WO2005023782A1 - Compose pyrimidine-4(ch)-one fusionne substitue - Google Patents

Compose pyrimidine-4(ch)-one fusionne substitue Download PDF

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WO2005023782A1
WO2005023782A1 PCT/JP2004/013268 JP2004013268W WO2005023782A1 WO 2005023782 A1 WO2005023782 A1 WO 2005023782A1 JP 2004013268 W JP2004013268 W JP 2004013268W WO 2005023782 A1 WO2005023782 A1 WO 2005023782A1
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group
alkyl
substituted
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PCT/JP2004/013268
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Japanese (ja)
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Masami Arai
Satoru Kaneko
Satoshi Shibuya
Tsuyoshi Watanabe
Kozo Oda
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Sankyo Company, Limited
X-Ceptor Therapeutics, Inc.
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Publication of WO2005023782A1 publication Critical patent/WO2005023782A1/fr

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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the present invention is intended to improve lipid metabolism abnormalities by regulating the action of Liver X recep to rs (LXR), or to control the production of inflammatory mediators to achieve excellent anti-atherosclerosis.
  • the present invention relates to a novel substituted fused pyrimidine-4 (3H) -one compound or a pharmacologically acceptable salt or ester thereof, which exhibits an action and an anti-inflammatory action.
  • the present invention provides a pharmaceutical composition containing a substituted fused-ring pyrimidine-4 (3H) -one compound or a pharmaceutically acceptable salt or ester thereof as an active ingredient, preferably atherosclerosis (hereinafter referred to as arteriosclerosis).
  • a pharmaceutical composition containing a substituted fused-ring pyrimidine-4 (3H) -one compound or a pharmaceutically acceptable salt or ester thereof as an active ingredient, preferably atherosclerosis (hereinafter referred to as arteriosclerosis).
  • the present invention relates to a substituted fused pyrimidine-4 (3H) -substituted compound or a pharmacological compound thereof for producing a pharmaceutical composition, preferably a pharmaceutical composition for treating or preventing the above-mentioned diseases.
  • a pharmaceutical composition preferably a pharmaceutical composition for treating or preventing the above-mentioned diseases.
  • the present invention provides a method for administering a pharmacologically effective amount of a substituted fused-ring pyrimidine-1 (3H) -one compound or a pharmaceutically acceptable salt or ester thereof to a warm-blooded animal (particularly a human).
  • the present invention relates to a method for treating or preventing the above-mentioned diseases.
  • the present invention relates to a method for producing a substituted fused-ring pyrimidine-14 (3H) -one compound or a pharmaceutically acceptable salt or ester thereof.
  • cardiovascular diseases eg, heart disease, cerebrovascular disease, renal disease, etc.
  • heart disease and cerebrovascular disease were the second and third leading causes of death in 2001, respectively, and the mortality rate from these diseases per 100,000 people was 1.17.8 And 107.07 people (Ministry of Health, Labor and Welfare, demographic statistics for fiscal 2001).
  • antihypertensive, antihyperlipidemic and antidiabetic drugs are used for the treatment of hypertension, hyperlipidemia and hyperglycemia, respectively.
  • Antihypertensives include a and blockers, diuretics, calcium antagonists, AC ⁇ inhibitors and A-II antagonists
  • antihyperlipidemics include HMG-CoA reductase inhibition Agents, anion exchange resins, nicotinic acid derivatives, probucol and fibrates, etc.
  • antidiabetic drugs such as insulin, sulfonylureas, metformin, and dalixones are used clinically. Have been. These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels.
  • a direct risk factor for cardiovascular diseases such as heart disease, cerebrovascular disease and kidney disease is arteriosclerosis with thickening of the arterial wall, which is caused by oxidized low density lipoprotein cholesterol (LDL-C) Is the formation of plaque due to accumulation in the arterial wall (Ross, R., Annu. Rev. Physiol. 1995, Vol. 57, p. 791-804; Steinberg, D., J. Biol. Chem. 1997 272, p.20963-20966). This plaque blocks blood flow and promotes the formation of blood clots.
  • LDL-C low density lipoprotein cholesterol
  • LXR nuclear receptor XR plays an important role in regulating lipid metabolism (Janowski, B., Willy, PJ, Falck, JR, Mange Isdorf, DJ, Nature, 1996, Vol. 383, p.728-731).
  • LXR ⁇ LXR ⁇
  • LXR / 3 LXRa is distributed in high proportions in the liver of mammals, in small amounts in the kidney, small intestine, spleen, and adrenal gland, and LXR / 3 is distributed in organs and tissues throughout the body.
  • LXR is regulated by the transcription of oxidized sterols in the macrophage of the blood vessel wall, induces the expression of ABCA 1 (ATP Binding Cassette Transpoter-1) and ApoE (Apol ipoprotein E), Promotes cholesterol abstraction and the reverse cholesterol transfer system to the liver (Lu, ⁇ . ⁇ ⁇ , Repa, JJ, Mangelsdorf, DJ, J. Biol. Chem., 2001, vol. 276, p. 37735-37738 ).
  • ABCA 1 ATP Binding Cassette Transpoter-1
  • ApoE Adoprotein E
  • LXR also induces ABCA1 expression in the small intestine and inhibits the absorption of dietary cholesterol from the gastrointestinal tract (Repa, JJ, Turley, SD, Lobaccaro, JA, Medina, J., Li, Shi., Lustig, K., Shan, B., Heyman, RA, Dietschy, JM, Mange Isdorf, DJ, Science, 2002, Vol. 289, p. 1524-1529).
  • drugs that regulate LXR should be used for the treatment of arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia or lipid-related diseases. It is expected to be useful in prevention.
  • Atherosclerosis is also considered a chronic inflammatory disease (Ross, R., N. Engl. J. Mecl., 1986, Vol. 314, p. 488-500).
  • LXR regulates immune function by regulating the expression of inflammatory mediators such as O-synthetic enzyme (nitric oxide synthase) ⁇ cycling xygenase-12 (COX-2) and interleukin-16 (IL-6). It has been reported to play an important role in the control of humans (Mangelsdorf, DJ, Tontonoz, P. et. Al., Nat. Med., 2003, Vol. 9, pp. 213-219).
  • LXR modulators are expected to suppress the onset and progression of arteriosclerosis due to the anti-inflammatory effect in addition to the improvement of lipid metabolism.
  • naturally occurring and synthetic LXR activators have been shown to reduce chemically induced dermatitis in animal models (Fowler, AJ, et.a, J. Invest. Dermatol. 2003, Volume 120, p.246-255).
  • LXR modulators are expected to be useful for treating various inflammatory diseases.
  • the present inventors have conducted intensive studies on the synthesis and pharmacological activity of the fused pyrimidine-4 (3H) -one compound in order to find a compound having excellent binding activity to LXR.
  • Fused Pyrimidine-4 (3H) -one Compounds Having Substituents Have Excellent Binding Activity to LXR The present invention was completed, and the present invention was completed.
  • the present invention exhibits excellent anti-atherosclerotic and anti-inflammatory effects by regulating the action of nuclear receptor LXR to improve lipid metabolism disorder or controlling the production of inflammatory mediators.
  • the present invention relates to a pharmaceutical composition containing a substituted fused-ring pyrimidine-14 (3H) -amine compound or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably atherosclerosis (hereinafter referred to as arteriosclerosis).
  • a pharmaceutical composition containing a substituted fused-ring pyrimidine-14 (3H) -amine compound or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably atherosclerosis (hereinafter referred to as arteriosclerosis).
  • the present invention relates to a pharmaceutical composition, preferably a substituted fused pyrimidine-14 (3H) -amine compound or a pharmacological compound thereof for producing a pharmaceutical composition for treating or preventing the above-mentioned diseases.
  • a pharmaceutical composition preferably a substituted fused pyrimidine-14 (3H) -amine compound or a pharmacological compound thereof for producing a pharmaceutical composition for treating or preventing the above-mentioned diseases.
  • the use of the above acceptable salts or esters is provided.
  • the present invention provides a method for administering a pharmacologically effective amount of a substituted fused-ring pyrimidine-4 (3H) -amine compound or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal (particularly a human). And a method for treating or preventing the above-mentioned diseases.
  • the present invention provides a method for producing a substituted condensed fused pyrimidine-1 (3H) -one compound or a pharmaceutically acceptable salt or ester thereof.
  • the present invention provides a compound represented by the general formula (I):
  • A represents a phenyl group or a 5- or 6-membered heteroaryl group
  • R 1 is R ′ a
  • 3 is a substituted C, -C 6 alkyl group (the substituents are the same or different, and are 1 to 4 groups selected from substituent groups); C 3 -C 8 cycloalkyl group, substituted-(; 8 cycloalkyl group (the substituents are the same or different, and are ⁇ to 4 groups selected from substituent group ⁇ ), C 2 -C 7 alkenyl group, substituted C 2 -C 7 alkenyl group (the substituents are the same or different and are 1 to 4 groups selected from substituent group ⁇ ), C 6 -C,.
  • Aryl group, substituted-( ⁇ aryl group (the substituents are the same or different, a group of substituents) is 1 to 3 groups selected from 3), (C 6 -C 10 7 reel)- (C 6 -C 6 alkyl) group, substituted (C 6 -C, 7 reel)-(C, -C s alkyl) group (Substituents of the aryl group are the same or different, and are selected from substituent groups.
  • the substituents of the alkyl group are the same or different and are 1 to 4 groups selected from a substituent group d), a 4- to 10-membered heterocyclyl group, 4 to 10-membered heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from a substituent group; 8), (4- to 10-membered heterocyclyl) — (C , -C 6 alkyl) group or substituted (4- to 10-membered heterocyclyl)-(C, -C 6 alkyl) group (substituents of the heterocyclyl group are the same or different, and a group of substituents) 1 to 3 groups selected from 3 and the substituents of the alkyl group are the same or different and represent a substituent group ⁇ 1 to 4 groups selected from 5)];
  • R ′ b is a substituted C, —C 6 alkyl group (the substituents are the same or different, and a group of substituents (1 to 4 selected from 5 group in a), C 3 -C 8 cycloalkyl group, a substituted C 3 -C 8 Shikuroaruwiru group (said substituents may be the same or different, 1 ⁇ optimum 4 groups selected from substituent group ⁇ 5 ), A C 2 -C 7 alkenyl group, a substituted C 2 -C 7 alkenyl group (the substituents are the same or different and are 1 to 4 groups selected from a substituent group ⁇ ), C 6 -C,.
  • Ariru group (said substituents may be the same or different, substituent group) is 1 to 3 groups selected from 8), ( C 6 -C, .aryl) — (-(; 6 alkyl) group, substituted (C 6 -C, .aryl) — (C, -C 6 alkyl) group (substituent of the aryl group) Are the same or different, 1 to 3 groups selected from the substituent group ⁇ , and the substituents of the alkyl group are the same or different, and the substituent groups (1 to 4 groups selected from 5), 4 To 10 membered heterocyclyl group, substituted 4 A 10-membered heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from a substituent group; 8), (a 4- to 10-membered heterocyclyl) (C,- C 6 alkyl) group or substituted (4- to 10-membered heterocyclyl)-(C
  • Ethynyl group (—C ⁇ CH); or
  • R 2 and R 3 are the same or different and are each a hydrogen atom, a -C 6 alkyl group, a halogeno Ci-C 6 alkyl group (the halogen C, -C 6 alkyl group is substituted with 1 to 7 halogeno groups; and C, -C 6 represents an alkyl group), a hydroxyl group, c, -c 6 alkoxy group, an amino group, c, -c 6 alkyl amino group, di (c, - c 6 Al kill) amino group (said alkyl group Are the same or different), a nitro group, a halogeno group, or R 2 and R 3 together represent -C 4 alkylenedioxy group;
  • R 4 and R 5 are the same or different and are each a hydrogen atom, a C, -C 6 alkyl group, a halogeno C, -C 3 alkyl group (the halogeno C, -C 6 alkyl group is a 1 to 7 halogen group, Represents a C, -C 6 alkyl group substituted with a), a hydroxyl group, a C, -C 6 alkoxy group, an amino group, a mercapto group, a C, -C 6 alkylthio group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl Group, cyano group or halogen group,
  • X represents a hydroxyl group or a C, -C 6 alkoxy group
  • Y is a c, -c 6 alkyl group, a substituted c, -c 6 alkyl group (the substituents are the same or different, and are 1 to 5 groups selected from a substituent group ⁇ ), C 3 -C 8 cycloalkyl group, substituted (: 3 -cycloalkyl group (the substituents are the same or different and are 1 to 5 groups selected from substituent group ⁇ ), (C 3 - C 8 cycloalkyl) one (C, -C 4 alkyl) group, substituted (C 3 - cycloalkyl) - (C, -C 4 alkyl) group (said substituents may be the same or different, substituents 1 to 5 groups selected from group ⁇ ), C 6 -C, aryl group, substituted C 6 -Cm aryl group (the substituents may be the same or different, and /?), (C 6 -C, .aryl) — (Ci-alkyl)
  • Two such alkyl groups may be taken together with the nitrogen atom of the amino group to form a 5- to 7-membered saturated heterocyclyl group having a nitrogen atom, an oxygen atom or a sulfur atom), a formylamino group
  • a C r C 7 alkylcarbonylamino group an N- (C 2 -C 7 alkylcarbonyl) -N- (C, -C 3 alkyl) amino group, a C 2 -C 7 alkoxycarbonylamino group, an N- (C r C 7 alkoxyl) -N- (C, -C 6 alkyl) amino, C, -C 6 alkylsulfonylamino, N- (C, -C 6 alkylsulfonyl)- N-(- C 6 alkyl) amino group, halogeno C, - C 6 alkylsulfonyl ⁇ amino group (said halogeno-C, - C 6 alkyl
  • a hydroxy C, -C 6 alkylamino group (the hydroxy C, -C 6 alkylamino group represents a Ci-C 6 alkylamino group substituted with 1 to 4 hydroxyl groups), Formylamino group, C 2 -C 7 alkylcarbonylamino group, formyl group, C 2 -C 7 alkylcarbonyl group, carboxyl group, C 2 -C 7 alkoxycarbonyl group, carbamoyl group, C 2 -C 7 alkylamino carbonyl group, a di (C, -C 6 Alkyl) ⁇ amino carbonyl group (said alkyl group may be the same or different), and, shows the group consisting Shiano group,
  • Substituent group (5 represents a group consisting of a substituent and an octalogeno group contained in the above-mentioned substituent group a.
  • R 4 and R 5 represent a hydrogen atom, and are represented by the formula —C (CF 3 ) 2 (X). Represents a group represented by C (CF 3 ) 2 (0H) substituted at the 3- or 4-position of the phenyl group to which the group is bonded;
  • position 1 is substituted with an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group, or a halogenoalkylsulfonylamino group, and further selected from the substituent group ⁇ .
  • a cycloalkyl group optionally substituted with 1 to 4 substituents;
  • the 1-position of the alkyl moiety is substituted with an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group, or an octogenoalkylsulfonylamino group.
  • the heterocyclyl moiety has one or more nitrogen atoms, and the substituent group may be substituted with 5 substituents selected from 8), and the methyl moiety may be substituted with an alkyl group.
  • the 1-position of the alkyl moiety is an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkoxycarbonylamino group, an alkylsulfonylamino group, an octalogenoalkylsulfonylamino group, (Alkylcarbonyl) -N- (alkyl) amino group,-(alkoxycarbonyl) -N- (alkyl) amino group, N- (alkylsulfonyl) (alkyl) amino group, or N- (octogenoalkylsulfo Diaryl) -arylalkyl group substituted by an N- (alkyl) amino group, and the arylalkyl group may be further substituted by 1 to 4 substituents selected from substituent group 8).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof, which exhibits an effective amount of pharmacological activity, and a carrier or diluent. I do.
  • the present invention provides the above pharmaceutical composition for treatment or prevention in a warm-blooded animal, wherein the warm-blooded animal is a disease which can be treated or prevented by regulating LXR function in a warm-blooded animal. possible.
  • the pharmaceutical composition is for treatment or prophylaxis in a warm-blooded animal, wherein the warm-blooded animal is atherosclerosis (including arteriosclerosis caused by the following diseases); atherosclerosis Disease; arteriosclerosis due to diabetes; hyperlipidemia; lipid-related diseases; inflammatory diseases caused by inflammatory cytokines; autoimmune diseases; cardiovascular diseases; cerebrovascular diseases;
  • the human being a disease selected from the group consisting of kidney disease; diabetes; diabetic complications; obesity; nephritis; hepatitis; cancer; and Alzheimer's disease.
  • the pharmaceutical composition is for treatment or prophylaxis in a warm-blooded animal, the warm-blooded animal being atherosclerosis (including arteriosclerosis caused by the following diseases); Atherosclerosis; arteriosclerosis caused by diabetes; hyperlipidemia; lipid-related disease; inflammatory disease caused by inflammatory site-induced inflammation; and diabetes. It can be a diseased human.
  • the drug The composition is for treatment or prophylaxis in a warm-blooded animal, wherein the warm-blooded animal can be a human with arteriosclerosis.
  • the present invention also provides a compound represented by the above general formula (I) or a pharmaceutically acceptable salt or ester thereof for use as a medicament.
  • the present invention also provides the use of one or more compounds represented by the above general formula (I) or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for treatment or prevention in a warm-blooded animal.
  • the warm-blooded animal may be a human that is a disease that can be treated or prevented by regulating LXR function in the warm-blooded animal.
  • the disease that can be treated or prevented by modulating LXR function in a warm-blooded animal includes arteriosclerosis (including arteriosclerosis caused by the following diseases); atherosclerosis; and diabetes.
  • Arteriosclerosis hyperlipidemia; lipid-related disease; inflammatory site-induced inflammatory disease; autoimmune disease; cardiovascular disease; cerebrovascular disease; renal disease; diabetes; Complications; obesity; nephritis; hepatitis; cancer; and Alzheimer's disease.
  • the disease is arteriosclerosis (including arteriosclerosis caused by the following diseases); atherosclerosis; arteriosclerosis caused by diabetes; hyperlipidemia; lipid-related disease; An inflammatory disease, which is a disease caused by an inflammatory site; and diabetes.
  • the disease is arteriosclerosis.
  • the present invention also provides a therapeutic or preventive treatment for a warm-blooded animal by administering to the warm-blooded animal an effective amount of the compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof.
  • the warm-blooded animal can be a human that is a disease that can be treated or prevented by modulation of LXR function in the warm-blooded animal.
  • the disease that can be treated or prevented by modulating LXR function in a warm-blooded animal includes arteriosclerosis (including arteriosclerosis caused by the following diseases); atherosclerosis; and diabetes.
  • Arteriosclerosis hyperlipidemia; lipid-related disease; inflammatory site-induced inflammatory disease; autoimmune disease; cardiovascular disease; cerebrovascular disease; renal disease; diabetes; Complications; obesity; nephritis; hepatitis; cancer; and Alzheimer's disease.
  • the disease is arteriosclerosis (including arteriosclerosis caused by the following diseases); atherosclerosis; arteriosclerosis caused by diabetes; hyperlipidemia; lipid-related disease; An inflammatory disease, which is a disease caused by an inflammatory site; and diabetes.
  • the condition is atherosclerosis.
  • the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt or ester thereof In the above, a preferred compound represented by the general formula (I) is
  • R ′ is R ′ a- ′ [R ′ a — ′ is a substituted CC 6 alkyl group (the substituents may be the same or different, and may be 1 to 4 selected from the above substituent group ⁇ ) Groups), C 6 -C ,.
  • the substituent group) is 1 to 3 groups selected from 8, and the substituents of the alkyl group are the same or different, and are the same or different, and the substituent group (1 to 4 groups selected from 5) ),
  • Aryl groups (the substituents are the same or different and are the same or different from the above substituent groups), and are 1 to 3 groups selected from 8), (C 6 -C 10 7 reel)-(C -C 6 alkyl) groups, substituted (C 6 - C 10 7 Lille) - (C, -C 6 alkyl) group (the substituent of the Ariru groups are the same or different, 1 to be selected from the above substituent group / 3 And the substituents of the alkyl group are the same or different, and are the same as the above substituent groups (1 to 4 groups selected from 5), a 4- to 10-membered heterocyclyl group, A 4- to 10-membered heterocyclyl group (the substituents are the same or different, and the above-mentioned substituent groups are 1 to 3 groups selected from 8), (4- to 10-membered heterocyclyl) C, -C 6 alkyl) group, or, substituted (heterocyclyl 4 to 1 0-membered) - (C
  • the substituents of the alkyl group are the same or different and are 1 to 4 groups selected from the above substituent group ⁇ 5.
  • Motodea Ru) indicates, Z 'b -' is, - NH-, one 0-, -S- or single S0 2 - group represented by the formula a group are] in; or,
  • R ′ is R ′ a — 2 [R ′ a — 2 is a substituted C, -C 4 alkyl group (the substituents may be the same or different 1 to 3 groups selected from the substituent group a 1), a 4- to 10-membered heterocyclyl group, a substituted 4- to 10-membered heterocyclyl group (the substituents may be the same or different , Substituent group / 31 1 or 2 groups selected from 1), (5- to 7-membered heterocyclyl)-(C, -C 4 alkyl) group or substituted (5- to 7-membered) Heterocyclyl) — (C “C 4 alkyl) group (Substituents of the heterocyclyl group are the same or different and are one or two groups selected from Substituent group i81.) Are the same or different and are 1 to 3 groups selected from substituent group ⁇ 1)];
  • R 1 b - - R lb 2 is substituted - alkyl group (said substituents may be the same or different Li, 1 selected from Substituent group 1 A 3- to 4-membered heterocyclyl group, a substituted 4- to 10-membered heterocyclyl group (the substituents may be the same or different, a group of substituents) 81 a two group), (heterocyclyl 5 to 7-membered) - (C, - C 4 alkyl) group, or, heterocyclyl substituted (5- to 7-membered) - (C, -C 4 alkyl) group (Substituents of the heterocyclyl group are the same or different, a group of substituents) 1 or 2 groups selected from 81.
  • the substituents of the alkyl group are the same or different, and the group of the substituents ⁇ 5 Z 1 b — 2 represents a group represented by —NH—, —0—, —S— or —S0 2 —].
  • Substituent group; 81 is a methyl group, an ethyl group, a trimethyl group, a 2,2,2-trifluoro group, a penyl group, a hydroxy C, -C 4 alkyl group ( hydroxy C, -C 4 alkyl groups, C substituted with 1 to 3 hydroxyl groups, shows a -C 4 alkyl group), amino C, - C 4 ⁇ alkyl group (said amino C, -C 4 alkyl group is C substituted with ⁇ to 3 amino groups, - shows the C 4 Al kill group), alkylamino C, -C 4 alkyl group (said alkylamino C -C 4 alkyl groups, one to three Bruno CI- C 4 Arukiruamino C substituted by group, the -C 4 alkyl group), Jiarukirua amino C, -C 4 alkyl group [the dialkyl ⁇ Mino C, -C 4 alkyl groups, one to three
  • a compound in which the substituent group ⁇ 51 is a group consisting of a substituent group, a chloro group, and a chloro group which are included in the substituent group a1;
  • R 1 a — 3 [R ′ a — 3 is a substituted C, —C 4 alkyl group (the substituents are the same or different and are selected from substituent group a 2; Or a 5- to 7-membered heterocyclyl group, or a substituted 5- to 7-membered heterocyclyl group (the substituents are the same or different and are selected from a substituent group ⁇ 2; Two groups)]; or,
  • R' b — 3 is a substituted C,- ⁇ alkyl group (the substituents may be the same or different, and a group of substituents (from 52) One or two selected groups), heterocyclyl— (C, -C 3 alkyl Le) group (heterocyclyl groups such is thienyl group, a thiazolyl group or a pyridyl group), or a substituted [heterocyclyl - (c, -c 3 alkyl) group (heterocyclyl groups such may, thienyl group, A thiazolyl group or a pyridyl group, the substituents of the heterocyclyl group are the same or different, and one or two groups selected from a substituent group i82, and the substituents of the alkyl group are the same or individually represents a 1 or a 2 groups) selected from substituent group [
  • substituent group P2 is a hydroxymethyl group, a hydroxyethyl group, a dihydroxyethyl group, a hydroxypropyl group, a dihydroxypropyl group, a hydroxybutyl group, a dihydroxybutyl group, an aminomethyl group, an aminoethyl group, an aminopropyl group, Methylaminoamino, ethylaminomethyl, propylaminomethyl, methylaminoethyl, ethylaminoethyl, propylaminoethyl, methylaminopropyl, ethylaminopropyl, propylaminopropyl, ( (Dimethylamino) methyl group, (diethylamino) methyl group, (dipropylamino) methyl group, (dimethylamino) ethyl group, (dimethylamino) ethyl group, (dimethylamino) e
  • Substituent group a2 includes a hydroxyl group, a hydroxymethoxy group, a hydroxyethoxy group, a dihydroxyethoxy group, a hydroxypropoxy group, a dihydroxypropoxy group, a hydroxybutoxy group, a dihydroxybutoxy group, an amino group, a methylamino group, an ethylamino group, A group consisting of a propylamino group, a dimethylamino group, a methylethylamino group, a methylpropylamino group, a getylamino group, an ethylpropylamino group, a dipropylamino group, a pyrrolidinyl group, and a carboxyl group;
  • a group of substituents (52 is a compound which is a group consisting of the substituents included in the above-mentioned substituent group r2,
  • R ′ is R la — 4
  • R ′ a — 4 is a phenyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a thiazolyl group, a triazolyl group, a pyridyl group, a pyrrolidinyl group, a morpholinyl group, or Substituted phenyl, pyrazolyl, imidazolyl, thiazolyl, thiazolyl, triazolyl, pyridyl, pyrrolidinyl, or morpholinyl groups (the substituents being the same or different, the above substituent groups) 82 Or a group selected from the group consisting of .1 to 2) or a compound of the formula — 0— R ′ b — 4 wherein R lb — 4 is a substituted ethyl group, propyl group, propyl Group or group A group represented by
  • R 2 and R 3 are the same or different and are each a hydrogen atom, a methyl group, an ethyl group, a trimethyl group, a 2,2,2-triethyl group, a pentafluoroethyl group, or a hydroxyl group , main Bok alkoxy group, an ethoxy group, an amino group, Mechiruamino group, Echiruamino group, Jimechiruamino group, Jechi Ruamino group, a nitro group, full Sairomoto, black port group, bromo group, or, R 2 and R 3 gar cord A compound that is a methylenedioxy or ethylenedioxy group,
  • R 2 and R 3 are the same or different and are a hydrogen atom, a methyl group, a hydroxyl group, a methoxy group, an amino group, a chloro group, or a cyclo group;
  • R 2 and R 3 are a hydrogen atom, a methoxy group, a chloro group, or a chloro group;
  • R 4 and R 5 are the same or different and are each a hydrogen atom, a C, -C 4 alkyl group, a C, -C 4 alkoxy group, an amino group, a carboxyl group, a chloro group, a cyclo group, or A compound that is a bromo group,
  • R 4 and R 5 are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a methoxy group, a fluoro group, or a cyclo group;
  • a group represented by the formula C (CF 3 ) 2 (X) is bonded to the group to which the group binds: 1 C (CF 3 ) 2 (0H
  • Y is -cycloalkyl group, substituted C 3 -C 6 cycloalkyl group (the substituents are the same or different and are ⁇ to 4 groups selected from substituent group ⁇ 1 ), (C 6 -C, .aryl) — (C, -C 2 alkyl), substituted (C 6 -C, .aryl) — (C, -C 2 alkyl)
  • a group of substituents) is 1 to 4 groups selected from 83), (4- to 10-membered terocyclyl)-(C, -C 2 alkyl) group, or substituted (4- to 10-membered heterocyclyl)-(C, -C 2 alkyl) group (the substituents are the same or different and are 1 to 4 groups selected from substituent group / 33) Yes,
  • Substituent group ⁇ ⁇ is a C r C 4 alkyl group, a C, -C 4 alkoxy group, a formyl group, a C 2 -C 5 alkylcarbonyl group, a formylamino group, a C 2 -C 5 alkyl carboxy group.
  • Y is a C 3 -C 5 cycloalkyl group, a substituted C 3 -C 5 cycloalkyl group (the substituents are the same or different, and 1 to 3 members selected from a substituent group ⁇ 2 Benzyl group, substituted benzyl group (the substituents are the same or different and are 1 to 3 groups selected from substituent group 84), (5 to 7 members (Terocyclyl) methyl group (the heterocyclyl group represents a 5- to 7-membered heterocyclyl group having one or more nitrogen atoms and optionally having an oxygen atom or a sulfur atom), or substituted ( 5- to 7-membered heterocyclyl) methyl group (The heterocyclyl group represents a 5- to 7-membered heterocyclyl group having at least one nitrogen atom and optionally having an oxygen atom or a sulfur atom. Groups are the same or different, and 1 to 3 groups selected from substituent group 4 It is a is) group,
  • Substituent group ⁇ 2 is a methyl group, an ethyl group, a methoxy group, an ethoxy group, a formyl group, a methyl carbonyl group, an ethyl carbonyl group, a formyl amino group, a methyl carbonyl amino group, Tylcarponylamino, methanesulfonylamino, ethanesulfonylamino, trifluromethanesulfonylamino, 2,2,2-trifluene, roethanesulfonylamino, pentaful, rozensulfonylamino , A group consisting of ⁇ ⁇ , ⁇ , ⁇ and ⁇
  • Substituent group) 84 is a methyl group, an ethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a methoxy group, an ethoxy group, a formyloxy group, a methylcarbonyl Amino group, ethylcarbonylamino group, methoxycarbonylamino group, ethoxycarbonylamino group, methanesulfonylamino group, ethanesulfonylamino group, trifluromethanesulfonylamino group, 2, 2, 2-Trifluoroethanesulfonylamino group, pen Full-year rotansulfonylamino, formyl, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylaminocarbonyl
  • Y is a cyclopropyl group, a cyclobutyl group, a substituted cyclopropyl group or a cyclobutyl group (the substituents are the same or different, and 1 is selected from the above-mentioned substituent group a2;
  • the heterocyclyl group includes imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, virazinyl group, pyrrolidinyl group, piperidinyl group, A morpholinyl group or a thiomorpholinyl group) or a substituted (5-
  • Y is a benzyl group, a pyridylmethyl group, or a substituted benzyl group or a pyridylmethyl group (the substituents are the same or different, and the above-mentioned substituent groups). Is a group of
  • A is a phenyl group, a thienyl group, a thiazolyl group, or a pyridyl group
  • A is a phenyl group, a phenyl group or a pyridyl group, or
  • R 1 selected from (1) to (4), R 2 and R 3 selected from (5) to (7), R 8 selected from (8) to (10) and R 5 , ( ⁇ ⁇ ), X selected from (1 2), a group represented by C (CF 3 ) 2 (X), Y selected from (13) to (16), and ( 17)
  • a compound obtained by arbitrarily combining ⁇ ⁇ selected from (19) or a pharmacologically acceptable salt or ester thereof is also suitable.
  • (20) is a group represented by R ′ 3 — ′ [R 1a — ′ is a substituted C, -C 6 alkyl group (the substituents are the same or different, and are 1 to a four groups), C 6 - C ,.
  • R ′ 3 — ′ is a substituted C, -C 6 alkyl group (the substituents are the same or different, and are 1 to a four groups), C 6 - C ,.
  • R 1a — ′ is a substituted C, -C 6 alkyl group (the substituents are the same or different, and are 1 to a four groups), C 6 - C ,.
  • R ′ b — ′ is a substituted C, -C 6 alkyl group (the substituents are the same or different and are selected from the above-mentioned substituent group ⁇ ; To 4 groups), C 6 -C ,.
  • Aryl group substituted C 6 -C 1D 7 reel group (the substituents are the same or different and are 1 to 3 groups selected from the above substituent group 3), (C 6 -C, 0 7 Lille) - (C, -C 6 alkyl) group, substituted (C 6 -C 10 Ariru) - (C r C 6 alkyl) group (the substituent of the Ariru groups are the same or different, the substituent 1 to 3 groups selected from Group 3, and the substituents of the alkyl group are the same or different, and are 1 to 4 groups selected from the above Substituent Group ⁇ 5), 4 To a 10-membered heterocyclyl group, a substituted 4- to 10-membered heterocyclyl group (the substituents are the same or different, and the above-mentioned substituent groups) are 1 to 3 groups selected from 8, 4- to 10-membered heterocyclyl)-(C r C 6 alkyl) group or substituted (4- to 0-membered heterocycly
  • R ′ has the same meaning as the above R 1 B — ′ or a C, —C 6 alkyl group; 2 C0NH-, or a group represented by] a group represented by one 0CH 2 C0 Jour e-,
  • R 2 and R 3 are the same or different, and each represents a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, a 2,2,2-trifluroethyl group, a pentafluroethyl group, a hydroxyl group, a methoxy group , E butoxy group, an amino group, Mechiruamino group, Echiruamino group, Jimechiruamino group, Jechiruami amino group, a nitro group, full Sairomoto, black port group, bromo group, or, taken with R 2 and R 3 gar cord,
  • a methylenedioxy group or an ethylenedioxy group, R 4 and R 5 are the same or different and each represents a hydrogen atom, a C, -C 4 alkyl group, a C, -C 4 alkoxy group, an amino group, a carboxyl group, a chloro group, a cyclo group, or a promoter Group
  • X is a hydroxyl group
  • Y is, Ji 3 - cycloalkyl, C 3 substituted - 6 cycloalkyl group (said substituents may be the same or different and are 1 to 4 groups selected from the substituent group alpha 1), (C 6 -C, .aryl) one (C r C 2 alkyl) group, substituted (C 6 -C, 0 aryl) one (C, -C 2 alkyl) group (the substituents may be the same or different
  • R 1 is, R 'a _ 2 [R ' a - 2 is C r C 4 alkyl group (the substituent which is substituted are the same or different makes, selected from the substituent group ⁇ 1 A 4- to 10-membered heterocyclyl group, a substituted 4- to 10-membered heterocyclyl group (the substituents may be the same or different and are selected from the above-mentioned substituent group 1) (1 to 2 groups), (5 to 7 membered heterocyclyl) — (C r C 4 alkyl) group, or substituted (5 to 7 membered heterocyclyl) — (C,- ⁇ alkyl) Group (substituents of the heterocyclyl group are the same or different, and are 1 to 2 groups selected from the above-mentioned substituent group i31. Substituents of the alkyl group are the same or different, and 5 is a group selected from 1 to 3)];
  • Z ′ b — 2 — R ′ b — 2 [wherein, is a substituted CrC 6 alkyl group (the substituents are the same or different, and the above substituent groups (1 1 Or a 3- to 4-membered heterocyclyl group, a substituted 4- to 10-membered heterocyclyl group (the substituents are the same or different, and are selected from the above-mentioned substitution group / 31) (5 or 7 membered heterocyclyl) — (C, —C 4 alkyl) group, or substituted (5 to 7 membered heterocyclyl) — (C, —C ( 4 alkyl) groups (Substituents of the heterocyclyl group are the same or different and are one or two groups selected from the above-mentioned substituent group / 31, and the substituents of the alkyl group are the same or different, indicates a is) 1 to 3 groups Ru is selected from the substituent group ⁇ 5 1, Z 'b -2 is
  • R 1 e- 2' - 2 are the R 'b - 2 and the same significance] wherein one C ⁇ C one R is a group represented by,
  • R 2 and R 3 are the same or different and are a hydrogen atom, a methyl group, a hydroxyl group, a methoxy group, an amino group, a chloro group, or a cyclo group;
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group, A mouth group or a black mouth group;
  • X is a hydroxyl group
  • Y is, c 3 - c 5 cycloalkyl group, c 3 substituted - c 5 cycloalkyl group (said substituents may be the same or different, above-mentioned substituent group 0; 1 to 3 groups selected from 2 Benzyl group, substituted benzyl group (the substituents are the same or different and are 1 to 3 groups selected from the above substituent group 34), (5- to 7-membered heterocyclyl) A) methyl group (the heterocyclyl group represents a 5- to 7-membered heterocyclyl group having at least one nitrogen atom and optionally having an oxygen atom or a sulfur atom), or substituted (5 To 7-membered heterocyclyl) methyl group (The heterocyclyl group represents a 5- to 7-membered heterocyclyl group having at least one nitrogen atom and optionally having an oxygen atom or a sulfur atom. Are the same or different, and the above substituent groups) selected from 84 A that ⁇ to
  • a compound wherein A is a phenyl group, a phenyl group or a pyridyl group
  • R 1 is R 1 [Ria- 3 is a substituted C, -C 4 alkyl group (the substituents are the same or different, and are 1 to 2 selected from the above substituent group T 2 Or a 5- to 7-membered heterocyclyl group, a substituted 5- to 7-membered heterocyclyl group (the substituents are the same or different and are selected from the above-mentioned substituent group j82). Or 2 groups)]; or
  • R lb — 3 is a substituted C, —C 4 alkyl group (the substituents may be the same or different, and the above substituent groups (5 A heterocyclyl- (C, -alkyl) group (the heterocyclyl group is a chenyl group, a thiazolyl group or a pyridyl group), or a substituted [ Heterocyclyl mono (C r C 3 alkyl)] group (The heterocyclyl group is a thienyl group, a thiazolyl group or a pyridyl group, and the substituents of the heterocyclyl group are the same or different.
  • substituents of the alkyl groups are the same or different, indicate the above-mentioned substituent group (5 a 1 to 2 groups 2 are selected from),
  • Z 1 b - 3 is, - 0-, -S- or single S0 2 -, a group represented by represented a group are 'in Ri,
  • R 2 and R 3 are a hydrogen atom, a methoxy group, a chloro group, or a chloro group;
  • R 4 and R 5 are a hydrogen atom, a methyl group or a methoxy group
  • Formula 1 A group represented by C (CF 3 ) 2 (X) is substituted at the 3- or 4-position of the phenyl group to which the group is bonded — a group represented by C (CF 3 ) 2 (0H) ,
  • Y is a cyclopropyl group, a cyclobutyl group, a substituted cyclopropyl group or a cyclobutyl group (the substituents are the same or different and are one or two groups selected from the above-mentioned substituent group ⁇ 2)
  • the heterocyclyl group may be an imidazolyl group, a xazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolidinyl group, a piperidiny
  • R ′ is R 1a — 4 [R ′ a — 4 is chenyl group, pyrazolyl group, imidazolyl group, thioxazolyl group, thiazolyl group, triazolyl group, pyridyl group, pyrrolidinyl group, molkilinyl Or a substituted phenyl, pyrazolyl, imidazolyl, thiazolyl, thiazolyl, triazolyl, pyridyl, pyrrolidinyl or morpholinyl group (the substituents being the same or different; showing a one to a two groups) selected from group) 8 2]; wherein - 0 in one RIH [wherein, r1 is substituted, Echiru group, a propyl group, a propyl group or a blanking ethyl group Wherein the substituents are the same or different and are one or two groups selected from the above-mentioned
  • R 2 and R 3 are a hydrogen atom, a methoxy group, a chloro group, or a chloro group;
  • R 4 and R 5 are a hydrogen atom, a methyl group or a methoxy group
  • Formula I A group represented by C (CF 3 ) 2 (X) substituted at the 3- or 4-position of the phenyl group to which the group is bonded is a group represented by C (CF 3 ) 2 (OH) ,
  • Y is a benzyl group, a pyridylmethyl group, or a substituted benzyl group or a pyridylmethyl group (the substituents are the same or different, and the above-mentioned substituent group).
  • a compound wherein A is a phenyl group
  • a pharmaceutical composition comprising, as an active ingredient, a compound represented by the general formula (I) described in any one of (1) to (24) or a pharmacologically acceptable salt or ester thereof;
  • Arteriosclerosis (including arteriosclerosis caused by the following diseases), atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, lipid-related disease, inflammatory site Inflammatory, autoimmune, cardiovascular, cerebrovascular, renal, diabetes, diabetic complications, obesity, nephritis, hepatitis, cancer, and Alzheimer's disease
  • the pharmaceutical composition according to (25) for treatment or prevention of a disease selected from the group:
  • Arteriosclerosis including arteriosclerosis caused by the following diseases), atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, lipid-related disease, inflammatory site
  • the pharmaceutical composition according to (25) for treating or preventing a disease selected from the group consisting of an inflammatory disease, which is a disease caused by, and diabetes.
  • the pharmaceutical composition is atherosclerosis (including arteriosclerosis caused by the following diseases), atherosclerosis: arteriosclerosis caused by diabetes, hyperlipidemia, lipid Related diseases, Inflammatory diseases caused by inflammatory site forces, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes, diabetic complications, obesity, nephritis, hepatitis, cancer, And a composition according to (29), which is a composition for treating or preventing a disease selected from the group consisting of Alheima disease,
  • the pharmaceutical composition comprises atherosclerosis (including arteriosclerosis caused by the following diseases), atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, and lipid-related disease.
  • atherosclerosis including arteriosclerosis caused by the following diseases
  • atherosclerosis including arteriosclerosis caused by the following diseases
  • arteriosclerosis caused by diabetes
  • hyperlipidemia and lipid-related disease.
  • the use according to (29) which is a composition for treating or preventing an inflammatory disease which is a disease caused by inflammatory site power-in, and a disease selected from the group consisting of diabetes.
  • the disease is atherosclerosis (including arteriosclerosis caused by the following diseases), atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, lipid-related disease, inflammatory disease Inflammatory disease, autoimmune disease, cardiovascular disease, cerebrovascular disease, kidney disease, diabetes, diabetic complications, obesity, nephritis, hepatitis, cancer, and Alzheimer's disease
  • arteriosclerosis including arteriosclerosis caused by the following diseases
  • arteriosclerosis caused by the following diseases
  • arteriosclerosis caused by diabetes
  • hyperlipidemia lipid-related disease
  • inflammatory disease Inflammatory disease
  • autoimmune disease autoimmune disease
  • cardiovascular disease cerebrovascular disease
  • kidney disease diabetes
  • diabetes diabetic complications
  • obesity nephritis
  • hepatitis cancer
  • Alzheimer's disease Alzheimer's disease
  • the disease is atherosclerosis (including arteriosclerosis caused by the following diseases), atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, lipid-related disease, inflammatory disease
  • the method according to (33), wherein the disease is selected from the group consisting of an inflammatory disease caused by cytotoxicity, and diabetes.
  • a compound represented by the general formula (I) described in any one of (1) to (24) or a pharmacologically acceptable salt or ester thereof, and an HMG-CoA reductase inhibitor as an active ingredient Also provided is a pharmaceutical composition containing
  • the “5- to 6-membered heteroaryl group in A in the general formula (I)” is a 5- to 6-membered aromatic containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • a heterocyclic group such as furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, thixazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiaxadiazolyl, 1,2,3-thiadiazolyl, tritriazolyl, It may be a trazolyl, bilanyl, pyridyl, pyridazinyl, pyrimidinyl or birazinyl group, preferably chenyl, thiazolyl or It is a pyridyl group, more preferably a pyridyl group.
  • R ⁇ c , R 2 , R 3 , R 4 , R 5 , Y, substituent group ⁇ and substituent group of the formula (I) 8 “(C, -C 6 ) alkyl group”, and the formula ( The C, -C 3 alkyl moiety of the ⁇ substituted alkyl group '' in R 1a , R lb and Y of I) is a linear or branched alkyl group having 1 to 6 carbon atoms, For example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl , 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl 1-pentyl group, 3-methyl-1-pentyl group, 2-ethyl-1-butyl group,
  • the C 3 -C 8 cycloalkyl portion of the “cycloalkyl group” is a cyclic alkyl group having 3 to 8 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloalkyl group to Petit group, or may be a consequent clever speech corruptible group, preferably, C 3 - is a C 6 cycloalkyl group, and more preferably, C 3 - a C 5 cycloalkyl group, and most preferably, It is a cyclopropyl group or a cyclobutyl group.
  • C 2 -C 7 alkenyl group in R la and R lb of the formula (I) and “substituted C 2 -C 7 alkenyl group” in R la and R ′ b of the formula (I)
  • the C 2 -C 7 alkenyl moiety is an alkenyl group having one carbon-carbon double bond and 2 to 7 carbon atoms, such as vinyl, 2-propenyl, 2-butenyl, 2 —Methyl—2-propenyl group, 2-pentenyl group, 2-methyl-2-butenyl group or 2-hexynyl group, preferably a C 2 -C 5 alkenyl group, More preferably, it is a 2-propenyl group or a 2-butenyl group, and most preferably, a 2-propenyl group.
  • the aryl moiety is an aromatic hydrocarbon having 6 to 10 carbon atoms and may be, for example, a phenyl group, an indenyl group or a naphthyl group, preferably a phenyl group or a naphthyl group. Preferably, it is a phenyl group.
  • C, -C 6 alkyl group substituted by aryl group such as benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, indenylmethyl group, 1-phenyl-2-ethyl 2-, 2-phenyl 1-ethyl, 2- (1-naphthyl)-1-ethyl, 2- (2-naphthyl)-1-ethyl, 1-phenyl- 1-propyl, 2 —Feuniru 1-propyl group,
  • It may be a 1-pentyl group, a 5-phenyl 1-hexyl group or a 6-phenyl 1-hexyl group, preferably a phenyl- (CrC 4 alkyl) group, more preferably Is a benzyl group, a 2-phenyl-1-ethyl group, a 3-phenyl-1-propyl group, or a 4-phenyl-1-butyl group.
  • the 4- to 10-membered heterocyclyl moiety of the “0-membered heterocyclyl group” is one to four selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • the above unsaturated heterocyclic group such as an azoninyl group, a 1,4,5,6-tetrahydropyrimidinyl group or a 2,3,6-tetrahydropyridinyl group is partially or completely formed. It can be a reduced group.
  • the heterocyclyl group in R la and R ′ b is preferably a 5- to 7-membered heterocyclyl group, more preferably a phenyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, or It is a liazolyl group, a pyridyl group, a pyrrolidinyl group, a morpholinyl group, more preferably a chenyl group, a thiazolyl group or a pyridyl group, and most preferably a chenyl group or a pyridyl group.
  • the heterocyclyl group in Y is preferably a 5- to 7-membered heterocyclyl group, more preferably has at least two nitrogen atoms, and may have an oxygen atom or a sulfur atom.
  • 7-membered heterocyclyl groups in particular, pyrrolyl group, azepinyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-oxodiazolyl group, 1,2,3-thiadiazolyl group
  • An unsaturated heterocyclic group such as a triazolyl group, a tetrazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a virazinyl group, or a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group
  • R 1 a and 11 of formula (I) "(4 to to 1 0-membered heterocyclyl) Single (C r C 6 alkyl) group” ⁇ beauty "substituted (heterocyclyl 4 to 1 0-membered) - (C, -C 6 alkylyl) group ”(4 to 10 members)
  • Rocyclyl) — (C r C 6 alkyl) moiety is the above C r C 6 alkyl group substituted with the above 4- to 10-membered heterocyclyl group, for example, a furylmethyl group, a furylethyl group, a furylpropyl group, Furyl butyl, furyl pentyl, furyl hexyl, phenylmethyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, methyl, pyrrolyl, pyrrolyl, Azepinylmethyl,
  • C, -C 4 alkyl is (5 to heterocyclyl 7-membered) one (C, -C 4 alkyl) group, more preferably, Choi two Lou (C, -C 3 alkyl) group, Chiazoriru (C, -C 3 alkyl) Or a pyridyl (C, -C 3 alkyl) group.
  • a ⁇ (4- to 10-membered heterocyclyl)-(C, -C 4 alkyl) group and a substituted (4- to 10-membered heterocyclyl)-(C, -alkyl) group in Y of the formula (I) the "(4 to Teroshikuri Le to I 0-membered) - (C, - C 4 alkyl) moieties are the C r C 4 alkyl group substituted by heterocyclyl groups the 4 to 1 0-membered, for example, furyl Methyl group, furylethyl group, furylpropyl group, furyl Butyl group, phenylmethyl group, phenylethyl group, phenylphenyl group, phenylyl group, pyrrolylmethyl group, pyrrolylethyl group, pyrrolylpropyl group, azepinylmethyl group, pyrazolylmethyl group, imidazolylmethyl group, oxazolylmethyl group
  • an imidazolylmethyl group an oxazolylmethyl group, an isocyanatexazolylmethyl group, a thiazolylmethyl group, an isothiazolylmethyl group, a pyridylmethyl group, or a pyridazinylmethyl group.
  • halogeno C, -C 6 alkyl group in R 2 , R ⁇ R ⁇ R 5 and the substituent group / 3 in the formula (I) is the above-mentioned C,-substituted with 7 to the following halogeno groups.
  • a C 6 alkyl group such as, for example, fluromethyl group, difluromethyl group, dichloromethyl group, dibromomethyl group, trifluromethyl group, trichloromethyl group, 2-fluroethyl group, 2-bromoethyl group, 2 —Croguchiethyl group, 2-Eodoethyl group, 2,2-Difluroethyl group, 2,2,2-Trifluroethyl group, Trichloroethyl group, Penfururoethyl group, 3-Furopropyl group, 3-Cropropyl group , A 4-full-year-old pentyl group, a 5-full-year-old pentyl group, or a 6-full-year-old hexyl group, preferably a C, -C 4 alkyl substituted with 1 to 5 halogen groups And more preferably a trimethyl romethyl group, a 2,2,2-trifluroe
  • R 2 , R 3 , the substituent group ⁇ , the substituent group, and the “C, -C 6 alkylamino group” in the substituent group a are one C, -C 6 alkyl group described above.
  • An amino group substituted by, for example, a methylamino group, an ethylamino group, a propylamino group (for example, a 1-propylamino group, a 2-propylamino group), an 1-butylamino group, a 2-butylamino group, or a 2-methyl — 1 — propylamino group, 2-methyl — 2-propylamino group, 1 — pentylamino group, 2-pentylamino group, 3-pentylamino group, 2-methyl-2-pentylamino group, 3-methyl-2-butylamino group, 1 1-hexylamino group, 2-hexylamino group, 3-hexylamino group, 2-methyl 1 1-pentylamino group, 3-methyl-1-pentylamino group, 2-ethyl-1-butylamino group, 2, 2 —Dimethyl ⁇ -butylamino group or 2,3-dimethyl-1-buty
  • Substituent group Q !, Substituent group; 3, and “Di (C, -C 6 alkyl) amino group” in Substituent group a are the same or different two An amino group substituted with a C, -C 6 alkyl group, for example, a dimethylamino group, a methylethylamino group, a methylpropylamino group [eg, an N- (1-propyl) -N-methylamino group, etc.] A methylbutylamino group [for example, Tyl) -M-methylamino group etc.], getylamino group, ethylpropylamino group [eg, N- (1-propyl) -diethylamino group etc.], dipropylamino group [eg, di (1-propyl) amido Group, di (2-propyl) amino group, etc.], di (1-butyl) amino group
  • the rv (C, -C 6 alkyl) amino group in the substituent group is a group in which two of the alkyl groups have a nitrogen atom, an oxygen atom or a sulfur atom together with the nitrogen atom of the amino group.
  • a 5- to 7-membered saturated heterocyclyl group may be formed, and the 5- to 7-membered saturated heterocyclyl group is, for example, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, or a perhydroazepinyl group. It is possible, preferably, a pyrrolidinyl group, a piperidyl group, a morpholinyl group, or a thiocyanine morpholinyl group, and more preferably, a piperidyl group or a molphurinyl group.
  • R 2 of formula (I), RRR ⁇ substituent group ⁇ , substituent group) 8, and substituent group (“octlogeno group” in 5 is a full-length group, a chloro group, a promo group, or , And preferably a full group, a black group or a bromo group, more preferably a full group or a black group, most preferably a full group. It is.
  • the “C, —C 4 alkylenedioxy group” in R 2 , R 3 and the substituent group j8 in the formula (I) is an alkylenedioxy group having 1 to 4 carbon atoms, for example, methylenedioxy Group, ethylene-1,2-dihydroxy group, 1-methylmethylenedioxy group, propylene-1,3-dioxy group, 1-methylethylene-2-dioxy group, 2-methylethylene -1,2-dihydroxy group, 1-ethylmethylenedioxy group, butylene-1,4-dihydroxy group, 1-methylpropylene-1,3-dioxy group, 2-methylpropylene-1, 3-dihydroxy, 3-methylpropylene-1,3-dioxy, 1-ethylethylene-1,2-dioxy Di-, 2-ethylethylene-1,2-dihydroxy group, 1,2-dimethylethylene-1,2-dioxy group, or 1-propylmethylenedioxy group; It is a C, -C 4 alkylenedioxy group, more preferably
  • a mercapto group for example, methylthio, ethylthio, 1-propylthio, 2-propylthio, 1-butylthio, 2-butylthio, 2-methyl-1-propylthio, 2-methyl-2-propylthio; Group, 1-pentylthio, 2-pentylthio, 3-pentylthio, 2-methyl-2-butylthio, 3-methyl-2-butylthio, 1-hexylthio, 2-hexylthio, 3-hexyl Xylthio group, 2-methyl-1-pentylthio group, 3-methyl-1-pentylthio group, 2-ethyl-1-butylbutyl group, 2,2-dimethyl-1-but
  • the “C 2 -C 7 alkoxycarbonyl group” in R 4 and R ⁇ substituent groups of the formula (I) 3 and the substituent group T is a carbonyl group substituted with the above C, -C 6 alkoxy group ( -CO-), for example, methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, 2-methyl- 1 1-propoxycarbonyl group, 2-methyl-2-propoxycarbonyl group, ⁇ 1-pentyl-l-xylcarbonyl group, 2-pentyl-l-xylcarboxyl group, 3-pentyl-l-xylcarboxyl group, 2-methyl-2-l-butanol Xycarbonyl group, 3-methyl-2-butoxycarbonyl group, hexylcarboxycarbonyl group, 2-hexyloxycarbonyl group, 3-hexyloxycarbonyl group, 2-
  • C 2 -C 7 alkyl group is a carbonyl group (-C00-) in which the carbon atom is A group substituted by a C, -C 6 alkyl group, such as methylcarbonyl, ethylcarbonyl, 1-propylcarbonyl, 2-propylcarbonyl, Butylcarbonyl group, 2-butylcarbonyl group, 2-methyl-1-propylcarbonyl group, 2-methyl-2-propylcarbonyl group, 1-pentylcarbonyl group, 2-pentylcarbonyl group Xy group, 3-pentyl carbonyl group, 2-methyl-2-butyl carbonyl group, 3-methyl-2-butyl carbonyl group, 1-hexyl carboxy group, 2-hexyl group Lecarponyl group, 3-hexylcarbonyl group, 2-methyl-1-pentylcarbonyl group,
  • the rc, -C 6 alkylsulfinyl group in the substituent group ⁇ and the substituent group / 3 in the formula (I) ” is a sulfinyl group (-S0-) substituted with the above-mentioned C r C 6 alkyl group, Methanesulfinyl, ethanesulfinyl, 1-propanesulfinyl, 2-propanesulfinyl, 1-butanesulfinyl, 2-butanesulfinyl, 2-methyl-1-propanesulfinyl, 2-methyl-2-propane Sulfinyl group, 1-Pentanesulfinyl group, 2-Pentanesulfinyl group, 3-Pentanesulfinyl group, 2-Methyl-2-butanesulfinyl group, 3-Methyl-2-butanesulfinyl group, 1-Hexanesulfinyl group, 2-To Xans
  • C, -C 6 alkylsulfinyl tree group in Substituent group ⁇ and Substituent group] 8 of formula (I), in the C r C 6 alkyl group substituted sulfonyl group (-S0 2 _) Yes, for example, methanesulfonyl group, ethanesulfonyl group, 1-propanesulfonyl group, 2-propanesulfonyl group, 1-butanesulfonyl group, 2-butanesulfonyl group, 2-methyl-1-propanesulfonyl group, 2-methylyl 2-propanesulfonyl group, 1-pentanesulfonyl group, 2-pentanesulfonyl group, 3-pentanesulfonyl group, 2-methyl-2-butanesulfonyl group, 3-methyl-2-butanesulfonyl group, 1-hexanesulfonyl group , 2-Hexanesul
  • the carbon atom of the carbonylamino group (—C0NH—) is - ⁇ Is a group substituted with an alkyl group, such as methylcarbonylamino group, ethylcarbonylamino group, 1-propylcarbonylamino group, 2-propylcarbonylamino group, ⁇ -butylcarbonylamino group.
  • the rc, -C 6 alkylsulfinyl nylamino group in the substituent group ⁇ and the substituent group 3 in the formula (I) ” is an amino group substituted with ⁇ the above C, -C 6 alkylsulfonyl groups.
  • halogeno C, -C 6 alkylsulfonylamino group in the substituent group ⁇ of the formula (I) and the substituent group; 8 is the above, wherein the alkyl part of the C, -C 6 alkylsulfonylamino group is 1 to 7 And a group substituted with one of the above halogeno groups.
  • the hydroxy C r C 6 alkyl group J in the substituent group i8 of the formula (I) is the above C, -C 6 alkyl group substituted with 1 to 4 hydroxyl groups, for example, hydroxymethyl group, Group (for example, 1-hydroxyethyl group, 2-hydroxyethyl group), dihydroxyethyl group (for example, 1,2-dihydroxyethyl group, etc.), hydroxypropyl group (for example, 1-hydroxyethyl group) —Propyl group, 2-hydroxy-1-propyl group, 3-hydroxy-1-propyl group, 1-hydroxy-2-propyl group, etc., dihydroxypropyl group (eg, 2,3-dihydroxy-1-propyl group, etc.), Hydroxybutyl group (for example, 1-hydroxy-1 Butyl, 2-hydroxy-l-butyl, 3-hydroxy-l-butyl, 4-hydroxy-l-butyl, 4-hydroxy-2-butyl, 3-hydroxy-2-butyl, 4-hydroxy-2-butyl
  • An aminoethyl group for example, 1-aminoethyl group, 2-aminoethyl group), a diaminoethyl group (for example, 1,2-diaminoethyl group, etc.), an aminopropyl group (for example, 1-amino-1-propyl group) , 2-amino-1-propyl group, 3-amino-1-propyl group, 1-amino-2-propyl group, etc., diaminopropyl group (eg, 2,3-diamino_1-propyl group, etc.), amino Butyl group (for example, 1-amino-1 monobutyl group, 2-amino-1-butyl group, 3-amino-1-butyl group, 4-amin
  • a C 4 alkyl group (the amino C,- ⁇ alkyl group is a C, -C 4 alkyl group substituted with 1 to 3 amino groups), more preferably an aminomethyl group, an aminoethyl group; Or an aminopropyl group, most preferably an aminomethyl group or an aminoethyl group (particularly, a 2-aminoethyl group).
  • alkylamino C, -C 6 alkyl group in substituent group j8 of formula (I), 1 to 4 above Symbol C, the C is substituted with -C 6 alkylamino group, - C 6 alkyl group
  • a methylaminomethyl group, an ethylaminomethyl group, a propylaminomethyl group for example, a (1-propylamino) methyl group, a (2-propylamino) methyl group]
  • a butylaminomethyl group for example, ( 1- (1-butylamino) methyl group, etc., (1-pentylamino) methyl group, (1-hexylamino) methyl group, methylaminoethyl group [eg, 1- (methylamino) ethyl group, 2- (methylamino) ethyl group]
  • Ethylaminoethyl group for example, 2- (ethylamino) eth
  • the dialkylamino C "C 6 alkyl group J in the substituent group i3 of the formula (I) is 1 to 4 di (C, -C 6 alkyl) amino groups (the alkyl groups are the same or different)
  • the above-mentioned C 6 -C 6 alkyl group for example, (dimethylamino) methyl group, (N-methyl-N-ethylamino) methyl group, (methylpropylamino) methyl group [for example, [N-methyl-N — (1-propyl) amino] methyl group, [N-methyl—N— (2-propyl) amino] methyl group,
  • Propyl group for example, 3-ethylamino-1 propyl group, etc.
  • (dipropylamino) propyl group [for example, 3- [di (1-propyl) amino] 11-propyl group, etc.], 3- [di ( 1-butyl) amino] — 1-propyl group, 2,3-di (dimethylamino) 1-l-propyl group, di-dimethylamino- 1-butyl group, 2-dimethylamino 1-l-butyl group, 3-dimethylamino 1-l Butyl group, 4-dimethylamino-1-butyl group, 4-dimethylamino-1-butyl group, 1-dimethylamino-2-butyl group, 3-dimethylamino-2-butyl group, 4 Dimethylamino-2-butyl group, 3-dimethylamino-2-methyl-1-propyl group, 1-dimethylamino-2-methyl-2-propyl group, 2,3-
  • a (getylamino) propyl group or a (dipropylamino) propyl group most preferably a (dimethylamino) methyl group or a (dimethylamino) ethyl group [particularly, a 2- (dimethylamino) ethyl group].
  • the “carboxy C, -C 6 alkyl group” in the substituent group) 3 of the formula (I) is the above C, -C 6 alkyl group substituted with 1 to 4 carboxyl groups, for example, carboxymethyl Group, carboxyethyl group (for example, 1-carboxyethyl group, 2-carboxyethyl group), dicarboxyl group (for example, 1,2-dicarboxyethyl group, etc.), carboxypropyl group (for example, 1-carboxy-1-propyl group, 2-carboxy-1-propyl group, 3-capoxy-1-propyl group, 1-carboxy-2-propyl group, etc., dicarboxypropyl group (for example, 2,3-dicarboxy-1 Propyl group, etc.), carboxybutyl group (for example, 1-hydroxyl 1-butyl group, 2-carboxy-1-butyl group, 3-carboxy- 1-butyl group, 4-hydroxyl oxy group) 2-hydroxypropyl
  • a C 2 -C 5 alkoxycarbonyl ⁇ amino group is a C 2 -C 5 alkoxycarbonyl ⁇ amino group, more preferably a methoxycarbonyl ⁇ amino group or ethoxycarbonyl ⁇ amino group, and most preferably a methoxycarbonyl ⁇ amino group.
  • N- (C 2 -C 7 alkoxycarbonyl) -N- (C, -C 6 alkyl) amino in the definition of R ′, R 2 , R 3 and the substituent group j8 in the formula (I) is 1 Amino groups substituted with one of the above CC 6 alkyl groups and ⁇ of the above C 2 -C 7 alkoxycarbonyl groups, for example, N-methoxycarbonyl-N-methylamino group, N-methoxy Carbonyl-N-ethylamino, N-methoxycarbonyl-propyl) amino, N-methoxycarbonyl-N- (2-propyl) amino, N-methoxycarbonyl-N- (1 —Butyl) amino group, N-methoxycarbonyl-N- (1-pentyl) amino group, N-methoxycarbonyl- —hexyl) amino group, M-ethoxycarbonyl-N-methylamino group, N- E
  • substituent group (I) ⁇ - in ⁇ (C, - C 6 alkylsulfonyl) - M - (C, - C 6 alkyl) Amino group ", one of the CI- C 6 alkyl group and one of the C, - is substituted by C s alkylsulfonyl group
  • C s alkylsulfonyl group Such as M-methanesulfonyl-M-methylamino, N-methanesulfonylethylamino, M-methanesulfonyl (1-propyl) amino, N-methanesulfonyl-N- (2- Propyl) amino group, M-methanesulfonyl-N- (1-butyl) amino group, N-methanesulfonyl-pentyl) amino group, N-methanesulfonyl-—hexyl) amino group, N-ethanesul
  • the ⁇ -(halogeno Ci-C 6 alkylsulfonyl) -N- (C, -C 6 alkyl) amino group in the substituent group 3 of the formula (I) is the above-mentioned M- (C, -C 6 alkylsulfonyl) -N- (C, -C 6 alkyl) alkyl Rusuruhoniru portion of amino group is a substituted group with 1 to 7 of the aforementioned eight Rogeno group, for example, M- full silo methanesulfonyl Mechiruamino group, N- Difluromethanesulfonyl-N-methylamino group, N-dichloromethanesulfonyl-N-methylamino group, N-dibromomethanesulfonyl-N-methylamino group, N-trifluromethanesulfonyl-N-methylamino group, N-trifluromethaneme
  • An amino group and more preferably, N- triflic old Rometansuruho two Le - M- Mechiruamino group or N - triflic silo methanesulfonyl - is N- Echiruamino group.
  • the “C 2 -C 7 alkylcarbonyl group” in the substituent group ⁇ and the substituent group / 3 of the formula (I) is a carbonyl group (-C0-) substituted with the above-mentioned C, -C 6 alkyl group,
  • the “C 2 -C 7 alkylaminocarbonyl group” in the substituent group ⁇ and the substituent group ⁇ 8 in the formula (I) is a carbonyl group (—C0—) substituted with the above C, —C 6 alkylamino group.
  • the “di (C, -C 6 alkyl) aminocarbonyl group in the substituent group ⁇ and the substituent group in the formula (I)” is a di (C, -C e alkyl) amino group (the alkyl group is the same Or different), for example, a (dimethylamino) carbonyl group, a (M-methyl-N-ethylamino) carbonyl group, a (methylpropylamino) carbonyl group [for example, Pill) -N-methylamino] carbonyl group, etc.), (getylamino) carbonyl group, (ethylpropylamino) carbonyl group [eg, [M- (1-propyl) -N-ethylamino] carbonyl group, etc.], (dipropylamino ) Carbonyl group [for example, [di (1-propyl) amino] carbonyl group, [di (2-propyl) amino] carbonyl group,
  • the hydroxy C “C 6 alkoxy group” in the substituent group (a) of the formula (I) is the above C, —C 6 alkoxy group substituted with 1 to 4 hydroxyl groups, for example, hydroxymethoxy Group, hydroxyoxy group (for example, 1-hydroxyethoxy group, 2-hydroxyethoxy group), dihydroxy mouthoxy group (for example, 1,2-dihydroxyethoxy group, etc.), hydroxypropoxy group
  • the “hydroxy C, -C 6 alkylamino group” in the substituent group T of the formula (I) is the above-mentioned C, -C 6 alkylamino group substituted with ⁇ to 4 hydroxyl groups, for example, hydroxymethylamino Group, hydroxyethylamino group (eg, 1-hydroxyethylamino group, 2-hydroxyethylamino group), dihydroxyethylamino group (eg, 1,2-dihydroxyethylamino group, etc.), hydroxy Propylamino group (for example, 1-hydroxy-1 monopropylamino group,
  • 2-hydroxy-1-propylamino group 3-hydroxyamino group, propylamino group, ⁇ -hydroxy-2-propylamino group, etc., dihydroxypropylamino group (for example, 2,3-dihydroxy-1-propylamino) Group), hydroxybutylamino group (for example, 1-hydroxy-11-butylamino group, 2-hydroxy-1-butylamino group, 3-hydroxy1-1-butylamino group, 4-hydroxy-1-butylamino group, 1-hydroxy-2 —Butylamino group, 3-hydroxy-2-butylamino group, 4-hydroxy-12-butylamino group, etc.),
  • 3-hydroxy-12-methyl-1-protylamino group 1-hydroxy-2-methyl-12-propylamino group, dihydroxybutylamino group (for example, 2,3-dihydroxy-11-butylamino group, 2,4-dihydroxy— 1-butylamino, 3,4-dihydroxy-1-pentylamino, etc.), 5-hydroxy-1-pentylamino, 5-hydroxy-2-pentylamino, 5-hydroxy-3-pentylamino, 4,5 —Dihydroxy-1- 1-pentylamino group, 3,4,5-trihydroxy-1-pentylamino group, 4-hydroxy-12-methyl-2-butylamino group, 4-hydroxy-3-methyl-2-butylamino group, 6 —Hyd mouth 1 1-hexylamino group, 6-hydroxy-12-hexylamino group, 6-hydroxy-3-hemi, xylamino group 5-hydroxy-2-methyl-1 - Penchiruamino group, 5-hydrin port carboxymethyl - 3-methyl-one 1
  • the substitution position of the group represented by the formula C (CF 3 ) 2 (X) is preferably the 3- or 4-position of the phenyl group to which the group is bonded, and most preferably the 4-position. Further, the group represented by the formula C (CF 3 ) 2 (X) is preferably a C (CF 3 ) 2 (0H) group.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable ester thereof has a basic group, it can be converted to a salt by reacting with an acid. ))
  • a pharmaceutically acceptable ester thereof having an acidic group can be converted into a salt by reacting with a base. If these salts are used in the treatment of disease, they must be pharmacologically acceptable.
  • the salt formed with the basic group of the compound represented by the general formula (I) of the present invention is preferably, for example, hydrohalic acid such as hydrochloride, hydrobromide and hydroiodide Salts; nitrates; perchlorates; sulfates; or inorganic salts such as phosphates; methanesulfonates, trifluromethanesulfonates, ethanesulfonates, and the like; , -C 6 salt with alkanesulfonic acid; C 6 -Ci which may be substituted with C, -C 4 alkyl such as benzenesulfonic acid salt and P-toluenesulfonic acid salt.
  • hydrohalic acid such as hydrochloride, hydrobromide and hydroiodide Salts
  • nitrates such as nitrates; perchlorates; sulfates; or inorganic salts such as phosphates; methanesulfonates
  • Salts with arylsulfonic acids acetates; malates; fumarates: succinates; citrates; tartrates; oxalates; or organic acid salts such as maleates; It can be an amino acid salt such as a salt, a lysine salt, an arginine salt, an ordinine salt, a glutamate, an aspartate, and more preferably a hydrohalide.
  • the salt formed with the acidic group of the compound represented by the general formula (I) of the present invention is preferably, for example, an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt; a calcium salt, a magnesium salt, and the like.
  • Ester salt Ethylenediamine salt, N-Methyldalcamine salt, Guanidine salt, Getylamine salt, Triethylamine salt, Dicyclohexylamine salt, ⁇ , ⁇ '-Dibenzylethylenediamine salt, Black mouth pro-force salt, Professional strength Amine salts such as organic amine salts such as sulfonic acid salts, diethanolamine salts, perbenzylphenethylamine salts, piperazine salts, tetramethylammonium salts, tris (hydroxymethyl) aminoamino salts; or glycine It may be an amino acid salt such as a salt, a lysine salt, an arginine salt, an ordinine salt, a glutamate, an aspartate, and more preferably an alkali metal salt.
  • an amino acid salt such as a salt, a lysine salt, an arginine salt, an ordinine salt, a glutamate, an aspartate,
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt or ester thereof is allowed to stand in the air or to absorb water during recrystallization to form a hydrate.
  • these hydrates are also included in the present invention.
  • the compounds of the present invention may incorporate other solvents to form solvates, which are also included in the present invention.
  • optical isomers including diastereomers
  • these isomers and mixtures thereof are represented by a single formula such as the formula (I).
  • the present invention includes each of these isomers and mixtures thereof (including racemates) in any ratio.
  • the present invention includes an ester of the compound represented by the general formula (I). These esters are compounds in which the hydroxyl group or carboxyl group of the compound represented by the general formula (I) is modified by adding a protecting group according to a method well known in the art (for example, "Protective Groups in Organic Synthesis”). , Second Edition 'Theodora. Greene and Peter G.. Wuts, 1991, John Wiley & Sons, Inc.).
  • this protecting group is not particularly limited. However, if the ester is to be used for the treatment of a disease, it must be pharmacologically acceptable; for example, the protecting group may be present when the compound is administered to a mammalian organism. It must be capable of forming a compound represented by the general formula (I) or a salt thereof by elimination in a metabolic process (for example, hydrolysis). That is, the pharmacologically acceptable ester is a “prodrug” of the compound represented by the general formula (I) of the present invention. However, when the ester of the compound represented by the general formula (I) of the present invention is used for other than treatment of a disease (for example, when used as an intermediate for the production of another compound), Need not be pharmacologically acceptable.
  • ester of the compound represented by formula (I) of the present invention is pharmacologically acceptable is easily determined.
  • the compound is intravenously administered to an experimental animal such as a rat or Mavus, and the body fluid of the animal is examined.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof Is detected, it is determined that the compound is a pharmacologically acceptable ester.
  • the compound represented by the general formula (I) of the present invention can be converted into an ester, and the ester can be, for example, a compound in which the hydroxyl group of the compound is esterified.
  • the ester residue may be a general protecting group if the esterified compound is used as an intermediate, or if the esterified compound is pharmacologically acceptable, It may be a protecting group that can be eliminated by metabolic processes in the living body (for example, hydrolysis).
  • the above general protecting groups are ester protecting groups that can be eliminated under chemical conditions such as hydrolysis, hydrogenolysis, electrolysis, and photolysis.
  • These general protecting groups used in the preparation of the compounds of the general formula (I) in which the hydroxyl groups have been modified are preferably, for example, the following:
  • an arylcarbonyl group which is a carbonyl group substituted with the above aryl group such as benzoyl, 1-naphthyl and 2-naphthyl; 2-bromobenzyl, 4-cyclobenzyl, 2,4,6-trifluorobenzyl and the like
  • a halogenoaryl group which is the arylcarbonyl group substituted with one or more halogeno groups of the above; a 2,4,6-trimethylbenzoyl, 4-toluoyl or the like one or more of the above C , -C 6 lower alkyl ⁇ reel Cal Boniru group is substituted the ⁇ reel carbonyl group with an alkyl group; one or more of the C, the Ariru substituted by -C 3 alkoxy group such as 4-Anisoiru A lower alkoxyaryl group that is a carbonyl group; a nitrated arylcarbonyl group that is the above arylcarbonyl group
  • Tetrahydropyran-2-yl 3-promotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydropyran-2-yl, 4-methyl Tetrahydroviranyl or tetra, which may be substituted with one or more substituents selected from the above C, -C 6 alkyl, halogen group or CrCe alkoxy, such as methoxytetrahydrothipyran-4-yl; A lahydrothiylvinyl group;
  • (V) One or more selected from the above C, -alkyl, octageno group or the above C, -C 6 alkoxy such as tetrahydrofuran-2-yl, tetrahydrofuran-2-furan, etc.
  • a tetrahydrofuranyl or tetrahydrothiofuranyl group which may be substituted with a substituent of
  • tri (C, -C 3 alkyl) silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-1-butylsilyl and triisopropylsilyl; or Triphenyl (-(; 6 alkyl) in which one or more alkyl moieties such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisobutylsilyl, and phenyldiisopropylsilyl are substituted with one or two aryl groups.
  • a silyl group such as a silyl group;
  • a (C, -C 3 alkoxy) ethyl group in which an ethyl group such as 1-ethoxyxyl and 1- (isopropoxy) ethyl is substituted with the Ci-C 6 alkoxy group; or 2,2 Substituted ethyl groups such as octalogenoethyl groups such as 1,2-trichloroethyl and the like;
  • aryl groups such as benzyl, 1-naphthylmethyl, 2-naphthylmethyl, diphenylmethyl, triphenylmethyl, 1-naphthyldiphenylmethyl, 9-anthrylmethyl, etc.
  • a C 6 alkyl group or 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl,
  • the aryl moiety such as 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl and the like is selected from the group consisting of -alkyl, -alkoxy, nitro, halogen, and cyano.
  • An aralkyl group such as the above C, -alkyl group substituted with one to three above-mentioned aryl groups substituted with one or more substituent groups;
  • (X) an alkenyloxycarbonyl group which is a carbonyl group substituted by an alkenyloxy group having 2 to 6 carbon atoms, such as vinyloxycarbonyl and aryloxycarbonyl;
  • the C, - C 6 alkoxy and 1 to may be substituted with two substituents selected from nitro, Araru kill old alkoxycarbonyl group is a carbonyl group substituted with Ararukiru old alkoxy group;
  • (xii) C, -C such as methanesulfonyl, trifluromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, and toluenesulfonyl. Ester-forming residues of sulfonic acids;
  • (XV) esters with mono- or di (C 6 -C, 0 aromatic hydrocarbon) carbonates such as monophenyl carbonate and diphenyl carbonate;
  • esters with mono- or di (C 6 -C, Q aromatic hydrocarbon) esters of phosphoric acid such as monophenyl phosphate and diphenyl phosphate are represented by the general formula (I).
  • Protecting groups as such ester residues are preferably, for example:
  • Substituents include the above C,-( ⁇ alkyl groups and Beauty one or more of the above - alkyl, ingenuity source is a methyl group substituted by the above substituted by c r c 6 alkyl or eight Rogeno group is a group which is also selected from the group consisting of optionally the Ariru group) Substituted carbonyl xyalkyl groups such as dioxolenylmethyl group;
  • a phthalidyl group which is a phthalidyl group which may be substituted with a substituent selected from the group consisting of the above C, -C 6 alkyl and the above C, -C 6 alkoxy, such as phthalidyl, dimethylphthalidyl, dimethyloxyphthalidyl, etc. ;
  • Hydroxyl is used to produce a compound represented by the modified formula (I), metabolic processes in vivo (e.g., hydrolysis) in the protecting group in which leaves, C, -C 2S Alkyl carbonyl groups and substituted carbonyl xyalkyl groups are preferred.
  • Suitable compounds represented by the general formula (I) may be the compounds shown in Tables 1 to 10 below. However, the compound of the present invention is not limited to these compounds.
  • Prl pyrazolyl Prld: Birazolidinyl
  • Tpm 1,4,5,6-tetrahydropyrimidini
  • Tpy 1,2,3,6-tetrahydropyridyl
  • H-788 6 (4-H0C0CH 2 -Ph *) H H-789 6 (4-H0C0CH 2 -Ph) 7-MeO H-790 7 (3-H0- 1-Azt) 6-F H-791 7 (3 -H0-l-Azt) 6-CI H
  • preferred compounds are exemplified compound numbers 1-24, 1-35, 1-39, 1-80, 1-81, 1-82, 1-102, 1-104, 1-106, 1 -131, 1-132, 1 -133, 1-135, 1-136, 1-140, 1-141, 1-142, 1-151, 1-180, 1 -181, G 196, 1 -198, G 199, 1-200, 1-201, G 234, 1-235, G 236, 1-238, 1-239, 1-240, 1-242, 1-248, G 249, 1-254, 1- 255, 1-305, 1 -307, 1-314, 1-315, 1-317, 1-345, 1-351, 1-352, 1-357, 1-362, 1'- 367, 1-368 , 1-371, 1-373, 1-374, 1-375, 1-376, 1-412, 1-423, 1-424, 1-425, 1-426, 1-427, 1-428, 1-429, 1-430, 1-434,
  • Illustrative compound number 1 — 3 68 2-benzyl 6— (2-pyridyl) — 3— ⁇ 4— [2,2,2-trifluoro-1-hydroxy-11- (trimethyl-methyl) ethyl] phenyl] 1 4 (3H)-quinazolinone,
  • Illustrative compound number 1 — 4 26 2-benzyl-6- (3-pyridyl) —3— ⁇ 4— [2, 2,
  • Illustrative Compound No. 1 — 788 [4- (2-benzyl-4-one-year-old oxo--3 -— ⁇ 4-—2,2,2-tritrifluro-1-one-hydroxy-1— (trifluoromethyl) ethyl] 1,3-dihydro-6-quinazolinyl) phenyl] acetic acid,
  • 8-1 701 2-[(5-Methoxy-2-pyridyl) ) Methyl] — 3— ⁇ 2-Methyl-4— [2,2,2-Trifluoro-1 —Hydroxy-1- (Trifluoromethyl) ethyl] Phenyl] 16— (1 H—Pyrazol-1-yl ) —4 (3 H) —Quinazolinone,
  • Illustrative Compound No. 8-1 720 6-Fluoro-2- (3-fluorophenyl)-7- (4-morpholinyl) -13- ⁇ 4— [2,2,2-trifluroyl-hydroxy-1-] (Trifluoromethyl) ethyl] 1 4 (3H) -quinazolinone,-Exemplified Compound No. ⁇ 0— 7 12: 2-benzyl-6- (2-hydroxyethoxy) — 7-methoxy-1 3- ⁇ 2-methyl-5- [2,2,2-trifluoro-1-hydroxy-1- 1- (trifluoromethyl) ethyl] phenyl ⁇ 1-4 (3H) -quinazolinone,
  • Illustrative compound number 10—7 15 2—benzyl—7— (2-hydroxyethoxy) —6—methoxy-1-3— ⁇ 2—methyl—5— [2,2,2-trifluro—1— Hydroxy 1- (trimethyl) methyl] 4- (3H) -quinazolinone or
  • a to X, R ′, R 2 , R 3 , R 4 , R 5 , A, X, Y, R ′% and R ′ b have the same meanings as described above.
  • B represents an oxygen atom, a sulfur atom, an imino group (—NH—) or (C r C 6 alkyl) imino group [—N ⁇ , — C 6 alkyl) —], and Hal represents a chloro group.
  • R a represents a hydrogen atom or a C, -C 6 alkyl group
  • R b represents a C, -C 6 alkyl group
  • R c has the same meaning as R ′ b
  • R f is, R' indicates a b as defined above or a hydrogen atom
  • R s is , R 'b as defined above, a hydrogen atom or a Asechiru group
  • R h represents a hydrogen atom, C r C 6 alkyl Group, amino group, C, - C 6 alkylamino group, or a di (C, - C 6 alkyl) amino group (
  • R d and R e represent the following combinations
  • R d hydrogen atom or methyl group
  • R e R ′ c
  • R d hydrogen atom
  • R e C, -C 6 alkyl group
  • R d C, -C 6 alkyl group
  • R e Ci-C 6 alkyl group
  • the leaving group in L is not particularly limited as long as it can be substituted by reacting with a nucleophile.
  • a group is, for example, a hydroxyl group; the above-mentioned Hal group; methanesulfonyloxy or ethanesulfonyloxy.
  • the group containing a metal atom in Met is not particularly limited as long as it can be used for the reaction of forming a carbon-carbon bond in the presence of a transition metal catalyst.
  • Examples of such a group include lithium and sodium.
  • An alkali metal such as lithium or potassium; a group represented by the formula: Mg (Hal) (where Hal is as defined above); a formula: B (0R a ) 2 (where R a is the same or A group represented by the formula ( 2) (where Ri is the same or different and represents C, -C 6 alkyl, or two A group represented by the formula: Si (R b ) 3 (where R b is as defined above); a formula represented by Sn A group represented by (R b ) 3 (where R b has the same meaning as described above); or a group represented by the formula: Zn (Hal) (where Hal has the same meaning as above).
  • Be a group preferably, - Mg (Hal) group, - B (0R a) 2 group, one B (Ri) 2 group, -Si (R b) 3 groups, one Sn (R b) 3 Or a Zn (Hal) group.
  • Protecting groups Amino groups in prot a is not particularly limited as long as it can protect amino groups in the reaction, such groups, hydrogenolysis, hydrolysis, such as electrolysis and photolysis Protecting group that can be removed by chemical reaction, for example, alkyl such as formyl, acetyl, propionyl, butyryl, isoptyryl, pentanoylyl, vivaloyl, valeryl, isovaleryl, cystanoyl, lauroyl, palmitolyl, stearoyl Carbonyl group; lower alkenyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, A lower alkoxy lower alkylcarbonyl group such as methoxyacetyl; an aliphatic acyl group such as an unsaturated alkylcarbonyl group such as (E) -2-methyl-2-butenoyl; benzoyl, ⁇ -naphthyl Arylcarbonyl groups
  • It may be a benzyl group which may be substituted with a lipo group, preferably a lower alkoxycarbonyl group or a benzyloxycarbonyl group which may be substituted with a lower alkyl, lower alkoxy or halogeno group. Is a t-butoxycarbonyl group or a benzyloxycarbonyl group.
  • the hydroxyl-protecting group in Prof. is not particularly limited as long as it can protect the hydroxyl group during the reaction, and such a group can be used for chemical reactions such as hydrogenolysis, hydrolysis, electrolysis and photolysis.
  • a protective group which can be removed more for example, an alkylcarbonyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, bivaloyl, valeryl, isovaleryl; a lower alkoxy lower alkylcarbonyl group such as methoxyacetyl; (E) an unsaturated alkyl group such as 2-methyl-2-butenoyl; an aliphatic group such as a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, and t-butoxycarbonyl; Azyl groups; benzoyl, ⁇ -naphthyl, 3-naphthy
  • the compound serving as the reaction substrate has a group that inhibits the target reaction, such as an amino group, a hydroxyl group, or a carboxyl group
  • protection of those groups as necessary A group may be introduced, and if necessary, the introduced protective group may be removed.
  • the protecting group for the group that inhibits the desired reaction is not particularly limited as long as it is a protecting group that is usually used to promote the reaction. For example, Green, TH, Wuts, PG., Protective Groups in Organic Synthesis. Third Edition,. 1999, John Wiley & Sons, Inc., and the like.
  • the protecting group is preferably a protecting group of the Amino group of the Prot a.
  • the protecting group is preferably a hydroxyl-protecting group in Prot b .
  • alkylidene groups such as methylene (one CH 2 —), ethylidene [—CH (CH 3 ) —], and isopropylidene [—C (CH 3 ) 2 —] It can be used to protect the two hydroxyl groups at the 1- and 2-positions or the ⁇ - and 3-positions with a single protecting group.
  • the protecting group is preferably a saturated lower alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl and t-butyl; Unsaturated lower alkyl groups such as aryl, 2-butenyl; methoxymethyl, ethoxyl Lower alkoxyalkyl groups such as tyl, tetrahydroviranyl and tetrahydrofuranyl; (lower alkoxy)-(lower alkoxy) alkyl groups such as 2-methoxyethoxymethyl; 2- (trimethylsilyl) ethoxymethyl groups; or benzyl, A benzyl group which may be substituted with a lower alkyl, lower alkoxy or halogeno group, such as 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, and more preferably a saturated lower alkyl And
  • the introduction reaction of the above-mentioned protecting group or the removal reaction of the protecting group can be carried out according to a conventional method (for example, Green, TH, Wuts, PG., Protective Groups in Organic Synthesis. Third Edition, 1999, John Wi I ey & Sons, In).
  • a conventional method for example, Green, TH, Wuts, PG., Protective Groups in Organic Synthesis. Third Edition, 1999, John Wi I ey & Sons, In.
  • each step of the methods A to X will be described.
  • Step A-1 comprises a compound (2) that is obtained by the method X described later, is known, or is easily obtained from a known compound, and is easily obtained from a known or known compound.
  • the compound (3) is reacted with the compound (3) and a compound (4) obtained by the method V or the method W described later, or known, or easily obtained from a known compound, to give the compound (I ) Is manufactured.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, and tetrahydrofuran Ethers such as dioxane, dimethoxetane, diethylene glycol dimethyl ether; ditriles such as acetonitrile, isoptyronitrile; formamide, N,
  • N-dimethylformamide N, N-dimethylacetamide, N-methyl-2-pyrrolidone
  • Amides such as N-methylpyrrolidinone and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; or N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine Mine, Dishik Mouth hexylamine, N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picoline,
  • the reagent used may be a phosphonic acid triester, such as triphenyl phosphonate, trimethyl phosphonate, preferably triphenyl phosphonate.
  • the base used is, for example, N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) 1-methylpyridine, quinoline, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazabicyclo [4,3 , 0] Nona-5-ene (DB N), 1,4-Diazabicyclo [2,2,2] octane (DA BCO), 1,8-Diazabicyclo [5,4,0] (DBU), preferably pyridine.
  • DB N 1,4-Diazabicyclo [2,2,2] octane
  • DBU 1,8-Diazabicyclo [5,4,0]
  • the reaction temperature varies depending on the solvent, starting materials, reagents and the like, but is usually 20 to 150 ° C, and preferably 50 to -20 ° C.
  • the reaction time varies depending on the solvent, starting materials, reagents, reaction temperature and the like, but is usually 1 to 24 hours, and preferably 1 to 8 hours.
  • the target compound of this step is isolated from the reaction mixture according to a conventional method.
  • a water-immiscible solvent eg, benzene, ethyl ether, ethyl acetate, etc.
  • the organic layer is washed with water and dried over anhydrous magnesium sulfate.
  • the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or silica gel column chromatography.
  • Step B-1 is a compound obtained by the below-mentioned method X, is known, or is easily obtained from a known compound [Compound (2a), in which Ra is a hydrogen atom], or An ester compound which is easily obtained by esterification of the obtained compound [a compound in which Ra is a C, -C 6 alkyl group in compound (2a)] and a known or known compound
  • This is a step of producing a compound (6) by reacting the easily obtained compound (5) with or without a condensing agent.
  • the reaction of B- 1 step is
  • the condensing agent used is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Carposimides such as 1,3-dicyclohexylcarposimide, 1,3-diisopropylcarposimide, polyester-3- (3-dimethylaminopropyl) carposimide; combinations of the above carposimides with the following bases; Of N-hydroxys such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-15-norbornene-2,3-dicarboximide;
  • 1,1'-Imidazoles such as quizaryldiimidazole, ⁇ , ⁇ '-Luponyldiimidazole;
  • Phosphates such as phenyl dichlorophosphate and polyphosphate esters
  • halogenosulfonyl isocyanates such as chlorosulfonyl isocyanate
  • halogenosilanes such as trimethylsilyl chloride and triethylsilyl chloride
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • aliphatic hydrocarbons such as hexane and heptane; benzene, toluene, and xylene Aromatic hydrocarbons; halogenated hydrocarbons such as methylene chloride, black form, carbon tetrachloride, dichloroethane, black benzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, propyl acetate, getyl carbonate Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, and diethylene glycol dimethyl ether; nitriles such as acetate nitrile and isobutyronitrile; or formamide; ⁇ , ⁇ —dimethylformami , New, Nyu- di
  • the base used is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate, or potassium carbonate; an alkali metal bicarbonate such as lithium bicarbonate, sodium bicarbonate, or potassium bicarbonate; Methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (te (rt-butyl) organic bases such as 1-4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, preferably organic bases, more preferably , Triethylamine, diisopropylethylamine or pyridine.
  • an alkali metal carbonate such as lithium carbonate, sodium carbonate, or potassium carbonate
  • the reaction temperature varies depending on the solvent, starting materials, reagents and the like, but is usually from 120 to 120 ° C, preferably from 0 to ⁇ 20 ° C.
  • the reaction time varies depending on the solvent, starting materials, reagents, reaction temperature and the like, but is usually 30 minutes to 2 days, preferably 1 to 12 hours.
  • the target compound of this step is isolated from the reaction mixture according to a conventional method. For example, if necessary, neutralize the reaction mixture, filter out any insolubles, if present, add water-immiscible solvents such as water and ethyl acetate to the reaction mixture, After extracting the compound, the organic layer is washed with water, dried using a drying agent such as anhydrous magnesium sulfate, and then the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization or silica gel column chromatography.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, and tetraethyl Ethers such as lahydrofuran, dioxane, dimethyloxetane, diethylene glycol dimethyl ether; nitritols such as acetate nitrile and isoptyronitrile; formamide, N,
  • N-dimethylformamide N, N-dimethylacetamide, N-methyl-2-pyrrolidone

Abstract

La présente invention concerne un composé représenté par la formule (I): (I). Dans cette formule A est phényle, etc.; R1 est R1a (R1a est alkyle substitué, etc.), -Z1b-R1b (R1b est alkyle substitué, etc. et Z1b est -NH-, etc.), -Z1c-R1c (R1c a la même signification que R1b ou est alkyle et Z1c est -C≡C-, etc.), -N(R1b)(R1c), etc.; chacun de R2 et R3 est hydrogène, éventuellement alkyle substitué, OH, etc.; chacun de R4 et R5 est hydrogène, éventuellement alkyle substitué alkyl, OH, etc.; X est OH ou alcoxy; et Y est éventuellement alkyle substitué, etc., sous réserve que lorsque Y est un groupe spécifique et A est phényle, puis chacun de R4 et R5 est hydrogène et -C(CF3)2(X) is -C(CF3)2(OH) lié au groupe phényle en position 3- ou 4 de ce groupe] ou un sel ou un ester de ce composé répondant aux normes pharmaceutique. Ces composé sont hautement actifs dans la liaison à LXR et conviennent comme médicament pour des anomaux à sang chaud ( et en particulier aussi pour les humains), de préférence comme médicament destiné au traitement et/ou à la prévention de l'artériosclérose, l'hyperlipidémie, de maladies inflammatoires, du diabète, etc..c
PCT/JP2004/013268 2003-09-05 2004-09-06 Compose pyrimidine-4(ch)-one fusionne substitue WO2005023782A1 (fr)

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WO2007050726A3 (fr) * 2005-10-26 2007-08-30 Bristol Myers Squibb Co Antagonistes du recepteur 1 de l'hormone de concentration de la melanine non basiques
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WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
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US9102653B2 (en) 2004-06-08 2015-08-11 Novartis Ag Substituted quinazolinones as vanilloid antagonists
US8809528B2 (en) 2004-06-08 2014-08-19 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US7960399B2 (en) 2004-06-08 2011-06-14 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US8211902B2 (en) 2004-06-08 2012-07-03 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
EP1764075A1 (fr) * 2004-07-02 2007-03-21 Sankyo Company, Limited Inhibiteur de la production de facteur tissulaire
EP1764075A4 (fr) * 2004-07-02 2010-08-04 Sankyo Co Inhibiteur de la production de facteur tissulaire
WO2007050726A3 (fr) * 2005-10-26 2007-08-30 Bristol Myers Squibb Co Antagonistes du recepteur 1 de l'hormone de concentration de la melanine non basiques
EP2298776A1 (fr) * 2005-10-26 2011-03-23 Bristol-Myers Squibb Company Dérivés du thienopyrimidinone comme antagonistes d'hormone 1 de concentration de mélanine
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WO2008065754A1 (fr) * 2006-11-30 2008-06-05 Kowa Company, Ltd. Composé de carbinol substitué
US8153634B2 (en) 2008-05-29 2012-04-10 Kowa Company, Ltd. Carbinol derivatives having cyclic linker
US7989433B2 (en) 2008-05-29 2011-08-02 Bristol-Myers Squibb Company Substituted thieno[3,2-D]pyrimidines as melanin concentrating hormone receptor-1 antagonists
EA018584B1 (ru) * 2008-05-29 2013-09-30 Кова Компани, Лтд. Замещённое карбинольное соединение, содержащее циклический линкер
CN102105452A (zh) * 2008-05-29 2011-06-22 兴和株式会社 具有环状连接基的取代甲醇化合物
WO2009144961A1 (fr) * 2008-05-29 2009-12-03 興和株式会社 Composé de carbinol substitué ayant un lieur cyclique
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
US9637481B2 (en) 2012-03-02 2017-05-02 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators for the treatment of dermal diseases, disorders and conditions
US9981913B2 (en) 2013-09-04 2018-05-29 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US10047055B2 (en) 2013-09-04 2018-08-14 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US10246419B2 (en) 2013-09-04 2019-04-02 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US11034657B2 (en) 2013-09-04 2021-06-15 Ellora Therapeutics, Inc. Liver X receptor (LXR) modulators
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
US11560390B2 (en) 2015-12-22 2023-01-24 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
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US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
US10588894B2 (en) 2017-06-21 2020-03-17 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11214536B2 (en) 2017-11-21 2022-01-04 Inspirna, Inc. Polymorphs and uses thereof
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