JPH11158133A - Phenol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound capable of simultaneously exhibiting an excellent low specific gravity lipoprotein oxidation-inhibiting action and an acylcoenzyme.cholesterol.acyltraferase-inhibiting action, capable of showing also excellent oral absorbability, and useful for treating and preventing arteriosclerotic diseases. SOLUTION: A compound of formula I [R<1a> is OH; R<1b> and R<1c> are each H, a 1-4C alkyl, wherein at least one of R<1b> and R<1c> is the 1-4C alkyl; R<2> is a 1-6C alkyl; R<3> is a five or six-membered cyclic heteroaryl (amino) group containing one or two heterogenous atoms selected from N, O and S, cyano, OH or the like; A is a single bond, a 1-4C alkylene], its salt. For example, 4-t-butyl-3-[3-(4-hydroxy-3,5-dimethylphenyl)octanoylamino]benzamide. The compound of formula I is obtained by removing a protecting group from a compound of formula II (R<4> is an OH-protecting group) and subsequently allowing the compound of formula II to react with boron tribromide or trimethylsilane iodide in an inactive solvent, when R<4> is methyl.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an arterial artery having excellent low-density lipoprotein (hereinafter abbreviated as LDL) oxidation inhibitory action and acylcoenzyme / cholesterol / acyltransferase (hereinafter abbreviated as ACAT) inhibitory action. The present invention relates to phenol derivatives useful as therapeutic or prophylactic agents for sclerosing diseases, pharmacologically acceptable salts thereof, and medicaments containing them.

[0002]

BACKGROUND OF THE INVENTION Atherosclerosis is the most important cause of ischemic heart disease such as angina and myocardial infarction. A major cause of atherosclerosis is that foam cells below the vascular endothelial cells accumulate cholesterol esters. It is known that many factors are involved in the mechanism of atherosclerosis, and studies from various angles have been made. For example, Nature, No. 362
Vol., Pp. 801 (1993) [ Nature , 362 , 801 (199)
3).] Et al. Among them, oxidized LDL is regarded as one of the important factors. For example, British Medical Journal, 314, 629 (1997) [ BMJ. , 314 , 629 (1997)] ]] Describes that there is a correlation between the number of deaths due to coronary disease and the susceptibility to LDL oxidation. LDL is a type of serum lipoprotein and functions to carry cholesterol to various tissues of the body. For example, The New England Journal of Medicine, Vol. 320, No. 91
5 (1989) [ N. Engl. J. Med. , 302 , 915 (1989).]
LDL exuded into the intima through the endothelial cell layer of the artery
However, it undergoes oxidative modification, promotes monocyte migration, and causes monocyte-derived macrophages to remain in the intima. Then, oxidized LDL is taken up by macrophages, and macrophages that have taken up oxidized LDL indefinitely become foamy. It becomes cells and accumulates in the blood vessel wall to form plaque,
The involvement of oxidative modification of LDL in the mechanism of arteriosclerosis has been described. Drugs having an inhibitory effect on LDL oxidation include LDL
It has been already known that by suppressing the oxidation of, macrophages are prevented from foaming and the formation and development of atheromatous lesions are suppressed. As a compound having an LDL oxidation inhibitory action, for example, probucol and the like are known.

[0003]

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[0004] It is also known that atherosclerosis is correlated with hypercholesterolemia. Cholesterol in food is absorbed by the intestinal mucosal cells as free cholesterol, where it is esterified by ACAT and translocates into the blood as cholesterol esters.
Thus, ACAT inhibitors are expected to inhibit cholesterol esterification in foam cells, reduce cholesterol accumulation, and suppress the formation and development of atheromatous lesions. As substances having an ACAT inhibitory action, amide and urea derivatives are disclosed in JP-A-9-143137 (EP07635524). ACAT and LDL oxidation are two important routes as a mechanism of atherosclerotic lesion formation, and a compound that inhibits both routes at the same time is a better therapeutic or prophylactic agent for arteriosclerosis than conventional ones. It was thought that it could be. However, a compound having both the LDL oxidation inhibitory action and the ACAT inhibitory action has not been known, and development of such a compound has been desired.

[0005]

DISCLOSURE OF THE INVENTION The inventors of the present invention have long and intensively studied the synthesis of various phenol derivatives and their pharmacological activities with the aim of developing compounds having both excellent LDL oxidation inhibitory activity and ACAT inhibitory activity. As a result, a phenol derivative having a unique structure has an excellent LDL oxidation inhibitory action and an ACAT inhibitory action, shows excellent oral absorption, and has a therapeutic or preventive effect (particularly a therapeutic effect) for arteriosclerotic diseases. ) To complete the present invention. The present invention provides an excellent L
A phenol derivative having a DL oxidation inhibitory action and an ACAT inhibitory action or a pharmacologically acceptable salt thereof, a production method thereof, an intermediate useful for their synthesis, and a therapeutic or prophylactic agent for atherosclerotic disease, There is provided a medicine containing the phenol derivative or a pharmacologically acceptable salt thereof.

[0006]

The phenol derivative of the present invention has the general formula (I).

[0007]

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In the above formula, R ^1a represents a hydroxyl group, R ^1b and R ^1c are the same or different and represent a hydrogen atom or a C ₁ -C ₄ alkyl group (provided that one of R ^1b and R ^1c is , C ₁ −
It represents a C ₄ alkyl group. ), R ² is a C ₄ -C ₆ alkyl group, and R ³ is a 5- to 6-membered heteroatom containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms.
Membered cyclic saturated heterocyclyl group; 5- or 6-membered cyclic heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; selected from the group consisting of nitrogen, oxygen and sulfur atoms 1 to 2 heteroatoms
5- or 6-membered cyclic heteroarylamino group containing: cyano group; hydroxyl group; hydroxyiminomethyl group; carboxy group; carbamoyl group; mono (C ₁ -C ₆ alkyl) carbamoyl group; di (C ₁ -C ₆ alkyl) A carbamoyl group; or a C ₁ -C ₆ alkanoylamino group;
Represents a single bond or a C ₁ -C ₄ alkylene group.

The active ingredient of the medicament of the present invention is a phenol derivative having the general formula (I).

In the above general formula (I), “C ₁ -C ₄ alkyl group” in the definition of R ^1b and R ^1c includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl A straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms such as a s-butyl group or a t-butyl group, preferably a methyl group or an ethyl group, and particularly preferably a methyl group. It is.

[0011] "C ₄ in the above At a, the R ² definition -
“C ₆ alkyl group” includes, for example, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-
Ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1
-Methylpentyl group, 3,3-dimethylbutyl group, 2,
2-dimethylbutyl group, 1,1-dimethylbutyl group,
A linear or branched alkyl group having 4 to 6 carbon atoms such as a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group or a 2-ethylbutyl group; It is preferably a butyl group, an isobutyl group, a pentyl group or a hexyl group, and particularly preferably a pentyl group.

In the above description, “C ₁ -C
_A " ₄ alkylene group" is, for example, a methylene group, a methylmethylene group, a dimethylmethylene group, an ethylene group, a propylene group, a trimethylene group, a tetramethylene group, a 1-methyltrimethylene group, a 2-methyltrimethylene group or a 3-methyltrimethylene group. It may be a linear or branched alkylene group having 1 to 4 carbon atoms such as a methylene group, preferably a methylene group, an ethylene group or a trimethylene group, more preferably a methylene group or an ethylene group. And particularly preferably a methylene group.

[0013] The above-mentioned At a, "nitrogen in the definition of R ^3,
A 5- to 6-membered cyclic saturated heterocyclyl group containing one or two heteroatoms selected from the group consisting of oxygen and sulfur atoms is, for example, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolidinyl group Or a pyrazolidinyl group, preferably a piperazinyl group, a morpholinyl group or a thiomorpholinyl group, and particularly preferably a 4-morpholinyl group.

[0014] The above-mentioned At a, "nitrogen in the definition of R ^3,
5- or 6-membered cyclic heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of oxygen and sulfur atoms "
Is, for example, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group. It is an imidazolyl group, a thiazolyl group or an oxazolyl group, particularly preferably a 2-oxazolyl group.

[0015] The above-mentioned At a, "nitrogen in the definition of R ^3,
The 5- or 6-membered cyclic heteroarylamino group containing one or two heteroatoms selected from the group consisting of oxygen and sulfur atoms is, for example, a furylamino group, a thienylamino group, a pyrrolylamino group, an imidazolylamino group, a pyrazolyl group. Amino group, thiazolylamino group, isothiazolylamino group, oxazolylamino group, isoxazolylamino group, pyridylamino group, pyrazinylamino group, pyrimidinylamino group or pyridazinylamino group, preferably imidazolyl It is an amino group, a thiazolylamino group or an oxazolylamino group, particularly preferably a 2-thiazolylamino group.

In the above description, "mono (C ₁ -C ₆ alkyl) carbamoyl group" in the definition of R ³ includes, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutyl It may be a carbamoyl group, an s-butylcarbamoyl group, a t-butylcarbamoyl group, a pentylcarbamoyl group or a hexylcarbamoyl group, preferably a mono (C ₁ -C ₄ ) alkylcarbamoyl group, more preferably a methylcarbamoyl group Or an ethylcarbamoyl group, particularly preferably a methylcarbamoyl group.

[0017] At a above, "di (C in the definition of R ³
_{A “1-} C ₆ alkyl) carbamoyl group” is, for example, N,
N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-methyl-N-isopropylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-
Dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-dibutylcarbamoyl group,
N-diisobutylcarbamoyl group, N, N-di-s-butylcarbamoyl group, N, N-di-t-butylcarbamoyl group, N, N-dipentylcarbamoyl group or N, N
-Dihexylcarbamoyl group, preferably di (C
₁ -C ₄ alkyl) carbamoyl group, more preferably N, N- dimethylcarbamoyl group, N- ethyl -N-
It is a methylcarbamoyl group or an N, N-diethylcarbamoyl group, particularly preferably an N, N-dimethylcarbamoyl group.

[0018] The above At a "C ₁ in the definition of R ³ -
"C ₆ alkanoylamino group" represents a linear or branched alkanoylamino group having 1 to 6 carbon atoms, for example,
Formylamino group, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, pivaloylamino group or hexanoylamino group, preferably C
A ₂ -C ₅ alkanoylamino group, more preferably a butyrylamino group or pivaloylamino group, particularly preferably a pivaloylamino group.

In the compound (I) of the present invention, preferred compounds are those represented by the general formula (Ia), the general formula (Ib) or the general formula (Ib)
c)

[0020]

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(Wherein R ^1a , R ^1b , R ^1c , R ² , R
³ and A are as defined above. And more preferably the general formula (Ia) or the general formula (Ic)
And particularly preferably those having the general formula (Ic).

When R ³ in the compound (I) of the present invention is a heteroarylamino group, the corresponding pharmacologically acceptable salt can be obtained by treating the compound with an acid according to a conventional method. For example, compound (I) is treated with a corresponding acid in a solvent (eg, ethers, particularly dioxane) at room temperature for 5 to 30 minutes, and the precipitated crystals are collected by filtration or the solvent is distilled off under reduced pressure. Can be obtained by Such salts include mineral salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfonate, trifluoromethanesulfonate, Sulfonates such as ethanesulfonate, benzenesulfonate or p-toluenesulfonate; carboxylates such as fumarate, succinate, citrate, tartrate, oxalate or maleate; Or an amino acid salt such as glutamate or aspartate. The compound (I) of the present invention or a salt thereof may be left in the air, or
By recrystallization, water may be absorbed, adsorbed water may be attached, or a hydrate may be formed. Compound salts containing such water are also included in the present invention.

The compound (I) of the present invention or a salt thereof is
There are stereoisomers having an asymmetric carbon in the molecule, each of which is in the R-coordination or S-coordination. You.

In the compound (I) of the present invention, preferred compounds include (1) compounds in which R ^1b and R ^1c are the same or different and are a hydrogen atom, a methyl group or an ethyl group;
(2) a compound wherein R ^1b and R ^1c are the same or different and are a hydrogen atom or a methyl group; (3) a compound wherein R ^1b and R ^1c are a methyl group; (4) a compound wherein R ² is a butyl group or isobutyl Group, a compound that is a pentyl group or a hexyl group,
(5) a compound wherein R ² is a pentyl group, (6) R ³
Are piperazinyl, morpholinyl, thiomorpholinyl, imidazolyl, thiazolyl, oxazolyl, imidazolylamino, thiazolylamino, oxazolylamino, cyano, hydroxyl, hydroxyiminomethyl, carboxy, carbamoyl, mono (C
₁ -C ₄₎ alkylcarbamoyl group, a di (C ₁ -C ₄ alkyl) carbamoyl group, compounds which are butyrylamino group or pivaloylamino group, (7) R ^3, 4-morpholinyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group , 2-thiazolylamino, cyano, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl, N-ethyl-N
A compound which is -methylcarbamoyl, N, N-diethylcarbamoyl or pivaloylamino, (8) R
A compound wherein ³ is a 2-oxazolyl group, a cyano group, a carbamoyl group, a methylcarbamoyl group or an N, N-dimethylcarbamoyl group; (9) a compound wherein A is a single bond, a methylene group, an ethylene group or a trimethylene group; 1
0) A compound in which A is a single bond or a methylene group can be mentioned. For R ^1b and R ^1c , a suitable order increases in the order of (1) to (3), and for R ² , (4)
From (5) the preferred ranking goes up, and for R ³ ,
The preferred ranking increases in the order of (6) to (8), and the preferred ranking of A increases in the order of (9) to (10).

The compounds having the general formula (I) include (1)-(3), (4)-(5), (6)-
It is also possible to select 2 to 4 from the group consisting of (8) and (9)-(10), and arbitrarily combine them.
For example, (11) R ^1b and R ^1c are the same or different and are a hydrogen atom, a methyl group or an ethyl group, and R ² is
A butyl group, an isobutyl group, a pentyl group or a hexyl group, and R ³ is Group, hydroxyl group, hydroxyiminomethyl group, carboxy group, carbamoyl group,
A mono (C ₁ -C ₄ ) alkylcarbamoyl group, a di (C ₁
-C ₄ alkyl) carbamoyl group, a butyrylamino group or pivaloylamino group, A is a single bond, a methylene group, compound is an ethylene group or trimethylene group, (1
2) R ^1b and R ^1c are the same or different and are a hydrogen atom or a methyl group, R ² is a pentyl group, and R ³ is
4-morpholinyl group, imidazolyl group, thiazolyl group,
An oxazolyl group, a 2-thiazolylamino group, a cyano group,
A carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, an N, N-dimethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group, an N, N-diethylcarbamoyl group or a pivaloylamino group, wherein A is a single bond or a methylene group; Certain compounds, (13) R ^1b and R ^1c
Is a methyl group, R ² is a pentyl group, and R ³ is
Compounds which are a 2-oxazolyl group, a cyano group, a carbamoyl group, a methylcarbamoyl group or an N, N-dimethylcarbamoyl group, wherein A is a single bond or a methylene group, can be mentioned. (1
The preferred ranking increases in the order of 3).

The representative compounds of the present invention include, for example, the compounds described in the following table, but the present invention is not limited to these compounds.

The abbreviations in the table are as follows.

[0028] Ac: acetyl Bu: butyl group Bu ^i: isobutyl group Bu ^t: tert-butyl group BYR: butyryl group Et: ethyl group Hx: hexyl group HXA: hexanoyl Imid (2): 2- imidazolyl group Me: Methyl group Mor (4): 4-morpholinyl group Oxa (2): 2-oxazolyl Oxa (4): 4-oxazolyl Oxa (5): 5-oxazolyl Piz (1): 1-piperazinyl group Piv: pivaloyl group Pn: pentyl Pr ^i: isopropyl group Thiz (2): 2- thiazolyl group Thiz (4): 4- thiazolyl Thiz (5): 5- thiazolyl group Tmor (4): 4- Chiomoruhoniru group

[0029]

[Table 1]

[0030]

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──────────────────────────────────── Compound R ^1a R ^1b R ^1c R ² A- R ³ number ──────────────────────────────────── 1 2-OH 3-Me H Bu Piz ( 1) 2 2-OH 3-Me H Bu Mor (4) 3 2-OH 3-Me H Bu Tmor (4) 4 2-OH 3-Me H Bu Imid (2) 5 2-OH 3-Me H Bu Bu Thiz (2) 6 2-OH 3-Me H Bu Thiz (4) 7 2-OH 3-Me H Bu Thiz (5) 8 2-OH 3-Me H Bu Oxa (2) 9 2-OH 3-Me H Bu Oxa (4) 10 2-OH 3-Me H Bu Oxa (5) 11 2-OH 3-Me H Bu NHImid (2) 12 2-OH 3-Me H Bu NHThiz (2) 13 2-OH 3 -Me H Bu NHThiz (4) 14 2-OH 3-Me H Bu NHThiz (5) 15 2-OH 3-Me H Bu NHOxa (2) 16 2-OH 3-Me H Bu NHOxa (4) 17 2- OH 3-Me H Bu NHOxa (5) 18 2-OH 3-Me H Bu CH ₂ CH ₂ CH ₂ CN 19 2-OH 3-Me H Bu CH ₂ OH 20 2-OH 3-Me H Bu CH (CH ₃ ) CH ₂ CH = NOH 21 2-OH 3-Me H Bu CH ₂ COOH 22 2-OH 3-Me H Bu CONH ₂ 23 2-OH 3-Me H Bu CH ₂ CONH ₂ 24 2-OH 3-Me H Bu CONHMe 25 2-OH 3-Me H Bu CONHEt 26 2-OH 3-Me H Bu CON (Me) ₂ 27 2-OH 3-Me H Bu CON (Me) Et 28 2-OH 3-Me H Bu CON (Et) ₂ 29 2-OH 3-Me H Bu CH ₂ CH ₂ CH ₂ CH ₂ CONHHx 30 2-OH 3-Me H Bu CH ₂ NHHxa 31 2-OH 3-Me H Bu ⁱ Piz (1) 32 2-OH 3-Me H Bu ⁱ Mor (4) 33 2-OH 3-Me H Bu ⁱ Tmor (4) 34 2-OH 3-Me H Bu ⁱ Imid (2) 35 2-OH 3-Me H Bu ⁱ Thiz (2) 36 2-OH 3-Me H Bu ⁱ Thiz (4) 37 2-OH 3-Me H Bu ⁱ Thiz ( 5) 38 2-OH 3-Me H Bu ⁱ Oxa (2) 39 2-OH 3-Me H Bu ⁱ Oxa (4) 40 2-OH 3-Me H Bu ⁱ Oxa (5) 41 2-OH 3- Me H Bu ⁱ NHImid (2) 42 2-OH 3-Me H Bu ⁱ NHThiz (2) 43 2-OH 3-Me H Bu ⁱ NHThiz (4) 44 2-OH 3-Me H Bu ⁱ NHThiz (5) 45 2-OH 3-Me H Bu ⁱ NHOxa (2) 46 2-OH 3-Me H Bu ⁱ NHOxa (4) 47 2-OH 3-Me H Bu ⁱ NHOxa (5) 48 2-OH 3-Me H Bu ⁱ CN 49 2-OH 3-Me H Bu ⁱ CH ₂ OH 50 2-OH 3-Me H Bu ⁱ CH ₂ CH ₂ CH = NOH 51 2-OH 3-Me H Bu ⁱ CH ₂ CH ₂ CH ₂ COOH 52 2-OH 3-Me H Bu ⁱ CONH ₂ 53 2-OH 3-Me H Bu ⁱ CONHMe 54 2-OH 3-Me H Bu ⁱ CONHEt 55 2-OH 3-Me H Bu ⁱ CON (Me) ₂ 56 2-OH 3-Me H Bu ⁱ CON (Me) Et 57 2-OH 3-Me H Bu ⁱ CON (Et) ₂ 58 2-OH 3-Me H Pn Piz (1) 59 2-OH 3-Me H Pn CH ₂ Piz (1) 60 2-OH 3-Me H Pn Mor (4) 61 2-OH 3-Me H P n CH ₂ Mor (4) 62 2-OH 3-Me H Pn Tmor (4) 63 2-OH 3-Me H Pn CH ₂ Tmor (4) 64 2-OH 3-Me H Pn Imid (2) 65 2 -OH 3-Me H Pn CH ₂ Imid (2) 66 2-OH 3-Me H Pn Thiz (2) 67 2-OH 3-Me H Pn Thiz (4) 68 2-OH 3-Me H Pn Thiz ( 5) 69 2-OH 3-Me H Pn CH ₂ Thiz (2) 70 2-OH 3-Me H Pn CH ₂ Thiz (4) 71 2-OH 3-Me H Pn CH ₂ Thiz (5) 72 2- OH 3-Me H Pn Oxa (2) 73 2-OH 3-Me H Pn Oxa (4) 74 2-OH 3-Me H Pn Oxa (5) 75 2-OH 3-Me H Pn CH ₂ Oxa (2 ) 76 2-OH 3-Me H Pn CH ₂ Oxa (4) 77 2-OH 3-Me H Pn CH ₂ Oxa (5) 78 2-OH 3-Me H Pn NHImid (2) 79 2-OH 3- Me H Pn CH ₂ NHImid (2) 80 2-OH 3-Me H Pn NHThiz (2) 81 2-OH 3-Me H Pn NHThiz (4) 82 2-OH 3-Me H Pn NHThiz (5) 83 2 -OH 3-Me H Pn CH ₂ NHThiz (2) 84 2-OH 3-Me H Pn CH ₂ NHThiz (4) 85 2-OH 3-Me H Pn CH ₂ NHThiz (5) 86 2-OH 3-Me H Pn NHOxa (2) 87 2-OH 3-Me H Pn NHOxa (4) 88 2-OH 3-Me H Pn NHOxa (5) 89 2-OH 3-Me H Pn CH ₂ NHOxa (2) 90 2- OH 3-Me H Pn CH ₂ NHOxa (4) 91 2-OH 3-Me H Pn CH ₂ NHOxa (5) 92 2-OH 3-Me H Pn CN 93 2-OH 3-Me H Pn CH ₂ CN 94 2-OH 3-Me H Pn OH 95 2-OH 3-Me H Pn CH = NOH 96 2-OH 3-Me H Pn COOH 97 2-OH 3-Me H Pn CONH ₂ 98 2-OH 3-Me H Pn CH ₂ CONH ₂ 99 2-OH 3-Me H Pn CONHMe 100 2-OH 3-Me H Pn CH ₂ CONHMe 101 2-OH 3-Me H Pn CONHEt 102 2-OH 3-Me H Pn CH ₂ CONHEt 103 2-OH 3-Me H Pn CON (Me) ₂ 104 2-OH 3-Me H Pn CH ₂ CON (Me) ₂ 105 2 -OH 3-Me H Pn CH ₂ CH ₂ CON (Me) ₂ 106 2-OH 3-Me H Pn CON (Me) Et 107 2-OH 3-Me H Pn CH ₂ CON (Me) Et 108 2-OH 3-Me H Pn CON (Et) ₂ 109 2-OH 3-Me H Pn CH ₂ CON (Et) ₂ 110 2-OH 3-Me H Pn NHAc 111 2-OH 3-Me H Pn CH ₂ NHAc 112 2 -OH 3-Me H Pn NHByr 113 2-OH 3-Me H Pn CH ₂ NHByr 114 2-OH 3-Me H Pn NHPiv 115 2-OH 3-Me H Pn CH ₂ NHPiv 116 2-OH 3-Et H Pn Piz (1) 117 2-OH 3-Et H Pn Mor (4) 118 2-OH 3-Et H Pn Tmor (4) 119 2-OH 3-Et H Pn Imid (2) 121 2-OH 3- Et H Pn Thiz (4) 122 2-OH 3-Et H Pn Thiz (5) 123 2-OH 3-Et H Pn Oxa (2) 124 2-OH 3-Et H Pn Oxa (4) 125 2-OH 3-Et H Pn Oxa (5) 126 2-OH 3-Et H Pn NHImid (2) 127 2-OH 3-Et H Pn NHThiz (2) 128 2-OH 3-Et H Pn NHThiz (4) 129 2 -OH 3-Et H Pn NHThiz (5) 130 2-OH 3-Et H Pn NHOxa (2) 131 2-OH 3-Et H Pn NHOxa (4) 132 2-OH 3-Et H Pn NHOxa (5) 13 3 2-OH 3-Et H Pn CONH ₂ 134 2-OH 3-Et H Pn CONHMe 135 2-OH 3-Et H Pn CONHEt 136 2-OH 3-Et H Pn CON (Me) ₂ 137 2-OH 3 -Et H Pn CON (Me) Et 138 2-OH 3-Et H Pn CON (Et) ₂ 139 2-OH 3-Et H Pn NHByr 140 2-OH 3-Et H Pn NHPiv 141 2-OH 4-Me H Pn Mor (4) 142 2-OH 4-Me H Pn Oxa (2) 143 2-OH 4-Me H Pn Oxa (4) 144 2-OH 4-Me H Pn Oxa (5) 145 2-OH 4 -Me H Pn NHThiz (2) 146 2-OH 4-Me H Pn NHThiz (4) 147 2-OH 4-Me H Pn NHThiz (5) 148 2-OH 4-Me H Pn CN 149 2-OH 4- Me H Pn CONH ₂ 150 2-OH 4-Me H Pn CONHMe 151 2-OH 4-Me H Pn CON (Me) ₂ 152 2-OH 4-Pr H Pn Oxa (2) 153 2-OH 4-Pr H Pn Oxa (4) 154 2-OH 4-Pr H Pn Oxa (5) 155 2-OH 5-Me H Pn Mor (4) 156 2-OH 5-Me H Pn Oxa (2) 157 2-OH 5- Me H Pn Oxa (4) 158 2-OH 5-Me H Pn Oxa (5) 159 2-OH 5-Me H Pn NHThiz (2) 160 2-OH 5-Me H Pn NHThiz (4) 161 2-OH 5-Me H Pn NHThiz (5) 162 2-OH 5-Me H Pn CN 163 2-OH 5-Me H Pn CONH ₂ 164 2-OH 5-Me H Pn CONHMe 165 2-OH 5-Me H Pn CON (Me) ₂ 166 2-OH 5-Bu H Pn NHThiz (2) 167 2-OH 5-Bu H Pn NHThiz (4) 168 2-OH 5-Bu H Pn NHThiz (5) 169 2-OH 6-Me H Pn Piz (1) 17 0 2-OH 6-Me H Pn Oxa (2) 171 2-OH 6-Me H Pn Oxa (4) 172 2-OH 6-Me H Pn Oxa (5) 173 2-OH 6-Me H Pn NHThiz ( 2) 174 2-OH 6-Me H Pn NHThiz (4) 175 2-OH 6-Me H Pn NHThiz (5) 176 2-OH 6-Me H Pn CN 177 2-OH 6-Me H Pn CONH ₂ 178 2-OH 6-Me H Pn CONHMe 179 2-OH 6-Me H Pn CON (Me) ₂ 180 2-OH 6-Bu ^t H Pn CONH ₂ 181 2-OH 3-Me 4-Me Pn Mor (4) 182 2-OH 3-Me 4-Me Pn Oxa (2) 183 2-OH 3-Me 4-Me Pn Oxa (4) 184 2-OH 3-Me 4-Me Pn Oxa (5) 185 2-OH 3 -Me 4-Me Pn NHThiz (2) 186 2-OH 3-Me 4-Me Pn NHThiz (4) 187 2-OH 3-Me 4-Me Pn NHThiz (5) 188 2-OH 3-Me 4-Me Pn CN 189 2-OH 3-Me 4-Me Pn CONH ₂ 190 2-OH 3-Me 4-Me Pn CONHMe 191 2-OH 3-Me 4-Me Pn CON (Me) ₂ 192 2-OH 3-Pr 4-Me Pn NHThiz (2) 193 2-OH 3-Pr 4-Me Pn NHThiz (4) 194 2-OH 3-Pr 4-Me Pn NHThiz (5) 195 2-OH 3-Me 4-Me Pn CH ₂ CH ₂ CH ₂ CH ₂ CN 196 2-OH 3-Me 4-Me Pn CON (Hx) ₂ 197 2-OH 3-Me 4-Et Hx CON (Hx) ₂ 198 2-OH 3-Me 4-Bu Bu Mor (4) 199 2-OH 3-Me 4-Bu Pn CH ₂ CH ₂ Oxa (2) 200 2-OH 3-Me 4-Bu Pn CH ₂ CH ₂ Oxa (4) 201 2-OH 3-Me 4-Bu Pn CH ₂ CH ₂ Oxa (5) 202 2-OH 3-Bu 4-Bu Hx CONHHx 203 2-OH 3-Me 5-Me Pn Mor (4) 204 2-OH 3-Me 5-Me Pn Oxa (2) 205 2-OH 3-Me 5-Me Pn Oxa (4) 206 2-OH 3 -Me 5-Me Pn Oxa (5) 207 2-OH 3-Me 5-Me Pn NHThiz (2) 208 2-OH 3-Me 5-Me Pn NHThiz (4) 209 2-OH 3-Me 5-Me Pn NHThiz (5) 210 2-OH 3-Me 5-Me Pn CN 211 2-OH 3-Me 5-Me Pn CONH ₂ 212 2-OH 3-Me 5-Me Pn CONHMe 213 2-OH 3-Me 5 -Me Pn CON (Me) ₂ 214 2-OH 3-Me 6-Me Pn Mor (4) 215 2-OH 3-Me 6-Me Pn Oxa (2) 216 2-OH 3-Me 6-Me Pn Oxa (4) 217 2-OH 3-Me 6-Me Pn Oxa (5) 218 2-OH 3-Me 6-Me Pn NHThiz (2) 219 2-OH 3-Me 6-Me Pn NHThiz (4) 220 2 -OH 3-Me 6-Me Pn NHThiz (5) 221 2-OH 3-Me 6-Me Pn CN 222 2-OH 3-Me 6-Me Pn CONH ₂ 223 2-OH 3-Me 6-Me Pn CONHMe 224 2-OH 3-Me 6-Me Pn CON (Me) ₂ 225 2-OH 4-Me 5-Me Pn Mor (4) 226 2-OH 4-Me 5-Me Pn Oxa (2) 227 2-OH 4-Me 5-Me Pn Oxa (4) 228 2-OH 4-Me 5-Me Pn Oxa (5) 229 2-OH 4-Me 5-Me Pn NHThiz (2) 230 2-OH 4-Me 5- Me Pn NHThiz (4) 231 2-OH 4-Me 5-Me Pn NHThiz (5) 232 2-OH 4-Me 5-Me Pn CN 233 2-OH 4-Me 5-Me Pn CONH ₂ 234 2-OH 4-Me 5-Me Pn CONHMe 235 2-OH 4-Me 5-Me Pn CON (Me) ₂ 236 2-OH 4-Me 6-Me Pn Mor (4) 237 2-OH 4-Me 6-Me Pn Oxa (2) 238 2-OH 4-Me 6-Me Pn Oxa (4) 239 2-OH 4-Me 6-Me Pn Oxa (5) 240 2-OH 4-Me 6-Me Pn NHThiz (2) 241 2-OH 4-Me 6-Me Pn NHThiz (4) 242 2-OH 4-Me 6-Me Pn NHThiz (5) 243 2-OH 4 -Me 6-Me Pn CN 244 2-OH 4-Me 6-Me Pn CONH ₂ 245 2-OH 4-Me 6-Me Pn CONHMe 246 2-OH 4-Me 6-Me Pn CON (Me) ₂ 247 2 -OH 5-Me 6-Me Pn Mor (4) 248 2-OH 5-Me 6-Me Pn Oxa (2) 249 2-OH 5-Me 6-Me Pn Oxa (4) 250 2-OH 5-Me 6-Me Pn Oxa (5) 251 2-OH 5-Me 6-Me Pn NHThiz (2) 252 2-OH 5-Me 6-Me Pn NHThiz (4) 253 2-OH 5-Me 6-Me Pn NHThiz (5) 254 2-OH 5-Me 6-Me Pn CN 255 2-OH 5-Me 6-Me Pn CONH ₂ 256 2-OH 5-Me 6-Me Pn CONHMe 257 2-OH 5-Me 6-Me Pn CON (Me) ₂ 258 3-OH 2-Me H Pn Mor (4) 259 3-OH 2-Me H Pn CH ₂ Mor (4) 260 3-OH 2-Me H Pn Oxa (2) 261 3- OH 2-Me H Pn Oxa (4) 262 3-OH 2-Me H Pn Oxa (5) 263 3-OH 2-Me H Pn CH ₂ Oxa (2) 264 3-OH 2-Me H Pn CH ₂ Oxa (4) 265 3-OH 2-Me H Pn CH ₂ Oxa (5) 266 3-OH 2-Me H Pn NHThiz (2) 267 3-OH 2-Me H Pn NHThiz (4) 268 3-OH 2- Me H Pn NHThiz (5) 269 3-OH 2-Me H Pn CH ₂ Thiz (2) 270 3-OH 2-Me H P n CH ₂ Thiz (4) 271 3-OH 2-Me H Pn CH ₂ Thiz (5) 272 3-OH 2-Me H Pn CN 273 3-OH 2-Me H Pn CONH ₂ 274 3-OH 2-Me H Pn CONHMe 275 3-OH 2-Me H Pn CON (Me) ₂ 276 3-OH 4-Me H Pn Mor (4) 277 3-OH 4-Me H Pn Oxa (2) 278 3-OH 4-Me H Pn Oxa (4) 279 3-OH 4-Me H Pn Oxa (5) 280 3-OH 4-Me H Pn NHThiz (2) 281 3-OH 4-Me H Pn NHThiz (4) 282 3-OH 4 -Me H Pn NHThiz (5) 283 3-OH 4-Me H Pn CN 284 3-OH 4-Me H Pn CONH ₂ 285 3-OH 4-Me H Pn CONHMe 286 3-OH 4-Me H Pn CON ( Me) ₂ 287 3-OH 5-Me H Pn Mor (4) 288 3-OH 5-Me H Pn Oxa (2) 289 3-OH 5-Me H Pn Oxa (4) 290 3-OH 5-Me H Pn Oxa (5) 291 3-OH 5-Me H Pn NHThiz (2) 292 3-OH 5-Me H Pn NHThiz (4) 293 3-OH 5-Me H Pn NHThiz (5) 294 3-OH 5- Me H Pn CN 295 3-OH 5-Me H Pn CONH ₂ 296 3-OH 5-Me H Pn CONHMe 297 3-OH 5-Me H Pn CON (Me) ₂ 298 3-OH 6-Me H Pn Piz ( 1) 299 3-OH 6-Me H Pn Mor (4) 300 3-OH 6-Me H Pn Oxa (2) 301 3-OH 6-Me H Pn Oxa (4) 302 3-OH 6-Me H Pn Oxa (5) 303 3-OH 6-Me H Pn NHThiz (2) 304 3-OH 6-Me H Pn NHThiz (4) 305 3-OH 6-Me H Pn NHThiz (5) 306 3-OH 6-Me H Pn CN 307 3-OH 6-Me H Pn CONH ₂ 308 3-OH 6-Me H Pn CONHMe 309 3-OH 6-Me H Pn CON (Me) ₂ 310 3-OH 2-Me 4-Me Bu Piz (1) 311 3-OH 2-Me 4-Me Bu Mor (4) 312 3-OH 2-Me 4-Me Bu Tmor (4) 313 3-OH 2-Me 4-Me Bu Imid (2) 314 3-OH 2-Me 4-Me Bu Thiz (2) 315 3-OH 2-Me 4-Me Bu Thiz (4) 316 3-OH 2-Me 4-Me Bu Thiz (5) 317 3-OH 2-Me 4-Me Bu Oxa (2) 318 3-OH 2 -Me 4-Me Bu Oxa (4) 319 3-OH 2-Me 4-Me Bu Oxa (5) 320 3-OH 2-Me 4-Me Bu NHImid (2) 321 3-OH 2-Me 4-Me Bu NHThiz (2) 322 3-OH 2-Me 4-Me Bu NHThiz (4) 323 3-OH 2-Me 4-Me Bu NHThiz (5) 324 3-OH 2-Me 4-Me Bu NHOxa (2) 325 3-OH 2-Me 4-Me Bu NHOxa (4) 326 3-OH 2-Me 4-Me Bu NHOxa (5) 327 3-OH 2-Me 4-Me Bu CN 328 3-OH 2-Me 4 -Me Bu OH 329 3-OH 2-Me 4-Me Bu CH = NOH 330 3-OH 2-Me 4-Me Bu COOH 331 3-OH 2-Me 4-Me Bu CONH ₂ 332 3-OH 2-Me 4-Me Bu CONHMe 333 3-OH 2-Me 4-Me Bu CONHEt 334 3-OH 2-Me 4-Me Bu CON (Me) ₂ 335 3-OH 2-Me 4-Me Bu CON (Me) Et 336 3-OH 2-Me 4-Me Bu CON (Et) ₂ 337 3-OH 2-Me 4-Me Bu NHByr 338 3-OH 2-Me 4-Me Bu NHPiv 339 3-OH 2-Me 4-Me Bu ⁱ Piz (1) 340 3-OH 2-Me 4-Me Bu ⁱ Mor (4) 341 3-OH 2-Me 4-Me Bu ⁱ Tmor (4) 342 3-OH 2-Me 4-Me Bu ⁱ Imid (2) 343 3-OH 2-Me 4-Me Bu ⁱ Thiz (2) 344 3-OH 2-Me 4-Me Bu ⁱ Thiz (4) 345 3-OH 2-Me 4-Me Bu ⁱ Oza (5) 346 3-OH 2-Me 4-Me Bu ⁱ Oxa (2) 347 3-OH 2-Me 4-Me Bu ⁱ Oxa ( 4) 348 3-OH 2-Me 4-Me Bu ⁱ Oxa (5) 349 3-OH 2-Me 4-Me Bu ⁱ NHImid (2) 350 3-OH 2-Me 4-Me Bu ⁱ NHThiz (2) 351 3-OH 2-Me 4-Me Bu ⁱ NHThiz (4) 352 3-OH 2-Me 4-Me Bu ⁱ NHThiz (5) 353 3-OH 2-Me 4-Me Bu ⁱ NHOxa (2) 354 3 -OH 2-Me 4-Me Bu ⁱ NHOxa (4) 355 3-OH 2-Me 4-Me Bu ⁱ NHOxa (5) 356 3-OH 2-Me 4-Me Bu ⁱ CN 357 3-OH 2-Me 4-Me Bu ⁱ OH 358 3-OH 2-Me 4-Me Bu ⁱ CH = NOH 359 3-OH 2-Me 4-Me Bu ⁱ COOH 360 3-OH 2-Me 4-Me Bu ⁱ CONH ₂ 361 3 -OH 2-Me 4-Me Bu ⁱ CONHMe 362 3-OH 2-Me 4-Me Bu ⁱ CONHEt 363 3-OH 2-Me 4-Me Bu ⁱ CON (Me) ₂ 364 3-OH 2-Me 4- Me Bu ⁱ CON (Me) Et 365 3-OH 2-Me 4-Me Bu ⁱ CON (Et) ₂ 366 3-OH 2-Me 4-Me Bu ⁱ NHByr 367 3-OH 2-Me 4-Me Bu ⁱ NHPiv 368 3-OH 2-Me 4-Me Pn Piz (1) 369 3-OH 2-Me 4-Me Pn CH ₂ Piz (1) 370 3-OH 2-Me 4-Me Pn Mor (4) 371 3 -OH 2-Me 4-Me Pn CH ₂ Mor (4) 372 3-OH 2-Me 4-Me Pn Tmor (4) 373 3- OH 2-Me 4-Me Pn CH ₂ Tmor (4) 374 3-OH 2-Me 4-Me Pn Imid (2) 375 3-OH 2-Me 4-Me Pn CH ₂ Imid (2) 376 3-OH 2-Me 4-Me Pn Thiz (2) 377 3-OH 2-Me 4-Me Pn Thiz (4) 378 3-OH 2-Me 4-Me Pn Thiz (5) 379 3-OH 2-Me 4- Me Pn CH ₂ Thiz (2) 380 3-OH 2-Me 4-Me Pn CH ₂ Thiz (4) 381 3-OH 2-Me 4-Me Pn CH ₂ Thiz (5) 382 3-OH 2-Me 4 -Me Pn Oxa (2) 383 3-OH 2-Me 4-Me Pn Oxa (4) 384 3-OH 2-Me 4-Me Pn Oxa (5) 385 3-OH 2-Me 4-Me Pn CH ₂ Oxa (2) 386 3-OH 2-Me 4-Me Pn CH ₂ Oxa (4) 387 3-OH 2-Me 4-Me Pn CH ₂ Oxa (5) 388 3-OH 2-Me 4-Me Pn NHImid (2) 389 3-OH 2 -Me 4-Me Pn CH 2 NHImid (2) 390 3-OH 2-Me 4-Me Pn NHThiz (2) 391 3-OH 2-Me 4-Me Pn NHThiz (4) 392 3-OH 2-Me 4-Me Pn NHThiz (5) 393 3-OH 2-Me 4-Me Pn CH ₂ NHThiz (2) 394 3-OH 2-Me 4-Me Pn CH ₂ NHThiz (4) 395 3-OH 2-Me 4-Me Pn CH ₂ NHThiz (5) 396 3-OH 2-Me 4-Me Pn NHOxa (2) 397 3-OH 2-Me 4-Me Pn NHOxa (4) 398 3-OH 2-Me 4-Me Pn NHOxa (5) 399 3-OH 2-Me 4-Me Pn CH ₂ NHOxa (2) 400 3-OH 2-Me 4-Me Pn CH ₂ NHOxa (4) 401 3-OH 2 -Me 4-Me Pn CH ₂ NHOxa (5) 402 3-OH 2-Me 4-Me Pn CN 403 3-OH 2-Me 4-Me P n CH ₂ CN 404 3-OH 2-Me 4-Me Pn OH 405 3-OH 2-Me 4-Me Pn CH ₂ OH 406 3-OH 2-Me 4-Me Pn CH = NOH 407 3-OH 2- Me 4-Me Pn CH ₂ CH = NOH 408 3-OH 2-Me 4-Me Pn COOH 409 3-OH 2-Me 4-Me Pn CH ₂ COOH 410 3-OH 2-Me 4-Me Pn CONH ₂ 411 3-OH 2-Me 4-Me Pn CH ₂ CONH ₂ 412 3-OH 2-Me 4-Me Pn CONHMe 413 3-OH 2-Me 4-Me Pn CH ₂ CONHMe 414 3-OH 2-Me 4-Me Pn CONHEt 415 3-OH 2-Me 4-Me Pn CH ₂ CONHEt 416 3-OH 2-Me 4-Me Pn CON (Me) ₂ 417 3-OH 2-Me 4-Me Pn CH ₂ CON (Me) ₂ 418 3-OH 2-Me 4-Me Pn CON (Me) Et 419 3-OH 2-Me 4-Me Pn CH ₂ CON (Me) Et 420 3-OH 2-Me 4-Me Pn CON (Et) ₂ 421 3-OH 2-Me 4-Me Pn CH ₂ CON (Et) ₂ 422 3-OH 2-Me 4-Me Pn NHByr 423 3-OH 2-Me 4-Me Pn CH ₂ NHByr 424 3-OH 2- Me 4-Me Pn NHPiv 425 3-OH 2-Me 4-Me Pn CH ₂ NHPiv 426 3-OH 2-Me 4-Me Hx Piz (1) 427 3-OH 2-Me 4-Me Hx Mor (4) 428 3-OH 2-Me 4-Me Hx Tmor (4) 429 3-OH 2-Me 4-Me Hx Imid (2) 430 3-OH 2-Me 4-Me Hx Thiz (2) 431 3-OH 2 -Me 4-Me Hx Thiz (4) 432 3-OH 2-Me 4-Me Hx Thiz (5) 433 3-OH 2-Me 4-Me Hx Oxa (2) 434 3-OH 2-Me 4-Me Hx Oxa (4) 435 3-OH 2-Me 4-Me Hx Oxa (5) 436 3-OH 2-Me 4-Me Hx NHImid (2) 437 3-OH 2-Me 4-Me Hx NHThiz (2) 438 3-OH 2-Me 4-Me Hx NHThiz (4) 439 3-OH 2 -Me 4-Me Hx NHThiz (5) 440 3-OH 2-Me 4-Me Hx NHOxa (2) 441 3-OH 2-Me 4-Me Hx NHOxa (4) 442 3-OH 2-Me 4-Me Hx NHOxa (5) 443 3-OH 2-Me 4-Me Hx CN 444 3-OH 2-Me 4-Me Hx OH 445 3-OH 2-Me 4-Me Hx CH = NOH 446 3-OH 2-Me 4-Me Hx COOH 447 3-OH 2-Me 4-Me Hx CONH ₂ 448 3-OH 2-Me 4-Me Hx CONHMe 449 3-OH 2-Me 4-Me Hx CONHEt 450 3-OH 2-Me 4 -Me Hx CON (Me) ₂ 451 3-OH 2-Me 4-Me Hx CON (Me) Et 452 3-OH 2-Me 4-Me Hx CON (Et) ₂ 453 3-OH 2-Me 4-Me Hx NHByr 454 3-OH 2-Me 4-Me Hx NHPiv 455 3-OH 2-Et 4-Me Pn Mor (4) 456 3-OH 2-Et 4-Me Pn Oxa (2) 457 3-OH 2- Et 4-Me Pn Oxa (4) 458 3-OH 2-Et 4-Me Pn Oxa (5) 459 3-OH 2-Et 4-Me Pn NHThiz (2) 460 3-OH 2-Et 4-Me Pn NHThiz (4) 461 3-OH 2-Et 4-Me Pn NHThiz (5) 462 3-OH 2-Et 4-Me Pn CN 463 3-OH 2-Et 4-Me Pn CONH ₂ 464 3-OH 2- Et 4-Me Pn CONHMe 465 3-OH 2-Et 4-Me Pn CON (Me) ₂ 466 3-OH 2-Me 4-Et Pn Mor (4) 467 3-OH 2-Me 4-Et Pn Oxa ( 2) 468 3-OH 2-Me 4-Et Pn Oxa (4) 469 3-OH 2-Me 4-Et P n Oxa (5) 470 3-OH 2-Me 4-Et Pn NHThiz (2) 471 3-OH 2-Me 4-Et Pn NHThiz (4) 472 3-OH 2-Me 4-Et Pn NHThiz (5) 473 3-OH 2-Me 4-Et Pn CN 474 3-OH 2-Me 4-Et Pn CONH ₂ 475 3-OH 2-Me 4-Et Pn CONHMe 476 3-OH 2-Me 4-Et Pn CON ( Me) ₂ 477 3-OH 2-Et 4-Et Pn Mor (4) 478 3-OH 2-Et 4-Et Pn Oxa (2) 479 3-OH 2-Et 4-Et Pn Oxa (4) 480 3 -OH 2-Et 4-Et Pn Oxa (5) 481 3-OH 2-Et 4-Et Pn NHThiz (2) 482 3-OH 2-Et 4-Et Pn NHThiz (4) 483 3-OH 2-Et 4-Et Pn NHThiz (5) 484 3-OH 2-Et 4-Et Pn CN 485 3-OH 2-Et 4-Et Pn CONH ₂ 486 3-OH 2-Et 4-Et Pn CONHMe 487 3-OH 2 -Et 4-Et Pn CON (Me) ₂ 488 3-OH 2-Me 5-Me Pn Mor (4) 489 3-OH 2-Me 5-Me Pn Oxa (2) 490 3-OH 2-Me 5- Me Pn Oxa (4) 491 3-OH 2-Me 5-Me Pn Oxa (5) 492 3-OH 2-Me 5-Me Pn NHThiz (2) 493 3-OH 2-Me 5-Me Pn NHThiz (4 ) 494 3-OH 2-Me 5-Me Pn NHThiz (5) 495 3-OH 2-Me 5-Me Pn CN 496 3-OH 2-Me 5-Me Pn CONH ₂ 497 3-OH 2-Me 5- Me Pn CONHMe 498 3-OH 2-Me 5-Me Pn CON (Me) ₂ 499 3-OH 2-Me 6-Me Pn Mor (4) 500 3-OH 2-Me 6-Me Pn Oxa (2) 501 3-OH 2-Me 6-Me Pn Oxa (4) 502 3-OH 2-Me 6-Me Pn Oxa (5) 503 3-OH 2 -Me 6-Me Pn NHThiz (2) 504 3-OH 2-Me 6-Me Pn NHThiz (4) 505 3-OH 2-Me 6-Me Pn NHThiz (5) 506 3-OH 2-Me 6-Me Pn CN 507 3-OH 2-Me 6-Me Pn CONH ₂ 508 3-OH 2-Me 6-Me Pn CONHMe 509 3-OH 2-Me 6-Me Pn CON (Me) ₂ 510 3-OH 4-Me 5-Me Pn Mor (4) 511 3-OH 4-Me 5-Me Pn Oxa (2) 512 3-OH 4-Me 5-Me Pn Oxa (4) 513 3-OH 4-Me 5-Me Pn Oxa (5) 514 3-OH 4-Me 5-Me Pn NHThiz (2) 515 3-OH 4-Me 5-Me Pn NHThiz (4) 516 3-OH 4-Me 5-Me Pn NHThiz (5) 517 3 -OH 4-Me 5-Me Pn CN 518 3-OH 4-Me 5-Me Pn CONH ₂ 519 3-OH 4-Me 5-Me Pn CONHMe 520 3-OH 4-Me 5-Me Pn CON (Me) ₂ 521 3-OH 4-Me 6-Me Pn Oxa (2) 523 3-OH 4-Me 6-Me Pn Oxa (4) 524 3-OH 4-Me 6-Me Pn Oxa (5) 525 3-OH 4-Me 6-Me Pn NHThiz (2) 526 3-OH 4-Me 6-Me Pn NHThiz (4) 527 3-OH 4-Me 6- Me Pn NHThiz (5) 528 3-OH 4-Me 6-Me Pn CN 529 3-OH 4-Me 6-Me Pn CONH ₂ 530 3-OH 4-Me 6-Me Pn CONHMe 531 3-OH 4-Me 6-Me Pn CON (Me) ₂ 532 3-OH 5-Me 6-Me Pn Mor (4) 533 3-OH 5-Me 6-Me Pn Oxa (2) 534 3-OH 5-Me 6-Me Pn Oxa (4) 535 3-OH 5-Me 6-Me Pn Oxa (5) 536 3-OH 5-Me 6-Me Pn NHThiz ( 2) 537 3-OH 5-Me 6-Me Pn NHThiz (4) 538 3-OH 5-Me 6-Me Pn NHThiz (5) 539 3-OH 5-Me 6-Me Pn CN 540 3-OH 5- Me 6-Me Pn CONH ₂ 541 3-OH 5-Me 6-Me Pn CONHMe 542 3-OH 5-Me 6-Me Pn CON (Me) ₂ 543 4-OH 2-Me H Pn Mor (4) 544 4 -OH 2-Me H Pn Oxa (2) 545 4-OH 2-Me H Pn Oxa (4) 546 4-OH 2-Me H Pn Oxa (5) 547 4-OH 2-Me H Pn NHThiz (2) 548 4-OH 2-Me H Pn NHThiz (4) 549 4-OH 2-Me H Pn NHThiz (5) 550 4-OH 2-Me H Pn CONH ₂ 551 4-OH 2-Me H Pn CONHMe 552 4- OH 2-Me H Pn CON (Me) ₂ 553 4-OH 3-Me H Pn Mor (4) 554 4-OH 3-Me H Pn Oxa (2) 555 4-OH 3-Me H Pn Oxa (4) 556 4-OH 3-Me H Pn Oxa (5) 557 4-OH 3-Me H Pn NHThiz (2) 558 4-OH 3-Me H Pn NHThiz (4) 559 4-OH 3-Me H Pn NHThiz (4) 5) 560 4-OH 3-Me H Pn CONH ₂ 561 4-OH 3-Me H Pn CONHMe 562 4-OH 3-Me H Pn CON (Me) ₂ 563 4-OH 5-Me H Pn Mor (4) 564 4-OH 5-Me H Pn Oxa (2) 565 4-OH 5-Me H Pn Oxa (4) 566 4-OH 5-Me H Pn Oxa (5) 567 4-OH 5-Me H Pn NHThiz ( 2) 568 4-OH 5-Me H Pn NHThiz (4) 569 4-OH 5-Me H Pn NHThiz (5) 570 4-OH 5-Me H Pn CONH ₂ 571 4-OH 5-Me H Pn CONHMe 572 4-OH 5-Me H Pn CON (Me) ₂ 57 3 4-OH 6-Me H Pn Mor (4) 574 4-OH 6-Me H Pn Oxa (2) 575 4-OH 6-Me H Pn Oxa (4) 576 4-OH 6-Me H Pn Oxa ( 5) 577 4-OH 6-Me H Pn NHThiz (2) 578 4-OH 6-Me H Pn NHThiz (4) 579 4-OH 6-Me H Pn NHThiz (5) 580 4-OH 6-Me H Pn CONH ₂ 581 4-OH 6-Me H Pn CONHMe 582 4-OH 6-Me H Pn CON (Me) ₂ 583 4-OH 2-Me 3-Me Pn Mor (4) 584 4-OH 2-Me 3- Me Pn Oxa (2) 585 4-OH 2-Me 3-Me Pn Oxa (4) 586 4-OH 2-Me 3-Me Pn Oxa (5) 587 4-OH 2-Me 3-Me Pn NHThiz (2 ) 588 4-OH 2-Me 3-Me Pn NHThiz (4) 589 4-OH 2-Me 3-Me Pn NHThiz (5) 590 4-OH 2-Me 3-Me Pn CONH ₂ 591 4-OH 2- Me 3-Me Pn CONHMe 592 4-OH 2-Me 3-Me Pn CON (Me) ₂ 593 4-OH 2-Me 5-Me Pn Mor (4) 594 4-OH 2-Me 5-Me Pn Oxa ( 2) 595 4-OH 2-Me 5-Me Pn Oxa (4) 596 4-OH 2-Me 5-Me Pn Oxa (5) 597 4-OH 2-Me 5-Me Pn NHThiz (2) 598 4- OH 2-Me 5-Me Pn NHThiz (4) 599 4-OH 2-Me 5-Me Pn NHThiz (5) 600 4-OH 2-Me 5-Me Pn CONH ₂ 601 4-OH 2-Me 5-Me Pn CONHMe 602 4-OH 2-Me 5-Me Pn CON (Me) ₂ 603 4-OH 2-Me 6-Me Pn Mor (4) 604 4-OH 2-Me 6-Me Pn Oxa (2) 605 4 -OH 2-Me 6-Me Pn Oxa (4) 606 4-OH 2-Me 6-Me Pn Oxa (5) 607 4-OH 2 -Me 6-Me Pn NHThiz (2) 608 4-OH 2-Me 6-Me Pn NHThiz (4) 609 4-OH 2-Me 6-Me Pn NHThiz (5) 610 4-OH 2-Me 6-Me Pn CONH ₂ 611 4-OH 2-Me 6-Me Pn CONHMe 612 4-OH 2-Me 6-Me Pn CON (Me) ₂ 613 4-OH 3-Me 5-Me Bu Piz (1) 614 4-OH 3-Me 5-Me Bu Mor (4) 615 4-OH 3-Me 5-Me Bu Tmor (4) 616 4-OH 3-Me 5-Me Bu Imid (2) 617 4-OH 3-Me 5- Me Bu Thiz (2) 618 4-OH 3-Me 5-Me Bu Thiz (4) 619 4-OH 3-Me 5-Me Bu Thiz (5) 620 4-OH 3-Me 5-Me Bu Oxa (2 ) 621 4-OH 3-Me 5-Me Bu Oxa (4) 622 4-OH 3-Me 5-Me Bu Oxa (5) 623 4-OH 3-Me 5-Me Bu NHImid (2) 624 4-OH 3-Me 5-Me Bu NHThiz (2) 625 4-OH 3-Me 5-Me Bu NHThiz (4) 626 4-OH 3-Me 5-Me Bu NHThiz (5) 627 4-OH 3-Me 5- Me Bu NHOxa (2) 628 4-OH 3-Me 5-Me Bu NHOxa (4) 629 4-OH 3-Me 5-Me Bu NHOxa (5) 630 4-OH 3-Me 5-Me Bu CN 631 4 -OH 3-Me 5-Me Bu OH 632 4-OH 3-Me 5-Me Bu CH = NOH 633 4-OH 3-Me 5-Me Bu COOH 634 4-OH 3-Me 5-Me Bu CONH ₂ 635 4-OH 3-Me 5-Me Bu CONHMe 636 4-OH 3-Me 5-Me Bu CONHEt 637 4-OH 3-Me 5-Me Bu CON (Me) ₂ 638 4-OH 3-Me 5-Me Bu CON (Me) Et 639 4-OH 3-Me 5-Me Bu CON (Et) ₂ 640 4-OH 3-Me 5-Me Bu NHByr 641 4-OH 3-Me 5-Me Bu NHPiv 642 4-OH 3-Me 5-Me Bu ⁱ Piz (1) 643 4-OH 3-Me 5-Me Bu ⁱ Mor (4) 644 4-OH 3-Me 5-Me Bu ⁱ Tmor (4) 645 4-OH 3-Me 5-Me Bu ⁱ Imid (2) 646 4-OH 3-Me 5-Me Bu ⁱ Thiz (2) 647 4-OH 3- Me 5-Me Bu ⁱ Thiz (4) 648 4-OH 3-Me 5-Me Bu ⁱ Thiz (5) 649 4-OH 3-Me 5-Me Bu ⁱ Oxa (2) 650 4-OH 3-Me 5 -Me Bu ⁱ Oxa (4) 651 4-OH 3-Me 5-Me Bu ⁱ Oxa (5) 652 4-OH 3-Me 5-Me Bu ⁱ NHImid (2) 653 4-OH 3-Me 5-Me Bu ⁱ NHThiz (2) 654 4-OH 3-Me 5-Me Bu ⁱ NHThiz (4) 655 4-OH 3-Me 5-Me Bu ⁱ NHThiz (5) 656 4-OH 3-Me 5-Me Bu ⁱ NHOxa (2) 657 4-OH 3-Me 5-Me Bu ⁱ NHOxa (4) 658 4-OH 3-Me 5-Me Bu ⁱ NHOxa (5) 659 4-OH 3-Me 5-Me Bu ⁱ CN 660 4-OH 3-Me 5-Me Bu ⁱ OH 661 4-OH 3-Me 5-Me Bu ⁱ CH = NOH 662 4-OH 3-Me 5-Me Bu ⁱ COOH 663 4-OH 3-Me 5-Me Bu ⁱ CONH ₂ 664 4-OH 3-Me 5-Me Bu ⁱ CONHMe 665 4-OH 3-Me 5-Me Bu ⁱ CONHEt 666 4-OH 3-Me 5-Me Bu ⁱ CON (Me) ₂ 667 4- OH 3-Me 5-Me Bu ⁱ CON (Me) Et 668 4-OH 3-Me 5-Me Bu ⁱ CON (Et) ₂ 669 4-OH 3-Me 5-Me Bu ⁱ NHByr 670 4-OH 3- Me 5-Me Bu ⁱ NHPiv 671 4-OH 3-Me 5-Me Pn Piz (1) 672 4-OH 3-Me 5 -Me Pn CH ₂ Piz (1) 673 4-OH 3-Me 5-Me Pn Mor (4) 674 4-OH 3-Me 5-Me Pn CH ₂ Mor (4) 675 4-OH 3-Me 5- Me Pn Tmor (4) 676 4-OH 3-Me 5-Me Pn CH ₂ Tmor (4) 677 4-OH 3-Me 5-Me Pn Imid (2) 678 4-OH 3-Me 5-Me Pn CH ₂ Imid (2) 679 4-OH 3-Me 5-Me Pn Thiz (2) 680 4-OH 3-Me 5-Me Pn Thiz (4) 681 4-OH 3-Me 5-Me Pn Thiz (5) 682 4-OH 3-Me 5-Me Pn CH ₂ Thiz (2) 683 4-OH 3-Me 5-Me Pn CH ₂ Thiz (4) 684 4-OH 3-Me 5-Me Pn CH ₂ Thiz (5) ) 685 4-OH 3-Me 5-Me Pn Oxa (2) 686 4-OH 3-Me 5-Me Pn Oxa (4) 687 4-OH 3-Me 5-Me Pn Oxa (5) 688 4-OH 3-Me 5-Me Pn CH ₂ Oxa (2) 689 4-OH 3-Me 5-Me Pn CH ₂ Oxa (4) 690 4-OH 3-Me 5-Me Pn CH ₂ Oxa (5) 691 4- OH 3-Me 5-Me Pn NHImid (2) 692 4-OH 3-Me 5-Me Pn CH ₂ NHImid (2) 693 4-OH 3-Me 5-Me Pn NHThiz (2) 694 4-OH 3- Me 5-Me Pn NHThiz (4) 695 4-OH 3-Me 5-Me Pn NHThiz (5) 696 4-OH 3-Me 5-Me Pn CH ₂ NHThiz (2) 697 4-OH 3-Me 5- Me Pn CH ₂ NHThiz (4) 698 4-OH 3-Me 5-Me Pn CH ₂ NHThiz (5) 699 4-OH 3-Me 5-Me Pn NHOxa (2) 700 4-OH 3-Me 5-Me Pn NHOxa (4) 701 4-OH 3-Me 5-Me Pn NHOxa (5) 702 4-OH 3-Me 5-Me Pn CH ₂ NHOxa (2) 703 4-OH 3-Me 5-Me Pn CH ₂ NHOxa (4) 704 4-OH 3-Me 5-Me Pn CH ₂ NHOxa (5) 705 4-OH 3-Me 5-Me Pn CN 706 4-OH 3-Me 5-Me Pn CH ₂ CN 707 4-OH 3-Me 5-Me Pn OH 708 4-OH 3-Me 5-Me Pn CH ₂ OH 709 4-OH 3-Me 5-Me Pn CH = NOH 710 4-OH 3-Me 5-Me Pn CH ₂ CH = NOH 711 4-OH 3-Me 5-Me Pn COOH 712 4-OH 3-Me 5-Me Pn CH ₂ COOH 713 4-OH 3-Me 5 -Me Pn CONH ₂ 714 4-OH 3-Me 5-Me Pn CH ₂ CONH ₂ 715 4-OH 3-Me 5-Me Pn CONHMe 716 4-OH 3-Me 5-Me Pn CH ₂ CONHMe 717 4-OH 3-Me 5-Me Pn CONHEt 718 4-OH 3-Me 5-Me Pn CH ₂ CONHEt 719 4-OH 3-Me 5-Me Pn CON (Me) ₂ 720 4-OH 3-Me 5-Me Pn CH ₂ CON (Me) ₂ 721 4-OH 3-Me 5-Me Pn CON (Me) Et 722 4-OH 3-Me 5-Me Pn CH ₂ CON (Me) Et 723 4-OH 3-Me 5-Me Pn CON (Et) ₂ 724 4-OH 3-Me 5-Me Pn CH ₂ CON (Et) ₂ 725 4-OH 3-Me 5-Me Pn NHByr 726 4-OH 3-Me 5-Me Pn CH ₂ NHByr 727 4-OH 3-Me 5-Me Pn NHPiv 728 4-OH 3-Me 5-Me Pn CH ₂ NHPiv 729 4-OH 3-Et 5-Me Pn Piz (1) 730 4-OH 3-Et 5- Me Pn CH ₂ Piz (1) 731 4-OH 3-Et 5-Me Pn Mor (4) 732 4-OH 3-Et 5-Me Pn CH ₂ Mor (4) 733 4-OH 3-Et 5-Me Pn Tmor (4) 734 4-OH 3-Et 5-Me Pn CH ₂ Tmor (4) 735 4-OH 3-Et 5-Me Pn Imid (2) 736 4-OH 3-Et 5-Me Pn CH ₂ Imid (2) 737 4-OH 3-Et 5-Me Pn Thiz (2) 738 4-OH 3-Et 5-Me Pn Thiz (4) 739 4-OH 3-Et 5-Me Pn Thiz (5) 740 4-OH 3-Et 5-Me Pn CH ₂ Thiz (2) 741 4-OH 3-Et 5-Me Pn CH ₂ Thiz (4) 742 4-OH 3-Et 5-Me Pn CH ₂ Thiz (5) 743 4-OH 3-Et 5-Me Pn Oxa (2) 744 4-OH 3-Et 5-Me Pn Oxa (4) 745 4-OH 3-Et 5-Me Pn Oxa (5) 746 4-OH 3-Et 5-Me Pn CH ₂ Oxa (2) 747 4-OH 3-Et 5-Me Pn CH ₂ Oxa (4) 748 4-OH 3-Et 5-Me Pn CH ₂ Oxa (5) 749 4-OH 3-Et 5-Me Pn NHImid (2) 750 4-OH 3 -Et 5-Me Pn CH ₂ NHImid (2) 751 4-OH 3-Et 5-Me Pn NHThiz (2) 752 4-OH 3-Et 5-Me Pn NHThiz (4) 753 4-OH 3-Et 5 -Me Pn NHThiz (5) 754 4-OH 3-Et 5-Me Pn CH ₂ NHThiz (2) 755 4-OH 3-Et 5-Me Pn CH ₂ NHThiz (4) 756 4-OH 3-Et 5- Me Pn CH ₂ NHThiz (5) 757 4-OH 3-Et 5-Me Pn NHOxa (2) 758 4-OH 3-Et 5-Me Pn NHOxa (4) 759 4-OH 3-Et 5-Me Pn NHOxa (5) 760 4-OH 3-Et 5-Me Pn CH ₂ NHOxa (2) 761 4-OH 3-Et 5-Me Pn CH ₂ NHOxa (4) 762 4-OH 3-Et 5-Me Pn CH ₂ NHOxa (5) 763 4-OH 3-Et 5-Me Pn CN 764 4-OH 3-Et 5-Me Pn CH ₂ CN 765 4 -OH 3-Et 5-Me Pn OH 766 4-OH 3-Et 5-Me Pn CH ₂ OH 767 4-OH 3-Et 5-Me Pn CH = NOH 768 4-OH 3-Et 5-Me Pn CH ₂ CH = NOH 769 4-OH 3-Et 5-Me Pn COOH 770 4-OH 3-Et 5-Me Pn CH ₂ COOH 771 4-OH 3-Et 5-Me Pn CONH ₂ 772 4-OH 3-Et 5-Me Pn CH ₂ CONH ₂ 773 4-OH 3-Et 5-Me Pn CONHMe 774 4-OH 3-Et 5-Me Pn CH ₂ CONHMe 775 4-OH 3-Et 5-Me Pn CONHEt 776 4-OH 3-Et 5-Me Pn CH ₂ CONHEt 777 4-OH 3-Et 5-Me Pn CON (Me) ₂ 778 4-OH 3-Et 5-Me Pn CH ₂ CON (Me) ₂ 779 4-OH 3- Et 5-Me Pn CON (Me) Et 780 4-OH 3-Et 5-Me Pn CH ₂ CON (Me) Et 781 4-OH 3-Et 5-Me Pn CON (Et) ₂ 782 4-OH 3- Et 5-Me Pn CH ₂ CON (Et) ₂ 783 4-OH 3-Et 5-Me Pn NHByr 784 4-OH 3-Et 5-Me Pn CH ₂ NHByr 785 4-OH 3-Et 5-Me Pn NHPiv 786 4-OH 3-Et 5-Me Pn CH ₂ NHPiv 787 4-OH 3-Me 5-Et Pn Piz (1) 788 4-OH 3-Me 5-Et Pn CH ₂ Piz (1) 789 4-OH 3-Me 5-Et Pn Mor (4) 790 4-OH 3-Me 5-Et Pn CH ₂ Mor (4) 791 4-OH 3-Me 5-Et Pn Tmor (4) 792 4-OH 3-Me 5-Et Pn CH ₂ Tmor (4) 793 4-OH 3-Me 5-Et Pn Imid (2) 794 4-OH 3-Me 5-Et Pn CH ₂ Imid (2) 795 4-OH 3-Me 5 -Et Pn Thiz (2) 796 4-OH 3-Me 5-Et Pn Th iz (4) 797 4-OH 3-Me 5-Et Pn Thiz (5) 798 4-OH 3-Me 5-Et Pn CH ₂ Thiz (2) 799 4-OH 3-Me 5-Et Pn CH ₂ Thiz (4) 800 4-OH 3-Me 5-Et Pn CH ₂ Thiz (5) 801 4-OH 3-Me 5-Et Pn Oxa (2) 802 4-OH 3-Me 5-Et Pn Oxa (4) 803 4-OH 3-Me 5-Et Pn Oxa (5) 804 4-OH 3-Me 5-Et Pn CH ₂ Oxa (2) 805 4-OH 3-Me 5-Et Pn CH ₂ Oxa (4) 806 4-OH 3-Me 5-Et Pn CH ₂ Oxa (5) 807 4-OH 3-Me 5-Et Pn NHImid (2) 808 4-OH 3-Me 5-Et Pn CH ₂ NHImid (2) 809 4 -OH 3-Me 5-Et Pn NHThiz (2) 810 4-OH 3-Me 5-Et Pn NHThiz (4) 811 4-OH 3-Me 5-Et Pn NHThiz (5) 812 4-OH 3-Me 5-Et Pn CH ₂ NHThiz (2) 813 4-OH 3-Me 5-Et Pn CH ₂ NHThiz (4) 814 4-OH 3-Me 5-Et Pn CH ₂ NHThiz (5) 815 4-OH 3- Me 5-Et Pn NHOxa (2) 816 4-OH 3-Me 5-Et Pn NHOxa (4) 817 4-OH 3-Me 5-Et Pn NHOxa (5) 818 4-OH 3-Me 5-Et Pn CH ₂ NHOxa (2) 819 4-OH 3-Me 5-Et Pn CH ₂ NHOxa (4) 820 4-OH 3-Me 5-Et Pn CH ₂ NHOxa (5) 821 4-OH 3-Me 5-Et Pn CN 822 4-OH 3-Me 5-Et Pn CH ₂ CN 823 4-OH 3-Me 5-Et Pn OH 824 4-OH 3-Me 5-Et Pn CH ₂ OH 825 4-OH 3-Me 5 -Et Pn CH = NOH 826 4-OH 3-Me 5-Et Pn CH ₂ CH = NOH 827 4-OH 3-Me 5-Et P n COOH 828 4-OH 3-Me 5-Et Pn CH ₂ COOH 829 4-OH 3-Me 5-Et Pn CONH ₂ 830 4-OH 3-Me 5-Et Pn CH ₂ CONH ₂ 831 4-OH 3- Me 5-Et Pn CONHMe 832 4-OH 3-Me 5-Et Pn CH ₂ CONHMe 833 4-OH 3-Me 5-Et Pn CONHEt 834 4-OH 3-Me 5-Et Pn CH ₂ CONHEt 835 4-OH 3-Me 5-Et Pn CON (Me) ₂ 836 4-OH 3-Me 5-Et Pn CH ₂ CON (Me) ₂ 837 4-OH 3-Me 5-Et Pn CON (Me) Et 838 4-OH 3-Me 5-Et Pn CH ₂ CON (Me) Et 839 4-OH 3-Me 5-Et Pn CON (Et) ₂ 840 4-OH 3-Me 5-Et Pn CH ₂ CON (Et) ₂ 841 4 -OH 3-Me 5-Et Pn NHByr 842 4-OH 3-Me 5-Et Pn CH ₂ NHByr 843 4-OH 3-Me 5-Et Pn NHPiv 844 4-OH 3-Me 5-Et Pn CH ₂ NHPiv 845 4-OH 3-Et 5-Et Pn Piz (1) 846 4-OH 3-Et 5-Et Pn CH ₂ Piz (1) 847 4-OH 3-Et 5-Et Pn Mor (4) 848 4- OH 3-Et 5-Et Pn CH ₂ Mor (4) 849 4-OH 3-Et 5-Et Pn Tmor (4) 850 4-OH 3-Et 5-Et Pn CH ₂ Tmor (4) 851 4-OH 3-Et 5-Et Pn Imid (2) 852 4-OH 3-Et 5-Et Pn CH ₂ Imid (2) 853 4-OH 3-Et 5-Et Pn Thiz (2) 854 4-OH 3-Et 5-Et Pn Thiz (4) 855 4-OH 3-Et 5-Et Pn Thiz (5) 856 4-OH 3-Et 5-Et Pn CH ₂ Thiz (2) 857 4-OH 3-Et 5-Et Pn CH ₂ Thiz (4) 858 4-OH 3-Et 5-Et Pn CH ₂ Thiz (5) 859 4-OH 3-Et 5-Et Pn Oxa (2) 860 4-OH 3-Et 5-Et Pn Oxa (4) 861 4-OH 3-Et 5-Et Pn Oxa (5) 862 4-OH 3-Et 5-Et Pn CH ₂ Oxa (2) 863 4-OH 3-Et 5-Et Pn CH ₂ Oxa (4) 864 4-OH 3-Et 5-Et Pn CH ₂ Oxa (5) 865 4-OH 3-Et 5-Et Pn NHImid (2) 866 4-OH 3-Et 5-Et Pn CH ₂ NHImid (2) 867 4-OH 3-Et 5-Et Pn NHThiz (2) 868 4- OH 3-Et 5-Et Pn NHThiz (4) 869 4-OH 3-Et 5-Et Pn NHThiz (5) 870 4-OH 3-Et 5-Et Pn CH ₂ NHThiz (2) 871 4-OH 3- Et 5-Et Pn CH ₂ NHThiz (4) 872 4-OH 3-Et 5-Et Pn CH ₂ NHThiz (5) 873 4-OH 3-Et 5-Et Pn NHOxa (2) 874 4-OH 3-Et 5-Et Pn NHOxa (4) 875 4-OH 3-Et 5-Et Pn NHOxa (5) 876 4-OH 3-Et 5-Et Pn CH ₂ NHOxa (2) 877 4-OH 3-Et 5-Et Pn CH ₂ NHOxa (4) 878 4-OH 3-Et 5-Et Pn CH ₂ NHOxa (5) 879 4-OH 3-Et 5-Et Pn CN 880 4-OH 3-Et 5-Et Pn CH ₂ CN 881 4-OH 3-Et 5-Et Pn OH 882 4-OH 3-Et 5-Et Pn CH ₂ OH 883 4-OH 3-Et 5-Et Pn CH = NOH 884 4-OH 3-Et 5-Et Pn CH ₂ CH = NOH 885 4-OH 3-Et 5-Et Pn COOH 886 4-OH 3-Et 5-Et Pn CH ₂ COOH 887 4-OH 3-Et 5-Et Pn CONH ₂ 888 4-OH 3 -Et 5-Et Pn CH ₂ CONH ₂ 889 4-OH 3-Et 5-Et Pn CONHMe 89 0 4-OH 3-Et 5-Et Pn CH ₂ CONHMe 891 4-OH 3-Et 5-Et Pn CONHEt 892 4-OH 3-Et 5-Et Pn CH ₂ CONHEt 893 4-OH 3-Et 5-Et Pn CON (Me) ₂ 894 4-OH 3-Et 5-Et Pn CH ₂ CON (Me) ₂ 895 4-OH 3-Et 5-Et Pn CON (Me) Et 896 4-OH 3-Et 5-Et Pn CH ₂ CON (Me) Et 897 4-OH 3-Et 5-Et Pn CON (Et) ₂ 898 4-OH 3-Et 5-Et Pn CH ₂ CON (Et) ₂ 899 4-OH 3-Et 5 -Et Pn NHByr 900 4-OH 3-Et 5-Et Pn CH ₂ NHByr 901 4-OH 3-Et 5-Et Pn NHPiv 902 4-OH 3-Et 5-Et Pn CH ₂ NHPiv 903 4-OH 3- Me 5-Me Hx Piz (1) 904 4-OH 3-Me 5-Me Hx Mor (4) 905 4-OH 3-Me 5-Me Hx Tmor (4) 906 4-OH 3-Me 5-Me Hx Imid (2) 907 4-OH 3-Me 5-Me Hx Thiz (2) 908 4-OH 3-Me 5-Me Hx Thiz (4) 909 4-OH 3-Me 5-Me Hx Thiz (5) 910 4-OH 3-Me 5-Me Hx Oxa (2) 911 4-OH 3-Me 5-Me Hx Oxa (4) 912 4-OH 3-Me 5-Me Hx Oxa (5) 913 4-OH 3- Me 5-Me Hx NHImid (2) 914 4-OH 3-Me 5-Me Hx NHThiz (2) 915 4-OH 3-Me 5-Me Hx NHThiz (4) 916 4-OH 3-Me 5-Me Hx NHThiz (5) 917 4-OH 3-Me 5-Me Hx NHOxa (2) 918 4-OH 3-Me 5-Me Hx NHOxa (4) 919 4-OH 3-Me 5-Me Hx NHOxa (5) 920 4-OH 3-Me 5-Me Hx CN 921 4-OH 3-Me 5-Me Hx OH 922 4-OH 3 -Me 5-Me Hx CH = NOH 923 4-OH 3-Me 5-Me Hx COOH 924 4-OH 3-Me 5-Me Hx CONH ₂ 925 4-OH 3-Me 5-Me Hx CONHMe 926 4-OH 3-Me 5-Me Hx CONHEt 927 4-OH 3-Me 5-Me Hx CON (Me) ₂ 928 4-OH 3-Me 5-Me Hx CON (Me) Et 929 4-OH 3-Me 5-Me Hx CON (Et) ₂ 930 4-OH 3-Me 5-Me Hx NHByr 931 4-OH 3-Me 5-Me Hx NHPiv 932 4-OH 5-Me 6-Me Pn Mor (4) 933 4-OH 5 -Me 6-Me Pn Oxa (2) 934 4-OH 5-Me 6-Me Pn Oxa (4) 935 4-OH 5-Me 6-Me Pn Oxa (5) 936 4-OH 5-Me 6-Me Pn NHThiz (2) 937 4-OH 5-Me 6-Me Pn NHThiz (4) 938 4-OH 5-Me 6-Me Pn NHThiz (5) 939 4-OH 5-Me 6-Me Pn CONH ₂ 940 4 -OH 5-Me 6-Me Pn CONHMe 941 4-OH 5-Me 6-Me Pn CON (Me) ₂ ────────────────────────好 適 Suitable compounds in the phenol derivative having the general formula (I) of the present invention include, for example, Exemplified Compound Nos. 60, 61 and 6
4, 69, 72, 73, 74, 75, 83, 92, 9
3, 97, 105, 108, 111, 115, 123,
152, 311, 317, 327, 331, 332, 3
33, 334, 336, 341, 342, 346, 35
6, 360, 620, 627, 630, 634, 63
7,649,659,663,664,666,67
3, 674, 675, 676, 677, 678, 67
9,680,681,682,683,684,68
5, 686, 687, 688, 689, 690, 69
1, 692, 693, 694, 695, 696, 69
7, 698, 699, 700, 701, 702, 70
3, 704, 705, 706, 707, 708, 70
9, 710, 711, 712, 713, 714, 71
5, 716, 717, 718, 719, 720, 72
1, 722, 723, 724, 763, 790, 80
1, 804, 910 or 920.

Further preferred compounds include Exemplified Compound Nos. 60, 61, 69, 72, 83, 92, 97, 10
5, 111, 115, 673, 674, 675, 67
6, 677, 678, 679, 680, 681, 68
2,683,684,685,686,687,68
8,689,690,691,692,693,69
4, 695, 696, 697, 698, 699, 70
0, 701, 702, 703, 704, 705, 70
6, 709, 710, 713, 714, 715, 71
6, 717, 718, 719, 720 or 723.

A particularly preferred compound is exemplified compound No. 61: 3- (2-hydroxy-3-
Methylphenyl) octanoic acid (2-t-butyl-5-morpholin-4-ylmethylphenyl) amide, Exemplified Compound No. 72: 3- (2-hydroxy-3-
Methylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide, Exemplified Compound No. 83: 3- (2-hydroxy-3-
[Methylphenyl) octanoic acid [2-t-butyl-5-
(Thiazol-2-ylaminomethyl) phenyl] amide, Exemplified Compound No. 97: 4-t-butyl-3- [3-
(2-hydroxy-3-methylphenyl) octanoylamino] benzamide, Exemplified Compound No. 105: 3- (2-hydroxy-3
[2-methylphenyl) octanoic acid [2-t-butyl-5-
(2-Dimethylcarbamoylethyl) phenyl] amide, Exemplified Compound No. 111: 3- (2-hydroxy-
3-methylphenyl) octanoic acid [5- (acetylaminomethyl) -2-t-butylphenyl] amide, Exemplified Compound No. 115: 3- (2-hydroxy-3)
[2-methylphenyl) octanoic acid [2-t-butyl-5-
(2,2-dimethylpropionylaminomethyl) phenyl] amide, Exemplified Compound No. 674: 3- (4-hydroxy-
3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-morpholin-4-ylmethylphenyl) amide, Exemplified Compound No. 679: 3- (4-hydroxy-
3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-thiazol-2-ylphenyl) amide, Exemplified Compound No. 682: 3- (4-hydroxy-
3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-thiazol-2-ylmethylphenyl) amide, Exemplified Compound No. 685: 3- (4-hydroxy-
3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide, Exemplified Compound No. 705: 3- (4-hydroxy-
3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-cyanophenyl) amide, Exemplified Compound No. 709: 3- (4-hydroxy-
3,5-dimethylphenyl) octanoic acid [2-t-butyl-5- (hydroxyiminomethyl) phenyl] amide, Exemplified Compound No. 713: 4-t-butyl-3- [3
-(4-hydroxy-3,5-dimethylphenyl) octanoylamino] benzamide, Exemplified Compound No. 714: 3- (4-hydroxy-
3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-carbamoylmethylphenyl) amide, Exemplified Compound No. 715: 4-t-butyl-3- [3
-(4-hydroxy-3,5-dimethylphenyl) octanoylamino] -N-methylbenzamide, or Exemplified Compound No. 719: 4-t-butyl-3- [3
-(4-hydroxy-3,5-dimethylphenyl) octanoylamino] -N, N-dimethylbenzamide.

[0034]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention is easily produced according to the following method.

[0035]

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[0036]

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In the above formula, R ^1a , R ^1b , R ^1c , R ² , R ³
And A have the same meanings as described above; R ⁴ represents a hydroxyl-protecting group; R ⁵ represents a C ₁ -C ₆ alkyl group;
u ^t represents a tertiary butyl group.

The “hydroxyl-protecting group” of R ⁴ can be generally used without any particular limitation as long as it is a group used as a hydroxyl-protecting group. For example, Protective Groups in Organic Synthesis , 2nd edition,
T. W. Green and P. G. FIG. M. Watts, John Wiley and Sons, Inc. [ProtectiveGr
oups in Organic Synthesis, 2nd edition, TWGreene
&PGMWuts; John Wiley & Sons, Inc.], and is preferably a methyl group (Me), a methoxymethyl group (MOM), a 2-methoxyethoxymethyl group (MEM), or a benzyloxymethyl group. (BOM), a benzyl group (Bn) or an acetyl group (Ac), particularly preferably a methyl group.

The "C ₁ -C ₆ alkyl group" for R ⁵ represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. Group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2
-Methylpentyl group, 1-methylpentyl group, 3,3-
Dimethylbutyl group, 2,2-dimethylbutyl group, 1,1
-Dimethylbutyl group, 1,2-dimethylbutyl group, 1,
It may be a 3-dimethylbutyl group, a 2,3-dimethylbutyl group or a 2-ethylbutyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably Is a methyl group.

Method A is a method for producing compound (I).

Step A1 (Deprotection) This step is a step of producing a compound (I) by removing the hydroxyl-protecting group (R ⁴ ) of the compound having the general formula (II).

For the removal of the protecting group, see Protective Groups in Organic Synthesis, Vol.
Edition, T. W. Green and P. G. FIG. M. Watts,
John Wiley and Sons, Inc. [Protecti
ve Groups in Organic Synthesis, 2nd edition, TWG
reene &PGMWuts; John Wiley & Sons, Inc.], for example, when R ⁴ is a methyl group, the compound (II) is converted to (1) triodor in an inert solvent. Compound (I) can be produced by reacting with boron iodide or (2) reacting with trimethylsilane iodide in an inert solvent. A1
The solvent used in the step (1) is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether. Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Or ethers such as diethylene glycol dimethyl ether; nitriles such as acetonitrile; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphorous triamide Amides such as bromide (HMPT); or to give a dimethyl sulfoxide or sulfoxides such as sulfolane, preferably a halogenated hydrocarbon (particularly dichloromethane). The reaction temperature in the step A1 (1) varies depending on the starting compound, the reagent, and the like.
It is usually -100 ° C to 50 ° C, preferably -78 ° C to 30 ° C. The reaction time of the step A1 (1) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 10 minutes to 12 hours, preferably 30 minutes to 3 hours. After completion of the reaction, the target compound of Step A1 (1) is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, an alcohol or the like (preferably methanol) is added to the reaction solution to decompose excess reagent, and after distilling off the solvent, water is poured into the reaction solution, and a water-immiscible solvent (for example, benzene or ether) is added. , Ethyl acetate, etc.), and after extraction, the organic layer is washed with water and dried using anhydrous magnesium sulfate, etc.
The target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization,
It can be further purified by reprecipitation or chromatography.

The solvent used in step A1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, the same solvent as used in step A1 (1) can be used. And are preferably halogenated hydrocarbons (especially chloroform). The reaction temperature in the step A1 (2) varies depending on the starting compound, the reagent and the like, but it is usually −78.
C. to 50.degree. C., preferably 0.degree.
The reaction time of the step A1 (2) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 2 hours. After the reaction,
The target compound of Step A1 (2) is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, a small amount of water is added to the reaction solution to decompose the excess reagent, the solvent is distilled off, water is poured into the reaction solution, and a water-immiscible solvent (such as benzene, Ethyl acetate, etc.)
After the organic layer is washed with water, it is dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Method B is a method for separately producing a compound having the general formula (IIa), a compound having the general formula (Ic) and a compound having the general formula (Id), which are the starting compounds of the method A.

Step B1 (Reduction) This step is a step of reacting a compound having the general formula (III) with a reducing agent in an inert solvent to produce a compound (IIa). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Or an aromatic hydrocarbon such as xylene; a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol. It can be an ether such as dimethyl ether, preferably an aromatic hydrocarbon (particularly toluene). The reducing agent used is, for example, an alkali metal borohydride such as lithium borohydride, an aluminum hydride compound such as lithium aluminum hydride or lithium triethoxide aluminum or diisobutylaluminum hydride. Such organoaluminum hydrides can be used, preferably diisobutylaluminum hydride. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -100 ° C to 50 ° C, preferably from -78 ° C to 30 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 10 minutes to 12 hours, preferably 30 minutes to 3 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, an alcohol or the like (preferably methanol) is added to the reaction solution to decompose excess reagent, and then the reaction solution is mixed with a saturated saline solution or a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.). And a desiccant (anhydrous magnesium sulfate or the like), and after filtration, the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step B2 (Oxidation) This step is a step of reacting compound (IIa) with an oxidizing agent in an inert solvent to produce a compound having the general formula (IV). The solvent used is not particularly limited as long as it does not inhibit the reaction and has some starting materials.
For example, aromatic hydrocarbons, such as benzene, toluene, or xylene; halogenated hydrocarbons, such as dichloromethane, chloroform, or dichloroethane; esters, such as ethyl acetate; Ethers; ketones such as acetone or methyl ethyl ketone; or nitriles such as acetonitrile or isobutyronitrile, preferably halogenated hydrocarbons (especially dichloromethane or chloroform). The oxidizing agent used is, for example, manganese oxides such as manganese dioxide; chromic acid compounds such as chromic anhydride-pyridine complex; reagents (dimethylsulfoxide and dicyclohexylcarbodiimide,
Oxalyl chloride, complexes with acetic anhydride or pentoxide or complexes with pyridine-sulfuric anhydride); 4-methylmorpholine using as catalyst a periodate oxide such as Dess-Martin reagent or tetrapropylammonium perruthenate. It can be a 4-oxide, preferably manganese oxides, especially manganese dioxide. The reaction temperature varies depending on the solvent, the raw material, the reagent, and the like, but is usually from -50 ° C to 100 ° C.
° C, preferably 0 ° C to 50 ° C. The reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature and the like, but is usually 1 hour to 24 hours, preferably 2 hours to 5 hours.
Time. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, when a catalyst is used, the catalyst is filtered off as appropriate, the solvent is distilled off, water is added to the reaction solution, and a water-immiscible solvent (for example, benzene, ether or ethyl acetate, etc.) is added. After extraction, the organic layer containing the target compound is washed with water, dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step B3 (Deprotection) This step is a step for producing a compound having the general formula (V) by removing the hydroxyl-protecting group (R ⁴ ) of the compound (IV). It can be performed under the same conditions as in the step.

Step B4 (Oximation) This step is carried out by reacting compound (V) with hydroxylamine or hydroxylamine hydrochloride in an inert solvent in the presence or absence (preferably in the presence) of a base. This is a step of producing compound (Ic). The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene or Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers; esters such as ethyl acetate or propyl acetate; nitriles such as acetonitrile; ketones such as acetone or methyl ethyl ketone; methanol, ethanol, propanol, iso- Alcohols such as lopanol, butanol or isobutanol; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphorous triamide (HMPT); sulfoxides such as dimethylsulfoxide or sulfolane Alcohols (especially methanol or ethanol)
It is. The base used is, for example, sodium carbonate,
Alkali metal carbonates such as potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; alkali metal acetates such as sodium acetate; lithium hydride, sodium hydride Or alkali metal hydrides such as potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide Alkali metal alkoxides such as sodium mercaptan or ethyl mercaptan sodium; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridyl , 4- (N, N- dimethylamino)
Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2]
Organic amines such as octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; lithium diisopropylamide Or, lithium alkylamides such as lithium dicyclohexylamide can be mentioned, and preferred are alkali metal acetates (particularly sodium acetate) or organic amines (particularly triethylamine). The reaction temperature varies depending on the starting compounds, reagents, etc.,
Usually, it is -50 ° C to 100 ° C, preferably -20 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours. After the reaction,
The target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, water is added to the obtained residue, and a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is extracted. Is washed with water, dried using anhydrous magnesium sulfate or the like, and 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 chromatography.

Step B5 (Dehydration) This step is a step of reacting compound (Ic) with a dehydrating agent in an inert solvent to produce compound (Id). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether. Such ethers; methanol, ethanol, propanol, isopropano-
Alcohols such as toluene, butanol or isobutanol; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphorous triamide (HMPT); or dimethylsulfoxide or sulfolane And preferably halogenated hydrocarbons (especially dichloromethane) or ethers (especially diethyl ether or tetrahydrofuran).
It is. The dehydrating agent to be used is not particularly limited as long as it is usually used for a dehydration reaction. For example, phosphorus halides such as phosphorus pentachloride, imidazoles such as carbonyldiimidazole (CDI) or It can be a dicycloalkylcarbodiimide such as dicyclohexylcarbodiimide (DCC), preferably carbonyldiimidazole. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -10 ° C to 100 ° C,
Preferably it is 0 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 5 days, preferably 12 hours to 3 days. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method in the same manner as in Step B4.

Starting compounds (VI), (IX) and (XI
I), (XV), (XVIII), (XIX), (XX
I), (XXII) and (XXIII) are known or are easily prepared according to known methods or methods analogous thereto.

The starting compounds (II) and (III) are known or are easily produced according to known methods or methods similar thereto. [For example, Japanese Patent Application Laid-Open No. 9-1431
No. 37 (EP07635524) and the like].

The starting compounds (II) and (III)
Is also produced by the following method.

[0053]

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[0054]

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[0055]

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[0056]

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[0057]

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[0058]

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[0059]

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In the above formula, R ^1a , R ^1b , R ^1c , R ² , R
^3, A, R ^4, R ⁵ and Bu ^t represents the same meaning as described above, R ^3a is nitrogen, 5-membered to contain 1 or 2 hetero atoms selected from the group consisting of oxygen and sulfur atoms 6 5- or 6-membered cyclic heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of a membered cyclic saturated heterocyclyl group, nitrogen, oxygen and sulfur atom, selected from the group consisting of nitrogen, oxygen and sulfur atoms A 5- or 6-membered cyclic heteroarylamino group containing 1 or 2 heteroatoms,
^3b is a 5- or 6-membered cyclic heteroaryl group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, R ^4a is a methyl group, R ⁶ is a hydrogen atom or C It indicates ₁ -C ₆ alkyl group, R ⁷ is C ₁ -C ₆
A represents an alkanoyl group, A ^a represents a C ₁ -C ₄ alkylene group, and X represents a halogen atom. R ^{3a represents} one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms.
5- or 6-membered cyclic saturated heterocyclyl group containing 1 to 2 "
Can be, for example, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolidinyl group or a pyrazolidinyl group, preferably a piperazinyl group, a morpholinyl group or a thiomorpholinyl group, and particularly preferably a 4-morpholinyl group. It is.

The “5- to 6-membered cyclic heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms” for R ^3a and R ^3b is, for example, a furyl group, a thienyl group. A, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group or pyridazinyl group, preferably imidazolyl group, thiazolyl group or oxazolyl group. And particularly preferably a 2-oxazolyl group.

The “5- or 6-membered cyclic heteroarylamino group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms” of R ^3a is, for example, a furylamino group, a thienylamino group. , Pyrrolylamino group, imidazolylamino group, pyrazolylamino group, thiazolylamino group, isothiazolylamino group, oxazolylamino group, isoxazolylamino group, pyridylamino group, pyrazinylamino group, pyrimidinylamino group or pyridazinylamino group And is preferably an imidazolylamino group, a thiazolylamino group or an oxazolylamino group, and particularly preferably a 2-thiazolylamino group.

The “C ₁ -C ₆ alkyl group” for R ⁶ represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. Group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2
-Methylpentyl group, 1-methylpentyl group, 3,3-
Dimethylbutyl group, 2,2-dimethylbutyl group, 1,1
-Dimethylbutyl group, 1,2-dimethylbutyl group, 1,
It may be a 3-dimethylbutyl group, a 2,3-dimethylbutyl group or a 2-ethylbutyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably Is a methyl group.

The “C ₁ -C ₆ alkanoyl group” for R ⁷ is
A linear or branched alkanoylamino group having 1 to 6 carbon atoms, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group,
It may be an isovaleryl group, a pivaloyl group or a hexanoyl group, preferably a C ₂ -C ₅ alkanoyl group, more preferably a butyryl group or a pivaloyl group, particularly preferably a pivaloyl group.

The “C ₁ -C ₄ alkylene group” of A ^a includes, for example, methylene group, methylmethylene group, dimethylmethylene group, ethylene group, propylene group, trimethylene group, tetramethylene group, 1-methyltrimethylene group, It may be a linear or branched alkylene group having 1 to 4 carbon atoms such as a 2-methyltrimethylene group or a 3-methyltrimethylene group, preferably a methylene group, an ethylene group or a trimethylene group. And more preferably a methylene group or an ethylene group, and particularly preferably a methylene group.

The "halogen atom" for X can be, for example, a fluorine, chlorine, bromine or iodine atom, preferably a chlorine or bromine atom.

In the method C, the compound (III) which is a starting compound of the method B and the compound represented by the general formula (II) which is a starting compound of the method A
This is a method for producing a compound having b) and a compound having general formula (IIc).

Step C1 (Protection) This step is a step for producing a compound having the general formula (VII) by protecting the hydroxyl group of the compound (VI).

Regarding the protection of the hydroxyl group, see Protective Groups in Organic Synthesis, Vol.
Edition, T. W. Green and P. G. FIG. M. Watts,
John Wiley and Sons, Inc. [Protecti
ve Groups in Organic Synthesis, 2nd edition, TWG
reene &PGMWuts; John Wiley & Sons, Inc.], for example, when R ⁴ is a methyl group, compound (VI) can be prepared by (1) the presence of a base in an inert solvent. The compound (VII) can be produced by reacting with methyl iodide below or (2) reacting with diazomethane in an inert solvent. The C1 (1)
The solvent used in the step is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, the solvent may be the same as that in Step B5. Formamide). The base used in Step C1 (1) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium ethoxide;
Alkali metal alkoxides such as potassium t-butoxide or lithium methoxide; mercaptan alkali metals such as sodium methyl mercaptan or sodium ethyl mercaptan; alkyl lithiums such as methyl lithium, ethyl lithium or butyl lithium; lithium diisopropylamide or It can be a lithium alkylamide, such as lithium dicyclohexylamide, preferably an alkali metal hydride, especially sodium hydroxide. The reaction temperature of the step C1 (1) varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. No. C
The reaction time of step 1 (1) varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 12 hours, preferably 10 minutes to 3 hours. After completion of the reaction, C1
The target compound of step (1) is collected from the reaction mixture according to a conventional method, similarly to step B4.

The solvent used in the step C1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Ethers such as dimethoxyethane or diethylene glycol dimethyl ether or alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol, preferably ethers (particularly diethyl ether) ). No. C
The reaction temperature of step 1 (2) varies depending on the starting compounds, reagents and the like, but is usually -20 ° C to 50 ° C, preferably 0 ° C.
C. to 30.degree. The reaction time of step C1 (2) varies depending on the starting compound, the reagent and the reaction temperature.
Minutes to 5 hours, preferably 30 minutes to 2 hours. After completion of the reaction, the target compound of Step C1 (2) is
Similarly to the step B4, it is collected from the reaction mixture according to a conventional method.

Step C2 (Formylation) In this step, compound (VI) is prepared in an inert solvent in the presence of a base.
I) is reacted with 1-formylpiperidine to give a compound of the general formula (V)
This is a step of producing a compound having III). The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. is there. The base used is, for example,
It can be the same as the step C1 (1), and is preferably an alkyl lithium (particularly, butyl lithium). The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10.
It is 0 ° C to 50 ° C, preferably -78 ° C to 0 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes.
Minutes to 1 hour. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example,
After completion of the reaction, the excess reagent is decomposed with an aqueous saturated ammonium chloride solution and the like, and the solvent is distilled off. In addition, after extracting the target compound, the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and then the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step C3 (Protection) This step is a step of protecting the hydroxyl group of the compound having the general formula (IX), and can be performed under the same conditions as in Step C1. Step C4 (Formylation) In this step, compound (X) is reacted with 1-formylpiperidine in an inert solvent in the presence of a base to give compound (VII).
This is a step of separately producing I), and can be performed under the same conditions as in Step C2. Step C5 (Knoevenagel reaction) This step is a step of producing a compound having the general formula (XI) by reacting compound (VIII) with malonic acid diethyl ester in an inert solvent in the presence of a base and an acid catalyst. . The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.For example, it may be an aromatic hydrocarbon such as benzene, toluene or xylene, and is preferably used. It is benzene. The base to be used is not particularly limited as long as it is used as a base in a usual reaction, and may be, for example, a secondary amine, and is preferably pyrrolidine or piperidine.
The acid to be used is not particularly limited as long as it is used as an acid in a usual reaction. For example, carboxylic acids can be used, and benzoic acid or acetic acid is preferable. The reaction temperature varies depending on the solvent, the raw material, the reagent, and the like.
C. to 150.degree. C., preferably 70.degree. C. to 120.degree. The reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature and the like, but is usually 1 hour to 48 hours, preferably 5 hours to 30 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, a water-immiscible solvent (for example, ethyl acetate or the like) is added to the reaction mixture, and the mixture is washed with water (using diluted hydrochloric acid or a saturated aqueous solution of sodium hydrogen carbonate if desired). The target compound is obtained by drying using magnesium or the like and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step C6 (Grignard reaction) In this step, the compound (XI) is reacted with the compound (Grignard reagent) having the general formula (XII) in an inert solvent to give a compound having the general formula (XIII). This is the manufacturing process. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
For example, it may be the same as Step B5, and is preferably an ether (particularly tetrahydrofuran). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -20 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 30 minutes to 1 hour. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method in the same manner as in Step C2.

Step C7 (Hydrolysis, Decarboxylation) In this step, compound (XIII) is treated with (1) an inert solvent in an alkali metal hydroxide (preferably sodium hydroxide, potassium hydroxide or water). (2) a step of producing a compound having the general formula (XIV) by heating in an inert solvent. The solvent used in Step C7 (1) does not inhibit the reaction,
There is no particular limitation as long as it dissolves the starting material to some extent, but ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether;
Alcohols such as isopropanol, butanol or isobutanol; water or a mixed solvent of the above organic solvent and water, preferably alcohol or a mixed solvent of alcohol and water, particularly preferably Is a mixed solvent of ethanol and water. The reaction temperature of Step C7 (1) varies depending on the starting compound, the reagent, and the like, but is usually from -10 ° C to 100 ° C.
° C, preferably 30 ° C to 80 ° C. C7
The reaction time of the step (1) varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 12 hours, preferably 1 hour to 5 hours. After the reaction is completed, C7
The target compound of the step (1) is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, an aqueous solution of sodium hydroxide is added to the reaction solution, and the aqueous layer is washed with a water-immiscible solvent (for example, benzene, ether, ethyl acetate, etc.), and then the solution is concentrated with concentrated hydrochloric acid or the like. The pH of the aqueous layer is acidified, and water-immiscible solvents (eg, benzene, ether,
The target compound is extracted using ethyl acetate and the like, and the extract is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. The compound obtained in this step can be used in the next step without purification.

The solvent used in the step C7 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Hydrogens; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; methanol , Ethanol, propanol, isopropanol, butanol or alcohols such as isobutanol, preferably aromatic hydrocarbons (especially xylene). The reaction temperature in Step C7 (2) varies depending on the starting compound, the reagent, and the like, but is usually 30 ° C to 200 ° C.
° C, preferably 70 ° C to 150 ° C. C7
The reaction time of the step (2) varies depending on the starting compounds, reagents and reaction temperature, but is usually 30 minutes to 12 hours, preferably 1 hour to 5 hours. After the reaction is completed, C7
(2) The target compound of the step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the target compound is obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step C8 (Condensation) In this step, compound (XIV) is reacted with a compound having the general formula (XV) in an inert solvent to give compound (III)
Is a step of producing, the usual method in the peptide synthesis method,
For example, the reaction is carried out according to the active ester method, the mixed acid anhydride method or the condensation method (preferably the active ester method).

The active ester method is carried out by reacting a compound (XIV) with an active esterifying agent in an inert solvent to produce an active ester, and then reacting the compound with the compound (XV) in an inert solvent. The solvent used in both reactions is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Halogenated hydrocarbons such as; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitriles such as acetonitrile or isobutyronitrile; or formamide, dimethylformamide, It may be an amide such as dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphorustriamide (HMPT), preferably ethers (particularly tetrahydrofuran), nitrile It is a class (particularly acetonitrile) or an amide (particularly dimethylformamide). The active esterifying agent used is
For example, it may be an N-hydroxy compound such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or a disulfide compound such as dipyridyl disulfide. The esterification reaction is suitably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The reaction temperature varies depending on the starting compounds, reagents, and the like.
20 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.).
The temperature is 20 ° C to 100 ° C (preferably 0 ° C to 50 ° C). The time required for the reaction varies depending on the starting compounds, the reagents, and the reaction temperature.
4 hours (preferably 1 hour to 12 hours). After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried with anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In the mixed acid anhydride method, the compound (XI) is prepared in an inert solvent in the presence or absence (preferably in the presence) of a base.
V) is reacted with a mixed acid anhydride agent to produce a mixed acid anhydride, and then the mixed acid anhydride is converted to a compound (X) in an inert solvent.
V). The solvent used in the reaction for producing the mixed acid anhydride is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or formamide, dimethylformamide, dimethylacetamide,
It can be an amide such as hexamethylphosphoramide (HMPA) or hexamethylphosphorus triamide (HMPT), preferably a halogenated hydrocarbon (dichloromethane). Mixed acid anhydride agent, for example, carbonate C ₁ -C ₄ alkyl halides such as halogenated oxalyl, ethyl chloroformate or chlorocarbonate, isobutyl, such as oxalyl chloride, C ₁ -C such as pivaloyl chloride
₅ Alkanoyl halides or C ₁ -C ₄ alkyl or diC ₆ -C ₁₄ arylcyanophosphates such as diethylcyanophosphate or diphenylcyanophosphate, preferably with oxalyl halides (especially oxalyl chloride) is there. The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino ) Pyridine, N,
N-dimethylaniline, N, N-diethylaniline,
1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.
0] Organic amines such as undec-7-ene (DBU), preferably organic amines (especially triethylamine). The reaction temperature in the reaction for producing the mixed acid anhydride varies depending on the starting compounds, reagents and the like, but is usually from -50 ° C to 100 ° C (preferably from -10 ° C to 50 ° C).
° C). The reaction time in the reaction for producing the mixed acid anhydride varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours). The solvent used in the reaction between the mixed acid anhydride and the compound (XV) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether or amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphorus triamide (HMPT) And preferably amides, especially dimethylformamide. Mixed acid anhydride and compound (XV)
The reaction temperature in the reaction varies depending on the starting compounds, reagents and the like, but is usually -30 ° C to 100 ° C (preferably 0 ° C).
° C to 80 ° C). Mixed acid anhydride and compound (XV)
The reaction time in the above reaction varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 24 hours (preferably 10 minutes to 12 hours). After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method.
For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. The obtained organic layer is washed with water, dried with anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The condensation method is carried out in an inert solvent in the presence of a condensing agent.
The reaction is carried out by reacting compound (IIb) with compound (XV). The condensing agent used is, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloro-pyridinium iodide-
Triethylamine can be mentioned, preferably carbonyldiimidazole. This reaction can be carried out under the same conditions as in the above-mentioned reaction for producing an active ester. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.)
Is added to extract the target compound. The extracted organic layer is washed with water, dried using anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step C9 (Hydrolysis) In this step, compound (III) is reacted with an alkali metal hydroxide (preferably sodium hydroxide, potassium hydroxide or lithium hydroxide) in an inert solvent, Compound (II
This is a step of producing b), and can be performed under the same conditions as in step C7 (1).

Step C10 (Condensation) In this step, compound (IIb) is optionally treated with hydrazine, ammonia, mono (C ₁ -C ₆ alkyl) amine or di (C ₁ -C ₆ alkyl) in an inert solvent. The step of producing a compound (IIc) by reacting with an amine, which is carried out by a conventional method in peptide synthesis, for example, an azide method, an active ester method, a mixed acid anhydride method or a condensation method (preferably a condensation method).

[0082] In the above method, the azide method comprises reacting compound (IIb) with hydrazine in an inert solvent [for example, formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) or hexamethylphosphorus triamide (HMPT). Amides, preferably dimethylformamide], -10
The reaction is carried out by reacting an amino acid hydrazide produced by reacting at a temperature of from 0 ° C. to 100 ° C. (preferably from 0 ° C. to 50 ° C.) with a nitrite compound, converting it to an azide compound, and then treating it with ammonia. The nitrite compound used is, for example, an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite. The reaction is suitably carried out in an inert solvent and the solvent used is, for example, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; Alternatively, it may be a pyrrolidone such as N-methylpyrrolidone, preferably an amide (particularly dimethylformamide). Two steps of the process (azidation and reaction with ammonia)
Is usually performed in one reaction solution. The reaction temperature varies depending on the starting compounds, reagents and the like, but usually, the azidation step is carried out at -70 ° C to 50 ° C (preferably -50 ° C to 0 ° C).
° C), and the reaction with ammonia is from -70 ° C to 50 ° C.
(Preferably −10 ° C. to 10 ° C.). The time required for the reaction varies depending on the starting compound, the reagent and the reaction temperature. Usually, the azidation step is 5 minutes to 3 hours (preferably 10 minutes to 1 hour), and the reaction with ammonia is 5 hours. To 7 days (preferably 10 hours to 5 days).
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extraction is performed. After washing the organic layer with water, it is dried using anhydrous magnesium sulfate or the like,
The target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization,
It can be further purified by reprecipitation or chromatography.

The active ester method, the mixed acid anhydride method and the condensation method can be carried out under the same conditions as in Step C8.

Method D is a process for producing a compound having the general formula (IId), which is a starting compound of Method A.

Step D1 (Amidation) In this step, the compound (IIb) obtained in Step C9 is reacted with aminoacetaldehyde dimethyl acetal in an inert solvent in the presence of a condensing agent to convert the general formula (XVI) This is a step for producing a compound having the same and can be performed under the same conditions as in Step C8.

Step D2 (Formylation) This step is a step of reacting compound (XVI) with paratosylic acid in an inert solvent to produce a compound having the general formula (XVII). The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Or aromatic hydrocarbons such as xylene;
Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; such as acetone or methyl ethyl ketone Ketones; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HM
PA) or hexamethylphosphorous triamide (HMP
An amide such as T); a sulfoxide such as dimethyl sulfoxide or sulfolane; or a mixed solvent of the above organic solvent and water, preferably a mixed solvent of a ketone (particularly acetone) and water. is there. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 150 ° C.
° C, preferably 50 ° C to 100 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 10 minutes to 12 hours, preferably 30 minutes to 4 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method in the same manner as in Step B4.

Step D3 (Ring-closure reaction) In this step, compound (XVII) is reacted with iodine and triphenylphosphine in an inert solvent to give compound (II).
This is the step of manufacturing d). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Or an aromatic hydrocarbon such as xylene; a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane;
Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethyl Amides such as phosphoramide (HMPA) or hexamethylphosphorus triamide (HMPT); or sulfoxides such as dimethyl sulfoxide or sulfolane;
Preferably, they are halogenated hydrocarbons (particularly dichloromethane). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually -20 ° C to 100 ° C, preferably 0 ° C.
C. to 50.degree. The reaction time varies depending on the starting compound, reagent and reaction temperature, but is usually 30 minutes to 12 hours, preferably 1 hour to 5 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method in the same manner as in Step B4.

Method E is a process for producing a compound having the general formula (IIf) and a compound having the general formula (IIg) which are the starting compounds of the method A.

Step E1 (Halogenation) In this step, compound (IIe) obtained by method B in an inert solvent in the presence of triphenylphosphine is treated with a tetrahalogenated carbon (preferably carbon tetrabromide or tetrabromide). (CCl 3) to produce a compound having the general formula (XVIII). The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
Preferably, they are halogenated hydrocarbons (preferably dichloromethane). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time depends on the starting compound, reagent,
Although it depends on the reaction temperature, it is usually from 5 minutes to 10 hours, preferably from 10 minutes to 3 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method in the same manner as in Step C7 (2).

Step E2 (Amination) In this step, compound (XVIII) is reacted with a compound having the general formula (XIX) in an inert solvent in the presence of sodium iodide to produce compound (IIf). It is a process. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, the solvent may be the same as that in Step A1 (1), and preferably the amides (Especially dimethylformamide). The reaction temperature varies depending on the starting compounds, reagents, etc.
C. to 150.degree. C., preferably 60.degree. C. to 120.degree. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 10 hours, preferably 1 minute.
0 minutes to 3 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water,
After drying using anhydrous magnesium sulfate or the like, the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.

Step E3 (Introduction of Amino Group) In this step, compound (XVIII) is reacted with (1) sodium iodide and sodium azide in an inert solvent, and then (2) an inert solvent. In this step, the compound is reacted with a reducing agent to produce a compound having the general formula (XX). The solvent used in the step E3 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include aliphatic solvents such as hexane, heptane, ligroin and petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene;
Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitro compounds such as nitromethane Nitriles such as acetonitrile or isobutyronitrile; formamide, dimethylformamide,
Dimethylacetamide, hexamethylphosphoramide (H
MPA) or hexamethylphosphorous triamide (HM
Amides such as PT); sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of the above organic solvent and water, and preferably a mixed solvent of amides (particularly dimethylformamide) and water. . E3
The reaction temperature of the step (1) varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time of the step E3 (1) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 5 minutes to 10 hours, preferably 10 minutes to 3 hours.
Time. After completion of the reaction, the target compound of Step E3 (1) is collected from the reaction mixture according to a conventional method, similarly to Step B4.

The solvent used in the step E3 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Ethers such as dimethoxyethane or diethylene glycol dimethyl ether or alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol, preferably alcohols (preferably alcohols) Is ethanol). The reducing agent used in the step E3 (2) is, for example, hydrogen (P
d is used as a catalyst), and is preferably hydrogen in the presence of a Pd catalyst. The reaction temperature in Step E3 (2) is:
The temperature is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C, depending on the starting compound, reagent and the like. The reaction time of the step E3 (2) varies depending on the starting compound, the reagent and the reaction temperature, but is usually 10 minutes to 24 hours, preferably 1 hour to 15 hours. After the reaction,
The target compound of Step E3 (2) is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the target compound is obtained by removing the catalyst by filtration and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, or chromatography.

Step E4 (Acylation) In this step, compound (XX) is prepared in an inert solvent in the presence of a base.
Is reacted with a compound having the general formula (XXI) to produce a compound (IIg). The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Hydrocarbons (particularly dichloromethane). The base used is
For example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; alkali metal acetates such as sodium acetate; Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3 .0] nona
5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.
4.0] Organic amines such as undec-7-ene (DBU), preferably organic amines (especially triethylamine). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually from 10 minutes to 10 minutes.
Time, preferably 30 minutes to 3 hours. After completion of the reaction, the target compound of this step is, similarly to Step E2,
It is collected from the reaction mixture according to a conventional method. In this step, dimethylaminopyridine or pyridine can be used as a catalyst.

Method F is a process for producing a compound having the general formula (IIh), which is a starting compound of Method A.

Step F1 (Condensation) This step is carried out in an inert solvent in the presence of a base by the general formula (XXI)
In this step, a compound having the general formula (XXIV) is reacted with a compound having the general formula (XXIII) to produce a compound having the general formula (XXIV). The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, it may be the same as that in Step A1 (1), Hydrocarbons (preferably dichloromethane). The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; an alkali such as sodium acetate Metal acetates; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl Mercaptan alkali metals such as sodium mercaptan or ethyl mercaptan sodium; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridyl , N, N
-Dimethylaniline, N, N-diethylaniline, 1,
5-diazabicyclo [4.3.0] non-5-ene,
1,4-diazabicyclo [2.2.2] octane (DA
BCO) or organic amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably organic amines (preferably pyridine). The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually 1 hour to 112 hours, preferably 3 hours to 10 hours. After the reaction,
The target compound of this step is collected from the reaction mixture according to a conventional method as in Step B4.

Step F2 (Mitsunobu Reaction) This step is carried out in Bullin Chemical Society Japan, Vol. 40, p. 2380 (1967) [ Bull.
According to the Mitsunobu reaction described in M. Soc. Jap. , 40 , 2380 (1967).], the dehydration condensation reaction of the compound (XXIV) with the corresponding compound (IIe) in an inert solvent in the presence of a phosphine and an azo compound. To produce a compound having the general formula (XXV). The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol It can be an ether such as dimethyl ether, preferably an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether, more preferably an aromatic hydrocarbon (particularly benzene). The phosphines used are, for example, trimethylphosphine, triethylphosphine, tripropylphosphine,
Tri-C ₁ -C ₆ alkylphosphines such as tributylphosphine, tripentylphosphine or trihexylphosphine; tri-C ₆ -C ₁₀ such as triphenylphosphine, triindenylphosphine or trinaphthylphosphine.
Aryl phosphines; or tolyl diphenyl phosphine, tolyl phosphine, trimesityl phosphine,
Tributylphenylphosphine or tri-6-ethyl-
It may be a tri-C ₆ -C ₁₀ arylphosphine which may have a C ₁ -C ₄ alkyl as a substituent, such as 2-naphthylphosphine, and preferably a tri-C ₁ -C ₆ alkylphosphine (particularly trimethylphosphine). , triethylphosphine, tripropylphosphine or tributylphosphine) or tri C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine, a tri-indenyl phosphine or trinaphthylphosphine), more preferably, tri C ₆ -C ₁₀ Aryl phosphines (especially triphenyl phosphines). Azo compounds employed are, for example, azodicarboxylic acid dimethyl, diethyl azodicarboxylate, be azodicarboxylate di -C ₁ -C ₄ alkyl such as azodicarboxylate dipropyl or azodicarboxylic acid dibutyl obtained, preferably azodicarboxylate Dimethyl or diethyl azodicarboxylate. The reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the starting compounds, reagents and reaction temperature, but is usually 5 minutes to 24 hours, preferably 10 minutes to 4 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, if any insolubles are present, they are filtered off and the solvent is distilled off to give the desired compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step F3 (Elimination Reaction) This step is a step of reacting compound (XXV) with a base in an inert solvent to produce compound (IIh). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
It may be the same as in the step (1), and is preferably a halogenated hydrocarbon (particularly, dichloromethane). The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium hydroxide, hydroxide Alkali metal hydroxides such as potassium or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; mercaptans such as sodium methyl mercaptan or sodium ethyl mercaptan Alkali metals: propylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-
(N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2. 2.2] Octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7
Organic amines such as -ene (DBU), preferably organic amines (preferably propylamine). The reaction temperature varies depending on the starting compounds, reagents, etc.,
It is usually -10 ° C to 100 ° C, preferably 0 ° C to 5 ° C.
0 ° C. The reaction time varies depending on the starting compound, the reagent and the reaction temperature, but is usually from 1 hour to 72 hours, preferably from 24 hours to 36 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method in the same manner as in Step E2.

In the method G, a compound having the general formula (IIi) which is a starting compound of the method A, a compound having the general formula (IIj), and a compound having the general formula (IIIa) which is a starting compound of the method B are produced. Is the way.

Step G1 (Wittig reaction) This step is carried out in an inert solvent in the presence of a base by the general formula (IV
In this step, a compound having the general formula (XXVI) is produced by reacting a compound having the formula (a) with a Wittig-Horner reagent (preferably ethyl 2-diethylphosphonoacetate). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include aromatic hydrocarbons such as benzene; diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane. Ethers; amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably ethers (particularly tetrahydrofuran) or amides ( Particularly, dimethylformamide). The base used is not particularly limited as long as it does not affect the other parts of the compound, and may be, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride, Preferably it is lithium hydride or sodium hydride. The reaction temperature varies depending on the solvent, raw materials, reagents and the like, but is usually -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C. The reaction time depends on the solvent, raw materials,
Although it depends on the reagent, the reaction temperature and the like, it is usually from 10 minutes to 12 hours, preferably from 30 minutes to 2 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method in the same manner as in Step B4.

Step G2 (Reduction of Double Bond) This step is a step of reacting compound (XXVI) with a reducing agent in an inert solvent to produce compound (IIIa). Step E3 (2) Is performed under the same conditions as described above.

Step G3 (Hydrolysis) In this step, compound (IIIa) is reacted with an alkali metal hydroxide (preferably sodium hydroxide, potassium hydroxide or lithium hydroxide) in an inert solvent, Compound (I
This is a step of producing Ii), which is performed under the same conditions as in Step C7 (1).

Step G4 (Condensation) In this step, the compound (II) is reacted in an inert solvent in the presence of a condensing agent.
reacting i) with ammonia, mono (C ₁ -C ₆ alkyl) amine or di (C ₁ -C ₆ alkyl) amine to produce compound (IIj) under the same conditions as in Step C8. Done.

Method H is a method for separately producing a compound having the general formula (VIIIa) wherein R ⁴ is a methyl group in compound (VIII) which is an intermediate compound of method C. Step H1 (Protection of Hydroxyl Group and Esterification of Carboxylic Acid) In this step, a compound having the general formula (XXVII) is reacted with (1) methyl iodide in an inert solvent in the presence of a base, or 2) A step of producing a compound having the general formula (XXVIII) by reacting with diazomethane in an inert solvent, and is carried out under the same conditions as in Step C1.

Step H2 (Reduction) This step is a step of reacting compound (XXVIII) with a reducing agent in an inert solvent to produce a compound having the general formula (XXIX). It is performed under conditions.

Step H3 (Oxidation) This step is a step of reacting compound (XXIX) with an oxidizing agent in an inert solvent to produce compound (VIIIa), which is carried out under the same conditions as in step B2. Will be

The compound having the above general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention has both excellent LDL oxidation inhibitory activity and ACAT inhibitory activity, exhibits excellent oral absorbability, and has low toxicity. Since it is weak, it is useful as a medicament [especially, a therapeutic or prophylactic (particularly a therapeutic) for arteriosclerotic diseases such as myocardial infarction].

When the compound (I) of the present invention or a pharmacologically acceptable salt thereof is used as a medicament or a therapeutic or prophylactic agent for the above-mentioned diseases, the compound itself or an appropriate pharmacologically acceptable salt is used. , Excipients, diluents, etc.
It can be administered orally by capsule, granule, powder or syrup, or parenterally by injection or suppository.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and metasilicate aluminate Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg, stearic acid, metal salts of stearic acid such as calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; Sulfate; glycol; fumaric acid; sodium benzoate; DL
Leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives. ), Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, low-substituted hydroxypropylcellulose). , Carboxymethylcellulose, calcium carboxymethylcellulose, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; and chemically modified starch and celluloses such as carboxymethylstarch, sodium carboxymethylstarch, and crosslinked polyvinylpyrrolidone.), Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol Alcohols; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (eg, commonly used sweeteners, sourness). , Fragrance, etc.), and a known method using additives such as a diluent. The amount used depends on the condition, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 1000 mg (preferably 500 mg), and in the case of intravenous administration, , Lower limit 1 mg per serving (preferably 5m
g), it is desirable to administer an upper limit of 500 mg (preferably 300 mg) to an adult 1 to 6 times a day according to symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto.

[0110]

EXAMPLES Example 1 4-t-butyl-3- [3- (4-hydroxy-3,5
-Dimethylphenyl) octanoylamino] benzamide (Exemplary Compound No .: 713) 4-t-butyl-3- [3- (4-
[Methoxy-3,5-dimethylphenyl) octanoylamino] benzamide (295 mg, 0.652 mmol
l) in methylene chloride (4 ml) was cooled to -78 ° C and a 1 M boron tribromide / methylene chloride solution (2.61 m
l) was added dropwise over 5 minutes. After stirring at −78 ° C. for 10 minutes, stirring at room temperature for 1.5 hours, cooling again to −78 ° C., dropwise addition of methanol (5 ml), returning to room temperature, and stirring for 1 hour.
Stirred for hours. After evaporating the solvent under reduced pressure, the obtained residue was extracted with ethyl acetate. The extract was washed with saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 15/1) to give the desired compound (268 mg, yield 94%). Melting point: 115.0-116.0 ° C .; IR spectrum (CHCl ₃ ) ν _max cm ⁻¹ : 3610, 3529, 34
15, 2960, 2931, 2859, 1678, 1587, 1488, 1378, 1153
; NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 0.85 (3H, t, J
= 6.0Hz), 1.23 (9H, s), 1.12-1.34 (6H, m), 1.56-1.72 (2H,
m), 2.20 (6H, s), 2.54 (1H, dd, J = 14.0Hz, J = 9.9Hz), 2.73
(1H, dd, J = 14.0Hz, J = 5.1Hz), 3.02-3.09 (1H, m), 4.85 (1
H, s), 5.59 (1H, brs), 6.23 (1H, brs), 6.85 (2H, s), 6.92
(1H, s), 7.39 (1H, d, J = 8.4Hz), 7.60 (1H, d, J = 8.4Hz), 7.
63 (1H, s).

Example 2 4-t-butyl-3- [3- (4-hydroxy-3,5
-Dimethylphenyl) octanoylamino] -N, N-
Dimethylbenzamide (Exemplary Compound No .: 719) 4-t-butyl-3- [3- (4-
Methoxy-3,5-dimethylphenyl) octanoylamino] -N, N-dimethylbenzamide (273 mg,
0.569 mmol) was reacted in the same manner as in Example 1 and worked up to give the desired compound (251 mg, yield 9).
5%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3611, 2960, 29
31, 2860, 1680, 1624, 1560, 1489, 1401, 1154, 1107
; NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 0.84 (3H, t, J
= 6.3Hz), 1.20 (9H, s), 1.12-1.31 (6H, m), 1.55-1.72 (2H,
m), 2.20 (6H, s), 2.54 (1H, dd, J = 14.0Hz, J = 9.6Hz), 2.68
(1H, dd, J = 14.0Hz, J = 5.3Hz), 3.01 (3H, s), 3.08 (3H, s),
2.96-3.12 (1H, m), 4.74 (1H, s), 6.84 (2H, s), 6.96 (1H,
s), 7.16 (1H, dd, J = 8.1Hz, J = 1.2Hz), 7.25 (1H, d, J = 1.2H
z), 7.32 (1H, d, J = 8.1Hz).

Example 3 4-t-butyl-3- [3- (4-hydroxy-3,5
-Dimethylphenyl) octanoylamino] -N-methylbenzamide (Exemplary Compound No .: 715) 4-t-butyl-3- [3- (4
-Methoxy-3,5-dimethylphenyl) octanoylamino] -N-methylbenzamide (230 mg, 0.1 mg).
493 mmol) was reacted in the same manner as in Example 1 and worked up to give the desired compound (210 mg, yield 94%).
%) As colorless crystals. Melting point: 204.5-205.5 ° C; IR spectrum (KBr) ν _max cm ^-1 : 3297, 2956, 2927,
2858, 1648, 1559, 1520, 1489, 1213, 1154; NMR spectrum (400 MHz, CDCl ₃ ) δppm: 0.84 (3H, t, J
= 6.0Hz), 1.22 (9H, s), 1.25 (6H, brs), 1.57-1.73 (2H, m),
2.19 (6H, s), 2.53 (1H, dd, J = 14.1Hz, J = 9.7Hz), 2.71 (1
H, dd, J = 14.1Hz, J = 5.3Hz), 2.96 (3H, d, J = 4.8Hz), 3.02-
3.09 (1H, m), 4.79 (1H, s), 6.20 (1H, br.s), 6.84 (2H, s),
6.93 (1H, s), 7.36 (1H, d, J = 8.3Hz), 7.55 (1H, dd, J = 8.3H
z, J = 1.4 Hz), 7.60 (1H, d, J = 1.4 Hz).

Example 4 3- (4-Hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide (Exemplary Compound No .: 685) The obtained 3- (4-methoxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide (124 mg,
0.260 mmol) was reacted as in Example 1,
Post-treatment provided the target compound (118 mg, yield 98%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3611, 3426, 296
0, 2931, 1679, 1577, 1556, 1489, 1406, 1153, 918; NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 0.85 (3H, t, J
= 5.6Hz), 1.24 (9H, s), 1.13-1.33 (6H, m), 1.57-1.74 (2H,
m), 2.21 (6H, s), 2.52 (1H, dd, J = 14.0Hz, J = 9.7Hz), 2.73
(1H, dd, J = 14.0Hz, J = 5.2Hz), 3.04-3.14 (1H, m), 4.80 (1
H, s), 6.80 (1H, s), 6.87 (2H, s), 7.21 (1H, s), 7.40 (1H,
d, J = 8.4Hz), 7.68 (1H, s), 7.80 (1H, d, J = 8.4Hz), 7.87 (1H
H, s).

Example 5 3- (4-Hydroxy-3,5-dimethylphenyl) octanoic acid [2-t-butyl-5- (hydroxyiminomethyl) phenyl] amide (exemplary compound number: 709) The resulting 3- (4-hydroxy-3,5-
Dimethylphenyl) octanoic acid (2-t-butyl-5-
Formylphenyl) amide (280 mg, 0.661 m
mol) in an ethanol (5 ml) solution under ice-cooling and stirring.
Sodium acetate (108 mg, 1.322 mmol) and hydroxylamine hydrochloride (59 mg, 0.859 mm)
ol), and the mixture was stirred at the same temperature for 30 minutes.
Stirred for hours. The solvent was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/2) to give the desired compound (267 mg, yield 92%). %) As a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3583, 2960, 293
1, 2860, 1732, 1679,1561, 1488, 1422, 1302, 1154,
945; NMR spectrum (400 MHz, CDCl ₃ ) δppm: 0.84 (3H, t, J
= 6.0Hz), 1.21 (9H, s), 1.03-1.33 (6H, m), 1.55-1.74 (2H,
m), 2.21 (6H, s), 2.52 (1H, dd, J = 14.0Hz, J = 9.7Hz), 2.70
(1H, dd, J = 14.0Hz, J = 5.1Hz), 3.02-3.12 (1H, m), 4.54 (1
H, s), 6.82 (1H, s), 6.85 (2H, s), 7.33 (2H, s), 7.38 (1H,
s), 7.51 (1H, s), 8.02 (1H, s).

Example 6 3- (4-Hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-cyanophenyl) amide (Exemplary Compound No .: 705) 3 obtained in Example 5 -(4-Hydroxy-3,5-dimethylphenyl) octanoic acid [2-t-butyl-5-
(Hydroxyiminomethyl) phenyl] amide (183
mg, 0.417 mmol) of methylene chloride (3 ml)
To the solution was added carbonyldiimidazole (135 mg, 0.1 mg).
834 mmol) and stirred at room temperature for 3 days. After evaporating the solvent under reduced pressure and extracting the obtained residue with ethyl acetate, the extract was washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, and the organic layer was dried over anhydrous magnesium sulfate. Was. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/1) to give the desired compound (164 mg, yield 94). %) As a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3431, 3140, 296
1, 2932, 2861, 2234,1775, 1692, 1472, 1387, 1292,
1162, 994; NMR spectrum (400 MHz, CDCl ₃ ) δppm: 0.86 (3H, t, J
= 5.8Hz), 1.29 (9H, s), 1.15-1.35 (6H, m), 1.60-1.80 (2H,
m), 2.21 (6H, s), 2.46-2.57 (1H, m), 2.70-2.80 (1H, m),
3.16-3.25 (1H, m), 6.93 (1H, s), 7.01 (2H, s), 7.36-7.49
(2H, m), 7.58 (1H, d, J = 1.3Hz), 8.31 (1H, s).

Example 7 4-t-butyl-3- [3- (2-hydroxy-3-methylphenyl) octanoylamino] benzamide
(Exemplary compound number: 97) 4-t-butyl-3- [3- (2
-Methoxy-3-methylphenyl) octanoylamino] benzamide (394 mg, 0.852 mmol)
Was reacted in the same manner as in Example 1 and worked up to give the desired compound (361 mg, quantitative) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3528, 3414, 333
8, 2961, 2932, 1732,1678, 1588, 1470, 1375, 1073,
1046; NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85-0.97 (3
H, m), 1.13-1.34 (6H, m), 1.21 (9H, s), 1.60-1.80 (2H,
m), 2.21 (3H, s), 2.52 (1H, dd, J = 10.8Hz, J = 15.3Hz), 2.9
2 (1H, dd, J = 3.5Hz, J = 15.3Hz), 3.52-3.64 (1H, m), 5.46-
5.72 (1H, m), 6.18-6.32 (1H, m), 6.84 (1H, t, J = 7.5Hz),
6.96-7.03 (2H, m), 7.17 (1H, s), 7.19 (1H, s), 7.41 (1H, d,
J = 8.4Hz), 7.53 (1H, s), 7.63 (1H, dd, J = 0.6Hz, J = 8.4H
z).

Example 8 3- (2-Hydroxy-3-methylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide (Exemplary Compound No. 72) Obtained in Reference Example 31 3- (2-methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide (452 mg, 0.9
77 mmol) was reacted in the same manner as in Example 1 and worked up to give the desired compound (289 mg, yield 65).
%) As a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3306, 2961, 293
2, 1665, 1450, 1471,1428, 1408, 1381, 1143, 1080,
918; NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.76-0.87 (3
H, m), 1.08-1.29 (6H, m), 1.20 (9H, s), 1.54-1.80 (2H,
m), 2.23 (3H, s), 2.52 (1H, dd, J = 10.7Hz, J = 15.3Hz), 2.9
5 (1H, dd, J = 3.4Hz, J = 15.3Hz), 3.56-3.65 (1H, m), 6.83 (1
(H, t, J = 7.5Hz), 6.95-7.06 (2H, m), 7.08 (1H, brs), 7.22
(1H, s), 7.26-7.34 (1H, m), 7.43 (1H, d, J = 8.3Hz), 7.67
(1H, s), 7.84 (1H, d, J = 8.3Hz), 7.91 (1H, s).

Example 9 3- (2-Hydroxy-3-methylphenyl) octanoic acid (2-t-butyl-5-morpholin-4-ylmethylphenyl) amide (Exemplified Compound No. 61) Obtained in Reference Example 34 3- (2-methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-morpholin-4-ylmethylphenyl) amide (197 mg,
0.398 mmol) was reacted in the same manner as in Example 1,
By post-treatment, the target compound (85 mg, yield 4)
4%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3291, 1661, 151
0, 1470, 1422, 1350, 1265, 1116, 1010, 864; NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.73-0.96 (3
H, m), 1.02-1.32 (6H, m), 1.18 (9H, s), 1.65-1.79 (2H,
m), 2.24 (3H, s), 2.42-2.53 (5H, m), 2.94 (1H, dd, J = 3.5H
z, J = 15.3Hz), 3.36-3.49 (2H, m), 3.51-3.77 (5H, m), 6.7
3-6.87 (2H, m), 6.96-7.04 (3H, m), 7.10-7.18 (2H, m), 7.
47 (1H, brs).

Example 10 3- (2-Hydroxy-3-methylphenyl) octanoic acid [5- (acetylaminomethyl) -2-t-butylphenyl] amide (Exemplary Compound No .: 111) Obtained in Reference Example 36 3- (2-methoxy-3-methylphenyl) octanoic acid [5- (acetylaminomethyl)
-2-t-butylphenyl] amide (220 mg, 0.
471 mmol) was reacted in the same manner as in Example 1 and worked up to give the desired compound (213 mg, quantitative).
Was obtained as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3447, 3308, 296
0, 2933, 1732, 1672,1570, 1514, 1470, 1424, 1373,
1080, 1046, 885; NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.76-0.90 (3
H, m), 1.04-1.32 (6H, m), 1.17 (9H, s), 1.62-1.79 (2H,
m), 2.01 (3H, s), 2.22 (3H, s), 2.50 (1H, dd, J = 10.7Hz, J =
15.2Hz), 2.92 (1H, dd, J = 3.4Hz, J = 15.2Hz), 3.53-3.65 (1
H, m), 4.32 (2H, d, J = 5.5Hz), 5.76-5.87 (1H, m), 6.83 (1
H, t, J = 7.5Hz), 6.95-7.12 (5H, m), 7.26-7.32 (2H, m).

Example 11 3- (2-Hydroxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (2,2-dimethylpropionylaminomethyl) phenyl] amide (exemplary compound number: 115) 3- (2-methoxy-3-methylphenyl) octanoic acid (5-aminomethyl-2-t-butylphenyl) amide obtained in Example 35 (119 mg, 0.234 mmol)
l) was reacted in the same manner as in Example 1 and worked up to give the target compound (111 mg, yield 96%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3464, 3286, 296
3, 2933, 1732, 1660,1570, 1511, 1470, 1423, 1367,
1081; NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.78-0.87 (3
H, m), 1.11-1.39 (6H, m), 1.18 (9H, s), 1.23 (9H, s), 1.6
9-1.82 (2H, m), 2.22 (3H, s), 2.49 (1H, dd, J = 11.0Hz, J = 1
5.3Hz), 2.92 (1H, dd, J = 3.2Hz, J = 15.3Hz), 3.51-3.65 (1
H, m), 4.27-4.42 (2H, m), 5.92-6.02 (1H, m), 6.82 (1H, t,
J = 7.5Hz), 6.95-7.19 (5H, m), 7.26-7.37 (2H, m).

Example 12 [2-t-butyl-5- (thiazol-2-ylaminomethyl) phenyl] amide 3- (2-hydroxy-3-methylphenyl) octanoic acid (Exemplary Compound No .: 83) Reference Example 3- (2-Methoxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (thiazol-2-ylaminomethyl) phenyl] amide (27
3 mg, 0.538 mmol) was reacted in the same manner as in Example 1 and post-treated to give the target compound (262 m
g, 99% yield) as an orange foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3429, 3293, 296
1, 2933, 2873, 1733,1663, 1534, 1470, 1423, 1153,
1080; NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 0.84-0.88 (3
H, m), 1.10-1.32 (6H, m), 1.17 (9H, s), 1.51-1.81 (2H,
m), 2.21 (3H, s), 2.49 (1H, dd, J = 11.0Hz, J = 15.3Hz), 2.9
2 (1H, dd, J = 3.4Hz, J = 15.3Hz), 3.49-3.63 (1H, m), 4.40 (2
H, s), 5.47-5.66 (1H, m), 6.50 (1H, d, J = 3.6Hz), 6.75 (1
H, brs), 6.83 (1H, t, J = 7.5Hz), 6.95-7.01 (2H, m), 7.06
(1H, s), 7.11 (1H, d, J = 3.6Hz), 7.15-7.17 (2H, m), 7.28-
7.40 (1H, m). Example 13 3- (2-Hydroxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (2-dimethylcarbamoylethyl) phenyl] amide (Exemplified Compound No .: 105) Obtained in Reference Example 43 3- (2-Methoxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (2-dimethylcarbamoylethyl) phenyl] amide (117
mg, 0.236 mmol) was reacted in the same manner as in Example 1 and post-treated to give the target compound (105 m
g, 93% yield) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3428, 3272, 296
0, 2933, 2873, 1638,1504, 1470, 1416, 1366, 1147,
1081, 884; NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.82-0.87 (3
H, m), 1.08-1.32 (6H, m), 1.17 (9H, s), 1.61-1.79 (2H,
m), 2.23 (3H, s), 2.47 (1H, dd, J = 11.0Hz, J = 15.3Hz), 2.5
3-2.61 (2H, m), 2.85-2.89 (3H, m), 2.95 (6H, s), 3.55-3.
65 (1H, m), 6.64 (1H, brs), 6.74-6.85 (1H, m), 6.95-7.03
(4H, m), 7.23-7.34 (1H, m), 7.49 (1H, s).

Reference Example 1 5-bromo-2-methoxy-1,3-dimethylbenzene 55% sodium hydride (16.3 g, 59.68 mm
ol) in dimethylformamide (150 ml) solution,
Under ice cooling and stirring, a solution of 4-bromo-2,6-dimethylphenol (10.0 g, 49.74 mmol) in dimethylformamide (100 ml) was added dropwise over 20 minutes, followed by stirring at room temperature for 30 minutes. The reaction solution was ice-cooled again,
Methyl iodide (8.47 g, 59.68 mmol) was added to 5
After dropwise addition over a period of minutes, the mixture was stirred at room temperature for 1.5 hours. The reaction solution was ice-cooled, water (200 ml) was added dropwise over 30 minutes, diluted with ethyl acetate, and the diluted solution was washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, and then the organic layer was dried. Dry using magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 0/1 to 1/5) to give the desired compound (10). 0.3 g, 97% yield) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2996, 2943, 286
3, 2831, 1731, 1591,1578, 1475, 1416, 1269, 1171,
1015.

Reference Example 2 4-Methoxy-3,5-dimethylbenzaldehyde 5-bromo-2-methoxy-1,3 obtained in Reference Example 1
-Dimethylbenzene (10.3 g, 47.89 mmol
l) in tetrahydrofuran (100 ml)
Under stirring at 8 ° C, n-butyllithium (1.56 M hexane solution, 33.8 ml) was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 30 minutes, and then 1-formylpiperidine (5.96 g, 52.68 mmol). ) Was added dropwise over 5 minutes and stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution (100 ml) was added to the reaction solution, and the mixture was added at room temperature for 30 minutes.
After stirring for minutes, the solvent was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate. The diluted solution was washed with saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/6) to give the target compound (6.9 g, 88%) as colorless. Obtained as an oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2958, 2945, 283
2, 2736, 1690, 1598,1482, 1386, 1303, 1135, 1011
.

Reference Example 3 2- (4-methoxy-3,5-dimethylbenzylidene)
Malonic acid diethyl ester 4-methoxy-3,5-dimethylbenzaldehyde (6.9 g, 42.02 mmol) obtained in Reference Example 2, diethyl malonate (7.66 ml, 50.43 mmol)
1) benzoic acid (154 mg, 1.261 mmol),
A solution of piperidine (0.166 ml, 1.681 mmol) in benzene (70 ml) was heated to reflux for 1 day using a Dean-Stark trap. After the temperature of the reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue. It was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1).
/ 5) to give the desired compound (1
2.8 g, quantitative) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2986, 2942, 172
6, 1626, 1484, 1378, 1298, 1147, 1071, 1013.

Reference Example 4 2- [1- (4-methoxy-3,5-dimethylphenyl) hexyl] malonic acid diethyl ester 2- (4-methoxy-3,5-dimethylbenzylidene) obtained in Reference Example 3 Malonic acid diethyl ester (1
N-pentylmagnesium bromide (1.0 M tetrahydrofuran solution,
55.5 ml) was added dropwise over 20 minutes, and the mixture was stirred at room temperature for 3 hours. The reaction solution was ice-cooled, a saturated aqueous ammonium chloride solution (300 ml) was added, and the solvent was distilled off under reduced pressure.
The obtained residue was diluted with ethyl acetate, washed with saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/5) to give the desired compound (13.5 g, yield). 85%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2934, 2862, 175
0, 1728, 1602, 1485,1466, 1371, 1300, 1177, 1147,
1019.

Reference Example 5 3- (4-methoxy-3,5-dimethylphenyl) octanoic acid (i) 2- [1- (4-methoxy-3,5-dimethylphenyl) hexyl] malonic acid The obtained 2- [1- (4-methoxy-3,5)
-Dimethylphenyl) hexyl] malonic acid diethyl ester (13.4 g, 35.40 mmol) in ethanol (150 ml) was treated with sodium hydroxide (7.10).
g, 17.70 mmol) in water (50 ml) and stirred at 60 ° C. for 4 hours. After evaporating the solvent under reduced pressure, a 10% aqueous sodium hydroxide solution was added to the obtained residue, and the mixture was washed with ether. The aqueous layer was ice-cooled, and the pH of the solution was acidified using concentrated hydrochloric acid. After extraction with ether, the extract was washed with saturated saline and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the target compound (11.2 g, yield 98%) as a colorless oily substance. (Ii) 3- (4-methoxy-3,5-dimethylphenyl) octanoic acid 2- [1- (4-methoxy-3,5-) obtained in (i)
Dimethylphenyl) hexyl] malonic acid (11.2 g,
34.74 mmol) in xylene (150 ml) was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10/1) to give the desired compound (8.1 g, yield 84).
%) As a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3515, 2931, 286
0, 1742, 1709, 1602, 1485, 1297, 1147, 1011.

Reference Example 6 4-t-butyl-3- [3- (4-methoxy-3,5-
Dimethylphenyl) octanoylaminobenzoic acid methyl ester 3- (4-methoxy-3,5-dimethylphenyl) octanoic acid obtained in Reference Example 5 (5.0 g, 17.960 m)
to a methylene chloride (50 ml) solution under ice-cooling and stirring, a catalytic amount of N, N-dimethylformamide was added, followed by oxalyl chloride (3.13 ml, 35.921 mm).
ol) was added dropwise over 3 minutes and stirred at room temperature for 1 hour.
By removing excess reagent and solvent under reduced pressure, an acid chloride was obtained as an intermediate. Next, 2-t-butyl-5-
Carbomethoxyaniline (4.5 g, 21.552 mm
ol) in a solution of N, N-dimethylacetamide (50 ml) in tetrahydrofuran (40 ml).
ml) solution was added dropwise over 20 minutes and then stirred overnight at room temperature. After evaporating the solvent under reduced pressure, ethyl acetate was added to the obtained residue, washed with saturated saline, and recrystallized using hexane and methylene chloride to give the desired compound (7.2 g, 86% ) Was obtained as colorless crystals. Melting point: 173.5-174.5 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3435, 2957, 293
2, 2861, 1721, 1682,1510, 1482, 1438, 1302, 1269,
1125, 1010.

Reference Example 7 4-t-butyl-3- [3- (4-methoxy-3,5-
Dimethylphenyl) octanoylamino] benzoic acid 4-t-butyl-3- [3- (4- (4-
Methoxy-3,5-dimethylphenyl) octanoylaminobenzoic acid methyl ester (3.35 g, 7.16)
To a suspension of 9 mmol) in methanol (70 ml) was added a solution of sodium hydroxide (2.30 g, 57.312 mmol) in water (10 ml), and the mixture was stirred at 60 ° C. for 30 minutes. The solvent was distilled off under reduced pressure, the pH of the obtained residue was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the extract was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. And dried. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is recrystallized from hexane and dichloromethane to give the desired compound (2.85).
g, 88%) as colorless crystals. Melting point: 180.0-181.0 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3089, 2960, 293
2, 2861, 1696, 1613,1568, 1482, 1427, 1299, 1148,
1011.

Reference Example 8 4-t-butyl-3- [3- (4-methoxy-3,5-
Dimethylphenyl) octanoylamino] benzamide 4-t-butyl-3- [3- (4- (4-
To a solution of [methoxy-3,5-dimethylphenyl) octanoylamino] benzoic acid (313 mg, 0.690 mmol) in acetonitrile (5 ml) was added carbonyldiimidazole (145 mg, 0.897 mmol), followed by stirring at room temperature for 1 hour. , Ammonia water (0.46 ml,
6.900 mmol) and stirred at room temperature for 2 hours.
After evaporating the solvent under reduced pressure and extracting the obtained residue with ethyl acetate, the extract was washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, and the organic layer was dried over anhydrous magnesium sulfate. Was. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / methanol = 1).
0/1) to give the desired compound (3
08 mg, 99% yield) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3530, 3415, 296
0, 2932, 1678, 1587,1482, 1377, 1148, 1011.

Reference Example 9 4-t-butyl-3- [3- (4-methoxy-3,5-
Dimethylphenyl) octanoylamino] -N, N-dimethylbenzamide 4-t-butyl-3- [3- (4-
Methoxy-3,5-dimethylphenyl) octanoylamino] benzoic acid (350 mg, 0.772 mmol)
Was reacted in the same manner as in Reference Example 8 (provided that dimethylamine hydrochloride was used instead of aqueous ammonia), followed by post-treatment to give the desired compound (368 mg, yield 99%).
Was obtained as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3467, 2954, 293
2, 1681, 1625, 1561,1484, 1401, 1148, 1106, 1011
.

Reference Example 10 4-t-butyl-3- [3- (4-methoxy-3,5-
Dimethylphenyl) octanoylamino] -N-methylbenzamide 4-t-butyl-3- [3- (4-
Methoxy-3,5-dimethylphenyl) octanoylamino] benzoic acid (335 mg, 0.739 mmol)
Was reacted in the same manner as in Reference Example 8 (provided that methylamine hydrochloride was used instead of aqueous ammonia), and post-treatment was performed to obtain the target compound (330 mg, yield 96%) as colorless crystals. . Melting point: 178.0-179.0 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3464, 2959, 293
2, 2861, 1661, 1537,1482, 1302, 1148, 1011.

Reference Example 11 4-t-butyl-N- (2,2-dimethoxyethyl)-
3- [3- (4-methoxy-3,5-dimethylphenyl) octanoylamino] benzamide 4-t-butyl-3- [3- (4-
[Methoxy-3,5-dimethylphenyl) octanoylamino] benzoic acid (595 mg, 1.312 mmol)
Was reacted in the same manner as in Reference Example 8 (however, aminoacetaldehyde dimethyl acetal was used instead of aqueous ammonia), followed by post-treatment to obtain the target compound (67).
(3 mg, 95% yield) as colorless crystals. Melting point: 147.0-148.0 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3454, 2956, 293
3, 2861, 1668, 1564,1530, 1484, 1131, 1071, 1011
.

Reference Example 12 4-t-butyl-3- [3- (4-methoxy-3,5-
Dimethylphenyl) octanoylamino] -N- (2-
Oxoethyl) benzamide 4-t-butyl-N- (2,2-
Dimethoxyethyl) -3- [3- (4-methoxy-3,
To a solution of 5-dimethylphenyl) octanoylamino] benzamide (660 mg, 1.221 mmol) in acetone (8 ml) and water (4 ml) was added paratosylic acid · 2.
A hydrate (70 mg, 0.366 mmol) was added, and the mixture was heated under reflux for 2 hours. After evaporating the solvent under reduced pressure and extracting the obtained residue with ethyl acetate, the extract was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, and the organic layer was dried using anhydrous magnesium sulfate. After filtration,
The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from hexane and dichloromethane to give the desired compound (473 mg, yield 78%) as colorless crystals. Melting point: 147.0-148.0 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3441, 2959, 293
2, 2860, 1734, 1668,1530, 1485, 1409, 1148, 1011
.

Reference Example 13 3- (4-Methoxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide iodine (483 mg, 1.900 mmol) and triphenyl Phosphine (498 mg, 1.900 mmol)
In a dichloromethane (10 ml) solution of 4-t-butyl-3- [3- (4-methoxy-
3,5-dimethylphenyl) octanoylamino] -N
-(2-oxoethyl) benzamide (470 mg,
0.950 mmol) and a solution of isopropylethylamine (0.65 ml, 3.801 mmol) in methylene chloride (5 ml) were added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure and extracting the obtained residue with ethyl acetate, the extract was diluted with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate,
The organic layer was washed successively with a 10% aqueous sodium thiosulfate solution and a saturated saline solution, and dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/2), and then recrystallized from hexane and dichloromethane. Thereby, the target compound (200 mg, yield 44%) was obtained as colorless crystals. Melting point: 177.0-178 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3474, 2960, 293
2, 2861, 1683, 1557, 1485, 1406, 1145, 1011, 917.

Reference Example 14 3- (4-Methoxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-hydroxymethylphenyl) amide 4-t-butyl-3 obtained in Reference Example 6 − [3- (4-
Methoxy-3,5-dimethylphenyl) octanoylaminobenzoic acid methyl ester (3.0 g, 6.415)
mmol) in toluene (50 ml) was added dropwise over 20 minutes with stirring at -78 ° C over 20 minutes, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 2 minutes. Stirred for hours. After the reaction solution was cooled again to -78 ° C, methanol (5m
1) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Then, a saturated saline solution (10 ml), ether (500 ml) and anhydrous magnesium sulfate (20 g) were added, and the mixture was stirred at room temperature for 1 hour and then filtered using celite. The solvent is distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/4) to give the desired compound (2.0 g, yield 71).
%) As a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3608, 2959, 293
1, 2861, 1608, 1573,1518, 1484, 1429, 1147, 1012
.

Reference Example 15 3- (4-Methoxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-formylphenyl) amide 3- (4-methoxy-3) obtained in Reference Example 14. , 5-Dimethylphenyl) octanoic acid (2-t-butyl-5-hydroxymethylphenyl) amide (1.50 g, 3.4
To a solution of 12 mmol) in chloroform (15 ml) was added manganese dioxide (4.65 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered using celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 4/1) to give the desired compound (980 mg, yield Rate 66
%) As a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3475, 2960, 293
2, 2860, 1699, 1609,1571, 1482, 1298, 1149, 1076,
1011.

REFERENCE EXAMPLE 16 3- (4-hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-formylphenyl) amide 3- (4-methoxy-3) obtained in Reference Example 15 , 5-Dimethylphenyl) octanoic acid (2-t-butyl-5-formylphenyl) amide (295 mg, 0.652 mm
ol) was reacted in the same manner as in Example 1 and worked up to give the desired compound (268 mg, 94%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3475, 2960, 293
2, 2860, 1699, 1609,1571, 1482, 1298, 1149, 1076,
1011.

Reference Example 17 1-methoxymethyloxy-3-methylbenzene 55% oily sodium hydride (5.25 g, 120 mm
ol) was suspended in dry N, N-dimethylformamide (90 ml) under a nitrogen stream, and N-N-dimethylformamide (10 ml) of O-cresol (10.0 g, 92.5 mmol) was suspended under ice-cooling and stirring. After the solution was added dropwise over 10 minutes, the mixture was stirred at 50 ° C. for 30 minutes. After cooling the reaction solution to room temperature, methoxymethyl chloride (9.05 m
1,120 mmol) was added dropwise over 10 minutes and stirred at room temperature for 13 hours. The reaction solution was diluted with water, extracted with ethyl acetate, the extract was washed with saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was distilled under reduced pressure (boiling point: 94 ° C,
15 mmHg) to obtain the desired compound (12.7).
g, yield 90%) as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.26 (3H, s),
3.49 (3H, s), 5.21 (2H, s), 6.91 (1H, t, J = 7.4Hz), 7.04
(1H, d, J = 7.4Hz), 7.14 (2H, t, J = 7.4Hz).

Reference Example 18 2-methoxymethyloxy-3-methylbenzaldehyde 1-methoxymethyloxy-3- obtained in Reference Example 17
Methylbenzene (12.1 g, 79.7 mmol)
Dissolved in dry tetrahydrofuran (200 ml) under a stream of nitrogen, and stirred at -78 ° C with n-butyllithium (1.6 M hexane solution, 54.8 ml, 87.7 mm).
ol) over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes and at 0 ° C for 1 hour. 1-Formylpiperidine (9.74 ml, 87.7 mmol) was added dropwise over 10 minutes, and the mixture was stirred at 0 ° C for 1.5 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was extracted with ethyl acetate.The extract was washed with brine and the organic layer was dried over anhydrous magnesium sulfate. And dried. After filtration, the solvent was distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/1) to give the desired compound (10.2 g, yield 7).
1%) as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.35 (3H, s),
3.60 (3H, s), 5.08 (2H, s), 7.17 (1H, t, J = 7.6Hz), 7.46
(1H, d, J = 7.6Hz), 7.70 (1H, dd, J = 1.4Hz, J = 7.6Hz), 10.32
(1H, s).

Reference Example 19 3- (2-methoxymethyloxy-3-methylphenyl) -2-ethoxycarbonyl-1-propenoic acid ethyl ester 2-methoxymethyloxy-3- obtained in Reference Example 18
Methylbenzaldehyde (10.6 g, 58.8 mmol
1) was reacted in the same manner as in Reference Example 3 and worked up to give the target compound (19.0 g, quantitative) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2985, 2940, 290
8, 2876, 1728, 1630,1446, 1376, 1278, 1263, 1159,
1096, 1072, 1031, 964.

Reference Example 20 3- (2-methoxymethyloxy-3-methylphenyl) -2-ethoxycarbonyloctanoic acid ethyl ester 3- (2-methoxymethyloxy-3-methylphenyl) obtained in Reference Example 19 -2-ethoxycarbonyl-1
-Propenoic acid ethyl ester (19.0 g, 58.8)
was reacted in the same manner as in Reference Example 4 and worked up to give the target compound (19.5 g, yield 84%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2984, 2960, 293
3, 1750, 1728, 1467,1370, 1302, 1159, 1096, 1071,
1036, 975.

Reference Example 21 3- (2-methoxymethyloxy-3-methylphenyl) octanoic acid 3- (2-methoxymethyloxy-3-methylphenyl) -2-ethoxycarbonyloctanoic acid obtained in Reference Example 20 Ethyl ester (19.5 g, 49.4 mmol
l) was reacted in the same manner as in Reference Example 5 and worked up to give the target compound (14.0 g, yield 99%) as a yellow oily substance. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3517, 2959, 293
1, 1737, 1709, 1601, 1468, 1438, 1159, 1071, 976.

Reference Example 22 3- (2-hydroxy-3-methylphenyl) octanoic acid chloride 3- (2-methoxymethyloxy-3-methylphenyl) octanoic acid obtained in Reference Example 21 (8.17 g, 2
7.8 mmol) was dissolved in dry dichloromethane (80 ml) under a nitrogen stream, oxalyl chloride (3.63 ml, 41.6 mmol) was added under ice-cooling and stirring, and a catalytic amount of N, N-dimethylformamide was added. The mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed sequentially with water and saturated saline,
The organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane / hexane).
Purification using ethyl acetate (5/1) gave the target compound (5.60 g, yield 75%) as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.76-0.94 (3
H, m), 1.14-1.46 (6H, m), 1.51-1.65 (3H, m), 2.31 (3H,
s), 2.71-2.85 (2H, m), 2.90-2.99 (1H, m), 6.98-7.05 (2
H, m), 7.09-7.14 (1H, m).

Reference Example 23 3- (2-hydroxy-3-methylphenyl) octanoic acid methyl ester 3- (2-hydroxy-3-methylphenyl) octanoic acid chloride obtained in Reference Example 22 (5.60 g, 18 .
9 mmol) in methanol (56 ml) under a nitrogen stream.
And triethylamine (5.25) under ice-cooling and stirring.
(37.7 mmol), and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate, washed sequentially with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 8/1).
The target compound (5.00) was purified by using
g, quantitative) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2956, 2931, 173
2, 1469, 1438, 1167, 1108, 1090, 1012.

Reference Example 24 3- (2-methoxy-3-methylphenyl) octanoic acid methyl ester 55% oily sodium hydride (990 mg, 22.7 m)
mol) was suspended in anhydrous N, N-dimethylformamide (30 ml) under a stream of nitrogen, and stirred under ice-cooling.
3- (2-hydroxy-3-methylphenyl) octanoic acid methyl ester (5.00 g, 18.9) obtained in
mmol) of N, N-dimethylformamide (20 m
l) After the solution was added dropwise over 5 minutes, the mixture was stirred at 50 ° C for 30 minutes, and then stirred under ice-cooling with methyl iodide (1.76 m
1,28.3 mmol) over 5 minutes and then stirred at room temperature for 2.5 hours. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in ethyl acetate, washed with water and saturated saline, and then the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/1) to give the desired compound (5.08 g, yield). 88%) as a pale yellow oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.74-0.90 (3
H, m), 1.01-1.31 (6H, m), 1.48-1.67 (2H, m), 2.30 (3H,
s), 2.58 (2H, d, J = 7.5Hz), 3.44-3.63 (1H, m), 3.60 (3H,
s), 3.76 (3H, s), 6.96-7.07 (3H, m).

Reference Example 25 3- (2-methoxy-3-methylphenyl) octanoic acid Methyl 3- (2-methoxy-3-methylphenyl) octanoate obtained in Reference Example 24 (5.08 g, 1
6.6 mmol) in ethanol (60 ml) and sodium hydroxide (1.99 g, 49.8 mmol).
A solution of l) in water (10 ml) was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in water, washed with ether, the pH of the aqueous layer was adjusted to 2 with concentrated hydrochloric acid, and extracted with ether, and the extract was saturated. After washing with a saline solution, the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 10/1) to give the desired compound (4.80 g, yield). 99%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3516, 2958, 293
1, 1742, 1709, 1593,1469, 1424, 1168, 1091, 1011
.

Reference Example 26 Methyl 4-t-butyl-3- [3- (2-methoxy-3-methylphenyl) octanoylamino] benzoate 3- (2-methoxy-3) obtained in Reference Example 25 -Methylphenyl) octanoic acid (4.80 g, 18.2 mmol)
1) was reacted in the same manner as in Reference Example 6 and worked up to give the target compound (7.77 g, yield 94%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3429, 2958, 293
2, 1721, 1683, 1611,1570, 1511, 1470, 1438, 1412,
1303, 1268, 1126, 1010.

Reference Example 27 4-t-butyl-3- [3- (2-methoxy-3-methylphenyl) octanoylamino] benzoic acid 4-t-butyl-3- [3 obtained in Reference Example 26 -(2
-Methoxy-3-methylphenyl) octanoylamino] benzoic acid methyl ester (3.94 g, 8.69)
was reacted in the same manner as in Reference Example 7 and post-treated to give the target compound (3.77 g, yield 99%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2960, 2873, 169
6, 1612, 1568, 1511,1470, 1424, 1299, 1168, 1010
.

Reference Example 28 4-t-butyl-3- [3- (2-methoxy-3-methylphenyl) octanoylamino] benzamide 4-t-butyl-3- [3- (2
-Methoxy-3-methylphenyl) octanoylamino] benzoic acid (750 mg, 1.71 mmol) was reacted in the same manner as in Reference Example 8 and post-treated to give the target compound (648 mg, yield 82%) as a colorless product. Obtained as a foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3529, 3414, 296
1, 2932, 1678, 1588, 1470, 1376, 1168, 1010.

Reference Example 29 4-t-butyl-N- (2,2-dimethoxyethyl)-
3- [3- (2-methoxy-3-methylphenyl) octanoylamino] benzamide 4-t-butyl-3- [3- (2
-Methoxy-3-methylphenyl) octanoylamino] benzoic acid (1.32 g, 3.00 mmol) was reacted in the same manner as in Reference Example 11 and post-treated to give the target compound (1.35 g, yield 85). %) As colorless crystals. Melting point: 128-133 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3691, 3464, 172
7, 1664, 1531, 1503,1470, 1408, 1367, 1284, 1130,
1070, 1011.

Reference Example 30 4-t-butyl-3- [3- (2-methoxy-3-methylphenyl) octanoylamino] -N- (2-oxoethyl) benzamide 4-t obtained in Reference Example 29 -Butyl-N- (2,2-
Dimethoxyethyl) -3- [3- (2-methoxy-3-
Methylphenyl) octanoylamino] benzamide (1.34 g, 2.54 mmol) was reacted in the same manner as in Reference Example 12 and post-treated to give the target compound (8
(20 mg, yield 67%) as colorless crystals. Melting point: 143-146 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3438, 2960, 293
2, 1734, 1668, 1564,1526, 1496, 1470, 1409, 1380,
1347, 1168, 1087, 1010.

Reference Example 31 3- (2-methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide 4-t-butyl- obtained in Reference Example 30 3- [3- (2
-Methoxy-3-methylphenyl) octanoylamino] -N- (2-oxoethyl) benzamide (809
mg, 1.68 mmol) was reacted in the same manner as in Reference Example 13 and post-treated to give the target compound (606 m
g, yield 78%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3474, 3428, 296
1, 2932, 1683, 1501,1470, 1427, 1406, 1367, 1142,
1011, 1102.

Reference Example 32 3- (2-methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-hydroxymethylphenyl) amide 4-t-butyl-3- [obtained in Reference Example 26 3- (2
-Methoxy-3-methylphenyl) octanoylamino] benzoic acid methyl ester (3.64 g, 8.02
mmol) was reacted in the same manner as in Reference Example 14 and worked up to give the target compound (3.23 g, yield 95%).
Was obtained as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3607, 3433, 296
0, 2932, 1731, 1679,1514, 1469, 1423, 1380, 1168,
1080, 1010.

Reference Example 33 3- (2-methoxy-3-methylphenyl) octanoic acid (5-bromomethyl-2-t-butylphenyl) amide 3- (2-methoxy-3-methylphenyl) amide obtained in Reference Example 32 Phenyl) octanoic acid (2-t-butyl-5-hydroxymethylphenyl) amide (1.21 g, 2.84 mm)
ol) and carbon tetrabromide (1.41 g, 4.26 mmol)
Was dissolved in dry dichloromethane (20 ml) under a nitrogen stream, and triphenylphosphine (1.4) was stirred under ice-cooling.
9 g, 5.69 mmol) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 7/1 to 2/1) to obtain the desired compound (1.08 g, yield). 78%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2960, 2932, 168
0, 1570, 1515, 1470,1422, 1366, 1300, 1167, 1081
.

Reference Example 34 3- (2-Methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-morpholin-4-ylmethylphenyl) amide The 3- (2-methoxy-3-methylphenyl) amide obtained in Reference Example 33 was obtained. Methoxy-3-methylphenyl) octanoic acid (5-bromomethyl-2-t-butylphenyl) amide (331 mg, 0.678 mmol)
l) was dissolved in anhydrous N, N-dimethylformamide (5 ml) under a nitrogen stream, and sodium iodide (102 m
g, 0.678 mmol) and morpholine (591 m
After stirring for 1 hour at 90 ° C. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and then the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the desired compound (305 mg, yield 91%) as a colorless foam. Obtained as material. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3467, 2962, 293
2, 1679, 1514, 1470, 1456, 1422, 1115, 1010, 864.

Reference Example 35 3- (2-methoxy-3-methylphenyl) octanoic acid (5-aminomethyl-2-t-butylphenyl) amide 3- (2-methoxy-3-methylphenyl) amide obtained in Reference Example 33 (Methylphenyl) octanoic acid (5-bromomethyl-2-t-butylphenyl) amide (741 mg, 1.52 mmol)
l) is converted to N, N-dimethylformamide (7.0 ml)
And water (1.4 ml), and a catalytic amount of sodium iodide was added thereto.
7 mg, 3.03 mmol) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate, washed successively with water and saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethanol (20 ml). Under a hydrogen atmosphere, 10% palladium-carbon (144 mg) was added, and the mixture was hydrogenated at room temperature for 13 hours. After filtering the reaction solution using Celite,
The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 5/1) to give the desired compound (622 mg, yield 96%) as a colorless foam. Obtained as material. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3436, 2960, 293
2, 1678, 1514, 1469,1423, 1366, 1167, 1087, 1011
.

REFERENCE EXAMPLE 36 3- (2-Methoxy-3-methylphenyl) octanoic acid [5- (acetylaminomethyl) -2-t-butylphenyl] amide 3- (2-methoxy) obtained in Reference Example 35 -3-Methylphenyl) octanoic acid (5-aminomethyl-2-t-butylphenyl) amide (315 mg, 0.742 mmol)
l), triethylamine (0.62 ml, 4.45 mm)
ol) and a catalytic amount of 4-dimethylaminopyridine were dissolved in dry dichloromethane (5.0 ml) under a nitrogen stream, and acetyl chloride (211 ml, 2.97) was stirred under ice-cooling and stirring.
(mmol) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: ethyl acetate) to give the desired compound (249 mg,
(72% yield) as colorless crystals. Melting point: 163-165 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3447, 2960, 2932, 1671,
1571, 1514, 1469, 1423, 1371, 1167, 1089, 1011.

Reference Example 37 3- (2-Methoxy-3-methylphenyl) octanoic acid {2-t-butyl-5-[(2,2-dimethylpropionylamino) methyl] phenyl} amide Obtained in Reference Example 35. 3- (2-methoxy-3-methylphenyl) octanoic acid (5-aminomethyl-2-t-butylphenyl) amide (301 mg, 0.709 mmol)
1) was reacted in the same manner as in Reference Example 36 (provided that pivaloyl chloride was used instead of acetyl chloride), and the mixture was post-treated to give the desired compound (149 mg, yield 41%).
Was obtained as colorless crystals. Melting point: 143-144 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3464, 2962, 293
3, 1661, 1571, 1514, 1469, 1422, 1367, 1087, 1011.

Reference Example 38 2,4-Dinitro-N-thiazol-2-ylbenzenesulfonamide 2-aminothiazole (2.10 g, 21.0 mmol)
l) and pyridine (3.24 ml, 40.0 mmol)
Was dissolved in dry dichloromethane (60 ml) under a stream of nitrogen, and a solution of 2,4-dinitrobenzenesulfonyl chloride (5.33 g, 20.0 mmol) in dichloromethane (130 ml) was added dropwise over 30 minutes with stirring under ice cooling. After that, the mixture was stirred at room temperature for 8 hours. After evaporating the solvent under reduced pressure, the obtained residue was diluted with ethyl acetate, washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained crude crystals were triturated with ether and hexane to give the desired compound (3.78 g) as red-brown crystals. Further, the mother liquor was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give the desired compound (119 mg) as red-brown crystals. (The target compound was obtained in a total of 3.90 g at a yield of 59%.) Melting point: 152-153 ° C; IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3303, 3109, 161
7, 1601, 1526, 1519,1511, 1454, 1341, 1313, 1283,
1137, 1062, 922, 846.

Reference Example 39 3- (2-Methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-{[(2,4-dinitrobenzenesulfonyl) thiazol-2-ylamino] methyl}
Phenyl) amide 3- (2-methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-hydroxymethylphenyl) amide (781 mg, 1.83 mm) obtained in Reference Example 32
ol), the 2,4-dinitro-N- obtained in Reference Example 38.
Thiazol-2-ylbenzenesulfonamide (664
mg, 2.01 mmol) and triphenylphosphine (576 mg, 2.20 mmol) were dissolved in dry benzene (14 ml) under a nitrogen stream, and dimethyl azodicarboxylate (321 mg, 2.20 m) was stirred at room temperature.
mol) of benzene (1 ml), and the mixture was stirred at the same temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent:
Purification using hexane / ethyl acetate = 2/1 to 1/1 gave the target compound (580 mg, yield 43).
%) As a foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3474, 3093, 296
0, 2932, 2873, 1732,1680, 1607, 1542, 1509, 1471,
1423, 1375, 1344, 1161, 1100, 1011, 834. Reference Example 40 3- (2-Methoxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (thiazol-2-ylaminomethyl) phenyl] amide 3- (2- Methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-
{[(2,4-dinitrobenzenesulfonyl) thiazol-2-ylamino] methyl} phenyl) amide (57
5 mg, 0.779 mmol) in dry dichloromethane (6 ml) and n-propylamine (3 ml)
Was added and stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give the desired compound (381 mg, yield 96). %) As an orange foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3430, 2960, 293
2, 2862, 1732, 1679, 1536, 1469, 1423, 1153, 1011.

Reference Example 41 3- {4-t-butyl-3- [3- (2-methoxy-3)
-Methylphenyl) octanoylamino] phenyl} propionic acid ethyl ester 3- (2-methoxy-3-methylphenyl) octanoic acid (2-t-butyl-5-hydroxymethylphenyl) amide (Reference Example 32) 990mg, 2.33mm
ol) was dissolved in dichloromethane (15 ml), manganese dioxide (10.0 g) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was filtered using celite, the filtrate was concentrated under reduced pressure to give an intermediate compound (944 m
g) was obtained. Then, 55% oily sodium hydride (1
17 mg, 2.67 mmol) in a nitrogen stream under dry N,
After suspending in N-dimethylformamide (10 ml), 2-ethylphosphonoacetic acid ethyl ester (0.531 ml, 2.67 mmol) was added dropwise over 5 minutes under ice-cooling and stirring, followed by stirring at room temperature for 30 minutes. Under ice-cooling and stirring, a solution of the intermediate compound (944 mg) obtained above in N, N-dimethylformamide (8 ml) was added dropwise over 5 minutes.
Stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate, washed successively with water and saturated saline, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain an intermediate compound (1.24 g). Next, the obtained intermediate compound was dissolved in ethanol (20 ml), and 10% palladium carbon was added under a hydrogen atmosphere.
Catalytic reduction was performed at room temperature for 2 hours. After the reaction solution is filtered using celite, the filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give the desired compound (1.08 g, 93% yield) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3470, 3431, 296
0, 2932, 2873, 2862,1728, 1679, 1514, 1469, 1422,
1375, 1302, 1166, 1012.

Reference Example 42 3- {4-t-butyl-3- [3- (2-methoxy-3)
-Methylphenyl) octanoylamino] phenyl} propionic acid 3- {4-t-butyl-3- [3
-(2-Methoxy-3-methylphenyl) octanoylamino] phenyl} propionic acid ethyl ester (1.
07g, 2.15 mmol) was reacted in the same manner as in Reference Example 7 and post-treated to give the target compound (1.00
g, quantitative) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2960, 2932, 287
3, 2861, 1741, 1711,1679, 1514, 1469, 1422, 1294,
1167, 1011.

Reference Example 43 3- (2-Methoxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (2-dimethylcarbamoylethyl) phenyl] amide 3- {4 -T-butyl-3- [3
-(2-Methoxy-3-methylphenyl) octanoylamino] phenyl} propionic acid (300 mg, 0.6
42 mmol), triethylamine (0.536 ml,
3.85 mmol), dimethylamine hydrochloride (79 m
g, 0.963 mmol) and 4-dimethylaminopyridine (78 mg, 0.642 mmol) were dissolved in dry dichloromethane (5 ml) under a nitrogen stream.
4,6-triisobenzenesulfonyl chloride (97 m
g, 0.321 mmol) and stirred at room temperature for 30 minutes. Again, 2,4,6-triisobenzenesulfonyl chloride (97 mg, 0.321 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, the same amount of reagent was added, and the mixture was stirred at the same temperature for 1 hour. After distilling off the solvent under reduced pressure,
The obtained residue was diluted with ethyl acetate, washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the desired compound (1).
27 mg, yield 40%) as a colorless foam. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3437, 2959, 293
2, 2862, 1676, 1637,1567, 1510, 1469, 1421, 1401,
1366, 1167, 1147, 1011.

Reference Example 44 4-methoxy-3,5-dimethylbenzoic acid methyl ester 55% oily sodium hydride (19.7 g, 0.451)
mol) were suspended in dimethylformamide (200 ml), and a solution of 4-hydroxy-3,5-dimethylbenzoic acid (30.0 g, 0.18 mol) in dimethylformamide (200 ml) was stirred under ice-cooling for 1.5 hours. After the addition, methyl iodide (28.1 ml,
0.45 mol), and the mixture was returned to room temperature and stirred for 4 hours. After the completion of the reaction, water was added under ice-cooling and stirring, the temperature was returned to room temperature, and the mixture was extracted with ethyl acetate. Dry using sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure to obtain the target compound (25.9 g, yield 74%) as a colorless oily substance. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2954, 2928, 285
7, 1714, 1604, 1438,1320, 1170, 1016, 906.

Reference Example 45 4-methoxy-3,5-dimethylbenzyl alcohol 4-methoxy-3,5-dimethylbenzoic acid methyl ester obtained in Reference Example 44 (25.8 g, 0.133 m
ol) in tetrahydrofuran (100
ml) and diisobutylaluminum hydride (1.0 M hexane solution, 200 m 2) was stirred at −78 ° C.
1,0.200 mol) was added dropwise, followed by stirring at room temperature for 5 hours. After completion of the reaction, methanol (50 ml) was added under ice cooling.
Was added thereto, and the mixture was stirred at room temperature for 30 minutes to decompose excess reagent. Then, saturated saline (10 ml), ether (500 ml) and magnesium sulfate (20 g) were added, and the mixture was stirred at room temperature for 1 hour. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3 / 1-2).
/ 1) to give the desired compound (1)
(2.8 g, 54%) as a colorless oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 3609, 2943, 288
2, 2829, 1485, 1384, 1377, 1142, 1017, 1010, 874.

Reference Example 46 4-methoxy-3,5-dimethylbenzaldehyde 4-methoxy-3,5-dimethylbenzyl alcohol obtained in Reference Example 45 (12.8 g, 70.5 mmol)
Manganese dioxide (38.4 g) was added to a methylene chloride (150 ml) solution of, and the mixture was stirred at room temperature for 2.5 hours.
Further, manganese dioxide (38.4 g) was added, and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. After filtering the reaction solution using Celite,
The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 6/1) to give the target compound (10.5 g, quantitative) as colorless. As an oil. IR spectrum (CHCl ₃ ) ν _max cm ^-1 : 2958, 2945, 283
2, 2736, 1690, 1598,1482, 1386, 1303, 1135, 1011
.

Test Example 1 LPO production inhibitory action Biochemical and Biophysical Research Communications, Vol. 95, No. 734 (198)
0) According to the method of Malvy et al. Described in [ BBRC. , 95 , 734 (1980).], The following experiment was conducted. (1) Reagent (a) 0.15 M potassium chloride (b) 0.1 M Tris-HCl buffer (pH 7.
4) (c) 0.5 mM ferrous sulfate hemihydrate (d) 50 mM L-cysteine (e) 0.67% 2-thiobarbituric acid (TB
A) 50% acetic acid solution (f) 10% trichloroacetic acid (TCA) (g) Solution A (a: b = 2: 1) (h) Solution B (c: d = 1: 1) (2) Enzyme solution ( Preparation of rat liver microsomes Wistar Imado rats (male 150 g-200 g) were anesthetized with pentobarbital (40 mg / kg, i.
p. ) And exsanguinated from the carotid artery. Immediately after removing the liver, it was washed with physiological saline and 0.25 of 5 times the wet weight of the liver.
M sucrose (0.001 M Tris-HCl buffer, pH 7.5) was added, and homogenized with a potter-type homogenizer. The obtained homogenate is added to Tommy RD.
-20III refrigeration centrifuge No. 6000 with 5 rotors
Centrifuged at 4 ° C. for 20 minutes at rpm. The supernatant was centrifuged at 30,000 rpm for 60 minutes at 4 ° C. in a Hitachi 65P ultracentrifuge RP30 rotor to obtain a microsomal fraction. The obtained microsomes were suspended in the above-mentioned buffer having a volume 0.38 times the wet weight of the liver, gently homogenized with a potter-type homogenizer, and then placed in a plastic vial.
Aliquots of each ml were stored at -80 ° C. The activity of each microsome was examined for each preparation.
9 ml of solution A was added to 1 and used. (3) Method To 1200 μl of solution A, 15 μl of a test compound dissolved in DMSO was added, and then 300 μl of an enzyme solution (rat liver microsome) was added, followed by preincubation at 37 ° C. for 5 minutes. The enzyme reaction was started by adding 30 μl of solution B, and after incubation at 37 ° C. for 30 minutes, 3 ml of ice-cooled 10% TCA was added to stop the reaction. After centrifugation at 3000 rpm for 10 minutes,
1 ml of 0.67% TBA acetic acid solution was added to
For 15 minutes. After cooling in running water, O
D was measured. Table 2 shows the results.

[0168]

[Table 2] ──────────────────────── Test compound% inhibition rate (concentration) ────────────── Example 3 98% (2.5 μg / ml) Example 4 98% (2.5 μg / ml) ────────.

Test Example 2 ACAT Inhibitory Activity (Liver Microsome) The ACAT inhibitory activity was determined according to Journal of Biological Chemistry, vol. 259, p. 815 (1984).
Years) [ J. Biol. Chem. , 259 , 815 (1984).], Which is a modified version of the in vitro test method of Ross et al. That is, from a Sprague-Dawley rat in which rat liver microsomes were fasted overnight, the method of Ross et al. , Ross et al ., Journal of Biological Chemistry, 257, 2453 (1982) [ J. Bio
l. Chem. , 257 , 2453 (1982).]｝, and the enzyme fraction was obtained. 100 μM [ ¹⁴ C] oleoyl (oleoy
l) -CoA, 2 mM dithiothreitol and 80 μM
To a 0.15 M potassium phosphate buffer (pH 7.4) containing bovine serum albumin, 60-100 μg of the microsomal fraction was added, and a fixed concentration of a test compound in dimethyl sulfoxide (DMSO) 5 μl (2.5% v / v) After the addition of v), the above-mentioned potassium phosphate buffer was added, and the total amount was 2
The volume was adjusted to 00 μl and heated at 37 ° C. for 4 minutes. Ethanol 1
After adding ml, the mixture was stirred to stop the enzyme reaction. 2 ml of hexane was added to the reaction solution, and after stirring, 1 ml of the hexane layer was removed, the solvent was distilled off under a nitrogen stream, and cholesterol oleate produced by the enzyme reaction was subjected to silica gel thin layer chromatography (developing solvent: hexane / hexane). After purification using diethyl ether / acetic acid = 85/15/1), the radioactivity was measured and defined as ACAT activity. The inhibition rate (%) was determined from the control activity value and the activity value when a test compound at a certain concentration was used, and the concentration (IC ₅₀ ) of the test compound required to inhibit ACAT activity by 50% was calculated. Table 3 shows the results.

[0170]

[Table 3] {Test compound IC ₅₀ (ng / ml)} {Example 3 39.4 Example 4 32.4}.

Test Example 3 ACAT Inhibitory Activity (Macrophage) β-Very low density lipoprotein (hereinafter β-VLD)
Preparation of L): Japanese white rabbits loaded with a 2% cholesterol diet for 2 weeks were fasted overnight, and blood samples were collected using ethylenediaminetetraacetic acid (final concentration: 5 mM, hereinafter abbreviated as EDTA) as an anticoagulant. . From the obtained plasma, a method such as Hatch and Lees [Hatch, FT. And Lee
s, RS., Adv . Lipid Res. , 6 , 1-68, (1968).
Prepare LDL (d <1.006 g / ml), 150 m
It was dialyzed (4 ° C.) against 10 mM sodium phosphate buffer (pH 7.4) containing M sodium chloride and used for the experiment. Preparation of macrophages: macrophages (hereinafter Mφ
Is abbreviated to the method of Edelson and Cohn [Edelso
n, PJ. and Cohn, ZA., 1976, in IN VITRO Methods in Cel
l-Mediated and Tumor Immunity, eds.Bloon, BR and Dav
id, JR., (Academic, New York), 330-340.]
The mice were collected from the abdominal cavity of a Y mouse (body weight: 20 to 30 g) using physiological saline (hereinafter abbreviated as PBS). These were pooled, and Mφ was collected by centrifugation at 4 ° C., 400 × g for 10 minutes, PBS was added, and Mφ was washed by centrifugation again. Mφ is 10% (vol /
vol) calf serum (FCS), penicillin (100un
it / ml) and streptomycin (100 μg /
ml) containing Dulbecco's modified Eagle's medium (D
The cells were suspended in MEM) so that the number of cells became 3 × 10 ⁶ cells / ml. Each 1 ml of this cell suspension is 35 ×
A 10 mm plastic petri dish was inoculated, transferred to a CO ₂ incubator (5% CO ₂ /95% air), and cultured at 37 ° C. for 2 hours. After washing twice with PBS, it was used for experiments. Measurement of ACAT inhibitory activity at Mφ: ACAT inhibitory activity at Mφ was determined by the method of Brown et al. [Brown, MS., Go
ldsteinJL., Krieger, M., Ho, YK. and Anderson, RGW. (197
9), J. Cell Biol. , 82 , 597-613]. β-
VLDL (final concentration: 50 μg cholesterol / m
l), [ ¹⁴ C] oleate / albumin (final concentration: 0.2
test compound dissolved in mM oleic acid, 0.6 mg / ml albumin) and ethanol was added to Mφ,
The cells were cultured in a CO ₂ incubator for 3 hours. PB cells
After washing three times with S, lipids were extracted with 1 ml of hexane / isopropanol (3: 2, vol / vol). After evaporating the extract to dryness under a nitrogen stream, using a silica gel thin layer chromatograph, hexane: diethyl ether: acetic acid = 85: 15: 1 with a developing solvent of Choline.
lesteryl [ ¹⁴ C] oleate was fractionated. By comparing the radioactivity of the Cholesteryl [ ¹⁴ C] oleate fraction between the control group and the test compound-added group, the concentration IC ₅₀ of the test compound required to inhibit ACAT activity by 50% was calculated.
Table 4 shows the results.

[0172]

[Table 4] {Test compound IC ₅₀ (ng / ml)} {Example 3 15.1 Example 4 14.9}.

Formulation Example 1 Hard Capsule Each of the standard bisecting hard gelatin capsules is filled with 100 m
A unit capsule is prepared by filling g of powdered compound of Example 6, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate, washing and drying.

[0174]

The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof has both excellent LDL oxidation inhibitory activity and ACAT inhibitory activity, exhibits excellent oral absorbability, and has toxicity. Since it is weak, it is useful as a medicine [especially, a therapeutic or prophylactic (particularly a therapeutic) for arteriosclerotic diseases].

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/195 A61K 31/195 31/275 31/275 31/415 31/415 31/42 31/42 31/425 31/425 31/495 31/495 31/535 605 31/535 605 31/54 31/54 C07C 237/42 C07C 237/42 251/36 251/36 251/48 251/48 255/44 255/44 271/20 271 / 20 C07D 233/64 101 C07D 233/64 101 233/88 233/88 263/32 263/32 263/48 263/48 277/28 277/28 277/42 277/42 295/12 295/12 AZ // C07C 59/64 C07C 59/64 69/734 69/734 Z (72) Inventor Seiichiro Koga 2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (13)

[Claims] 1. A compound of the general formula (I) [Wherein, R ^1a represents a hydroxyl group, and R ^1b and R ^1c are the same or different and each represent a hydrogen atom or C ₁
-C ₄ represents an alkyl group (provided that one of R ^1b and R ^1c represents a C ₁ -C ₄ alkyl group.), R ² represents a C ₄ -C ₆ alkyl group, R ³ is a nitrogen A 5- or 6-membered cyclic saturated heterocyclyl group containing one or two heteroatoms selected from the group consisting of oxygen and sulfur atoms; and one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms Including 5 or 6 members
5- or 6-membered cyclic heteroarylamino group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; cyano group; hydroxyl group; hydroxyiminomethyl group; carboxy group A carbamoyl group; a mono (C ₁ -C ₆ alkyl) carbamoyl group; a di (C ₁ -C ₆ alkyl) carbamoyl group;
Indicates ₁ -C ₆ alkanoylamino group, A is a single bond or a C ₁ -C ₄ alkylene group. Or a pharmacologically acceptable salt thereof. 2. The phenol derivative according to claim 1, wherein R ^1b and R ^1c are the same or different and are a hydrogen atom, a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof. 3. The phenol derivative according to claim 1, wherein R ^1b and R ^1c are the same or different and each is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. 4. The phenol derivative according to claim 1, wherein R ^1b and R ^1c are methyl groups, or a pharmacologically acceptable salt thereof. 5. The phenol derivative according to claim 1, wherein R ² is butyl, isobutyl, pentyl or hexyl, or a pharmaceutically acceptable salt thereof. 6. The phenol derivative according to claim 1, wherein R ² is a pentyl group, or a pharmaceutically acceptable salt thereof. 7. The method according to claim 1, wherein R ³ is a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an imidazolylamino group, or a thiazolylamino group. An oxazolylamino group, a cyano group, a hydroxyl group, a hydroxyiminomethyl group, a carboxy group, a carbamoyl group, a mono (C ₁ -C ₄ ) alkylcarbamoyl group, a di (C ₁ -C ₄ alkyl) carbamoyl group, a butyrylamino group or A phenol derivative which is a pivaloylamino group or a pharmacologically acceptable salt thereof. 8. The method according to claim 1, wherein R ³ is 4-morpholinyl, imidazolyl, thiazolyl, oxazolyl, 2-thiazolylamino, cyano, or carbamoyl. A methylcarbamoyl group, an ethylcarbamoyl group, an N, N-dimethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group,
A phenol derivative which is an N, N-diethylcarbamoyl group or a pivaloylamino group, or a pharmacologically acceptable salt thereof. 9. The method according to claim 1, wherein R ³ is a 2-oxazolyl group, a cyano group, a carbamoyl group, a methylcarbamoyl group or an N, N-dimethylcarbamoyl group. A phenol derivative or a pharmacologically acceptable salt thereof. 10. The phenol derivative according to claim 1, wherein A is a single bond, a methylene group, an ethylene group or a trimethylene group, or a pharmaceutically acceptable salt thereof. 11. The phenol derivative according to claim 1, wherein A is a single bond or a methylene group, or a pharmaceutically acceptable salt thereof. 12. A compound of the following group selected from claim 1: 3- (2-hydroxy-3-methylphenyl) octanoic acid (2-t-butyl-5-morpholin-4-ylmethylphenyl) amide; 3- (2-hydroxy-3-methylphenyl) octanoic acid (2-t-butyl-5-oxazol-2-ylphenyl) amide, 3- (2-hydroxy-3-methylphenyl) octanoic acid [2-t -Butyl-5- (thiazol-2-ylaminomethyl) phenyl] amide, 4-t-butyl-3- [3- (2-hydroxy-3-methylphenyl) octanoylamino] benzamide, 3- (2- [Hydroxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (2-dimethylcarbamoylethyl) phenyl] amide, 3- (2-hydroxy-3- [Tylphenyl) octanoic acid [5- (acetylaminomethyl) -2-t-butylphenyl] amide, 3- (2-hydroxy-3-methylphenyl) octanoic acid [2-t-butyl-5- (2,2- Dimethylpropionylaminomethyl) phenyl] amide, 3- (4-hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-morpholin-4-ylmethylphenyl) amide, 3- (4-hydroxy -3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-thiazol-2-ylphenyl) amide, 3- (4-hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl) -5-thiazol-2-ylmethylphenyl) amide, 3- (4-hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl) 5-oxazol-2-ylphenyl) amide, 3- (4-hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-cyanophenyl) amide, 3- (4-hydroxy- 3,5-dimethylphenyl) octanoic acid [2-t-butyl-5- (hydroxyiminomethyl) phenyl] amide, 4-t-butyl-3- [3- (4-hydroxy-3,5
-Dimethylphenyl) octanoylamino] benzamide, 3- (4-hydroxy-3,5-dimethylphenyl) octanoic acid (2-t-butyl-5-carbamoylmethylphenyl) amide, 4-t-butyl-3- [ 3- (4-hydroxy-3,5
-Dimethylphenyl) octanoylamino] -N-methylbenzamide or 4-tert-butyl-3- [3- (4-hydroxy-3,5
-Dimethylphenyl) octanoylamino] -N, N-
Dimethylbenzamide or a pharmacologically acceptable salt thereof. 13. A medicament comprising the phenol derivative or the pharmaceutically acceptable salt thereof according to claim 1 selected from claims 1 to 12.