivation and reward circuits, so the lack of dopamine in obese individuals may continue to eat pathologically as a way to compensate for the decreased activation of these circuits. Therefore, strategies aimed at improving dopamine function can be beneficial in the treatment of obesity. Amphetamines and amphetamine-like drugs suppress appetite by stimulating dopamine signals and have been used for decades Used as an appetite suppressant to treat obesity; however, its appetite suppressant effect involves high-risk addiction. In non-clinical studies in mice, rats and dogs, administration of the compound of formula (Ib) is associated with weight loss and/or weight gain and food intake. However, this compound does not show obvious potential for abuse; the compound of formula (Ib) is not boosted in a typical rat self-administration model and does not show significant reward properties in a position preference model. A 6-week clinical study in patients with severe depression examined the antidepressant efficacy of the compound of formula (Ib), which was associated with dose-related weight loss relative to placebo-treated patients. There was also an increase in reports of anorexia in the compound-treated group. For these reasons, the compound of formula (I) is particularly suitable for weight loss and obesity treatment.

或其藥學上可接受之鹽或酯；其中R為選自下列者所組成群組之成員：1至8個碳原子之烷基、鹵素、1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及1至3個碳原子之硫烷氧基；x為0至3之整數，其條件為當x為2或3時R可相同或不同；R₁及R₂為獨立選自氫、1至8個碳原子之烷基、芳基、芳烷基、3至7個碳原子之環烷基所組成群組；或R₁及R₂可合起來形成未經取代或經一個或多個烷基或芳基取代之5至7員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不直接彼此連 接或不直接與氧原子連接；其中對象減輕體重，因而治療肥胖。 On the one hand, the present invention is directed to treating obesity in a subject in need, including administering to the subject a therapeutically effective amount of a compound of formula (I):

Or a pharmaceutically acceptable salt or ester thereof; wherein R is a member selected from the group consisting of: an alkyl group of 1 to 8 carbon atoms, a halogen, an alkoxy group of 1 to 3 carbon atoms, a nitro group , Hydroxyl, trifluoromethyl and thioalkoxy of 1 to 3 carbon atoms; x is an integer from 0 to 3, provided that when x is 2 or 3, R may be the same or different; R ₁ and R ₂ are Independently selected from the group consisting of hydrogen, alkyl groups of 1 to 8 carbon atoms, aryl groups, aralkyl groups, and cycloalkyl groups of 3 to 7 carbon atoms; or R ₁ and R ₂ can be combined to form unsubstituted Or a 5- to 7-membered heterocyclic ring substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may include 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected to each other or Directly linked to oxygen atoms; in which the subject loses weight, thus treating obesity.

或其藥學上可接受之鹽或酯；其中R為選自下列者所組成群組之成員：1至8個碳原子之烷基、鹵素、1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及1至3個碳原子之硫烷氧基；x為0至3之整數，其條件為當x為2或3時R可相同或不同；R₁及R₂為獨立選自氫、1至8個碳原子之烷基、芳基、芳烷基、3至7個碳原子之環烷基所組成群組；或R₁及R₂可合起來形成未經取代或經一個或多個烷基或芳基取代之5至7員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不直接彼此連接或不直接與氧原子連接；其中對象減輕體重。 On the other hand, the present invention is a method for reducing weight or reducing weight gain of a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

Or a pharmaceutically acceptable salt or ester thereof; wherein R is a member selected from the group consisting of: an alkyl group of 1 to 8 carbon atoms, a halogen, an alkoxy group of 1 to 3 carbon atoms, a nitro group , Hydroxyl, trifluoromethyl and thioalkoxy of 1 to 3 carbon atoms; x is an integer from 0 to 3, provided that when x is 2 or 3, R may be the same or different; R ₁ and R ₂ are Independently selected from the group consisting of hydrogen, alkyl groups of 1 to 8 carbon atoms, aryl groups, aralkyl groups, and cycloalkyl groups of 3 to 7 carbon atoms; or R ₁ and R ₂ can be combined to form unsubstituted Or a 5- to 7-membered heterocyclic ring substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may include 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected to each other or Directly connected to oxygen atoms; in which the subject loses weight.

或其藥學上可接受之鹽或酯；其中R為選自下列者所組成群組之成員：1至8個碳原子之烷基、鹵素、1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及1至3個碳原子之硫烷氧基；x為0至3之整數，其條件為當x為2或3時R可相同或不同；R₁及R₂為獨立選自氫、1至8個碳原子之烷基、芳基、芳烷基、3至7個碳原子之環烷基所組成群組；或R₁及R₂可合起來形成未經取代或經一個或多個烷基或芳基取代之5至7員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不直接彼此連接或不直接與氧原子連接；其中對象減少食物攝取。 On the other hand, the present invention is a method for reducing food intake of a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

Or a pharmaceutically acceptable salt or ester thereof; wherein R is a member selected from the group consisting of: an alkyl group of 1 to 8 carbon atoms, a halogen, an alkoxy group of 1 to 3 carbon atoms, a nitro group , Hydroxyl, trifluoromethyl and thioalkoxy of 1 to 3 carbon atoms; x is an integer from 0 to 3, provided that when x is 2 or 3, R may be the same or different; R ₁ and R ₂ are Independently selected from the group consisting of hydrogen, alkyl groups of 1 to 8 carbon atoms, aryl groups, aralkyl groups, and cycloalkyl groups of 3 to 7 carbon atoms; or R ₁ and R ₂ can be combined to form unsubstituted Or a 5- to 7-membered heterocyclic ring substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may include 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected to each other or Directly connected to oxygen atoms; where the subject reduces food intake.

In some specific cases, the subject is an obese or morbidly obese person who needs to lose weight or reduce/prevent further weight gain. In some specific cases, the subject is overweight and in need of weight loss to the normal range and/or reduction/prevention of further weight gain or becoming obese. In some specific cases, the subject is a normal weight and wants to reduce/prevent weight gain.

In some specific examples of the above method, R is a member selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, a halogen, an alkoxy group of 1 to 3 carbon atoms, a nitro group, a hydroxyl group and a trifluoromethyl group . In some specific examples of the above method, R is a member selected from the group consisting of an alkyl group of 1 to 3 carbon atoms, a halogen, and an alkoxy group of 1 to 3 carbon atoms.

In some specific examples of the above method, R ₁ and R ₂ are independently selected from the group consisting of hydrogen, an alkyl group of 1 to 8 carbon atoms, an aryl group, an aralkyl group, and a cycloalkyl group of 3 to 7 carbon atoms . In some specific examples of the above method, R ₁ and R ₂ are independently selected from the group consisting of hydrogen and 1 to 8 carbon atoms. In some specific examples of the above method, R ₁ and R ₂ are independently selected from the group consisting of hydrogen and 1 to 3 carbon atoms.

It is generally understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those skilled in the art to provide chemically stable compounds that can be easily synthesized by techniques well known in the art and the methods provided herein.

或其藥學上可接受之鹽或酯。 In specific examples, the compound of formula (I) is a compound of formula (Ia):

Or a pharmaceutically acceptable salt or ester thereof.

In a specific example, the compound of formula (I) is (D) enantiomer, wherein R ₁ and R ₂ are hydrogen and x is 0 (compound Ib).

或其藥學上可接受之鹽或酯。此化合物為(R)鏡像異構物，如果以結構命名則為胺甲酸(R)-(β-胺基-苯丙基)酯。該化合物為右旋鏡像異構物及因此亦可命名為O-胺甲醯基-(D)-苯丙胺醇。此等名稱可在此說明書中交替使用。

Or a pharmaceutically acceptable salt or ester thereof. This compound is the (R) mirror image isomer, if it is named after the structure, it is carbamate (R)-(β-amino-phenylpropyl) ester. This compound is a dextrorotatory mirror image isomer and therefore can also be named O-aminomethanyl-(D)-amphetamine. These names can be used interchangeably in this manual.

The present invention includes the use of isolated enantiomers of compounds of formula (I) (eg, compounds of formula (Ia) or (Ib)). In a specific example, a pharmaceutical composition including an isolated S-spiegelmer of formula (I) is used to provide treatment to a subject. In another specific example, the R-mirror image of formula (I) including single ionization is used The medical composition of the structure provides treatment to the subject.

The present invention also includes the use of mixtures of enantiomers of formula (I). In one aspect of the present invention, an enantiomer is the majority. The majority of the enantiomers in the mixture are the enantiomers that are present in the mixture in greater amounts than any other enantiomers in the mixture, for example, in an amount greater than 50%. On the one hand, a kind of enantiomers account for 90% or 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% or more. In specific examples, the majority of the enantiomers in the composition including the compound of formula (I) are the S-spermoisomers of formula (I).

The present invention provides methods for using the enantiomers and mixtures of enantiomers of the compound represented by formula (I). The carbamate enantiomers of formula (I) contain an asymmetric chiral carbon atom at the benzyl position, which is the second aliphatic carbon adjacent to the benzene ring.

The isolated enantiomers are those that have substantially no corresponding enantiomers. Therefore, a single enantiomer refers to a compound that is separated by separation technology or prepared by eliminating the corresponding enantiomer.

The term "substantially not", as used herein, means that the compound consists of a significantly larger portion of an enantiomer. In a preferred embodiment, the compound contains at least about 90% by weight of an enantiomer. In other embodiments of the present invention, the compound contains at least about 99% by weight of an enantiomer.

The compound of formula (I) can be synthesized by methods well known to the skilled artisan. Use appropriate inorganic acid or organic acid (HX) to dissolve The salt and ester of the compound of formula (I) can be produced by treating the compound in the agent or by other methods well known to those with ordinary knowledge in the art.

The detailed reaction scheme for synthesizing the compound of formula (I) and representative examples for the manufacture of specific compounds have been described in USPat. No. 5,705,640, USPat. No. 5,756,817, USPat. No. 5,955,499, USPat. The entire content is incorporated into this article by reference.

It is obvious from formula (I) that some compounds of the invention have at least one and possibly more asymmetric carbon atoms. It means that the present invention includes the stereochemically pure isomer forms of the compounds and their racemates within its scope. The principles known in the art can be applied to obtain stereochemically pure isomer forms. The diastereomers can be separated by physical separation methods such as fractional crystallization and chromatography techniques, and by selective crystallization of diastereomer salts with optically active acids or bases or by chiral chromatography Method to separate the enantiomers from each other. It can also be synthesized from appropriate stereochemically pure starting materials, or using stereoselective reactions to produce pure stereoisomers.

During any process for preparing the compounds of the present invention, it may be necessary or preferable to protect sensitive or reactive groups on related molecules. It can be achieved through commonly used protective group methods, such as Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGMWuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999 Illustrated. Can use methods well known in the field at appropriate subsequent stages Remove the protecting group.

The compound can be administered to a subject by any common route of administration, including, but not limited to, oral, oral, topical, systemic (e.g., transdermal, nasal, or suppository), or parenteral (e.g., intramuscular, subcutaneous, or intravenous injection). The administration of the compound directly to the nervous system may include, for example, delivery via an intracranial or spinal needle or a catheter with or without a pump device to the brain, ventricle, lateral ventricle, Intrathecal, intracisternal, intraspinal or paraspinal route of administration. Depending on the route of administration, the compound of formula (I) can be composed into any dosage form. For example, dosage forms suitable for oral administration include solid dosage forms such as pills, caplets, lozenges, film-coated tablets, capsules, granules and powders (each including immediate release, time-dependent release, and sustained release formulations). Dosage forms suitable for oral administration also include liquid dosage forms such as solutions, syrups, elixirs, emulsions and suspensions. In addition, forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.

In some specific examples, the pharmaceutical composition of the present invention includes one or more compounds of formula (I) or salts or esters thereof without any pharmaceutical carriers or excipients. In other specific examples, the pharmaceutical composition of the present invention includes one or more compounds of formula (I) or their salts or esters which are closely blended with a pharmaceutical carrier according to common pharmaceutical compounding techniques. The carrier is an inert pharmaceutical excipient, including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweeteners, preservatives, dyes and coatings. When preparing the composition of oral dosage form, any conventional pharmaceutical carrier can be used. For example, for liquid oral preparations, suitable carriers and additives include water, glycols, oils, alcohol, flavoring agents, preservatives, coloring agents, etc.; for solid oral preparations, suitable carriers and additives include starch, Sugar, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.

The dosage form of the composition can be tablet, pill, capsule, semi-solid, powder, sustained release formula, solution, suspension, emulsion, syrup, elixirs, aerosol or any other suitable composition; and include at least A compound of the present invention is optionally combined with at least one pharmaceutically acceptable excipient. Those skilled in the art are familiar with appropriate excipients, and they can find formulations from such standard bibliography such as Alfonso AR: Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton Pa., 1985. For the method of composition, all the contents disclosed by it are incorporated into this article by reference and used for all purposes. Suitable liquid carriers, especially for injectable solutions, include water, saline solution, aqueous glucose solution and glycols.

The carbamate compound can be provided as an aqueous suspension. The aqueous suspension of the present invention may contain a urethane compound blended with excipients suitable for making aqueous suspensions. Such excipients may include, for example, suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and Dispersants or wetting agents such as naturally occurring phospholipids (such as lecithin), condensation products of alkylene oxide and fatty acids (such as polyoxyethylene stearate), ethylene oxide and long-chain aliphatic alcohols Condensation products (e.g., heptadecyl ethyleneoxy cetyl alcohol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleic acid Ester) or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (eg, polyoxyethylene sorbitan monooleate).

Aqueous suspensions may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, argentine Spartame or saccharin. The permeability of the formula can be adjusted.

The urethane compound can be suspended in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin, or a mixture thereof, and formulated for use in the oily suspension of the method. Oily suspensions may contain thickeners such as beeswax, paraffin wax or cetyl alcohol. Sweeteners can be added to provide a delicious oral preparation, such as glycerin, sorbitol or sucrose. Antioxidants such as ascorbic acid can be added to preserve these formulations. For examples of injection oily excipients, please refer to Minto, J. Pharmacol. Exp. Ther. 281:93 (1997). The pharmaceutical formula of the present invention can also be in the form of an oil-in-water emulsion. As mentioned above, the oil phase can be vegetable oil or mineral oil, or a mixture thereof.

Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth, naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono Oleic acid esters, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents, such as syrups and elixirs. Such formulations may also contain a demulcent, preservative or coloring agent.

The selected compound, alone or in combination with other appropriate ingredients, can be made into a spray formulation (ie, can be "nebulized") and administered via inhalation. The spray formulation can be put into an acceptable pressurized propellant, such as two Chlorodifluoromethane, propane, nitrogen, etc.

The formulations of the present invention are suitable for parenteral administration, such as, for example, via intra-articular (in-articular), intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes, and may include aqueous and non-aqueous, isotonic sterile injection solutions, It can contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient, and can contain suspending agents, cosolvents, thickeners, stabilizers and preservatives in aqueous and non-aqueous sterile suspension. Among the acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride. In addition, it is customary to use sterile fixed oils as a solvent or suspension medium. Any bland fixed oil containing synthetic mono- or diglycerides can be used for this purpose. In addition, fatty acids such as oleic acid can also be used to prepare injections. These solutions are sterile and generally contain no unwanted substances.

When the compound is sufficiently soluble, it can be directly dissolved in physiological saline with or without using a suitable organic solvent, such as propylene glycol or polyethylene glycol. A dispersion of finely divided compounds can be formed in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil, such as peanut oil. These formulations can be sterilized by common and well-known aseptic techniques. The formulation may contain pharmaceutically acceptable auxiliary substances that are required to approximate physiological conditions, such as pH adjusters and buffers, and toxicity adjusters, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.

The concentration of carbamate compounds in these formulations can vary greatly, mainly based on liquid volume, viscosity, body weight, etc., and are selected according to the particular mode of administration selected and the needs of the patient. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. The recommended formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Injection solutions and suspensions can be prepared from the above types of sterile powders, granules and tablets.

The carbamate compounds suitable for use in the practice of this invention can be administered orally. Depending on the type of composition, the size of the unit dose, the type of excipients and other factors well known to those skilled in the art, the amount of the compound of the present invention in the composition can vary greatly. Generally speaking, the final composition may include, for example, 0.000001% by weight (% w) to 100% w of urethane compounds, such as 0.00001% w to 50% w, and the rest are excipients or excipients Class etc.

Pharmaceutical formulations suitable for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art. Such carriers enable pharmaceutical formulations to be formulated into unit dosage forms of lozenges, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., which are suitable for patient ingestion. In other specific examples, a pharmaceutical formulation for oral administration can be formulated without using any pharmaceutically acceptable carrier.

Formulations suitable for oral administration may include (a) a liquid solution, such as an effective amount of a pharmaceutical formulation suspended in a diluent, such as water, saline or PEG 400; (b) capsules, bagged powders or lozenges, each containing a predetermined amount The active ingredient, such as liquid, solid, granule or gelatin; (c) a suspension in a suitable liquid; and (d) a suitable emulsion.

A pharmaceutical preparation for oral administration can be obtained by combining the compound of the present invention with a solid excipient, and the resulting mixture can be ground if necessary, and if necessary, after adding appropriate additional compounds, the granules are mixed to obtain lozenges or dragees. Suitable solid excipients are carbohydrates or protein fillers and include, but are not limited to, sugars, including lactose, sucrose, mannitol or sorbitol; corn, wheat, rice, potato or other plant starches; cellulose such as methyl fiber Cellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; and gums including gum arabic and tragacanth; and proteins such as gelatin and collagen.

If necessary, disintegrating agents or co-solvents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. The lozenge dosage form may contain one or more lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silica, talc, magnesium stearate, stearic acid , And other excipients, coloring agents, fillers, binders, diluents, buffers, wetting agents, preservatives, flavoring agents, dyes, disintegrating agents and pharmaceutically compatible carriers. The tablet-containing form may include flavored active ingredients such as sucrose, and jellybeans containing active ingredients in an inert base such as gelatin and glycerin, or sucrose and gum arabic emulsions and gelatins containing carriers known in the art in addition to the active ingredients. Glue etc.

The compounds of the present invention can also be administered in the form of suppositories for rectal administration. These formulations can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at normal temperature but liquid at the rectal temperature and thus dissolves in the rectum to release the drug. Such substances are cocoa butter and polyethylene alcohol.

The compounds of the present invention can also be administered via intranasal, intraocular, vaginal and intrarectal routes including suppositories, insufflations, powders and spray formulations (for examples of steroid inhalants, please refer to Rohatagi, J. Clin. Pharmacol. 35: 1187 (1995); Tjwa, Ann. Allergy Asthma Immunol. 75:107 (1995)).

The compound of the present invention can also be delivered transdermally. It can be formulated into sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, smears, powders and sprays via topical routes. .

The compound of the present invention can also be used as an encapsulated substance and the term "composition" may contain the active ingredient combined with the encapsulated substance to form a formulation, with or without other carriers. For example, the compounds of the present invention can also be delivered as microspheres for slow release in vivo. In a specific example, the microspheres can be administered via intradermal injection of microspheres containing drugs (eg, mifepristone), which are slowly released from the skin (see Rao, J. Biomater. Sci. Polym. Ed. 7: 623 (1995); as a biodegradable and injection gel formulation (please refer to, for example, Gao, Pharm. Res. 12: 857 (1995)); or as a micro for oral administration Pellets (please refer to, eg, Eyles, J. Pharm. Pharmacol. 49: 669 (1997)). Both transdermal and intradermal routes provide continuous delivery for several weeks or months. cachets can also be used ( Cachet) delivers the compounds of the invention.

In another specific example, the compound of the present invention can also be delivered using liposomes that are fused with cell membranes or through endocytosis, that is, using ligands attached to liposomes, and the lipid system is linked to the cell surface that causes endocytosis. Facial mask protein receptor. Active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, amine stearate or phospholipid choline.

Use liposomes, especially if the liposomes carry ligands specific to the target cells on the surface of the liposomes, otherwise it will be preferentially directed to specific organs. You can focus on the delivery of carbamate compounds to target cells in the body (please refer to , Al-Muhammed, J. Microencapsul. 13: 293 (1996); Chonn, Curr. Opin. Biotechnol. 6: 698 (1995); Ostro, Am. J. Hosp. Pharm. 46: 1576 (1989)).

Monoclonal antibodies coupled with compound molecules can also be used as individual carriers to deliver active drugs. Active drugs can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, piperanan copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartame phenol, or polyethylene oxide poly(ethylene oxide) substituted with palmitoyl residues. Lysine. Furthermore, active drugs can be coupled with biodegradable polymers suitable for regulating drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyε-caprolactone, polyhydroxybutyrate Cross-linked or amphiphilic block copolymer of acid, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate and hydrogel.

In some specific examples, the composition is in a unit dosage form such as lozenges, pills, capsules, powders, granules, sterile non-oral solutions or suspensions, metered sprays or liquid sprays, drops, ampoules, automatic injection devices or suppositories , For oral, parenteral, nasal, sublingual or rectal administration, Or for inhalation or insufflation for administration.

Alternatively, the composition may also be a dosage form suitable for once a week or once a month administration; for example, insoluble salts of the active compound, such as caprate, may be suitable for providing long-acting preparations for intramuscular injection.

The pharmaceutical composition herein, each dosage unit, such as tablet, capsule, powder, injection, one teaspoon, suppository, etc., contains the amount of active ingredient necessary to deliver an effective dose as described above. For example, the pharmaceutical composition herein, each dosage unit may contain about 10 to about 1000 mg of active ingredient, such as about 25 to about 600 mg of active ingredient, such as about 75 to about 400 mg of active ingredient, such as about 25, 50, 75 , 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575 or 600 mg or more or any range thereof .

In some specific examples of the present invention, the carbamate compound suitable for practicing the present invention is administered alone or in combination with at least one or more other compounds or therapeutic agents, for example, with other treatments for obesity and/or helps Medicaments that reduce weight or reduce food intake. Examples of therapeutic agents for treating obesity and reducing weight or reducing food intake include, but are not limited to, leptin, leptin agonist, fenfluramine, dexfenfluramine, phenidine Amine (phentermine), sibutramine, orlistan, neuropeptide Y1 or Y5 antagonist, cannabinoid CB 1 receptor antagonist or reverse agonist (e.g., rimonabant (rimonabant) ( ACOMPLIA), otenabant, ibinabant, surinabant), melanocortin receptor agonist (especially, melanocortin-4 receptor agonist ), hunger peptide antagonist, black MCH receptor antagonist, CD38 inhibitor, RP105 inhibitor, MD-1 inhibitor, PYY (3-36) or PYY (3-36) agonist, amylin or amylin agonist, CCK or CCK agonist, exendin or exendin agonist, CNTF or CNTF agonist, serotonin reuptake inhibitor, serotonin transport inhibitor, 5HT2c agonist, GLP- 1 or GLP-1 agonist, DPP-IV inhibitor, opioid antagonist, appetite hormone antagonist, metabolic glutamine fifth subtype receptor antagonist, histamine 3 antagonist/inverse agonist And topiramate.

In some specific examples of the present invention, the administration of the carbamate compound suitable for the practice of the present invention is performed together with behavior modification therapy, such as diet and/or exercise.

The method comprises the step of administering an effective amount of one of the carbamate compounds disclosed herein to a patient in need of treatment or prevention, and the carbamate compound is combined with one or more effective amounts of other compounds or therapeutic agents, and The compound or therapeutic agent has the ability to provide beneficial combination effects such as enhancing the utility of the compounds of the invention.

A pharmaceutically acceptable salt or ester means a salt or ester that is pharmaceutically acceptable and has desired pharmacological properties. Such salts include salts that may be formed by the acidic protons in the compound that can react with inorganic or organic bases. Suitable inorganic salts include those formed with alkali metals, such as sodium and potassium, magnesium, calcium and aluminum. Suitable organic salts include those formed with organic bases such as amine bases, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. The pharmaceutically acceptable salts may also contain acid addition salts, and the acid addition salts are derived from the amine part of the parent compound Organic acids (e.g., hydrochloric acid and hydrobromic acid) and organic acids (e.g., acetic acid, citric acid, maleic acid, and alkane- and aromatic-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid) are formed by the reaction. The pharmaceutically acceptable esters include esters formed from the carboxyl, sulfonyloxy and phosphinocarboxyl groups present in the compound. When two acid groups are present, the pharmaceutically acceptable salt or ester can be a mono-acid mono- or double-salt or ester; similarly, when there are more than two acid groups, some of these groups Or all can be salted or esterified.

The compounds named in the present invention can be presented in an unsalted or unesterified form, or a salted and/or esterified form, and the naming of such compounds means to include the initial (unsalted and unesterified) compound and Both of its pharmaceutically acceptable salts or esters. The present invention includes the pharmaceutically acceptable salt or ester form of formula (I). More than one crystal form of the enantiomers of formula (I) may exist and are equally included in the present invention.

In addition to the carbamate compound, the pharmaceutical composition of the present invention may optionally contain at least one other therapeutic agent suitable for treating obesity and/or reducing weight and/or reducing food intake. For example, the carbamate compound of formula (I) can be physically combined with other compounds into a fixed-dose compound to simplify their administration.

Many publications describe the method of formulating pharmaceutical compositions such as Pharmaceutical Dosage Forms: Tablets. Second Edition. Revised and Expanded. Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems.Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc., by quoting, incorporate all of its disclosures into this article and use them for all purposes.

Generally, the pharmaceutical composition is formulated to be sterile, substantially isometric and fully comply with all Good Manufacturing Practice (GMP) regulations of the US Food and Drug Administration.

The present invention provides methods for using carbamate compounds to treat or prevent obesity and/or reduce body weight and/or reduce food intake in a subject. The amount of the carbamate compound required to treat or prevent obesity is defined as the therapeutic or drug effective dose. The dosage scheduling and effective amount for this purpose, that is, the medication or dosage regimen depends on a variety of factors including disease stage, patient's physical state, age, etc. When calculating the dosage regimen for the patient, the mode of administration is also considered.

Considering the technology in the field and the present disclosure, those with ordinary knowledge in the field can determine the therapeutically effective amount of the specially substituted carbamate compound used in the practice of the present invention without doing too many experiments (please refer to, for example, Lieberman , Pharmaceutical Dosage Forms (Vols.1-3, 1992); Lloyd, 1999, The Art, Science and Technology of Pharmaceutical Compounding; and Pickar, 1999, Dosage Calculations). A therapeutically effective dose is also a dose that is more important than any toxic or harmful side effects in clinical terms. It should be further noted that for each specific object, it is necessary to evaluate and adjust the specific dosage regimen over time according to individual needs and the professional judgment of the person administering or supervising the compound.

For therapeutic purposes, it can be delivered continuously for an extended period of time, or in a repeated dosing regimen (eg, in hours, days, or Weekly repeated dosing regimen) and a single high-dose delivery of the composition or compound disclosed herein is administered to the subject. The pharmaceutical formulation of the present invention can be administered, for example, one or more times a day, 3 times a week, or once a week. In a specific example of the present invention, the pharmaceutical formulation of the present invention is orally administered once or twice a day.

In this regard, the therapeutically effective dose of the biologically active agent may include repeated doses within the extended treatment regimen, which therapeutically effective dose produces clinically significant results and provides the treatment of cataplexy. In this regard, the determination of the effective dose is generally based on animal model studies followed by human clinical trials and guided by the determination of effective doses and dosing regimens that significantly reduce the occurrence or severity of the target exposure signs or symptoms of the subject. Suitable models in this regard include, for example, murines, rats, pigs, cats, non-human primates, and other accepted animal model objects known in the art. Alternatively, in vitro models (eg, immune and histopathological tests) can be used to determine the effective dose.

Using this model, generally only ordinary calculations and adjustments are needed to determine the appropriate concentration and dosage of the therapeutically effective dose of the biologically active agent (e.g., oral, nasal, transdermal, intravenous or intramuscular Effective amount). However, the effective amount may vary depending on the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the progression of disease symptoms. In addition, factors related to the specific patient being treated, including the patient's age, weight, diet and time of administration, cause the need to adjust the dose.

In the exemplary embodiment of the present invention, a unit dosage form of the compound is formulated for use in a standard dosage regimen. In this way, the composition can be treated as a doctor The teacher's instructions are easily broken down into smaller doses. For example, the unit dose can be prepared as a powder, vial or ampoule in a packet and preferably in the form of a capsule or lozenge.

The effective administration of the carbamate compound of the present invention can be, for example, an oral or parenteral dose of about 0.01 mg/kg/dose to about 150 mg/kg/dose. For example, the administration may be about 0.1/mg/kg/dose to about 25 mg/kg/dose, for example, about 0.2 to about 18 mg/kg/dose, for example, about 0.5 to about 10 mg/kg/dose. Therefore, the therapeutically effective amount of the active ingredient may be for a subject having an average body weight, for example, 70 kg, for example, about 1 mg/day to about 7000 mg/day, such as about 10 to about 2000 mg/day, such as about 50 to About 600mg/day, such as about 10, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 600 mg/day or more or any range thereof. In a specific example, the compound of formula (I) is administered in a capsule form with a dose of about 150 mg to about 300 mg without excipients.

The method of the present invention also provides a kit for providing treatment or prevention of obesity and/or weight loss and/or reduction of food intake. When the pharmaceutical composition including one or more carbamate compounds of the present invention and possibly adding one or more other compounds for beneficial treatment is formulated in a suitable carrier, it can be placed in a suitable container and labeled for providing treatment Or prevent obesity and/or reduce weight and/or reduce food intake. In addition, another medicine including at least one other therapeutic agent can also be placed in the container and marked to treat the specified disease. Such labeling may include, for example, instructions regarding the amount, frequency, and method of administration of each drug.

After explaining the present invention, it will be explained in detail in the following embodiments To explain the present invention, the examples contained herein are only for illustrative purposes and are not meant to limit the present invention.

[Example] Example 1 Effects of R228060 on the body weight and food intake of rats

To carry out rat R228060 (formula (Ib)) 6-month repeated dose and 3-month recovery period oral toxicity study. Monitor body weight and food intake during the study.

body weight

Compared with control rats, the weight and weight gain of male rats taking 35mg HCl-salt/kg body weight/day R228060 was slightly lower, from the 8th week to the 12th week (weight gain: p<0.05) and from the 10th to the 12th week. Weeks (weight: p<0.05) reached statistical significance. Weight gain decreased by 6% in the 13th week and 5% in the 26th week. Oral administration of 35 mg HCl-salt/kg body weight/day R228060 for 6 consecutive months did not negatively affect the weight and weight gain of female rats.

Male rats taking 300 mg HCl-salt/kg body weight/day showed a significant reduction in body weight and weight gain from the first week of medication (p<0.001). Weight gain decreased by 27% at the 13th week and by 24% at the 26th week. Female rats of the same dose level showed moderate to significant weight gain (p<0.05 to 0.001), especially in the late period of medication. Compared to the control group, the weight gain decreased by 15% at the 13th week, and a 23% decrease was observed at the 26th week. The result was moderate weight loss (p<0.05 to 0.001).

Male rats taking 600/450mg HCl-salt/kg body weight/day R228060 showed weight and weight gain from the first week (p<0.001) Significantly reduced. Weight gain decreased by 33% at the 13th week and 32% at the 26th week. In female rats, the weight gain was recorded from the first week of administration to moderate to significant decrease (p<0.05 to 0.001). Weight gain decreased by 18% at the 13th week and 21% at the 26th week. This result is a moderate weight loss (p<0.05 to 0.001). The increase in weight gain from the first week of the recovery period proved that the male rats showed a partial return to normal (control group) weight after the treatment was discontinued. Compared with the control animals, the body weight was still slightly lower after the 3-month recovery period. Similarly, it was observed that the female rats also partially recovered their normal body weight. Compared with the control animals, the female rats treated with 600/450 mg HCl-salt/kg body weight/day had only slightly reduced body weight differences after the end of the recovery period.

The conclusion is that, starting from 35 mg HCl-salt/kg body weight/day in male rats and 300 mg HCl-salt/kg body weight/day in female rats, body weight and weight gain show dose-related reductions. After the treatment period, the weight gain of male and female rats decreased by 32% and 21%, respectively. After the end of the 3-month recovery period, the weight loss was partially recovered (male rats) to almost completely recovered (female rats).

Food intake

Especially during the first week of medication, both sexes observed dose-related food intake starting from 35mg HCl-salt/kg body weight/day in male rats and 300mg HCl-salt/kg body weight/day in female rats cut back. This result is a statistically significant reduction at the level of 300 and 600/450 mg HCl-salt/kg body weight/day. Depending on the dose level, the degree of normal food intake will be restored sooner or later. The food intake of male rats in the 600/450 mg HCl-salt/kg body weight class returned to normal about 12 weeks after starting the treatment. Female rats occurred earlier, and food intake returned to normal about 4 weeks after treatment. Usually, after returning to normal food intake, Then observe major changes in food intake. It is believed that the observed statistically significant increase in the food intake of female rats at 35, 300 and 600/450 mg HCl-salt/kg body weight is not related to toxicity.

The conclusion is that, especially in the first week of medication, dose-related ingestion starting from 35 mg HCl-salt/kg body weight/day for male rats and 300 mg HCl-salt/kg body weight/day for female rats was observed in both sexes. The amount is reduced. At the 300 and 600/450 mg HCl-salt/kg body weight levels, these reductions are statistically significant. Depending on the dose level and gender, the degree of normal food intake will be restored sooner or later. Compared with female rats, male rats' food intake returned to normal later. (About 12 or 4 weeks after the start of treatment, respectively).

Example 2 The effect of R228060 on dog weight and food intake

A 52-week repeated dose of R228060 (formula (I)b) in MiGru dogs and an oral toxicity study during the 13-week recovery period were conducted. During the study, monitor body weight and food intake (see Table 1).

body weight

During the first 4 days of treatment, it was observed that all male dogs treated with 25 or 50 mg/kg bw/day had weight loss, with an average weight loss of 0.3 kg and 0.7 kg, respectively. The high-dose male dog group lost an average weight of 0.8kg on the 21st day, and the body weight only returned to the initial value on the 126th day, while the male dog receiving 25mg/kg bw/day returned to the initial weight on the 35th day.

It was also observed that during the first 4 days of treatment, all female dogs treated with 10, 25 or 50 mg/kg bw/day had weight loss, with an average weight loss of 0.4 kg, 0.5 kg and 0.7 kg, respectively. High-dose female dog group The average weight loss was 0.8kg on day 21 and returned to initial weight on day 77. Female dogs receiving 10 or 25 mg/kg bw/day returned to their original weight on day 28 and 42 respectively.

Compared to the control group, a lower dose-related average weight gain is usually observed in the treatment group on day 182 and day 364.

Compared to the control group, group 4 female dogs had higher weight gain during the untreated period while group 4 male dogs had a slightly higher increase.

The values in parentheses indicate changes only during the untreated period.

Food intake

Compared to the control group, a male dog receiving 25 mg/kg bw/day had a reduced food intake (approximately -40%) during the first week of treatment.

Male dogs receiving 50 mg/kg bw/day mainly have reduced food intake (about -50% of the daily portion) during the first week of treatment, which is the more affected group and until the 42nd day and at the end of the treatment period Still have low food intake many times.

Three of the four female dogs receiving 10 mg/kg bw/day had slightly lower food intake (approximately -25% of the daily portion) during the first week of treatment. Female dogs receiving 25 mg/kg bw/day also had lower food intake (approximately -25% to -50% of the daily portion) during the first week of treatment. It was also observed that two female dogs had this phenomenon several times during the whole treatment period. It was observed that during the first week of treatment, all female dogs receiving 50 mg/kg bw/day had lower food intake, which was marked on 3/6 animals. Afterwards, food intake usually returns to normal values and only sporadic changes during the remaining treatment period. No effect on food intake of any animal during the untreated period was not observed.

Example 3 The effect of R228060 on human weight

A 6-week randomized, double-blind, parallel group, active and placebo-controlled study in adult subjects with severe depression (MDD) was conducted to evaluate the benefits of R228060. Monitor body weight during the study.

Table 2 summarizes the weight change from baseline to endpoint in the treatment group. Subjects in the 200-mg group receiving R228060 had an average weight loss of 0.6 kg and the 400-mg group had an average weight loss of 0.9 kg, while receiving placebo or paroxetine (paroxetine) subjects had 0.7 and 0.1 kg weight gains, respectively.

Table 3 shows the distribution of weight percentage changes from baseline to endpoint in the treatment group. Four subjects who received R228060 (1 in the 200-mg group [0.9%] and 3 in the 400-mg group [2.5%]) lost 7% or more of their body weight. The percentage of subjects in the R228060 group with no change in weight or weight loss of less than 7% was higher than that of safety Those in the placebo or paroxetine group. In contrast, the percentage of subjects with a weight gain of <7% in the placebo and paroxetine groups was higher than that in the R228060 group.

The average change in BMI from baseline to endpoint was small (R228060 200mg and 400mg were -0.2 and -0.3kg/m ² , respectively, compared to 0.2kg/m ² and 0 in the placebo and paroxetine groups, respectively).

All publications, patent applications, patents and other references cited in this article are incorporated by reference in their entire contents for teaching about presenting the cited sentences and paragraphs and other useful purposes.

Claims (16)

A therapeutically effective dose of the compound of formula (I)

The use of its pharmaceutically acceptable salt or ester is to prepare a pharmaceutical composition for the treatment of obesity by reducing body weight; wherein R ₁ and R ₂ are hydrogen, and x=0. A therapeutically effective dose of the compound of formula (I)

The use of its pharmaceutically acceptable salt or ester is to prepare a pharmaceutical composition for reducing weight or weight gain; wherein R ₁ and R ₂ are hydrogen, and x=0. A therapeutically effective dose of the compound of formula (I)

The use of its pharmaceutically acceptable salt or ester is to prepare a pharmaceutical composition for reducing food intake; wherein R ₁ and R ₂ are hydrogen, and x=0. The use described in any one of items 1 to 3 in the scope of the patent application, wherein the compound of formula (I) is of formula (I) substantially free of other enantiomers Enantiomers or a mixture of enantiomers in which one of the enantiomers of formula (I) accounts for the majority. For the purposes described in item 4 of the scope of patent application, the enantiomers of formula (I) account for the majority of about 90% or more. For the purposes described in item 4 of the scope of patent application, the enantiomers of formula (I) account for 98% or more of the majority. For the purposes described in item 4 of the scope of patent application, the enantiomers are (R) or (D) enantiomers. For the purposes described in item 4 of the scope of patent application, the enantiomers are (S) or (L) enantiomers. The use described in item 4 of the scope of patent application, wherein the enantiomers of formula (I) which are substantially free of other enantiomers are compounds of formula (Ib) or compounds of formula (Ib) in which the majority of the enantiomers Mixture:

Or a pharmaceutically acceptable salt or ester thereof. For the use described in item 9 of the scope of patent application, the compound of formula (Ib) accounts for about 90% or more. For the use described in item 9 of the scope of patent application, the compound of formula (Ib) accounts for about 98% or more. The use according to any one of items 1 to 3 in the scope of the patent application, wherein the effective amount of the compound of formula (I) is about 0.01 mg/kg/dose to about 150 mg/kg/dose. The use according to any one of items 1 to 3 in the scope of the patent application, wherein the effective amount of the compound of formula (I) is about 1 mg/day to about 7000 mg/day. The use according to any one of items 1 to 3 in the scope of the patent application, wherein the compound of formula (I) is administered orally. The use according to any one of items 1 to 3 in the scope of the patent application, wherein the compound of formula (I) is administered in the form of a capsule or lozenge. The use according to one of items 1 to 3 in the scope of the patent application, wherein the compound of formula (I) is administered in the form of a capsule with a dose of about 10 mg to about 1000 mg without any excipients.