WO2010098298A1

WO2010098298A1 - Pharmaceutical composition comprising combination of compound having nutrient digestion/absorption inhibitory activity and cyclohexanecarboxamide derivative

Info

Publication number: WO2010098298A1
Application number: PCT/JP2010/052677
Authority: WO
Inventors: 日出男雪岡
Original assignee: 塩野義製薬株式会社
Priority date: 2009-02-27
Filing date: 2010-02-23
Publication date: 2010-09-02
Also published as: TW201032805A; AR075631A1

Abstract

Disclosed is a pharmaceutical composition which comprises a combination of a compound having a nutrient digestion/absorption inhibitory activity, a pharmaceutically acceptable salt thereof or a solvate of the compound or salt, and a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate of the compound or salt. The pharmaceutical composition is found to significantly reduce the body weight. Consequently, the pharmaceutical composition is useful for treatment or prevention of obesity and obesity-related diseases. (In the formula, R¹ represents an alkyl group; R² represents hydrogen or an alkyl group; and Z represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted cyclic hydrocarbon group, or a substituted or unsubstituted heterocyclic group.)

Description

Pharmaceutical composition comprising a combination of a compound capable of inhibiting digestion and absorption of nutrients and a cyclohexanecarboxamide derivative

The present invention relates to a pharmaceutical composition comprising a combination of a compound having an inhibitory action on digestion and absorption of nutrients and a cyclohexanecarboxamide derivative. Specifically, the present invention relates to a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof. The pharmaceutical composition is very useful for the prevention or treatment of obesity or obesity-related diseases.

Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as a major risk factor for health problems. The body mass index (BMI) is a simple index of the height-weight ratio that is commonly used to classify an adult (over 15 years old) group or individual as overweight or obese. It is defined as the body weight (kg / m ² ) expressed in kilograms divided by the height squared in meters. According to the World Health Organization, BMI of 25 kg / m ² or more is “overweight” and 30 kg / m ² or more is “obese”. On the other hand, the Japanese Society of Obesity considers BMI to be 25 kg / m ² or more as “obesity”. This is because the number of obesity-related diseases including diabetes and dyslipidemia increases according to BMI, and the average value of the number of diseases becomes 1.0 or more at 25 kg / m ² . According to a 2005 survey by the World Health Organization, around 1.6 billion people worldwide are overweight and at least 400 million people are obese. Obesity is mainly caused by an increase in the ratio of caloric intake to physical activity and consumption in daily life. The number of obese people is increasing due to an increase in the intake of high fat and high sugar content foods in recent years, and more than 700 million people are expected to be diagnosed as obese worldwide in 2015.

As agents for preventing or treating obesity, compounds having an appetite suppressing action (selective serotonin reuptake inhibitors such as fenfluramine and fluoxetine, mazindol, etc.), compounds having an action to suppress digestion and absorption of nutrients, and the like are known. . Examples of the compound having an action to suppress digestion and absorption of nutrients include compounds having an action to suppress saccharide absorption (α-glucosidase inhibitors, SGLT-2 inhibitors, etc.), compounds having an action to suppress fat absorption, and the like. Examples of the compound having a fat absorption inhibitory action include a lipase inhibitor (a compound having a gastric lipase inhibitory action, a compound having a pancreatic lipase inhibitory action, etc.), a bile acid adsorption resin, and the like.

Orlistat is an anti-obesity drug having pancreatic lipase inhibitory action. Non-Patent Document 1 reports that in a one-year clinical trial, obesity patients of 1/3 or more in the orlistat administration group showed a weight loss of 10% or more compared to the body weight before administration.

Furthermore, dapagliflozin (SGLT-2 inhibitor), a compound that has a carbohydrate absorption inhibitory effect, and orlistat (THL), a compound that has a fat absorption inhibitory effect, show a body weight gain inhibitory action, but also a food intake enhancing action. It is known (see non-patent document 2, especially FIG. 3 and non-patent document 3).

Non-Patent Document 4 reports that MK-0557, known as an NPY Y5 receptor antagonist, did not show clinically significant weight loss in obese patients. The literature strongly suggests that inhibiting the NPY Y5 receptor does not significantly affect weight loss. MK-0557 is represented by the following structural formula.

Non-Patent Document 5 reports that simultaneous administration of orlistat and MK-0557 did not significantly reduce body weight compared to single-dose administration of orlistat. The document strongly suggests that inhibiting the NPY Y5 receptor does not increase the weight loss efficiency of orlistat.
Combinations and combinations of orlistat and NPY Y5 receptor antagonist are described in

Patent Documents

1, 2, and 3 and the like. However, examples and specific data are not described in the patent document, and actual effects are not disclosed or suggested.

Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ) Is known to have an NPY Y5 receptor-specific antagonistic action (Patent Documents 4 and 5).

In Non-Patent Document 6, in a one-year clinical trial, obesity patients more than 1/3 of the group administered with compound (a), which is one of the compounds represented by the above formula (I), are compared with the body weight before administration. It has been reported that it showed a weight loss of 5% or more. Patent Document 5 describes that the compound represented by the above formula (I) exhibits an antifeedant action. Compound (a) is represented by the following structural formula.

However, neither document discloses nor suggests a pharmaceutical composition obtained by combining a compound having an action of inhibiting the digestion and absorption of nutrients with a compound represented by the above formula (I).

International Publication No. WO2003 / 072577 International Publication No. WO2004 / 014884 International Publication No. WO2004 / 009015 International Publication No. WO01 / 37826 International Publication No. WO2006 / 001318

An object of the present invention is to provide a pharmaceutical composition that is very useful for the prevention or treatment of obesity or obesity-related diseases.

As a result of diligent research, the present inventors have found the following results. Formula (I), which is a compound having a digestive absorption inhibitory action on nutrients and a cyclohexanecarboxamide derivative:

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ) Significantly reduced body weight in a dose-dependent manner in obese model mice. Furthermore, when a compound represented by formula (I) having an NPY Y5 receptor antagonistic activity and a compound having a digestive absorption inhibitory effect on nutrients are used in combination, the weight loss more than additive is seen compared to the total of the respective compound treatments. It was. That is, unlike the description of Non-Patent Document 5, the body weight suppression in the combined use was larger than the sum of the treatments of each compound alone. Considering that non-patent document 5 describes that inhibition of NPY Y5 receptor does not increase the weight loss efficiency of orlistat, this additive weight suppression effect is not an NPY Y5 receptor antagonistic action. This is considered to be due to the action specific to the compound represented by the formula (I). A compound having an action of suppressing the digestion and absorption of nutrients exhibits an effect of enhancing feeding while showing an action of suppressing weight gain as described in Non-Patent Document 2, Non-Patent Document 3, and the like. The present inventor also shows that the combined use of a compound having an inhibitory action on digestion and absorption of nutrients and a compound represented by formula (I) suppresses the feeding enhancement effect induced by the compound having an inhibitory action on digestion and absorption of nutrients. I found. Therefore, it is considered that the pharmaceutical composition of the present invention can exhibit a very strong weight-loss effect as compared with a single agent of a compound having an action to suppress digestion and absorption of nutrients. Therefore, the pharmaceutical composition of the present invention is very useful as an agent for treating or preventing obesity.

That is, the present invention relates to the following.
(1) a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(2) The pharmaceutical composition according to (1), wherein the pharmaceutical composition is a combination drug.
(3) A pharmaceutical composition comprising a compound having a nutrient digestive absorption inhibitory action, a pharmaceutically acceptable salt thereof, or a solvate thereof, and formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group The pharmaceutical composition according to (1), which comprises a drug containing a compound represented by (2), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the compound having an action to inhibit digestion and absorption of nutrients is a compound having an action to inhibit fat absorption.
(5) The pharmaceutical composition according to (4), wherein the compound having an action of inhibiting fat absorption is a compound having an action of inhibiting pancreatic lipase.
(6) The pharmaceutical composition according to (5), wherein the compound having pancreatic lipase inhibitory action is orlistat.
(7) The compound represented by the formula (I) is

The pharmaceutical composition according to any one of (1) to (6), which is a compound represented by the formula:
(8) The pharmaceutical composition according to any one of (1) to (7), which is used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
(9) Obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, lipid metabolism disorder, arteriosclerosis, hyperuricemia, gout, fatty liver, endometrial cancer, breast cancer, prostate cancer, (8) The pharmaceutical composition according to (8), which is colorectal cancer, osteoarthritis, low back pain, obstructive sleep apnea syndrome, coronary artery disease, cerebral infarction, menstrual abnormality, Praderwilli syndrome, Frehrich syndrome or Pickwick syndrome.
(10) Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof,
An agent for enhancing the effect of preventing or treating obesity or obesity-related diseases of a drug containing a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof.
(11) containing a compound having an action to inhibit digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group Or a pharmaceutically acceptable salt thereof or a solvate thereof, an agent for enhancing the effect of preventing or treating obesity or obesity-related diseases.
(12) Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a drug containing a solvate thereof,
A drug comprising a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(13) for use in combination with a compound containing a nutrient digestive absorption inhibitory action, a pharmaceutically acceptable salt thereof or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(14) The drug according to (12) or (13), which is used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity.

Furthermore, the following invention is also included in the scope of the present invention.
(15) a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof in combination, and a method for preventing or treating obesity or obesity-related diseases or for managing weight in obesity.
(16) To produce a pharmaceutical composition used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity,
A compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof, and
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(17) a compound having an action to inhibit digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof in combination. A method of inducing or promoting weight loss, or maintaining or managing body weight.
(18) for producing a pharmaceutical composition used for inducing or promoting weight loss, or for maintaining or managing body weight;
A compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof, and
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(19) Inducing or promoting weight loss, or maintaining or managing body weight,
A compound having an action of inhibiting the digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(20) Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group And the step of administering a pharmaceutically acceptable salt or solvate thereof,
A method for enhancing the effect of preventing or treating obesity or an obesity-related disease of a drug containing a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(21) A method for producing a potentiating agent for preventing or treating obesity or obesity-related diseases of a drug containing a compound having an action to suppress digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(22) To enhance the prevention or treatment effect of obesity or obesity-related diseases of a drug containing a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(23) including a step of administering a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group The method of enhancing the prevention or treatment effect of the obesity or obesity related disease of the chemical | medical agent containing the compound shown by these, its pharmaceutically acceptable salt, or those solvates.
(24) Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group For producing an agent for enhancing the preventive or therapeutic effect of obesity or obesity-related diseases of a drug containing a compound represented by (2), a pharmaceutically acceptable salt thereof, or a solvate thereof:
Use of a compound having a digestive absorption inhibitory action on nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(25) Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group For enhancing the prophylactic or therapeutic effect of obesity or obesity-related diseases of a drug containing a compound represented by (1), a pharmaceutically acceptable salt thereof or a solvate thereof,
A compound having a digestive absorption inhibitory effect on nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(26) a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof,
(1) The manufacturing method of the pharmaceutical composition of description.

The pharmaceutical composition of the present invention is very useful as a therapeutic or prophylactic agent for obesity or obesity-related diseases. In addition, the pharmaceutical composition is very useful for weight management in obesity.

Cumulative body weight change after 4 weeks of administration to obese model mice Difference in body weight between control and treatment groups on the last day of the study

“A compound having an action of inhibiting the digestion and absorption of nutrients” is known as a drug for preventing or treating obesity, and examples thereof include a compound having an action of inhibiting carbohydrate absorption, a compound having an action of inhibiting fat absorption, and the like. As a compound having a carbohydrate absorption inhibitory action, an α-glucosidase inhibitor (acarbose, a compound that inhibits the action of an enzyme that decomposes disaccharides into monosaccharides and suppresses carbohydrate absorption from the digestive tract to the bloodstream) Voglibose et al .: Japanese Pharmacology Journal 118: 340-346 (2001), Pharmacology Biochemistry Behavior 19: 71-78 (1983)), SGLT-2 inhibitor (dapagliflozin, a compound that suppresses carbohydrate reabsorption from the kidney) Remogliflozin, KGT-1075, etc .: Journal of Medicinal Chemistry 52 (7): 1785-1794 (2009)). As the “compound having an inhibitory action on digestion and absorption of nutrients” in the present application, dapagliflozin, remogliflozin, a compound having an action of suppressing fat absorption, and the like are preferable.
The “compound having a fat absorption inhibitory effect” includes a lipase inhibitor (a compound having a gastric lipase inhibitory action, a compound having a pancreatic lipase inhibitory action, etc.), a bile acid adsorption resin and the like.
“Bile acid adsorption resin” includes cholestyramine, cholestyramide and the like. The anion exchange resins cholestyramine and cholestyramide bind to bile acids in the digestive tract and inhibit fat absorption (Expert Opinion on Investigational Drugs 15: 1337-51 (2006)).
“Compounds having pancreatic lipase inhibitory activity” include orlistat, lipstatin, pancricin, cetiristat and the like. Lipstatin (US Pat. No. 4,598,089) is a natural product of microbial origin, and orlistat is a hydrogenated version of lipstatin. Pancrisin is an analogue of orlistat (Journal of Antibiotics, 47 (12): 1369-1375 (1994)). Cetiristat is a pancreatic lipase inhibitor with a different chemical structure from orlistat (Current Opinion in Investigational Drugs 9: 414-21 (2008)).
“Orlistat” is a known compound for the control or prevention of obesity and dyslipidemia. Its chemical name is N-formyl-L-leucine, ester with (3S, 4S) -3-hexyl-4-[(2S) -2-hydroxytridecyl] -2-oxetanone. Non-patent document 1 describes orlistat's weight gain inhibitory action. A method for producing orlistat, drugs and the like are disclosed below. US Pat. No. 4,598,089, US Pat. No. 5,246,960, US Pat. No. 4,931,463, US Pat. No. 5,175,186, US Pat. No. 4,983,746, US Pat. No. 5,245,056, US Pat. No. 5,399,720, International Publication No. WO97 / 032409, International Publication No. WO00 / 09122, International Publication No. WO00 / 09123, European Patent No. 524495.

“A compound having an inhibitory action on the digestion and absorption of nutrients” exhibits an effect of enhancing feeding in addition to the inhibitory action on the digestion and absorption of nutrients. Non-Patent Document 3 describes that dapagliflozin, which is a compound having an inhibitory action on carbohydrate absorption, shows an effect of enhancing feeding while showing an inhibitory action on weight gain. Furthermore, Non-Patent Document 2 describes that orlistat, which is a compound having a fat absorption inhibitory action, exhibits a body weight gain inhibitory action while exhibiting an eating enhancing action.

The cyclohexane carboxamide derivative used in the pharmaceutical composition of the present invention is a compound shown below.
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.

“Alkyl” means straight or branched alkyl having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, Examples include n-nonyl and n-decyl. R ¹ is particularly preferably isopropyl or t-butyl.

As the substituent of “alkyl”, for example,
(1) halogen;
(2) cyano;
(3) (i) hydroxy, (ii) alkoxy, (iii) mercapto, (iv) alkylthio, each optionally substituted with one or more substitutable groups selected from the substituent group β defined below. (V) acyl, (vi) acyloxy, (vii) carboxy, (viii) alkoxycarbonyl, (ix) imino, (x) carbamoyl, (xi) thiocarbamoyl, (xii) alkylcarbamoyl, (xiii) alkylthiocarbamoyl, xiv) amino, (xv) alkylamino, (xvi) heterocyclic carbonyl and the like.

Substituent group β is halogen, optionally protected hydroxy, mercapto, alkoxy, alkenyl, amino, alkylamino, alkoxycarbonylamino, alkylthio, acyl, carboxy, alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, phenoxy , Alkylphenyl, alkoxyphenyl, halogenophenyl, naphthyl and heterocyclic groups.

“Alkenyl” means a straight or branched alkenyl having 2 to 10 carbon atoms having one or more double bonds at an arbitrary position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.

Substituents for “alkenyl” include halogen, alkoxy, alkenyl, amino, alkylamino, alkoxycarbonylamino, alkylthio, acyl, carboxy, alkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, alkylphenyl, alkoxyphenyl, naphthyl and Examples thereof include one or more substituents selected from heterocyclic groups.

“Alkoxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.

The substituent of “alkoxy” includes one or more groups selected from the above substituent group β, and is preferably phenyl, alkylphenyl, alkoxyphenyl, naphthyl, or a heterocyclic group.

"Alkylthio", "alkylcarbamoyl", "alkylthiocarbamoyl", "alkylamino", "alkylsulfinyl", "alkylsulfonyl", "alkylsulfamoyl", "hydroxyalkyl", "alkylphenyl", "alkoxyalkyl" , “Halogenoalkyl” or “phenylalkylthio” is the same as the above “alkyl”.

The alkoxy moiety of “alkoxycarbonyl”, “alkoxyalkyl”, “alkoxycarbonylamino”, “alkoxyphenyl” or “phenylalkoxy” is the same as the above “alkoxy”.

As the substituent of “amino”, the above substituent group β, substituted or unsubstituted benzoyl and substituted or unsubstituted heterocyclic carbonyl (wherein the substituent is one or more selected from hydroxy, alkyl, alkoxy and alkylthio) 1 or more substituents selected from (substituents).

“Hydrocarbon cyclic group” includes “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl” and “aryl”.
“Cycloalkyl” means cyclic alkyl having 3 to 8 carbon atoms. Includes 5 or 6 cyclic alkyls. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
“Cycloalkenyl” means one having one or more double bonds at any position in the cycloalkyl ring. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like.
“Bicycloalkyl” means a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two rings share two or more atoms. Specific examples include bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl.
“Aryl” means a monocyclic or polycyclic aromatic carbocyclic group. Including phenyl, naphthyl, anthryl, phenanthryl and the like. Also included are aryls fused with other non-aromatic hydrocarbon cyclic groups. For example, indanyl, indenyl, biphenylyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned. Particularly preferred is phenyl.

Examples of the substituent of the “hydrocarbon cyclic group” include one or more groups selected from the substituent group α and the above substituent group β, and any position may be substituted.

Substituent group α is (1) halogen;
(2) oxo;
(3) Cyano;
(4) Nitro;
(5) an imino optionally substituted with alkyl or hydroxy;
(6) (i) hydroxy, (ii) alkyl, (iii) alkenyl, (iv) alkoxy, (v) carboxy, each optionally substituted with one or more substitutable groups selected from substituent group β , (Vi) alkoxycarbonyl, (vii) acyl, (viii) acyloxy, (ix) imino, (x) mercapto, (xi) alkylthio, (xii) carbamoyl, (xiii) alkylcarbamoyl, (xiv) cycloalkylcarbamoyl, (Xv) thiocarbamoyl, (xvi) alkylthiocarbamoyl, (xvii) alkylsulfinyl, (xviii) alkylsulfonyl, (xix) sulfamoyl, (xx) alkylsulfamoyl and (xxi) cycloalkylsulfamoyl;
(7) each substituted with one or more substituents selected from substituent group β, alkyl, alkoxyalkyl, optionally protected hydroxyalkyl, halogenoalkyl, alkylsulfonyl and arylsulfonyl, (i) Cycloalkyl, (ii) cycloalkenyl, (iii) cycloalkyloxy, (iv) amino and (v) alkylenedioxy; and (8) one or more selected from the substituent group β, alkyl, halogenoalkyl and oxo, respectively. Optionally substituted (i) phenyl, (ii) naphthyl, (iii) phenoxy, (iv) phenylalkoxy, (v) phenylthio, (vi) phenylalkylthio, (vii) phenylazo, (viii) hetero Cyclic group, (ix) heterocyclic oxy, (x) heterocyclic thio O, (xi) heterocyclic carbonyl and (xii) heterocyclic sulfonyl.

The cycloalkyl part of “cycloalkylcarbamoyl”, “cycloalkylsulfamoyl” and “cycloalkyloxy” is the same as the above “cycloalkyl”.
The aryl part of “arylsulfonyl” is the same as the above “aryl”.

“Heterocyclic group” means a group derived from a heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring. For example, a 4- to 8-membered (preferably 5- to 7-membered) ring or a ring obtained by condensing 2 to 3 of these rings, wherein at least one ring is a hetero atom optionally selected from O, S and N A group derived from a ring having 1 to 3 rings in the ring. When a plurality of rings are condensed rings, any ring may have a bond.
Specifically, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, indolyl, isoindolyl, indazolyl, indolylinyl , Isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, Thiadiazolyl, benzofuryl, isobenzofuryl, ben Thienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, naphthyridinyl, tetrahydroquinolyl, tetrahydrobenzothienyl, carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathii Nyl, phenoxazinyl, dibenzofuryl, dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl Tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothi It encompasses Zoriru like. Particularly preferred are imidazolyl, benzothiazolyl, isothiazolyl, benzopyranyl, morpholino, pyridyl, quinolyl and pyrimidyl.
Examples of the substituent of the “heterocyclic group” are the same as those in the case where the “hydrocarbon cyclic group” is substituted.
The heterocyclic moiety of “heterocyclic oxy”, “heterocyclic thio”, “heterocyclic carbonyl” and “heterocyclic sulfonyl” is the same as the above “heterocyclic group”.

“Acyl” includes the following.
(1) Linear or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10, preferably 1 to 6, and more preferably 1 to 4 carbon atoms.
(2) Cycloalkylcarbonyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms.
(3) Arylcarbonyl having 7 to 11 carbon atoms.
Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
The acyl part of “acyloxy” is the same as above.

Protecting groups for “optionally protected hydroxy” and “optionally protected hydroxyalkyl” include all commonly used hydroxy protecting groups. For example, acyl (acetyl, trichloroacetyl, benzoyl etc.), alkoxycarbonyl (t-butoxycarbonyl etc.), alkylsulfonyl (methanesulfonyl etc.), alkoxyalkyl (methoxymethyl etc.), trialkylsilyl (t-butyldimethylsilyl etc.), etc. Is mentioned.

“Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
The halogen part of “halogenophenyl” and “halogenoalkyl” is the same as the above “halogen”.

“Alkylene” means a divalent group of 1 to 6 consecutive methylenes. A divalent group in which 2 to 6 methylenes are continuous and a divalent group in which 3 to 6 methylenes are continuous are included. Examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Particularly preferred is tetramethylene.
The alkylene part of “alkylenedioxy” is the same as the above “alkylene”, preferably methylenedioxy or ethylenedioxy.

When the compound represented by the formula (I) has an asymmetric carbon atom, it includes racemates and all stereoisomers (diastereomers, enantiomers, etc.). Further, when the compound represented by the formula (I) has one or more double bonds and geometric isomers exist for the substituent arrangement of the double bonds, both of them are included.

“Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, And salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.

Examples of the “solvate” include a hydrate of a compound or a salt thereof, an alcohol solvate, and the like. For example, monohydrate, dihydrate, monoalcohol hydrate, dialcohol solvate and the like can be mentioned.

The prodrug of the compound contained in the pharmaceutical composition of the present invention is included in the range of the compound contained in the pharmaceutical composition of the present invention. The prodrug of the compound contained in the pharmaceutical composition of the present invention is a functional derivative of the compound contained in the pharmaceutical composition of the present invention, and the compound contained in the pharmaceutical composition of the present invention is easily converted in vivo. Converted. Therefore, the “compound” contained in the pharmaceutical composition of the present invention is a compound specifically disclosed as an element of the pharmaceutical composition of the present invention or, in some cases, a compound not specifically disclosed, but obesity and And a compound that is converted into the specific compound in vivo after administration to a patient with an obesity-related disease. The usual procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs ed (ed. H. Bundgaard, Elsevier, 1985).

As the compound represented by the formula (I) used in the pharmaceutical composition of the present invention, the following compounds, pharmaceutically acceptable salts thereof, or solvates thereof are particularly preferable.

More preferably, the following compounds are mentioned.

Non-patent document 6 describes the weight gain inhibitory action of the compound represented by the formula (I). Patent Document 5 describes that the compound represented by the formula (I) shows not only a weight gain inhibitory action but also an eating inhibitory action.

The compound represented by the formula (I) used in the above pharmaceutical composition of the present invention is International Publication No. WO01 / 37826, International Publication No. WO2003 / 076374, International Publication No. WO2006 / 001318, Japanese Unexamined Patent Publication No. 2005-255630. It can be prepared by the method described in 1.

Specifically, the following method is mentioned, for example.

(In the formula, Hal is halogen, and other symbols are as defined above.)
Process A
Compound (IV) is reacted with compound (V) having substituent R ¹ corresponding to the target compound in an appropriate solvent in the presence of a base, if necessary, to give compound (II).
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water, and mixed solvents thereof. Can be mentioned. Preferred are dioxane, dichloromethane and the like.
Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
The reaction temperature is about 0 ° C. to 50 ° C., preferably about 20 ° C. to 30 ° C.
The reaction time is about 5 minutes to 30 hours, preferably about 5 to 20 hours.
As the compounds (IV) and (V), known compounds may be used, or compounds synthesized from known compounds by a conventional method may be used.

Process B
Compound (II) is reacted with compound (III) having substituents Z and R ² corresponding to the target compound in a suitable solvent.
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water, and mixed solvents thereof. Can be mentioned. Preferred are dimethylformamide, tetrahydrofuran, ethyl acetate and the like.
If necessary, a condensing agent such as 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylamino) carbodiimide (WSCD; water-soluble carbodiimide) and / or 1-hydroxybenzotriazole, 3,4 The reaction may be carried out in the presence of an acidic additive such as dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine.
The reaction temperature is about 0 ° C. to 50 ° C., preferably about 20 to 30 ° C.
The reaction time is about 5 minutes to 30 hours, preferably about 5 to 20 hours.

If necessary, the amino group of the compound may be protected by a conventional method at an appropriate stage. As the protecting group, phthalimide, alkoxycarbonyl, alkenyloxycarbonyl, halogenoalkoxycarbonyl, arylalkoxycarbonyl, trialkylsilyl, alkylsulfonyl, halogenoalkylsulfonyl, arylsulfonyl, alkylcarbonyl, arylcarbonyl and the like can be used.
After the protection, it is subjected to the reaction in each of the above steps, and may be deprotected by treating with an acid or base in an appropriate solvent at an appropriate stage. As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof are used. Examples of the base include hydrazine, pyridine, sodium hydroxide, and potassium hydroxide, and examples of the acid include hydrochloric acid, trifluoroacetic acid, hydrofluoric acid, and the like.

The pharmaceutical composition of the present invention is useful for the prevention or treatment of diseases associated with excessive fat accumulation in the body due to excessive food intake and lack of exercise, such as obesity and obesity-related diseases.

“Obesity” is defined as an excessive accumulation of adipose tissue, but at present there is no accurate, simple and practical method for measuring body fat mass, and an index required from height and weight, body mass index ( BMI) is used. BMI is defined as body weight per height (kg / m ² ) expressed in square meters. According to definitions by the World Health Organization and the National Institutes of Health, patients with a BMI of 25 kg / m ² or more are determined to be overweight, and patients with a 30 kg / m ² or more are determined to be obese.
However, compared with Caucasians, the incidence of obesity-related diseases increases in Orientals with a lower body mass index (BMI). For example, in Japan, there are many patients who develop one or more obesity-related diseases such as diabetes and dyslipidemia even when the BMI is about 25 kg / m ² . Therefore, the Japanese Society for Obesity defines BMI of 25 kg / m ² or more as obesity.

An obese patient in need of medical intervention is a person who has a BMI of 30 kg / m ² or more and develops an obesity-related disease, a person who has a BMI of 30 kg / m ² or more and has not developed an obesity-related disease, or For example, a person who develops at least two obesity-related diseases has a BMI of 25 kg / m ² or more and / or a visceral fat area (VFA) of 100 cm ² or more. Examples of obesity-related diseases include hypertension, impaired glucose tolerance, diabetes, dyslipidemia, dyslipidemia, hyperuricemia, gout, fatty liver, coronary artery disease, cerebral infarction and the like.

As used herein, “obesity” (obesity) includes obesity caused by any cause including genetic or environmental.

“An obesity-related disease” is a disease associated with, caused by, or caused by obesity. Examples of obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, dyslipidemia, dyslipidemia, arteriosclerosis, hyperuricemia, gout, fatty liver, endometrial cancer, breast cancer , Prostate cancer, colon cancer, osteoarthritis, low back pain, obstructive sleep apnea syndrome, coronary artery disease (coronary heart disease), cerebral infarction, menstrual abnormalities, Praderwilli syndrome, Freirich syndrome, Pickwick syndrome, etc. It is done. The pharmaceutical composition of the present invention is also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy. The pharmaceutical composition of the present invention is also useful for the treatment of Alzheimer's disease.

“Metabolic syndrome” is defined in the 3rd report (ATP-III) of the “National Cholesterol Education Plan Expert Panel on Detection, Evaluation, and Treatment of Adult High Blood Cholesterol” (ES Ford) JAMA, vol. 287 (3), January 16, 2002, p356-359). Briefly, a person with three or more symptoms of abdominal obesity, excess triglycerides, low HDL cholesterol, hypertension, fasting hyperglycemia is defined as a metabolic syndrome.

“Diabetes” includes both insulin-dependent diabetes (IDDM®, type I diabetes) and non-insulin-dependent diabetes (NIDDM, type II diabetes). Type I diabetes is caused by an absolute deficiency of insulin, a hormone that regulates glucose utilization. Type II diabetes occurs even when insulin levels are normal or elevated and occurs because the tissue is unable to respond properly to insulin. Many patients with type II diabetes are also obese. The pharmaceutical compositions of the present invention are useful for the treatment of both type I and type II diabetes. The pharmaceutical composition of the present invention is particularly effective for the treatment of type II diabetes. The pharmaceutical composition of the present invention is also useful for the treatment and / or prevention of gestational diabetes.

“Treatment” for obesity and obesity-related diseases refers to administration of the pharmaceutical composition of the present invention to reduce or maintain the weight of obese patients. As a result of the treatment, it is possible to reduce the weight of the obese patient compared to the weight of the obese patient just before the start of administration of the pharmaceutical composition of the invention. As another outcome of treatment, it is possible to prevent weight loss resulting from past diet, exercise, or medication from being reweighted. Another outcome of treatment is the development and / or reduction in severity of obesity-related diseases. As a result of treatment, maintenance of weight loss or weight management is possible. Treatment appropriately reduces the patient's food and caloric intake, including reduced total food intake or reduced intake of certain food ingredients such as carbohydrates and fats, impaired nutrient absorption, reduced metabolic rate It is possible to suppress the weight of a patient who needs to be suppressed or lose weight, or to manage the weight. Treatment can result in changes in metabolic rate, such as increased metabolic rate, and / or minimize metabolic resistance normally caused by weight loss, rather than suppression or additional suppression of metabolic rate reduction It is.

“Prevention” of obesity and obesity-related diseases refers to administration of the pharmaceutical composition of the present invention to reduce or maintain the weight of a person at risk for obesity. As a result of prevention, the weight of the subject can be reduced compared to the weight of a person at risk for obesity immediately before the start of administration of the pharmaceutical composition of the invention. Another outcome of prevention is to prevent weight loss as a result of past diet, exercise or drug therapy from being reweighted (weight management). Another consequence of prevention is the prevention of the development of obesity when a person at risk for obesity is treated before it begins. Another outcome of prevention is the development of obesity-related diseases and / or reduction in severity when treatment is performed before obesity begins in a person at risk for obesity. Another consequence of prevention is an extension of resistance to weight gain. Another consequence of prevention is the prevention of weight reweighting. Furthermore, when starting treatment for a patient who is already obese, the above “treatment” can prevent the onset, progression or severity of an obesity-related disease.

The pharmaceutical composition of the present invention comprises:
A compound having an action of inhibiting the digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group A pharmaceutical composition comprising a combination of the compounds represented by
Here, the “pharmaceutical composition to be combined” includes an embodiment in which each compound is used as a combination and an embodiment in which the compounds are administered simultaneously.
The present invention also includes a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof,
The manufacturing method of said pharmaceutical composition is also included.
In detail, the pharmaceutical composition of the present invention includes:
A compound having an action of inhibiting the digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group Or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising
A compound comprising a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof or a solvate thereof.

The pharmaceutical composition of the present invention comprises a compound having an action of inhibiting digestion and absorption of the nutrient used, a pharmaceutically acceptable salt or solvate thereof, and a compound represented by the formula (I), a pharmaceutically acceptable It is not limited to the quantity ratio of a salt or those solvates.

When the pharmaceutical composition of the present invention is a compounding agent, the compound having the action of inhibiting digestion and absorption of the compounded nutrient, the compound represented by the formula (I) for its pharmaceutically acceptable salt or solvate thereof, The weight ratio of the pharmaceutically acceptable salt or solvate thereof is, for example, 100: 1 to 1: 100, preferably 10: 1 to 1:10, more preferably 5: 1 to 1: 5. It is.

When the pharmaceutical composition of the present invention is a kit, a compound having a digestive absorption inhibitory action of nutrients provided in the kit, a pharmaceutically acceptable salt thereof or a compound represented by the formula (I) for a solvate thereof, The weight ratio of the pharmaceutically acceptable salt or solvate thereof is, for example, 100: 1 to 1: 100, preferably 10: 1 to 1:10, more preferably 5: 1 to 1: 5. It is.

Examples of the kit that is the pharmaceutical composition of the present invention include the following kits, but these do not limit the present invention.
a) In the same package
A first orally-administered drug comprising a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient, and
A kit comprising a second orally administered drug comprising a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient.
b) In the same package
A compound having a digestive absorption inhibitory effect on nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof as an admixture with a pharmaceutically acceptable carrier and / or excipient, and
A kit comprising a vial for intravenous infusion comprising a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient.
c) In the same package
A first enclosing chamber containing a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient; and
A kit (infusion pack) comprising a second enclosing chamber containing the compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient. ).
d) In the same package
A compound having a nutrient digestive absorption inhibitory action, a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient, and
A kit comprising a package insert describing a method of use in combination with a drug containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.
e) In the same package
A drug comprising a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof as a mixture with a pharmaceutically acceptable carrier and / or excipient, and
A kit comprising a package insert describing a method of using a compound having a digestive absorption inhibitory action of a nutrient, a pharmaceutically acceptable salt thereof, or a drug containing a solvate thereof in combination.

The number of each vial, each drug, etc. contained in one package of the kit is not limited. For example, there are 1 to 5 each vial or each drug. Preferably, there are 1 to 3 each vial or each drug.

In the present specification, “drug” means a composition containing a compound as an active ingredient. “Orally administered drug” means a drug administered using an oral route of administration.

When the pharmaceutical composition of the present invention is used as a kit, a drug containing the compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is pre-administered, and then digestion and absorption of nutrients You may administer the chemical | medical agent containing the compound which has an inhibitory effect, its pharmaceutically acceptable salt, or those solvates.
In another embodiment, a compound containing a nutrient digestive absorption inhibitor, a pharmaceutically acceptable salt thereof or a drug containing a solvate thereof is pre-administered, and then a compound represented by formula (I): An agent containing the pharmaceutically acceptable salt or solvate thereof may be administered.
In another aspect, a compound containing a nutrient digestive absorption inhibitor, a pharmaceutically acceptable salt or solvate thereof, a compound represented by formula (I), and a pharmaceutically acceptable Or a salt-containing solvate may be administered simultaneously.

The drug used in the pharmaceutical composition of the present invention can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered.

Excipients, binders, wetting agents suitable for the dosage form of an effective amount of a compound (a compound having an action of inhibiting digestion and absorption of nutrients or a compound represented by formula (I)) used in the pharmaceutical composition of the present invention, Various pharmaceutical additives such as a disintegrant, a lubricant, and a diluent can be mixed as necessary to obtain a pharmaceutical preparation. In the case of injections, the active ingredient may be sterilized with an appropriate carrier to give a preparation.

Examples of the excipient include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like.
Examples of the binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone.
Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate.
Examples of the lubricant include talc, magnesium stearate or macrogol.
As a suppository base, cacao butter, macrogol, methyl cellulose, or the like can be used.
When preparing as a liquid or emulsion or suspension injection, add commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. Also good. In the case of oral administration, flavoring agents, fragrances and the like may be added.

The dose of the drug used in the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, administration route, etc., but it is effective when administered orally to adults. The compound having the action of inhibiting digestion and absorption of nutrients used in the pharmaceutical composition of the present invention as a component or the compound represented by the formula (I) is usually 0.05 to 100 mg / kg / day, preferably 0.1 Within the range of -50 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, the compound having the action of inhibiting the digestion and absorption of nutrients used in the pharmaceutical composition of the present invention, which is an active ingredient, or the compound represented by the formula (I) is usually 0. 005 to 50 mg / kg / day, preferably 0.01 to 10 mg / kg / day. This may be administered once to several times a day.

When the compound having the action of inhibiting the digestion and absorption of nutrients contained in the drug in the kit of the present invention is orlistat, the drug is administered 1 to 3 times a day or in a form of sustained release. About 20 mg to about 1200 mg per day, preferably about 60 mg to about 600 mg, more preferably about 120 mg to about 400 mg can be administered. More preferably, 120 mg of the drug is administered three times a day or in a sustained release form. Formulation of a drug containing orlistat in the kit of the present invention is also disclosed in, for example, US Pat. No. 6,0049,996.

Examples of the method of using the pharmaceutical composition of the present invention include the following, but these do not limit the present invention.
(1) A compound having an action to inhibit digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof, and a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof Of obesity or obesity-related diseases administered together as part of the same drug (prophylaxis or treatment method of administering the above-mentioned combination preparation).
(2) a compound having a digestive absorption inhibitory action of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof as part of an appropriate administration regime for the purpose of obtaining a combination therapy benefit; A method of preventing or treating obesity or obesity-related diseases, wherein a drug containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is separately administered (prevention or Method of treatment).

Appropriate dosing regimens, doses for each administration, and specific dosing intervals for each drug will depend on the specific combination of drugs used, the condition of the patient and the severity of the condition, etc.

Examples of administration regimes include the following. These do not limit the dosage regimen of the pharmaceutical composition of the present invention.
(1) of a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof, and a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof The combination is administered once to three times a day.
(2) A compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a compound containing a solvate thereof, a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a salt thereof Drugs containing solvates are co-administered once to three times daily.
(3) A compound comprising a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, administered once a day and having an action of inhibiting digestion and absorption of nutrients; Drugs containing acceptable salts or solvates thereof are administered 1 to 3 times daily.
(4) A compound containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is administered, and after several days to several weeks, a compound represented by formula (I), A drug containing a pharmaceutically acceptable salt or a solvate thereof and a compound having an action to inhibit digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a drug containing a solvate thereof are used in combination.
(5) A compound having the action of inhibiting the digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a drug containing a solvate thereof, and a compound represented by the formula (I) after several days to several weeks , A pharmaceutically acceptable salt thereof or a drug containing a solvate thereof, and a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a drug containing a solvate thereof .

The pharmaceutical composition of the present invention can also be used in combination with other antiobesity agents. Moreover, the pharmacotherapy by administration of the pharmaceutical composition of the present invention can be used in combination with diet therapy, exercise therapy, other drug therapy, and the like.

“Diet therapy” includes reduced diet therapy, low calorie diet (LCD) therapy, very low calorie diet (VLCD) therapy, reduced calorie diet (RCD) therapy, and the like.
“Reduced diet” is a light diet that reduces daily calorie intake to about 1200 kcal.
“Low calorie diet” is a diet that limits the daily calorie intake to about 600-1000 kcal. For example, the low-calorie is ingested by a well-balanced diet, the low-calorie is ingested by a diet rich in special nutrients such as a high-fat diet, a low-calorie diet, and a high-protein, low-calorie diet.
“Very low calorie diet” is a diet that limits the daily calorie intake to about 200-600 kcal. Semi-starvation therapy for severely obese people.
The “reduced calorie diet” is a diet therapy in which a meal obtained by subtracting about 800 kcal from the necessary daily calorie amount calculated from the basal metabolism is taken.

When using the pharmaceutical composition of the present invention in combination with anti-obesity therapy, various dosage regimens can be utilized. Examples include the following.
(1) Diet therapy and / or exercise therapy and drug therapy using the pharmaceutical composition of the present invention are started simultaneously.
(2) In order to start drug therapy using the pharmaceutical composition of the present invention, diet therapy and / or exercise therapy is performed for several days to several weeks, and the body weight is reduced to some extent.

The present invention also includes the following modes.
-A compound having an action to inhibit digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof in combination. A method of inducing or promoting weight loss, or maintaining or managing body weight.
The compound having the action of inhibiting the digestion and absorption of nutrients and the compound represented by the formula (I) contained in the pharmaceutical composition of the present invention have an action of inducing weight suppression, a function of promoting weight suppression and It shows the action of maintaining or managing body weight.

Further, the present invention includes the following.
-Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof,
An agent for enhancing the effect of preventing or treating obesity or obesity-related diseases of a drug containing a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
-Containing a compound having an action to inhibit digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof or a solvate thereof,
Formula (I):

Wherein R ¹ is alkyl,
R ² is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group Or a pharmaceutically acceptable salt thereof or a solvate thereof, an agent for enhancing the effect of preventing or treating obesity or obesity-related diseases.
The compound having the action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof is obesity of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. The effect of preventing or treating obesity-related diseases can be enhanced. The compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound having an action to suppress digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or an obesity of a solvate thereof. The effect of preventing or treating obesity-related diseases can be enhanced. Therefore, the pharmaceutical composition of the present invention can prevent or treat obesity or obesity-related diseases very efficiently compared to the case where each compound is used alone.

Hereinafter, the present invention will be described in more detail with reference to examples carried out using orlistat as a compound having an action of inhibiting digestion and absorption of nutrients and using compound (a) as a compound represented by formula (I). Does not limit the invention.

Seven-week-old male C57BL / 6J mice (20.4-24.2 g, purchased from CLEA Japan, Inc.) were fed with a high fat diet (Test Diet) for 5 weeks to induce obesity. Thereafter, an aqueous solution of 0.5% hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) was orally administered twice a day (8: 30-11: 00: 00, 14: 30-17: 00 pm) for 4 weeks. Accustomed to it. The mice were divided into the following 6 groups based on the weight of the mice and the average weight change during the 4-week acclimatization period. That is, control group (0.5% hydroxypropylmethylcellulose 10 ml / kg), compound (a) 50 mg / kg group, orlistat 12.5 mg / kg group, orlistat 25 mg / kg group, compound (a) 50 mg / kg + orlistat 12. 5 mg / kg group, compound (a) 50 mg / kg + orlistat 25 mg / kg group. Twice a day (8: 30-11: 00 AM, 15: 00-18: 00 PM), continuous administration was performed for 4 weeks. The mouse body weight at the start of drug administration was 30.1-34.9 g. As a result of continuous administration for 4 weeks, the average body weight was 0.9 g of suppression in the compound (a) 50 mg / kg group, 0.6 g of suppression in the orlistat 12.5 mg / kg group, and 25 mg / kg in the orlistat group compared to the control group. It became 2.1g suppression. In the co-administration group, the suppression was 2.5 g in the compound (a) 50 mg / kg + orlistat 12.5 mg / kg group, and the suppression was 4.2 g in the compound (a) 50 mg / kg + orlistat 25 mg / kg group. From these results, when the compound (a) and orlistat were co-administered, an effect of suppressing body weight more than additive was observed. That is, the effect more than the addition compared with the sum of the action of each drug alone was obtained (see FIG. 1 and FIG. 2. In FIG. 2, the compound (a) + orlistat is 50 mg / kg of the compound (a). kg + Orlistat 25 mg / kg group).
On the other hand, the amount of food intake for 4 weeks was 2.5 g of suppression in the compound (a) 50 mg / kg group, an increase of 7.6 g in the orlistat 12.5 mg / kg group, and 14 in the orlistat 25 mg / kg group compared to the control group. Increased by 5 g. In the co-administration group, the increase was 7.4 g in the compound (a) 50 mg / kg + orlistat 12.5 mg / kg group, and in the compound (a) 50 mg / kg + orlistat 25 mg / kg group, the increase was 8.4 g. These results indicate that the feeding enhancement effect of orlistat is suppressed by co-administration with compound (a).

Claims

A compound having an action of inhibiting the digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R 1 is alkyl,
R 2 is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a combination drug.
A pharmaceutical composition comprising a compound having a nutrient digestive absorption inhibitory activity, a pharmaceutically acceptable salt thereof or a solvate thereof and a formula (I):

Wherein R 1 is alkyl,
R 2 is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group The pharmaceutical composition of Claim 1 which is a kit containing the chemical | medical agent containing the compound shown by this, its pharmaceutically acceptable salt, or those solvates.
The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound having an inhibitory action on digestion and absorption of nutrients is a compound having an action of suppressing fat absorption.
The pharmaceutical composition according to claim 4, wherein the compound having a fat absorption inhibitory action is a compound having a pancreatic lipase inhibitory action.
The pharmaceutical composition according to claim 5, wherein the compound having pancreatic lipase inhibitory action is orlistat.
The compound of formula (I) is

The pharmaceutical composition according to any one of claims 1 to 6, which is a compound represented by the formula:
The pharmaceutical composition according to any one of claims 1 to 7, which is used for prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
Obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, lipid metabolism disorder, arteriosclerosis, hyperuricemia, gout, fatty liver, endometrial cancer, breast cancer, prostate cancer, colon cancer, The pharmaceutical composition according to claim 8, which is osteoarthritis, low back pain, obstructive sleep apnea syndrome, coronary artery disease, cerebral infarction, menstrual abnormality, Praderwilli syndrome, Frehrich syndrome or Pickwick syndrome.
Formula (I):

Wherein R 1 is alkyl,
R 2 is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof,
An agent for enhancing the effect of preventing or treating obesity or obesity-related diseases of a drug containing a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Containing a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula (I):

Wherein R 1 is alkyl,
R 2 is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group Or a pharmaceutically acceptable salt thereof or a solvate thereof, an agent for enhancing the effect of preventing or treating obesity or obesity-related diseases.
Formula (I):

Wherein R 1 is alkyl,
R 2 is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a drug containing a solvate thereof,
A drug comprising a compound having an action of inhibiting digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof.
For use in combination with a compound having a nutrient digestive absorption inhibitory action, a pharmaceutically acceptable salt thereof or a solvate thereof,
Formula (I):

Wherein R 1 is alkyl,
R 2 is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
The drug according to claim 12 or 13, which is used for prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
A compound having an action of inhibiting the digestion and absorption of nutrients, a pharmaceutically acceptable salt thereof, or a solvate thereof;
Formula (I):

Wherein R 1 is alkyl,
R 2 is hydrogen or alkyl,
Z is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted hydrocarbon cyclic group, or substituted or unsubstituted heterocyclic group ), A pharmaceutically acceptable salt thereof, or a solvate thereof,
The manufacturing method of the pharmaceutical composition of Claim 1.