WO2017094743A1

WO2017094743A1 - PHARMACEUTICAL COMPOSITION HAVING TYPE I 11β HYDROXYSTEROID DEHYDROGENASE INHIBITORY ACTIVITY

Info

Publication number: WO2017094743A1
Application number: PCT/JP2016/085471
Authority: WO
Inventors: 道賢畑中
Original assignee: 塩野義製薬株式会社
Priority date: 2015-11-30
Filing date: 2016-11-30
Publication date: 2017-06-08

Abstract

An agent for the treatment and/or prevention of conditions associated with hyperglucocorticoidemia, characterized in containing as an active ingredient a compound indicated by formula (I): (where ring A is (II), ring B is a substituted or unsubstituted aromatic heterocycle or the like, R¹ is hydrogen or a substituted or unsubstituted alkyl, R² is -OR⁵ or -SR⁵, R³ is a group indicated by the formula: ：- CH = CH - C (R^aR^b) - R^c- R^d, R^a and R^b are each independently hydrogen or a substituted or unsubstituted alkyl or the like, R^c is - (CH₂) n - (where n is an integer of 0 to 3), R^d is hydrogen, a halogen, or the like, R⁴ is a substituted or unsubstituted alkyl or -OR⁶, R⁵ is a substituted or unsubstituted alkyl or the like, R⁶ is hydrogen or -CONR⁷R⁸, R⁷ and R⁸ are each independently hydrogen or a substituted or unsubstituted alkyl) or a pharmaceutically acceptable salt thereof.

Description

Pharmaceutical composition having activity of inhibiting type I 11β hydroxysteroid dehydrogenase

The present invention has a type I 11β-hydroxysteroid dehydrogenase type 1 (hereinafter referred to as 11β-HSD-1) inhibitory activity, a pharmaceutical agent, particularly a therapeutic agent for a pathological condition involving hyperglucocorticoidemia, and The present invention relates to a compound useful as a preventive agent.

11β-HSD-1 is an enzyme that converts 11β-dehydrosteroid, which is an inactive steroid, into an active steroid, and is considered to have important significance in the basal metabolism of the living body (Non-patent Document 1). The 11β-HSD-1 knockout mouse is resistant to hyperglycemia associated with obesity and stress (Non-patent Document 2). Furthermore, the same phenomenon was observed in humans when carbenoxolone, an 11β-HSD-1 inhibitor, was administered (Non-patent Document 3).
These findings suggest the possibility that a selective inhibitor of this enzyme is a therapeutic agent in non-insulin-dependent diabetes mellitus and obesity (Non-patent Document 4).
Non-patent document 5 describes that 11β-HSD-1-KO mice are resistant to muscle atrophy induced by chronic administration of corticosterone, but no example of administration of a compound is described. Absent.
Patent Document 1 discloses a compound having 11β-HSD-1 inhibitory activity, but the compound of the present invention is useful for the treatment and / or prevention of pathological conditions involving hyperglucocorticoidemia, particularly muscle atrophy. That is not disclosed.

WO2008 / 142986

An object of the present invention is to provide a therapeutic and / or prophylactic agent excellent in a pathological condition involving hyperglucocorticoidemia.

The present invention
(1) Formula (I):

(Where
Ring A is

And
Ring B is a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen or substituted or unsubstituted alkyl;
R ² is —OR ⁵ or —SR ⁵ ;
R ³ is a group represented by the formula: —CH═CH—C (R ^a R ^b ) —R ^c —R ^d ,
R ^a and R ^b are each independently hydrogen, substituted or unsubstituted alkyl or halogen;
R ^c is — (CH ₂ ) n— (where n is an integer from 0 to 3);
R ^d is hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a group represented by the formula: —C (═O) —NR ^g R ^h , or A group represented by the formula: —NR ⁱ R ^j ,
R ^g and R ^h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted Or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or R ⁱ and R ^j which are unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxy or substituted or unsubstituted carbamoyl Each independently represents hydrogen, carboxy, hydroxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or Unsubstituted cycloal Ruoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted nonaromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted A cycloalkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, a substituted or unsubstituted nonaromatic heterocyclic carbonyl, or a substituted or unsubstituted sulfamoyl,
R ⁴ is substituted or unsubstituted alkyl or —OR ⁶ ;
R ⁵ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted unsubstituted An aromatic heterocyclic group,
R ⁶ is hydrogen or —CONR ⁷ R ⁸ ,
R ⁷ and R ⁸ are each independently hydrogen, or substituted or unsubstituted alkyl), or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic and / or prophylactic agent for a pathological condition in which symptom is involved.
(2) The compound represented by the formula (I) is
Formula (II):

(Wherein ring A, R ¹ , R ² and R ³ have the same meanings as (1) above), the compound of the above (1) or a pharmaceutically acceptable salt thereof is effective. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, characterized by containing as a component.
(3) Ring A is represented by formula (III):

(Wherein R ⁴ has the same meaning as (1) above) and contains the compound of the above (1) or (2) or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, which is characterized.
(4) Hyperglucocorticoidemia, comprising as an active ingredient the compound according to any one of (1) to (3) above, wherein R ¹ is hydrogen, or a pharmaceutically acceptable salt thereof. Therapeutic and / or prophylactic agent for pathological conditions involving
(5) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein R ² is —OR ⁵ (where R ⁵ has the same meaning as (1) above). A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, characterized by comprising as an active ingredient.
(6) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein R ² is —SR ⁵ (where R ⁵ has the same meaning as (1) above). A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, characterized by comprising as an active ingredient.
(7) The compound according to any one of (1) to (6) above, wherein R ⁵ is substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof as an active ingredient, A therapeutic and / or prophylactic agent for a pathological condition involving glucocorticoidemia.
(8) R ^a and R ^b each independently contains, as an active ingredient, the compound according to the above (1) to (7) or a pharmaceutically acceptable salt thereof, which is substituted or unsubstituted alkyl. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia.
(9) Any one of the above (1) to (8), wherein R ^d is halogen, hydroxy, cyano, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group A therapeutic and / or prophylactic agent for a pathological condition associated with hyperglucocorticoidemia, comprising the described compound or a pharmaceutically acceptable salt thereof as an active ingredient.
(10) R ^d is represented by the formula: —C (═O) —NR ^g R ^h, wherein R ^g and R ^h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy or A compound represented by any one of the above (1) to (8) or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia.
(11) R ^d is represented by the formula: —NR ⁱ R ^j wherein R ⁱ and R ^j are each independently hydrogen, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted An alkylcarbonyl or a substituted or unsubstituted non-aromatic heterocyclic carbonyl.) Or a pharmaceutically acceptable salt thereof, which is a group represented by any one of the above (1) to (8) A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, characterized by containing as a component.
(12) R ⁴ is —OR ⁶ , —CH ₂ OH, —CH ₂ OCONR ⁷ R ⁸ or —CH ₂ NHCOR ¹² , wherein R ¹² is substituted or unsubstituted alkyl, and R ⁶ to R ⁸ are the above ( 1) and a pharmaceutically acceptable salt thereof as an active ingredient, wherein the hyperglucocorticoidemia is the same as 1) Therapeutic and / or prophylactic agent for pathological conditions involving
(13) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (12) above, wherein R ⁷ and R ⁸ are each independently hydrogen or substituted or unsubstituted alkyl. A therapeutic and / or prophylactic agent for a pathological condition associated with hyperglucocorticoidemia, characterized by comprising:
(14) The compound represented by the formula (I) is
Formula (II):

Wherein ring A is represented by formula (III):

(Wherein R ⁴ is —OH or —OC (═O) NH ₂ ),
R ¹ is hydrogen;
R ² is —OR ⁵ or —SR ⁵ ;
R ⁵ is isopropyl;
R ³ is the formula: —CH═CH—C (CH ₃ ) ₂ —NH (—C═O) —CH ₃ )) or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic and / or prophylactic agent for a pathological condition associated with hyperglucocorticoidemia, characterized by comprising:
(15) The therapeutic and / or prophylactic agent according to any one of (1) to (14) above, wherein the pathological condition associated with hyperglucocorticoidemia is muscle atrophy.
(16) The therapeutic and / or prophylactic agent according to (15) above, wherein the pathological condition involving hyperglucocorticoidemia is a disease that decreases muscle mass.
(17) The therapeutic and / or prophylactic agent according to (15) above, wherein the pathological condition involving hyperglucocorticoidemia is a disease that increases fat mass.
(18) The therapeutic and / or prophylactic agent according to (15) above, wherein the pathological condition associated with hyperglucocorticoidemia is a disease that increases neutral fat.
(19) The therapeutic and / or prophylactic agent according to (15) above, wherein the pathological condition associated with hyperglucocorticoidemia is a disease that increases free fatty acids.
(20) A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, comprising a compound having an HSD1 inhibitory action or a pharmaceutically acceptable salt thereof as an active ingredient.
(21) The therapeutic and / or prophylactic agent according to (20) above, wherein the pathological condition involving hyperglucocorticoidemia is muscle atrophy.
(22) Formula (I) for the treatment and / or prevention of pathologies involving hyperglucocorticoidemia:

(Where
Ring A is

And
Ring B is a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen or substituted or unsubstituted alkyl;
R ² is —OR ⁵ or —SR ⁵ ;
R ³ is a group represented by the formula: —CH═CH—C (R ^a R ^b ) —R ^c —R ^d ,
R ^a and R ^b are each independently hydrogen, substituted or unsubstituted alkyl or halogen;
R ^c is — (CH ₂ ) n— (where n is an integer from 0 to 3);
R ^d is hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a group represented by the formula: —C (═O) —NR ^g R ^h , or A group represented by the formula: —NR ⁱ R ^j ,
R ^g and R ^h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted Or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or R ⁱ and R ^j which are unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxy or substituted or unsubstituted carbamoyl Each independently represents hydrogen, carboxy, hydroxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or Unsubstituted cycloal Ruoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted nonaromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted A cycloalkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, a substituted or unsubstituted nonaromatic heterocyclic carbonyl, or a substituted or unsubstituted sulfamoyl,
R ⁴ is substituted or unsubstituted alkyl or —OR ⁶ ;
R ⁵ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted unsubstituted An aromatic heterocyclic group,
R ⁶ is hydrogen or —CONR ⁷ R ⁸ ,
R ⁷ and R ⁸ are each independently hydrogen or substituted or unsubstituted alkyl) or a pharmaceutically acceptable salt thereof.
(23) Formula (I):

(Where
Ring A is

And
Ring B is a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen or substituted or unsubstituted alkyl;
R ² is —OR ⁵ or —SR ⁵ ;
R ³ is a group represented by the formula: —CH═CH—C (R ^a R ^b ) —R ^c —R ^d ,
R ^a and R ^b are each independently hydrogen, substituted or unsubstituted alkyl or halogen;
R ^c is — (CH ₂ ) n— (where n is an integer from 0 to 3);
R ^d is hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a group represented by the formula: —C (═O) —NR ^g R ^h , or A group represented by the formula: —NR ⁱ R ^j ,
R ^g and R ^h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted Or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or R ⁱ and R ^j which are unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxy or substituted or unsubstituted carbamoyl Each independently represents hydrogen, carboxy, hydroxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or Unsubstituted cycloal Ruoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted nonaromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted A cycloalkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, a substituted or unsubstituted nonaromatic heterocyclic carbonyl, or a substituted or unsubstituted sulfamoyl,
R ⁴ is substituted or unsubstituted alkyl or —OR ⁶ ;
R ⁵ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted unsubstituted An aromatic heterocyclic group,
R ⁶ is hydrogen or —CONR ⁷ R ⁸ ,
R ⁷ and R ⁸ are each independently hydrogen, or a substituted or unsubstituted alkyl), or a pharmaceutically acceptable salt thereof, and administered as an active ingredient, high glucocorticoid blood A method for treating and / or preventing a disease state in which a disease is involved.
(24) A compound having an inhibitory action on HSD1 or a pharmaceutically acceptable salt thereof (preferably a compound represented by the formula (I) of the above (1) or a pharmaceutically acceptable salt thereof, particularly preferably a compound I- 30 or a compound I-168, or a pharmaceutically acceptable salt thereof)) as an active ingredient, and an agent for inhibiting muscle mass loss caused in a high glucocorticoid state.
(25) A compound having an inhibitory action on HSD1 or a pharmaceutically acceptable salt thereof (preferably a compound represented by the formula (I) in the above (1) or a pharmaceutically acceptable salt thereof, particularly preferably compound I- 30 or Compound I-168, or a pharmaceutically acceptable salt thereof)) as an active ingredient, and an inhibitor of fat mass increase caused in a high glucocorticoid state.
(26) A compound having an inhibitory action on HSD1 or a pharmaceutically acceptable salt thereof (preferably a compound represented by formula (I) in the above (1) or a pharmaceutically acceptable salt thereof, particularly preferably compound I- 30 or a compound I-168, or a pharmaceutically acceptable salt thereof)) as an active ingredient, and a neutral fatty acid increase inhibitor caused in a high glucocorticoid state.
(27) A compound having an inhibitory action on HSD1 or a pharmaceutically acceptable salt thereof (preferably a compound represented by the formula (I) of (1) above or a pharmaceutically acceptable salt thereof, particularly preferably Compound I- 30 or a compound I-168, or a pharmaceutically acceptable salt thereof)) as an active ingredient, and an inhibitor of increase in free fatty acid caused in a high glucocorticoid state.
Is included.

The therapeutic agent and / or preventive agent for a pathological condition involving hyperglucocorticoidemia of the present invention is very useful as an excellent therapeutic agent and / or prophylactic agent for muscle atrophy involving hyperglucocorticoidemia. In particular, the therapeutic agent and / or prophylactic agent for a disease state involving hyperglucocorticoidemia of the present invention is useful for patients who have developed muscle atrophy due to hypercortisolemia. Furthermore, an excellent therapeutic agent and / or preventive agent for diseases that decrease muscle mass, hyperlipidemia, diseases that increase triglycerides, and / or diseases that increase free fatty acids, which are associated with hyperglucocorticoidemia As very useful.
Here, as usefulness as a medicine, it is a compound with high metabolic stability, low induction of drug metabolizing enzymes, small inhibition of drug metabolizing enzymes that metabolize other drugs, and high oral absorbability The point includes a point having a small clearance, a point having low toxicity, particularly a cardiotoxicity, or a point having a sufficiently long half-life for exhibiting a medicinal effect.

Effect of Compound I-168 on Atrogin and MuRF1 Expression Changes by Cortisone Treatment in C2C12 Cells 11β-HSD1 activity in muscle 1 hour after single administration Muscle 11β-HSD1 activity 24 hours after a single dose Effects on mice by cortisone pellet transplantation and effects of repeated oral administration of compounds (each muscle) Effects on mice by cortisone pellet transplantation and effects of repeated oral administration of compounds (grip strength) Effects of corticosterone administration on subcutaneous fat in mice and effects of repeated oral administration of compound I-30 Effects of corticosterone administration on epididymal fat in mice and effects of repeated oral administration of compound I-30 Effects of corticosterone administration on gastrocnemius muscle in mice and effects of repeated oral administration of compound I-30 Effects of corticosterone administration on the anterior tibial muscle of mice and the effect of repeated oral administration of compound I-30 Effect of corticosterone administration on the amount of neutral fat in the blood of mice and the effect of repeated oral administration of Compound I-30 Effect of corticosterone administration on free fatty acids in the blood of mice and the effect of repeated oral administration of compound I-30. In FIGS. 6-11, * indicates p <0.05 vs solvent (CORT 0 ug / mL), Dunnett test , # Indicates that a significant difference was obtained in the p <0.05-vs solvent (corticosterone 30 ug / mL) or solvent (CORT 100 ug / mL) and Student's t test.

The terms used in this specification are explained below. In the present specification, each term has the same meaning whether used alone or in combination with other terms.

“Halogen” includes fluorine, chlorine, bromine and iodine. Particularly preferred are fluorine, chlorine and bromine.

“Alkyl” means a linear or branched alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Examples include butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred is alkyl having 1 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.

“Alkenyl” means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, and examples thereof include vinyl, 1-propenyl, 2 -Propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like.

“Alkynyl” means linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. It is done. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.

“Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Group and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.

The “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings share one carbon atom. Specific examples include spiro [3.4] octyl.

“Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the following groups are exemplified.

“Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 15 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, preferably cyclopropenyl, cyclobutenyl. , Cyclopentenyl and cyclohexenyl. Cycloalkenyl also includes a bridged cyclic hydrocarbon group having an unsaturated bond in the ring. Examples thereof include a group having 1 to 2 double bonds in the ring of the bridged cyclic hydrocarbon group exemplified for the above cycloalkyl.

“Aryl” means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1- Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like. Preferable is phenyl or naphthyl (1-naphthyl, 2-naphthyl).

“Aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is a substitutable optional group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. Means a group which may have a bond at the position.
The fused aromatic heterocyclic group has 1 to 4 5 to 8 5 to 8 membered aromatic rings which may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. It means a group which may have a bond at any substitutable position which is fused with a member aromatic carbocyclic ring or other 5- to 8-membered aromatic heterocycle.

Examples of the “aromatic heterocyclic group” include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl). , 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg, 1,2,4- Triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl ( Examples: 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) Zolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl) 4-pyridyl), pyridazinyl (eg: 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg: 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (eg: 3-furazanyl), pyrazinyl (eg: 2 -Pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzo Enyl (eg, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] Thienyl), benzimidazolyl (eg, 1-benzimidazolyl, 2-benzimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), benzothiazolyl, dibenzofuryl, benzoxazolyl, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl) ), Cinnolinyl (eg, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl) 7-quinazolinyl, 8-ki Nazolinyl), quinolyl (eg 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg 1-phthalazinyl, 5-phthalazinyl, 6- Phthalazinyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1-indolyl, 2 -In-drill, 3-in-drill, 4-India , 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, fanadinyl (eg 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (eg 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl) and the like.

The “non-aromatic heterocyclic group” may contain 1 to 4 oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring, and has a bond at any substitutable position. Means a non-aromatic heterocyclic group. Further, such a non-aromatic heterocyclic group may be further bridged with an alkyl chain having 1 to 4 carbon atoms, such as a cycloalkane (preferably a 5 to 6 membered ring), an aromatic carbocycle or an aromatic heterocycle. The ring may be condensed. If it is non-aromatic, it may be saturated or unsaturated. A 5- to 8-membered ring is preferred. For example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, Examples thereof include 3-morpholinyl, morpholino, tetrahydropyranyl and the following groups.

“Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or "Unsubstituted aryl", "substituted or unsubstituted heteroaryl", "substituted or unsubstituted heterocycle", "substituted or unsubstituted alkylsulfonyl", "substituted or unsubstituted cycloalkylsulfonyl", "substituted or "Unsubstituted arylsulfonyl", "substituted or unsubstituted heteroarylsulfonyl", "substituted or unsubstituted heterocyclesulfonyl", "substituted or unsubstituted alkyloxy", "substituted or unsubstituted acyl", "substituted Or unsubstituted alkyloxycarbonyl ”,“ position Or “unsubstituted cycloalkyloxycarbonyl”, “substituted or unsubstituted aryloxycarbonyl”, “substituted or unsubstituted heteroaryloxycarbonyl”, “substituted or unsubstituted heterocycleoxycarbonyl”, “substituted or unsubstituted” Substituents in “alkylcarbonyl of”, “substituted or unsubstituted cycloalkylcarbonyl”, “substituted or unsubstituted arylcarbonyl”, “substituted or unsubstituted heteroarylcarbonyl” or “substituted or unsubstituted heterocyclecarbonyl”. as, for example, hydroxy, carboxy, halogen, halogenated alkyl _{_{_{_{(eg: CF 3, CH 2 CF 3}}}} , CH 2 CCl 3), nitro, nitroso, cyano, alkyl (e.g. methyl, ethyl, isopropyl, ter -Butyl), alkenyl (eg vinyl), alkynyl (eg ethynyl), cycloalkyl (eg cyclopropyl, adamantyl), hydroxyalkyl (eg hydroxymethyl), cycloalkylalkyl (eg cyclohexylmethyl, adamantylmethyl) , Cycloalkenyl (eg: cyclopropenyl), aryl (eg: phenyl, naphthyl), arylalkyl (eg: benzyl, phenethyl), aromatic heterocyclic group (eg: pyridyl, furyl), aromatic heterocyclic alkyl (eg: : Pyridylmethyl), non-aromatic heterocyclic group (eg piperidyl), non-aromatic heterocyclic alkyl (eg morpholylmethyl), alkyloxy (eg methoxy, ethoxy, propoxy, butoxy), halogenated alkyloxy (eg : OCF ₃ ), alkenyloxy (eg, vinyl) Oxy, allyloxy), aryloxy (eg phenyloxy), alkyloxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), arylalkyloxy (eg benzyloxy), amino (eg alkylamino (eg : Methylamino, ethylamino, dimethylamino), acylamino (example: acetylamino, benzoylamino), arylalkylamino (example: benzylamino, tritylamino), hydroxyamino, alkylaminoalkyl (example: diethylaminomethyl), sulfamoyl, etc. Selected from the group consisting of It may be substituted with 1 to 4 such substituents.

Substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted thiocarbamoyl” and “substituted or unsubstituted sulfamoyl” include alkyl, alkenyl, aryl, aromatic Heterocyclic group, alkylcarbonyl, arylcarbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, alkyloxycarbonyl, aryloxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, sulfamoyl, alkyl Examples include sulfonyl, carbamoyl, cycloalkylsulfonyl, arylsulfonyl, aromatic heterocyclic sulfonyl, non-aromatic heterocyclic sulfonyl, acyl, hydroxy, sulfonyl, sulfinyl, amino and the like.

Formula (I):

Preferred embodiments of ring A, ring B, R ¹ , R ² and R ^{3 in} the compound represented by The following possible combinations of compounds are preferred:

As ring A,

Is mentioned.
Preferably,

Is mentioned.
In particular, as ring A,

Is preferred.
Ring A includes both isomers of syn and anti.

Ring B includes substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle.
Preferred are furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, morpholino, morpholinyl, piperidyl, piperidino, piperazinyl, pyrrolidinyl, tetrahydrothienyl.
In particular, as ring B, pyrazolyl is preferable.
Ring B may have a substituent other than R ² and R ³ .

R ¹ includes hydrogen or substituted or unsubstituted alkyl. Preferably, hydrogen, methyl, ethyl, n-propyl and isopropyl are used. Hydrogen is particularly preferable.

R ² includes a group represented by —OR ⁵ or —SR ⁵ .
In particular, —OR ⁵ is preferable.
Another response is preferably -SR ⁵ .

Examples of R ³ include a group represented by the formula: —CH═CH—C (R ^a R ^b ) —R ^c —R ^d .
R ^a and R ^b each independently include hydrogen, substituted or unsubstituted alkyl, or halogen.
Preferably each independently, a substituted or unsubstituted alkyl is mentioned.
Particularly preferably, both include methyl.
Examples of R ^c include — (CH ₂ ) n— (where n is an integer of 0 to 3). Here, as n, 0 or 1 is preferable, and 0 is particularly preferable.
R ^d includes hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, represented by the formula: —C (═O) —NR ^g R ^h Examples include a group represented by the group or formula: —NR ⁱ R ^j .
Preferable R ^d includes halogen, hydroxy, cyano, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
Another preferred R ^d is the formula: —C (═O) —NR ^g R ^h, where R ^g and R ^h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl And oxy or substituted or unsubstituted carbamoyl).
Another preferred R ^d is preferably represented by the formula: —NR ⁱ R ^j where R ⁱ and R ^j are each independently hydrogen, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted Or a substituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic carbonyl group).
R ^g and R ^h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, And substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted carbamoyl.
R ⁱ and R ^j are each independently hydrogen, carboxy, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl Substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted Non-aromatic heterocyclic sulfonyl, substituted Or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted nonaromatic heterocyclic ring Oxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted nonaromatic heterocyclic carbonyl Or substituted or unsubstituted sulfamoyl is mentioned.
R ⁴ includes substituted or unsubstituted alkyl or —OR ⁶ .
Preferably —OR ⁶ , —CH ₂ OH, —CH ₂ OCONR ⁷ R ⁸ or —CH ₂ NHCOR ¹² , (R ⁶ is hydrogen or —CONR ⁷ R ⁸ , and R ⁷ and R ⁸ are each independently hydrogen. Or a substituted or unsubstituted alkyl group, and R ¹² is a substituted or unsubstituted alkyl group).
R ⁷ and R ⁸ are each independently hydrogen or substituted or unsubstituted alkyl.
Preferably, each independently hydrogen, methyl or ethyl.

m and p are each independently an integer of 1 to 3.
m is preferably 1 or 2. p is preferably 1.
As the compound represented by the formula (I) or the compound having an HSD1 inhibitory action, the following two compounds are particularly preferable.

A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia characterized by containing a compound having an HSD1 inhibitory action or a pharmaceutically acceptable salt thereof as an active ingredient is preferred. Examples of the compound having a HSD1 inhibitory action or a pharmaceutically acceptable salt thereof include the following compounds.

Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt , Triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt or other aliphatic amine salt; N, N-dibenzylethylenediamine, venetamine salt or other aralkylamine salt; pyridine salt, picoline salt, quinoline salt, isoquinoline Heterocyclic aromatic amine salts such as salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyl Examples include quaternary ammonium salts such as trioctylammonium salt and tetrabutylammonium salt; basic amino acid salts such as arginine salt and lysine salt.
Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.

The solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.

“Hyperglucocorticoidemia” refers to a condition in which cortisol, cortisone and / or corticosterone is chronically higher than a reference value, and particularly includes “hypercortisolemia”. Specifically, it refers to a state in which cortisol within 2 hours from waking up is 10 μg / mL or more, preferably 24.0 μg / mL or more.
The “pathological condition involving hyperglucocorticoidemia” refers to a pathological condition caused by becoming a state of hyperglucocorticoidemia due to an endogenous and / or exogenous cause.

The general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
(When R ² = −OR ⁵ )

(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (II-A) may be a known compound or a compound derived from a known compound by a conventional method. Pro means a protecting group, and examples of the protecting group include alkyl and the like.

First Step This is a step for producing a compound represented by the formula (II-B) by reacting a compound represented by the formula (II-A) with hydrazine.
Solvents include N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons (eg, dichloromethane) , Chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (eg, Acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water, and mixed solvents thereof. Preferably, alcohols (eg, methanol, ethanol, t-butanol, etc.) can be used. More preferably, Pro-OH may be used. The reaction may be performed at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 48 hours.

Second Step The second step is a step for producing a compound represented by the formula (II-C) by reacting a compound represented by the formula (II-B) with a compound represented by R ⁵ X in the presence of a base.
As the solvent, the solvent described in Step 1 can be used. Preferably, ketones (eg, acetone, methyl ethyl ketone, etc.) and N-dimethylformamide may be used. Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal sodium, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like. Preferably, a metal carbonate (eg, sodium carbonate, calcium carbonate, potassium carbonate, cesium carbonate, etc.) may be used. The reaction may be performed at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 48 hours.

Third Step This is a step for producing a compound represented by the formula (II-D) by hydrolyzing a compound represented by the formula (II-C).
As the solvent, the solvent described in Step 1 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water and a mixed solvent thereof may be used. As the base, the base described in Step 2 can be used. Preferably, a metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.) may be used. The reaction may be performed at −20 to 40 ° C. for 0.5 to 24 hours.

Fourth Step The fourth step is a step for producing a compound represented by the formula (IA) by reacting a compound represented by the formula (II-D) with a compound represented by the formula (ring A—NH—R ¹ ).
As the solvent, the solvent described in Step 1 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) and N-dimethylformamide may be used. As the base, the base described in Step 2 can be used. Preferably, an organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used. In the reaction, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSCI) or 1,3-dicyclohexylcarbodiimide (DCCD) can be used as a condensing agent. As an additive, N-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu) can be used. The reaction may be carried out for 0.5 to 24 hours at a temperature from −20 ° C. to reflux of the solvent used.
(When R ² = −SR ⁵ )

Fifth step is a step of producing a compound represented by the formula (II-E) by converting a hydroxy group of a compound represented by the formula (II-B) into chlorine.
As the solvent, phosphorus oxychloride (POCl ₃ ) may be used. The reaction may be carried out at a temperature at which phosphorus oxychloride is refluxed from −20 ° C. for 0.5 to 24 hours.

Sixth Step In this step, the compound represented by the formula (II-E) is reacted with the compound represented by R ⁵ SH in the presence of a base to produce a compound represented by the formula (II-F).
As the solvent, the solvent described in Step 1 can be used. Preferably, ketones (eg, acetone, methyl ethyl ketone, etc.) and N-dimethylformamide may be used. As the base, the base described in Step 2 can be used. Preferably, metal hydrides (eg, sodium hydride), metal carbonates (eg, sodium carbonate, calcium carbonate, potassium carbonate, cesium carbonate, etc.) may be used. The reaction may be performed at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 48 hours.

Seventh step The seventh step is a step of hydrolyzing the compound represented by the formula (II-E) to produce the compound represented by the formula (II-F).
What is necessary is just to carry out similarly to the said 3rd process.

Eighth step In the eighth step, the compound represented by the formula (II-F) is reacted with the compound represented by the formula (ring A-NH-R ¹ ) to produce the compound represented by the formula (IB).
What is necessary is just to carry out similarly to the said 4th process.

(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (II-G) may be a known compound or a compound derived from a known compound by a conventional method. )

Ninth step The ninth step is a step of reacting a compound represented by the formula (II-G) with a compound represented by the formula (ring A-NH-R ¹ ) to produce a compound represented by the formula (IC).
What is necessary is just to carry out similarly to the said 4th process.

(In the formula, each symbol is as defined above, and the compound represented by the formula (II-H) may be a known compound or a compound derived from a known compound by a conventional method. Pro and Pro ′ mean protecting groups. Examples of Pro and Pro ′ include methyl group, ethyl group, benzyl group, benzoyl group, t-butyl group, etc. Hal means halogen.)

Tenth step The tenth step is a step of reacting a compound represented by the formula (II-H) with hydrazine to produce a compound represented by the formula (II-1).
What is necessary is just to perform like the said 1st process.

Eleventh step is a step of producing a compound represented by the formula (II-J) by oxidizing a compound represented by the formula (II-I).
As the oxidizing agent, metal salts such as IBX (2-iodoxybenzoic acid), chromium, manganese, silver, metal oxides, and organic oxidizing agents can be used.
As the solvent, the solvent described in Step 1 can be used. Preferably, acetonitrile or esters (eg, methyl acetate, ethyl acetate, etc.) may be used.
The reaction may be performed at room temperature or at a temperature at which the solvent used is refluxed for 0.5 to 24 hours.
This oxidation reaction step can also be performed under conditions such as Swern oxidation and TEMPO oxidation.

Twelfth step is a step of producing a compound represented by the formula (II-L) by a Wittig reaction between a compound represented by the formula (II-J) and a compound represented by the formula (II-K).
As the solvent, the solvent described in Step 1 can be used. Preferably, esters (eg, methyl acetate, ethyl acetate, etc.) and ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
As the base, the base described in Step 2 can be used. Preferably, an organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
The reaction may be performed at −20 to 40 ° C. for 0.5 to 48 hours.

Thirteenth step The thirteenth step is a step for producing a compound represented by the formula (II-M) by reacting a compound represented by the formula (II-L) with R ^b -Hal in the presence of a base.
As the solvent, the solvent described in Step 1 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
As the base, the base described in Step 2 can be used. Preferably, metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), LDA may be used.
The reaction may be performed at −78 to 40 ° C. for 0.5 to 24 hours.

14th step The 14th step is a step for producing a compound represented by the formula (II-N) by deprotecting a compound represented by the formula (II-M) under strongly acidic conditions.
As the strong acid, for example, trifluoroacetic acid or sulfuric acid can be used.
As the solvent, the solvent described in Step 1 can be used. Preferably, halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) may be used.
The reaction may be performed at −78 to 40 ° C. for 0.5 to 24 hours.

Fifteenth step is a step of producing a compound represented by the formula (II-O) by reacting a compound represented by the formula (II-N) with an amine.
What is necessary is just to carry out similarly to the said 4th process.

Sixteenth step is a step of producing a compound represented by the formula (II-P) by deprotecting the compound represented by the formula (II-O).
What is necessary is just to carry out similarly to the said 3rd process.

Seventeenth Step The seventeenth step is a step for producing a compound represented by the formula (ID) by reacting a compound represented by the formula (II-P) with a compound represented by the formula (II-Q).
What is necessary is just to carry out similarly to the said 4th process.

Eighteenth step The eighteenth step is a step for reducing a compound represented by the formula (ID) to produce a compound represented by the formula (IE).
A catalytic hydrogenation reaction using a transition metal catalyst may be performed. As the transition metal catalyst, platinum, palladium, rhodium, ruthenium, nickel or the like can be used.
As the solvent, the solvent described in Step 1 can be used. Preferably, alcohols (eg, methanol, ethanol, t-butanol, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), water, a mixed solvent thereof or the like may be used. .
The reaction may be performed in the presence of hydrogen and a transition metal catalyst at 20 to 50 ° C. for 0.5 to 48 hours.

(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (II-R) may be a known compound or a compound derived from a known compound by a conventional method. Pro represents a protecting group, and examples of the protecting group include a methyl group, an ethyl group, a benzyl group, a benzoyl group, and a t-butyl group.

24th step is a step of converting a compound represented by the formula (II-R) into a compound represented by the formula (II-T).
In this step, one of R ⁱ and R ^j is hydrogen, and the other is substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted This is a reaction step in the case of substituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, or substituted or unsubstituted heterocycleoxycarbonyl. The compound represented by the formula (II-R) may be reacted with a corresponding alcohol or amine.
As the solvent, the solvent described in Step 1 can be used. Preferably, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) and ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
The reaction may be carried out for 0.5 to 24 hours at a temperature from −20 ° C. to reflux of the solvent used.

(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (II-N) may be a known compound, or a compound derived from a known compound by a conventional method. (Pro represents a protecting group, and examples of the protecting group include a methyl group, an ethyl group, a benzyl group, a benzoyl group, a t-butyl group, etc. Hal represents a halogen.)

Twenty-fifth step is a step of reducing the compound represented by the formula (II-N) to produce the compound represented by the formula (II-V). A compound represented by the formula (II-N) and ethyl chlorocarbonate are reacted to form an active ester, and then reacted with a reducing agent.
As the solvent, the solvent described in Step 1 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
Examples of the reducing agent include sodium triacetoxyhydroborate, sodium borohydride, lithium tetrahydroborate, pyridine borane complex, tetrahydrofuran borane complex, dimethyl sulfide borane complex and 2-picoline borane complex. Preferably, it is sodium borohydride.
The reaction may be performed at −20 to 50 ° C. for 0.5 to 24 hours.

Twenty-sixth step is a step of producing a compound represented by the formula (II-W) by deprotecting the compound represented by the formula (II-V).
What is necessary is just to perform like the said process 3.

Twenty-seventh step is a step of reacting a compound represented by the formula (II-W) with a compound represented by the formula (II-Q) to produce a compound represented by the formula (IH).
What is necessary is just to perform like the said process 4.

Twenty-eighth step is a step of producing a compound represented by the formula (IJ) by reducing a compound represented by the formula (IH).
What is necessary is just to carry out similarly to the said process 18 above.

Twenty-ninth step is a step of producing a compound represented by the formula (IK) by halogenating a compound represented by the formula (IH).
As the solvent, the solvent described in Step 1 can be used. Preferably, halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) may be used.
As the halogenating agent, DAST ((diethylamino) sulfur trifluoride), NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), CBr ₄ , PBr ₃ , PBr ₅ may be used.
The reaction may be carried out at a temperature from −78 ° C. to reflux of the solvent used for 0.5 to 24 hours.

30th step is a step of producing a compound represented by the formula (IL) by halogenating a compound represented by the formula (IJ).
What is necessary is just to carry out similarly to the said process 29 above.

(Wherein R ^g and R ^h are hydrogen, and other symbols are as defined above, and the compound represented by the formula (II-O) may be a known compound. (Pro may mean a protecting group, and examples of the protecting group include a methyl group, an ethyl group, a benzyl group, a benzoyl group, and a t-butyl group.)

Thirty-first step is a step of dehydrating a compound represented by the formula (II-O) to produce a compound represented by the formula (II-X). The reaction may be carried out in halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) with trifluoroacetic anhydride and pyridine at −20 ° C. to 40 ° C. for 0.5 to 10 hours.

Thirty-second step This is a step for producing a compound represented by the formula (II-Y) by deprotecting the compound represented by the formula (II-X).
What is necessary is just to carry out similarly to the said process 18 above.

Thirty-third step The thirty-third step is a step for producing a compound represented by the formula (IM) by reacting a compound represented by the formula (II-Y) with a compound represented by the formula (II-Q).
What is necessary is just to perform like the said process 4.

Thirty-fourth step is a step of reducing a compound represented by the formula (IM) to produce a compound represented by the formula (IN).
What is necessary is just to carry out similarly to the said process 18 above.

(Wherein each symbol has the same meaning as described above, and the compound represented by the formula (II-A) may be a known compound or a compound derived from a known compound by a conventional method. Pro means a protecting group, and examples of the protecting group include a methyl group, an ethyl group, a benzyl group, a benzoyl group, a t-butyl group, etc. Pro '' means a protecting group, and the protecting group includes t- (Butyl group, trityl group, benzyl group, p-methoxybenzyl group, silyl group, methanesulfonyl group, acyl group, etc.)

Thirty-fifth step is a step of producing a compound represented by the formula (II-AA) by reacting a compound represented by the formula (II-A) with a compound represented by the formula (II-Z).
What is necessary is just to perform like the said 1st process.

Thirty-sixth step is a step of producing a compound represented by the formula (II-AB) by halogenating a compound represented by the formula (II-AA).
For example, it can be halogenated under the conditions described in Example 3 of WO2007 / 058346.
In the case of chlorination, phosphorous oxychloride may be used for reaction for 0.5 to 24 hours from −20 ° C. to a temperature at which phosphorus oxychloride is refluxed. At this time, the solvent described in Step 1 can be used as the solvent, but it may not be used.
In the case of bromination, PBr ₃ can be used in the same manner. Moreover, a fluorine body can be obtained by making potassium fluoride act on a corresponding chlorine body.

Thirty-seventh step is a step of producing a compound represented by the formula (IO) from a compound represented by the formula (II-AB).

Various substituents of the compounds of the present invention are (1) Alan R.Katriszly et al., Comprehensive Heterocyclic Chemistry (2) Alan R.Katriszly etKaal., Comprehensive Heterocyclic Chemistry II (3) RODD'S CH It can be introduced with reference to COMPOUNDS.

The compound of the present invention has excellent type I 11β hydroxysteroid dehydrogenase inhibitory activity. Therefore, it is used for the treatment or prevention of diseases involving type I 11β hydroxysteroid dehydrogenase, particularly diseases such as hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and / or syndrome X. be able to. In particular, it is useful in the treatment or prevention of diabetes.

The compound used in the present invention can be administered orally or parenterally. In the case of oral administration, the compound used in the present invention is a usual preparation, for example, solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs It can be used also as any dosage form. In the case of parenteral administration, the compound used in the present invention can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used. In particular, it is preferable to use it as an oral preparation.
Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent. The preparation of the compound used in the present invention is produced by a known method using well-known and readily available components.
The dose of the compound used in the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually about 0.05 mg to 3000 mg per day for an adult when administered orally, preferably May be administered in an amount of about 0.1 mg to 1000 mg divided if necessary. In the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per day for an adult. In administration, it can be used in combination with other therapeutic agents.

The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.
In addition,
Formula (III ')

The group shown by is equivalent to the following groups.

To a solution of Compound II-1 (diethyl ethoxymethylenemalonate, 10 g) in N, N-dimethylformamide (50 ml) was added 80% hydrazine ethanol (4.4 g) in N, N-dimethylformamide (50 ml) over about 15 minutes. And dripped. Thereafter, potassium carbonate (6.4 g) was added and stirred at 80 ° C. for 2 hours, and then isobutyl bromide (7.6 mL) was added and stirred at 120 ° C. for 1.5 hours. After completion of the reaction, the reaction mixture was poured into 0.5M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution. After drying with sodium sulfate, the solvent was distilled off. The residue was dissolved in a small amount of ethyl acetate, hexane was added under ice cooling, and the precipitated crystals were collected by filtration. Drying gave Compound II-2 (4.6 g).
IBX (7.5 g) was added to an ethyl acetate solution (160 ml) of compound II-2 (5.7 g), and the mixture was heated to reflux for 6 hours. After completion of the reaction, the insoluble material was filtered off and the solvent was distilled off to give compound II-3 (5.6 g). Used in the next reaction without purification.
A phosphonium salt (13.5 g) was added to a tetrahydrofuran solution (40 ml) of compound II-3 (5.6 g), and triethylamine (3.4 g) was added dropwise thereto over 20 minutes. Then, it stirred at room temperature for 3 hours. After completion of the reaction, water (40 ml) was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound II-4 (5.2 g).
A solution (60 ml) of diisopropylamine (1.3 ml) in tetrahydrofuran was cooled to −78 ° C., and n-butyllithium (3.25 ml, 2.8 M hexane solution) was added dropwise. After stirring at the same temperature for 30 minutes, a tetrahydrofuran solution (40 ml) of compound II-4 (2.8 g) was added, and the mixture was further stirred for 30 minutes. Next, iodomethane (1.4 ml) was added, and the temperature was gradually raised to 0 ° C. After 3 hours, the mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound II-5 (2.42 g).
To a dichloromethane solution (100 ml) of compound II-5 (19.4 g) was added trifluoroacetic acid (50 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off, diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain Compound II-6 (16.6 g).
Triethylamine (152 μl) and ethyl chlorocarbonate (84 μl) were added to a solution of compound II-6 (237 mg) in tetrahydrofuran (3 ml) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Next, sodium borohydride (69 mg) and water (1 ml) were added at 0 ° C., and the mixture was stirred for 20 minutes. After completion of the reaction, an aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound II-7 (185 mg).
A dichloromethane solution (5 ml) of compound II-7 (185 mg) was cooled to −78 ° C., DAST (102 μl) was added, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound II-8 (62 mg).
To a mixed solution of compound II-8 (61.6 mg) in tetrahydrofuran (1 ml) -methanol (1 ml) was added 2N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the mixture was acidified with 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound II-9 (60.1 mg). Used in the next reaction without purification.
A solution of Compound II-9 (60.1 mg) in dimethylformamide (3 ml) was added to hydroxyadamantanamine (38.8 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (48.5 mg), 1-hydroxybenzotriazole. (8.5 mg) and triethylamine (50 μl) were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the mixture was acidified with 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. The residue was purified by silica gel column chromatography to obtain compound II-10 (62 mg).
A tetrahydrofuran solution (1.2 ml) of Compound II-10 (54 mg) was cooled to −45 ° C., chlorosulfonyl isocyanate (22 μ) was added, and the mixture was stirred at −30 ° C. for 2 hours. Next, sodium hydrogen carbonate (74 mg) and water (24 μl) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over sodium sulfate, and the residue was purified by silica gel column chromatography to obtain compound I-1 (51 mg).
(Compound I-1) NMR (DMSO-d6); δ (ppm) 0.95 (d, J = 6.6 Hz, 6H), 1.30 (s, 3H), 1.36 (s, 3H), 1.41 (d, J = 12.4 Hz, 2H), 1.94-2.10 (m, 12H), 2.46-2.53 (m, 2H), 3.94 (s, 1H), 4.10 (d, J = 6.3Hz, 2H), 6.08-6.16 (m, 1H) , 6.20 (br, 2H), 6.92 (d, J = 14.2Hz, 1H), 7.50 (d, J = 6.6Hz, 1H), 7.94 (s, 1H)
The following compounds were synthesized in the same manner. About each compound, the measurement result of NMR or log k 'was shown.
Here, log k ′ is a value representing the degree of lipophilicity and is calculated by the following equation.
log k ′ = log (t _R −t ₀ ) / t ₀
t _R : retention time of compound under gradient conditions t ₀ : XTerra MS C18 5 μm, 2.1 × 100 mm column (Waters) was used for measuring the retention time of the standard substance not retained on the column, and the flow rate was 0.25 mL. It was measured by applying a linear gradient of acetonitrile / pH 6.8 buffer (5:95 to 95: 5/20 minutes) per minute.

(Compound I-6) NMR (DMSO-d6); δ (ppm) 0.96 (t, J = 7.5 Hz, 3H), 0.97 (d, J = 6.6 Hz, 6H), 1.32-1.36 (m.2H), 1.40 (s, 6H), 1.58-1.75 (m, 6H), 1.89-2.11 (m, 8H), 3.86-3.91 (m, 1H), 4.07 (d, J = 6.3Hz, 2H), 4.42 (s, 1H), 6.35 (d, J = 14.1Hz, 1H), 6.76 (d, J = 14.1Hz, 1H), 7.38 (d, J = 6.9Hz, 1H), 7.67 (s, 1H), 7.95 (s, 1H)

(Compound I-7) NMR (DMSO-d6); δ (ppm) 0.98 (d, J = 6.8 Hz, 6H), 1.42 (d, J = 13.1 Hz, 2H), 1.52 (s, 6H), 1.95- 2.11 (m, 12H), 3.96 (s, 1H), 4.15 (d, J = 6.3Hz, 2H), 6.20 (br, 2H), 6.24 (d, J = 14.2Hz, 1H), 7.10 (d, J = 14.2Hz, 1H), 7.55 (d, J = 6.1Hz, 1H), 8.04 (s, 1H)

(Compound I-8) log k ′ = 0.883

(Compound I-9) NMR (DMSO-d6); δ (ppm) 0.97 (d, J = 6.6 Hz, 6H), 1.40-1.44 (m, 8H), 1.94-2.10 (m, 12H), 2.90 (s , 3H), 3.94-3.96 (m, 1H), 4.11 (d, J = 6.3Hz, 2H), 6.20 (br, 2H), 6.33 (d, J = 14.4Hz, 1H), 6.92 (d, J = 14.4Hz, 1H), 7.24 (s, 1H), 7.50 (d, J = 6.8Hz, 1H), 7.98 (s, 1H)

(Compound I-18) log k ′ = 0.866

(Compound I-19) log k ′ = 0.907

(Compound I-22) log k ′ = 0.879

(Compound I-23) log k ′ = 0.864

(Compound I-24) log k ′ = 0.876

(Compound I-25) log k ′ = 0.87

(Compound I-26) log k ′ = 0.895

(Compound I-27) log k ′ = 0.903

(Compound I-28) log k ′ = 0.927

(Compound I-29) NMR (CDCl3); δ (ppm) 1.39 (d, J = 6.3 Hz, 6H), 1.51 (s, 6H), 1.55-2.11 (m, 13H), 3.62 (s, 3H), 3.73 (s, 2H), 4.14-4.16 (m, 1H), 4.61 (br, 2H), 4.67-4.75 (m, 1H), 4.83 (m, 1H), 6.36 (d, J = 14.2Hz, 1H) , 6.53 (d, J = 7.3Hz, 1H), 6.83 (d, J = 14.2Hz, 1H), 7.86 (s, 1H)

(Compound I-30) NMR (CDCl3); δ (ppm) 1.39 (d, J = 6.3 Hz, 6H), 1.54 (s, 6H), 1.59-1.78 (m, 4H), 1.96 (s, 3H), 2.13-2.29 (m, 9H), 4.20-4.23 (m, 1H), 4.43 (br, 2H), 4.67-4.75 (m, 1H), 5.46 (s, 1H), 6.36 (d, J = 14.2Hz, 1H), 6.47 (d, J = 7.6Hz, 1H), 6.81 (d, J = 14.2Hz, 1H), 7.85 (s, 1H)

(Compound I-31) log k ′ = 0.819

(Compound I-32) NMR (CDCl3); δ (ppm) 1.39 (d, J = 6.3 Hz, 6H), 1.54 (s, 6H), 1.56-2.10 (m, 13H), 1.96 (s, 3H), 3.73 (s, 2H), 4.14-4.16 (m, 1H), 4.63 (br, 2H), 4.67-4.75 (m, 1H), 5.48 (s, 1H), 6.36 (d, J = 14.2Hz, 1H) , 6.56 (d, J = 7.8Hz, 1H), 6.82 (d, J = 14.2Hz, 1H), 7.86 (s, 1H)

(Compound I-34) log k ′ = 0.877

(Compound I-35) log k ′ = 0.922

(Compound I-36) NMR (DMSO-d6): δ (ppm) 1.08 (d, J = 6.6 Hz, 6H), 1.47-1.74 (m, 19H), 1.54 (s, 3H), 1.64 (s, 3H ), 1.89-1.98 (m, 2H), 2.10-2.24 (m, 6H), 3.98 (d, J = 6.9Hz, 2H), 4.14-4.20 (m, 1H), 5.42 (s, 1H), 6.38 ( d, J = 14.4Hz, 1H), 6.38 (s, 1H), 6.86 (d, J = 14.4Hz, 1H), 7.80 (s, 1H).

(Compound I-43) log k ′ = 0.851

(Compound I-44) NMR (CDCl3); δ (ppm) 1.08 (d, J = 6.7 Hz, 6H), 1.51 (s, 6H), 1.58-2.06 (m, 13H), 2.07-2.20 (m, 1H ), 2.24-2.36 (m, 1H), 3.41 (d, J = 6.2Hz, 2H), 3.62 (s, 3H), 3.98 (d, J = 6.7Hz, 2H), 3.99-4.02 (m, 1H) , 4.82 (s, 1H), 6.37 (d, J = 14.2Hz, 1H), 6.49 (d, J = 7.6Hz, 1H), 6.87 (d, J = 14.2Hz, 1H), 7.82 (s, 1H)

(Compound I-45) log k ′ = 0.865

(Compound I-46) log k ′ = 0.913

(Compound I-47) NMR (CDCl3): δ (ppm) 1.08 (d, J = 6.6 Hz, 6H), 1.51-1.84 (m, 8H), 1.58 (s, 3H), 1.66 (s, 3H), 1.88-1.98 (m, 2H), 2.06-2.24 (m, 4H), 3.41 (s, 3H), 3.80 (s, 2H), 3.98 (d, J = 6.6Hz, 2H), 4.14-4.20 (m, 1H), 6.35 (d, J = 8.1Hz, 1H), 6.41 (d, J = 14.1Hz, 1H), 6.52 (s, 1H), 6.87 (d, J = 14.1Hz, 1H), 7.81 (s, 1H).

(Compound I-48) NMR (DMSO-d6): δ (ppm) 0.85 (t, J = 7.2 Hz, 3H), 0.96 (d, J = 6.6 Hz, 6H), 1.35-1.56 (m, 4H), 1.40 (s, 6H), 1.90-2.16 (m, 14H), 3.91-3.98 (m, 1H), 4.07 (d, J = 6.3Hz, 2H), 6.21 (br, 2H), 6.35 (d, J = 14.4Hz, 1H), 6.76 (d, J = 14.4Hz, 1H), 7.47 (d, J = 6.3Hz, 1H), 7.72 (s, 1H).

(Compound I-49) log k ′ = 0.945

(Compound I-50) log k ′ = 0.989

(Compound I-51) log k ′ = 0.882

(Compound I-52) NMR (CDCl3): δ (ppm) 1.07 (d, J = 6.6 Hz, 6H), 1.51-1.84 (m, 8H), 1.60 (s, 3H), 1.62 (s, 3H), 1.88-1.98 (m, 2H), 2.05-2.24 (m, 4H), 3.99 (d, J = 6.6Hz, 2H), 4.14-4.20 (m, 1H), 4.39 (s, 2H), 6.36 (d, J = 7.5Hz, 1H), 6.44 (d, J = 14.4Hz, 1H), 6.58 (s, 1H), 6.86-6.96 (m, 3H), 7.00-7.06 (m, 1H), 7.28-7.36 (m , 2H), 7.81 (s, 1H).

(Compound I-53) NMR (CDCl3): δ (ppm) 1.09 (d, J = 6.9 Hz, 6H), 1.38-1.84 (m, 8H), 1.47 (s, 3H), 1.63 (s, 3H), 1.88-2.00 (m, 2H), 2.08-2.26 (m, 4H), 2.42 (t, J = 7.5Hz, 2H), 2.93 (t, J = 7.5Hz, 2H), 3.99 (d, J = 6.9Hz , 2H), 4.12-4.20 (m, 1H), 5.29 (s, 1H), 6.33 (d, J = 14.1Hz, 1H), 6.39 (s, 1H), 6.84 (d, J = 14.1Hz, 1H) , 7.14-7.32 (m, 5H), 7.82 (s, 1H).

(Compound I-55) NMR (DMSO-d6); δ (ppm) 0.97 (d, J = 6.6 Hz, 6H), 1.27 (s, 6H), 1.35 (d, J = 12.1 Hz, 2H), 1.61- 1.72 (m, 6H), 1.89-2.04 (m, 6H), 2.57 (d, J = 4.3Hz, 3H), 3.87-3.91 (m, 1H), 4.10 (d, J = 6.3Hz, 2H), 4.44 (s, 1H), 6.33 (d, J = 14.2Hz, 1H), 6.78 (d, J = 14.7Hz, 1H), 7.39 (d, J = 6.1Hz, 1H), 7.52-7.56 (m, 1H) , 7.98 (s, 1H)

(Compound I-56) log k ′ = 0.838

(Compound I-61) log k ′ = 0.841

(Compound I-63) NMR (DMSO-d6); δ (ppm) 0.98 (d, J = 6.8 Hz, 6H), 1.27 (s, 6H), 1.39-1.51 (m, 8H), 1.87-2.03 (m , 6H), 3.00 (d, J = 5.6Hz, 2H), 3.88 (s, 1H), 4.10 (d, J = 6.3Hz, 2H), 4.37 (t, J = 5.6Hz, 1H), 6.37 (d , J = 14.4Hz, 1H), 6.81 (d, J = 14.4Hz, 1H), 6.95 (s, 1H), 7.15 (s, 1H), 7.41 (d, J = 7.1Hz, 1H), 7.98 (s , 1H)

(Compound I-64) log k ′ = 0.814

(Compound I-65) log k ′ = 0.838

(Compound I-66) log k ′ = 0.886

(Compound I-68) log k ′ = 0.85

(Compound I-69) log k ′ = 0.866

(Compound I-70) log k ′ = 0.882

(Compound I-71) log k ′ = 0.868

(Compound I-72) NMR (DMSO-d6); δ (ppm) 0.96-1.01 (m, 9H), 1.27 (s, 6H), 1.34 (d, J = 12.1 Hz, 2H), 1.61-1.72 (m , 6H), 1.89-2.04 (m, 6H), 3.03-3.08 (m, 2H), 3.89 (s, 1H), 4.10 (d, J = 6.6Hz, 2H), 4.44 (s, 1H), 6.34 ( d, J = 14.4Hz, 1H), 6.78 (d, J = 14.4Hz, 1H), 7.39 (d, J = 6.6Hz, 1H), 7.57 (t, J = 5.4Hz, 1H), 7.98 (s, 1H)

(Compound I-73) log k ′ = 0.876

(Compound I-74) log k ′ = 0.896

(Compound I-75) log k ′ = 0.95

(Compound I-76) log k ′ = 0.946

(Compound I-77) log k ′ = 0.926

(Compound I-78) log k ′ = 0.955

(Compound I-79) log k ′ = 0.818

(Compound I-80) log k ′ = 0.852

(Compound I-81) log k ′ = 0.813

(Compound I-83) log k ′ = 0.87

To a dimethylformamide solution (8 ml) of propan-2-thiol (413 μl), 60% sodium hydride (169 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Thereafter, a dimethylformamide solution (8 ml) of compound II-30 (800 mg) was added dropwise, and the mixture was further stirred for 2 hours. After completion of the reaction, the mixture was poured into 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound II-33 (738 mg).
Compound I-160 was synthesized from Compound II-33 in the same manner as in the above Example.
(Compound I-160) NMR (CDCl3); δ (ppm) 1.28 (d, J = 6.8Hz, 6H), 1.53-2.20 (m, 19H), 3.30-3.37 (m, 1H), 3.63 (s, 3H ), 4.25 (d, J = 7.3Hz, 1H), 4.91 (s, 1H), 6.56 (d, J = 14.2Hz, 1H), 7.40 (d, J = 14.2Hz, 1H), 7.96 (d, J = 7.6Hz, 1H), 8.20 (s, 1H)
The following compounds were synthesized in the same manner.

(Compound I-161) NMR (CDCl3); δ (ppm) 1.12 (t, J = 7.2Hz, 3H), 1.29 (d, J = 6.8Hz, 6H), 1.43 (s, 6H), 1.58-2.22 ( m, 13H), 3.24-3.34 (m, 3H), 4.26 (brs, 1H), 5.76 (brs, 1H), 6.64 (d, J = 14.2Hz, 1H), 7.42 (d, J = 14.2Hz, 1H ), 7.92 (d, J = 7.8Hz, 1H), 8.22 (s, 1H)

(Compound I-162) NMR (CDCl3); δ (ppm) 1.12 (t, J = 7.2Hz, 3H), 1.29 (d, J = 6.6Hz, 6H), 1.43 (s, 6H), 1.64-2.28 ( m, 13H), 3.24-3.34 (m, 3H), 4.30 (brs, 1H), 4.55 (s, 2H), 5.74 (s, 1H), 6.64 (d, J = 13.9Hz, 1H), 7.42 (d , J = 13.9Hz, 1H), 7.92 (d, J = 7.6Hz, 1H), 8.

(Compound I-164) NMR (CDCl3); δ (ppm) 1.28 (d, J = 6.6 Hz, 6H), 1.54 (s, 6H), 1.64-2.28 (m, 13H), 3.30-3.37 (m, 1H ), 3.63 (s, 3H), 4.30 (d, J = 7.1Hz, 1H), 4.57 (s, 2H), 4.96 (s, 1H), 6.56 (d, J = 13.9Hz, 1H), 7.39 (d , J = 13.9Hz, 1H), 7.95 (d, J = 7.8Hz, 1H), 8.20 (s, 1H)

(Compound I-165) NMR (d6-DMSO); δ (ppm) 1.17 (d, J = 6.4 Hz, 6H), 1.38-1.56 (m, 8H), 1.77-2.18 (m, 14H), 3.32-3.40 (m, 1H), 4.00-4.07 (m, 1H), 6.00-6.40 (s, 2H), 6.55 (d, J = 14.0Hz, 1H), 7.29 (d, J = 14.0Hz, 1H), 7.79- 7.90 (m, 2H), 8.07 (s, 1H)

(Compound I-166) NMR (d6-DMSO); δ (ppm) 1.18 (d, J = 6.8Hz, 6H), 1.38-1.58 (m, 8H), 1.77-2.18 (m, 14H), 3.02 (d , J = 5.6Hz, 2H), 3.32-3.40 (m, 1H), 3.93-4.00 (m, 1H), 4.39 (t, J = 5.6Hz, 1H), 6.55 (d, J = 14.0Hz, 1H) , 7.29 (d, J = 14.0Hz, 1H), 7.84 (s, 1H), 7.91 (d, J = 7.2Hz, 1H), 8.07 (s, 1H)

(Compound I-167) NMR (d6-DMSO); δ (ppm) 1.18 (d, J = 5.6Hz, 6H), 1.44 (s, 6H), 1.50-2.07 (m, 16H), 3.32-3.40 (m , 1H), 3.98-4.10 (m, 3H), 6.55 (d, J = 14.0Hz, 1H), 7.09 (s, 1H), 7.29 (d, J = 14.0Hz, 1H), 7.66 (s, 1H) , 7.85 (s, 1H), 7.92 (d, J = 6.0Hz, 1H), 8.08 (s, 1H), 8.33 (s, 1H)

(Compound I-168) NMR (CDCl3); δ (ppm) 1.29 (d, J = 6.6 Hz, 6H), 1.57-2.20 (m, 22H), 3.31-3.38 (m, 1H), 4.25 (d, J = 6.6Hz, 1H), 5.59 (s, 1H), 6.55 (d, J = 14.2Hz, 1H), 7.39 (d, J = 14.2Hz, 1H), 7.96 (d, J = 7.8Hz, 1H), 8.19 (s, 1H)
The following compounds were synthesized as in the above examples.

(Compound I-169) NMR (DMSO-d6); δ (ppm) 1.25-2.03 (m, 25H), 2.58 (d, J = 4.3Hz, 3H), 3.90 (brs, 1H), 4.42 (s, 1H ), 4.88-4.94 (m, 1H), 6.35 (d, J = 14.2Hz, 1H), 6.77 (d, J = 14.2Hz, 1H), 7.30 (d, J = 6.8Hz, 1H), 7.52 (brs , 1H), 8.03 (s, 1H)

(Compound I-170) NMR (DMSO-d6); δ (ppm) 1.00 (t, J = 7.1Hz, 3H), 1.25-2.03 (m, 25H), 3.04-3.10 (m, 2H), 3.89 (brs , 1H), 4.42 (s, 1H), 4.89-4.94 (m, 1H), 6.35 (d, J = 14.4Hz, 1H), 6.77 (d, J = 14.4Hz, 1H), 7.31 (d, J = 6.8Hz, 1H), 7.57 (t, J = 5.2Hz, 1H), 8.02 (s, 1H)

(Compound I-171) NMR (DMSO-d6); δ (ppm) 1.26-2.10 (m, 25H), 2.58 (d, J = 4.6Hz, 3H), 3.97 (brs, 1H), 4.89-4.96 (m , 1H), 6.19 (brs, 2H), 6.35 (d, J = 14.4Hz, 1H), 6.77 (d, J = 14.4Hz, 1H), 7.38 (d, J = 6.3Hz, 1H), 7.53 (brs , 1H), 8.04 (s, 1H)

(Compound I-172) NMR (DMSO-d6); δ (ppm) 1.00 (t, J = 7.2Hz, 3H), 1.25-2.10 (m, 25H), 3.04-3.11 (m, 2H), 3.96 (brs , 1H), 4.90-4.97 (m, 1H), 6.20 (brs, 2H), 6.35 (d, J = 14.4Hz, 1H), 6.77 (d, J = 14.4Hz, 1H), 7.38 (d, J = 7.1Hz, 1H), 7.57 (t, J = 5.4Hz, 1H), 8.04 (s, 1H)

(Compound I-173) NMR (DMSO-d6); δ (ppm) 0.87 (t, J = 7.3 Hz, 3H), 1.24 (d, J = 6.1 Hz, 6H), 1.33-2.07 (m, 23H), 3.88 (brs, 1H), 4.42 (s, 1H), 4.87-4.93 (m, 1H), 6.35 (d, J = 14.4Hz, 1H), 6.75 (d, J = 14.4Hz, 1H), 7.31 (d , J = 7.3Hz, 1H), 7.69 (s, 1H), 8.00 (s, 1H)

(Compound I-174) NMR (DMSO-d6); δ (ppm) 0.87 (t, J = 7.3 Hz, 3H), 1.24 (d, J = 6.1 Hz, 6H), 1.40-2.10 (m, 23H), 3.96 (brs, 1H), 4.89-4.95 (m, 1H), 6.20 (brs, 2H), 6.36 (d, J = 14.4Hz, 1H), 6.75 (d, J = 14.4Hz, 1H), 7.38 (d , J = 6.6Hz, 1H), 7.69 (s, 1H), 8.01 (s, 1H)

(Compound I-179) NMR (DMSO-d6); δ (ppm) 1.25 (d, J = 6.1 Hz, 6H), 1.35-2.03 (m, 19H), 3.31 (s, 3H), 3.76 (s, 2H ), 3.89 (brs, 1H), 4.43 (s, 1H), 4.86-4.93 (m, 1H), 6.39 (d, J = 14.4Hz, 1H), 6.79 (d, J = 14.4Hz, 1H), 7.31 (d, J = 7.1Hz, 1H), 7.40 (s, 1H), 8.01 (s, 1H)

(Compound I-180) NMR (DMSO-d6); δ (ppm) 1.25 (d, J = 6.1 Hz, 6H), 1.41-2.10 (m, 19H), 3.31 (s, 3H), 3.76 (s, 2H ), 3.95 (brs, 1H), 4.87-4.94 (m, 1H), 6.19 (brs, 2H), 6.39 (d, J = 14.4Hz, 1H), 6.79 (d, J = 14.4Hz, 1H), 7.36 -7.40 (m, 2H), 8.02 (s, 1H)

(Test Example 1)
Evaluation of 11β-HSD1 inhibitors (Evaluation of compounds against human 11β-HSD1)
Inhibitors include 50 mM sodium phosphate buffer (pH 7.5), bovine serum albumin (1 mg / ml), NADPH (0.42 mg / ml), glucose-6-phosphate (1.26 mg / ml), glucose-6 -Substrate cortisone (5 μM) was added after preincubation for 30 minutes at room temperature in a reaction solution composed of phosphate dehydrgenase and enzyme (total 10 μl). After reacting at 37 ° C. for 2 hours, XL-665-labeled cortisol solution (5 μl) and Cryptate-labeled anti-cortisol antibody solution (5 μl) were added, and after 2 hours of reaction at room temperature, fluorescence intensity (HTRF method) was measured. Cortisol concentration was calculated from a standard curve prepared with cortisol of known concentration for each experiment.
The concentration of cortisol produced when no inhibitor was included was taken as the control value, and the inhibitory curve plotting the inhibition rate against the control value at each concentration of the inhibitor was the 50% inhibitory concentration (IC50 value) against 11β-HSD1 of the inhibitor. Calculated.

(Test Example 2)
Evaluation method of 11β-HSD1 inhibitor (Compound evaluation for mouse 11β-HSD1)
Inhibitors include 50 mM sodium phosphate buffer (pH 7.5), bovine serum albumin (1 mg / ml), NADPH (0.42 mg / ml), glucose-6-phosphate (1.26 mg / ml), glucose-6 -Substrate 11-dehydrocorticosterone (2 μM) was added after preincubation for 30 minutes at room temperature in a reaction solution consisting of phosphate dehydrogenase and enzyme (total volume 10 μl). After reacting at 37 ° C. for 2 hours, XL-665-labeled cortisol solution (5 μl) and Cryptate-labeled anti-cortisol antibody solution (5 μl) were added, and after 2 hours of reaction at room temperature, the fluorescence intensity was measured (HTRF method). Corticosterone concentration was calculated from a standard curve prepared with corticosterone of known concentration for each experiment.
The concentration of corticosterone produced when no inhibitor was included was taken as the control value, and the inhibitory curve of the inhibitor against 11β-HSD1 (IC50 value) was plotted from the inhibition rate against the control value at each concentration of the inhibitor. ) Was calculated.

The results of Test Examples 1 and 2 are shown below.
Compound I-7: human IC ₅₀ = 3.4 nM, mouse IC ₅₀ = 0.41 nM
Compound I-9: human IC ₅₀ = 11 nM, mouse IC ₅₀ = 1.7 nM
Compound I-29: human IC ₅₀ = 8.7 nM, mouse IC ₅₀ = 0.19 nM
Compound I-30: human IC ₅₀ = 35.1 nM, mouse IC ₅₀ = 2 nM
Compound I-36: human IC ₅₀ = 1.2 nM, mouse IC ₅₀ = 1 nM
Compound I-63: human IC ₅₀ = 1.4 nM, mouse IC ₅₀ = 0.21 nM
Compound I-77: human _IC 50 = _0.62nM,

mouse

_IC 50 = 0.23 nM
Compound I-168: human IC ₅₀ = 6.6 nM, mouse IC ₅₀ = 1.6 nM

(Test Example 3)
Examination of Oral Absorption of 11β-HSD1 Inhibitor for Diabetes Experimental Materials and Methods (1) Animals Used 6-week-old male C57BL / 6J Jcl mice were purchased from CLEA Japan, and after 1-week preliminary breeding, 7-week-old Used in the experiment.
(2) Breeding conditions The mice are kept in a breeding environment with a temperature of 23 ± 2 ° C and humidity of 55 ± 10%. The lighting is cycled from 8:00 to 20:00 and from 20:00 to 8:00. Is set. During the preliminary breeding and the experiment period, solid feed (CE-2, Nippon Claire) and sterile tap water were freely given.
(3) Identification of individual and cage An individual number was marked on the tail of the mouse with oil-based ink for identification. The cage was labeled with the name of the person responsible for the test, date of arrival, strain, sex, and supplier, and was kept at 20 / cage during preliminary breeding. After the start of the experiment, the animals were raised at 3 animals / cage.
(4) Setting of dose and grouping Groups were set as follows according to the doses of oral administration and intravenous administration.
Oral administration 20 mg / kg (n = 3)
Intravenous administration 5 mg / kg (n = 3)
(5) Preparation of administration liquid The preparation method was shown below. A suspension was prepared using 0.5% methylcellulose (1500 cP) as an oral administration medium. N, N-dimethylacetamide / polyethylene glycol 400 (= 1/2) was used as an intravenous administration medium to prepare a solubilized solution.
(6) Administration method Oral administration was forcibly administered into the stomach with an oral sonde at a rate of 10 mL / kg. Intravenous administration was carried out from the tail vein with a glass syringe at a rate of 2.5 mL / kg.
(7) Evaluation items Blood was collected at a time point from the heart, and the drug concentration in plasma was measured using HPLC or LC / MS / MS.
(8) Statistical analysis Regarding the plasma concentration transition, the area under the plasma concentration-time curve (AUC) was calculated using the non-linear minimum program WinNonlin (registered trademark), and the biologic was calculated from the AUC of the oral administration group and intravenous administration group. Availability was calculated.

9-10 week old male ob / ob mice were used in the HSD1 inhibitory activity evaluation method experiments using isolated adipose tissue. The test compound 30-50 mg / kg was orally administered to the animals, and after 8 and 16 hours, visceral fat was removed under chloral hydrate anesthesia, and the HSD1 activity in fat was measured. The HSD1 inhibitory activity of the test compound was calculated by taking the 0.5% methylcellulose solution orally and giving the HSD1 activity in fat of animals treated in the same manner as 100.
Add about 3 times the amount of phosphate buffer (50 mM sodium phosphate (pH 7.5), bovine serum albumin (1 mg / ml)) to approximately 200 mg of the extracted visceral fat to prepare a homogenate solution, and measure HSD1 enzyme activity It was used for. HSD1 enzyme activity was measured using 60 μl of reaction solution (50 mM sodium phosphate buffer (pH 7.5), bovine serum albumin (1 mg / ml), NADPH (0.42 mg / ml), glucose-6-phosphate (1.26 mg / ml), glucose-6-phosphate dehydrgenase) and 20 μl of fat homogenate solution were mixed, and 20 μl of 10 μM 11-DHC solution was added as a substrate, and then the reaction was started. The reaction was carried out at 37 ° C. for 60 minutes, and the reaction was stopped by adding 200 μl of ethyl acetate. As an internal standard for analysis, 10 μl (20 pmol / μl) of dexamethasone solution was added, followed by centrifugation (15000 rpm × 3 min, rt), and 150 μl of supernatant was collected. The supernatant was dried under reduced pressure, and the resulting residue was dissolved in 60 μl of a water-methanol solution (H 2 O: methanol = 45: 55), and corticosterone was quantified by HPLC. Corticosterone was measured based on a calibration curve prepared in advance with a relative ratio to the amount of the internal standard dexamethasone.

(Test Example 4)
In Vitro Model Cell Culture C2C12: Mouse myoblast cell line C2C12 cells were cultured in the appropriate media described below and maintained at 37 ° C., 95-98% humidity and 5% CO ₂ .
In normal culture, the cells were cultured in DMEM Low Glucose (GIBCO) + 10% fetal bovine serum (FBS, GIBCO) + Penicillin (100 units / mL, GIBCO) + Streptomycin (100 ug / mL, GIBCO).
In order to differentiate cells, 24 hours after the start of culture in a normal culture medium, DMEM Low Glucose (GIBCO) + 2% horse serum (HS, GIBCO) + Penicillin (100 units / mL, GIBCO) + Streptomycin (100ug / mL, GIBCO ). When differentiated cells were used, cells cultured in this medium for 3 days or longer were used.

(Test Example 5)
Effects of compounds on changes in Atrogin and MuRF1 expression by cortisone treatment in C2C12 cells In this test example, the effects of glucocorticoid on Atrogin and MuRF1 expression in vitro, and the effects of compounds on the increase in Atrogin and MuRF1 expression by cortisone treatment were examined.
Effect of Compound on Atrogin and MuRF1 Expression Increase by Cortisone Treatment Differentiated C2C12 cells were treated with each concentration of Compound I-168 (Compound H), and 1 hour later, 1 uM cortisone (Sigma) was treated. After 24 hours, total RNA was extracted using RNAesay mini kit (QIAGEN) according to the manufacturer's recommended protocol.
The extracted total RNA was reverse-transcribed into cDNA according to a standard protocol using High Capacity cDNA Reverse Transcription Kits (Applied Biosystems). For quantitative PCR, Power SYBR Green Master Mix (Applied Biosystems) was used. RPS18 was used as an endogenous control.
The primer sequence used to measure the expression level of mouse Atrogin is
FW primer: CTGGAAATAATGGATGGCCACA;
RV primer: TGGAACCAAAGGCTCCCAAG
Was used.
The primer sequence used to measure the expression level of mouse MuRF1 is
FW primer: TGTCTCACGGTTGAGGTGCCCTA;
RV primer: CACCAGCATGGGATAGGCAGTAC
Was used.
The primer sequence used to measure the expression level of mouse RPS18 is
FW primer: TTCTGGCCAACGGTCTAGACACAC;
RV primer: CCAGTGGTCTTGGTTGCTGA
Was used.
As a result, 1 uM cortisone treatment increased Atrogin and MuRF1 mRNA expression levels by 2.23 times and 1.50 times, respectively, and the pretreatment with compound I-168 (Compound H) suppressed these gene expression increases in a dose-dependent manner and significantly. From this result, it was shown that 11β-HSD1 inhibitor suppresses cortisone-induced muscle atrophy in vitro (FIG. 1).

(Test Example 6)
Effect of single oral administration of compound on 11β-HSD1 activity in muscle In this test example, the inhibitory effect of 11β-HSD1 activity in muscle by oral administration of compound was examined.
11β-HSD1 activity in muscle 1 hour after a single dose Male adult mouse CBF1 mice (10-12 weeks old, Claire, Japan) were orally administered a suspension of Compound I-168 (Compound H) 0.1-10 mg / kg The gastrocnemius muscle was removed 1 hour after administration and frozen immediately after removal.
Add 3 times the amount of tissue homogenized to the gastrocnemius muscle (100 mM Tris-HCl (pH 7.5), 150 mM NaCl) and grind muscle tissue using TissueLyser II (Qiagen) in a room maintained at 4 degrees A muscle homogenate was created.
For 20 uL of muscle homogenate, 50 mM sodium phosphate buffer containing 1.9 mg / mL Nicotinamide adenine dinucleotide phosphate (Sigma), 5.8 mg / mL Glucose-6-phosphate (Sigma), 0.5% Glucose-6-phosphate dehydrogenase (Sigma) ( 60 μL of pH 7.5 buffer solution and 20 uL of reaction substrate (11-dehydrocorticosterone, 10 uM) were added. Then, it incubated at 37 degreeC for 2 hours. After completion of the reaction, steroids were extracted using ethyl acetate, HPCL (2690 (Waters, Separations module), 2487 (Waters, Dual λ absorbance detector), LichroCART 75-4 Supersphere 60 RP-select B (Merck KGaA, Column )) Was used to quantify the steroid concentration contained in the extract.
As a result, oral administration of the compound inhibited corticosterone production of muscle homogenate in a dose-dependent manner, and corticosterone production was inhibited 99% by administration of 10 mg / kg. This result shows that the activity of 11β-HSD1 is sufficiently suppressed in the gastrocnemius muscle 1 hour after oral administration of the compound (FIG. 2).
11β-HSD1 activity in muscle 24 hours after the initial administration of the compound Oral administration of a suspension of compound I-168 (Compound H) 3-30 mg / kg to male adult mouse CBF1 mice (10-12 weeks old, Claire, Japan) did. Six hours after the first administration, the same dose of the compound as that of the first administration was orally administered. Furthermore, 24 hours after the first administration, the gastrocnemius muscle was removed and frozen immediately after removal.
Add 3 times the amount of tissue homogenized to the gastrocnemius muscle (100 mM Tris-HCl (pH 7.5), 150 mM NaCl) and grind muscle tissue using TissueLyser II (Qiagen) in a room maintained at 4 degrees A muscle homogenate was created.
For 20 uL of muscle homogenate, 50 mM sodium phosphate buffer containing 1.9 mg / mL Nicotinamide adenine dinucleotide phosphate (Sigma), 5.8 mg / mL Glucose-6-phosphate (Sigma), 0.5% Glucose-6-phosphate dehydrogenase (Sigma) ( 60 μL of pH 7.5) buffer solution and 20 uL of reaction substrate (11-dehydrocorticosterone, 10 uM) were added. Then, it incubated at 37 degreeC for 2 hours. After completion of the reaction, steroids were extracted using ethyl acetate, HPCL (2690 (Waters, Separations module), 2487 (Waters, Dual λ absorbance detector), LichroCART 75-4 Supersphere 60 RP-select B (Merck KGaA, Column )) Was used to quantify the steroid concentration contained in the extract.
As a result, the corticosterone production of muscle homogenate was suppressed 24 hours after the first administration of the compound, and about 47% was suppressed at 30 mg / kg. From these results, it was confirmed that the activity of 11β-HSD1 was also suppressed in gastrocnemius muscle 24 hours after the initial administration of the compound (FIG. 3).

(Test Example 7)
Effects on mice by transplantation of cortisone pellets and effects of repeated oral administration of compounds In this test example, the effects of transplantation of sustained release pellets of cortisone subcutaneously to mice and the effects of repeated administration of compounds on it were examined.
A cortisone pellet was subcutaneously transplanted to C57BL / 6J (male 10 weeks old, Claire, Japan) under anesthesia to produce a cortisone pellet transplanted animal. After transplanting cortisone pellets, Compound I-168 (Compound H) 30 mg / kg dissolved in 0.5% methylcellulose (Wako Pure Chemical Industries) for 9 days at a dose of 10 mL / kg, twice a day, Orally administered. Body weight was measured on the day of transplantation and on the 2nd, 3rd, 5th, 8th, and 9th days after transplantation. The amount of food consumption was calculated as the amount of food consumed for 24 hours from the sixth day after transplantation. The grip strength test was performed using DEF002 (SD instruments) on the 8th day after transplantation. On the 9th day after transplantation, blood was collected from the abdominal aorta under anesthesia, then the tibialis anterior (TA), gastrocnemius (GA), extensor digitorum longus (EDL), foot, Plantars (PLANT) were isolated and weighed. Plasma was separated from the obtained blood sample, steroid was extracted using ethyl acetate, HPCL (2690 (Waters, Separations module), 2487 (Waters, Dual λ absorbance detector), LichroCART 75-4 Supersphere 60 RP- The concentration of steroid contained in the extract was quantified using select B (Merck KGaA, Column).
As a result, blood cortisone concentration and cortisol concentration increased by transplanting cortisone pellets. Repeated administration of the compound to cortisone pellet transplanted animals further increased blood cortisone levels and decreased blood cortisol levels. In addition, transplantation of cortisone pellets decreased body weight and food consumption, decreased the weight of TA, GA, EDL, and plant, and decreased grip strength (FIGS. 4 and 5). These effects of cortisone pellet implantation were suppressed by repeated administration of the compound.

(Test Example 8)
Effects of Corticosterone on Mice and Effects of Repeated Oral Compound Administration In this test example, the effects of administering corticosterone to mice and the effects of repeated administration of the compound on it were examined.
Corticosterone solution (Sigma Aldrich, dissolved in 1% ethanol, supplied as 30 ug / mL or 100 ug / mL) was given to C57BL / 6J (male, 10 weeks old, Claire, Japan) and at the same time compound I-30 (30 mg / mL) kg, 10 mL / kg) was orally administered twice a day.
Animals were dissected 4 weeks after the start of dosing, and subcutaneous fat (FIG. 6), epididymal fat (FIG. 7), gastrocnemius muscle (FIG. 8), and anterior tibial muscle weight (FIG. 9) were measured. The fat weight increased in a dose-dependent manner with corticosterone, and this increase was significantly suppressed by Compound I-30.
In addition, skeletal muscle weight was decreased in a dose-dependent manner by corticosterone, and this decrease was significantly suppressed by Compound I-30.
When blood glucose and blood lipid at the time of dissection were measured, corticosterone did not change blood glucose, but neutral fat (FIG. 10) and free fatty acid (FIG. 11) were dose-dependent. In both cases, the change was suppressed by Compound I-30.
From the above results, it was suggested that fat accumulation, muscle atrophy, and dyslipidemia appearing with excess corticosterone are suppressed by Compound I-30.

Formulation Examples 1 to 8 shown below are merely examples, and are not intended to limit the scope of the invention in any way. The term “active ingredient” means a compound of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

(Formulation example 1)
Hard gelatin capsules are manufactured using the following ingredients:
Dose (mg / capsule)
Active ingredient 250
Starch (dried) 200

Magnesium stearate

10
Total 460mg

(Formulation example 2)
Tablets are manufactured using the following ingredients:
Dose (mg / tablet)
Active ingredient 250
Cellulose (microcrystal) 400
Silicon dioxide (fume) 10
Stearic acid 5
665mg total
The ingredients are mixed and compressed into tablets each weighing 665 mg.

(Formulation example 3)
An aerosol solution is prepared containing the following ingredients:
weight
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (chlorodifluoromethane) 74.00
Total 100.00
The active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to −30 ° C. and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.

(Formulation example 4)
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
The active ingredients, starch, and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.

(Formulation example 5)
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.

(Formulation example 6)
A suppository containing 225 mg of active ingredient is prepared as follows:
Active ingredient 225mg
Saturated fatty acid glyceride 2000mg
Total 2225mg
The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.

(Formulation example 7)
A suspension containing 50 mg of active ingredient is prepared as follows:
Active ingredient 50mg
Sodium carboxymethylcellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Fragrance q. v.
Dye q. v.
5ml in total with purified water
The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add the benzoic acid solution and perfume diluted with a portion of the water and stir. Then add a sufficient amount of water to the required volume.

(Formulation Example 8)
The intravenous formulation is manufactured as follows:
Active ingredient 100mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.

As is clear from the above test examples, the compound according to the present invention is very useful as a therapeutic and / or prophylactic agent excellent in a pathological condition involving hyperglucocorticoidemia.

Claims

Formula (I):

(Where
Ring A is

And
Ring B is a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R 1 is hydrogen or substituted or unsubstituted alkyl;
R 2 is —OR 5 or —SR 5 ;
R 3 is a group represented by the formula: —CH═CH—C (R a R b ) —R c —R d ,
R a and R b are each independently hydrogen, substituted or unsubstituted alkyl or halogen;
R c is — (CH 2 ) n— (where n is an integer from 0 to 3);
R d is hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a group represented by the formula: —C (═O) —NR g R h , or A group represented by the formula: —NR i R j ,
R g and R h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted Or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or R i and R j which are unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxy or substituted or unsubstituted carbamoyl Each independently represents hydrogen, carboxy, hydroxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or Unsubstituted cycloal Ruoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted nonaromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted A cycloalkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, a substituted or unsubstituted nonaromatic heterocyclic carbonyl, or a substituted or unsubstituted sulfamoyl,
R 4 is substituted or unsubstituted alkyl or —OR 6 ;
R 5 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted unsubstituted An aromatic heterocyclic group,
R 6 is hydrogen or —CONR 7 R 8 ,
R 7 and R 8 are each independently hydrogen, or substituted or unsubstituted alkyl), or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic and / or prophylactic agent for a pathological condition in which symptom is involved.
The compound of formula (I) is
Formula (II):

(Wherein ring A, R 1 , R 2 and R 3 have the same meaning as in claim 1), the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, characterized by comprising.
Ring A is of formula (III):

(Wherein R 4 has the same meaning as in claim 1), the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia.
The treatment of a disease state involving hyperglucocorticoidemia, comprising as an active ingredient the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen. Agent and / or prophylactic agent.
The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R 2 is -OR 5 (wherein R 5 is as defined in claim 1). A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia characterized by
R 2 is —SR 5 (wherein R 5 has the same meaning as in claim 1), containing the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia characterized by
R 5 is characterized in that it contains a compound or active ingredient a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, a substituted or unsubstituted alkyl, involving high glucocorticoid viremia A therapeutic and / or prophylactic agent for the pathological condition.
A high glucocorticoid comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R a and R b are each independently substituted or unsubstituted alkyl. A therapeutic and / or prophylactic agent for a pathological condition involving blood glucose.
9. The compound according to claim 1, wherein R d is halogen, hydroxy, cyano, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutical thereof. A therapeutic and / or prophylactic agent for a pathological condition associated with hyperglucocorticoidemia, comprising a top acceptable salt as an active ingredient.
R d is of the formula: —C (═O) —NR g R h where R g and R h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy or substituted or non-substituted A hyperglucocorticoidemia comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient. Therapeutic and / or prophylactic agent for pathological conditions involving
R d is of the formula: —NR i R j where R i and R j are each independently hydrogen, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylcarbonyl Or a substituted or unsubstituted non-aromatic heterocyclic carbonyl.) Containing the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, which is characterized.
R 4 is —OR 6 , —CH 2 OH, —CH 2 OCONR 7 R 8 or —CH 2 NHCOR 12 , wherein R 12 is substituted or unsubstituted alkyl, and R 6 to R 8 are as defined in claim 1. 12. A therapeutic agent for a pathological condition involving hyperglucocorticoidemia, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient. And / or prophylactic agent.
R 7 and R 8 are each independently hydrogen or substituted or unsubstituted alkyl, containing the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia.
The compound of formula (I) is
Formula (II):

Wherein ring A is represented by formula (III):

(Wherein R 4 is —OH or —OC (═O) NH 2 ),
R 1 is hydrogen;
R 2 is —OR 5 or —SR 5 ;
R 5 is isopropyl;
R 3 is represented by the formula: —CH═CH—C (CH 3 ) 2 —NH (—C═O) —CH 3 ), or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic and / or prophylactic agent for a pathological condition involving hyperglucocorticoidemia, characterized by comprising.
The therapeutic and / or prophylactic agent according to claim 1, wherein the pathological condition involving hyperglucocorticoidemia is muscle atrophy.
Formula (I) for the treatment and / or prevention of pathologies involving hyperglucocorticoidemia:

(Where
Ring A is

And
Ring B is a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R 1 is hydrogen or substituted or unsubstituted alkyl;
R 2 is —OR 5 or —SR 5 ;
R 3 is a group represented by the formula: —CH═CH—C (R a R b ) —R c —R d ,
R a and R b are each independently hydrogen, substituted or unsubstituted alkyl or halogen;
R c is — (CH 2 ) n— (where n is an integer from 0 to 3);
R d is hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a group represented by the formula: —C (═O) —NR g R h , or A group represented by the formula: —NR i R j ,
R g and R h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted Or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or R i and R j which are unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxy or substituted or unsubstituted carbamoyl Each independently represents hydrogen, carboxy, hydroxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or Unsubstituted cycloal Ruoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted nonaromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted A cycloalkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, a substituted or unsubstituted nonaromatic heterocyclic carbonyl, or a substituted or unsubstituted sulfamoyl,
R 4 is substituted or unsubstituted alkyl or —OR 6 ;
R 5 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted unsubstituted An aromatic heterocyclic group,
R 6 is hydrogen or —CONR 7 R 8 ,
R 7 and R 8 are each independently hydrogen or substituted or unsubstituted alkyl) or a pharmaceutically acceptable salt thereof.
Formula (I):

(Where
Ring A is

And
Ring B is a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R 1 is hydrogen or substituted or unsubstituted alkyl;
R 2 is —OR 5 or —SR 5 ;
R 3 is a group represented by the formula: —CH═CH—C (R a R b ) —R c —R d ,
R a and R b are each independently hydrogen, substituted or unsubstituted alkyl or halogen;
R c is — (CH 2 ) n— (where n is an integer from 0 to 3);
R d is hydrogen, halogen, hydroxy, carboxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, A substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a group represented by the formula: —C (═O) —NR g R h , or A group represented by the formula: —NR i R j ,
R g and R h are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted Or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or R i and R j which are unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxy or substituted or unsubstituted carbamoyl Each independently represents hydrogen, carboxy, hydroxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic Heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or Unsubstituted cycloal Ruoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted nonaromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted A cycloalkylcarbonyl, a substituted or unsubstituted arylcarbonyl, a substituted or unsubstituted aromatic heterocyclic carbonyl, a substituted or unsubstituted nonaromatic heterocyclic carbonyl, or a substituted or unsubstituted sulfamoyl,
R 4 is substituted or unsubstituted alkyl or —OR 6 ;
R 5 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted unsubstituted An aromatic heterocyclic group,
R 6 is hydrogen or —CONR 7 R 8 ,
R 7 and R 8 are each independently hydrogen, or a substituted or unsubstituted alkyl), or a pharmaceutically acceptable salt thereof, and administered as an active ingredient, high glucocorticoid blood A method for treating and / or preventing a disease state in which a disease is involved.