JP2002326935A - Medicine containing nitrogen-containing heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine containing a nitrogen-containing heterocyclic derivative, its pharmacologically permissible salt, its ester or other derivative, and to provide an agent for inhibiting ileac bile acid transporter. SOLUTION: The medicine contains a nitrogen-containing heterocyclic derivative expressed by general formula (Ia) [R<1> , R<2> , R<3> and R<4> are each H, hydroxy or a lower alkoxy; R<5> is an aryl or a substituted aryl; R<6> is a group of CONR<7> R<8> (R<7> is a 1-10C alkyl or the like; and R<8> is an aryl or the like)], its pharmacologically permissible salt, its ester or other derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the above general formula (I)
The present invention relates to a medicament containing a compound having a), a pharmacologically acceptable salt thereof, an ester or other derivative thereof.

The present invention also relates to a compound having the above general formula (I) [including a compound having the general formula (Ia)] or a compound having the above general formula (II), a pharmaceutically acceptable salt thereof, The present invention relates to an ileal bile acid transporter inhibitor (particularly, a therapeutic or preventive agent for hyperlipidemia and / or arteriosclerosis) containing an ester or other derivative as an active ingredient.

[0003]

2. Description of the Related Art Hyperlipidemia is one of the three major risk factors for ischemic heart disease, and it is widely known that lowering high blood cholesterol is particularly useful for treating or preventing ischemic heart disease. It recognized. As currently available therapeutic agents for hyperlipidemia, for example, HMG-CoA reductase inhibitors and anion exchange resins are known, and these agents treat or prevent hyperlipidemia or arteriosclerosis. [Am. J. Cardiol., 76, 899-905 (199
Five)].

[0004] HMG-CoA reductase inhibitors not only have a cholesterol synthesis inhibitory effect, but also have LDL (low depletion) in the liver.
It has the effect of taking up blood cholesterol and promoting its excretion into bile by increasing nsity lipoprotein (Science, 232, 34 (1986)).
The usefulness and safety of these drugs are widely recognized and used by many patients.

[0005] Further, the anion exchange resin adsorbs bile acids and prevents reabsorption of bile acids in the intestine, thereby promoting the conversion of cholesterol to bile acids in the liver. N. Engl. J. Med., 302, 1219
-1222 (1980)]. As such an anion exchange resin, for example, a method using cholestyramine has already been put to practical use, and since the drug is hardly absorbed into the body, hyperlipidemia in children who are required to be more safe is required. It is regarded as a first-line drug in the treatment of diseases. However, cholestyramine has the drawbacks that it is extremely difficult for patients to take because cholestyramine has an extremely large dose per dose and further has a rough feel of the resin when taken in the mouth. In addition, the anion exchange resin also adsorbs and discharges certain kinds of vitamins, minerals, drugs, and the like. Therefore, it is necessary to consider replenishment of vitamins and changes in the administration method of concomitant drugs, and thus there are many problems.

In recent years, a protein has been cloned that acts in the first step of bile acid reabsorption in the ileum, an ileal bile acid transporter [Wong MH et al, J. Bio.
l. Chem., 269, 1340-1347 (1994)]. It is thought that if ileal bile acid transporter activity can be inhibited, a pharmacological effect similar to that of cholestyramine can be obtained. Attempted [Wess
G. et al, J. Med. Chem., 37, 873-875 (1994)].

Compound (I) of the present invention [Compound (Ia)
Or compounds similar to (II) include the following.

(1) Japanese Patent Application Laid-Open No. 7-145152 (W
This publication discloses the following general formula (a)

[0009]

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[In the above compound (a), A is a carbonyl group, B is CR ³ R ⁴ , R ³ and R ⁴ are the same or different and are each a substitutable lower alkyl group, and W is an oxygen atom. X ¹ and X ² are trifluoromethyl groups, hydroxy groups and the like, and Y ¹ , Y ² , Y ³ , Y ⁴ and Z are hydrogen atoms, halogens, alkyls and the like. ] Is disclosed.

The above compound (a) has an oxo group as an essential substituent at the 2-position of the quinoline skeleton, but the compound (I) of the present invention is characterized in that it does not have an oxo group at the 2-position of the quinoline skeleton. And the compound (a).

The compound (a) has an oxo group as an essential substituent at the 4-position of the quinoline skeleton, whereas the compound (II) of the present invention has a hydroxy group at the 4-position of the quinoline skeleton. And the compound (a).

Further, the above compound (a) has a substitutable lower alkyl group at the 3-position of the quinoline skeleton, and the compounds (I) and (II) of the present invention have a disubstituted carbamoyl group as an essential substituent. In that it differs from the above compound (a).

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most, only the following compounds are disclosed in the exemplified compound table.

[0015]

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The above compound (a) is disclosed as a smooth muscle relaxant, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(2) JP-A-6-316522 (E
P614664A) In this publication, a 1,7-disubstituted-4-oxo-3-quinolinecarboxylic acid derivative represented by the following general formula (b)

[0018]

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[In the above compound (b), R ¹ is a protecting group for hydrogen or a carboxyl group, R ² and R ³ are organic groups, and Z is CH. ] Is disclosed.

The compound (b) has a carboxyl group or a protected carboxyl group at the 3-position of the quinoline skeleton, and the compounds (I) and (II) of the present invention have a di-substituted carbamoyl group as an essential substituent. Is different from the above compound (b).

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0022]

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The above compound (b) is disclosed as a cell adhesion inhibitor, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(3) JP-A-4-226980 (E
This publication discloses the following general formula (c)

[0025]

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[In the above compound (c), R ¹ is an aryl group, R ² is a hydroxy group, R ³ is hydrogen or the like, R ⁴ is a lower alkyl group, and A is CH or the like. X is -NH-, and n is 0 or 1. ]
Are disclosed.

The above-mentioned compound (c) has a carbamoyl group mono-substituted with an azabicyclooctane ring or the like at the 3-position of the quinoline skeleton as an essential substituent. Compounds (I) and (II) of the present invention The difference is that the quinoline skeleton has a carbamoyl group di-substituted with an alkyl or alkenyl group and a substitutable aryl group at the 3-position.

The compound (b) has a hydroxy group as an essential substituent at the 4-position of the quinoline skeleton.
The compound (I) of the present invention has the above-mentioned compound (b) in that it has an oxo group as an essential substituent at the 4-position of the quinoline skeleton.
Is different from

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0030]

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The compound (c) has been disclosed as a 5-HT3 antagonist and an antiemetic agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(4) JP-A-57-171975 (EP59698A) This publication discloses the following general formula (d)

[0033]

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[In the above compound (d), R ¹ , R ² and R ³ are hydrogen and the like, R ⁴ is lower alkyl, an optionally substituted phenyl group and the like, and R ⁵ is an optionally substituted phenyl group. a phenyl group, R ¹³ is a lower alkyl group, a ¹
Is a hydroxy group or the like, and A ² is an oxygen atom or the like. ]
Are disclosed.

The above compound (d) has an oxo group or the like as an essential substituent at the 2-position of the quinoline skeleton, but the compound (I) of the present invention has no substituent at the 2-position of the quinoline skeleton. Is different. Further, the compound (d) has a hydroxy group or the like as an essential substituent at the 4-position of the quinoline skeleton and has no oxo group, but the compound (I) of the present invention has an oxo group as an essential substituent. Is also different.

Further, the gazette does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0037]

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The above compound (d) is disclosed as a cell-mediated immunity enhancer, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(5) Japanese Patent Application Laid-Open No. 2-152996 This publication discloses the following general formula (e)

[0040]

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[In the above compound (e), R ¹ is a phenyl group, R ² is a hydrogen atom or a lower alkyl group, R ³ is a phenyl lower alkyl group which may have a substituent, or R ² and R ³ may form a heterocyclic ring with the nitrogen atom to which they are bonded. ] Is disclosed.

The above compound (e) has an oxo group as an essential substituent at the 2-position of the quinoline skeleton, but the compound (I) of the present invention has no substituent at the 2-position of the quinoline skeleton. Different. Further, the compound (e) has a hydroxy group or the like as an essential substituent at the 4-position of the quinoline skeleton, but the compound (I) of the present invention is different in that it has an oxo group as an essential substituent. The compounds (I) and (II) of the present invention have an aryl group which may be substituted as an essential substituent of the carbamoyl group at the 3-position of the quinoline skeleton. Also has no aryl group which may be substituted as a substituent.

Furthermore, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) is selected, at most only the following compounds are disclosed.

[0044]

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The above compound (e) is disclosed as a leukotriene antagonist, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(6) US Pat. No. 5,622,967 This publication discloses the following general formula (f):

[0047]

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[In the above compound (f), X is -CO
A group having N (R) ₂ , wherein R is a lower alkyl group, a hydroxy lower alkyl group, an aralkyl group, etc., Y is an aryl group, and Z is a heterocyclic ring. ] Is disclosed.

The compound (f) has a ring such as a heterocyclic ring as an essential substituent at the 7-position of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention have a heterocyclic ring at the 7-position of the quinoline skeleton. They differ in that they do not have a ring such as a ring. Compounds (I) and (II) of the present invention have an aryl group which may be substituted as an essential substituent of the carbamoyl group at the 3-position of the quinoline skeleton.
Another difference is that it does not have an aryl group which may be substituted as a substituent of the carbamoyl group.

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0051]

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The above compound (f) is disclosed as a calpain inhibitor, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(7) JP-A-6-271570 (E
This publication discloses the following general formula (g)

[0054]

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[0055] In [the compound (g), A is CH, R ₁ and R ₂ are a hydrogen atom, a halogen or the like, R ₃
Is a heterocyclic ring such as piperazine, R ₄ is an amine residue, R ₅ is a hydrogen atom, R ₆ is a group of —NR ₁₇ R ₁₈ , R ₁₇ and R ₁₈ are a hydrogen atom, an alkyl Group. And an intermediate of the compound (g), the following formula (g ′)

[0056]

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[In the above compound (g '), A,
R ₁ , R ₂ , R ₄ , R ₅ and R ₆ have the same meanings as described above, and E is a halogen atom. ] Is disclosed.

The compounds (g) and (g ′) have a hydrogen or alkyl group as a substituent of the carbamoyl group at the 3-position of the quinoline skeleton, but the compounds (I) and (II) of the present invention are essential. Are different in that they have an optionally substituted aryl group.

Further, the above compound (g) has a ring such as piperazine as an essential substituent at the 7-position of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention have a ring at the 7-position of the quinoline skeleton. Is not present as a substituent.
The compound (g ′) has a halogen atom as an essential substituent at the 7-position of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention have a halogen atom at the 7-position of the quinoline skeleton. It is also different in that it does not.

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0061]

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Further, the above compound (g) is disclosed as an antiviral agent, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(8) WO98 / 23608 In this publication, the following general formula (h)

[0064]

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[In the above compound (h), R ¹ is a heterocyclic ring such as pyridine, U is a single bond or alkylene, and W is a group having -CON (R ¹⁰ )-(alkylene)-. , R ¹⁰ is hydrogen, alkyl, aryl, aralkyl group, R ¹⁴ is phenyl (C ₁ -C ₄₎ alkyl group, Y is a carbamoyl group substituted. ] Is disclosed.

The compounds (I) and (II) of the present invention have an alkyl or alkenyl group and an optionally substituted aryl group as essential substituents of the carbamoyl group at the 3-position of the quinoline skeleton. The compound (h) is different in that it does not have an alkyl group or an alkenyl group and an aryl group which may be substituted at the same time as a substituent of the carbamoyl group.

Further, the compound (h) has a heterocyclic ring such as pyridine as an essential substituent in the benzene ring portion of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention Another difference is that the quinoline skeleton has no hetero ring as a substituent in the benzene ring portion.

Further, the compounds (I) and (II) of the present invention
Has an optionally substituted aryl group as an essential substituent at position 1 of the quinoline skeleton, and the compound (h)
Are also different in that they do not have an aryl group at position 1 of the quinoline skeleton.

Further, in this gazette, compounds having a structure similar to those of the compounds (I) and (II) of the present invention are not specifically disclosed at all, and the compound (I) of the present invention is not disclosed. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0070]

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The above compound (h) has been disclosed as an anti-inflammatory agent and an anticancer agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(9) US Pat. No. 4,959,363 In this publication, the following general formula (i)

[0073]

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[In the above compound (i), R ¹ is a phenyl group, R ² and R ⁶ are a hydrogen atom, a halogen atom, etc., R ⁷ is a heterocycle such as a pyridyl group, and R is a hydrogen atom. , An alkyl group or the like. ] Is disclosed.

The compound (i) has a mono-substituted carbamoyl group at the 3-position of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention have a di-substituted carbamoyl group. Different.

Further, the above compound (i) has a heterocyclic ring such as pyridine as an essential substituent at the 7-position of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention have The difference is that the compound does not have a hetero ring as a substituent.

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0078]

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The above compound (i) has been disclosed as an antibacterial agent for herpes virus and the like, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(10) JP-A-2-138260 (EP317991A) In this publication, the following general formula (j)

[0081]

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[In the above compound (j), WXYZR
Is N-CH = CC = O, N-CH_Two-CH-C = O
Or N-CH_Two-C = C-OH, and R¹And R^TwoIs
A hydrogen atom, a lower alkoxy group, ^ThreeIs phenyl,
A heterocyclic ring such as pyridyl, wherein m and n are 0 or 1
Is a number. ] Is disclosed.

The compound (j) has a monosubstituted carbamoyl group at the 3-position of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention have a disubstituted carbamoyl group. Different.

Further, this publication does not specifically disclose any compound having a structure similar to those of the compounds (I) and (II) of the present invention, and discloses the compound (I) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0085]

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The above compound (j) has been disclosed as an analgesic and an anti-inflammatory agent, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(11) US Pat. No. 3,819,637 This publication discloses the following general formula (k)

[0088]

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[In the above compound (k), R ₁ ″ ″ is
R ₂ ′ ″ and R ₃ ″ ″ are hydrogen, R ₆ is hydrogen or an alkyl group, and m is 0 or 1. ] Is disclosed.

The compound (k) has an ester group as an essential substituent at the 3-position of the quinoline skeleton, but the compounds (I) and (II) of the present invention have no ester group and are disubstituted. The difference is in having a carbamoyl group.

The compound (k) has a phenyl group as an essential substituent at the 2-position of the quinoline skeleton, whereas the compounds (I) and (II) of the present invention have a substituent at the 2-position of the quinoline skeleton. They differ in not having them.

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0093]

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The compound (k) has been disclosed as a contraceptive and a cholesterol-lowering agent, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(12) JP-A-1-319463 (EP343398A) This publication discloses the following general formula (L)

[0096]

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[In the above compound (L), R¹Is
Time C₁~ C_Three1, 2 or 3 positions with alkyl or halogen
C that may be replaced₆~ C_TenRepresents an aryl, R^TwoIs C₁
~ C_FourAlkyl, C₁~ C_FourX represents alkoxy or the like;^TwoIs
Hydrogen, C₁~ C_ThreeX represents alkyl or halogen;^ThreeIs
Hydrogen, C ₁~ C_ThreeAlkyl, C₁~ C_ThreeAlkoxy or halo
A represents -CH- or the like, and Y represents an ester
Group, -CONR^FourR^FiveAnd R^FourIs C₁~ C_ThreeAlkyl
And R^FiveIs C₁~ C_ThreeAlkyl, optionally substituted
And optionally phenyl. ] Is disclosed.
ing.

The compound (L) is a compound of the formula (C ₆₎ which may be substituted at the 1-position of the quinoline skeleton with a halogen or an alkyl group.
Although having a C ₁₀ aryl group, the compounds (I) and (II) of the present invention have a difference in that, when the compound has an aryl group substituted at the 1-position of the quinoline skeleton, the compound has a hydroxy group or a lower alkoxy group as a substituent. I do.

The compound (L) includes a compound having a C ₁ -C ₄ alkoxy group at the 7-position of the quinoline skeleton and an unsubstituted aryl group at the 1-position of the quinoline skeleton.
When the compound (Ia) of the present invention has an unsubstituted aryl group at the 1-position of the quinoline skeleton, R ² is a hydrogen atom and R ^{3 is}
Is different from the above-mentioned compound (L) and the compound of the present invention also in that a compound having a lower alkoxy group is excluded.

Further, this publication does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0101]

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The above compound (L) is disclosed as an antibacterial agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(13) JP-A-1-254666 (EP310917A) In this publication, the following general formula (M)

[0104]

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[In the above compound (M), R ¹ represents phenyl which may be optionally substituted, and R ² represents hydrogen, C ₁
-C ₄ represents alkyl, etc., X ² is hydrogen, a nitro, etc., X ³ is hydrogen, a halogen, etc., A is shows the -CH- etc., Y is carboxyl group, an ester group, -CONR
^{4 represents} R ⁵ , R ⁴ represents C ₁ -C ₃ alkyl, and R ⁵ represents
C ₁ -C ₃ alkyl and optionally substituted phenyl are shown, and Z ¹ and Z ² are hydrogen, C ₁ -C ₃ alkyl and the like. ] Is disclosed.

The compound (M) is a compound represented by the formula (7)
Has --CR as an essential substituent^TwoZ¹Z ^TwoHave a book
Compounds (I) and (II) of the present invention can be used in the 7-position of the quinoline ring.
Has a hydrogen atom, a hydroxy group or a lower alkoxy group.
The difference is.

Further, the gazette does not specifically disclose any compound having a structure similar to the structures of the compounds (I) and (II) of the present invention. Even if a compound closest to the structure of (II) and (II) is selected, at most only the following compounds are disclosed.

[0108]

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The above compound (k) is disclosed as an antibacterial agent, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

[0110]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted long-term studies on the synthesis of a derivative having an ileal bile acid transporter inhibitory activity and its pharmacological activity. The present inventors have found that the present invention has an excellent inhibitory effect on the ileal bile acid transporter and is useful for preventing or treating arteriosclerosis and / or hyperlipidemia, and thus completed the present invention.

Another object of the present invention is to provide a medicine containing a nitrogen-containing heterocyclic derivative as an active ingredient.

[0112]

(1) A medicament of the present invention comprises a nitrogen-containing heterocyclic derivative having the following general formula (Ia):
It contains its pharmacologically acceptable salts, its esters or other derivatives.

[0113]

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[Wherein, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group, and R ⁵ is an aryl group, a hydroxy group or a lower group; An aryl group substituted with 1 to 5 alkoxy groups, wherein R ⁶ is a group having the formula —CONR ⁷ R ⁸ (where R ⁷ is a C ₁ -C ₁₀ alkyl group or a C ₂ -C ₁₀ alkenyl R ⁸ represents an aryl group, an aromatic heterocyclic group,
An aryl group substituted by 1 to 5 groups with a group selected from substituent group a or an aromatic heterocyclic group substituted with 1 to 5 groups with a group selected from substituent group a is shown. ), Where R
^{When 2} is a hydrogen atom and R ³ is a lower alkoxy group,
R ⁵ represents an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups. ], Its pharmacologically acceptable salt, its ester or other derivatives. <Substituent group a> halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group,
A lower alkylthio group, a lower aliphatic acyloxy group, an aromatic acyloxy group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a carboxy group and a lower alkoxycarbonyl group.

In the present invention, preferred medicaments include the following compounds. (2) a compound wherein R ¹ and R ⁴ are hydrogen atoms, (3)
A compound wherein R ² is a hydrogen atom, (4) a compound wherein R ² is a hydroxy group or a lower alkoxy group, (5)
A compound wherein R ³ is a hydroxy group or a lower alkoxy group, (6) a compound wherein R ⁵ is an aryl group, (7)
R ⁵ is a hydroxy group or a lower alkoxy group;
A compound which is an aryl group substituted with 1 to 5 substituents, (8)
R ⁵ is a compound which is an aryl group substituted by one or two hydroxy groups or lower alkoxy groups, (9) R 5
^A compound wherein ⁵ is a 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl group, (10)
A compound wherein R ⁷ is a C ₁ -C ₁₀ alkyl group, (11)
A compound wherein R ⁷ is a C ₁ -C ₆ alkyl group, (12)
A compound wherein R ⁷ is a C ₁ -C ₄ alkyl group, (13)
A compound wherein R ⁷ is a methyl group or an ethyl group, (1
4) a compound wherein R ⁸ is an aromatic heterocyclic group or an aromatic heterocyclic group substituted with 1 to 5 groups selected from a substituent group a, (15) R ⁸ is an aryl group or a substituent Group a
(16) R ⁸ is an aryl group or an aryl group substituted by 1 or 2 groups with a group selected from substituent group a. Compound (17) wherein R ⁸ is an aryl group or an aryl group having 1 or 2 substituents (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group). A compound selected from the group consisting of
8) a compound wherein R ⁸ is an aryl group or a substituted or unsubstituted aryl group (the substituent is a group selected from a halogen atom, a hydroxy group and a lower alkoxy group); R ⁸ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-
Methoxyphenyl, 3,4-difluorophenyl, 3,
A compound which is a 5-difluorophenyl or 3,5-dichlorophenyl group, (20) any one compound selected from the following, 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 1- (4-hydroxyphenyl) -6,7-dimethoxy-4-oxo-1 , 4-Dihydroquinoline-3-
Carboxylic acid N-ethyl-N-phenylamide, 1-
(4-hydroxyphenyl) -6,7-dimethoxy-4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1 , 4-Dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 6,7-
Dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-methoxyphenyl) -6,7-dimethoxy- 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N-
(4-fluorophenyl) amide, 1- (4-methoxyphenyl) -6,7-dimethoxy-4-oxo-1,4
-Dihydro-quinoline-3-carboxylic acid N-methyl-
N- (4-methoxyphenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-
1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 1-
(3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (3 4-dimethoxyphenyl) -6,7-
Dimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (4-methoxyphenyl) -6,
7,8-Trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-
Fluorophenyl) amide, 1- (4-methoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4
-Dihydro-quinoline-3-carboxylic acid N-methyl-
N- (4-methoxyphenyl) amide, 1- (3,4-
Dimethoxyphenyl) -6,7,8-trimethoxy-4
-Oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7,8
-Trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 6,7-dimethoxy-1- (4-
(Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo- 1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl- N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1-
(4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3
-Fluorophenyl) amide, 7-methoxy-1- (4
-Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, 1- (4-methoxyphenyl) -7-dimethoxy-4-oxo-1 , 4-Dihydroquinoline-3-
Carboxylic acid N-ethyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-
1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-hydroxyphenyl) -4-oxo-
1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N- Ethyl-N- (3,5-
Difluorophenyl) amide, 1- (4-hydroxyphenyl) -7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 7-methoxy-1- (4 -Hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid N-methyl-N-phenylamide, and 7
-Methoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N
-Methyl-N- (3-fluorophenyl) amide.

Further, the ileal bile acid transporter inhibitor (preferably a therapeutic or prophylactic agent for hyperlipidemia and / or arteriosclerosis) of the present invention has the following general formula (I) or (I):
A compound having I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof. (21) General formula (I)

[0117]

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Or the general formula (II)

[0119]

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[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a hydroxy group or a lower alkoxy group, and R ⁵ is an aryl group, a hydroxy group or An aryl group substituted with 1 to 5 lower alkoxy groups, wherein R ⁶ is a group having the formula —CONR ⁷ R ⁸ (where R ⁷ is a C ₁ -C ₁₀ alkyl group or a C ₂ -C ₁₀ R ⁸ represents an alkenyl group, and R ⁸ represents an aryl group, an aromatic heterocyclic group, an aryl group substituted with 1 to 5 substituents selected from a substituent group a, or a group selected from 1 to 5 substituent groups a. 5 represents an aromatic heterocyclic group substituted by 5). ], Its pharmacologically acceptable salt, its ester or other derivatives. <Substituent group a> halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group,
A lower alkylthio group, a lower aliphatic acyloxy group, an aromatic acyloxy group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a carboxy group and a lower alkoxycarbonyl group.

In the present invention, suitable ileal bile acid transporter inhibitors include the following compounds. (22) a compound having the general formula (I), (23) a compound having the general formula (II), (24) R ¹ and R
⁴ is a hydrogen atom, (25) a compound wherein R ² is a hydrogen atom, (26) a compound wherein R ² is a hydroxy group or a lower alkoxy group, (27) a compound wherein R ³ is a hydroxy group or a lower group A compound which is an alkoxy group, (2
8) a compound in which R ⁵ is an aryl group; (29) R ⁵
Is a hydroxy group or a lower alkoxy group;
(30) R ⁵ is a compound which is a monosubstituted aryl group.
Is a hydroxy group or a lower alkoxy group,
(31) R ⁵ is a compound which is a substituted aryl group.
Is a 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl group, (32)
A compound wherein R ⁷ is a C ₁ -C ₁₀ alkyl group, (33)
A compound wherein R ⁷ is a C ₁ -C ₆ alkyl group, (34)
A compound wherein R ⁷ is a C ₁ -C ₄ alkyl group, (35)
A compound wherein R ⁷ is a methyl group or an ethyl group, (3
6) a compound wherein R ⁸ is an aromatic heterocyclic group or an aromatic heterocyclic group substituted by 1 to 5 groups selected from a substituent group a, (37) R ⁸ is an aryl group or a substituent Group a
(38) R ⁸ is an aryl group or an aryl group substituted by 1 or 2 groups with a group selected from the substituent group a. A compound, (39) wherein R ⁸ is an aryl group or an aryl group having 1 or 2 substituents (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group; A compound selected from the group consisting of
0) a compound in which R ⁸ is an aryl group or a substituted or unsubstituted aryl group (the substituent is a group selected from a halogen atom, a hydroxy group and a lower alkoxy group); R ⁸ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-
A compound which is a methoxyphenyl, 3,5-difluorophenyl or 3,5-dichlorophenyl group, (42)
Any one compound selected from the following, 1- (4-
(Hydroxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-
Methyl-N-phenylamide, 1- (4-hydroxyphenyl) -6,7-dimethoxy-4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid N-ethyl-N-
Phenylamide, 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-
Difluorophenyl) amide, 6,7-dimethoxy-1
-(4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo -1,4-dihydroquinoline-
3-carboxylic acid N-ethyl-N-phenylamide, 1
-(4-methoxyphenyl) -6,7-dimethoxy-4
-Oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-methoxyphenyl) -6,7-dimethoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl)
Amide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 1- (3,4-dimethoxyphenyl)
-6,7-Dimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-
Fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4
-Dihydro-quinoline-3-carboxylic acid N-methyl-
N- (4-methoxyphenyl) amide, 1- (4-methoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N
-Methyl-N- (4-fluorophenyl) amide, 1-
(4-methoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (3 4-dimethoxyphenyl) -6,7,
8-Trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7,8 -Trimethoxy-4-oxo-1,
4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 7-methoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl -N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-methoxyphenyl) -4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,
4-dihydroquinoline-3-carboxylic acid N-ethyl-
N- (3,5-difluorophenyl) amide, 6,7-
Dimethoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N
-Ethyl-N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N -(3-fluorophenyl)
Amide, 7-methoxy-1- (4-methoxyphenyl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4
-Dihydroquinoline-3-carboxylic acid N-ethyl-N
-(3,5-difluorophenyl) amide, 1- (4-
(Methoxyphenyl) -7-dimethoxy-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N- Methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 7 -Methoxy-1- (4-hydroxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl)
Amide, 1- (4-hydroxyphenyl) -7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl ) -4-oxo-
1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N- Methyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl)
-4-Hydroxy-6,7-dimethoxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-
(Methoxyphenyl) -4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl)
Amide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7-dimethoxy-2-oxo-1,2-
Dihydroquinoline-3-carboxylic acid N-methyl-N-
(4-Fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-
(4-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2-oxo-1,
N-methyl 2-dihydroquinoline-3-carboxylate
N-phenylamide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2
-Oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide,
1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-
(4-methoxyphenyl) amide, 1- (4-hydroxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide, 1- (4-hydroxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-
Ethyl-N-phenylamide, 1- (4-hydroxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl ) Amide, 1- (4
-Hydroxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3-fluorophenyl) amide, 1- (4-hydroxyphenyl) -4-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 1- (4-hydroxyphenyl) -4 -Hydroxy-7-methoxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, 1-
(4-methoxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 1- (4
-Methoxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-methoxyphenyl) -4-hydroxy- 7-methoxy-2
-Oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide,
1- (4-methoxyphenyl) -4-hydroxy-7-
Methoxy-2-oxo-1,2-dihydroquinoline-3
-Carboxylic acid N-ethyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N -Methyl-N- (3,5
-Difluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluoro Phenyl) amide, 1
-(4-methoxyphenyl) -4-hydroxy-6,7
-Dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide,
1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-methoxyphenyl) -4-hydroxy-
6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl)
-4-Hydroxy-6,7-dimethoxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3-fluorophenyl) amide, 1- (4-
(Methoxyphenyl) -4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide and 1- (4 -Methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-ethyl 2-dihydroquinoline-3-carboxylate
N- (3,5-difluorophenyl) amide.

In the above formula, the “halogen atom” in the definition of the substituent group “a” is a fluorine, chlorine, bromine or iodine atom,
Preferably it is a fluorine atom or a chlorine atom, most preferably a fluorine atom.

In the above formula, the “lower alkyl group” in the definition of the substituent group “a” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,
t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3
-Dimethylbutyl, 2,2-dimethylbutyl, 1,1-
A linear or branched alkyl group having 1 to 6 carbon atoms such as dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl And is preferably a C ₁ -C ₄ alkyl group, more preferably a C ₁ -C ₂ alkyl group, and most preferably a methyl group.

In the above formula, the “halogeno lower alkyl group” in the definition of the substituent group “a” refers to a group in which the above “lower alkyl group” is substituted by a halogen atom, for example, trifluoromethyl, trichloromethyl, difluoromethyl, Dichloromethyl, dibromomethyl, fluoromethyl, 2,
2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, , 2
A halogeno lower alkyl group having 1 to 6 carbon atoms such as a dibromoethyl group, preferably a halogeno C ₁ -C ₄ alkyl group, more preferably a halogeno C ₁ -C ₂ alkyl group, Most preferably, it is a trifluoromethyl group.

In the above formula, “lower alkoxy group” in the definition of R ¹ , R ² , R ³ , R ⁴ and the substituent group “a” and “1 to 5 substituents of hydroxy or lower alkoxy group in the definition of R ⁵ ” The "lower alkoxy group" of the "substituted aryl group" represents a group in which the above "lower alkyl group" is bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t- Butoxy, pentoxy, isopentoxy,
2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy,
-Methylpentoxy, 3,3-dimethylbutoxy, 2,
2-dimethylbutoxy, 1,1-dimethylbutoxy,
A straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms such as 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy;
An ₁ -C ₄ alkoxy group, more preferably a C ₁ -C ₂ alkoxy group, most preferably a methoxy group.

In the above formula, the “lower alkylthio group” in the definition of the substituent group “a” indicates a group in which the above “lower alkyl group” is bonded to a sulfur atom, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,
Isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3 -Dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-
Dimethylbutylthio, 1,3-dimethylbutylthio,
1 to 6 carbon atoms such as 2,3-dimethylbutylthio group
Linear or branched alkylthio groups, preferably
An ₁ -C ₄ alkylthio group, more preferably a C ₁ -C ₂ alkylthio group, most preferably a methylthio group.

In the above formula, the term "lower aliphatic acyloxy group" in the definition of the substituent group a represents a hydrogen atom or a group in which a saturated or unsaturated chain hydrocarbon group is bonded to a carbonyloxy group. C1-C7 linear chains such as oxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloyloxy, crotonoyloxy groups Or a branched lower aliphatic acyloxy group, preferably an acetyloxy or propionyloxy group, and most preferably an acetyloxy group.

In the above formula, "aryl group", "aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups" in the definition of R ⁵ and R ⁸ and "substituent group a
Aryl group substituted with 1 to 5 groups selected from
Examples of the aryl moiety include an aromatic hydrocarbon group having 6 to 10 carbon atoms such as phenyl, indenyl and naphthyl, and a phenyl group is preferable.

In the above formula, the “aromatic acyloxy group” in the definition of the substituent group “a” indicates a group in which the aryl group is bonded to a carbonyloxy group.
-Indenylcarbonyl, 2-indenylcarbonyl,
It is a 1-naphthoyl or 2-naphthoyl group, preferably a benzoyl group.

In the above formula, “mono-lower alkylamino group” in the definition of the substituent group “a” has the same meaning as described above in which one “lower alkyl group” is bonded to an amino group. Amino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, Hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3
-Dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3
A mono-C ₁ -C ₆ alkylamino group such as -dimethylbutylamino, 2-ethylbutylamino group, preferably a mono-C ₁ -C ₄ alkylamino group, more preferably a mono-C ₁ -C ₄ alkylamino group. an ₁ -C ₂ alkylamino group, and most preferably a methylamino group.

In the above formula, the “di-lower alkylamino group” in the definition of the substituent group “a” is the above “lower alkyl group”
Represents a group bonded to two amino groups, for example, di-C ₁ -C such as dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino group. ₆ alkylamino group, preferably a di -C ₁ -C ₄ alkylamino group, more preferably a di- -C ₁ -C ₂ alkylamino group, most preferably a dimethylamino group.

In the above formula, the “lower alkoxycarbonyl group” in the definition of the substituent group “a” refers to a group in which the above “lower alkoxy group” is bonded to a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl,
Isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2 1,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl,
A lower alkoxycarbonyl group having 2 to 7 carbon atoms such as 1,3-dimethylbutoxycarbonyl and 2,3-dimethylbutoxycarbonyl;
A ₂ -C ₅ alkoxycarbonyl group, more preferably C
A ₂ -C ₃ alkoxycarbonyl group, most preferably a methoxycarbonyl group.

In the above formula, the aromatic heterocyclic moiety of the “aromatic heterocyclic group” and the “aromatic heterocyclic group substituted with 1 to 5 hydroxy groups or lower alkoxy groups” in the definition of R ⁸ is a sulfur atom A 5- to 7-membered heterocyclic group containing 1 to 3 oxygen atoms and / or nitrogen atoms, for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,2 3-oxadiazolyl,
Examples include aromatic heterocyclic groups such as triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In such an aromatic heterocyclic group, preferably a 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group fused to a benzene ring, more preferably thienyl, furyl, Pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, or a thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group condensed with a benzene ring, more preferably,
A furyl, thienyl or pyridyl group, most preferably 2-thienyl, 3-thienyl, 2-pyridyl, 3-
A pyridyl or 4-pyridyl group.

In the above formula, "C ₁ -C ₁₀ " in the definition of R ⁷
The “alkyl group” includes, for example, the aforementioned “lower alkyl group”, heptyl, 1-methylhexyl, 2-methylhexyl,
-Methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, octyl, 1-methylheptyl, 2- Methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl , 5-methyloctyl, 6-methyloctyl,
1-propylhexyl, 2-ethylheptyl, 6,6-
Dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl,
It is a linear or branched alkyl group having 1 to 10 carbon atoms such as 3,7-dimethyloctyl or 7,7-dimethyloctyl group, preferably a C ₁ -C ₆ alkyl group, more preferably Is a C ₁ -C ₄ alkyl group, most preferably a methyl group or an ethyl group.

In the above formula, “C ₂ -C ₁₀ ” in the definition of R ⁷
“Alkenyl group” includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl,
-Methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-
2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1- Ethyl-3-butenyl, 1-pentenyl,
2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-
3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-
4-pentenyl, 1-hexenyl, 2-hexenyl, 3
Examples thereof include linear or branched alkenyl groups having 2 to 10 carbon atoms, such as -hexenyl, 4-hexenyl and 5-hexenyl, and are preferably C ₂ -C ₆ alkenyl groups, more preferably is a C ₂ -C ₄ alkenyl group, most preferably a 2-propenyl group.

In the above, specific examples of the “aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups” in the definition of R ⁵ include, for example, 2-, 3
-Or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2,3-dihydroxyphenyl, 3,4
-Dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,
5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 5-methoxyinden-2-yl, 5-methoxynaphthalen-2-yl, 5-methoxynaphthalene-1
-Yl group, preferably an aryl group substituted with one or two hydroxy groups or lower alkoxy groups, most preferably 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxy Phenyl,
A 4-methoxyphenyl or 3,4-dimethoxyphenyl group.

In the above, specific examples of the “aryl group substituted by 1 to 5 groups selected from the substituent group a” in the definition of R ⁸ include, for example, the above “hydroxy group or lower alkoxy group having 1 to 5 aryl groups”. 5 to 5 substituted aryl groups ", 2-, 3- or 4-fluorophenyl,
2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4 -Ethylphenyl, 2-, 3
-Or 4-trifluoromethylphenyl, 2-, 3
-Or 4-methylthiophenyl, 2-, 3- or 4-ethylthiophenyl, 2-, 3- or 4-formyloxyphenyl, 2-, 3- or 4-acetyloxyphenyl, 2-, 3- or 4 -Propionyloxyphenyl, 2-, 3- or 4-benzoyloxyphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methylaminophenyl, 2
-, 3- or 4-dimethylaminophenyl, 3,4
-Difluorophenyl, 3,4-dichlorophenyl,
3,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3- Fluoro-4
-Methoxyphenyl, 4-methyl-2-methoxyphenyl, 6-fluoro-4-methyl-2-methoxyphenyl, 5-fluoroinden-3-yl, 5-fluoroinden-3-yl, 5-methylindene-3 -Ill, 5
-Methoxyinden-3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl, 5-methylinden-2-yl, 5-fluoronaphthalen-2-
Yl, 5-fluoronaphthalen-2-yl, 5-methylnaphthalen-2-yl, 5-fluoronaphthalen-1-
Yl, 5-fluoronaphthalen-1-yl and 5-methylnaphthalen-1-yl groups, preferably 1 to 2 substituted aryl groups, more preferably 1 to 2
Individually substituted aryl group (the substituent is a halogen atom,
It is a group selected from a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group. ), More preferably an aryl group substituted by 1 or 2 (the substituent is a group selected from a halogen atom, a hydroxy group and a lower alkoxy group), and most preferably 3-fluorophenyl,
A 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,5-difluorophenyl or 3,5-dichlorophenyl group.

In the above, specific examples of “an aromatic heterocyclic group substituted by 1 to 5 groups selected from the substituent group a” in the definition of R ⁸ include, for example, 3-, 4- or 5- -Fluorofuran-2-yl, 2-, 4- or 5-fluorofuran-3-yl, 3-, 4- or 5-hydroxyfuran-2-yl, 2-, 4- or 5-hydroxyfuran-3 -Yl, 3-, 4- or 5-methylfuran-2-yl, 2-, 4- or 5-
Methylfuran-3-yl, 3-, 4- or 5-methoxyfuran-2-yl, 2-, 4- or 5-methoxyfuran-3-yl, 3-, 4- or 5-methylthiofuran-2- Yl, 2-, 4- or 5-methylthiofuran-3-yl, 4- or 5-acetyloxyfuran-2-yl, 2-, 4- or 5-acetyloxyfuran-3-yl, 4- or 5 -Formyloxyfuran-2-yl, 2-, 4- or 5-formyloxyfuran-3-yl, 4- or 5-benzoyloxyfuran-2-yl, 2-, 4- or 5-benzoyloxyfuran- 3-yl, 3-, 4- or 5
-Fluorothiophen-2-yl, 3-, 4- or 5-bromothiophen-2-yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or 5-methylthiophen-2 -Yl, 2-, 4- or 5-methylthiophen-3-yl, 3-, 4- or 5-ethylthiophen-2-yl, 2-, 4- or 5-ethylthiophen-3-yl, 3- , 4- or 5-methoxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl, 3-, 4-
Or 5-methylthiothiophen-2-yl, 2-,
4- or 5-methylthiothiophen-3-yl, 3
-, 4- or 5-acetyloxythiophene-2-
Yl, 2-, 4- or 5-acetyloxythiophen-3-yl, 3-, 4- or 5-formyloxythiophen-2-yl, 2-, 4- or 5-formyloxythiophen-3-yl, 3-, 4- or 5
-Benzoyloxythiophen-2-yl, 2-, 4-
Or 5-benzoyloxythiophen-3-yl,
3-, 4- or 5-carboxythiophen-2-yl, 2-, 4- or 5-carboxythiophen-3
-Yl, 3-, 4- or 5-methoxycarbonylthiophen-2-yl, 2-, 4- or 5-methoxycarbonylthiophen-3-yl, 3- or 4-fluorothiazol-5-yl, 3- or 4-hydroxythiazol-5-yl, 3- or 4-methylthiazol-5-yl, 3-, 4- or 5-fluorobenzothiophen-2-yl, 2-, 4- or 5-
Fluorobenzothiophen-3-yl, 3-, 4- or 5-bromobenzothiophen-2-yl, 2-, 4
-Or 5-bromobenzothiophen-3-yl, 3
-, 4- or 5-hydroxybenzothiophene-2
-Yl, 2-, 4- or 5-hydroxybenzothiophen-3-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 2-, 4- or 5-methylbenzothiophen-3-yl , 3-, 4- or 5
-Methoxybenzothiophen-2-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl,
-, 5-, 6- or 7-methylbenzothiazole-
2-yl, 2- or 4-fluoropyridin-3-yl, 2- or 3-fluoropyridin-4-yl, 2
-Or 4-hydroxypyridin-3-yl, 2- or 3-hydroxypyridin-4-yl, 2- or 4-methylpyridin-3-yl, 2- or 3-methylpyridin-4-yl, 2- or 4-methoxypyridin-4-yl, 2- or 3-methoxypyridin-4-yl, 2- or 4-methylthiopyridin-3
-Yl, 2- or 3-methylthiopyridin-4-yl, 2- or 4-acetyloxypyridin-3-yl, 2- or 3-acetyloxypyridin-4-yl, 2- or 4-formyloxypyridine- 3-yl, 2- or 3-formyloxypyridin-4-yl, 2- or 4-benzoyloxypyridin-3-
Yl, 2- or 3-benzoyloxypyridine-4
-Yl group, preferably a 5- or 6-membered aromatic heterocyclic group substituted with 1 or 2 or a 5- or 6-membered aromatic heterocyclic group condensed with a benzene ring, more preferably In
A 5- or 6-membered aromatic heterocyclic group substituted with 1 or 2 or a 5- or 6-membered aromatic heterocyclic group condensed with a benzene ring (the substituent is a halogen atom, a hydroxy group, a lower alkyl group,
It is a group selected from a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxy group and a lower alkoxycarbonyl group. And more preferably a 1 to 2 substituted 5- or 6-membered aromatic heterocyclic group (the substituent is a group selected from a carboxy group and a lower alkoxycarbonyl group), Still more preferably, it is a 1- or 2-substituted thienyl or pyridyl group (the substituent is a group selected from a carboxy group and a lower alkoxycarbonyl group), and most preferably, 2-carboxy. -Thiophen-3-yl or 2-methoxycarbonyl-thiophen-3-yl group.

"Pharmacologically acceptable salt thereof" means that the compound (I) or (II) of the present invention is reacted with an acid when it has a basic group such as an amino group.
Also, when it has an acidic group such as a carboxy group, it can be made into a salt by reacting with a base,
Show the salt.

As the salt based on a basic group,
Inorganic acid salts such as hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates and phosphates; methanesulfonic acid Salts, lower alkane sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate,
aryl sulfonates such as p-toluenesulfonate, acetate, malate, fumarate, succinate,
Organic acid salts such as citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate. And most preferably an organic acid salt.

On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an aluminum salt; Metal salts such as salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts,
Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) amino Amine salts such as organic salts such as methane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates.

The compound represented by the general formula (I) or (II) of the present invention absorbs water by being left in the air or recrystallized to absorb adsorbed water or to form a hydrate. In some cases, such a hydrate is included in the salt of the present invention.

The compound having the general formula (I) or (II) of the present invention may have various isomers since an asymmetric carbon atom may be present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, general formula (I) or (II). Accordingly, the present invention includes all these isomers and mixtures of these isomers in any proportion.

The “ester” in the above description refers to the ester of the compound (I) or (II) of the present invention, since the compound can be converted into an ester. And an ester in which each ester residue is a `` general protecting group '' or a `` protecting group which can be cleaved in vivo by a biological method such as hydrolysis ''. Say.

"General protecting group" means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.

As the “general protecting group” for the “ester of hydroxy group”, preferably, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, -Methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,
3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-
Dimethyltetradecanoyl, heptadecanoyl, 15-
Alkanoyl groups such as methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, henicosanoyl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, and methoxyacetyl Acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-
A "substituted lower aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as 2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); benzoyl, arylcarbonyl groups such as α-naphthoyl and β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl,
-A lower alkylated arylcarbonyl group such as toluoyl, and a lower alkoxylated aryl such as 4-anisoyl-
Nitrated arylcarbonyl groups such as 4-carbonylbenzoyl, 2-nitrobenzoyl and 2-nitrobenzoyl;
"Substituted aromatic acyl groups" such as lower alkoxycarbonylated arylcarbonyl groups such as (methoxycarbonyl) benzoyl and arylated arylcarbonyl groups such as 4-phenylbenzoyl; methoxycarbonyl, ethoxycarbonyl , Lower alkoxycarbonyl groups such as propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl; halogens such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; An “alkoxycarbonyl group” such as a lower alkoxycarbonyl group substituted with an alkylsilyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4- Le, tetrahydrothiopyran-2-
“Tetrahydropyranyl or tetrahydrothiopyranyl group” such as yl, 4-methoxytetrahydrothiopyran-4-yl; “tetrahydrofuranyl or tetrahydrothiofuran” such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl A tri-lower alkylsilyl group such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenyl “Silyl group” such as tri-lower alkylsilyl group substituted by one or two aryl groups such as isopropylsilyl and phenyldiisopropylsilyl; methoxymethyl,
Lower alkoxymethyl groups such as 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl Groups, "alkoxymethyl groups" such as halogeno lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1- (isopropoxy) ethyl and the like Lower alkoxylated ethyl group,
"Substituted ethyl group" such as an ethyl halide group such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9- Lower alkyl groups substituted with one to three aryl groups such as anthrylmethyl, 4-methylbenzyl, 2,4,4
6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-
"Aralkyl groups" such as lower alkyl, lower alkoxy such as cyanobenzyl, lower alkoxy, nitro, halogen, lower alkyl groups substituted with one to three aryl groups having an aryl ring substituted with a cyano group; vinyl “Alkenyloxycarbonyl group” such as oxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl like,
An "aralkyloxycarbonyl group" in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups may be mentioned.

The term “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” means that it is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. Refers to a protecting group, whether such a derivative is administered by intravenous injection to experimental animals such as rats and mice,
Subsequent examination of the body fluids of the animals allows the determination of the ability to detect the original compound or its pharmacologically acceptable salt, and the determination of the "hydroxyl ester" by "biological such as hydrolysis in vivo". Protecting group that can be cleaved by the method ''
As preferably, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-
Isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1
-Valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-
1 such as acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl
-("Lower aliphatic acyl" oxy) "lower alkyl group", cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexyl Carbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1-
1- such as cyclohexylcarbonyloxybutyl
1- (acyloxy) "lower alkyl group" such as ("cycloalkyl" carbonyloxy) "lower alkyl group", 1-("aromatic acyl" oxy) "lower alkyl group" such as benzoyloxymethyl; methoxycarbonyl Oxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxy Carbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- ( Pentyloxycarbonyloxy)
Ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy)
Propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl , 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1
-(Propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- ( Hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1-
(Isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy)
(Lower alkoxycarbonyloxy) alkyl groups such as pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl;
(5-phenyl-2-oxo-1,3-dioxolene-
4-yl) methyl, [5- (4-methylphenyl) -2
-Oxo-1,3-dioxolen-4-yl] methyl,
[5- (4-methoxyphenyl) -2-oxo-1,3
-Dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolene-
4-yl] methyl, [5- (4-chlorophenyl) -2
-Oxo-1,3-dioxolen-4-yl] methyl,
(2-oxo-1,3-dioxolen-4-yl) methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,
3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) “Carbonyloxy lower alkyl group” such as methyl, oxodioxorenylmethyl group such as (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; phthalidyl, dimethylphthalidyl,
“Phthalidyl group” such as dimethoxyphthalidyl: the above “lower aliphatic acyl group”: the above “aromatic acyl group”:
"Succinic acid half ester salt residue": "phosphate ester salt residue": "ester forming residue such as amino acid": carbamoyl group: carbamoyl group substituted with one or two lower alkyl groups: Examples thereof include “1- (acyloxy) alkyloxycarbonyl group” such as baroyloxymethyloxycarbonyl, and preferably “carbonyloxyalkyl group”.

On the other hand, the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group” is preferably methoxyethyl,
1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl ,
Lower alkoxy lower alkyl groups such as isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, 2
Lower alkoxylated lower alkoxy lower alkyl groups such as methoxyethoxymethyl, "aryl" oxy "lower alkyl groups" such as phenoxymethyl, 2,2,2
“Alkoxyalkyl groups” such as halogenated lower alkoxy lower alkyl groups such as trichloroethoxymethyl and bis (2-chloroethoxy) methyl; “lower alkoxy” carbonyl “lower alkyl groups” such as methoxycarbonylmethyl; “Cyano“ lower alkyl ”such as cyanomethyl and 2-cyanoethyl;“ lower alkyl ”thiomethyl such as methylthiomethyl and ethylthiomethyl;“ aryl ”thiomethyl such as phenylthiomethyl and naphthylthiomethyl A "lower alkyl" sulfonyl "lower alkyl group" optionally substituted with halogen "such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl; Like "" Le "sulfonyl" lower alkyl group "", the "1- (acyloxy)" lower alkyl group "", the "phthalidyl group"; the "aryl group";
The "lower alkyl group"; the "carboxyalkyl group" such as carboxymethyl; and the "amide-forming residue of amino acid" such as phenylalanine.

The "other derivative" means a derivative other than the "pharmacologically acceptable salt" and the "ester thereof" when the compound (I) or (II) of the present invention has an amino group. Derivatives are shown because
Such derivatives include, for example, amide derivatives such as acyl groups.

Specific examples of the compound having the general formula (I) or (II) of the present invention include, for example, the following Tables 1 and 2.
However, the present invention is not limited to these compounds. The compounds shown in Tables 1 and 2 correspond to the compounds of formulas (I ′) and (II ′), respectively.
Having the structural formula

In Tables 1 and 2, the substituent of R ⁵ is as follows.

[0152]

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The abbreviations in the table are as follows. Ac: acetyl group All: allyl group Bu: butyl group iBu: isobutyl group sBu: s-butyl group tBu: t-butyl group Bun: butenyl group Bz: benzyl group Et: ethyl group Fur (2): furan-2-yl Group Fur (3): Furan-3-yl group cHx: Cyclohexyl group Me: Methyl group Mor (4): Morpholin-4-yl group Np (2): Naphthalen-2-yl group Ph: Phenyl group Piz (1) : Piperazin-1-yl group Pn: pentyl group cPn: cyclopentyl group iPn: isopentyl group Pr: propyl group iPr: isopropyl group Prd (1): pyrrolidin-1-yl group Prd (2): pyrrolidin-2-yl group Prd (3): pyrrolidin-3-yl group Pyrd (2): pyridine-2 Il group Pyrd (3): pyridin-3-yl group Pyrd (4): pyridin-4-yl group Thi (2): thiophen-2-yl group Thi (3): thiophen-3-yl group Vin: vinyl group . [Table 1]

[0154]

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[0155]  Compd.n R R^Five R⁶ No. Substituent No.  1-1 1 H (R-1) -CON (Et)_Two 1-2 1 H (R-1) -CONHPh 1-3 1 H (R-1) -CONHCHMePh 1-4 1 H (R-1) -CONHCHMe (4-MeO-Ph) 1-5 1 H (R -1) -CONHCHMe (3,5-diF-Ph) 1-6 1 H (R-1) -CON (Me) Ph 1-7 1 H (R-1) -CONMe (4-F-Ph) 1 -8 1 H (R-1) -CONMe (4-MeO-Ph) 1-9 1 H (R-1) -CONMe (3,4-diF-Ph) 1-10 1 H (R-1)- CONMe (3,5-diF-Ph) 1-11 1 H (R-1) -CONMe (3,4-diMeO-Ph) 1-12 1 H (R-1) -CONMe (3,5-diMeO- Ph) 1-13 1 H (R-1) -COCH_TwoCH (Et)_Two 1-14 1 H (R-1) -cPn 1-15 1 H (R-1) -Ph 1-16 1 H (R-1) -Bz 1-17 1 H (R-1)-(CH_Two)_TwoPh 1-18 1 H (R-1) -Me 1-19 1 H (R-1) -iPr 1-20 1 H (R-1) -Bu 1-221 H (R-1) -iBu 1 -22 1 H (R-1) -sBu 1-23 1 H (R-1) -tBu 1-24 1 H (R-1) -iPn 1-25 1 H (R-1) -CH_TwoCH (Et)_Two 1-26 1 H (R-1)-(CH_Two)_TwoCH (Et)_Two 1-27 1 H (R-1) -1-Et-Bu 1-28 1 H (R-1) -1-Et-Pn 1-29 1 H (R-1) -All 1-30 1 H ( R-3) -CON (Me) Ph 1-31 1 H (R-3) -COCH (Et)_Two 1-32 1 H (R-3) -COCH_TwoCH (Et)_Two 1-33 1 H (R-3) -iBu 1-34 1 H (R-3) -CH_TwoCH (Et)_Two 1-35 1 H (R-3) -Bz 1-36 1 H (R-5) -CONHCH (Et)_Two 1-37 1 H (R-5) -CONHtBu 1-38 1 H (R-5) -CONH (4-Cl-Bz) 1-39 1 H (R-5) -CON (Me) Ph 1-40 1 H (R-5) -COCH (Et)_Two 1-41 1 H (R-5) -COCH_TwoCH (Et)_Two 1-42 1 H (R-5) -iBu 1-43 1 H (R-5) -CH_TwoCH (Et)_Two 1-44 1 H (R-5) -Bz 1-45 1 H (R-6) -CONHCH (Et)_Two 1-46 1 H (R-6) -CONHtBu 1-47 1 H (R-6) -CONH (4-Cl-Bz) 1-48 1 H (R-6) -CON (Me) Ph 1-49 1 H (R-6) -COCH (Et)_Two 1-50 1 H (R-6) -COCH_TwoCH (Et)_Two 1-51 1 H (R-6) -iBu 1-52 1 H (R-6) -CH_TwoCH (Et)_Two 1-53 1 H (R-6) -Bz 1-54 1 H (R-14) -CONHCH (Et)_Two 1-55 1 H (R-14) -CONHtBu 1-56 1 H (R-14) -CONH (4-Cl-Bz) 1-57 1 H (R-14) -CON (Me) Ph 1-58 1 H (R-14) -COCH (Et)_Two 1-59 1 H (R-14) -COCH_TwoCH (Et)_Two 1-60 1 H (R-14) -iBu 1-61 1 H (R-14) -CH_TwoCH (Et)_Two 1-62 1 H (R-14) -Bz 1-63 1 H (R-2) -CON (Me) Ph 1-64 1 H (R-4) -CON (Me) Ph 1-65 1 H ( (R-15) -CON (Me) Ph 1-66 1 H (R-16) -CON (Me) Ph 1-67 1 H (R-17) -CON (Me) Ph 1-68 1 5-OH ( R-1) -CON (Me) Ph 1-69 1 5-OH (R-1) -COCH (Et)_Two 1-70 1 5-OH (R-1) -COCH_TwoCH (Et)_Two 1-71 1 5-OH (R-1) -iBu 1-72 1 5-OH (R-1) -CH_TwoCH (Et)_Two 1-73 1 5-OH (R-1) -Bz 1-74 1 5-OH (R-1) -cPn 1-75 1 5-OH (R-2) -Bz 1-76 16-OH ( (R- 1) -iBu 1-77 16-OH (R- 1) -CON (Me) Ph 1-78 16-OH (R- 2) -CON (Me) Ph 1-79 16-OH ( R- 3) -CON (Me) Ph 1-80 16-OH (R-5) -CONHPh 1-81 16-OH (R-5) -CONHCHMePh 1-82 16-OH (R-5) -CONHCHMe (4-MeO-Ph) 1-83 16-OH (R-5) -CONHCHMe (3,5-diF-Ph) 1-84 16-OH (R-5) -CONH (CH_Two)_TwoPh 1-85 16-OH (R-5) -CON (Me) Ph 1-86 16-OH (R-5) -CON (Et) Ph 1-87 16-OH (R-5)- CONMe (4-F-Ph) 1-88 16-OH (R-5) -CONMe (4-MeO-Ph) 1-89 16-OH (R-5) -CONMe (3,4-diF- Ph) 1-90 16-OH (R-5) -CONMe (3,5-diF-Ph) 1-91 16-OH (R-5) -CONMe (3,4-diMeO-Ph) 1- 92 1 6-OH (R-5) -CONMe (3,5-diMeO-Ph) 1-93 16-OH (R-5) -cPn 1-94 16-OH (R-5) -Ph 1 -95 16-OH (R-5) -Bz 1-96 16-OH (R-5)-(CH_Two)_TwoPh 1-97 16-OH (R-5) -iPr 1-98 16-OH (R-5) -Bu 1-99 16-OH (R-5) -iBu 1-100 16-OH (R-5) -tBu 1-101 1 6-OH (R-5) -iPn 1-102 1 6-OH (R-5) -CH_TwoCH (Et)_Two 1-103 1 6-OH (R-5)-(CH_Two)_TwoCH (Et)_Two 1-104 1 6-OH (R-5) -1-Et-Bu 1-105 1 6-OH (R-5) -1-Et-Pn 1-106 16-OH (R-6) -CONHPh 1-107 16-OH (R-6) -CONHCHMePh 1-108 16-OH (R-6) -CONHCHMe (4-MeO-Ph) 1-109 16-OH (R-6) -CONHCHMe ( 3,5-diF-Ph) 1-110 1 6-OH (R-6) -CONH (CH_Two)_TwoPh 1-111 16-OH (R-6) -CON (Me) Ph 1-112 16-OH (R-6) -CON (Et) Ph 1-113 16-OH (R-6)- CONMe (4-F-Ph) 1-114 1 6-OH (R-6) -CONMe (4-MeO-Ph) 1-115 1 6-OH (R-6) -CONMe (3,4-diF- Ph) 1-116 16-OH (R-6) -CONMe (3,5-diF-Ph) 1-117 16-OH (R-6) -CONMe (3,4-diMeO-Ph) 1- 118 1 6-OH (R-6) -CONMe (3,5-diMeO-Ph) 1-119 1 6-OH (R-6) -cPn 1-120 1 6-OH (R-6) -Bz 1 -121 1 6-OH (R-6)-(CH_Two)_TwoPh 1-122 16-OH (R-6) -iPr 1-123 16-OH (R-6) -Bu 1-124 16-OH (R-6) -sBu 1-125 16-OH (R-6) -tBu 1-126 1 6-OH (R-6) -iPn 1-127 1 6-OH (R-6) -CH_TwoCH (Et)_Two 1-128 1 6-OH (R-6)-(CH_Two)_TwoCH (Et)_Two 1-129 1 6-OH (R-6) -1-Et-Bu 1-130 1 6-OH (R-6) -1-Et-Pn 1-131 16-OH (R-7) -CON (Me) Ph 1-132 1 6-OH (R-8) -CON (Me) Ph 1-133 16-OH (R-11) -CON (Me) Ph 1-134 16-OH (R- 12) -CON (Me) Ph 1-135 1 6-OH (R-14) -CONHPh 1-136 1 6-OH (R-14) -CONHCHMePh 1-137 1 6-OH (R-14) -CONHCHMe (4-MeO-Ph) 1-138 1 6-OH (R-14) -CONHCHMe (3,5-diF-Ph) 1-139 1 6-OH (R-14) -CONH (CH_Two)_TwoPh 1-140 16-OH (R-14) -CON (Me) Ph 1-141 16-OH (R-14) -CON (Et) Ph 1-142 16-OH (R-14)- CONMe (4-F-Ph) 1-143 1 6-OH (R-14) -CONMe (4-MeO-Ph) 1-144 1 6-OH (R-14) -CONMe (3,4-diF- Ph) 1-145 1 6-OH (R-14) -CONMe (3,5-diF-Ph) 1-146 1 6-OH (R-14) -CONMe (3,4-diMeO-Ph) 1- 147 1 6-OH (R-14) -CONMe (3,5-diMeO-Ph) 1-148 1 6-OH (R-14) -cPn 1-149 1 6-OH (R-14) -Bz 1 -150 1 6-OH (R-14)-(CH_Two)_TwoPh 1-151 16-OH (R-14) -iPr 1-152 16-OH (R-14) -Bu 1-153 16-OH (R-14) -sBu 1-154 16-OH (R-14) -tBu 1-155 16-OH (R-14) -iPn 1-156 16-OH (R-14) -CH_TwoCH (Et)_Two 1-157 1 6-OH (R-14)-(CH_Two)_TwoCH (Et)_Two 1-158 1 6-OH (R-14) -1-Et-Bu 1-159 1 6-OH (R-14) -1-Et-Pn 1-160 1 6-OH (R-15) -CON (Me) Ph 1-161 16-OH (R-16) -CON (Me) Ph 1-162 16-OH (R-17) -CON (Me) Ph 1-163 17-OH (R- 1) -CH_TwoCH (Et)_Two 1-164 1 7-OH (R-6) -CON (Me) Ph 1-165 1 7-OH (R-14) -CON (Me) Ph 1-166 18-OH (R-6) -CON (Me) Ph 1-167 1 8-OH (R-14) -CON (Me) Ph 1-168 1 8-OH (R- 1) -CON (Me) Ph 1-169 1 8-OH (R- 2) -CON (Me) Ph 1-170 18-OH (R-3) -CON (Me) Phz 1-171 18-OH (R-4) -CON (Me) Ph 1-172 18- OH (R-5) -CON (Me) Ph 1-173 1 8-OH (R-7) -CON (Me) Ph 1-174 1 8-OH (R-8) -CON (Me) Ph 1- 175 1 8-OH (R-9) -CON (Me) Ph 1-176 1 8-OH (R-10) -CON (Me) Ph 1-177 16-MeO (R-1) -CONHPh 1- 178 1 6-MeO (R-1) -CONHCHMePh 1-179 1 6-MeO (R-1) -CON (Me) Ph 1-180 16-MeO (R-1) -CON (Et) Ph 1- 181 1 6-MeO (R- 1) -CONMe (4-F-Ph) 1-182 1 6-MeO (R-1) -CONMe (4-Cl-Ph) 1-183 1 6-MeO (R- 1) -CONMe (4-MeO-Ph) 1-184 1 6-MeO (R-1) -CONMe (3,4-diF-Ph) 1-185 1 6-MeO (R-1) -CONMe (3 , 5-diF-Ph) 1-186 16-MeO (R-1) -CONMe (3,4-diMeO-Ph) 1-187 16-MeO (R-1) -CONMe (3,5-diMeO -Ph) 1-188 16-MeO (R-1) -cPn 1-189 16-MeO (R-1) -Bz 1-190 16-MeO (R-1)-(CH_Two)_TwoPh 1-191 16-MeO (R-1) -iPr 1-192 16-MeO (R-1) -Bu 1-193 16-MeO (R-1) -iBu 1-194 16-MeO (R-1) -tBu 1-195 1 6-MeO (R-1) -iPn 1-196 1 6-MeO (R-1) -1-Et-Bu 1-197 1 6-MeO (R-1 ) -1-Et-Pn 1-198 1 6-MeO (R- 2) -COCH_TwoCH (Et)_Two 1-199 1 6-MeO (R- 2) -COCH (Et)_Two 1-200 1 6-MeO (R-2) -CONHPh 1-201 1 6-MeO (R-2) -CONHCHMePh 1-202 16-MeO (R-2) -CONHCHMe (4-MeO-Ph) 1 -203 16-MeO (R-2) -CONHCHMe (3,5-diF-Ph) 1-204 16-MeO (R-2) -CONH (CH_Two)_TwoPh 1-205 16-MeO (R- 2) -CON (Me) Ph 1-206 16-MeO (R- 2) -CON (Et) Ph 1-207 16-MeO (R- 2)- CONMe (4-F-Ph) 1-208 16-MeO (R- 2) -CONMe (4-Cl-Ph) 1-209 16-MeO (R- 2) -CONMe (4-MeO-Ph) 1-210 1 6-MeO (R- 2) -CONMe (3,4-diF-Ph) 1-211 1 6-MeO (R- 2) -CONMe (3,5-diF-Ph) 1-212 1 6-MeO (R- 2) -CONMe (3,4-diMeO-Ph) 1-213 1 6-MeO (R-2) -CONMe (3,5-diMeO-Ph) 1-214 1 6-MeO ( (R- 2) -cPn 1-215 16-MeO (R- 2) -Ph 1-216 16-MeO (R- 2) -Bz 1-217 16-MeO (R- 2)-(CH_Two)_TwoPh 1-218 16-MeO (R- 2) -Me 1-219 16-MeO (R- 2) -iPr 1-220 16-MeO (R- 2) -Bu 1-221 16-MeO (R-2) -iBu 1-222 16-MeO (R-2) -sBu 1-223 16-MeO (R-2) -tBu 1-224 16-MeO (R-2) -iPn 1 -225 1 6-MeO (R-2) -CH_TwoCH (Et)_Two 1-226 1 6-MeO (R-2)-(CH_Two)_TwoCH (Et)_Two 1-227 1 6-MeO (R- 2) -1-Et-Bu 1-228 1 6-MeO (R- 2) -1-Et-Pn 1-229 16-MeO (R- 3) -COCH_TwoCH (Et)_Two 1-230 1 6-MeO (R-3) -COCH (Et)_Two 1-231 1 6-MeO (R-3) -CONHPh 1-232 1 6-MeO (R-3) -CONHCHMePh 1-233 1 6-MeO (R-3) -CONHCHMe (4-MeO-Ph) 1 -234 16-MeO (R-3) -CONHCHMe (3,5-diF-Ph) 1-235 16-MeO (R-3) -CONH (CH_Two)_TwoPh 1-236 16-MeO (R-3) -CON (Me) Ph 1-237 16-MeO (R-3) -CON (Et) Ph 1-238 16-MeO (R-3)- CONMe (4-F-Ph) 1-239 16-MeO (R-3) -CONMe (4-Cl-Ph) 1-240 16-MeO (R-3) -CONMe (4-MeO-Ph) 1-241 1 6-MeO (R-3) -CONMe (3,4-diF-Ph) 1-242 1 6-MeO (R-3) -CONMe (3,5-diF-Ph) 1-243 1 6-MeO (R-3) -CONMe (3,4-diMeO-Ph) 1-244 1 6-MeO (R-3) -CONMe (3,5-diMeO-Ph) 1-245 1 6-MeO ( (R-3) -cPn 1-246 16-MeO (R-3) -Ph 1-247 16-MeO (R-3) -Bz 1-248 16-MeO (R-3)-(CH_Two)_TwoPh 1-249 16-MeO (R-3) -Me 1-250 16-MeO (R-3) -iPr 1-251 16-MeO (R-3) -Bu 1-252 16-MeO (R-3) -iBu 1-253 1 6-MeO (R-3) -sBu 1-254 16-MeO (R-3) -tBu 1-255 1 6-MeO (R-3) -iPn 1 -256 1 6-MeO (R-3) -CH_TwoCH (Et)_Two 1-257 1 6-MeO (R-3)-(CH_Two)_TwoCH (Et)_Two 1-258 1 6-MeO (R-3) -1-Et-Bu 1-259 16-MeO (R-3) -1-Et-Pn 1-260 16-MeO (R-4) -CONHCHMePh 1-261 1 6-MeO (R-4) -CON (Me) Ph 1-262 1 6-MeO (R-4) -cPn 1-263 16-MeO (R-4) -iBu 1-264 1 6-MeO (R-5) -COCH_TwoCH (Et)_Two 1-265 1 6-MeO (R-5) -COCH (Et)_Two 1-266 16-MeO (R-5) -COPh 1-267 16-MeO (R-5) -CO (4-Cl-Ph) 1-268 16-MeO (R-5) -CONHBu 1 -269 1 6-MeO (R-5) -CON (Et)_Two 1-270 1 6-MeO (R-5) -CONHCH_TwoCH (Et)_Two 1-271 1 6-MeO (R-5) -CONHCH (Et)_Two 1-272 1 6-MeO (R-5) -CONHcPn 1-273 16-MeO (R-5) -CONHcHx 1-274 16-MeO (R-5) -CONHPh 1-275 1 6-MeO ( R- 5) -CONHBz 1-276 16-MeO (R-5) -CONH (3-F-Bz) 1-277 16-MeO (R-5) -CONH (4-Cl-Bz) 1- 278 1 6-MeO (R-5) -CONHCHMePh 1-279 16-MeO (R-5) -CONHCHMe (4-MeO-Ph) 1-280 16-MeO (R-5) -CONHCHMe (3, 5-diF-Ph) 1-281 1 6-MeO (R-5) -CONH (CH_Two)_TwoPh 1-282 1 6-MeO (R-5) -CONHCH_TwoCH (Me) Ph 1-283 1 6-MeO (R-5) -CONHCH_TwoCH (OH) Ph 1-284 16-MeO (R-5) -CONH (CH_Two)_Two(4-Cl-Ph) 1-285 1 6-MeO (R-5) -CONHCH_TwoCH (Me) Np (2) 1-286 1 6-MeO (R-5) -CONH (CH_Two)_TwoMor (4) 1-287 1 6-MeO (R-5) -CONHCH_TwoFur (2) 1-288 1 6-MeO (R-5) -CONHCH_TwoFur (3) 1-289 1 6-MeO (R-5) -CONHCH_TwoPrd (2) 1-290 1 6-MeO (R-5) -CONHCH_TwoPrd (3) 1-291 1 6-MeO (R-5) -CONHCH (Me) Prd (3) 1-292 16-MeO (R-5) -COPrd (1) 1-293 1 6-MeO ( R-5) -COMor (4) 1-294 1 6-MeO (R-5) -COPiz (1) 1-295 16-MeO (R-5) -CO [4-Me-Piz (1)] 1-296 1 6-MeO (R-5) -CONH (CH_Two)_TwoNH_Two 1-297 1 6-MeO (R-5) -CONHCH_TwoCO_TwoEt 1-298 16-MeO (R-5) -CON (Me) Ph 1-299 16-MeO (R-5) -CON (Et) Ph 1-300 16-MeO (R-5)- CONMe (4-F-Ph) 1-301 16-MeO (R-5) -CONMe (4-Cl-Ph) 1-302 16-MeO (R-5) -CONMe (4-MeO-Ph) 1-303 1 6-MeO (R-5) -CONMe (3,4-diF-Ph) 1-304 1 6-MeO (R-5) -CONMe (3,5-diF-Ph) 1-305 1 6-MeO (R-5) -CONMe (3,4-diMeO-Ph) 1-306 1 6-MeO (R-5) -CONMe (3,5-diMeO-Ph) 1-307 1 6-MeO ( R-5) -CON (Me) Bz 1-308 16-MeO (R-5) -cPn 1-309 16-MeO (R-5) -cHx 1-310 16-MeO (R-5) -Ph 1-311 16-MeO (R-5) -4-Cl-Ph 1-312 16-MeO (R-5) -Bz 1-313 16-MeO (R-5)-(3, 4,5-triMeO-Bz) 1-314 1 6-MeO (R-5)-(CH_Two)_TwoPh 1-315 16-MeO (R-5) -Thi (2) 1-316 16-MeO (R-5) -Thi (3) 1-317 16-MeO (R-5) -Me 1 -318 16-MeO (R-5) -Et 1-319 16-MeO (R-5) -Pr 1-320 16-MeO (R-5) -iPr 1-321 16-MeO (R -5) -Bu 1-322 16-MeO (R-5) -iBu 1-323 16-MeO (R-5) -sBu 1-324 16-MeO (R-5) -tBu 1-325 16-MeO (R-5) -Pn 1-326 1 6-MeO (R-5) -iPn 1-327 16-MeO (R-5) -1-Me-Bu 1-328 16-MeO (R-5) -CH (Et)_Two 1-329 1 6-MeO (R-5) -CH_TwoCH (Et)_Two 1-330 1 6-MeO (R-5)-(CH_Two)_TwoCH (Et)_Two 1-331 16-MeO (R-5) -1-Et-Bu 1-332 16-MeO (R-5) -1-Et-Pn 1-333 16-MeO (R-6) -COiPr 1-334 16-MeO (R-6) -COiBu 1-335 16-MeO (R-6) -COCH_TwoCH (Et)_Two 1-336 1 6-MeO (R-6) -COCH (Et)_Two 1-337 16-MeO (R-6) -COPh 1-338 16-MeO (R-6) -CO (4-Cl-Ph) 1-339 16-MeO (R-6) -COBz 1 -340 1 6-MeO (R-6) -CONH_Two 1-341 16-MeO (R-6) -CONHMe 1-342 16-MeO (R-6) -CONHEt 1-343 16-MeO (R-6) -CONHPr 1-344 16-MeO ( R-6) -CONHBu 1-345 1 6-MeO (R-6) -CON (Me)_Two 1-346 1 6-MeO (R-6) -CON (Et)_Two 1-347 16-MeO (R-6) -CONHiPr 1-348 16-MeO (R-6) -CONHiBu 1-349 16-MeO (R-6) -CONHtBu 1-350 16-MeO ( R-6) -CONHCH_TwoCH (Et)_Two 1-351 1 6-MeO (R-6) -CONHCH (Et)_Two 1-352 1 6-MeO (R-6) -CONHcPn 1-353 16-MeO (R-6) -CONHcHx 1-354 16-MeO (R-6) -CONHPh 1-355 1 6-MeO ( R-6) -CONHBz 1-356 16-MeO (R-6) -CONH (3-F-Bz) 1-357 16-MeO (R-6) -CONH (4-Cl-Bz) 1- 358 1 6-MeO (R-6) -CONHCHMePh 1-359 1 6-MeO (R-6) -CONHCHMe (4-MeO-Ph) 1-360 16-MeO (R-6) -CONHCHMe (3, 5-diF-Ph) 1-361 1 6-MeO (R-6) -CONH (CH_Two)_TwoPh 1-362 16-MeO (R-6) -CONHCH_TwoCH (Me) Ph 1-363 1 6-MeO (R-6) -CONHCH_TwoCH (OH) Ph 1-364 16-MeO (R-6) -CONH (CH_Two)_Two(4-Cl-Ph) 1-365 1 6-MeO (R-6) -CONHCH_TwoCH (Me) Np (2) 1-366 16-MeO (R-6) -CONH (CH_Two)_TwoMor (4) 1-367 1 6-MeO (R-6) -CONHCH_TwoFur (2) 1-368 1 6-MeO (R-6) -CONHCH_TwoFur (3) 1-369 1 6-MeO (R-6) -CONHCH_TwoPrd (2) 1-370 1 6-MeO (R-6) -CONHCH_TwoPrd (3) 1-371 16-MeO (R-6) -CONHCH (Me) Prd (3) 1-372 16-MeO (R-6) -COPrd (1) 1-373 16-MeO ( R-6) -COMor (4) 1-374 16-MeO (R-6) -COPiz (1) 1-375 16-MeO (R-6) -CO [4-Me-Piz (1)] 1-376 1 6-MeO (R-6) -CONH (CH_Two)_TwoNH_Two 1-377 1 6-MeO (R-6) -CONH (CH_Two)_TwoN (Me)_Two 1-378 1 6-MeO (R-6) -CONHCH_TwoCO_TwoH 1-379 1 6-MeO (R-6) -CONHCH_TwoCO_TwoMe 1-380 1 6-MeO (R-6) -CONHCH_TwoCO_TwoEt 1-381 16-MeO (R-6) -CON (Me) Ph 1-382 16-MeO (R-6) -CON (Et) Ph 1-383 16-MeO (R-6)- CONMe (4-F-Ph) 1-384 16-MeO (R-6) -CONMe (4-Cl-Ph) 1-385 16-MeO (R-6) -CONMe (4-MeO-Ph) 1-386 1 6-MeO (R-6) -CONMe (3,4-diF-Ph) 1-387 1 6-MeO (R-6) -CONMe (3,5-diF-Ph) 1-388 1 6-MeO (R-6) -CONMe (3,4-diMeO-Ph) 1-389 1 6-MeO (R-6) -CONMe (3,5-diMeO-Ph) 1-390 16-MeO ( R-6) -CON (Me) Bz 1-391 16-MeO (R-6) -CONMe (4-F-Bz) 1-392 16-MeO (R-6) -CONMe (4-MeO- Bz) 1-393 16-MeO (R-6) -cPn 1-394 16-MeO (R-6) -cHx 1-395 16-MeO (R-6) -Ph 1-396 16- MeO (R-6) -4-Cl-Ph 1-397 1 6-MeO (R-6) -Bz 1-398 1 6-MeO (R-6)-(4-MeO-Bz) 1-399 1 6-MeO (R-6)-(3,4-diMeO-Bz) 1-400 16-MeO (R-6)-(3,4,5-triMeO-Bz) 1-401 1 6-MeO ( R-6)-(CH_Two)_TwoPh 1-402 1 6-MeO (R-6)-(CH_Two)_ThreePh 1-403 16-MeO (R-6) -Thi (2) 1-404 16-MeO (R-6) -Thi (3) 1-405 16-MeO (R-6) -Fur ( 3) 1-406 16-MeO (R-6) -Me 1-407 16-MeO (R-6) -Et 1-408 16-MeO (R-6) -Pr 1-409 1 6- MeO (R-6) -iPr 1-410 16-MeO (R-6) -Bu 1-411 16-MeO (R-6) -iBu 1-412 16-MeO (R-6) -sBu 1-413 16-MeO (R-6) -tBu 1-414 16-MeO (R-6) -Pn 1-415 16-MeO (R-6) -iPn 1-416 16-MeO ( R-6) -1-Me-Bu 1-417 1 6-MeO (R-6) -CH (Et)_Two 1-418 1 6-MeO (R-6) -CH_TwoCH (Et)_Two 1-419 1 6-MeO (R-6)-(CH_Two)_TwoCH (Et)_Two 1-420 1 6-MeO (R-6) -1-Et-Bu 1-421 1 6-MeO (R-6) -1-Et-Pn 1-422 1 6-MeO (R-6) -Vin 1-423 1 6-MeO (R-6) -Bun 1-424 16-MeO (R-6) -3- (3-Me-Bun) 1-425 16-MeO (R-7) -CONHPh 1-426 1 6-MeO (R-7) -CONHCHMePh 1-427 1 6-MeO (R-7) -CON (Me) Ph 1-428 16-MeO (R-7) -CON (Et) Ph 1-429 1 6-MeO (R-7) -CONMe (4-F-Ph) 1-430 16-MeO (R-7) -CONMe (4-Cl-Ph) 1-431 16-MeO ( R-7) -CONMe (4-MeO-Ph) 1-432 16-MeO (R-7) -CONMe (3,4-diF-Ph) 1-433 16-MeO (R-7) -CONMe (3,5-diF-Ph) 1-434 1 6-MeO (R-7) -CONMe (3,4-diMeO-Ph) 1-435 16-MeO (R-7) -CONMe (3,5 -diMeO-Ph) 1-436 16-MeO (R-7) -cPn 1-437 16-MeO (R-7) -Bz 1-438 16-MeO (R-7)-(CH_Two)_TwoPh 1-439 16-MeO (R-7) -iPr 1-440 16-MeO (R-7) -Bu 1-441 16-MeO (R-7) -iBu 1-442 16-MeO (R-7) -tBu 1-443 16-MeO (R-7) -iPn 1-444 16-MeO (R-7) -1-Et-Bu 1-445 16-MeO (R-7 ) -1-Et-Pn 1-446 16-MeO (R-8) -CONHPh 1-447 16-MeO (R-8) -CONHCHMePh 1-448 16-MeO (R-8) -CON ( Me) Ph 1-449 1 6-MeO (R-8) -CON (Et) Ph 1-450 1 6-MeO (R-8) -CONMe (4-F-Ph) 1-451 1 6-MeO ( R-8) -CONMe (4-Cl-Ph) 1-452 16-MeO (R-8) -CONMe (4-MeO-Ph) 1-453 16-MeO (R-8) -CONMe (3 , 4-diF-Ph) 1-454 16-MeO (R-8) -CONMe (3,5-diF-Ph) 1-455 16-MeO (R-8) -CONMe (3,4-diMeO -Ph) 1-456 16-MeO (R-8) -CONMe (3,5-diMeO-Ph) 1-457 16-MeO (R-8) -cPn 1-458 16-MeO (R- 8) -Bz 1-459 1 6-MeO (R-8)-(CH_Two)_TwoPh 1-460 16-MeO (R-8) -iPr 1-461 16-MeO (R-8) -Bu 1-462 16-MeO (R-8) -iBu 1-463 16-MeO (R-8) -tBu 1-464 16-MeO (R-8) -iPn 1-465 16-MeO (R-8) -1-Et-Bu 1-466 16-MeO (R-8 ) -1-Et-Pn 1-467 16-MeO (R-9) -CONHCHMePh 1-468 16-MeO (R-9) -CON (Me) Ph 1-469 16-MeO (R-9 ) -cPn 1-470 16-MeO (R-9) -iBu 1-471 16-MeO (R-10) -CONHCHMePh 1-472 16-MeO (R-10) -CON (Me) Ph 1 -473 16-MeO (R-10) -cPn 1-474 16-MeO (R-10) -iBu 1-475 16-MeO (R-11) -CONHPh 1-476 16-MeO (R -11) -CONHCHMePh 1-477 16-MeO (R-11) -CON (Me) Ph 1-478 16-MeO (R-11) -CON (Et) Ph 1-479 16-MeO (R -11) -CONMe (4-F-Ph) 1-480 16-MeO (R-11) -CONMe (4-Cl-Ph) 1-481 16-MeO (R-11) -CONMe (4- MeO-Ph) 1-482 16-MeO (R-11) -CONMe (3,4-diF-Ph) 1-483 16-MeO (R-11) -CONMe (3,5-diF-Ph) 1-484 1 6-MeO (R-11) -CONMe (3,4-diMeO-Ph) 1-485 1 6-MeO (R-11) -CONMe (3,5-diMeO-Ph) 1-486 1 6-MeO (R-11) -cPn 1-487 1 6-MeO (R-11) -Bz 1-488 1 6-MeO (R-11)-(CH_Two)_TwoPh 1-489 16-MeO (R-11) -iPr 1-490 16-MeO (R-11) -Bu 1-491 16-MeO (R-11) -iBu 1-492 16-MeO (R-11) -tBu 1-493 16-MeO (R-11) -iPn 1-494 16-MeO (R-11) -1-Et-Bu 1-495 16-MeO (R-11 ) -1-Et-Pn 1-496 1 6-MeO (R-12) -CONHCHMePh 1-497 1 6-MeO (R-12) -CON (Me) Ph 1-498 1 6-MeO (R-12 ) -cPn 1-499 16-MeO (R-12) -iBu 1-500 16-MeO (R-13) -CONHCHMePh 1-501 16-MeO (R-13) -CON (Me) Ph 1 -502 16-MeO (R-13) -cPn 1-503 16-MeO (R-13) -iBu 1-504 16-MeO (R-14) -COCH_TwoCH (Et)_Two 1-505 1 6-MeO (R-14) -COCH (Et)_Two 1-506 16-MeO (R-14) -COPh 1-507 16-MeO (R-14) -CO (4-Cl-Ph) 1-508 16-MeO (R-14) -CONHBu 1 -509 1 6-MeO (R-14) -CON (Et)_Two 1-510 1 6-MeO (R-14) -CONHCH_TwoCH (Et)_Two 1-511 1 6-MeO (R-14) -CONHCH (Et)_Two 1-512 16-MeO (R-14) -CONHcPn 1-513 16-MeO (R-14) -CONHcHx 1-514 16-MeO (R-14) -CONHPh 1-515 16-MeO ( R-14) -CONHBz 1-516 16-MeO (R-14) -CONH (3-F-Bz) 1-517 16-MeO (R-14) -CONH (4-Cl-Bz) 1- 518 16-MeO (R-14) -CONHCHMePh 1-519 16-MeO (R-14) -CONHCHMe (4-MeO-Ph) 1-520 16-MeO (R-14) -CONHCHMe (3, 5-diF-Ph) 1-521 1 6-MeO (R-14) -CONH (CH_Two)_TwoPh 1-522 1 6-MeO (R-14) -CONHCH_TwoCH (Me) Ph 1-523 16-MeO (R-14) -CONHCH_TwoCH (OH) Ph 1-524 16-MeO (R-14) -CONH (CH_Two)_Two(4-Cl-Ph) 1-525 16-MeO (R-14) -CONHCH_TwoCH (Me) Np (2) 1-526 16-MeO (R-14) -CONH (CH_Two)_TwoMor (4) 1-527 1 6-MeO (R-14) -CONHCH_TwoFur (2) 1-528 1 6-MeO (R-14) -CONHCH_TwoFur (3) 1-529 1 6-MeO (R-14) -CONHCH_TwoPrd (2) 1-530 1 6-MeO (R-14) -CONHCH_TwoPrd (3) 1-531 1 6-MeO (R-14) -CONHCH (Me) Prd (3) 1-532 16-MeO (R-14) -COPrd (1) 1-533 16-MeO ( R-14) -COMor (4) 1-534 16-MeO (R-14) -COPiz (1) 1-535 16-MeO (R-14) -CO [4-Me-Piz (1)] 1-536 1 6-MeO (R-14) -CONH (CH_Two)_TwoNH_Two 1-537 1 6-MeO (R-14) -CONHCH_TwoCO_TwoEt 1-538 16-MeO (R-14) -CON (Me) Ph 1-539 16-MeO (R-14) -CON (Et) Ph 1-540 16-MeO (R-14)- CONMe (4-F-Ph) 1-541 16-MeO (R-14) -CONMe (4-Cl-Ph) 1-542 16-MeO (R-14) -CONMe (4-MeO-Ph) 1-543 1 6-MeO (R-14) -CONMe (3,4-diF-Ph) 1-544 1 6-MeO (R-14) -CONMe (3,5-diF-Ph) 1-545 1 6-MeO (R-14) -CONMe (3,4-diMeO-Ph) 1-546 1 6-MeO (R-14) -CONMe (3,5-diMeO-Ph) 1-547 1 6-MeO ( (R-14) -CON (Me) Bz 1-548 16-MeO (R-14) -cPn 1-549 16-MeO (R-14) -cHx 1-550 16-MeO (R-14) -Ph 1-551 16-MeO (R-14) -4-Cl-Ph 1-552 16-MeO (R-14) -Bz 1-553 16-MeO (R-14)-(3, 4,5-triMeO-Bz) 1-554 1 6-MeO (R-14)-(CH_Two)_TwoPh 1-555 16-MeO (R-14) -Thi (2) 1-556 16-MeO (R-14) -Thi (3) 1-557 16-MeO (R-14) -Me 1 -558 16-MeO (R-14) -Et 1-559 16-MeO (R-14) -Pr 1-560 16-MeO (R-14) -iPr 1-561 16-MeO (R -14) -Bu 1-562 16-MeO (R-14) -iBu 1-563 16-MeO (R-14) -sBu 1-564 16-MeO (R-14) -tBu 1-565 16-MeO (R-14) -Pn 1-566 16-MeO (R-14) -iPn 1-567 16-MeO (R-14) -1-Me-Bu 1-568 16-MeO (R-14) -CH (Et)_Two 1-569 1 6-MeO (R-14) -CH_TwoCH (Et)_Two 1-570 1 6-MeO (R-14)-(CH_Two)_TwoCH (Et)_Two 1-571 16-MeO (R-14) -1-Et-Bu 1-572 16-MeO (R-14) -1-Et-Pn 1-573 16-MeO (R-15) -CONHPh 1-574 16-MeO (R-15) -CONHCHMePh 1-575 16-MeO (R-15) -CON (Me) Ph 1-576 16-MeO (R-15) -CON (Et) Ph 1-577 16-MeO (R-15) -CONMe (4-F-Ph) 1-578 16-MeO (R-15) -CONMe (4-Cl-Ph) 1-579 16-MeO ( (R-15) -CONMe (4-MeO-Ph) 1-580 16-MeO (R-15) -CONMe (3,4-diF-Ph) 1-581 16-MeO (R-15) -CONMe (3,5-diF-Ph) 1-582 16-MeO (R-15) -CONMe (3,4-diMeO-Ph) 1-583 16-MeO (R-15) -CONMe (3,5 -diMeO-Ph) 1-584 16-MeO (R-15) -cPn 1-585 16-MeO (R-15) -Bz 1-586 16-MeO (R-15)-(CH_Two)_TwoPh 1-587 16-MeO (R-15) -iPr 1-588 16-MeO (R-15) -Bu 1-589 16-MeO (R-15) -iBu 1-590 16-MeO (R-15) -tBu 1-591 16-MeO (R-15) -iPn 1-592 16-MeO (R-15) -1-Et-Bu 1-593 16-MeO (R-15 ) -1-Et-Pn 1-594 16-MeO (R-16) -CONHPh 1-595 16-MeO (R-16) -CONHCHMePh 1-596 16-MeO (R-16) -CON ( Me) Ph 1-597 16-MeO (R-16) -CON (Et) Ph 1-598 16-MeO (R-16) -CONMe (4-F-Ph) 1-599 16-MeO ( (R-16) -CONMe (4-Cl-Ph) 1-600 16-MeO (R-16) -CONMe (4-MeO-Ph) 1-601 16-MeO (R-16) -CONMe (3 , 4-diF-Ph) 1-602 16-MeO (R-16) -CONMe (3,5-diF-Ph) 1-603 16-MeO (R-16) -CONMe (3,4-diMeO -Ph) 1-604 16-MeO (R-16) -CONMe (3,5-diMeO-Ph) 1-605 16-MeO (R-16) -cPn 1-606 16-MeO (R- 16) -Bz 1-607 16-MeO (R-16)-(CH_Two)_TwoPh 1-608 16-MeO (R-16) -iPr 1-609 16-MeO (R-16) -Bu 1-610 16-MeO (R-16) -iBu 1-611 16-MeO (R-16) -tBu 1-612 16-MeO (R-16) -iPn 1-613 16-MeO (R-16) -1-Et-Bu 1-614 16-MeO (R-16 ) -1-Et-Pn 1-615 16-MeO (R-17) -COCH_TwoCH (Et)_Two 1-616 1 6-MeO (R-17) -COCH (Et)_Two 1-617 16-MeO (R-17) -CONHPh 1-618 16-MeO (R-17) -CONHCHMePh 1-619 16-MeO (R-17) -CONHCHMe (4-MeO-Ph) 1 -620 16-MeO (R-17) -CONHCHMe (3,5-diF-Ph) 1-621 16-MeO (R-17) -CONH (CH_Two)_TwoPh 1-622 16-MeO (R-17) -CON (Me) Ph 1-623 16-MeO (R-17) -CON (Et) Ph 1-624 16-MeO (R-17)- CONMe (4-F-Ph) 1-625 16-MeO (R-17) -CONMe (4-Cl-Ph) 1-626 16-MeO (R-17) -CONMe (4-MeO-Ph) 1-627 1 6-MeO (R-17) -CONMe (3,4-diF-Ph) 1-628 1 6-MeO (R-17) -CONMe (3,5-diF-Ph) 1-629 1 6-MeO (R-17) -CONMe (3,4-diMeO-Ph) 1-630 1 6-MeO (R-17) -CONMe (3,5-diMeO-Ph) 1-631 1 6-MeO ( (R-17) -cPn 1-632 16-MeO (R-17) -Ph 1-633 16-MeO (R-17) -Bz 1-634 16-MeO (R-17)-(CH_Two)_TwoPh 1-635 16-MeO (R-17) -Me 1-636 16-MeO (R-17) -iPr 1-637 16-MeO (R-17) -Bu 1-638 16-MeO (R-17) -iBu 1-639 16-MeO (R-17) -sBu 1-640 16-MeO (R-17) -tBu 1-641 16-MeO (R-17) -iPn 1 -642 1 6-MeO (R-17) -CH_TwoCH (Et)_Two 1-643 1 6-MeO (R-17)-(CH_Two)_TwoCH (Et)_Two 1-644 16-MeO (R-17) -1-Et-Bu 1-645 16-MeO (R-17) -1-Et-Pn 1-646 17-Me0 (R-1) -CON (Me) Ph 1-647 1 7-Me0 (R-1) -COCH (Et)_Two 1-648 1 7-Me0 (R-1) -COCH_TwoCH (Et)_Two 1-649 1 7-Me0 (R-1) -COPh 1-650 1 7-Me0 (R-1) -cPn 1-651 17-Me0 (R-1) -Bz 1-652 1 7-Me0 ( R- 1) -iPr 1-653 17-Me0 (R- 1) -iBu 1-654 17-Me0 (R- 1) -CH_TwoCH (Et)_Two 1-655 17-Me0 (R-1) -All 1-656 18-MeO (R-6) -CON (Me) Ph 1-657 18-MeO (R-14) -CON (Me) Ph 1-658 1 6-EtO (R-6) -CON (Me) Ph 1-659 16-EtO (R-14) -CON (Me) Ph 1-660 17-EtO (R-1) -CON (Me) Ph 1-661 1 7-EtO (R- 2) -CON (Me) Ph 1-662 17-EtO (R-3) -CON (Me) Ph 1-663 1 7-EtO (R- 4) -CON (Me) Ph 1-664 1 7-EtO (R-5) -CON (Me) Ph 1-665 17-EtO (R-6) -CON (Me) Ph 1-666 1 7- EtO (R-7) -CON (Me) Ph 1-667 17-EtO (R-8) -CON (Me) Ph 1-668 17-EtO (R-9) -CON (Me) Ph 1- 669 1 7-EtO (R-10) -CON (Me) Ph 1-670 17-EtO (R-11) -CON (Me) Ph 1-671 17-EtO (R-12) -CON (Me ) Ph 1-672 1 7-EtO (R-13) -CON (Me) Ph 1-673 1 7-EtO (R-14) -CON (Me) Ph 1-674 1 7-EtO (R-15) -CON (Me) Ph 1-675 1 7-EtO (R-16) -CON (Me) Ph 1-676 17-EtO (R-17) -CON (Me) Ph 1-677 1 7-EtO ( R-18) -CON (Me) Ph 1-678 1 6-OH (R-6) -CON (Me) Ph 1-679 1 6-OH (R-14) -CON (Me) Ph 1-680 1 7-OH (R-6) -CON (Me) Ph 1-681 1 7-OH (R-14) -CON (Me) Ph 1-682 36-OH 7-OH 8-OH (R-1) -CON (Me) Ph 1-683 36-OH 7-OH 8-OH (R-2) -CON (Me) Ph 1-684 36-OH 7-OH 8-OH (R-3) -CON (Me) Ph 1-685 3 6-OH 7-OH 8-OH (R-5) -CONHPh 1-686 36-OH 7-OH 8-OH (R-5) -CONHCHMePh 1-687 36-OH 7-OH 8-OH (R-5) -CONHCHMe (4- MeO-Ph) 1-688 36-OH 7-OH 8-OH (R-5) -CONHCHMe (3,5-diF-Ph) 1-689 36-OH 7-OH 8-OH (R-5 ) -CONH (CH_Two)_TwoPh 1-690 3 6-OH 7-OH 8-OH (R-5) -CON (Me) Ph 1-691 3 6-OH 7-OH 8-OH (R-5) -CON (Et) Ph 1 -692 36-OH 7-OH 8-OH (R-5) -CONMe (4-F-Ph) 1-693 36-OH 7-OH 8-OH (R-5) -CONMe (4-MeO -Ph) 1-694 3 6-OH 7-OH 8-OH (R-5) -CONMe (3,4-diF-Ph) 1-695 36-OH 7-OH 8-OH (R-5) -CONMe (3,5-diF-Ph) 1-696 36-OH 7-OH 8-OH (R-5) -CONMe (3,4-diMeO-Ph) 1-697 3 6-OH 7-OH 8-OH (R-5) -CONMe (3,5-diMeO-Ph) 1-698 3 6-OH 7-OH 8-OH (R-5) -cPn 1-699 36-OH 7-OH 8 -OH (R-5) -Ph 1-700 3 6-OH 7-OH 8-OH (R-5) -Bz 1-701 36-OH 7-OH 8-OH (R-5)-(CH_Two)_TwoPh 1-702 36-OH 7-OH 8-OH (R-5) -iPr 1-703 36-OH 7-OH 8-OH (R-5) -Bu 1-704 36-OH 7- OH 8-OH (R-5) -iBu 1-705 36-OH 7-OH 8-OH (R-5) -tBu 1-706 36-OH 7-OH 8-OH (R-5)- iPn 1-707 3 6-OH 7-OH 8-OH (R-5) -CH_TwoCH (Et)_Two 1-708 3 6-OH 7-OH 8-OH (R-5)-(CH_Two)_TwoCH (Et)_Two 1-709 3 6-OH 7-OH 8-OH (R-5) -1-Et-Bu 1-710 3 6-OH 7-OH 8-OH (R-5) -1-Et-Pn 1- 711 3 6-OH 7-OH 8-OH (R-6) -CONHPh 1-712 36-OH 7-OH 8-OH (R-6) -CONHCHMePh 1-713 36-OH 7-OH 8- OH (R-6) -CONHCHMe (4-MeO-Ph) 1-714 36-OH 7-OH 8-OH (R-6) -CONHCHMe (3,5-diF-Ph) 1-715 3 6- OH 7-OH 8-OH (R-6) -CONH (CH_Two)_TwoPh 1-716 36-OH 7-OH 8-OH (R-6) -CON (Me) Ph 1-717 36-OH 7-OH 8-OH (R-6) -CON (Et) Ph 1 -718 36-OH 7-OH 8-OH (R-6) -CONMe (4-F-Ph) 1-719 36-OH 7-OH 8-OH (R-6) -CONMe (4-MeO -Ph) 1-720 3 6-OH 7-OH 8-OH (R-6) -CONMe (3,4-diF-Ph) 1-721 36-OH 7-OH 8-OH (R-6) -CONMe (3,5-diF-Ph) 1-722 3 6-OH 7-OH 8-OH (R-6) -CONMe (3,4-diMeO-Ph) 1-723 3 6-OH 7-OH 8-OH (R-6) -CONMe (3,5-diMeO-Ph) 1-724 36-OH 7-OH 8-OH (R-6) -cPn 1-725 36-OH 7-OH 8 -OH (R-6) -Bz 1-726 3 6-OH 7-OH 8-OH (R-6)-(CH_Two)_TwoPh 1-727 36-OH 7-OH 8-OH (R-6) -iPr 1-728 36-OH 7-OH 8-OH (R-6) -Bu 1-729 36-OH 7- OH 8-OH (R-6) -sBu 1-730 36-OH 7-OH 8-OH (R-6) -tBu 1-731 36-OH 7-OH 8-OH (R-6)- iPn 1-732 3 6-OH 7-OH 8-OH (R-6) -CH_TwoCH (Et)_Two 1-733 3 6-OH 7-OH 8-OH (R-6)-(CH_Two)_TwoCH (Et)_Two 1-734 3 6-OH 7-OH 8-OH (R-6) -1-Et-Bu 1-735 3 6-OH 7-OH 8-OH (R-6) -1-Et-Pn 1- 736 3 6-OH 7-OH 8-OH (R-7) -CON (Me) Ph 1-737 3 6-OH 7-OH 8-OH (R-8) -CON (Me) Ph 1-738 3 6-OH 7-OH 8-OH (R-11) -CON (Me) Ph 1-739 3 6-OH 7-OH 8-OH (R-12) -CON (Me) Ph 1-740 3 6- OH 7-OH 8-OH (R-14) -CONHPh 1-741 3 6-OH 7-OH 8-OH (R-14) -CONHCHMePh 1-742 3 6-OH 7-OH 8-OH (R- 14) -CONHCHMe (4-MeO-Ph) 1-743 36-OH 7-OH 8-OH (R-14) -CONHCHMe (3,5-diF-Ph) 1-744 36-OH 7-OH 8-OH (R-14) -CONH (CH_Two)_TwoPh 1-745 3 6-OH 7-OH 8-OH (R-14) -CON (Me) Ph 1-746 3 6-OH 7-OH 8-OH (R-14) -CON (Et) Ph 1 -747 3 6-OH 7-OH 8-OH (R-14) -CONMe (4-F-Ph) 1-748 3 6-OH 7-OH 8-OH (R-14) -CONMe (4-MeO -Ph) 1-749 3 6-OH 7-OH 8-OH (R-14) -CONMe (3,4-diF-Ph) 1-750 3 6-OH 7-OH 8-OH (R-14) -CONMe (3,5-diF-Ph) 1-751 3 6-OH 7-OH 8-OH (R-14) -CONMe (3,4-diMeO-Ph) 1-752 3 6-OH 7-OH 8-OH (R-14) -CONMe (3,5-diMeO-Ph) 1-753 36-OH 7-OH 8-OH (R-14) -cPn 1-754 36-OH 7-OH 8 -OH (R-14) -Bz 1-755 3 6-OH 7-OH 8-OH (R-14)-(CH_Two)_TwoPh 1-756 36-OH 7-OH 8-OH (R-14) -iPr 1-757 36-OH 7-OH 8-OH (R-14) -Bu 1-758 36-OH 7- OH 8-OH (R-14) -sBu 1-759 3 6-OH 7-OH 8-OH (R-14) -tBu 1-760 3 6-OH 7-OH 8-OH (R-14)- iPn 1-761 3 6-OH 7-OH 8-OH (R-14) -CH_TwoCH (Et)_Two 1-762 3 6-OH 7-OH 8-OH (R-14)-(CH_Two)_TwoCH (Et)_Two 1-763 3 6-OH 7-OH 8-OH (R-14) -1-Et-Bu 1-764 3 6-OH 7-OH 8-OH (R-14) -1-Et-Pn 1- 765 3 6-OH 7-OH 8-OH (R-15) -CON (Me) Ph 1-766 3 6-OH 7-OH 8-OH (R-16) -CON (Me) Ph 1-767 3 6-OH 7-OH 8-OH (R-17) -CON (Me) Ph 1-768 26-MeO 7-MeO (R-1) -CONHPh 1-769 26-MeO 7-MeO (R- 1) -CONHCHMePh 1-770 2 6-MeO 7-MeO (R-1) -CON (Me) Ph 1-771 2 6-MeO 7-MeO (R-1) -CON (Et) Ph 1-772 2 6-MeO 7-MeO (R-1) -CONMe (4-F-Ph) 1-773 2 6-MeO 7-MeO (R-1) -CONMe (4-Cl-Ph) 1-774 2 6- MeO 7-MeO (R- 1) -CONMe (4-MeO-Ph) 1-775 26-MeO 7-MeO (R-1) -CONMe (3,4-diF-Ph) 1-776 2 6- MeO 7-MeO (R-1) -CONMe (3,5-diF-Ph) 1-777 2 6-MeO 7-MeO (R-1) -CONMe (3,4-diMeO-Ph) 1-778 2 6-MeO 7-MeO (R-1) -CONMe (3,5-diMeO-Ph) 1-779 26-MeO 7-MeO (R-1) -cPn 1-780 26-MeO 7-MeO ( R-1) -Bz 1-781 26-MeO 7-MeO (R-1)-(CH_Two)_TwoPh 1-782 26-MeO 7-MeO (R-1) -iPr 1-783 26-MeO 7-MeO (R-1) -Bu 1-784 26-MeO 7-MeO (R-1) -iBu 1-785 2 6-MeO 7-MeO (R-1) -tBu 1-786 26-MeO 7-MeO (R-1) -iPn 1-787 26 6-MeO 7-MeO (R-1 ) -1-Et-Bu 1-788 26-MeO 7-MeO (R- 1) -1-Et-Pn 1-789 26-MeO 7-MeO (R- 2) -COCH_TwoCH (Et)_Two 1-790 2 6-MeO 7-MeO (R-2) -COCH (Et)_Two 1-791 26-MeO 7-MeO (R-2) -CONHPh 1-792 26-MeO 7-MeO (R-2) -CONHCHMePh 1-793 26-MeO 7-MeO (R-2)- CONHCHMe (4-MeO-Ph) 1-794 26-MeO 7-MeO (R-2) -CONHCHMe (3,5-diF-Ph) 1-795 26-MeO 7-MeO (R-2)- CONH (CH_Two)_TwoPh 1-796 26-MeO 7-MeO (R- 2) -CON (Me) Ph 1-797 26-MeO 7-MeO (R- 2) -CON (Et) Ph 1-798 26-MeO 7-MeO (R- 2) -CONMe (4-F-Ph) 1-799 26-MeO 7-MeO (R- 2) -CONMe (4-Cl-Ph) 1-800 26-MeO 7- MeO (R-2) -CONMe (4-MeO-Ph) 1-801 26-MeO 7-MeO (R-2) -CONMe (3,4-diF-Ph) 1-802 26-MeO 7- MeO (R- 2) -CONMe (3,5-diF-Ph) 1-803 26-MeO 7-MeO (R- 2) -CONMe (3,4-diMeO-Ph) 1-804 26-MeO 7-MeO (R-2) -CONMe (3,5-diMeO-Ph) 1-805 26-MeO 7-MeO (R-2) -cPn 1-806 26-MeO 7-MeO (R-2 ) -Ph 1-807 26-MeO 7-MeO (R- 2) -Bz 1-808 26-MeO 7-MeO (R-2)-(CH_Two)_TwoPh 1-809 26-MeO 7-MeO (R- 2) -Me 1-810 26-MeO 7-MeO (R- 2) -iPr 1-811 26-MeO 7-MeO (R- 2) -Bu 1-812 2 6-MeO 7-MeO (R-2) -iBu 1-813 26-MeO 7-MeO (R-2) -sBu 1-814 26-MeO 7-MeO (R-2 ) -tBu 1-815 26-MeO 7-MeO (R- 2) -iPn 1-816 26-MeO 7-MeO (R-2) -CH_TwoCH (Et)_Two 1-817 2 6-MeO 7-MeO (R-2)-(CH_Two)_TwoCH (Et)_Two 1-818 26-MeO 7-MeO (R- 2) -1-Et-Bu 1-819 26-MeO 7-MeO (R-2) -1-Et-Pn 1-820 26-MeO 7 -MeO (R-3) -COCH_TwoCH (Et)_Two 1-821 2 6-MeO 7-MeO (R-3) -COCH (Et)_Two 1-822 26-MeO 7-MeO (R-3) -CONHPh 1-823 26-MeO 7-MeO (R-3) -CONHCHMePh 1-824 26-MeO 7-MeO (R-3)- CONHCHMe (4-MeO-Ph) 1-825 26-MeO 7-MeO (R-3) -CONHCHMe (3,5-diF-Ph) 1-826 26-MeO 7-MeO (R-3)- CONH (CH_Two)_TwoPh 1-827 26-MeO 7-MeO (R- 3) -CON (Me) Ph 1-828 26-MeO 7-MeO (R-3) -CON (Et) Ph 1-829 26-MeO 7-MeO (R-3) -CONMe (4-F-Ph) 1-830 2 6-MeO 7-MeO (R-3) -CONMe (4-Cl-Ph) 1-831 26-MeO 7- MeO (R-3) -CONMe (4-MeO-Ph) 1-832 26-MeO 7-MeO (R-3) -CONMe (3,4-diF-Ph) 1-833 26-MeO 7- MeO (R-3) -CONMe (3,5-diF-Ph) 1-834 26-MeO 7-MeO (R-3) -CONMe (3,4-diMeO-Ph) 1-835 26-MeO 7-MeO (R-3) -CONMe (3,5-diMeO-Ph) 1-836 26-MeO 7-MeO (R-3) -cPn 1-837 26-MeO 7-MeO (R-3 ) -Ph 1-838 26-MeO 7-MeO (R-3) -Bz 1-839 26-MeO 7-MeO (R-3)-(CH_Two)_TwoPh 1-840 26-MeO 7-MeO (R-3) -Me 1-841 26-MeO 7-MeO (R-3) -iPr 1-842 26-MeO 7-MeO (R-3) -Bu 1-843 2 6-MeO 7-MeO (R-3) -iBu 1-844 26-MeO 7-MeO (R-3) -sBu 1-845 26-MeO 7-MeO (R-3 ) -tBu 1-846 26-MeO 7-MeO (R-3) -iPn 1-847 26-MeO 7-MeO (R-3) -CH_TwoCH (Et)_Two 1-848 2 6-MeO 7-MeO (R-3)-(CH_Two)_TwoCH (Et)_Two 1-849 26-MeO 7-MeO (R- 3) -1-Et-Bu 1-850 26-MeO 7-MeO (R-3) -1-Et-Pn 1-851 26-MeO 7 -MeO (R-4) -CONHCHMePh 1-852 26-MeO 7-MeO (R-4) -CON (Me) Ph 1-853 26-MeO 7-MeO (R-4) -cPn 1-854 2 6-MeO 7-MeO (R-4) -iBu 1-855 2 6-MeO 7-MeO (R-5) -COCH_TwoCH (Et)_Two 1-856 2 6-MeO 7-MeO (R-5) -COCH (Et)_Two 1-857 26-MeO 7-MeO (R-5) -COPh 1-858 26-MeO 7-MeO (R-5) -CO (4-Cl-Ph) 1-859 26-MeO 7- MeO (R-5) -CONHBu 1-860 2 6-MeO 7-MeO (R-5) -CON (Et)_Two 1-861 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCH (Et)_Two 1-862 2 6-MeO 7-MeO (R-5) -CONHCH (Et)_Two 1-863 26-MeO 7-MeO (R-5) -CONHcPn 1-864 26-MeO 7-MeO (R-5) -CONHcHx 1-865 26-MeO 7-MeO (R-5)- CONHPh 1-866 2 6-MeO 7-MeO (R-5) -CONHBz 1-867 26-MeO 7-MeO (R-5) -CONH (3-F-Bz) 1-868 26-MeO 7 -MeO (R-5) -CONH (4-Cl-Bz) 1-869 26-MeO 7-MeO (R-5) -CONHCHMePh 1-870 26-MeO 7-MeO (R-5) -CONHCHMe (4-MeO-Ph) 1-871 26-MeO 7-MeO (R-5) -CONHCHMe (3,5-diF-Ph) 1-872 26-MeO 7-MeO (R-5) -CONH (CH_Two)_TwoPh 1-873 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCH (Me) Ph 1-874 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCH (OH) Ph 1-875 26-MeO 7-MeO (R-5) -CONH (CH_Two)_Two(4-Cl-Ph) 1-876 26-MeO 7-MeO (R-5) -CONHCH_TwoCH (Me) Np (2) 1-877 2 6-MeO 7-MeO (R-5) -CONH (CH_Two)_TwoMor (4) 1-878 2 6-MeO 7-MeO (R-5) -CONHCH_TwoFur (2) 1-879 2 6-MeO 7-MeO (R-5) -CONHCH_TwoFur (3) 1-880 2 6-MeO 7-MeO (R-5) -CONHCH_TwoPrd (2) 1-881 2 6-MeO 7-MeO (R-5) -CONHCH_TwoPrd (3) 1-882 2 6-MeO 7-MeO (R-5) -CONHCH (Me) Prd (3) 1-883 26-MeO 7-MeO (R-5) -COPrd (1) 1- 884 2 6-MeO 7-MeO (R-5) -COMor (4) 1-885 26-MeO 7-MeO (R-5) -COPiz (1) 1-886 26-MeO 7-MeO (R -5) -CO [4-Me-Piz (1)] 1-887 2 6-MeO 7-MeO (R-5) -CONH (CH_Two)_TwoNH_Two 1-888 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCO_TwoEt 1-889 26-MeO 7-MeO (R-5) -CON (Me) Ph 1-890 26-MeO 7-MeO (R-5) -CON (Et) Ph 1-891 26-MeO 7-MeO (R-5) -CONMe (4-F-Ph) 1-892 26-MeO 7-MeO (R-5) -CONMe (4-Cl-Ph) 1-893 26-MeO 7- MeO (R-5) -CONMe (4-MeO-Ph) 1-894 26-MeO 7-MeO (R-5) -CONMe (3,4-diF-Ph) 1-895 26-MeO 7- MeO (R-5) -CONMe (3,5-diF-Ph) 1-896 26-MeO 7-MeO (R-5) -CONMe (3,4-diMeO-Ph) 1-897 26-MeO 7-MeO (R-5) -CONMe (3,5-diMeO-Ph) 1-898 2 6-MeO 7-MeO (R-5) -CON (Me) Bz 1-899 26-MeO 7-MeO (R-5) -cPn 1-900 26-MeO 7-MeO (R-5) -cHx 1-901 26-MeO 7-MeO (R-5) -Ph 1-902 26-MeO 7- MeO (R-5) -4-Cl-Ph 1-903 26-MeO 7-MeO (R-5) -Bz 1-904 26-MeO 7-MeO (R-5)-(3,4, 5-triMeO-Bz) 1-905 2 6-MeO 7-MeO (R-5)-(CH_Two)_TwoPh 1-906 26-MeO 7-MeO (R-5) -Thi (2) 1-907 26-MeO 7-MeO (R-5) -Thi (3) 1-908 26-MeO 7- MeO (R-5) -Me 1-909 26-MeO 7-MeO (R-5) -Et 1-910 26-MeO 7-MeO (R-5) -Pr 1-911 26-MeO 7 -MeO (R-5) -iPr 1-912 26-MeO 7-MeO (R-5) -Bu 1-913 26-MeO 7-MeO (R-5) -iBu 1-914 26-MeO 7-MeO (R-5) -sBu 1-915 2 6-MeO 7-MeO (R-5) -tBu 1-916 26-MeO 7-MeO (R-5) -Pn 1-917 2 6- MeO 7-MeO (R-5) -iPn 1-918 26-MeO 7-MeO (R-5) -1-Me-Bu 1-919 26-MeO 7-MeO (R-5) -CH ( Et)_Two 1-920 2 6-MeO 7-MeO (R-5) -CH_TwoCH (Et)_Two 1-921 2 6-MeO 7-MeO (R-5)-(CH_Two)_TwoCH (Et)_Two 1-922 26-MeO 7-MeO (R-5) -1-Et-Bu 1-923 26-MeO 7-MeO (R-5) -1-Et-Pn 1-924 26-MeO 7 -MeO (R-6) -COiPr 1-925 26-MeO 7-MeO (R-6) -COiBu 1-926 26-MeO 7-MeO (R-6) -COCH_TwoCH (Et)_Two 1-927 2 6-MeO 7-MeO (R-6) -COCH (Et)_Two 1-928 26-MeO 7-MeO (R-6) -COPh 1-929 26-MeO 7-MeO (R-6) -CO (4-Cl-Ph) 1-930 26-MeO 7- MeO (R-6) -COBz 1-931 2 6-MeO 7-MeO (R-6) -CONH_Two 1-932 26-MeO 7-MeO (R-6) -CONHMe 1-933 26-MeO 7-MeO (R-6) -CONHEt 1-934 26-MeO 7-MeO (R-6)- CONHPr 1-935 26-MeO 7-MeO (R-6) -CONHBu 1-936 26-MeO 7-MeO (R-6) -CON (Me)_Two 1-937 2 6-MeO 7-MeO (R-6) -CON (Et)_Two 1-938 26-MeO 7-MeO (R-6) -CONHiPr 1-939 26-MeO 7-MeO (R-6) -CONHiBu 1-940 26-MeO 7-MeO (R-6)- CONHtBu 1-941 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCH (Et)_Two 1-942 2 6-MeO 7-MeO (R-6) -CONHCH (Et)_Two 1-943 26-MeO 7-MeO (R-6) -CONHcPn 1-944 26-MeO 7-MeO (R-6) -CONHcHx 1-945 26-MeO 7-MeO (R-6)- CONHPh 1-946 2 6-MeO 7-MeO (R-6) -CONH (3,4-diF-Ph) 1-947 26-MeO 7-MeO (R-6) -CONH (3,5-diF -Ph) 1-948 2 6-MeO 7-MeO (R-6) -CONH (4-MeO-Ph) 1-949 26-MeO 7-MeO (R-6) -CONHBz 1-950 2 6- MeO 7-MeO (R-6) -CONH (3-F-Bz) 1-951 26-MeO 7-MeO (R-6) -CONHCHMecHx 1-952 26-MeO 7-MeO (R-6) -CONHCHMePh 1-953 26-MeO 7-MeO (R-6) -CONHCHMe (4-MeO-Ph) 1-954 26-MeO 7-MeO (R-6) -CONHCHMe (3,4-diF- Ph) 1-955 26-MeO 7-MeO (R-6) -CONHCHMe (3,5-diF-Ph) 1-956 26-MeO 7-MeO (R-6) -CONH (CH_Two)_TwoPh 1-957 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCH (Me) Ph 1-958 26-MeO 7-MeO (R-6) -CONHCH_TwoCH (OH) Ph 1-959 26-MeO 7-MeO (R-6) -CONH (CH_Two)_Two(4-Cl-Ph) 1-960 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCH (Me) Np (2) 1-961 2 6-MeO 7-MeO (R-6) -CONH (CH_Two)_TwoMor (4) 1-962 2 6-MeO 7-MeO (R-6) -CONHCH_TwoFur (2) 1-963 2 6-MeO 7-MeO (R-6) -CONHCH_TwoFur (3) 1-964 2 6-MeO 7-MeO (R-6) -CONHCH_TwoPrd (2) 1-965 2 6-MeO 7-MeO (R-6) -CONHCH_TwoPrd (3) 1-966 26-MeO 7-MeO (R-6) -CONHCH (Me) Prd (3) 1-967 26-MeO 7-MeO (R-6) -CONHCH (Me) Pyr ( 4) 1-968 26-MeO 7-MeO (R-6) -COPrd (1) 1-969 26-MeO 7-MeO (R-6) -COMor (4) 1-970 26-MeO 7 -MeO (R-6) -COPiz (1) 1-971 2 6-MeO 7-MeO (R-6) -CO [4-Me-Piz (1)] 1-972 26-MeO 7-MeO ( R-6) -CONH (CH_Two)_TwoNH_Two 1-973 2 6-MeO 7-MeO (R-6) -CONH (CH_Two)_TwoN (Me)_Two 1-974 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCO_TwoH 1-975 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCO_TwoMe 1-976 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCO_TwoEt 1-977 26-MeO 7-MeO (R-6) -CON (Me) Ph 1-978 26-MeO 7-MeO (R-6) -CON (Et) Ph 1-979 26-MeO 7-MeO (R-6) -CONMe (4-F-Ph) 1-980 26-MeO 7-MeO (R-6) -CONMe (4-Cl-Ph) 1-981 26-MeO 7- MeO (R-6) -CONMe (4-MeO-Ph) 1-982 2 6-MeO 7-MeO (R-6) -CONMe (3,4-diF-Ph) 1-983 26-MeO 7- MeO (R-6) -CONMe (3,5-diF-Ph) 1-984 26-MeO 7-MeO (R-6) -CONMe (3,4-diMeO-Ph) 1-985 26-MeO 7-MeO (R-6) -CONMe (3,5-diMeO-Ph) 1-986 26-MeO 7-MeO (R-6) -CON (Me) Bz 1-987 26-MeO 7-MeO (R-6) -CONMe (4-F-Bz) 1-988 26-MeO 7-MeO (R-6) -CONMe (4-MeO-Bz) 1-989 26-MeO 7-MeO (R -6) -cPn 1-990 26-MeO 7-MeO (R-6) -cHx 1-991 26-MeO 7-MeO (R-6) -Ph 1-992 26-MeO 7-MeO ( R- 6) -4-Cl-Ph 1-993 26-MeO 7-MeO (R-6) -Bz 1-994 26-MeO 7-MeO (R-6)-(4-MeO-Bz) 1-995 2 6-MeO 7-MeO (R-6)-(3,4-diMeO-Bz) 1-996 26-MeO 7-MeO (R-6)-(3,4,5-triMeO- Bz) 1-997 2 6-MeO 7-MeO (R-6)-(CH_Two)_TwoPh 1-998 2 6-MeO 7-MeO (R-6)-(CH_Two)_ThreePh 1-999 26-MeO 7-MeO (R-6) -Thi (2) 1-1000 26-MeO 7-MeO (R-6) -Thi (3) 1-1001 26-MeO 7- MeO (R-6) -Fur (3) 1-1002 2 6-MeO 7-MeO (R-6) -Me 1-1003 26-MeO 7-MeO (R-6) -Et 1-1004 26 -MeO 7-MeO (R-6) -Pr 1-1005 26-MeO 7-MeO (R-6) -iPr 1-1006 26-MeO 7-MeO (R-6) -Bu 1-1007 2 6-MeO 7-MeO (R-6) -iBu 1-1008 2 6-MeO 7-MeO (R-6) -sBu 1-1009 26-MeO 7-MeO (R-6) -tBu 1-1010 26-MeO 7-MeO (R-6) -Pn 1-1011 26-MeO 7-MeO (R-6) -iPn 1-1012 26-MeO 7-MeO (R-6) -1-Me -Bu 1-1013 2 6-MeO 7-MeO (R-6) -CH (Et)_Two 1-1014 2 6-MeO 7-MeO (R-6) -CH_TwoCH (Et)_Two 1-1015 2 6-MeO 7-MeO (R-6)-(CH_Two)_TwoCH (Et)_Two 1-1016 26-MeO 7-MeO (R-6) -1-Et-Bu 1-1017 26-MeO 7-MeO (R-6) -1-Et-Pn 1-1018 26-MeO 7 -MeO (R-6) -Vin 1-1019 26-MeO 7-MeO (R-6) -Bun 1-1020 26-MeO 7-MeO (R-6) -3- (3-Me-Bun ) 1-1021 2 6-MeO 7-MeO (R-7) -CONHPh 1-1022 2 6-MeO 7-MeO (R-7) -CONHCHMePh 1-1023 26-MeO 7-MeO (R-7) -CON (Me) Ph 1-1024 2 6-MeO 7-MeO (R-7) -CON (Et) Ph 1-1025 2 6-MeO 7-MeO (R-7) -CONMe (4-F-Ph ) 1-1026 2 6-MeO 7-MeO (R-7) -CONMe (4-Cl-Ph) 1-1027 2 6-MeO 7-MeO (R-7) -CONMe (4-MeO-Ph) 1 -1028 26-MeO 7-MeO (R-7) -CONMe (3,4-diF-Ph) 1-1029 26-MeO 7-MeO (R-7) -CONMe (3,5-diF-Ph) ) 1-1030 2 6-MeO 7-MeO (R-7) -CONMe (3,4-diMeO-Ph) 1-1031 26-MeO 7-MeO (R-7) -CONMe (3,5-diMeO -Ph) 1-1032 2 6-MeO 7-MeO (R-7) -cPn 1-1033 26-MeO 7-MeO (R-7) -Bz 1-1034 26-MeO 7-MeO (R- 7)-(CH_Two)_TwoPh 1-1035 26-MeO 7-MeO (R-7) -iPr 1-1036 26-MeO 7-MeO (R-7) -Bu 1-1037 26-MeO 7-MeO (R-7) -iBu 1-1038 2 6-MeO 7-MeO (R-7) -tBu 1-1039 26-MeO 7-MeO (R-7) -iPn 1-1040 26-MeO 7-MeO (R-7 ) -1-Et-Bu 1-1041 26-MeO 7-MeO (R-7) -1-Et-Pn 1-1042 26-MeO 7-MeO (R-8) -CONHPh 1-1043 26 -MeO 7-MeO (R-8) -CONHCHMePh 1-1044 26-MeO 7-MeO (R-8) -CON (Me) Ph 1-1045 26-MeO 7-MeO (R-8) -CON (Et) Ph 1-1046 2 6-MeO 7-MeO (R- 8) -CONMe (4-F-Ph) 1-1047 2 6-MeO 7-MeO (R-8) -CONMe (4-Cl- Ph) 1-1048 2 6-MeO 7-MeO (R-8) -CONMe (4-MeO-Ph) 1-1049 26-MeO 7-MeO (R-8) -CONMe (3,4-diF- Ph) 1-1050 2 6-MeO 7-MeO (R-8) -CONMe (3,5-diF-Ph) 1-1051 2 6-MeO 7-MeO (R-8) -CONMe (3,4- diMeO-Ph) 1-1052 26-MeO 7-MeO (R-8) -CONMe (3,5-diMeO-Ph) 1-1053 26-MeO 7-MeO (R-8) -cPn 1-1054 2 6-MeO 7-MeO (R-8) -Bz 1-1055 2 6-MeO 7-MeO (R-8)-(CH_Two)_TwoPh 1-1056 26-MeO 7-MeO (R-8) -iPr 1-1057 26-MeO 7-MeO (R-8) -Bu 1-1058 26-MeO 7-MeO (R-8) -iBu 1-1059 2 6-MeO 7-MeO (R-8) -tBu 1-1060 26-MeO 7-MeO (R-8) -iPn 1-1061 26-MeO 7-MeO (R-8 ) -1-Et-Bu 1-1062 26-MeO 7-MeO (R-8) -1-Et-Pn 1-1063 26-MeO 7-MeO (R-9) -CONHCHMePh 1-1064 26 -MeO 7-MeO (R-9) -CON (Me) Ph 1-1065 26-MeO 7-MeO (R-9) -cPn 1-1066 26-MeO 7-MeO (R-9) -iBu 1-1067 2 6-MeO 7-MeO (R-10) -CONHCHMePh 1-1068 26-MeO 7-MeO (R-10) -CON (Me) Ph 1-1069 26-MeO 7-MeO (R -10) -cPn 1-1070 2 6-MeO 7-MeO (R-10) -iBu 1-1071 26-MeO 7-MeO (R-11) -CONHPh 1-1072 26-MeO 7-MeO ( (R-11) -CONHCHMePh 1-1073 2 6-MeO 7-MeO (R-11) -CON (Me) Ph 1-1074 26-MeO 7-MeO (R-11) -CON (Et) Ph 1- 1075 2 6-MeO 7-MeO (R-11) -CONMe (4-F-Ph) 1-1076 2 6-MeO 7-MeO (R-11) -CONMe (4-Cl-Ph) 1-1077 2 6-MeO 7-MeO (R-11) -CONMe (4-MeO-Ph) 1-1078 2 6-MeO 7-MeO (R-11) -CONMe (3,4-diF-Ph) 1-1079 2 6-MeO 7-MeO (R-11) -CONMe (3,5-diF-Ph) 1-1080 2 6-MeO 7-MeO (R-11) -CONMe (3,4-diMeO-Ph) 1- 1081 2 6-MeO 7-MeO (R-11) -CONMe (3,5-d iMeO-Ph) 1-1082 26-MeO 7-MeO (R-11) -cPn 1-1083 26-MeO 7-MeO (R-11) -Bz 1-1084 26-MeO 7-MeO (R -11)-(CH_Two)_TwoPh 1-1085 26-MeO 7-MeO (R-11) -iPr 1-1086 26-MeO 7-MeO (R-11) -Bu 1-1087 26-MeO 7-MeO (R-11) -iBu 1-1088 26-MeO 7-MeO (R-11) -tBu 1-1089 26-MeO 7-MeO (R-11) -iPn 1-1090 26-MeO 7-MeO (R-11 ) -1-Et-Bu 1-1091 26-MeO 7-MeO (R-11) -1-Et-Pn 1-1092 26-MeO 7-MeO (R-12) -CONHCHMePh 1-1093 26 -MeO 7-MeO (R-12) -CON (Me) Ph 1-1094 26-MeO 7-MeO (R-12) -cPn 1-1095 26-MeO 7-MeO (R-12) -iBu 1-1096 26-MeO 7-MeO (R-13) -CONHCHMePh 1-1097 26-MeO 7-MeO (R-13) -CON (Me) Ph 1-1098 26-MeO 7-MeO (R -13) -cPn 1-1099 2 6-MeO 7-MeO (R-13) -iBu 1-1100 2 6-MeO 7-MeO (R-14) -COCH_TwoCH (Et)_Two 1-1101 2 6-MeO 7-MeO (R-14) -COCH (Et)_Two 1-1102 2 6-MeO 7-MeO (R-14) -COPh 1-1103 2 6-MeO 7-MeO (R-14) -CO (4-Cl-Ph) 1-1104 26-MeO 7- MeO (R-14) -CONHBu 1-1105 2 6-MeO 7-MeO (R-14) -CON (Et)_Two 1-1106 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCH (Et)_Two 1-1107 2 6-MeO 7-MeO (R-14) -CONHCH (Et)_Two 1-1108 26-MeO 7-MeO (R-14) -CONHcPn 1-1109 26-MeO 7-MeO (R-14) -CONHcHx 1-1110 26-MeO 7-MeO (R-14)- CONHPh 1-1111 26-MeO 7-MeO (R-14) -CONHBz 1-1112 26-MeO 7-MeO (R-14) -CONH (3-F-Bz) 1-1113 26-MeO 7 -MeO (R-14) -CONH (4-Cl-Bz) 1-1114 2 6-MeO 7-MeO (R-14) -CONHCHMePh 1-1115 2 6-MeO 7-MeO (R-14) -CONHCHMe (4-MeO-Ph) 1-1116 26-MeO 7-MeO (R-14) -CONHCHMe (3,5-diF-Ph) 1-1117 26-MeO 7-MeO (R-14) -CONH (CH_Two)_TwoPh 1-1118 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCH (Me) Ph 1-1119 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCH (OH) Ph 1-1120 2 6-MeO 7-MeO (R-14) -CONH (CH_Two)_Two(4-Cl-Ph) 1-1121 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCH (Me) Np (2) 1-1122 2 6-MeO 7-MeO (R-14) -CONH (CH_Two)_TwoMor (4) 1-1123 2 6-MeO 7-MeO (R-14) -CONHCH_TwoFur (2) 1-1124 2 6-MeO 7-MeO (R-14) -CONHCH_TwoFur (3) 1-1125 2 6-MeO 7-MeO (R-14) -CONHCH_TwoPrd (2) 1-1126 2 6-MeO 7-MeO (R-14) -CONHCH_TwoPrd (3) 1-1127 2 6-MeO 7-MeO (R-14) -CONHCH (Me) Prd (3) 1-1128 2 6-MeO 7-MeO (R-14) -COPrd (1) 1- 1129 26-MeO 7-MeO (R-14) -COMor (4) 1-1130 26-MeO 7-MeO (R-14) -COPiz (1) 1-1131 26-MeO 7-MeO (R -14) -CO [4-Me-Piz (1)] 1-1132 2 6-MeO 7-MeO (R-14) -CONH (CH_Two)_TwoNH_Two 1-1133 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCO_TwoEt 1-1134 26-MeO 7-MeO (R-14) -CON (Me) Ph 1-1135 26-MeO 7-MeO (R-14) -CON (Et) Ph 1-1136 26-MeO 7-MeO (R-14) -CONMe (4-F-Ph) 1-1137 2 6-MeO 7-MeO (R-14) -CONMe (4-Cl-Ph) 1-1138 26-MeO 7- MeO (R-14) -CONMe (4-MeO-Ph) 1-1139 2 6-MeO 7-MeO (R-14) -CONMe (3,4-diF-Ph) 1-1140 2 6-MeO 7- MeO (R-14) -CONMe (3,5-diF-Ph) 1-1141 2 6-MeO 7-MeO (R-14) -CONMe (3,4-diMeO-Ph) 1-1142 2 6-MeO 7-MeO (R-14) -CONMe (3,5-diMeO-Ph) 1-1143 26-MeO 7-MeO (R-14) -CON (Me) Bz 1-1144 26-MeO 7-MeO (R-14) -cPn 1-1145 26-MeO 7-MeO (R-14) -cHx 1-1146 26-MeO 7-MeO (R-14) -Ph 1-1147 26-MeO 7- MeO (R-14) -4-Cl-Ph 1-1148 26-MeO 7-MeO (R-14) -Bz 1-1149 26-MeO 7-MeO (R-14)-(3,4, 5-triMeO-Bz) 1-1150 2 6-MeO 7-MeO (R-14)-(CH_Two)_TwoPh 1-1151 26-MeO 7-MeO (R-14) -Thi (2) 1-1152 26-MeO 7-MeO (R-14) -Thi (3) 1-1153 26-MeO 7- MeO (R-14) -Me 1-1154 26-MeO 7-MeO (R-14) -Et 1-1155 26-MeO 7-MeO (R-14) -Pr 1-1156 26-MeO 7 -MeO (R-14) -iPr 1-1157 26-MeO 7-MeO (R-14) -Bu 1-1158 26-MeO 7-MeO (R-14) -iBu 1-1159 26-MeO 7-MeO (R-14) -sBu 1-1160 2 6-MeO 7-MeO (R-14) -tBu 1-1161 26-MeO 7-MeO (R-14) -Pn 1-1162 2 6- MeO 7-MeO (R-14) -iPn 1-1163 26-MeO 7-MeO (R-14) -1-Me-Bu 1-1164 26-MeO 7-MeO (R-14) -CH ( Et)_Two 1-1165 2 6-MeO 7-MeO (R-14) -CH_TwoCH (Et)_Two 1-1166 2 6-MeO 7-MeO (R-14)-(CH_Two)_TwoCH (Et)_Two 1-1167 26-MeO 7-MeO (R-14) -1-Et-Bu 1-1168 26-MeO 7-MeO (R-14) -1-Et-Pn 1-1169 26-MeO 7 -MeO (R-15) -CONHPh 1-1170 2 6-MeO 7-MeO (R-15) -CONHCHMePh 1-1171 2 6-MeO 7-MeO (R-15) -CON (Me) Ph 1-1172 2 6-MeO 7-MeO (R-15) -CON (Et) Ph 1-1173 2 6-MeO 7-MeO (R-15) -CONMe (4-F-Ph) 1-1174 2 6-MeO 7 -MeO (R-15) -CONMe (4-Cl-Ph) 1-1175 2 6-MeO 7-MeO (R-15) -CONMe (4-MeO-Ph) 1-1176 26-MeO 7-MeO (R-15) -CONMe (3,4-diF-Ph) 1-1177 2 6-MeO 7-MeO (R-15) -CONMe (3,5-diF-Ph) 1-1178 2 6-MeO 7 -MeO (R-15) -CONMe (3,4-diMeO-Ph) 1-1179 26-MeO 7-MeO (R-15) -CONMe (3,5-diMeO-Ph) 1-1180 2 6- MeO 7-MeO (R-15) -cPn 1-1181 26-MeO 7-MeO (R-15) -Bz 1-1182 26-MeO 7-MeO (R-15)-(CH_Two)_TwoPh 1-1183 26-MeO 7-MeO (R-15) -iPr 1-1184 26-MeO 7-MeO (R-15) -Bu 1-1185 26-MeO 7-MeO (R-15) -iBu 1-1186 26-MeO 7-MeO (R-15) -tBu 1-1187 26-MeO 7-MeO (R-15) -iPn 1-1188 26-MeO 7-MeO (R-15 ) -1-Et-Bu 1-1189 26-MeO 7-MeO (R-15) -1-Et-Pn 1-1190 26-MeO 7-MeO (R-16) -CONHPh 1-1191 26 -MeO 7-MeO (R-16) -CONHCHMePh 1-1192 2 6-MeO 7-MeO (R-16) -CON (Me) Ph 1-1193 26-MeO 7-MeO (R-16) -CON (Et) Ph 1-1194 2 6-MeO 7-MeO (R-16) -CONMe (4-F-Ph) 1-1195 2 6-MeO 7-MeO (R-16) -CONMe (4-Cl- Ph) 1-1196 26-MeO 7-MeO (R-16) -CONMe (4-MeO-Ph) 1-1197 26-MeO 7-MeO (R-16) -CONMe (3,4-diF- Ph) 1-1198 26-MeO 7-MeO (R-16) -CONMe (3,5-diF-Ph) 1-1199 26-MeO 7-MeO (R-16) -CONMe (3,4- diMeO-Ph) 1-1200 2 6-MeO 7-MeO (R-16) -CONMe (3,5-diMeO-Ph) 1-1201 26-MeO 7-MeO (R-16) -cPn 1-1202 26-MeO 7-MeO (R-16) -Bz 1-1203 26-MeO 7-MeO (R-16)-(CH_Two)_TwoPh 1-1204 26-MeO 7-MeO (R-16) -iPr 1-1205 26-MeO 7-MeO (R-16) -Bu 1-1206 26-MeO 7-MeO (R-16) -iBu 1-1207 26-MeO 7-MeO (R-16) -tBu 1-1208 26-MeO 7-MeO (R-16) -iPn 1-1209 26-MeO 7-MeO (R-16 ) -1-Et-Bu 1-1210 2 6-MeO 7-MeO (R-16) -1-Et-Pn 1-1211 2 6-MeO 7-MeO (R-17) -COCH_TwoCH (Et)_Two 1-1212 2 6-MeO 7-MeO (R-17) -COCH (Et)_Two 1-1213 26-MeO 7-MeO (R-17) -CONHPh 1-1214 26-MeO 7-MeO (R-17) -CONHCHMePh 1-1215 26-MeO 7-MeO (R-17)- CONHCHMe (4-MeO-Ph) 1-1216 26-MeO 7-MeO (R-17) -CONHCHMe (3,5-diF-Ph) 1-1217 26-MeO 7-MeO (R-17)- CONH (CH_Two)_TwoPh 1-1218 26-MeO 7-MeO (R-17) -CON (Me) Ph 1-1219 26-MeO 7-MeO (R-17) -CON (Et) Ph 1-1220 26-MeO 7-MeO (R-17) -CONMe (4-F-Ph) 1-1221 2 6-MeO 7-MeO (R-17) -CONMe (4-Cl-Ph) 1-1222 26-MeO 7- MeO (R-17) -CONMe (4-MeO-Ph) 1-1223 2 6-MeO 7-MeO (R-17) -CONMe (3,4-diF-Ph) 1-1224 2 6-MeO 7- MeO (R-17) -CONMe (3,5-diF-Ph) 1-1225 26-MeO 7-MeO (R-17) -CONMe (3,4-diMeO-Ph) 1-1226 26-MeO 7-MeO (R-17) -CONMe (3,5-diMeO-Ph) 1-1227 26-MeO 7-MeO (R-17) -cPn 1-1228 26-MeO 7-MeO (R-17 ) -Ph 1-1229 26-MeO 7-MeO (R-17) -Bz 1-1230 26-MeO 7-MeO (R-17)-(CH_Two)_TwoPh 1-1231 26-MeO 7-MeO (R-17) -Me 1-1232 26-MeO 7-MeO (R-17) -iPr 1-1233 26-MeO 7-MeO (R-17) -Bu 1-1234 26-MeO 7-MeO (R-17) -iBu 1-1235 26-MeO 7-MeO (R-17) -sBu 1-1236 26-MeO 7-MeO (R-17 ) -tBu 1-1237 26-MeO 7-MeO (R-17) -iPn 1-1238 26-MeO 7-MeO (R-17) -CH_TwoCH (Et)_Two 1-1239 2 6-MeO 7-MeO (R-17)-(CH_Two)_TwoCH (Et)_Two 1-1240 2 6-MeO 7-MeO (R-17) -1-Et-Bu 1-1241 26-MeO 7-MeO (R-17) -1-Et-Pn 1-1242 26-MeO 7 -MeO (R-18) -cPn 1-1243 26-MeO 7-MeO (R-18) -Bu 1-1244 26-MeO 7-MeO (R-18) -iBu 1-1245 26-MeO 7-MeO (R-18) -CH_TwoCH (Et)_Two 1-1246 3 6-MeO 7-MeO 8-MeO (R-1) -CON (Me) Ph 1-1247 3 6-MeO 7-MeO 8-MeO (R-1) -COCH (Et)_Two 1-1248 3 6-MeO 7-MeO 8-MeO (R-1) -COCH_TwoCH (Et)_Two 1-1249 3 6-MeO 7-MeO 8-MeO (R-1) -iBu 1-1250 3 6-MeO 7-MeO 8-MeO (R-1) -CH_TwoCH (Et)_Two 1-1251 3 6-MeO 7-MeO 8-MeO (R-1) -CON (Me) Ph 1-1252 3 6-MeO 7-MeO 8-MeO (R-1) -CON (Me) Ph 1- 1253 3 6-MeO 7-MeO 8-MeO (R-5) -CONHPh 1-1254 3 6-MeO 7-MeO 8-MeO (R-5) -CONHCHMePh 1-1255 3 6-MeO 7-MeO 8- MeO (R-5) -CONHCHMe (4-MeO-Ph) 1-1256 3 6-MeO 7-MeO 8-MeO (R-5) -CONHCHMe (3,5-diF-Ph) 1-1257 3 6- MeO 7-MeO 8-MeO (R-5) -CONH (CH_Two)_TwoPh 1-1258 3 6-MeO 7-MeO 8-MeO (R-5) -CON (Me) Ph 1-1259 3 6-MeO 7-MeO 8-MeO (R-5) -CON (Et) Ph 1 -1260 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (4-F-Ph) 1-1261 36-MeO 7-MeO 8-MeO (R-5) -CONMe (4-MeO -Ph) 1-1262 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (3,4-diF-Ph) 1-1263 36-MeO 7-MeO 8-MeO (R-5) -CONMe (3,5-diF-Ph) 1-1264 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (3,4-diMeO-Ph) 1-1265 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (3,5-diMeO-Ph) 1-1266 36-MeO 7-MeO 8-MeO (R-5) -cPn 1-1267 3 6-MeO 7-MeO 8 -MeO (R-5) -Ph 1-1268 3 6-MeO 7-MeO 8-MeO (R-5) -Bz 1-1269 3 6-MeO 7-MeO 8-MeO (R-5)-(CH_Two)_TwoPh 1-1270 36-MeO 7-MeO 8-MeO (R-5) -iPr 1-1271 36-MeO 7-MeO 8-MeO (R-5) -Bu 1-1272 36-MeO 7- MeO 8-MeO (R-5) -iBu 1-1273 3 6-MeO 7-MeO 8-MeO (R-5) -tBu 1-1274 36-MeO 7-MeO 8-MeO (R-5)- iPn 1-1275 3 6-MeO 7-MeO 8-MeO (R-5) -CH_TwoCH (Et)_Two 1-1276 3 6-MeO 7-MeO 8-MeO (R-5)-(CH_Two)_TwoCH (Et)_Two 1-1277 3 6-MeO 7-MeO 8-MeO (R-5) -1-Et-Bu 1-1278 3 6-MeO 7-MeO 8-MeO (R-5) -1-Et-Pn 1- 1279 3 6-MeO 7-MeO 8-MeO (R-6) -CONHPh 1-1280 3 6-MeO 7-MeO 8-MeO (R-6) -CONHCHMePh 1-1281 3 6-MeO 7-MeO 8- MeO (R-6) -CONHCHMe (4-MeO-Ph) 1-1282 3 6-MeO 7-MeO 8-MeO (R-6) -CONHCHMe (3,5-diF-Ph) 1-1283 3 6- MeO 7-MeO 8-MeO (R-6) -CONH (CH_Two)_TwoPh 1-1284 3 6-MeO 7-MeO 8-MeO (R-6) -CON (Me) Ph 1-1285 3 6-MeO 7-MeO 8-MeO (R-6) -CON (Et) Ph 1 -1286 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (4-F-Ph) 1-1287 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (4-MeO -Ph) 1-1288 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (3,4-diF-Ph) 1-1289 36-MeO 7-MeO 8-MeO (R-6) -CONMe (3,5-diF-Ph) 1-1290 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (3,4-diMeO-Ph) 1-1291 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (3,5-diMeO-Ph) 1-1292 36-MeO 7-MeO 8-MeO (R-6) -cPn 1-1293 3 6-MeO 7-MeO 8 -MeO (R-6) -Bz 1-1294 3 6-MeO 7-MeO 8-MeO (R-6)-(CH_Two)_TwoPh 1-1295 36-MeO 7-MeO 8-MeO (R-6) -iPr 1-1296 36-MeO 7-MeO 8-MeO (R-6) -Bu 1-1297 36-MeO 7- MeO 8-MeO (R-6) -sBu 1-1298 3 6-MeO 7-MeO 8-MeO (R-6) -tBu 1-1299 36-MeO 7-MeO 8-MeO (R-6)- iPn 1-1300 3 6-MeO 7-MeO 8-MeO (R-6) -CH_TwoCH (Et)_Two 1-1301 3 6-MeO 7-MeO 8-MeO (R-6)-(CH_Two)_TwoCH (Et)_Two 1-1302 3 6-MeO 7-MeO 8-MeO (R-6) -1-Et-Bu 1-1303 3 6-MeO 7-MeO 8-MeO (R-6) -1-Et-Pn 1- 1304 3 6-MeO 7-MeO 8-MeO (R-7) -CON (Me) Ph 1-1305 3 6-MeO 7-MeO 8-MeO (R-8) -CON (Me) Ph 1-1306 3 6-MeO 7-MeO 8-MeO (R-11) -CON (Me) Ph 1-1307 3 6-MeO 7-MeO 8-MeO (R-12) -CON (Me) Ph 1-1308 3 6- MeO 7-MeO 8-MeO (R-14) -CONHPh 1-1309 3 6-MeO 7-MeO 8-MeO (R-14) -CONHCHMePh 1-1310 36-MeO 7-MeO 8-MeO (R- 14) -CONHCHMe (4-MeO-Ph) 1-1311 3 6-MeO 7-MeO 8-MeO (R-14) -CONHCHMe (3,5-diF-Ph) 1-1312 3 6-MeO 7-MeO 8-MeO (R-14) -CONH (CH_Two)_TwoPh 1-1313 3 6-MeO 7-MeO 8-MeO (R-14) -CON (Me) Ph 1-1314 3 6-MeO 7-MeO 8-MeO (R-14) -CON (Et) Ph 1 -1315 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (4-F-Ph) 1-1316 36-MeO 7-MeO 8-MeO (R-14) -CONMe (4-MeO -Ph) 1-1317 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,4-diF-Ph) 1-1318 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,5-diF-Ph) 1-1319 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,4-diMeO-Ph) 1-1320 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,5-diMeO-Ph) 1-1321 36-MeO 7-MeO 8-MeO (R-14) -cPn 1-1322 36-MeO 7-MeO 8 -MeO (R-14) -Bz 1-1323 3 6-MeO 7-MeO 8-MeO (R-14)-(CH_Two)_TwoPh 1-1324 36-MeO 7-MeO 8-MeO (R-14) -iPr 1-1325 36-MeO 7-MeO 8-MeO (R-14) -Bu 1-1326 36-MeO 7- MeO 8-MeO (R-14) -sBu 1-1327 3 6-MeO 7-MeO 8-MeO (R-14) -tBu 1-1328 3 6-MeO 7-MeO 8-MeO (R-14)- iPn 1-1329 3 6-MeO 7-MeO 8-MeO (R-14) -CH_TwoCH (Et)_Two 1-1330 3 6-MeO 7-MeO 8-MeO (R-14)-(CH_Two)_TwoCH (Et)_Two 1-1331 3 6-MeO 7-MeO 8-MeO (R-14) -1-Et-Bu 1-1332 3 6-MeO 7-MeO 8-MeO (R-14) -1-Et-Pn 1- 1333 3 6-MeO 7-MeO 8-MeO (R-15) -CON (Me) Ph 1-1334 3 6-MeO 7-MeO 8-MeO (R-16) -CON (Me) Ph 1-1335 3 6-MeO 7-MeO 8-MeO (R-17) -CON (Me) Ph 1-1336 26-Me0 7-OH (R-6) -CON (Me) Ph 1-1337 26-Me0 7- OH (R-6) -COCH (Et)_Two 1-1338 2 6-Me0 7-OH (R-6) -COCH_TwoCH (Et)_Two 1-1339 2 6-Me0 7-OH (R-6) -iBu 1-1340 26-Me0 7-OH (R-6) -CH_TwoCH (Et)_Two 1-1341 2 6-Me0 7-OH (R-14) -CON (Me) Ph 1-1342 2 6-Me0 7-OH (R-14) -COCH (Et)_Two 1-1343 2 6-Me0 7-OH (R-14) -COCH_TwoCH (Et)_Two 1-1344 2 6-Me0 7-OH (R-14) -iBu 1-1345 2 6-Me0 7-OH (R-14) -CH_TwoCH (Et)_Two 1-1346 2 6-OH 7-MeO (R-1) -CON (Me) Ph 1-1347 26-OH 7-MeO (R-1) -COCH (Et)_Two 1-1348 2 6-OH 7-MeO (R-1) -COCH_TwoCH (Et)_Two 1-1349 2 6-OH 7-MeO (R-1) -iBu 1-1350 2 6-OH 7-MeO (R-1) -CH_TwoCH (Et)_Two 1-1351 2 6-OH 7-MeO (R-1) -CON (Me) Ph 1-1352 2 6-OH 7-MeO (R-1) -COCH (Et)_Two 1-1353 2 6-OH 7-MeO (R-1) -COCH_TwoCH (Et)_Two 1-1354 2 6-OH 7-MeO (R-6) -CON (Me) Ph 1-1355 26-OH 7-MeO (R-6) -COCH (Et)_Two 1-1356 2 6-OH 7-MeO (R-6) -COCH_TwoCH (Et)_Two 1-1357 26-OH 7-MeO (R-6) -iBu 1-1358 26-OH 7-MeO (R-6) -CH_TwoCH (Et)_Two 1-1359 2 6-OH 7-MeO (R-14) -CON (Me) Ph 1-1360 26-OH 7-MeO (R-14) -COCH (Et)_Two 1-1361 2 6-OH 7-MeO (R-14) -COCH_TwoCH (Et)_Two 1-1362 26-OH 7-MeO (R-14) -iBu 1-1363 26-OH 7-MeO (R-14) -CH_TwoCH (Et)_Two 1-1364 2 6-OH 7-MeO (R-15) -CON (Me) Ph 1-1365 2 6-OH 7-MeO (R-16) -CON (Me) Ph 1-1366 26-AcO 7 -AcO (R-6) -CON (Me) Ph 1-1367 26-AcO 7-AcO (R-14) -CON (Me) Ph 1-1368 1 7-MeO (R-5) -CON (Me ) Ph 1-1369 1 7-MeO (R-14) -CON (Me) Ph 1-1370 26-AcO 7-AcO (R-15) -CON (Me) Ph 1-1371 26-AcO 7- AcO (R-16) -CON (Me) Ph 1-1372 26-MeO 7-MeO (R-6) -CONMe (3-Cl-Ph) 1-1373 26-MeO 7-MeO (R-6 ) -CONMe (3-F-Ph) 1-1374 1 6-MeO (R-18) -CON (Me) Ph 1-1375 1 7-MeO (R-6) -CON (Me) Ph 1-1376 2 6-MeO 7-MeO (R-6) -CONMe [2-CO_TwoMe-Thi (3)] 1-1377 2 6-MeO 7-MeO (R-6) -CONEt [2-CO_TwoMe-Thi (3)] 1-1378 2 6-MeO 7-MeO (R-6) -CONMePyrd (2) 1-1379 2 6-MeO 7-MeO (R-6) -CONEtPyrd (2) 1-1380 26-MeO 7-MeO (R-6) -CONMePyrd (3) 1-1381 26-MeO 7-MeO (R-6) -CONEtPyrd (3) 1-1382 26-MeO 7-MeO (R- 6) -CONMePyrd (4) 1-1383 2 6-MeO 7-MeO (R-6) -CONEtPyrd (4) 1-1384 2 6-MeO 7-MeO (R-6) -CONEt (3,5-diF -Ph) 1-1385 2 6-MeO 7-MeO (R-3) -CONEt (3,5-diF-Ph) 1-1386 2 6-MeO 7-MeO (R-3) -CONMe (3-F -Ph) 1-1387 1 7-MeO (R-6) -CONMe (3,5-diF-Ph) 1-1388 1 7-MeO (R-6) -CONEt (3,5-diF-Ph) 1 -1389 1 7-MeO (R-6) -CON (Et) Ph 1-1390 1 7-MeO (R-6) -CONMe (3-F-Ph) 1-1391 17-MeO (R-3) -CONMe (3,5-diF-Ph) 1-1392 1 7-MeO (R-3) -CONEt (3,5-diF-Ph) 1-1393 1 7-MeO (R-3) -CON (Me ) Ph 1-1394 1 7-MeO (R-3) -CON (Et) Ph 1-1395 1 7-MeO (R-3) -CONMe (3-F-Ph)  [Table 2]

[0156]

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[0157]  Compd.n R R^Five R⁶ No. Substituent No.  2-1 1 H (R-1) -CON (Et)_Two 2-2 1 H (R-1) -CONHPh 2-3 1 H (R-1) -CONHCHMePh 2-4 1 H (R-1) -CONHCHMe (4-MeO-Ph) 2-5 1 H (R -1) -CONHCHMe (3,5-diF-Ph) 2-6 1 H (R-1) -CON (Me) Ph 2-7 1 H (R-1) -CONMe (4-F-Ph) 2 -8 1 H (R-1) -CONMe (4-MeO-Ph) 2-9 1 H (R-1) -CONMe (3,4-diF-Ph) 2-10 1 H (R-1)- CONMe (3,5-diF-Ph) 2-11 1 H (R-1) -CONMe (3,4-diMeO-Ph) 2-12 1 H (R-1) -CONMe (3,5-diMeO- Ph) 2-13 1 H (R-1) -COCH_TwoCH (Et)_Two 2-14 1 H (R-1) -cPn 2-15 1 H (R-1) -Ph 2-16 1 H (R-1) -Bz 2-17 1 H (R-1)-(CH_Two)_TwoPh 2-18 1 H (R-1) -Me 2-19 1 H (R-1) -iPr 1-20 1 H (R-1) -Bu 2-21 1 H (R-1) -iBu 2 -22 1 H (R-1) -sBu 2-23 1 H (R-1) -tBu 2-24 1 H (R-1) -iPn 2-25 1 H (R-1) -CH_TwoCH (Et)_Two 2-26 1 H (R-1)-(CH_Two)_TwoCH (Et)_Two 2-27 1 H (R- 1) -2-Et-Bu 2-28 1 H (R- 1) -2-Et-Pn 2-29 1 H (R- 1) -All 2-30 1 H ( R-3) -CON (Me) Ph 2-31 1 H (R-3) -COCH (Et)_Two 2-32 1 H (R-3) -COCH_TwoCH (Et)_Two 2-33 1 H (R-3) -iBu 2-34 1 H (R-3) -CH_TwoCH (Et)_Two 2-35 1 H (R-3) -Bz 2-36 1 H (R-5) -CONHCH (Et)_Two 2-37 1 H (R-5) -CONHtBu 2-38 1 H (R-5) -CONH (4-Cl-Bz) 2-39 1 H (R-5) -CON (Me) Ph 2-40 1 H (R-5) -COCH (Et)_Two 2-41 1 H (R-5) -COCH_TwoCH (Et)_Two 2-42 1 H (R-5) -iBu 2-43 1 H (R-5) -CH_TwoCH (Et)_Two 2-44 1 H (R-5) -Bz 2-45 1 H (R-6) -CONHCH (Et)_Two 2-46 1 H (R-6) -CONHtBu 2-47 1 H (R-6) -CONH (4-Cl-Bz) 2-48 1 H (R-6) -CON (Me) Ph 2-49 1 H (R-6) -COCH (Et)_Two 2-50 1 H (R-6) -COCH_TwoCH (Et)_Two 2-51 1 H (R-6) -iBu 2-52 1 H (R-6) -CH_TwoCH (Et)_Two 2-53 1 H (R-6) -Bz 2-54 1 H (R-14) -CONHCH (Et)_Two 2-55 1 H (R-14) -CONHtBu 2-56 1 H (R-14) -CONH (4-Cl-Bz) 2-57 1 H (R-14) -CON (Me) Ph 2-58 1 H (R-14) -COCH (Et)_Two 2-59 1 H (R-14) -COCH_TwoCH (Et)_Two 2-60 1 H (R-14) -iBu 2-61 1 H (R-14) -CH_TwoCH (Et)_Two 2-62 1 H (R-2) -CON (Me) Ph 2-63 1 H (R-4) -CON (Me) Ph 2-64 1 H (R-15) -CON (Me) Ph 2- 65 1 H (R-16) -CON (Me) Ph 2-66 1 H (R-17) -CON (Me) Ph 2-67 1 5-OH (R-1) -CON (Me) Ph 2- 68 1 5-OH (R-1) -COCH (Et)_Two 2-69 1 5-OH (R-1) -COCH_TwoCH (Et)_Two 2-70 1 5-OH (R-1) -iBu 2-71 1 5-OH (R-1) -CH_TwoCH (Et)_Two 2-72 1 5-OH (R-1) -Bz 2-73 1 5-OH (R-1) -cPn 2-74 1 5-OH (R-2) -Bz 2-75 1 5-OH ( (R- 2) -CON (Me) Ph 2-76 16-OH (R- 1) -iBu 2-77 16-OH (R-1) -CON (Me) Ph 2-78 16-OH ( R- 2) -CON (Me) Ph 2-79 16-OH (R-3) -CON (Me) Ph 2-80 16-OH (R-5) -CONHPh 2-81 16-OH ( R-5) -CONHCHMePh 2-82 16-OH (R-5) -CONHCHMe (4-MeO-Ph) 2-8316-OH (R-5) -CONHCHMe (3,5-diF-Ph) 2-84 1 6-OH (R-5) -CONH (CH_Two)_TwoPh 2-85 16-OH (R-5) -CON (Me) Ph 2-86 16-OH (R-5) -CON (Et) Ph 2-87 16-OH (R-5)- CONMe (4-F-Ph) 2-88 1 6-OH (R-5) -CONMe (4-MeO-Ph) 2-89 16-OH (R-5) -CONMe (3,4-diF- Ph) 2-90 1 6-OH (R-5) -CONMe (3,5-diF-Ph) 2-91 16-OH (R-5) -CONMe (3,4-diMeO-Ph) 2- 92 1 6-OH (R-5) -CONMe (3,5-diMeO-Ph) 2-93 16-OH (R-5) -cPn 2-94 16-OH (R-5) -Ph 2 -95 16-OH (R-5) -Bz 2-96 16-OH (R-5)-(CH_Two)_TwoPh 2-97 16-OH (R-5) -iPr 2-98 16-OH (R-5) -Bu 2-99 16-OH (R-5) -iBu 2-100 16-OH (R-5) -tBu 2-101 16-OH (R-5) -iPn 2-102 16-OH (R-5) -CH_TwoCH (Et)_Two 2-103 1 6-OH (R-5)-(CH_Two)_TwoCH (Et)_Two 2-104 16-OH (R-5) -1-Et-Bu 2-105 16-OH (R-5) -1-Et-Pn 2-106 16-OH (R-6) -CONHPh 2-107 16-OH (R-6) -CONHCHMePh 2-108 16-OH (R-6) -CONHCHMe (4-MeO-Ph) 2-109 16-OH (R-6) -CONHCHMe ( 3,5-diF-Ph) 2-110 16-OH (R-6) -CONH (CH_Two)_TwoPh 2-111 16-OH (R-6) -CON (Me) Ph 2-112 16-OH (R-6) -CON (Et) Ph 2-113 16-OH (R-6)- CONMe (4-F-Ph) 2-114 16-OH (R-6) -CONMe (4-MeO-Ph) 2-115 16-OH (R-6) -CONMe (3,4-diF- Ph) 2-116 16-OH (R-6) -CONMe (3,5-diF-Ph) 2-117 16-OH (R-6) -CONMe (3,4-diMeO-Ph) 2- 118 1 6-OH (R-6) -CONMe (3,5-diMeO-Ph) 2-119 16-OH (R-6) -cPn 2-120 16-OH (R-6) -Bz 2 -121 1 6-OH (R-6)-(CH_Two)_TwoPh 2-122 16-OH (R-6) -iPr 2-123 16-OH (R-6) -Bu 2-124 16-OH (R-6) -sBu 2-125 16-OH (R-6) -tBu 2-126 16-OH (R-6) -iPn 2-127 16-OH (R-6) -CH_TwoCH (Et)_Two 2-128 1 6-OH (R-6)-(CH_Two)_TwoCH (Et)_Two 2-129 16-OH (R-6) -1-Et-Bu 2-130 16-OH (R-6) -1-Et-Pn 2-131 16-OH (R-7) -CON (Me) Ph 2-132 16-OH (R-8) -CON (Me) Ph 2-133 16-OH (R-11) -CON (Me) Ph 2-134 16-OH (R- 12) -CON (Me) Ph 2-135 16-OH (R-14) -CONHPh 2-136 16-OH (R-14) -CONHCHMePh 2-137 16-OH (R-14) -CONHCHMe (4-MeO-Ph) 2-138 16-OH (R-14) -CONHCHMe (3,5-diF-Ph) 2-139 16-OH (R-14) -CONH (CH_Two)_TwoPh 2-140 16-OH (R-14) -CON (Me) Ph 2-141 16-OH (R-14) -CON (Et) Ph 2-142 16-OH (R-14)- CONMe (4-F-Ph) 2-143 1 6-OH (R-14) -CONMe (4-MeO-Ph) 2-144 16-OH (R-14) -CONMe (3,4-diF- Ph) 2-145 1 6-OH (R-14) -CONMe (3,5-diF-Ph) 2-146 16-OH (R-14) -CONMe (3,4-diMeO-Ph) 2- 147 16-OH (R-14) -CONMe (3,5-diMeO-Ph) 2-148 16-OH (R-14) -cPn 2-149 16-OH (R-14) -Bz 2 -150 1 6-OH (R-14)-(CH_Two)_TwoPh 2-151 16-OH (R-14) -iPr 2-152 16-OH (R-14) -Bu 2-153 16-OH (R-14) -sBu 2-154 16-OH (R-14) -tBu 2-155 16-OH (R-14) -iPn 2-156 16-OH (R-14) -CH_TwoCH (Et)_Two 2-157 1 6-OH (R-14)-(CH_Two)_TwoCH (Et)_Two 2-158 16-OH (R-14) -1-Et-Bu 2-159 16-OH (R-14) -1-Et-Pn 2-160 16-OH (R-15) -CON (Me) Ph 2-161 16-OH (R-16) -CON (Me) Ph 2-162 16-OH (R-17) -CON (Me) Ph 2-163 17-OH (R- 1) -CH_TwoCH (Et)_Two 2-164 1 7-OH (R-6) -CON (Me) Ph 2-165 1 7-OH (R-14) -CON (Me) Ph 2-166 18-OH (R-6) -CON (Me) Ph 2-167 1 8-OH (R-14) -CON (Me) Ph 2-168 1 8-OH (R-1) -CON (Me) Ph 2-169 1 8-OH (R- 2) -CON (Me) Ph 2-170 18-OH (R-3) -Bz 2-171 18-OH (R-4) -CON (Me) Ph 2-172 18-OH (R- 5) -CON (Me) Ph 2-173 1 8-OH (R-7) -CON (Me) Ph 2-174 1 8-OH (R-8) -CON (Me) Ph 2-175 1 8- OH (R-9) -CON (Me) Ph 2-176 1 8-OH (R-10) -CON (Me) Ph 2-177 16-MeO (R-1) -CONHPh 2-178 1 6- MeO (R-1) -CONHCHMePh 2-179 16-MeO (R-1) -CON (Me) Ph 2-180 16-MeO (R-1) -CON (Et) Ph 2-181 1 6- MeO (R-1) -CONMe (4-F-Ph) 2-182 1 6-MeO (R-1) -CONMe (4-Cl-Ph) 2-183 16-MeO (R-1) -CONMe (4-MeO-Ph) 2-184 16-MeO (R-1) -CONMe (3,4-diF-Ph) 2-185 16-MeO (R-1) -CONMe (3,5-diF -Ph) 2-186 1 6-MeO (R-1) -CONMe (3,4-diMeO-Ph) 2-187 1 6-MeO (R-1) -CONMe (3,5-diMeO-Ph) 2 -188 16-MeO (R-1) -cPn 2-189 16-MeO (R-1) -Bz 2-190 16-MeO (R-1)-(CH_Two)_TwoPh 2-191 16-MeO (R-1) -iPr 2-192 16-MeO (R-1) -Bu 2-193 16-MeO (R-1) -iBu 2-194 16-MeO (R- 1) -tBu 2-195 16-MeO (R- 1) -iPn 2-196 16-MeO (R- 1) -1-Et-Bu 2-197 16-MeO (R- 1 ) -1-Et-Pn 2-198 16-MeO (R- 2) -COCH_TwoCH (Et)_Two 2-199 1 6-MeO (R- 2) -COCH (Et)_Two 2-200 16-MeO (R-2) -CONHPh 2-201 16-MeO (R-2) -CONHCHMePh 2-202 16-MeO (R-2) -CONHCHMe (4-MeO-Ph) 2 -203 16-MeO (R- 2) -CONHCHMe (3,5-diF-Ph) 2-204 16-MeO (R-2) -CONH (CH_Two)_TwoPh 2-205 16-MeO (R-2) -CON (Me) Ph 2-206 16-MeO (R-2) -CON (Et) Ph 2-207 16-MeO (R-2)- CONMe (4-F-Ph) 2-208 16-MeO (R-2) -CONMe (4-Cl-Ph) 2-209 16-MeO (R-2) -CONMe (4-MeO-Ph) 2-210 1 6-MeO (R- 2) -CONMe (3,4-diF-Ph) 2-211 1 6-MeO (R-2) -CONMe (3,5-diF-Ph) 2-212 1 6-MeO (R- 2) -CONMe (3,4-diMeO-Ph) 2-213 1 6-MeO (R-2) -CONMe (3,5-diMeO-Ph) 2-214 1 6-MeO ( R- 2) -cPn 2-215 16-MeO (R- 2) -Ph 2-216 16-MeO (R- 2) -Bz 2-217 16-MeO (R- 2)-(CH_Two)_TwoPh 2-218 16-MeO (R-2) -Me 2-219 16-MeO (R-2) -iPr 2-220 16-MeO (R-2) -Bu 2-221 16-MeO (R-2) -iBu 2-222 16-MeO (R-2) -sBu 2-223 16-MeO (R-2) -tBu 2-224 16-MeO (R-2) -iPn 2 -225 1 6-MeO (R-2) -CH_TwoCH (Et)_Two 2-226 1 6-MeO (R-2)-(CH_Two)_TwoCH (Et)_Two 2-227 16-MeO (R-2) -1-Et-Bu 2-228 16-MeO (R-2) -1-Et-Pn 2-229 16-MeO (R-3) -COCH_TwoCH (Et)_Two 2-230 1 6-MeO (R-3) -COCH (Et)_Two 2-231 16-MeO (R-3) -CONHPh 2-232 16-MeO (R-3) -CONHCHMePh 2-233 16-MeO (R-3) -CONHCHMe (4-MeO-Ph) 2 -234 16-MeO (R-3) -CONHCHMe (3,5-diF-Ph) 2-235 16-MeO (R-3) -CONH (CH_Two)_TwoPh 2-236 16-MeO (R-3) -CON (Me) Ph 2-237 16-MeO (R-3) -CON (Et) Ph 2-238 16-MeO (R-3)- CONMe (4-F-Ph) 2-239 1 6-MeO (R-3) -CONMe (4-Cl-Ph) 2-240 16-MeO (R-3) -CONMe (4-MeO-Ph) 2-241 1 6-MeO (R-3) -CONMe (3,4-diF-Ph) 2-242 1 6-MeO (R-3) -CONMe (3,5-diF-Ph) 2-243 1 6-MeO (R-3) -CONMe (3,4-diMeO-Ph) 2-244 1 6-MeO (R-3) -CONMe (3,5-diMeO-Ph) 2-245 1 6-MeO ( R- 3) -cPn 2-246 16-MeO (R-3) -Ph 2-247 16-MeO (R-3) -Bz 2-248 16-MeO (R-3)-(CH_Two)_TwoPh 2-249 16-MeO (R-3) -Me 2-250 16-MeO (R-3) -iPr 2-251 16-MeO (R-3) -Bu 2-252 16-MeO (R-3) -iBu 2-253 16-MeO (R-3) -sBu 2-254 16-MeO (R-3) -tBu 2-255 16-MeO (R-3) -iPn 2 -256 1 6-MeO (R-3) -CH_TwoCH (Et)_Two 2-257 1 6-MeO (R-3)-(CH_Two)_TwoCH (Et)_Two 2-258 16-MeO (R-3) -1-Et-Bu 2-259 16-MeO (R-3) -1-Et-Pn 2-260 16-MeO (R-4) -CONHCHMePh 2-261 1 6-MeO (R-4) -CON (Me) Ph 2-262 1 6-MeO (R-4) -cPn 2-263 16-MeO (R-4) -iBu 2-264 1 6-MeO (R-5) -COCH_TwoCH (Et)_Two 2-265 1 6-MeO (R-5) -COCH (Et)_Two 2-266 16-MeO (R-5) -COPh 2-267 16-MeO (R-5) -CO (4-Cl-Ph) 2-268 16-MeO (R-5) -CONHBu 2 -269 1 6-MeO (R-5) -CON (Et)_Two 2-270 1 6-MeO (R-5) -CONHCH_TwoCH (Et)_Two 2-271 1 6-MeO (R-5) -CONHCH (Et)_Two 2-272 1 6-MeO (R-5) -CONHcPn 2-273 16-MeO (R-5) -CONHcHx 2-274 16-MeO (R-5) -CONHPh 2-275 1 6-MeO ( R-5) -CONHBz 2-276 16-MeO (R-5) -CONH (3-F-Bz) 2-277 16-MeO (R-5) -CONH (4-Cl-Bz) 2- 278 16-MeO (R-5) -CONHCHMePh 2-279 16-MeO (R-5) -CONHCHMe (4-MeO-Ph) 2-280 16-MeO (R-5) -CONHCHMe (3, 5-diF-Ph) 2-281 1 6-MeO (R-5) -CONH (CH_Two)_TwoPh 2-282 1 6-MeO (R-5) -CONHCH_TwoCH (Me) Ph 2-283 1 6-MeO (R-5) -CONHCH_TwoCH (OH) Ph 2-284 16-MeO (R-5) -CONH (CH_Two)_Two(4-Cl-Ph) 2-285 1 6-MeO (R-5) -CONHCH_TwoCH (Me) Np (2) 2-286 16-MeO (R-5) -CONH (CH_Two)_TwoMor (4) 2-287 1 6-MeO (R-5) -CONHCH_TwoFur (2) 2-288 1 6-MeO (R-5) -CONHCH_TwoFur (3) 2-289 1 6-MeO (R-5) -CONHCH_TwoPrd (2) 2-290 1 6-MeO (R-5) -CONHCH_TwoPrd (3) 2-291 16-MeO (R-5) -CONHCH (Me) Prd (3) 2-292 16-MeO (R-5) -COPrd (1) 2-293 16-MeO ( R-5) -COMor (4) 2-294 16-MeO (R-5) -COPiz (1) 2-295 16-MeO (R-5) -CO [4-Me-Piz (1)] 2-296 1 6-MeO (R-5) -CONH (CH_Two)_TwoNH_Two 2-297 1 6-MeO (R-5) -CONHCH_TwoCO_TwoEt 2-298 16-MeO (R-5) -CON (Me) Ph 2-299 16-MeO (R-5) -CON (Et) Ph 2-300 16-MeO (R-5)- CONMe (4-F-Ph) 2-301 1 6-MeO (R-5) -CONMe (4-Cl-Ph) 2-302 1 6-MeO (R-5) -CONMe (4-MeO-Ph) 2-303 1 6-MeO (R-5) -CONMe (3,4-diF-Ph) 2-304 1 6-MeO (R-5) -CONMe (3,5-diF-Ph) 2-305 1 6-MeO (R-5) -CONMe (3,4-diMeO-Ph) 2-306 1 6-MeO (R-5) -CONMe (3,5-diMeO-Ph) 2-307 1 6-MeO ( R-5) -CON (Me) Bz 2-308 16-MeO (R-5) -cPn 2-309 16-MeO (R-5) -cHx 2-310 16-MeO (R-5) -Ph 2-311 16-MeO (R-5) -4-Cl-Ph 2-312 16-MeO (R-5) -Bz 2-313 16-MeO (R-5)-(3, 4,5-triMeO-Bz) 2-314 1 6-MeO (R-5)-(CH_Two)_TwoPh 2-315 1 6-MeO (R-5) -Thi (2) 2-316 1 6-MeO (R-5) -Thi (3) 2-317 1 6-MeO (R-5) -Me2 -318 16-MeO (R-5) -Et 2-319 16-MeO (R-5) -Pr 2-320 16-MeO (R-5) -iPr 2-321 16-MeO (R -5) -Bu 2-322 16-MeO (R-5) -iBu 2-323 16-MeO (R-5) -sBu 2-324 16-MeO (R-5) -tBu 2-325 16-MeO (R-5) -Pn 2-326 16-MeO (R-5) -iPn 2-327 16-MeO (R-5) -1-Me-Bu 2-328 16-MeO (R-5) -CH (Et)_Two 2-329 1 6-MeO (R-5) -CH_TwoCH (Et)_Two 2-330 1 6-MeO (R-5)-(CH_Two)_TwoCH (Et)_Two 2-331 1 6-MeO (R-5) -1-Et-Bu 2-332 16-MeO (R-5) -1-Et-Pn 2-333 16-MeO (R-6) -COiPr 2-334 1 6-MeO (R-6) -COiBu 2-335 1 6-MeO (R-6) -COCH_TwoCH (Et)_Two 2-336 1 6-MeO (R-6) -COCH (Et)_Two 2-337 16-MeO (R-6) -COPh 2-338 16-MeO (R-6) -CO (4-Cl-Ph) 2-339 16-MeO (R-6) -COBz 2 -340 1 6-MeO (R-6) -CONH_Two 2-341 16-MeO (R-6) -CONHMe 2-342 16-MeO (R-6) -CONHEt 2-343 16-MeO (R-6) -CONHPr 2-344 16-MeO ( R-6) -CONHBu 2-345 1 6-MeO (R-6) -CON (Me)_Two 2-346 1 6-MeO (R-6) -CON (Et)_Two 2-347 1 6-MeO (R-6) -CONHiPr 2-348 16-MeO (R-6) -CONHiBu 2-349 16-MeO (R-6) -CONHtBu 2-350 1 6-MeO ( R-6) -CONHCH_TwoCH (Et)_Two 2-351 1 6-MeO (R-6) -CONHCH (Et)_Two 2-352 1 6-MeO (R-6) -CONHcPn 2-353 1 6-MeO (R-6) -CONHcHx 2-354 16-MeO (R-6) -CONHPh 2-355 1 6-MeO ( R- 6) -CONHBz 2-356 16-MeO (R-6) -CONH (3-F-Bz) 2-357 16-MeO (R-6) -CONH (4-Cl-Bz) 2- 358 1 6-MeO (R-6) -CONHCHMePh 2-359 1 6-MeO (R-6) -CONHCHMe (4-MeO-Ph) 2-360 16-MeO (R-6) -CONHCHMe (3, 5-diF-Ph) 2-361 1 6-MeO (R-6) -CONH (CH_Two)_TwoPh 2-362 1 6-MeO (R-6) -CONHCH_TwoCH (Me) Ph 2-363 1 6-MeO (R-6) -CONHCH_TwoCH (OH) Ph 2-364 1 6-MeO (R-6) -CONH (CH_Two)_Two(4-Cl-Ph) 2-365 1 6-MeO (R-6) -CONHCH_TwoCH (Me) Np (2) 2-366 1 6-MeO (R-6) -CONH (CH_Two)_TwoMor (4) 2-367 1 6-MeO (R-6) -CONHCH_TwoFur (2) 2-368 1 6-MeO (R-6) -CONHCH_TwoFur (3) 2-369 1 6-MeO (R-6) -CONHCH_TwoPrd (2) 2-370 1 6-MeO (R-6) -CONHCH_TwoPrd (3) 2-371 16-MeO (R-6) -CONHCH (Me) Prd (3) 2-372 16-MeO (R-6) -COPrd (1) 2-373 16-MeO ( R-6) -COMor (4) 2-374 1 6-MeO (R-6) -COPiz (1) 2-375 1 6-MeO (R-6) -CO [4-Me-Piz (1)] 2-376 16-MeO (R-6) -CONH (CH_Two)_TwoNH_Two 2-377 1 6-MeO (R-6) -CONH (CH_Two)_TwoN (Me)_Two 2-378 1 6-MeO (R-6) -CONHCH_TwoCO_TwoH 2-379 1 6-MeO (R-6) -CONHCH_TwoCO_TwoMe 2-380 1 6-MeO (R-6) -CONHCH_TwoCO_TwoEt 2-381 16-MeO (R-6) -CON (Me) Ph 2-382 16-MeO (R-6) -CON (Et) Ph 2-383 16-MeO (R-6)- CONMe (4-F-Ph) 2-384 1 6-MeO (R-6) -CONMe (4-Cl-Ph) 2-385 1 6-MeO (R-6) -CONMe (4-MeO-Ph) 2-386 1 6-MeO (R-6) -CONMe (3,4-diF-Ph) 2-387 1 6-MeO (R-6) -CONMe (3,5-diF-Ph) 2-388 1 6-MeO (R-6) -CONMe (3,4-diMeO-Ph) 2-389 1 6-MeO (R-6) -CONMe (3,5-diMeO-Ph) 2-390 16-MeO ( R-6) -CON (Me) Bz 2-391 16-MeO (R-6) -CONMe (4-F-Bz) 2-392 16-MeO (R-6) -CONMe (4-MeO- Bz) 2-393 16-MeO (R-6) -cPn 2-394 16-MeO (R-6) -cHx 2-395 16-MeO (R-6) -Ph 2-396 16- MeO (R-6) -4-Cl-Ph 2-397 1 6-MeO (R-6) -Bz 2-398 1 6-MeO (R-6)-(4-MeO-Bz) 2-399 1 6-MeO (R-6)-(3,4-diMeO-Bz) 2-400 1 6-MeO (R-6)-(3,4,5-triMeO-Bz) 2-401 1 6-MeO ( R-6)-(CH_Two)_TwoPh 2-402 16-MeO (R-6)-(CH_Two)_ThreePh 2-403 16-MeO (R-6) -Thi (2) 2-404 16-MeO (R-6) -Thi (3) 2-405 16-MeO (R-6) -Fur ( 3) 2-406 16-MeO (R-6) -Me 2-407 16-MeO (R-6) -Et 2-408 16-MeO (R-6) -Pr 2-409 16- MeO (R-6) -iPr 2-410 16-MeO (R-6) -Bu 2-411 16-MeO (R-6) -iBu 2-412 16-MeO (R-6) -sBu 2-413 16-MeO (R-6) -tBu 2-414 16-MeO (R-6) -Pn 2-415 16-MeO (R-6) -iPn 2-416 16-MeO ( R-6) -1-Me-Bu 2-417 16-MeO (R-6) -CH (Et)_Two 2-418 16-MeO (R-6) -CH_TwoCH (Et)_Two 2-419 1 6-MeO (R-6)-(CH_Two)_TwoCH (Et)_Two 2-420 16-MeO (R-6) -1-Et-Bu 2-421 16-MeO (R-6) -1-Et-Pn 2-422 16-MeO (R-6) -Vin 2-423 16-MeO (R-6) -Bun 2-424 16-MeO (R-6) -3- (3-Me-Bun) 2-425 16-MeO (R-7) -CONHPh 2-426 16-MeO (R-7) -CONHCHMePh 2-427 16-MeO (R-7) -CON (Me) Ph 2-428 16-MeO (R-7) -CON (Et) Ph 2-429 16-MeO (R-7) -CONMe (4-F-Ph) 2-430 16-MeO (R-7) -CONMe (4-Cl-Ph) 2-431 16-MeO ( R- 7) -CONMe (4-MeO-Ph) 2-432 1 6-MeO (R-7) -CONMe (3,4-diF-Ph) 2-433 1 6-MeO (R-7) -CONMe (3,5-diF-Ph) 2-434 16-MeO (R-7) -CONMe (3,4-diMeO-Ph) 2-435 16-MeO (R-7) -CONMe (3,5 -diMeO-Ph) 2-436 16-MeO (R-7) -cPn 2-437 16-MeO (R-7) -Bz 2-438 16-MeO (R-7)-(CH_Two)_TwoPh 2-439 16-MeO (R-7) -iPr 2-440 16-MeO (R-7) -Bu 2-441 16-MeO (R-7) -iBu 2-442 16-MeO (R-7) -tBu 2-443 16-MeO (R-7) -iPn 2-444 16-MeO (R-7) -1-Et-Bu 2-445 16-MeO (R-7 ) -1-Et-Pn 2-446 16-MeO (R-8) -CONHPh 2-447 16-MeO (R-8) -CONHCHMePh 2-448 16-MeO (R-8) -CON ( Me) Ph 2-449 16-MeO (R-8) -CON (Et) Ph 2-450 16-MeO (R-8) -CONMe (4-F-Ph) 2-451 16-MeO ( R-8) -CONMe (4-Cl-Ph) 2-452 16-MeO (R-8) -CONMe (4-MeO-Ph) 2-453 16-MeO (R-8) -CONMe (3 , 4-diF-Ph) 2-454 1 6-MeO (R-8) -CONMe (3,5-diF-Ph) 2-455 1 6-MeO (R-8) -CONMe (3,4-diMeO -Ph) 2-456 1 6-MeO (R-8) -CONMe (3,5-diMeO-Ph) 2-457 16-MeO (R-8) -cPn 2-458 16-MeO (R- 8) -Bz 2-459 1 6-MeO (R-8)-(CH_Two)_TwoPh 2-460 16-MeO (R-8) -iPr 2-461 16-MeO (R-8) -Bu 2-462 16-MeO (R-8) -iBu 2-463 16-MeO (R-8) -tBu 2-464 16-MeO (R-8) -iPn 2-465 16-MeO (R-8) -1-Et-Bu 2-466 16-MeO (R-8 ) -1-Et-Pn 2-467 16-MeO (R-9) -CONHCHMePh 2-468 16-MeO (R-9) -CON (Me) Ph 2-469 16-MeO (R-9 ) -cPn 2-470 16-MeO (R-9) -iBu 2-471 16-MeO (R-10) -CONHCHMePh 2-472 16-MeO (R-10) -CON (Me) Ph 2 -473 16-MeO (R-10) -cPn 2-474 16-MeO (R-10) -iBu 2-475 16-MeO (R-11) -CONHPh 2-476 16-MeO (R -11) -CONHCHMePh 2-477 16-MeO (R-11) -CON (Me) Ph 2-478 16-MeO (R-11) -CON (Et) Ph 2-479 16-MeO (R -11) -CONMe (4-F-Ph) 2-480 16-MeO (R-11) -CONMe (4-Cl-Ph) 2-481 16-MeO (R-11) -CONMe (4- MeO-Ph) 2-482 16-MeO (R-11) -CONMe (3,4-diF-Ph) 2-483 16-MeO (R-11) -CONMe (3,5-diF-Ph) 2-484 1 6-MeO (R-11) -CONMe (3,4-diMeO-Ph) 2-485 1 6-MeO (R-11) -CONMe (3,5-diMeO-Ph) 2-486 1 6-MeO (R-11) -cPn 2-487 1 6-MeO (R-11) -Bz 2-488 1 6-MeO (R-11)-(CH_Two)_TwoPh 2-489 16-MeO (R-11) -iPr 2-490 16-MeO (R-11) -Bu 2-491 16-MeO (R-11) -iBu 2-492 16-MeO (R-11) -tBu 2-493 16-MeO (R-11) -iPn 2-494 16-MeO (R-11) -1-Et-Bu 2-495 16-MeO (R-11 ) -1-Et-Pn 2-496 16-MeO (R-12) -CONHCHMePh 2-497 16-MeO (R-12) -CON (Me) Ph 2-498 16-MeO (R-12 ) -cPn 2-499 16-MeO (R-12) -iBu 2-500 16-MeO (R-13) -CONHCHMePh 2-501 16-MeO (R-13) -CON (Me) Ph 2 -502 16-MeO (R-13) -cPn 2-503 16-MeO (R-13) -iBu 2-504 16-MeO (R-14) -COCH_TwoCH (Et)_Two 2-505 1 6-MeO (R-14) -COCH (Et)_Two 2-506 16-MeO (R-14) -COPh 2-507 16-MeO (R-14) -CO (4-Cl-Ph) 2-508 16-MeO (R-14) -CONHBu 2 -509 1 6-MeO (R-14) -CON (Et)_Two 2-510 1 6-MeO (R-14) -CONHCH_TwoCH (Et)_Two 2-511 1 6-MeO (R-14) -CONHCH (Et)_Two 2-512 16-MeO (R-14) -CONHcPn 2-513 16-MeO (R-14) -CONHcHx 2-514 16-MeO (R-14) -CONHPh 2-515 16-MeO ( R-14) -CONHBz 2-516 1 6-MeO (R-14) -CONH (3-F-Bz) 2-517 1 6-MeO (R-14) -CONH (4-Cl-Bz) 2- 518 16-MeO (R-14) -CONHCHMePh 2-519 16-MeO (R-14) -CONHCHMe (4-MeO-Ph) 2-520 16-MeO (R-14) -CONHCHMe (3, 5-diF-Ph) 2-521 1 6-MeO (R-14) -CONH (CH_Two)_TwoPh 2-522 1 6-MeO (R-14) -CONHCH_TwoCH (Me) Ph 2-523 1 6-MeO (R-14) -CONHCH_TwoCH (OH) Ph 2-524 16-MeO (R-14) -CONH (CH_Two)_Two(4-Cl-Ph) 2-525 1 6-MeO (R-14) -CONHCH_TwoCH (Me) Np (2) 2-526 16-MeO (R-14) -CONH (CH_Two)_TwoMor (4) 2-527 1 6-MeO (R-14) -CONHCH_TwoFur (2) 2-528 1 6-MeO (R-14) -CONHCH_TwoFur (3) 2-529 1 6-MeO (R-14) -CONHCH_TwoPrd (2) 2-530 1 6-MeO (R-14) -CONHCH_TwoPrd (3) 2-531 16-MeO (R-14) -CONHCH (Me) Prd (3) 2-532 16-MeO (R-14) -COPrd (1) 2-533 16-MeO ( R-14) -COMor (4) 2-534 16-MeO (R-14) -COPiz (1) 2-535 1 6-MeO (R-14) -CO [4-Me-Piz (1)] 2-536 1 6-MeO (R-14) -CONH (CH_Two)_TwoNH_Two 2-537 1 6-MeO (R-14) -CONHCH_TwoCO_TwoEt 2-538 16-MeO (R-14) -CON (Me) Ph 2-539 16-MeO (R-14) -CON (Et) Ph 2-540 16-MeO (R-14)- CONMe (4-F-Ph) 2-541 1 6-MeO (R-14) -CONMe (4-Cl-Ph) 2-542 16-MeO (R-14) -CONMe (4-MeO-Ph) 2-543 1 6-MeO (R-14) -CONMe (3,4-diF-Ph) 2-544 1 6-MeO (R-14) -CONMe (3,5-diF-Ph) 2-545 1 6-MeO (R-14) -CONMe (3,4-diMeO-Ph) 2-546 1 6-MeO (R-14) -CONMe (3,5-diMeO-Ph) 2-547 1 6-MeO ( (R-14) -CON (Me) Bz 2-548 16-MeO (R-14) -cPn 2-549 16-MeO (R-14) -cHx 2-550 16-MeO (R-14) -Ph 2-551 16-MeO (R-14) -4-Cl-Ph 2-552 16-MeO (R-14) -Bz 2-553 16-MeO (R-14)-(3, (4,5-triMeO-Bz) 2-554 1 6-MeO (R-14)-(CH_Two)_TwoPh 2-555 16-MeO (R-14) -Thi (2) 2-556 16-MeO (R-14) -Thi (3) 2-557 16-MeO (R-14) -Me 2 -558 16-MeO (R-14) -Et 2-559 16-MeO (R-14) -Pr 2-560 16-MeO (R-14) -iPr 2-561 16-MeO (R -14) -Bu 2-562 16-MeO (R-14) -iBu 2-563 16-MeO (R-14) -sBu 2-564 16-MeO (R-14) -tBu 2-565 16-MeO (R-14) -Pn 2-566 16-MeO (R-14) -iPn 2-567 16-MeO (R-14) -1-Me-Bu 2-568 16-MeO (R-14) -CH (Et)_Two 2-569 1 6-MeO (R-14) -CH_TwoCH (Et)_Two 2-570 1 6-MeO (R-14)-(CH_Two)_TwoCH (Et)_Two 2-571 16-MeO (R-14) -1-Et-Bu 2-572 16-MeO (R-14) -1-Et-Pn 2-573 16-MeO (R-15) -CONHPh 2-574 16-MeO (R-15) -CONHCHMePh 2-575 16-MeO (R-15) -CON (Me) Ph 2-576 16-MeO (R-15) -CON (Et) Ph 2-577 16-MeO (R-15) -CONMe (4-F-Ph) 2-578 16-MeO (R-15) -CONMe (4-Cl-Ph) 2-579 16-MeO ( R-15) -CONMe (4-MeO-Ph) 2-580 16-MeO (R-15) -CONMe (3,4-diF-Ph) 2-581 16-MeO (R-15) -CONMe (3,5-diF-Ph) 2-582 16-MeO (R-15) -CONMe (3,4-diMeO-Ph) 2-583 16-MeO (R-15) -CONMe (3,5 -diMeO-Ph) 2-584 16-MeO (R-15) -cPn 2-585 16-MeO (R-15) -Bz 2-586 16-MeO (R-15)-(CH_Two)_TwoPh 2-587 16-MeO (R-15) -iPr 2-588 16-MeO (R-15) -Bu 2-589 16-MeO (R-15) -iBu 2-590 16-MeO (R-15) -tBu 2-591 16-MeO (R-15) -iPn 2-592 16-MeO (R-15) -1-Et-Bu 2-593 16-MeO (R-15 ) -1-Et-Pn 2-594 16-MeO (R-16) -CONHPh 2-595 16-MeO (R-16) -CONHCHMePh 2-596 16-MeO (R-16) -CON ( Me) Ph 2-597 1 6-MeO (R-16) -CON (Et) Ph 2-598 16-MeO (R-16) -CONMe (4-F-Ph) 2-599 16-MeO ( (R-16) -CONMe (4-Cl-Ph) 2-600 16-MeO (R-16) -CONMe (4-MeO-Ph) 2-601 16-MeO (R-16) -CONMe (3 , 4-diF-Ph) 2-602 16-MeO (R-16) -CONMe (3,5-diF-Ph) 2-603 16-MeO (R-16) -CONMe (3,4-diMeO -Ph) 2-604 16-MeO (R-16) -CONMe (3,5-diMeO-Ph) 2-605 16-MeO (R-16) -cPn 2-606 16-MeO (R- 16) -Bz 2-607 1 6-MeO (R-16)-(CH_Two)_TwoPh 2-608 16-MeO (R-16) -iPr 2-609 16-MeO (R-16) -Bu 2-610 16-MeO (R-16) -iBu 2-611 16-MeO (R-16) -tBu 2-612 16-MeO (R-16) -iPn 2-613 16-MeO (R-16) -1-Et-Bu 2-614 16-MeO (R-16 ) -1-Et-Pn 2-615 16-MeO (R-17) -COCH_TwoCH (Et)_Two 2-616 1 6-MeO (R-17) -COCH (Et)_Two 2-617 16-MeO (R-17) -CONHPh 2-618 16-MeO (R-17) -CONHCHMePh 2-619 16-MeO (R-17) -CONHCHMe (4-MeO-Ph) 2 -620 16-MeO (R-17) -CONHCHMe (3,5-diF-Ph) 2-621 16-MeO (R-17) -CONH (CH_Two)_TwoPh 2-622 16-MeO (R-17) -CON (Me) Ph 2-623 16-MeO (R-17) -CON (Et) Ph 2-624 16-MeO (R-17)- CONMe (4-F-Ph) 2-625 16-MeO (R-17) -CONMe (4-Cl-Ph) 2-626 16-MeO (R-17) -CONMe (4-MeO-Ph) 2-627 1 6-MeO (R-17) -CONMe (3,4-diF-Ph) 2-628 1 6-MeO (R-17) -CONMe (3,5-diF-Ph) 2-629 1 6-MeO (R-17) -CONMe (3,4-diMeO-Ph) 2-630 1 6-MeO (R-17) -CONMe (3,5-diMeO-Ph) 2-631 1 6-MeO ( (R-17) -cPn 2-632 16-MeO (R-17) -Ph 2-633 16-MeO (R-17) -Bz 2-634 16-MeO (R-17)-(CH_Two)_TwoPh 2-635 16-MeO (R-17) -Me 2-636 16-MeO (R-17) -iPr 2-637 16-MeO (R-17) -Bu 2-638 16-MeO (R-17) -iBu 2-639 16-MeO (R-17) -sBu 2-640 16-MeO (R-17) -tBu 2-641 16-MeO (R-17) -iPn 2 -642 1 6-MeO (R-17) -CH_TwoCH (Et)_Two 2-643 1 6-MeO (R-17)-(CH_Two)_TwoCH (Et)_Two 2-644 16-MeO (R-17) -1-Et-Bu 2-645 16-MeO (R-17) -1-Et-Pn 2-646 17-Me0 (R-1) -CON (Me) Ph 2-647 1 7-Me0 (R-1) -COCH (Et)_Two 2-648 1 7-Me0 (R-1) -COCH_TwoCH (Et)_Two 2-649 1 7-Me0 (R-1) -COPh 2-650 17-Me0 (R-1) -cPn 2-651 17-Me0 (R-1) -Ph 2-652 17-Me0 ( R- 1) -Bz 2-653 17-Me0 (R- 1) -iPr 2-654 17-Me0 (R- 1) -iBu 2-655 17-Me0 (R- 1) -CH_TwoCH (Et)_Two 2-656 1 7-Me0 (R-1) -All 2-657 17-Me0 (R-5) -CON (Me) Ph 2-658 17-Me0 (R-5) -COCH (Et)_Two 2-659 1 7-Me0 (R-5) -COCH_TwoCH (Et)_Two 2-660 17-Me0 (R-5) -COPh 2-661 17-Me0 (R-5) -cPn 2-662 17-Me0 (R-5) -Ph 2-663 17-Me0 ( (R-5) -Bz 2-664 17-Me0 (R-5) -iPr 2-665 17-Me0 (R-5) -iBu 2-666 17-Me0 (R-5) -CH_TwoCH (Et)_Two 2-667 17-Me0 (R-5) -All 2-668 17-Me0 (R-6) -CON (Me) Ph 2-669 17-Me0 (R-6) -COCH (Et)_Two 2-670 1 7-Me0 (R-6) -COCH_TwoCH (Et)_Two 2-671 17-Me0 (R-6) -COPh 2-672 17-Me0 (R-6) -cPn 2-673 17-Me0 (R-6) -Ph 2-674 17-Me0 ( (R-6) -Bz 2-675 17-Me0 (R-6) -iPr 2-676 17-Me0 (R-6) -iBu 2-677 17-Me0 (R-6) -CH_TwoCH (Et)_Two 2-678 17-Me0 (R-6) -All 2-679 18-MeO (R-6) -CON (Me) Ph 2-680 18-MeO (R-14) -CON (Me) Ph 2-681 1 6-EtO (R-6) -CON (Me) Ph 2-682 1 6-EtO (R-14) -CON (Me) Ph 2-683 1 7-EtO (R-1) -CON (Me) Ph 2-684 1 7-EtO (R- 2) -CON (Me) Ph 2-685 1 7-EtO (R-3) -CON (Me) Ph 2-686 1 7-EtO (R- 4) -CON (Me) Ph 2-687 1 7-EtO (R-5) -CON (Me) Ph 2-688 17-EtO (R-6) -CON (Me) Ph 2-689 1 7- EtO (R-7) -CON (Me) Ph 2-690 1 7-EtO (R-8) -CON (Me) Ph 2-691 17-EtO (R-9) -CON (Me) Ph 2- 692 1 7-EtO (R-10) -CON (Me) Ph 2-693 1 7-EtO (R-11) -CON (Me) Ph 2-694 1 7-EtO (R-12) -CON (Me ) Ph 2-695 1 7-EtO (R-13) -CON (Me) Ph 2-696 1 7-EtO (R-14) -CON (Me) Ph 2-697 1 7-EtO (R-15) -CON (Me) Ph 2-698 1 7-EtO (R-16) -CON (Me) Ph 2-699 1 7-EtO (R-17) -CON (Me) Ph 2-700 1 7-EtO ( R-18) -CON (Me) Ph 2-701 1 6-OH (R-6) -CON (Me) Ph 2-702 1 6-OH (R-14) -CON (Me) Ph 2-703 1 7-OH (R-6) -CON (Me) Ph 2-704 1 7-OH (R-14) -CON (Me) Ph 2-705 2 6-OH 7-OH (R-1) -iBu 2 -706 3 6-OH 7-OH 8-OH (R-1) -CON (Me) Ph 2-707 36-OH 7-OH 8-OH (R-2) -CON (Me) Ph 2-708 3 6-OH 7-OH 8-OH (R-3) -CON (Me) Ph 2-709 3 6-OH 7-OH 8-OH (R-5) -CONHPh 2-710 3 6-OH 7-OH 8-OH (R-5) -CONHCHMePh 2-711 3 6- OH 7-OH 8-OH (R-5) -CONHCHMe (4-MeO-Ph) 2-712 3 6-OH 7-OH 8-OH (R-5) -CONHCHMe (3,5-diF-Ph) 2-713 3 6-OH 7-OH 8-OH (R-5) -CONH (CH_Two)_TwoPh 2-714 36-OH 7-OH 8-OH (R-5) -CON (Me) Ph 2-715 36-OH 7-OH 8-OH (R-5) -CON (Et) Ph 2 -716 3 6-OH 7-OH 8-OH (R-5) -CONMe (4-F-Ph) 2-717 3 6-OH 7-OH 8-OH (R-5) -CONMe (4-MeO -Ph) 2-718 3 6-OH 7-OH 8-OH (R-5) -CONMe (3,4-diF-Ph) 2-719 3 6-OH 7-OH 8-OH (R-5) -CONMe (3,5-diF-Ph) 2-720 36-OH 7-OH 8-OH (R-5) -CONMe (3,4-diMeO-Ph) 2-721 36-OH 7-OH 8-OH (R-5) -CONMe (3,5-diMeO-Ph) 2-722 36-OH 7-OH 8-OH (R-5) -cPn 2-723 36-OH 7-OH 8 -OH (R-5) -Ph 2-724 36-OH 7-OH 8-OH (R-5) -Bz 2-725 36-OH 7-OH 8-OH (R-5)-(CH_Two)_TwoPh 2-726 36-OH 7-OH 8-OH (R-5) -iPr 2-727 36-OH 7-OH 8-OH (R-5) -Bu 2-728 36-OH 7- OH 8-OH (R-5) -iBu 2-729 3 6-OH 7-OH 8-OH (R-5) -tBu 2-730 3 6-OH 7-OH 8-OH (R-5)- iPn 2-731 3 6-OH 7-OH 8-OH (R-5) -CH_TwoCH (Et)_Two 2-732 3 6-OH 7-OH 8-OH (R-5)-(CH_Two)_TwoCH (Et)_Two 2-733 3 6-OH 7-OH 8-OH (R-5) -1-Et-Bu 2-734 36-OH 7-OH 8-OH (R-5) -1-Et-Pn 2- 735 3 6-OH 7-OH 8-OH (R-6) -CONHPh 2-736 36-OH 7-OH 8-OH (R-6) -CONHCHMePh 2-737 36-OH 7-OH 8- OH (R-6) -CONHCHMe (4-MeO-Ph) 2-738 36-OH 7-OH 8-OH (R-6) -CONHCHMe (3,5-diF-Ph) 2-739 3 6- OH 7-OH 8-OH (R-6) -CONH (CH_Two)_TwoPh 2-740 3 6-OH 7-OH 8-OH (R-6) -CON (Me) Ph 2-741 3 6-OH 7-OH 8-OH (R-6) -CON (Et) Ph 2 -742 3 6-OH 7-OH 8-OH (R-6) -CONMe (4-F-Ph) 2-743 3 6-OH 7-OH 8-OH (R-6) -CONMe (4-MeO -Ph) 2-744 3 6-OH 7-OH 8-OH (R-6) -CONMe (3,4-diF-Ph) 2-745 3 6-OH 7-OH 8-OH (R-6) -CONMe (3,5-diF-Ph) 2-746 3 6-OH 7-OH 8-OH (R-6) -CONMe (3,4-diMeO-Ph) 2-747 36-OH 7-OH 8-OH (R-6) -CONMe (3,5-diMeO-Ph) 2-748 36-OH 7-OH 8-OH (R-6) -cPn 2-749 36-OH 7-OH 8 -OH (R-6) -Bz 2-750 3 6-OH 7-OH 8-OH (R-6)-(CH_Two)_TwoPh 2-751 36-OH 7-OH 8-OH (R-6) -iPr 2-752 36-OH 7-OH 8-OH (R-6) -Bu 2-753 36-OH 7- OH 8-OH (R-6) -sBu 2-754 36-OH 7-OH 8-OH (R-6) -tBu 2-755 36-OH 7-OH 8-OH (R-6)- iPn 2-756 3 6-OH 7-OH 8-OH (R-6) -CH_TwoCH (Et)_Two 2-757 3 6-OH 7-OH 8-OH (R-6)-(CH_Two)_TwoCH (Et)_Two 2-758 3 6-OH 7-OH 8-OH (R-6) -1-Et-Bu 2-759 36-OH 7-OH 8-OH (R-6) -1-Et-Pn 2- 760 3 6-OH 7-OH 8-OH (R-7) -CON (Me) Ph 2-761 3 6-OH 7-OH 8-OH (R-8) -CON (Me) Ph 2-762 3 6-OH 7-OH 8-OH (R-11) -CON (Me) Ph 2-763 3 6-OH 7-OH 8-OH (R-12) -CON (Me) Ph 2-764 3 6- OH 7-OH 8-OH (R-14) -CONHPh 2-765 36-OH 7-OH 8-OH (R-14) -CONHCHMePh 2-766 36-OH 7-OH 8-OH (R- 14) -CONHCHMe (4-MeO-Ph) 2-767 3 6-OH 7-OH 8-OH (R-14) -CONHCHMe (3,5-diF-Ph) 2-768 3 6-OH 7-OH 8-OH (R-14) -CONH (CH_Two)_TwoPh 2-769 3 6-OH 7-OH 8-OH (R-14) -CON (Me) Ph 2-770 3 6-OH 7-OH 8-OH (R-14) -CON (Et) Ph 2 -771 3 6-OH 7-OH 8-OH (R-14) -CONMe (4-F-Ph) 2-772 3 6-OH 7-OH 8-OH (R-14) -CONMe (4-MeO -Ph) 2-773 3 6-OH 7-OH 8-OH (R-14) -CONMe (3,4-diF-Ph) 2-774 3 6-OH 7-OH 8-OH (R-14) -CONMe (3,5-diF-Ph) 2-775 3 6-OH 7-OH 8-OH (R-14) -CONMe (3,4-diMeO-Ph) 2-776 36-OH 7-OH 8-OH (R-14) -CONMe (3,5-diMeO-Ph) 2-777 36-OH 7-OH 8-OH (R-14) -cPn 2-778 36-OH 7-OH 8 -OH (R-14) -Bz 2-779 3 6-OH 7-OH 8-OH (R-14)-(CH_Two)_TwoPh 2-780 36-OH 7-OH 8-OH (R-14) -iPr 2-781 36-OH 7-OH 8-OH (R-14) -Bu 2-782 36-OH 7- OH 8-OH (R-14) -sBu 2-783 3 6-OH 7-OH 8-OH (R-14) -tBu 2-784 36-OH 7-OH 8-OH (R-14)- iPn 2-785 3 6-OH 7-OH 8-OH (R-14) -CH_TwoCH (Et)_Two 2-786 3 6-OH 7-OH 8-OH (R-14)-(CH_Two)_TwoCH (Et)_Two 2-787 36-OH 7-OH 8-OH (R-14) -1-Et-Bu 2-788 36-OH 7-OH 8-OH (R-14) -1-Et-Pn 2- 789 3 6-OH 7-OH 8-OH (R-15) -CON (Me) Ph 2-790 3 6-OH 7-OH 8-OH (R-16) -CON (Me) Ph 2-791 3 6-OH 7-OH 8-OH (R-17) -CON (Me) Ph 2-792 2 6-MeO 7-MeO (R-1) -COCH_TwoCH (Et)_Two 2-793 26-MeO 7-MeO (R-1) -CONHPh 2-794 26-MeO 7-MeO (R-1) -CONHCHMePh 2-795 26-MeO 7-MeO (R-1)- CON (Me) Ph 2-796 26-MeO 7-MeO (R-1) -CON (Et) Ph 2-797 26-MeO 7-MeO (R-1) -CONMe (4-F-Ph) 2-798 26-MeO 7-MeO (R-1) -CONMe (4-Cl-Ph) 2-799 26-MeO 7-MeO (R-1) -CONMe (4-MeO-Ph) 2- 800 26-MeO 7-MeO (R-1) -CONMe (3,4-diF-Ph) 2-801 26-MeO 7-MeO (R-1) -CONMe (3,5-diF-Ph) 2-802 26-MeO 7-MeO (R-1) -CONMe (3,4-diMeO-Ph) 2-803 26-MeO 7-MeO (R-1) -CONMe (3,5-diMeO- Ph) 2-804 26-MeO 7-MeO (R-1) -cPn 2-805 26-MeO 7-MeO (R-1) -Bz 2-806 26-MeO 7-MeO (R-1 )-(CH_Two)_TwoPh 2-807 26-MeO 7-MeO (R-1) -iPr 2-808 26-MeO 7-MeO (R-1) -Bu 2-809 26-MeO 7-MeO (R-1) -iBu 2-810 26-MeO 7-MeO (R-1) -tBu 2-811 26-MeO 7-MeO (R-1) -iPn 2-812 26-MeO 7-MeO (R-1 ) -CH_TwoCH (Et)_Two 2-813 26-MeO 7-MeO (R- 1) -1-Et-Bu 2-814 26-MeO 7-MeO (R-1) -1-Et-Pn 2-815 26-MeO 7 -MeO (R- 2) -COCH_TwoCH (Et)_Two 2-816 26-MeO 7-MeO (R-2) -COCH (Et)_Two 2-817 26-MeO 7-MeO (R-2) -CONHPh 2-818 26-MeO 7-MeO (R-2) -CONHCHMePh 2-819 26-MeO 7-MeO (R-2)- CONHCHMe (4-MeO-Ph) 2-820 2 6-MeO 7-MeO (R-2) -CONHCHMe (3,5-diF-Ph) 2-821 26-MeO 7-MeO (R-2)- CONH (CH_Two)_TwoPh 2-822 26-MeO 7-MeO (R- 2) -CON (Me) Ph 2-823 26-MeO 7-MeO (R-2) -CON (Et) Ph 2-824 26-MeO 7-MeO (R- 2) -CONMe (4-F-Ph) 2-825 2 6-MeO 7-MeO (R- 2) -CONMe (4-Cl-Ph) 2-826 26-MeO 7- MeO (R- 2) -CONMe (4-MeO-Ph) 2-827 26-MeO 7-MeO (R- 2) -CONMe (3,4-diF-Ph) 2-828 26-MeO 7- MeO (R-2) -CONMe (3,5-diF-Ph) 2-829 26-MeO 7-MeO (R-2) -CONMe (3,4-diMeO-Ph) 2-830 26-MeO 7-MeO (R-2) -CONMe (3,5-diMeO-Ph) 2-831 2 6-MeO 7-MeO (R-2) -cPn 2-832 26-MeO 7-MeO (R-2 ) -Ph 2-833 26-MeO 7-MeO (R- 2) -Bz 2-834 26-MeO 7-MeO (R-2)-(CH_Two)_TwoPh 2-835 26-MeO 7-MeO (R- 2) -Me 2-836 26-MeO 7-MeO (R- 2) -iPr 2-837 26-MeO 7-MeO (R- 2) -Bu 2-838 26-MeO 7-MeO (R-2) -iBu 2-839 26-MeO 7-MeO (R-2) -sBu 2-840 26-MeO 7-MeO (R-2 ) -tBu 2-841 26-MeO 7-MeO (R- 2) -iPn 2-842 26-MeO 7-MeO (R- 2) -CH_TwoCH (Et)_Two 2-843 2 6-MeO 7-MeO (R-2)-(CH_Two)_TwoCH (Et)_Two 2-844 26-MeO 7-MeO (R- 2) -1-Et-Bu 2-845 26-MeO 7-MeO (R-2) -1-Et-Pn 2-846 26-MeO 7 -MeO (R-3) -COCH_TwoCH (Et)_Two 2-847 26-MeO 7-MeO (R-3) -COCH (Et)_Two 2-848 26-MeO 7-MeO (R-3) -CONHPh 2-849 26-MeO 7-MeO (R-3) -CONHCHMePh 2-850 26-MeO 7-MeO (R-3)- CONHCHMe (4-MeO-Ph) 2-851 26-MeO 7-MeO (R-3) -CONHCHMe (3,5-diF-Ph) 2-852 26-MeO 7-MeO (R-3)- CONH (CH_Two)_TwoPh 2-853 26-MeO 7-MeO (R-3) -CON (Me) Ph 2-854 26-MeO 7-MeO (R-3) -CON (Et) Ph 2-855 26-MeO 7-MeO (R-3) -CONMe (4-F-Ph) 2-856 26-MeO 7-MeO (R-3) -CONMe (4-Cl-Ph) 2-857 26-MeO 7- MeO (R-3) -CONMe (4-MeO-Ph) 2-858 26-MeO 7-MeO (R-3) -CONMe (3,4-diF-Ph) 2-859 26-MeO 7- MeO (R-3) -CONMe (3,5-diF-Ph) 2-860 2 6-MeO 7-MeO (R-3) -CONMe (3,4-diMeO-Ph) 2-861 26-MeO 7-MeO (R-3) -CONMe (3,5-diMeO-Ph) 2-862 26-MeO 7-MeO (R-3) -cPn 2-863 26-MeO 7-MeO (R-3 ) -Ph 2-864 26-MeO 7-MeO (R-3) -Bz 2-865 26-MeO 7-MeO (R-3)-(CH_Two)_TwoPh 2-866 26-MeO 7-MeO (R-3) -Me 2-867 26-MeO 7-MeO (R-3) -iPr 2-868 26-MeO 7-MeO (R-3) -Bu 2-869 2 6-MeO 7-MeO (R-3) -iBu 2-870 26-MeO 7-MeO (R-3) -sBu 2-871 26-MeO 7-MeO (R-3 ) -tBu 2-872 26-MeO 7-MeO (R-3) -iPn 2-873 26-MeO 7-MeO (R-3) -CH_TwoCH (Et)_Two 2-874 2 6-MeO 7-MeO (R-3)-(CH_Two)_TwoCH (Et)_Two 2-875 26-MeO 7-MeO (R-3) -1-Et-Bu 2-876 26-MeO 7-MeO (R-3) -1-Et-Pn 2-877 26-MeO 7 -MeO (R-4) -CONHCHMePh 2-878 26-MeO 7-MeO (R-4) -CON (Me) Ph 2-879 26-MeO 7-MeO (R-4) -cPn 2-880 2 6-MeO 7-MeO (R-4) -iBu 2-881 26-MeO 7-MeO (R-5) -COCH_TwoCH (Et)_Two 2-882 2 6-MeO 7-MeO (R-5) -COCH (Et)_Two 2-883 26-MeO 7-MeO (R-5) -COPh 2-884 26-MeO 7-MeO (R-5) -CO (4-Cl-Ph) 2-885 26-MeO 7- MeO (R-5) -CONHBu 2-886 2 6-MeO 7-MeO (R-5) -CON (Et)_Two 2-887 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCH (Et)_Two 2-888 26-MeO 7-MeO (R-5) -CONHCH (Et)_Two 2-889 26-MeO 7-MeO (R-5) -CONHcPn 2-890 26-MeO 7-MeO (R-5) -CONHcHx 2-891 26-MeO 7-MeO (R-5)- CONHPh 2-892 26-MeO 7-MeO (R-5) -CONHBz 2-893 26-MeO 7-MeO (R-5) -CONH (3-F-Bz) 2-894 26-MeO 7 -MeO (R-5) -CONH (4-Cl-Bz) 2-895 26-MeO 7-MeO (R-5) -CONHCHMePh 2-896 26-MeO 7-MeO (R-5) -CONHCHMe (4-MeO-Ph) 2-897 26-MeO 7-MeO (R-5) -CONHCHMe (3,5-diF-Ph) 2-898 26-MeO 7-MeO (R-5) -CONH (CH_Two)_TwoPh 2-899 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCH (Me) Ph 2-900 26-MeO 7-MeO (R-5) -CONHCH_TwoCH (OH) Ph 2-901 2 6-MeO 7-MeO (R-5) -CONH (CH_Two)_Two(4-Cl-Ph) 2-902 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCH (Me) Np (2) 2-903 2 6-MeO 7-MeO (R-5) -CONH (CH_Two)_TwoMor (4) 2-904 2 6-MeO 7-MeO (R-5) -CONHCH_TwoFur (2) 2-905 2 6-MeO 7-MeO (R-5) -CONHCH_TwoFur (3) 2-906 2 6-MeO 7-MeO (R-5) -CONHCH_TwoPrd (2) 2-907 2 6-MeO 7-MeO (R-5) -CONHCH_TwoPrd (3) 2-908 26-MeO 7-MeO (R-5) -CONHCH (Me) Prd (3) 2-909 26-MeO 7-MeO (R-5) -COPrd (1) 2- 910 2 6-MeO 7-MeO (R-5) -COMor (4) 2-911 26-MeO 7-MeO (R-5) -COPiz (1) 2-912 26-MeO 7-MeO (R -5) -CO [4-Me-Piz (1)] 2-913 2 6-MeO 7-MeO (R-5) -CONH (CH_Two)_TwoNH_Two 2-914 2 6-MeO 7-MeO (R-5) -CONHCH_TwoCO_TwoEt 2-915 26-MeO 7-MeO (R-5) -CON (Me) Ph 2-916 26-MeO 7-MeO (R-5) -CON (Et) Ph 2-917 26-MeO 7-MeO (R-5) -CONMe (4-F-Ph) 2-918 26-MeO 7-MeO (R-5) -CONMe (4-Cl-Ph) 2-919 26-MeO 7- MeO (R-5) -CONMe (4-MeO-Ph) 2-920 26-MeO 7-MeO (R-5) -CONMe (3,4-diF-Ph) 2-921 26-MeO 7- MeO (R-5) -CONMe (3,5-diF-Ph) 2-922 26-MeO 7-MeO (R-5) -CONMe (3,4-diMeO-Ph) 2-923 26-MeO 7-MeO (R-5) -CONMe (3,5-diMeO-Ph) 2-924 26-MeO 7-MeO (R-5) -CON (Me) Bz 2-925 26-MeO 7-MeO (R-5) -cPn 2-926 26-MeO 7-MeO (R-5) -cHx 2-927 26-MeO 7-MeO (R-5) -Ph 2-928 26-MeO 7- MeO (R-5) -4-Cl-Ph 2-929 26-MeO 7-MeO (R-5) -Bz 2-930 26-MeO 7-MeO (R-5)-(3,4, 5-triMeO-Bz) 2-931 2 6-MeO 7-MeO (R-5)-(CH_Two)_TwoPh 2-932 26-MeO 7-MeO (R-5) -Thi (2) 2-933 26-MeO 7-MeO (R-5) -Thi (3) 2-934 26-MeO 7- MeO (R-5) -Me 2-935 26-MeO 7-MeO (R-5) -Et 2-936 26-MeO 7-MeO (R-5) -Pr 2-937 26-MeO 7 -MeO (R-5) -iPr 2-938 26-MeO 7-MeO (R-5) -Bu 2-939 26-MeO 7-MeO (R-5) -iBu 2-940 26-MeO 7-MeO (R-5) -sBu 2-941 26-MeO 7-MeO (R-5) -tBu 2-942 26-MeO 7-MeO (R-5) -Pn 2-943 26- MeO 7-MeO (R-5) -iPn 2-944 26-MeO 7-MeO (R-5) -1-Me-Bu 2-945 26-MeO 7-MeO (R-5) -CH ( Et)_Two 2-946 2 6-MeO 7-MeO (R-5) -CH_TwoCH (Et)_Two 2-947 26-MeO 7-MeO (R-5)-(CH_Two)_TwoCH (Et)_Two 2-948 26-MeO 7-MeO (R-5) -1-Et-Bu 2-949 26-MeO 7-MeO (R-5) -1-Et-Pn 2-950 26-MeO 7 -MeO (R-6) -COiPr 2-951 26-MeO 7-MeO (R-6) -COiBu 2-952 26-MeO 7-MeO (R-6) -COCH_TwoCH (Et)_Two 2-953 26-MeO 7-MeO (R-6) -COCH (Et)_Two 2-954 26-MeO 7-MeO (R-6) -COPh 2-955 26-MeO 7-MeO (R-6) -CO (4-Cl-Ph) 2-956 26-MeO 7- MeO (R-6) -COBz 2-957 26-MeO 7-MeO (R-6) -CONH_Two 2-958 26-MeO 7-MeO (R-6) -CONHMe 2-959 26-MeO 7-MeO (R-6) -CONHEt 2-960 26-MeO 7-MeO (R-6)- CONHPr 2-961 26-MeO 7-MeO (R-6) -CONHBu 2-962 26-MeO 7-MeO (R-6) -CON (Me)_Two 2-963 2 6-MeO 7-MeO (R-6) -CON (Et)_Two 2-964 26-MeO 7-MeO (R-6) -CONHiPr 2-965 26-MeO 7-MeO (R-6) -CONHiBu 2-966 26-MeO 7-MeO (R-6)- CONHtBu 2-967 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCH (Et)_Two 2-968 26-MeO 7-MeO (R-6) -CONHCH (Et)_Two 2-969 26-MeO 7-MeO (R-6) -CONHcPn 2-970 26-MeO 7-MeO (R-6) -CONHcHx 2-971 26-MeO 7-MeO (R-6)- CONHPh 2-972 26-MeO 7-MeO (R-6) -CONH (3,4-diF-Ph) 2-973 26-MeO 7-MeO (R-6) -CONH (3,5-diF -Ph) 2-974 2 6-MeO 7-MeO (R-6) -CONH (4-MeO-Ph) 2-975 26-MeO 7-MeO (R-6) -CONHBz 2-976 2 6- MeO 7-MeO (R-6) -CONH (3-F-Bz) 2-977 26-MeO 7-MeO (R-6) -CONH (4-Cl-Bz) 2-978 26-MeO 7 -MeO (R-6) -CONHCHMePh 2-979 26-MeO 7-MeO (R-6) -CONHCHMe (4-MeO-Ph) 2-980 26-MeO 7-MeO (R-6) -CONHCHMe (3,5-diF-Ph) 2-981 26-MeO 7-MeO (R-6) -CONH (CH_Two)_TwoPh 2-982 26-MeO 7-MeO (R-6) -CONHCH_TwoCH (Me) Ph 2-983 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCH (OH) Ph 2-984 26-MeO 7-MeO (R-6) -CONH (CH_Two)_Two(4-Cl-Ph) 2-985 26-MeO 7-MeO (R-6) -CONHCH_TwoCH (Me) Np (2) 2-986 2 6-MeO 7-MeO (R-6) -CONH (CH_Two)_TwoMor (4) 2-987 2 6-MeO 7-MeO (R-6) -CONHCH_TwoFur (2) 2-988 2 6-MeO 7-MeO (R-6) -CONHCH_TwoFur (3) 2-989 2 6-MeO 7-MeO (R-6) -CONHCH_TwoPrd (2) 2-990 2 6-MeO 7-MeO (R-6) -CONHCH_TwoPrd (3) 2-991 26-MeO 7-MeO (R-6) -CONHCH (Me) Pyr (3) 2-992 26-MeO 7-MeO (R-6) -CONHCH (Me) Pyr ( 4) 2-993 26-MeO 7-MeO (R-6) -COPrd (1) 2-994 26-MeO 7-MeO (R-6) -COMor (4) 2-995 26-MeO 7 -MeO (R-6) -COPiz (1) 2-996 26-MeO 7-MeO (R-6) -CO [4-Me-Piz (1)] 2-997 26-MeO 7-MeO ( R-6) -CONH (CH_Two)_TwoNH_Two 2-998 26-MeO 7-MeO (R-6) -CONH (CH_Two)_TwoN (Me)_Two 2-999 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCO_TwoH 2-1000 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCO_TwoMe 2-1001 2 6-MeO 7-MeO (R-6) -CONHCH_TwoCO_TwoEt 2-1002 26-MeO 7-MeO (R-6) -CON (Me) Ph 2-1003 26-MeO 7-MeO (R-6) -CON (Et) Ph 2-1004 26-MeO 7-MeO (R-6) -CONMe (4-F-Ph) 2-1005 26-MeO 7-MeO (R-6) -CONMe (4-Cl-Ph) 2-1006 26-MeO 7- MeO (R-6) -CONMe (4-MeO-Ph) 2-1007 26-MeO 7-MeO (R-6) -CONMe (3,4-diF-Ph) 2-1008 26-MeO 7- MeO (R-6) -CONMe (3,5-diF-Ph) 2-1009 26-MeO 7-MeO (R-6) -CONMe (3,4-diMeO-Ph) 2-1010 26-MeO 7-MeO (R-6) -CONMe (3,5-diMeO-Ph) 2-1011 26-MeO 7-MeO (R-6) -CON (Me) Bz 2-1012 26-MeO 7-MeO (R-6) -CONMe (4-F-Bz) 2-1013 26-MeO 7-MeO (R-6) -CONMe (4-MeO-Bz) 2-1014 26-MeO 7-MeO (R -6) -cPn 2-1015 26-MeO 7-MeO (R-6) -cHx 2-1016 26-MeO 7-MeO (R-6) -Ph 2-1017 26-MeO 7-MeO ( R-6) -4-Cl-Ph 2-1018 26-MeO 7-MeO (R-6) -Bz 2-1019 26-MeO 7-MeO (R-6)-(4-MeO-Bz) 2-1020 2 6-MeO 7-MeO (R-6)-(3,4-diMeO-Bz) 2-1021 26-MeO 7-MeO (R-6)-(3,4,5-triMeO- Bz) 2-1022 2 6-MeO 7-MeO (R-6)-(CH_Two)_TwoPh 2-1023 26-MeO 7-MeO (R-6)-(CH_Two)_ThreePh 2-1024 26-MeO 7-MeO (R-6) -Thi (2) 2-1025 26-MeO 7-MeO (R-6) -Thi (3) 2-1026 26-MeO 7- MeO (R-6) -Fur (3) 2-1027 26-MeO 7-MeO (R-6) -Me 2-1028 26-MeO 7-MeO (R-6) -Et 2-1029 26 -MeO 7-MeO (R-6) -Pr 2-1030 26-MeO 7-MeO (R-6) -iPr 2-1031 26-MeO 7-MeO (R-6) -Bu 2-1032 2 6-MeO 7-MeO (R-6) -iBu 2-1033 2 6-MeO 7-MeO (R-6) -sBu 2-1034 26-MeO 7-MeO (R-6) -tBu 2-1035 26-MeO 7-MeO (R-6) -Pn 2-1036 26-MeO 7-MeO (R-6) -iPn 2-1037 26-MeO 7-MeO (R-6) -1-Me -Bu 2-1038 2 6-MeO 7-MeO (R-6) -CH (Et)_Two 2-1039 2 6-MeO 7-MeO (R-6) -CH_TwoCH (Et)_Two 2-1040 2 6-MeO 7-MeO (R-6)-(CH_Two)_TwoCH (Et)_Two 2-1041 26-MeO 7-MeO (R-6) -1-Et-Bu 2-1042 26-MeO 7-MeO (R-6) -1-Et-Pn 2-1043 26-MeO 7 -MeO (R-6) -Vin 2-1044 26-MeO 7-MeO (R-6) -Bun 2-1045 26-MeO 7-MeO (R-6) -3- (3-Me-Bun ) 2-1046 2 6-MeO 7-MeO (R-7) -CONHPh 2-1047 2 6-MeO 7-MeO (R-7) -CONHCHMePh 2-1048 26-MeO 7-MeO (R-7) -CON (Me) Ph 2-1049 26-MeO 7-MeO (R-7) -CON (Et) Ph 2-1050 26-MeO 7-MeO (R-7) -CONMe (4-F-Ph ) 2-1051 2 6-MeO 7-MeO (R-7) -CONMe (4-Cl-Ph) 2-1052 2 6-MeO 7-MeO (R-7) -CONMe (4-MeO-Ph) 2 -1053 2 6-MeO 7-MeO (R-7) -CONMe (3,4-diF-Ph) 2-1054 26-MeO 7-MeO (R-7) -CONMe (3,5-diF-Ph) ) 2-1055 26-MeO 7-MeO (R-7) -CONMe (3,4-diMeO-Ph) 2-1056 26-MeO 7-MeO (R-7) -CONMe (3,5-diMeO -Ph) 2-1057 26-MeO 7-MeO (R-7) -cPn 2-1058 26-MeO 7-MeO (R-7) -Bz 2-1059 26-MeO 7-MeO (R- 7)-(CH_Two)_TwoPh 2-1060 26-MeO 7-MeO (R-7) -iPr 2-1061 26-MeO 7-MeO (R-7) -Bu 2-1062 26-MeO 7-MeO (R-7) -iBu 2-1063 26-MeO 7-MeO (R-7) -tBu 2-1064 26-MeO 7-MeO (R-7) -iPn 2-1065 26-MeO 7-MeO (R-7 ) -1-Et-Bu 2-1066 26-MeO 7-MeO (R-7) -1-Et-Pn 2-1067 26-MeO 7-MeO (R-8) -CONHPh 2-1068 2 6 -MeO 7-MeO (R-8) -CONHCHMePh 2-1069 2 6-MeO 7-MeO (R-8) -CON (Me) Ph 2-1070 26 6-MeO 7-MeO (R-8) -CON (Et) Ph 2-1071 26-MeO 7-MeO (R-8) -CONMe (4-F-Ph) 2-1072 26-MeO 7-MeO (R-8) -CONMe (4-Cl- Ph) 2-1073 26-MeO 7-MeO (R-8) -CONMe (4-MeO-Ph) 2-1074 26-MeO 7-MeO (R-8) -CONMe (3,4-diF- Ph) 2-1075 2 6-MeO 7-MeO (R-8) -CONMe (3,5-diF-Ph) 2-1076 26-MeO 7-MeO (R-8) -CONMe (3,4- diMeO-Ph) 2-1077 26-MeO 7-MeO (R-8) -CONMe (3,5-diMeO-Ph) 2-1078 26-MeO 7-MeO (R-8) -cPn 2-1079 26-MeO 7-MeO (R-8) -Bz 2-1080 26-MeO 7-MeO (R-8)-(CH_Two)_TwoPh 2-1081 26-MeO 7-MeO (R-8) -iPr 2-1082 26-MeO 7-MeO (R-8) -Bu 2-1083 26-MeO 7-MeO (R-8) -iBu 2-1084 26-MeO 7-MeO (R-8) -tBu 2-1085 26-MeO 7-MeO (R-8) -iPn 2-1086 26-MeO 7-MeO (R-8 ) -1-Et-Bu 2-1087 26-MeO 7-MeO (R-8) -1-Et-Pn 2-1088 26-MeO 7-MeO (R-9) -CONHCHMePh 2-1089 26 -MeO 7-MeO (R-9) -CON (Me) Ph 2-1090 26-MeO 7-MeO (R-9) -cPn 2-1091 26-MeO 7-MeO (R-9) -iBu 2-1092 26-MeO 7-MeO (R-10) -CONHCHMePh 2-1093 26-MeO 7-MeO (R-10) -CON (Me) Ph 2-1094 26-MeO 7-MeO (R -10) -cPn 2-1095 26-MeO 7-MeO (R-10) -iBu 2-1096 26-MeO 7-MeO (R-11) -CONHPh 2-1097 26-MeO 7-MeO ( (R-11) -CONHCHMePh 2-1098 26-MeO 7-MeO (R-11) -CON (Me) Ph 2-1099 26-MeO 7-MeO (R-11) -CON (Et) Ph 2- 1100 2 6-MeO 7-MeO (R-11) -CONMe (4-F-Ph) 2-1101 2 6-MeO 7-MeO (R-11) -CONMe (4-Cl-Ph) 2-1102 2 6-MeO 7-MeO (R-11) -CONMe (4-MeO-Ph) 2-1103 2 6-MeO 7-MeO (R-11) -CONMe (3,4-diF-Ph) 2-1104 2 6-MeO 7-MeO (R-11) -CONMe (3,5-diF-Ph) 2-1105 2 6-MeO 7-MeO (R-11) -CONMe (3,4-diMeO-Ph) 2- 1106 2 6-MeO 7-MeO (R-11) -CONMe (3,5-d iMeO-Ph) 2-1107 26-MeO 7-MeO (R-11) -cPn 2-1108 26-MeO 7-MeO (R-11) -Bz 2-1109 26-MeO 7-MeO (R -11)-(CH_Two)_TwoPh 2-1110 26-MeO 7-MeO (R-11) -iPr 2-1111 26-MeO 7-MeO (R-11) -Bu 2-1112 26-MeO 7-MeO (R-11) -iBu 2-1113 26-MeO 7-MeO (R-11) -tBu 2-1114 26-MeO 7-MeO (R-11) -iPn 2-1115 26-MeO 7-MeO (R-11 ) -1-Et-Bu 2-1116 26-MeO 7-MeO (R-11) -1-Et-Pn 2-1117 26-MeO 7-MeO (R-12) -CONHCHMePh 2-1118 2 6 -MeO 7-MeO (R-12) -CON (Me) Ph 2-1119 26-MeO 7-MeO (R-12) -cPn 2-1120 26-MeO 7-MeO (R-12) -iBu 2-1121 26-MeO 7-MeO (R-13) -CONHCHMePh 2-1122 26-MeO 7-MeO (R-13) -CON (Me) Ph 2-1123 26-MeO 7-MeO (R -13) -cPn 2-1124 26-MeO 7-MeO (R-13) -iBu 2-1125 26-MeO 7-MeO (R-14) -COCH_TwoCH (Et)_Two 2-1126 2 6-MeO 7-MeO (R-14) -COCH (Et)_Two 2-1127 26-MeO 7-MeO (R-14) -COPh 2-1128 26-MeO 7-MeO (R-14) -CO (4-Cl-Ph) 2-1129 26-MeO 7- MeO (R-14) -CONHBu 2-1130 2 6-MeO 7-MeO (R-14) -CON (Et)_Two 2-1131 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCH (Et)_Two 2-1132 2 6-MeO 7-MeO (R-14) -CONHCH (Et)_Two 2-1133 26-MeO 7-MeO (R-14) -CONHcPn 2-1134 26-MeO 7-MeO (R-14) -CONHcHx 2-1135 26-MeO 7-MeO (R-14)- CONHPh 2-1136 26-MeO 7-MeO (R-14) -CONHBz 2-1137 26-MeO 7-MeO (R-14) -CONH (3-F-Bz) 2-1138 26-MeO 7 -MeO (R-14) -CONH (4-Cl-Bz) 2-1139 26-MeO 7-MeO (R-14) -CONHCHMePh 2-1140 26-MeO 7-MeO (R-14) -CONHCHMe (4-MeO-Ph) 2-1141 26-MeO 7-MeO (R-14) -CONHCHMe (3,5-diF-Ph) 2-1142 26-MeO 7-MeO (R-14) -CONH (CH_Two)_TwoPh 2-1143 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCH (Me) Ph 2-1144 26-MeO 7-MeO (R-14) -CONHCH_TwoCH (OH) Ph 2-1145 2 6-MeO 7-MeO (R-14) -CONH (CH_Two)_Two(4-Cl-Ph) 2-1146 26-MeO 7-MeO (R-14) -CONHCH_TwoCH (Me) Np (2) 2-1147 2 6-MeO 7-MeO (R-14) -CONH (CH_Two)_TwoMor (4) 2-1148 2 6-MeO 7-MeO (R-14) -CONHCH_TwoFur (2) 2-1149 2 6-MeO 7-MeO (R-14) -CONHCH_TwoFur (3) 2-1150 2 6-MeO 7-MeO (R-14) -CONHCH_TwoPrd (2) 2-1151 2 6-MeO 7-MeO (R-14) -CONHCH_TwoPrd (3) 2-1152 2 6-MeO 7-MeO (R-14) -CONHCH (Me) Prd (3) 2-1153 2 6-MeO 7-MeO (R-14) -COPrd (1) 2- 1154 2 6-MeO 7-MeO (R-14) -COMor (4) 2-1155 26-MeO 7-MeO (R-14) -COPiz (1) 2-1156 2 6-MeO 7-MeO (R -14) -CO [4-Me-Piz (1)] 2-1157 2 6-MeO 7-MeO (R-14) -CONH (CH_Two)_TwoNH_Two 2-1158 2 6-MeO 7-MeO (R-14) -CONHCH_TwoCO_TwoEt 2-1159 26-MeO 7-MeO (R-14) -CON (Me) Ph 2-1160 26-MeO 7-MeO (R-14) -CON (Et) Ph 2-1161 26-MeO 7-MeO (R-14) -CONMe (4-F-Ph) 2-1162 2 6-MeO 7-MeO (R-14) -CONMe (4-Cl-Ph) 2-1163 26-MeO 7- MeO (R-14) -CONMe (4-MeO-Ph) 2-1164 26-MeO 7-MeO (R-14) -CONMe (3,4-diF-Ph) 2-1165 26-MeO 7- MeO (R-14) -CONMe (3,5-diF-Ph) 2-1166 26-MeO 7-MeO (R-14) -CONMe (3,4-diMeO-Ph) 2-1167 26-MeO 7-MeO (R-14) -CONMe (3,5-diMeO-Ph) 2-1168 26-MeO 7-MeO (R-14) -CON (Me) Bz 2-1169 26-MeO 7-MeO (R-14) -cPn 2-1170 26-MeO 7-MeO (R-14) -cHx 2-1171 26-MeO 7-MeO (R-14) -Ph 2-1172 26-MeO 7- MeO (R-14) -4-Cl-Ph 2-1173 2 6-MeO 7-MeO (R-14) -Bz 2-1174 26-MeO 7-MeO (R-14)-(3,4, 5-triMeO-Bz) 2-1175 2 6-MeO 7-MeO (R-14)-(CH_Two)_TwoPh 2-1176 26-MeO 7-MeO (R-14) -Thi (2) 2-1177 26-MeO 7-MeO (R-14) -Thi (3) 2-1178 26-MeO 7- MeO (R-14) -Me 2-1179 26-MeO 7-MeO (R-14) -Et 2-1180 26-MeO 7-MeO (R-14) -Pr 2-1181 26-MeO 7 -MeO (R-14) -iPr 2-1182 26-MeO 7-MeO (R-14) -Bu 2-1183 26-MeO 7-MeO (R-14) -iBu 2-1184 26-MeO 7-MeO (R-14) -sBu 2-1185 26-MeO 7-MeO (R-14) -tBu 2-1186 26-MeO 7-MeO (R-14) -Pn 2-1187 26- MeO 7-MeO (R-14) -iPn 2-1188 26-MeO 7-MeO (R-14) -1-Me-Bu 2-1189 26-MeO 7-MeO (R-14) -CH ( Et)_Two 2-1190 2 6-MeO 7-MeO (R-14) -CH_TwoCH (Et)_Two 2-1191 2 6-MeO 7-MeO (R-14)-(CH_Two)_TwoCH (Et)_Two 2-1192 26-MeO 7-MeO (R-14) -1-Et-Bu 2-1193 26-MeO 7-MeO (R-14) -1-Et-Pn 2-1194 26-MeO 7 -MeO (R-15) -CONHPh 2-1195 2 6-MeO 7-MeO (R-15) -CONHCHMePh 2-1196 26-MeO 7-MeO (R-15) -CON (Me) Ph 2-1197 26-MeO 7-MeO (R-15) -CON (Et) Ph 2-1198 26-MeO 7-MeO (R-15) -CONMe (4-F-Ph) 2-1199 26-MeO 7 -MeO (R-15) -CONMe (4-Cl-Ph) 2-1200 2 6-MeO 7-MeO (R-15) -CONMe (4-MeO-Ph) 2-1201 26-MeO 7-MeO (R-15) -CONMe (3,4-diF-Ph) 2-1202 2 6-MeO 7-MeO (R-15) -CONMe (3,5-diF-Ph) 2-1203 26-MeO 7 -MeO (R-15) -CONMe (3,4-diMeO-Ph) 2-1204 26-MeO 7-MeO (R-15) -CONMe (3,5-diMeO-Ph) 2-1205 2 6- MeO 7-MeO (R-15) -cPn 2-1206 26-MeO 7-MeO (R-15) -Bz 2-1207 26-MeO 7-MeO (R-15)-(CH_Two)_TwoPh 2-1208 26-MeO 7-MeO (R-15) -iPr 2-1209 26-MeO 7-MeO (R-15) -Bu 2-1210 26-MeO 7-MeO (R-15) -iBu 2-1211 26-MeO 7-MeO (R-15) -tBu 2-1212 26-MeO 7-MeO (R-15) -iPn 2-1213 26-MeO 7-MeO (R-15 ) -1-Et-Bu 2-1214 26-MeO 7-MeO (R-15) -1-Et-Pn 2-1215 26-MeO 7-MeO (R-16) -CONHPh 2-1216 2 6 -MeO 7-MeO (R-16) -CONHCHMePh 2-1217 26-MeO 7-MeO (R-16) -CON (Me) Ph 2-1218 26-MeO 7-MeO (R-16) -CON (Et) Ph 2-1219 26-MeO 7-MeO (R-16) -CONMe (4-F-Ph) 2-1220 26-MeO 7-MeO (R-16) -CONMe (4-Cl- Ph) 2-1221 2 6-MeO 7-MeO (R-16) -CONMe (4-MeO-Ph) 2-1222 26-MeO 7-MeO (R-16) -CONMe (3,4-diF- Ph) 2-1223 26-MeO 7-MeO (R-16) -CONMe (3,5-diF-Ph) 2-1224 26-MeO 7-MeO (R-16) -CONMe (3,4- diMeO-Ph) 2-1225 26-MeO 7-MeO (R-16) -CONMe (3,5-diMeO-Ph) 2-1226 26-MeO 7-MeO (R-16) -cPn 2-1227 2 6-MeO 7-MeO (R-16) -Bz 2-1228 2 6-MeO 7-MeO (R-16)-(CH_Two)_TwoPh 2-1229 26-MeO 7-MeO (R-16) -iPr 2-1230 26-MeO 7-MeO (R-16) -Bu 2-1231 26-MeO 7-MeO (R-16) -iBu 2-1232 2 6-MeO 7-MeO (R-16) -tBu 2-1233 26-MeO 7-MeO (R-16) -iPn 2-1234 26-MeO 7-MeO (R-16) ) -1-Et-Bu 2-1235 26-MeO 7-MeO (R-16) -1-Et-Pn 2-1236 26-MeO 7-MeO (R-17) -COCH_TwoCH (Et)_Two 2-1237 2 6-MeO 7-MeO (R-17) -COCH (Et)_Two 2-1238 26-MeO 7-MeO (R-17) -CONHPh 2-1239 26-MeO 7-MeO (R-17) -CONHCHMePh 2-1240 26-MeO 7-MeO (R-17)- CONHCHMe (4-MeO-Ph) 2-1241 26-MeO 7-MeO (R-17) -CONHCHMe (3,5-diF-Ph) 2-1242 26-MeO 7-MeO (R-17)- CONH (CH_Two)_TwoPh 2-1243 26-MeO 7-MeO (R-17) -CON (Me) Ph 2-1244 26-MeO 7-MeO (R-17) -CON (Et) Ph 2-1245 26-MeO 7-MeO (R-17) -CONMe (4-F-Ph) 2-1246 2 6-MeO 7-MeO (R-17) -CONMe (4-Cl-Ph) 2-1247 26-MeO 7- MeO (R-17) -CONMe (4-MeO-Ph) 2-1248 2 6-MeO 7-MeO (R-17) -CONMe (3,4-diF-Ph) 2-1249 26-MeO 7- MeO (R-17) -CONMe (3,5-diF-Ph) 2-1250 26-MeO 7-MeO (R-17) -CONMe (3,4-diMeO-Ph) 2-1251 26-MeO 7-MeO (R-17) -CONMe (3,5-diMeO-Ph) 2-1252 26-MeO 7-MeO (R-17) -cPn 2-1253 26-MeO 7-MeO (R-17 ) -Ph 2-1254 2 6-MeO 7-MeO (R-17) -Bz 2-1255 26-MeO 7-MeO (R-17)-(CH_Two)_TwoPh 2-1256 26-MeO 7-MeO (R-17) -Me 2-1257 26-MeO 7-MeO (R-17) -iPr 2-1258 26-MeO 7-MeO (R-17) -Bu 2-1259 26-MeO 7-MeO (R-17) -iBu 2-1260 26-MeO 7-MeO (R-17) -sBu 2-1261 26-MeO 7-MeO (R-17) ) -tBu 2-1262 26-MeO 7-MeO (R-17) -iPn 2-1263 26-MeO 7-MeO (R-17) -CH_TwoCH (Et)_Two 2-1264 2 6-MeO 7-MeO (R-17)-(CH_Two)_TwoCH (Et)_Two 2-1265 26-MeO 7-MeO (R-17) -1-Et-Bu 2-1266 26-MeO 7-MeO (R-17) -1-Et-Pn 2-1267 26-MeO 7 -MeO (R-18) -cPn 2-1268 26-MeO 7-MeO (R-18) -Bu 2-1269 26-MeO 7-MeO (R-18) -iBu 2-1270 26-MeO 7-MeO (R-18) -CH_TwoCH (Et)_Two 2-1271 36-MeO 7-MeO 8-MeO (R-1) -CON (Me) Ph 2-1272 36-MeO 7-MeO 8-MeO (R-1) -COCH (Et)_Two 2-1273 3 6-MeO 7-MeO 8-MeO (R-1) -COCH_TwoCH (Et)_Two 2-1274 3 6-MeO 7-MeO 8-MeO (R-1) -iBu 2-1275 3 6-MeO 7-MeO 8-MeO (R-1) -CH_TwoCH (Et)_Two 2-1276 3 6-MeO 7-MeO 8-MeO (R-1) -CON (Me) Ph 2-1277 3 6-MeO 7-MeO 8-MeO (R-1) -CON (Et) Ph 2- 1278 3 6-MeO 7-MeO 8-MeO (R-5) -CONHPh 2-1279 3 6-MeO 7-MeO 8-MeO (R-5) -CONHCHMePh 2-1280 3 6-MeO 7-MeO 8- MeO (R-5) -CONHCHMe (4-MeO-Ph) 2-1281 36-MeO 7-MeO 8-MeO (R-5) -CONHCHMe (3,5-diF-Ph) 2-1282 3 6- MeO 7-MeO 8-MeO (R-5) -CONH (CH_Two)_TwoPh 2-1283 36-MeO 7-MeO 8-MeO (R-5) -CON (Me) Ph 2-1284 36-MeO 7-MeO 8-MeO (R-5) -CON (Et) Ph 2 -1285 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (4-F-Ph) 2-1286 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (4-MeO -Ph) 2-1287 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (3,4-diF-Ph) 2-1288 3 6-MeO 7-MeO 8-MeO (R-5) -CONMe (3,5-diF-Ph) 2-1289 36-MeO 7-MeO 8-MeO (R-5) -CONMe (3,4-diMeO-Ph) 2-1290 36-MeO 7-MeO 8-MeO (R-5) -CONMe (3,5-diMeO-Ph) 2-1291 3 6-MeO 7-MeO 8-MeO (R-5) -cPn 2-1292 3 6-MeO 7-MeO 8 -MeO (R-5) -Ph 2-1293 36-MeO 7-MeO 8-MeO (R-5) -Bz 2-1294 36-MeO 7-MeO 8-MeO (R-5)-(CH_Two)_TwoPh 2-1295 36-MeO 7-MeO 8-MeO (R-5) -iPr 2-1296 36-MeO 7-MeO 8-MeO (R-5) -Bu 2-1297 36-MeO 7- MeO 8-MeO (R-5) -iBu 2-1298 3 6-MeO 7-MeO 8-MeO (R-5) -tBu 2-1299 36-MeO 7-MeO 8-MeO (R-5)- iPn 2-1300 3 6-MeO 7-MeO 8-MeO (R-5) -CH_TwoCH (Et)_Two 2-1301 3 6-MeO 7-MeO 8-MeO (R-5)-(CH_Two)_TwoCH (Et)_Two 2-1302 3 6-MeO 7-MeO 8-MeO (R-5) -1-Et-Bu 2-1303 3 6-MeO 7-MeO 8-MeO (R-5) -1-Et-Pn 2- 1304 3 6-MeO 7-MeO 8-MeO (R-6) -CONHPh 2-1305 3 6-MeO 7-MeO 8-MeO (R-6) -CONHCHMePh 2-1306 3 6-MeO 7-MeO 8- MeO (R-6) -CONHCHMe (4-MeO-Ph) 2-1307 36-MeO 7-MeO 8-MeO (R-6) -CONHCHMe (3,5-diF-Ph) 2-1308 3 6- MeO 7-MeO 8-MeO (R-6) -CONH (CH_Two)_TwoPh 2-1309 3 6-MeO 7-MeO 8-MeO (R-6) -CON (Me) Ph 2-1310 3 6-MeO 7-MeO 8-MeO (R-6) -CON (Et) Ph 2 -1311 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (4-F-Ph) 2-1312 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (4-MeO -Ph) 2-1313 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (3,4-diF-Ph) 2-1314 3 6-MeO 7-MeO 8-MeO (R-6) -CONMe (3,5-diF-Ph) 2-1315 36-MeO 7-MeO 8-MeO (R-6) -CONMe (3,4-diMeO-Ph) 2-1316 36-MeO 7-MeO 8-MeO (R-6) -CONMe (3,5-diMeO-Ph) 2-1317 36-MeO 7-MeO 8-MeO (R-6) -cPn 2-1318 36-MeO 7-MeO 8 -MeO (R-6) -Bz 2-1319 3 6-MeO 7-MeO 8-MeO (R-6)-(CH_Two)_TwoPh 2-1320 36-MeO 7-MeO 8-MeO (R-6) -iPr 2-1321 36-MeO 7-MeO 8-MeO (R-6) -Bu 2-1322 36-MeO 7- MeO 8-MeO (R-6) -iBu 2-1323 36-MeO 7-MeO 8-MeO (R-6) -tBu 2-1324 36-MeO 7-MeO 8-MeO (R-6)- iPn 2-1325 3 6-MeO 7-MeO 8-MeO (R-6) -CH_TwoCH (Et)_Two 2-1326 3 6-MeO 7-MeO 8-MeO (R-6)-(CH_Two)_TwoCH (Et)_Two 2-1327 3 6-MeO 7-MeO 8-MeO (R-6) -1-Et-Bu 2-1328 36-MeO 7-MeO 8-MeO (R-6) -1-Et-Pn 2- 1329 3 6-MeO 7-MeO 8-MeO (R-7) -CON (Me) Ph 2-1330 3 6-MeO 7-MeO 8-MeO (R-8) -CON (Me) Ph 2-1331 3 6-MeO 7-MeO 8-MeO (R-11) -CON (Me) Ph 2-1332 3 6-MeO 7-MeO 8-MeO (R-12) -CON (Me) Ph 2-1333 3 6- MeO 7-MeO 8-MeO (R-14) -COCH_TwoCH (Et)_Two 2-1334 3 6-MeO 7-MeO 8-MeO (R-14) -CONHPh 2-1335 3 6-MeO 7-MeO 8-MeO (R-14) -CONHCHMePh 2-1336 36-MeO 7-MeO 8-MeO (R-14) -CONHCHMe (4-MeO-Ph) 2-1337 3 6-MeO 7-MeO 8-MeO (R-14) -CONHCHMe (3,5-diF-Ph) 2-1338 3 6-MeO 7-MeO 8-MeO (R-14) -CONH (CH_Two)_TwoPh 2-1339 3 6-MeO 7-MeO 8-MeO (R-14) -CON (Me) Ph 2-1340 3 6-MeO 7-MeO 8-MeO (R-14) -CON (Et) Ph 2 -1341 36-MeO 7-MeO 8-MeO (R-14) -CONMe (4-F-Ph) 2-1342 36-MeO 7-MeO 8-MeO (R-14) -CONMe (4-MeO -Ph) 2-1343 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,4-diF-Ph) 2-1344 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,5-diF-Ph) 2-1345 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,4-diMeO-Ph) 2-1346 3 6-MeO 7-MeO 8-MeO (R-14) -CONMe (3,5-diMeO-Ph) 2-1347 36-MeO 7-MeO 8-MeO (R-14) -cPn 2-1348 3 6-MeO 7-MeO 8 -MeO (R-14) -Bz 2-1349 3 6-MeO 7-MeO 8-MeO (R-14)-(CH_Two)_TwoPh 2-1350 36-MeO 7-MeO 8-MeO (R-14) -iPr 2-1351 36-MeO 7-MeO 8-MeO (R-14) -Bu 2-1352 36-MeO 7- MeO 8-MeO (R-14) -sBu 2-1353 3 6-MeO 7-MeO 8-MeO (R-14) -tBu 2-1354 36-MeO 7-MeO 8-MeO (R-14)- iPn 2-1355 3 6-MeO 7-MeO 8-MeO (R-14) -CH_TwoCH (Et)_Two 2-1356 3 6-MeO 7-MeO 8-MeO (R-14)-(CH_Two)_TwoCH (Et)_Two 2-1357 3 6-MeO 7-MeO 8-MeO (R-14) -1-Et-Bu 2-1358 3 6-MeO 7-MeO 8-MeO (R-14) -1-Et-Pn 2- 1359 3 6-MeO 7-MeO 8-MeO (R-15) -CON (Me) Ph 2-1360 3 6-MeO 7-MeO 8-MeO (R-16) -CON (Me) Ph 2-1361 3 6-MeO 7-MeO 8-MeO (R-17) -CON (Me) Ph 2-1362 2 6-Me0 7-OH (R-6) -CON (Me) Ph 2-1363 2 6-Me0 7- OH (R-6) -COCH (Et)_Two 2-1364 2 6-Me0 7-OH (R-6) -COCH_TwoCH (Et)_Two 2-1365 26-Me0 7-OH (R-6) -iBu 2-1366 26-Me0 7-OH (R-6) -CH_TwoCH (Et)_Two 2-1367 26-Me0 7-OH (R-6)-(CH_Two)_TwoCH (Et)_Two 2-1368 26-Me0 7-OH (R-14) -CON (Me) Ph 2-1369 26-Me0 7-OH (R-14) -COCH (Et)_Two 2-1370 2 6-Me0 7-OH (R-14) -COCH_TwoCH (Et)_Two 2-1371 2 6-Me0 7-OH (R-14) -iBu 2-1372 26-Me0 7-OH (R-14) -CH_TwoCH (Et)_Two 2-1373 2 6-Me0 7-OH (R-14)-(CH_Two)_TwoCH (Et)_Two 2-1374 2 6-OH 7-MeO (R-1) -CON (Me) Ph 2-1375 2 6-OH 7-MeO (R-1) -COCH (Et)_Two 2-1376 2 6-OH 7-MeO (R-1) -COCH_TwoCH (Et)_Two 2-1377 26-OH 7-MeO (R-1) -iBu 2-1378 26-OH 7-MeO (R-1) -CH_TwoCH (Et)_Two 2-1379 2 6-OH 7-MeO (R-1) -CON (Me) Ph 2-1380 26-OH 7-MeO (R-1) -COCH (Et)_Two 2-1381 2 6-OH 7-MeO (R-1) -COCH_TwoCH (Et)_Two 2-1382 26-OH 7-MeO (R-6) -CON (Me) Ph 2-1383 26-OH 7-MeO (R-6) -COCH (Et)_Two 2-1384 2 6-OH 7-MeO (R-6) -COCH_TwoCH (Et)_Two 2-1385 26-OH 7-MeO (R-6) -iBu 2-1386 26-OH 7-MeO (R-6) -CH_TwoCH (Et)_Two 2-1387 2 6-OH 7-MeO (R-6) -CH_TwoCH_TwoCH (Et)_Two 2-1388 26-OH 7-MeO (R-14) -CON (Me) Ph 2-1389 26-OH 7-MeO (R-14) -COCH_TwoCH (Et)_Two 2-1390 2 6-OH 7-MeO (R-14) -iBu 2-1391 26-OH 7-MeO (R-14) -CH_TwoCH (Et)_Two 2-1392 26-OH 7-MeO (R-15) -CON (Me) Ph 2-1393 26-OH 7-MeO (R-16) -CON (Me) Ph 2-1394 26-AcO 7 -AcO (R-6) -CON (Me) Ph 2-1395 2 6-AcO 7-AcO (R-14) -CON (Me) Ph 2-1396 1 7-Me0 (R-3) -CON (Me ) Ph 2-1397 1 7-Me0 (R-3) -CON (Et) Ph 2-1398 1 7-Me0 (R-3) -CONMe (3-F-Ph) 2-1399 1 7-Me0 (R -3) -CONEt (3-F-Ph) 2-1400 1 7-Me0 (R-3) -CONMe (3,5-diF-Ph) 2-1401 17-Me0 (R-3) -CONEt ( 3,5-diF-Ph) 2-1402 1 7-Me0 (R-6) -CON (Me) Ph 2-1403 17-Me0 (R-6) -CON (Et) Ph 2-1404 1 7- Me0 (R-6) -CONMe (3-F-Ph) 2-1405 1 7-Me0 (R-6) -CONEt (3-F-Ph) 2-1406 17-Me0 (R-6) -CONMe (3,5-diF-Ph) 2-1407 1 7-Me0 (R-6) -CONEt (3,5-diF-Ph) 2-1408 26-MeO 7-Me0 (R-6) -CON ( Me) Ph 2-1409 2 6-MeO 7-Me0 (R-6) -CON (Et) Ph 2-1410 26-MeO 7-Me0 (R-6) -CONMe (3-F-Ph) 2- 1411 26-MeO 7-Me0 (R-6) -CONEt (3-F-Ph) 2-1412 26-MeO 7-Me0 (R-6) -CONMe (3,5-diF-Ph) 2- 1413 2 6-MeO 7-Me0 (R-6) -CONEt (3,5-diF-Ph)  In Tables 1 and 2 above, compounds suitable as pharmaceuticals
Are exemplified compound numbers: 1-57, 1-179, 1-181, 1-183, 1-185,
1-381, 1-383, 1-385, 1-387, 1-538, 1-540, 1-542, 1
-544, 1-770, 1-772, 1-774, 1-776, 1-827, 1-828, 1-
833, 1-977 to 1-981, 1-983, 1-1019, 1-1134, 1-1136,
1-1138, 1-1140, 1-1246, 1-1284, 1-1286, 1-1287, 1-1
289, 1-1313, 1-1315, 1-1316, 1-1318,1-1351, 1-135
4, 1-1359, 1-1364, 1-1365, 1-1368, 1-1372-1-1379,
 1-1381-1-1383 and 1-1384-1-1395
More preferred compounds include, for example, compound numbers: 1-57, 1-181, 1-183, 1-381, 1-383,
 1-385, 1-387, 1-538,1-540, 1-542, 1-544, 1-770, 1
-772, 1-774, 1-776, 1-827, 1-828, 1-833, 1-977 ~ 1-
981, 1-983, 1-1019, 1-1134, 1-1136, 1-1138, 1-114
0, 1-1246, 1-1284, 1-1286, 1-1287, 1-1289, 1-1313,
 1-1315, 1-1316, 1-1318, 1-1351, 1-1354, 1-1359, 1
-1364, 1-1365, 1-1368, 1-1372-1-1379, 1-1381-1-1
383 and 1-1384 to 1-1395, which are more preferable.
Examples of the compounds include: Exemplified compound numbers: 1-57, 1-381, 1-383, 1-385, 1-538,
1-540, 1-542, 1-770, 1-772, 1-774, 1-827, 1-828, 1
-833, 1-977 to 1-981, 1-983, 1-1019, 1-1134, 1-1136,
 1-1138, 1-1140, 1-1284, 1-1286, 1-1287, 1-1289, 1
-1313, 1-1315, 1-1316, 1-1318, 1-1351, 1-1354, 1-1
359, 1-1368, 1-1372-1-1379, 1-1381-1-1383 and 1-1
384 to 1-1395, and the most preferred compound
Compound No. 1-827: 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroxy
Norin-3-carboxylic acid N-methyl-N-phenyla
Mido, Compound No. 1-828: 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroxy
Norin-3-carboxylic acid N-ethyl-N-phenyla
Mido, Compound No. 1-833: 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroxy
Norin-3-carboxylic acid N-methyl-N- (3,5-
Difluorophenyl) amide, Compound No. 1-977: 6,7-dimethoxy-1- (4-methoxy)
(Xyphenyl) -4-oxo-1,4-dihydroquinolyl
3-Carboxylic acid N-methyl-N-phenylamido
Compound number 1-978: 6,7-dimethoxy-1- (4-meth
(Xyphenyl) -4-oxo-1,4-dihydroquinolyl
3-Carboxylic acid N-ethyl-N-phenylamido
Compound number 1-979: 1- (4-methoxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydro-
Quinoline-3-carboxylic acid N-methyl-N- (4-f
Fluorophenyl) amide, Compound No. 1-981: 1- (4-methoxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydro-
Quinoline-3-carboxylic acid N-methyl-N- (4-meth
Toxiphenyl) amide, Compound No. 1-983: 6,7-dimethoxy-1- (4-meth
(Toxyphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carboxylic acid N-methyl-N- (3,5-di
Fluorophenyl) amide, Compound No. 1-1136: 1- (3,4-dimethoxyphenyl)
Ru) -6,7-dimethoxy-4-oxo-1,4-dihi
Dro-quinoline-3-carboxylic acid N-methyl-N-
(4-fluorophenyl) amide, Compound No. 1-1138: 1- (3,4-dimethoxyphenyl)
Ru) -6,7-dimethoxy-4-oxo-1,4-dihi
Dro-quinoline-3-carboxylic acid N-methyl-N-
(4-methoxyphenyl) amide, Compound No. 1-1286: 1- (4-methoxyphenyl)-
6,7,8-trimethoxy-4-oxo-1,4-dihi
Dro-quinoline-3-carboxylic acid N-methyl-N-
(4-fluorophenyl) amide, Compound No. 1-1287: 1- (4-methoxyphenyl)-
6,7,8-trimethoxy-4-oxo-1,4-dihi
Dro-quinoline-3-carboxylic acid N-methyl-N-
(4-methoxyphenyl) amide, Compound No. 1-1315: 1- (3,4-dimethoxyphenyl)
) -6,7,8-trimethoxy-4-oxo-1,4
-Dihydro-quinoline-3-carboxylic acid N-methyl-
N- (4-fluorophenyl) amide, Compound No. 1-1316: 1- (3,4-dimethoxyphenyl)
) -6,7,8-trimethoxy-4-oxo-1,4
-Dihydro-quinoline-3-carboxylic acid N-methyl-
N- (4-methoxyphenyl) amide, Compound No. 1-1373: 6,7-dimethoxy-1- (4-meth
(Toxyphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carboxylic acid N-methyl-N- (3-fluoro
Rophenyl) amide, Compound No. 1-1375: 7-methoxy-1- (4-methoxy)
Phenyl) -4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-methyl-N-phenylamide, Compound No. 1-1384: 6,7-dimethoxy-1- (4-meth
(Toxyphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carboxylic acid N-ethyl-N- (3,5-di
Fluorophenyl) amide, Compound No. 1-1385: 6,7-dimethoxy-1- (4-h
(Droxyphenyl) -4-oxo-1,4-dihydroxy
Norin-3-carboxylic acid N-ethyl-N- (3,5-
Difluorophenyl) amide, Compound No. 1-1386: 6,7-dimethoxy-1- (4-meth
(Toxyphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carboxylic acid N-methyl-N- (3-fluoro
Compound number 1-1387: 7-methoxy-1- (4-methoxy)
Phenyl) -4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-methyl-N-phenylamide, Compound No. 1-1388: 7-methoxy-1- (4-methoxy
Phenyl) -4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-ethyl-N- (3,5-difluoro
L-phenyl) amide, compound number 1-1389: 1- (4-methoxyphenyl) -7
-Dimethoxy-4-oxo-1,4-dihydroquinoline
-3-carboxylic acid N-ethyl-N-phenylamide, Compound No. 1-1390: 7-methoxy-1- (4-methoxy
Phenyl) -4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-methyl-N- (3-fluorophene
Nil) amide, Compound No. 1-1391: 7-methoxy-1- (4-hydroxy
(Ciphenyl) -4-oxo-1,4-dihydroquinoline
-3-carboxylic acid N-methyl-N-phenylamide, compound No. 1-1392: 7-methoxy-1- (4-hydroxy
(Ciphenyl) -4-oxo-1,4-dihydroquinoline
-3-carboxylic acid N-ethyl-N- (3,5-difur
Orophenyl) amide, Compound No. 1-1393: 1- (4-hydroxyphenyl)-
7-dimethoxy-4-oxo-1,4-dihydroquinol
3-Carboxylic acid N-ethyl-N-phenylamido
Compound number 1-1394: 7-methoxy-1- (4-hydroxy
(Ciphenyl) -4-oxo-1,4-dihydroquinoline
-3-carboxylic acid N-methyl-N-phenylamide,
And Compound No. 1-1395: 7-methoxy-1- (4-hydroxy
(Ciphenyl) -4-oxo-1,4-dihydroquinoline
-3-carboxylic acid N-methyl-N- (3-fluorofuran
Enyl) amide.

In Tables 1 and 2 above, compounds suitable as ileal bile acid transporter inhibitors are exemplified by compound numbers: 1-57, 1-179, 1-181, 1-183, 1-185 ,
1-381, 1-383, 1-385, 1-387, 1-538, 1-540, 1-542, 1
-544, 1-646, 1-770, 1-772, 1-774, 1-776, 1-827, 1-
828, 1-833, 1-977 to 1-981, 1-983, 1-1019, 1-1134, 1
-1136, 1-1138, 1-1140, 1-1246, 1-1284, 1-1286, 1-1
287, 1-1289, 1-1313, 1-1315, 1-1316, 1-1318, 1-135
1, 1-1354, 1-1359, 1-1364, 1-1365, 1-1368, 1-1369,
1-1372 to 1-1379, 1-1381 to 1-1383, 1-1384 to 1-1395, 2
-181, 2-183, 2-383, 2-385, 2-411, 2-418, 2-540, 2-
542, 2-562, 2-572, 2-646, 2-668, 2-797, 2-799, 2-
809,2-812, 2-1004, 2-1006, 2-1032, 2-1041, 2-1161,
2-1163, 2-1183, 2-1190,2-1192, 2-1193, 2-1274〜2-
1276, 2-1311, 2-1312, 2-1322, 2-1325, 2-1327,2-133
9, 2-1341, 2-1342, 2-1355, 2-1357, 2-1374, 2-1382,
2-1388 and 2-1396 to 2-1413 can be mentioned, and more preferable compounds are exemplified compound numbers: 1-57, 1-181, 1-183, 1-381, 1-383,
1-385, 1-387, 1-538,1-540, 1-542, 1-544, 1-646, 1
-770, 1-772, 1-774, 1-776, 1-827, 1-828, 1-833, 1-
977〜1-981, 1-983, 1-1019, 1-1134, 1-1136, 1-1138,
1-1140, 1-1246, 1-1284, 1-1286, 1-1287, 1-1289, 1
-1313, 1-1315, 1-1316, 1-1318, 1-1351, 1-1354, 1-1
359, 1-1364, 1-1365, 1-1368, 1-1369, 1-1372-1-137
9, 1-1381 to 1-1383, 1-1384 to 1-1395, 2-181, 2-183, 2
-383, 2-385, 2-411, 2-418, 2-540, 2-542, 2-562, 2-
572, 2-646, 2-668, 2-797, 2-799, 2-809, 2-812, 2-1
004, 2-1006, 2-1032, 2-1041, 2-1161, 2-1163, 2-118
3, 2-1190, 2-1192, 2-1193, 2-1274, 2-1275, 2-1276,
2-1311, 2-1312, 2-1322, 2-1325, 2-1327, 2-1339, 2
-1341, 2-1342, 2-1355, 2-1357, 2-1374, 2-1382, 2-1
388 and 2-1396 to 2-1413, and more preferable compounds are exemplified compound numbers: 1-57, 1-381, 1-383, 1-385, 1-538,
1-540, 1-542, 1-646, 1-770, 1-772, 1-774, 1-827, 1
-828, 1-833, 1-977 to 1-981, 1-983, 1-1019, 1-1134,
1-1136, 1-1138, 1-1140, 1-1284, 1-1286, 1-1287, 1-
1289, 1-1313, 1-1315, 1-1316, 1-1318, 1-1351, 1-13
54, 1-1359, 1-1368, 1-1369, 1-1372 to 1-1379, 1-1381
~ 1-1383, 1-1384 ~ 1-1395, 2-383, 2-385, 2-540, 2-5
42, 2-668, 2-797, 2-799, 2-1004, 2-1006, 2-1032, 2-
1161, 2-1163, 2-1183, 2-1190, 2-1276, 2-1311, 2-13
12, 2-1322, 2-1325, 2-1327, 2-1339, 2-1341, 2-134
2, 2-1355 and 2-1396 to 2-1413, and the most preferable compound is the compound number 1-646: 7-methoxy-1-phenyl-4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-methyl-N-phenylamide, Compound No. 1-827: 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, Compound No. 1-828: 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, compound number 1-833: 1- (4-hydroxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-
Compound number 1-977: 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, Compound No. 1-978: 6,7-Dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, Compound No. 1-979 : 1- (4-methoxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydro-
Quinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, Compound No. 1-981: 1- (4-methoxyphenyl)-
6,7-dimethoxy-4-oxo-1,4-dihydro-
Quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, Compound No. 1-983: 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydro Quinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, Compound No. 1-1136: 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1 , 4-Dihydro-quinoline-3-carboxylic acid N-methyl-N-
(4-fluorophenyl) amide, Compound No. 1-1138: N-methyl 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylate -N-
(4-methoxyphenyl) amide, Compound No. 1-1286: 1- (4-methoxyphenyl)-
6,7,8-Trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N-
(4-fluorophenyl) amide, Compound No. 1-1287: 1- (4-methoxyphenyl)-
6,7,8-Trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N-
(4-methoxyphenyl) amide, Compound No. 1-1315: 1- (3,4-dimethoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4
-Dihydro-quinoline-3-carboxylic acid N-methyl-
N- (4-fluorophenyl) amide, compound number 1-1316: 1- (3,4-dimethoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4
-Dihydro-quinoline-3-carboxylic acid N-methyl-
N- (4-methoxyphenyl) amide, compound number 1-1373: 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl- N- (3-fluorophenyl) amide, Compound No. 1-1375: 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-methyl-N-phenylamide, compound number 1-1384: 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N -Ethyl-N- (3,5-difluorophenyl) amide, Compound No. 1-1385: 6,7-dimethoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid The acid N-ethyl-N- (3,5-
Compound No. 1-1386: 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3- Compound No. 1-1387: 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-methyl-N-phenylamide, Compound No. 1-1388: 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, Compound No. 1-1389: 1- (4-methoxyphenyl) -7
-Dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, Compound No. 1-1390: 7-methoxy-1- (4-methoxyphenyl) -4-oxo- 1,4-dihydroquinoline-
3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, Compound No. 1-1391: 7-methoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3- Carboxylic acid N-methyl-N-phenylamide, Compound No. 1-1392: 7-methoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N -(3,5-difluorophenyl) amide, compound number 1-1393: 1- (4-hydroxyphenyl)-
7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, compound number 1-1394: 7-methoxy-1- (4-hydroxyphenyl) -4-oxo -1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, compound number 1-1395: 7-methoxy-1- (4-hydroxyphenyl) -4-oxo-1,4-dihydroquinoline -3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, compound number 2-1004: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-methyl 2-dihydroquinoline-3-carboxylate
N- (4-fluorophenyl) amide, Compound No. 2-006: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-methyl 2-dihydroquinoline-3-carboxylate
N- (4-methoxyphenyl) amide, compound number 2-1161: 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3- Carboxylic acid N-methyl-N- (4-fluorophenyl) amide, Compound No. 2-1163: 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7-dimethoxy-2-oxo-1,2 -Dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, Compound No. 2-1311: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7,8-trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, Compound No. 2-1312: 1- (4 -Methoxyphenyl) -4
-Hydroxy-6,7,8-trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, Compound No. 2-1339: 1- (3 , 4-Dimethoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2
-Oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, compound number 2-1341: 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7,8- Trimethoxy-2
-Oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, Compound No. 2-1342: 1- (3,4-dimethoxyphenyl) -4-hydroxy-6 , 7,8-Trimethoxy-2
-Oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, compound number 2-1396: 1- (4-hydroxyphenyl)-
4-hydroxy-7-methoxy-2-oxo-1,2-
Dihydroquinoline-3-carboxylic acid N-methyl-N-
Phenylamide, Compound No. 2-1397: 1- (4-hydroxyphenyl)-
4-hydroxy-7-methoxy-2-oxo-1,2-
Dihydroquinoline-3-carboxylic acid N-ethyl-N-
Phenylamide, Compound No. 2-1398: 1- (4-hydroxyphenyl)-
4-hydroxy-7-methoxy-2-oxo-1,2-
Dihydroquinoline-3-carboxylic acid N-methyl-N-
(3-fluorophenyl) amide, Compound No. 2-1399: 1- (4-hydroxyphenyl)-
4-hydroxy-7-methoxy-2-oxo-1,2-
Dihydroquinoline-3-carboxylic acid N-ethyl-N-
(3-fluorophenyl) amide, Compound No. 2-1400: 1- (4-hydroxyphenyl)-
4-hydroxy-7-methoxy-2-oxo-1,2-
Dihydroquinoline-3-carboxylic acid N-methyl-N-
(3,5-difluorophenyl) amide, Compound No. 2-1401: 1- (4-hydroxyphenyl)-
4-hydroxy-7-methoxy-2-oxo-1,2-
Dihydroquinoline-3-carboxylic acid N-ethyl-N-
(3,5-difluorophenyl) amide, Compound No. 2-1402: 1- (4-methoxyphenyl) -4
-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, Compound No. 2-1403: 1- (4-methoxyphenyl) -4
-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, Compound No. 2-1404: 1- (4-methoxyphenyl) -4
-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-
(3-fluorophenyl) amide, compound number 2-1405: 1- (4-methoxyphenyl) -4
-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N-
(3-fluorophenyl) amide, Compound No. 2-1406: 1- (4-methoxyphenyl) -4
-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-
(3,5-difluorophenyl) amide, compound number 2-1407: 1- (4-methoxyphenyl) -4
-Hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N-
(3,5-difluorophenyl) amide, compound number 2-1408: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-methyl 2-dihydroquinoline-3-carboxylate
N-phenylamide, Compound No. 2-1409: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-ethyl 2-dihydroquinoline-3-carboxylate
N-phenylamide, Compound No. 2-1410: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-methyl 2-dihydroquinoline-3-carboxylate
N- (3-fluorophenyl) amide, compound number 2-1411: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-ethyl 2-dihydroquinoline-3-carboxylate
N- (3-fluorophenyl) amide, Compound No. 2-1412: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-methyl 2-dihydroquinoline-3-carboxylate
N- (3,5-difluorophenyl) amide, and compound number 2-1413: 1- (4-methoxyphenyl) -4
-Hydroxy-6,7-dimethoxy-2-oxo-1,
N-ethyl 2-dihydroquinoline-3-carboxylate
N- (3,5-difluorophenyl) amide can be mentioned.

[0159]

BEST MODE FOR CARRYING OUT THE INVENTION The general formulas (I) and (I) of the present invention
The compound having I) can be produced according to the method described below.

The compound having the general formula (Ia) of the present invention can be produced by a method similar to the method for producing the compound having the general formula (I).

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

[0162]

Embedded image

In the above formula, R¹, R^Two, R^Three, R^Four, R^Five,
And R⁶Has the same meaning as described above, and R^1a, R^2a,
R^3a, R^4a, R^5aAnd R^6aIs R¹, R^Two, R^Three, R^Four, R
^Five, And R⁶Amino, ar
Droxy and / or carboxy groups may be protected
Other R which is an amino, hydroxy and / or carboxy group
¹, R^Two, R^Three, R^Four, R^Five, And R⁶Group in the definition of group
Represents the same group as ⁹And R^{9 '}Are the same or different
And a hydrogen atom, a hydroxy group, a lower alkoxy group or
Represents a halogen atom;^TenIs a hydrogen atom or a hydroxy group
Represents a protecting group of¹¹Is a hydrogen atom, a hydroxy group or
Represents a lower alkoxy group, W is usually a nucleophilic residue
There is no particular limitation as long as it is a leaving group.
Halogen atoms such as iodine, bromine and iodine; methoxy, eth
Lower alkoxy groups such as xyl; trichloromethyloxy
Trihalogenomethyloxy groups such as methane; methanesulfo
Lower alkyl such as niloxy and ethanesulfonyloxy
Cansulfonyloxy group; trifluoromethanesulfoni
Like ruoxy and pentafluoroethanesulfonyloxy
Halogeno lower alkane sulfonyloxy group;
Sulfonyloxy, p-toluenesulfonyloxy,
aryls such as p-nitrobenzenesulfonyloxy
Sulfonyloxy groups can be mentioned, most preferably
Is a halogen atom and a lower alkoxy group.

In the above, the “protecting group” of the “optionally protected amino group” in the definition of R ^6a is not particularly limited as long as it is an amino group protecting group used in the field of synthetic organic chemistry. For example, lower aliphatic acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl,
"Aliphatic acyls" such as halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; and lower alkylcarbonyl groups substituted with lower alkoxy such as methoxyacetyl; Is bonded to a C ₇ -C ₁₁ aromatic acyl group, 2-bromobenzoyl,
- halogeno C ₇ -C ₁₁ aromatic acyl group such as chloro benzoyl, 2,4,6-trimethylbenzoyl, 4-C ₇ -C such substituted with lower alkyl as toluoyl ₁₁
An aromatic acyl group, 4-C ₇ -C ₁₁ aromatic acyl group such substituted lower alkoxy as anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl C ₇ -C ₁₁ aromatic that such substituted with nitro as yl family acyl group, 2- (methoxycarbonyl) C ₇ -C ₁₁ aromatic acyl group substituted with a lower alkoxycarbonyl as benzoyl, 4-phenylbenzoyl ants like yl - C ₇ substituted by Le -C ₁₁
"Aromatic acyls" such as aromatic acyl groups; lower alkoxycarbonyl substituted with halogen or tri-lower alkylsilyl such as the lower alkoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl "Alkoxycarbonyls" such as a group; "alkenyloxycarbonyls" such as vinyloxycarbonyl and allyloxycarbonyl;
"One or two lower alkoxy or nitro groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, Aralkyloxycarbonyls whose aryl ring may be substituted "; tri-lower alkylsilyls such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl Groups substituted by three groups selected from aryl, lower alkyl, aryl such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl, etc. Le "silyl ethers" such groups; benzyl,
Substituted with one to three aryl groups such as phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl group, 4-methylbenzyl, 2,4,6
-Trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl,
Lower alkyl such as bis (2-nitrophenyl) methyl, piperonyl, lower alkoxy, nitro, halogen,
"Aralkyls" such as lower alkyl groups substituted with one to three aryl groups having an aryl ring substituted with cyano;
Or N, N-dimethylaminomethylene, benzylidene,
4-methoxybenzylidene, 4-nitrobenzylidene,
A "substituted methylene group forming a Schiff base", such as salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenylmethylene; An acyl group, a C ₇ -C ₁₁ aromatic acyl group or an alkoxycarbonyl group, more preferably a lower alkoxycarbonyl group, most preferably a t-butoxycarbonyl group.

In the above, R ^1a , R ^2a , R ^3a , R ^4a ,
The “protecting group” of the “optionally protected hydroxy group” in the definition of R ^5a and R ^6a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of organic synthetic chemistry. Has the same meaning as
A lower aliphatic acyl group, a C ₇ -C ₁₁ aromatic acyl group, a lower alkoxycarbonyl group or a (lower alkoxy) methyl group, more preferably a lower aliphatic acyl group or a (lower alkoxy) methyl group; Most preferably, it is an acetyl group or a methoxymethyl group.

In the above, the “protecting group” of the “optionally protected carboxy group” in the definition of R ^6a is not particularly limited as long as it is a carboxy group protecting group used in the field of synthetic organic chemistry. For example, it has the same meaning as described above, and is preferably a lower alkyl group or a benzyl group.

The step A1 is a step for producing the compound (II), in which the compound having the general formula (III) is prepared in the presence or absence (preferably in the absence) of an inert solvent.
After reacting with a compound having the general formula (IV), the amino, hydroxy and / or carboxy group protecting groups in R ^1a , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a are optionally removed. Done.

Compound (I) in the absence of an inert solvent
The reaction temperature for reacting II) with compound (IV) is
It usually varies from 150 ° C to 350 ° C, depending on the starting compound.
° C (preferably 200 ° C to 300 ° C).

Compound (I) in the absence of an inert solvent
The reaction time for reacting II) with compound (IV) is as follows:
The time is usually 30 minutes to 24 hours (preferably 1 hour to 12 hours), depending on the starting compound, reaction temperature and the like.

Compound (II) in the presence of an inert solvent
When reacting I) with compound (IV), the inert solvent used is not particularly limited as long as it is inert to this reaction, and examples thereof include hexane, heptane, ligroin, and petroleum ether. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene, xylene and triisopropylbenzene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; Methyl acetate, acetic acid Esters such as ethyl, propyl acetate, butyl acetate, diethyl carbonate;
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t -Butanol, isoamyl alcohol, diethylene glycol,
Alcohols such as glycerin, octanol, cyclohexanol, methyl cellosolve; acetonitrile;
Nitriles such as isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; and preferably aromatic hydrocarbons. (Most preferably, triisopropylbenzene).

Compound (II) in the presence of an inert solvent
The reaction temperature at the time of reacting I) with the compound (IV) varies depending on the starting compound, the solvent and the like, but is usually from 150 ° C to 300 ° C (preferably from 200 ° C to 250 ° C).

Compound (II) in the presence of an inert solvent
The reaction time for the reaction of I) with the compound (IV) varies depending on the starting compound, solvent, reaction temperature and the like.
0 minutes to 24 hours (preferably 1 hour to 12 hours)
It is.

The removal of the protecting groups for the amino, hydroxy and carboxy groups depends on the type of the protecting group.
(Protective Groups in Organic Synthesis), John Wi
ley & Sons: JFWMcOmis, (Protective Groups in Or
ganicChemistry), by the method described in Plenum Press as follows.

When the amino-protecting group is a silyl, a compound which generates a fluorine anion, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride, is usually used. And removed by treating with.

The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Is preferred.

The reaction temperature and the reaction time are not particularly limited, but the reaction is usually carried out at 0 ° C. to 50 ° C. for 10 minutes to 18 hours.

When the protecting group for the amino group is an aliphatic acyl, an aromatic acyl, an alkoxycarbonyl or a substituted methylene group forming a Schiff base, an acid or a base is added in the presence of an aqueous solvent. Can be removed.

The acid used in the above reaction is not particularly limited as long as it is a commonly used acid and does not inhibit the reaction. Examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, and the like.
Inorganic acids such as perchloric acid, phosphoric acid and nitric acid, preferably hydrochloric acid.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound. Preferably, the base is an alkali metal such as lithium carbonate, sodium carbonate and potassium carbonate. Carbonates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; ammonia water ,
Ammonia, such as concentrated ammonia-methanol.

The solvent used in the above reaction is not particularly limited as long as it is a solvent used in a usual hydrolysis reaction. Examples thereof include methanol, ethanol, n-propanol and isopropanol. Alcohols such as toluene, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve;
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether;
Water; a mixed solvent of water and the above organic solvent; and preferably ethers (most preferably dioxane).

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the acid or base to be used, and are not particularly limited. Let react for ~ 10 hours.

When the amino-protecting group is an aralkyl or aralkyloxycarbonyl, it is usually brought into contact with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). The method of removing or using an oxidizing agent is preferred.

The solvent used for the removal by catalytic reduction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; methyl acetate,
Esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; Such organic acids; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers,
Organic acids or water (most preferably alcohols or organic acids).

The catalyst used for the removal by the catalytic reduction is not particularly limited as long as it is generally used for the catalytic reduction reaction.
Carbon, Raney-nickel, platinum oxide, platinum black, rhodium-
Aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate are used.

Although the pressure is not particularly limited, it is usually 1 to 1
Performed at 0 atm.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
For 5 minutes to 24 hours.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.

Examples of such organic solvents include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, and the like. Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and sulfoxides such as dimethyl sulfoxide; And preferably halogenated hydrocarbons, ethers or sulfoxides (most preferably halogenated hydrocarbons or sulfoxides).

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

When the amino-protecting group is an aralkyl, the protecting group can be removed using an acid.

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid,
Inorganic acids such as phosphoric acid; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and organic acids such as trifluoromethanesulfonic acid; zinc chloride; Tin chloride, boron trichloride, boron trifluoride,
A Lewis acid such as boron tribromide; an acidic ion exchange resin; preferably an inorganic or organic acid (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid).

The inert solvent used in the first-stage reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol. , Isobutanol, t-butanol, Soamiruaruko - le, diethylene glycol, glycerin, octanol, cyclohexanol, alcohol such as methyl cellosolve - Le acids;
Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; water; or water or a mixed solvent of the above solvents; preferably ethers, alcohols or water (most preferably Is dioxane, tetrahydrofuran, ethanol or water.

The reaction temperature depends on the starting compound, the acid used,
Although it depends on the solvent and the like, it is usually from -20 ° C to the boiling point (preferably 0 ° C to 100 ° C).

The reaction time depends on the starting compound, the acid used,
The time is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours), although it depends on the solvent, the reaction temperature and the like.

When the amino-protecting group is an alkenyloxycarbonyl, the amino-protecting group is usually substituted aliphatic methylene, aromatic acyl, alkoxycarbonyl or a substituted methylene group forming a Schiff base. It is carried out by treating with a base in the same manner as the conditions for the removal reaction in the case of a group.

In the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be performed with few side reactions.

When a silyl is used as a protecting group for a hydroxy group, a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride is usually formed. Treated with compounds or
Or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p
-It can be removed by treatment with an organic acid such as toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid.

In the case of removal by fluorine anion,
The reaction may be accelerated by adding organic acids such as formic acid, acetic acid and propionic acid.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Preferably, diethyl ether or diisopropyl ether is used.
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water;

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
(Preferably 10 ° C. to 50 ° C.) for 1 hour to 24 hours.

When the hydroxy-protecting group is an aralkyl or aralkyloxycarbonyl, it is usually brought into contact with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). The method of removing or using an oxidizing agent is preferred.

The solvent used for the removal by catalytic reduction is not particularly limited as long as it does not participate in the present reaction, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; toluene, benzene , Xylene and other aromatic hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; methanol; Ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoric triamide; fatty acids such as formic acid and acetic acid; water; a mixed solvent of the above solvents; Preferably they are alcohols (most preferably methanol).

As the catalyst used for the removal by the catalytic reduction, if it is usually used for the catalytic reduction reaction,
Although not particularly limited, for example, palladium-carbon, palladium-black, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium- Carbon.

The pressure is not particularly limited, but is usually 1 to 1
Performed at 0 atm.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
(Preferably 20 ° C. to 70 ° C.) for 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the reaction, but is preferably a water-containing organic solvent.

As such an organic solvent, ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; diethyl ether, tetrahydrofuran; Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide.

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and the reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

Further, in liquid ammonia or methano-
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
-78 ° C in alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve.
At ~ 0 ° C, it can also be removed by the action of alkali metals such as metallic lithium and metallic sodium.

Further, it can be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide in a solvent.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride; or acetonitrile. Nitriles;
A mixed solvent of the above solvents.

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the like, but are usually carried out at 0 ° C. to 50 ° C. for 5 minutes to 72 hours.

In the case where the reaction substrate has a sulfur atom,
Preferably, aluminum chloride-sodium iodide is used.

When the protecting group for the hydroxy group is an aliphatic acyl, an aromatic acyl or an alkoxycarbonyl group, it is removed by treating with a base in a solvent.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, and examples thereof include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide; Metal alkoxides such as sodium ethoxide and potassium t-butoxide; ammonia such as aqueous ammonia and concentrated ammonia-methanol; preferably alkali metal hydroxides, metal alkoxides or ammonia (Most preferably alkali metal hydroxides or metal alkoxides) It is the earth).

The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; water; mixed solvents of the above solvents are preferred.

The reaction temperature and reaction time vary depending on the starting compound, the base used, the solvent and the like, and are not particularly limited.
In order to suppress side reactions, usually -20 ° C to 150 ° C
For 1 to 10 hours.

When the protecting group for the hydroxy group is an alkoxymethyl, a tetrahydropyranyl, a tetrahydrothiopyranyl, a tetrahydrofuranyl, a tetrahydrothiofuranyl or a substituted ethyl, it is usually used in a solvent. , By treatment with an acid.

The acid used is not particularly limited as long as it is generally used as a Bronsted acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or Bronsted acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and organic acids such as p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cations such as Dowex 50W Exchange resins can also be used.

The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Such ethers; methanol, ethanol
Alcohols such as toluene, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; a mixed solvent of the above solvents; preferably ethers (most preferably tetrahydrofuran) or alcohols ( Most preferably, methanol).

The reaction temperature and the reaction time vary depending on the starting compound, the acid used, the solvent and the like, but are usually from -10 ° C to 200 ° C (preferably 0 ° C to 150 ° C) for 5 minutes to 48 hours. (Preferably 30 minutes to 10 hours).

When the protecting group for the hydroxy group is an alkenyloxycarbonyl, the conditions for the removal reaction when the protecting group for the hydroxy group is the above-mentioned aliphatic acyl, aromatic acyl or alkoxycarbonyl are usually used. In the same manner as in the above, it is achieved by treating with a base.

In the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate is simple, and the reaction is carried out with few side reactions. Can be.

When the protecting group for the carboxy group is a lower alkyl group or a lower alkyl group substituted with one to three aryls which may be substituted with lower alkyl, lower alkoxy, nitro, halogen or cyano, This is achieved by treating with a base in the same manner as in the removal reaction when the hydroxy-protecting group is an aliphatic acyl, an aromatic acyl or an alkoxycarbonyl.

The removal of the protecting group for the amino, hydroxy and / or carboxy groups can be carried out in any order by sequentially performing the desired removal reactions.

After completion of the reaction, the desired compound (II)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step A2 is a step of producing a compound having the general formula (VI), and in the presence or absence (preferably in the absence) of an inert solvent, a compound having the general formula (V) Is reacted with the compound (IV), if necessary, by protecting the hydroxy group at the 4-position of the quinoline ring. The same is done.

The method for protecting the hydroxy group at the 4-position of the quinoline ring varies depending on the type of the protecting group, but is generally a method well known in the art of organic synthetic chemistry, for example, TW.
Green, (Protective Groups in Organic Synthesis), J
ohn Wiley & Sons: JFWMcOmis, (Protective Groups
in Organic Chemistry), Plenum Press.

For example, the quinoline ring 4 of compound (VI)
As a method for protecting the hydroxy group at a position, an inert solvent (preferably a ketone such as acetone) is used in the presence or absence of a base (preferably in the presence of an alkali metal carbonate such as potassium carbonate). Below), compound (VI) in which the 4-position of the quinoline ring is a hydroxy group is represented by the following formula R ¹⁰ -W (VII) or R ¹⁰ -OR ¹⁰ (VIII) And R ¹⁰ is a hydroxy-protecting group. ] At -20 ° C to the reflux temperature of the solvent (preferably 0 ° C to the reflux temperature of the solvent used) for 10 minutes to 3 days (preferably 1 hour to 6 hours).
Time) to carry out the reaction.

The method for separately protecting the hydroxy group at the 4-position of the quinoline ring of the compound (VI) with a lower aliphatic acyl group, a C ₇ -C ₁₁ aromatic acyl group or a lower alkoxycarbonyl group is described below. (Preferably in the presence of a halogenated hydrocarbon such as methylene chloride) in the presence or absence of a condensing agent and a base (preferably
In the presence of carbodiimides such as dicyclohexylcarbodiimide), and 4 (quinoline) ring in compound (V).
A compound having a hydroxy group at the position is represented by the following formula: R ¹⁰ -OH (IX) [wherein R ¹⁰ has the same meaning as described above. ]
And -20 ° C to 80 ° C (preferably 0 ° C to room temperature)
The reaction is performed for 10 minutes to 3 days (preferably, 30 minutes to 1 day).

After completion of the reaction, the desired compound (VI)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step A3 is a step of producing compound (II). Compound (VI) is reacted with compound (VI) in an inert solvent in the presence or absence (preferably in the presence) of a base. Is reacted with a Ullman reaction [Synth. Comm., 1996, 38, in the presence of a transition metal such as copper, palladium or nickel.
77] and, if desired, R ^1a , R ^2a , R ^3a , R ^4a , R
It is carried out by removing the protecting groups of the amino, hydroxy and / or carboxy groups in ^5a and R ^6a .

The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Such ethers; methanol, ethanol
Alcohols such as n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; a mixed solvent of the above solvents; and preferably halogenated hydrocarbons (most preferably dichlorobenzene). .

Examples of the base used in the above reaction include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; and alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide; Alkali metal alkoxides such as sodium ethoxide and potassium t-butoxide; 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), 1,8
-Diazabicyclo [5.4.0] -7-undecene (D
Organic amines such as BU); preferably alkali metal carbonates (most preferably potassium carbonate).

The reaction temperature varies depending on the starting compound, base, catalyst, solvent and the like, but is usually from 100 ° C. to 300 ° C. (preferably from 150 ° C. to 200 ° C.).

The reaction time varies depending on the starting compound, base, catalyst, solvent, reaction temperature and the like, but is usually from 15 minutes to 4 minutes.
8 hours (preferably 1 hour to 30 hours).

If desired, R ^1a , R ^2a , R ^3a , R
^The method for removing the protecting group for the amino, hydroxy and / or carboxy group in ^4a , R ^5a and R ^6a is the same as the method for removing the protecting group for the amino, hydroxy and / or carboxy group in Step A1 of Method A described above. Done.

After completion of the reaction, the desired compound (II) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step A4 is a step of producing a compound having the general formula (XIII), and in an inert solvent in the presence or absence (preferably in the presence) of a base, a compound of the general formula (XII)
The compound having I) and the compound having the general formula (XII) are subjected to Ullman reaction in the presence of copper powder, and this step is performed in the same manner as the above-mentioned Method A, Step A3.

Step A5 is a step for producing a compound having the general formula (XV), and in an inert solvent in the presence or absence (preferably in the presence) of a base, compound (XII)
It is carried out by reacting I) with a compound having the general formula (XIV).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol; Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide Amides; nitriles such as acetonitrile; water; or a mixed solvent of water or the above solvents; and preferably ketones (most preferably acetone).

As the base used in the above reaction, for example, those similar to the ones used in the above-mentioned Method A, Step A3 can be mentioned. is there.

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from -20 ° C to 150 ° C, preferably from 0 ° C to 100 ° C.

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

After completion of the reaction, the desired compound (XV) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step A6 is a step of producing compound (II), which is carried out in an inert solvent in the presence of a base.
V) by a Dieckmann-type cyclization reaction [Chem. Hetrocycl.compd., 1
994,829], if desired, R ^1a , R ^2a , R ^3a ,
Amino, hydroxy and / or R ^4a , R ^5a and R ^6a
It is carried out by removing the protecting group of the carboxy group.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol
Alcohols such as n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve Amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent of the above solvents; preferably alcohols (most preferably ethanol-
Le).

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned Method A, Step A3, preferably alkali metal alkoxides (preferably sodium ethoxide). It is.

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from -20 ° C to 100 ° C.
° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually from 5 minutes to 50 hours (preferably from 30 minutes to 24 hours).

R ^1a , R ^2a , R ^3a , R
^The method for removing the protecting group for the amino, hydroxy and / or carboxy group in ^4a , R ^5a and R ^6a is the same as the method for removing the protecting group for the amino, hydroxy and / or carboxy group in Step A1 of Method A described above. Done.

After completion of the reaction, the desired compound (II)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

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

[0256]

Embedded image

[0257]

Embedded image

In the above formula, R¹, R^Two, R^Three, R^Four, R^Five,
R⁶, R^1a, R^2a, R^3a, R^4a, R^5a, R^6a, R⁷,
R⁸, R⁹, R^{9 '}And W have the same meaning as described above.
Then R^8aIs R⁸Group contained as a substituent in the group
The hydroxy, hydroxy and / or carboxy groups are protected
May be an amino, hydroxy and / or carboxy group
Other R ⁸A group similar to the group in the definition of the group¹²
Represents a hydroxy group or a lower alkoxy group, and X represents
Indicates a logen atom.

Step B1 is a step of producing a compound having the general formula (XVII), and converting the compound (III) into a compound of the general formula (XVII) in the presence or absence (preferably in the absence) of an inert solvent. The reaction is carried out by reacting the compound with XVI).

Compound (I) in the absence of an inert solvent
The reaction temperature for the reaction of II) with the compound (XVI) varies depending on the starting compound, but is usually from 150 ° C to 3 ° C.
The temperature is 50 ° C (preferably 200 ° C to 300 ° C).

Compound (I) in the absence of an inert solvent
The reaction time for the reaction of II) with the compound (XVI) varies depending on the starting compound, the reaction temperature and the like.
0 minutes to 24 hours (preferably 1 hour to 12 hours)
It is.

Compound (II) in the presence of an inert solvent
When reacting I) with compound (XVI), the inert solvent to be used is not particularly limited as long as it is inert to the present reaction. Aliphatic hydrocarbons; Aromatic hydrocarbons such as benzene, toluene, xylene and triisopropylbenzene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; Methyl acetate, acetic acid Esters such as ethyl, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol , Isopropanol, n-butyl Roh - le, isobutanol - Le, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethyl Amides such as phosphoric acid triamide;
Water; or a mixed solvent of the above solvents, and is preferably an aromatic hydrocarbon (most preferably, triisopropylbenzene).

Compound (II) in the presence of an inert solvent
The reaction temperature when reacting I) with compound (XVI) is as follows:
The temperature is usually from 100 ° C. to 300 ° C. (preferably from 150 ° C. to 250 ° C.) although it varies depending on the starting compound, the solvent and the like.

Compound (II) in the presence of an inert solvent
The reaction time when reacting I) with compound (XVI) is as follows:
Depending on the starting compound, solvent, reaction temperature, etc.,
It is 30 minutes to 24 hours (preferably 1 hour to 12 hours).

After completion of the reaction, the desired compound of the present reaction (XVI
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B2 is a step of producing compound (I). Compound (XVII) is reacted with polyphosphoric acid or concentrated sulfuric acid in the presence or absence (preferably in the absence) of an inert solvent. After reacting with a dehydrating agent such as a mixture of acetic acid,
It is carried out by removing the protecting group of amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a if desired.

Compound (X) in the absence of an inert solvent
The reaction temperature at the time of reacting VII) with the dehydrating agent varies depending on the starting compound, but is usually 0 ° C to 200 ° C (preferably 50 ° C to 150 ° C).

Compound (X) in the absence of an inert solvent
The reaction time when the VII) is reacted with the dehydrating agent varies depending on the starting compound, the reaction temperature and the like, but is usually from 5 minutes to 2 minutes.
4 hours (preferably 15 minutes to 12 hours).

Compound (XV) in the presence of an inert solvent
When reacting II) with a dehydrating agent, the inert solvent used is not particularly limited as long as it is inert to the present reaction. For example, hexane, heptane, ligroin,
Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride and tetrachloroethylene; acetic acid Esters such as methyl, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether;
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
Alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; formamide;
Amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; and preferably halogenated hydrocarbons (most preferably tetrachloroethylene).

Compound (XV) in the presence of an inert solvent
The reaction temperature at the time of reacting II) with the dehydrating agent varies depending on the raw material compound, the solvent and the like, but is usually 0 ° C to 200 ° C.
(Preferably 50 ° C. to 150 ° C.).

Compound (XV) in the presence of an inert solvent
The reaction time for reacting II) with a dehydrating agent varies depending on the starting compound, solvent, reaction temperature and the like, but is usually from 5 minutes to 24 hours (preferably from 15 minutes to 12 hours).

R ^1a , R ^2a , R ^3a , R
^The method for removing the protecting group for the amino, hydroxy and / or carboxy group in ^4a , R ^5a and R ^6a is the same as the method for removing the protecting group for the amino, hydroxy and / or carboxy group in Step A1 of Method A described above. Done.

After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B3 is a step for producing a compound having the general formula (XIX), and in an inert solvent, a reactive derivative (acid halides, active esters or mixed acid anhydrides) of compound (XVIII) ), In the presence of a base, in the presence of a typical metal salt such as magnesium chloride,
The reaction is performed by reacting with compound (XIV).

The method for producing the reactive derivative of the compound (XVIII) is carried out in the same manner as in the above-mentioned Method A, Step A3.

The inert solvent used when reacting the reactive derivative of the compound (XVIII) with the compound (XIV) is not particularly limited as long as it is inert to the present reaction. Heptane, ligroin,
Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate; Esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol Alcohols such as toluene, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; acetonitrile Nitriles such as isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; Amides or nitriles (most preferably dichloromethane, dimethylformamide or acetonitrile).

The base used in reacting the reactive derivative of compound (XVIII) with compound (XIV) includes, for example, the same bases as those used in the above-mentioned Method A, Step A3. Preferably they are organic amines (most preferably triethylamine).

The reaction temperature for reacting the reactive derivative of the compound (XVIII) with the compound (XIV) varies depending on the starting compound, the base, the solvent and the like.
The temperature is 20 ° C to 100 ° C (preferably 0 ° C to 50 ° C).

The reaction time for reacting the reactive derivative of the compound (XVIII) with the compound (XIV) depends on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually from 5 minutes to 50 hours. Preferably, it is 30 minutes to 24 hours.

After completion of the reaction, the desired compound (XI)
X) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B4 is a step for producing a compound having the general formula (XX), in an inert solvent in the presence or absence (preferably in the presence) of a salt such as sodium chloride or the like. This is carried out by heating (XIX) to cause a decarboxylation reaction.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as heptane, ligroin or petroleum ether; benzene , Toluene, xylene, aromatic hydrocarbons; dichloromethane, 1,
Halogenated hydrocarbons such as 2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide;
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane; and preferably sulfoxides (most preferably dimethylsulfoxide).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually 50 ° C. to 300 ° C. (preferably 100 ° C.).
° C to 250 ° C).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 24 hours).

In carrying out this reaction, water may be added.

After completion of the reaction, the desired compound (XX)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B5 is a step of producing a compound having the general formula (XXII), which comprises reacting the compound (XX) with a compound having the general formula (XXI) in an inert solvent in the presence of an acid. It is performed by

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate; Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitriles such as acetonitrile, isobutyronitrile; formamide, dimethylformamide, dimethyl Acetamide, amides such as hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; is, preferably, (most preferably, acetic anhydride) esters is.

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction. Examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid,
Inorganic acids such as phosphoric acid; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, and organic acids such as trifluoromethanesulfonic acid; zinc chloride; Tin chloride, boron trichloride, boron trifluoride,
Lewis acids such as boron tribromide; acidic ion exchange resins; preferably organic acids (most preferably acetic anhydride).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually 50 ° C. to 300 ° C. (preferably 80 ° C.).
To 250 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 24 hours).

After completion of the reaction, the desired compound (XXI
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B6 is a step for producing a compound having the general formula (XXIII), which is carried out by reacting the compound (XXII) with the compound (XII) in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate; Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-
Propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol
Alcohols such as toluene, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide Water; or a mixed solvent of the above solvents;
And preferably alcohols (most preferably ethanol).

The reaction temperature varies depending on the starting compound, the solvent and the like, but is usually -100 ° C to 100 ° C (preferably -100 ° C).
50 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually from 5 minutes to 50 hours (preferably from 15 minutes to 24 hours).

After completion of the reaction, the desired compound (XXI
II) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. After washing with water, etc., after drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc.,
It is obtained by distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B7 is a step of preparing compound (I). After subjecting compound (XXIII) to the Ullman reaction, if desired, R ^1a , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a are prepared.
By removing the protecting group of the amino, hydroxy and / or carboxy group in the above.

Step B8 is a step of producing a compound having the general formula (XXV), and converting the compound (III) into a compound of the general formula (III) in the presence or absence (preferably in the absence) of an inert solvent. XXIV), and this step is carried out in the same manner as in the above-mentioned Method B, Step B1.

Step B9 is a step of producing a compound having the general formula (XXVI), in which compound (XXV) is reacted with polyphosphoric acid or in the presence or absence (preferably in the absence) of an inert solvent. This step is carried out by reacting with a dehydrating agent such as a mixture of concentrated sulfuric acid and acetic anhydride. This step is carried out in the same manner as the above-mentioned Method B, Step B2.

Step B10 is a step for producing a compound (I). The compound (XXVI) is reacted with a compound having the general formula (XXVII) in an inert solvent, and if necessary, R ^1a and R ^2a are reacted. , R ^3a , R ^4a , R ^5a and R ^6a by removing the protecting groups of the amino, hydroxy and / or carboxy groups.

When R ⁹ is a halogen atom in compound (XXVI), compound (XXVI) is reacted with compound (XXVII) in an inert solvent in the presence or absence (preferably in the presence) of a base. This is done by letting

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide Amides; nitriles such as acetonitrile; water; or a mixed solvent of water or the above solvents; and preferably ketones (most preferably acetone).

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned Method A, Step A3. is there.

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from -20 ° C to 150 ° C, preferably from 0 ° C to 100 ° C.

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

When R ⁹ is a hydrogen atom in compound (XXVI), the reaction is carried out by reacting compound (XXVI) with compound (XXVII) in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene and the like aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-
Butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,
Alcohols such as octanol, cyclohexanol, and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; and sulfoxides such as dimethyl sulfoxide. Sulfolane; or a mixed solvent of the above-mentioned solvents; and preferably ethers (most preferably tetrahydrofuran).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually 0 ° C. to 200 ° C.
(Preferably 10 ° C. to 120 ° C.).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

When R ⁹ is a hydroxy group in compound (XXVI), compound (XXVI) is added in an inert solvent.
Alternatively, the reaction is performed by reacting a reactive derivative thereof (acid halides, active esters, or mixed acid anhydrides) with compound (XXVII).

In the acid halide method, compound (XXVI) is converted into a halogenating agent (eg, oxalyl chloride, thionyl chloride, thionyl bromide, oxalic acid chloride,
Oxalic acid dichloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.) to produce acid halides. The reaction is carried out in the presence (preferably in the presence).

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned Method A, Step A3. Preferably, organic amines (most preferably pyridine) are used. It is.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Kind;
Sulfoxides such as dimethyl sulfoxide; sulfolane; preferably halogenated hydrocarbons, ethers or amides (most preferably dichloromethane, chloroform, tetrahydrofuran or dimethylformamide).

The reaction temperature varies depending on the starting compounds, reagents, etc., but the reaction between the halogenating agent and the compound (XXVI) and the reaction between the acid halides and the compound (XXVII) are also
The reaction temperature is usually −20 ° C. to 150 ° C., preferably the reaction between the halogenating agent and the compound (XXVI) is −10 ° C. to 1 ° C.
00 ° C, and the reaction between the acid halides and the compound (XXVII) is at -20 ° C to 100 ° C.

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like, but the halogenating agent and the compound (XXVI)
And the reaction of the acid halides with the compound (XXVII) are usually carried out for 30 minutes to 80 hours (preferably 1 hour).
Hours to 48 hours).

In the active ester method, the compound (XXVI) is reacted with an active esterifying agent in an inert solvent to produce active esters, and then, in an inert solvent in the presence or absence of a base (preferably). Is carried out in the presence of a compound (XXVII)).

The active esterifying agent used in the above reaction is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or the like. Compounds; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carbonyldiimidazole; triphenylphosphine; diphenylphosphoryl azide.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane,
Halogenated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide and dimethylformamide Amides such as dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane;
And preferably ethers or amides (most preferably dioxane, tetrahydrofuran or dimethylformamide).

As the base used in the above reaction, for example, the same bases as those used in the above-mentioned acid halide method can be mentioned.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is generally -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the active esterification reaction.
In the reaction of the active ester with the compound (XXVII),
-20 ° C to 100 ° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like. However, the active esterification reaction and the reaction of the active ester with the compound (XXVII) are usually 3 hours.
0 minutes to 80 hours (preferably 1 hour to 48 hours)
It is.

In the mixed acid anhydride method, the compound (X) is prepared in an inert solvent in the presence or absence (preferably in the presence) of a base.
XVI) is reacted with a mixed acid anhydride agent to produce mixed acid anhydrides, and then reacted with the mixed acid anhydrides and compound (XXVII) in an inert solvent.

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned acid halide method, and are preferably organic amines (most preferably pyridine).

Examples of mixed acid anhydride agents used in the above reaction include lower alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate; lower alkanoyl halides such as pivaloyl chloride; diethyl cyanophosphonate; A di-lower alkyl or diaryl cyanophosphoric acid such as diphenyl phosphonate, preferably a lower alkyl carbonate carbonate (most preferably isobutyl chlorocarbonate).

The inert solvent used in producing the mixed acid anhydrides is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, hexane, heptane, ligroin Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether Ethers such as, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and dimethyl sulfoxide Sulfoxy S; sulfolane; is, preferably halogenated hydrocarbons or amides (most preferably dichloromethane or dimethylformamide) is.

The reaction temperature in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents and the like.
It is 50 ° C to 100 ° C (preferably 0 ° C to 60 ° C).

The reaction time in the reaction for producing the mixed acid anhydrides varies depending on the starting compounds, reagents, reaction temperature and the like, but is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours). is there.

The reaction between the mixed acid anhydrides and compound (XXVII) is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base. The solvent is the same as that used in the reaction for producing the mixed acid anhydrides described above.

The reaction temperature in the reaction of the mixed acid anhydrides with the compound (XXVII) varies depending on the starting compounds, reagents and the like, but is usually from -30 ° C to 100 ° C (preferably 0 ° C).
To 80 ° C.).

The reaction time in the reaction of the mixed acid anhydrides with the compound (XXVII) varies depending on the starting compound, the reagent, the reaction temperature and the like, but is usually from 5 minutes to 24 hours (preferably from 30 minutes to 16 hours). Time).

When di-lower alkyl cyanophosphoric acid or diaryl cyanophosphoric acid is used in this reaction, compound (XXVI) and compound (XXVII) can be directly reacted in the presence of a base.

When R ⁹ is a lower alkoxy group in compound (XXVI), in the presence or absence (preferably absence) of an inert solvent, in the presence or absence of base (preferably non-existence) In the presence), by reacting compound (XXVI) with compound (XXVII).

Compound (XXVI) and compound (XXVI)
Examples of the base used in the reaction for reacting I) include the same bases as those used in the above-mentioned Method A, Step A3, and are preferably organic amines (most preferably pyridine). is there.

Compound (XXVI) and compound (XXVI)
The inert solvent used in the reaction for reacting I) is not particularly limited as long as it is inert to the present reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol
Alcohols such as n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; or a mixed solvent of the above solvents; preferably ethers or amides (most preferably tetrahydrofuran, dioxane or Dimethylformamide).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from 0 ° C. to 200 ° C.
(Preferably 50 ° C. to 150 ° C.).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

After completion of the reaction, the target compound (I) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B11 is a step for producing a compound having the general formula (XXIX), and in the presence or absence (preferably absence) of an inert solvent, the compound (III)
Is reacted with a compound having the general formula (XXVIII), and this step is performed in the same manner as in the above-mentioned Method B, Step B1.

Step B12 is a step of producing compound (I). Compound (XXV) is reacted with polyphosphoric acid or concentrated sulfuric acid in the presence or absence (preferably in the absence) of an inert solvent. After reacting with a dehydrating agent such as a mixture of acetic acid,
It is carried out by removing the protecting group of amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a , R ^4a , R ^5a and R ^6a if desired.

Starting compounds (III), (IV),
(V), (VII), (VIII), (IX),
(X), (XI), (XII), (XIV), (XV
I), (XXI), (XXIV), (XXVII) and (XXVIII) are known or are easily produced according to known methods or methods analogous thereto. [For example, J.Me
d. Chem. Soc., 120 (37), 9722 (1998); Org.Synth., 250
(1941) etc.].

The compounds of the present invention having the above general formula (Ia), their pharmaceutically acceptable salts, their esters or other derivatives are useful as medicaments.

Further, the compound represented by the above general formula (I) or (I)
The compound having I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof has an excellent ileal bile acid transporter inhibitory action, and particularly has an effect on hyperlipidemia and / or
Or it is useful as a prophylactic or therapeutic agent for arteriosclerosis.

When the compound of the present invention having the above general formula (I) or (II), its pharmaceutically acceptable salt or its ester is used as the above-mentioned therapeutic or prophylactic agent,
As such or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., for example, tablets, capsules, granules,
It can be administered orally by 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 such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid; Sodium sulfate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Derivatives can be mentioned.) Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, , Low-substituted hydroxypropyl Cellulose derivatives such as loin, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked sodium carboxymethylcellulose; and chemically modified starch celluloses such as carboxymethylstarch, sodium carboxymethylstarch, and crosslinked polyvinylpyrrolidone.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Dehydroacetic acid; and sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method.

The dosage depends on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably 10 mg) and the upper limit is 2000 mg (preferably 4 mg) per dose.
00 mg), in the case of intravenous administration, 0.1 mg (preferably 1 mg) per day, 500 mg per day
(Preferably 300 mg) per adult per day
It is desirable to administer from 6 to 6 times depending on the symptoms.

[0347]

The production examples, examples and preparation examples are shown below.
The present invention will be described in more detail, but the scope of the present invention is not limited thereto.

Production Example 1 1- (3,4-dimethoxyphenyl) -4-hydroxy
-6,7,8-Trimethoxy-2-oxo-1,2-di
Hydroquinoline-3-carboxylic acid N-methyl-N-phenyl
Enylamide (Exemplified Compound No. 2-1339) (1a) 2-[(3,4-dimethoxyphenyl) amino] -3,4,5-trimethoxybenzoic acid methyl ester 2-bromo-3,4,5-trimethoxybenzoic acid 13.
A mixture of 7 g, 3,4-dimethoxyaniline 14.4 g, potassium carbonate 3.25 g, copper 0.3 g, pyridine 2.06 g, and 25 ml of water was heated under reflux for 2 hours. After acidification with hydrochloric acid, the solid was collected by filtration and dissolved in methylene chloride. The filtrate was further extracted with methylene chloride, and the combined methylene chloride layer was subjected to silica gel column chromatography (elution solvent: ethyl acetate / methylene chloride =
1/4). The obtained solid was washed with hexane / isopropyl ether, and 12.3 g of 2-
[(3,4-dimethoxyphenyl) amino] -3,4
5-Trimethoxybenzoic acid was obtained. This was dissolved in 20 ml of N, N-dimethylformamide, and 5.66 g of potassium carbonate and 3.2 ml of methyl iodide were added at 0 ° C.
Stirred for hours. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and dried over sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1/3) to obtain 4.18 g of the title compound as yellow crystals. NMR spectrum (CDCl ₃ ) δ ppm: 3.59 (3H, s), 3.81 (3
H, s), 3.83 (3H, s), 3.85 (3H, s), 3.88 (3H, s), 3.96
(3H, s), 6.40 (1H, dd, J = 2.5, 8.5Hz), 6.52 (1H, d, J
= 2.5Hz), 6.73 (1H, d, J = 8.6Hz), 7.28 (1H, s).

(1b) 2-[(3,4-dimethoxyphenyl)-[(N-methyl-N-phenylcarbamoyl)
[Acetyl] amino] -3,4,5-trimethoxybenzoic acid methyl ester N-methyl-N-phenyl-malonic acid amide 720 mg
Of oxalic acid chloride in 10 ml of methylene chloride
5 ml and a few drops of N, N-dimethylformamide were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure,
Dissolved in 3 ml of methylene chloride. This acid chloride solution was treated with 342 mg of 2-[(3,4-dimethoxyphenyl) amino] -3,4,5-trimethoxybenzoic acid methyl ester obtained in Production Example (1a) and pyridine 0.4
The mixture was added to a 15 ml solution of acetone at 0 ° C. and stirred at the same temperature for 2 hours. Water was added to the reaction solution and extracted with ethyl acetate.
The ethyl acetate layer was washed with 1N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate / methylene chloride = 1 /
The compound was separated and purified in 2) to give the title compound as a yellow oil.
16 mg were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 3.01-3.95 (23H, m),
6.50-6.75 (1H, m), 6.96-7.38 (8H, m).

(1c) 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2
-Oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide 2-[(3,4-dimethoxyphenyl)-((N-methyl-N -Phenylcarbamoyl) acetyl) amino] -3,4,5-trimethoxybenzoic acid methyl ester 215 mg of ethanol 15 m
To the solution was added 0.4 ml of a 20% sodium ethoxide / ethanol solution, and the mixture was stirred at room temperature for 2 hours. 1 in the reaction solution
After adding normal hydrochloric acid and concentrating under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and dried over sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate / methylene chloride = 1/1) to obtain 82 mg of the title compound as a pale red solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.13 and 3.22 (total
3H, s), 3.48 (3H, s), 3.75 (3H, s), 3.85 (3H, s), 3.87
(3H, s), 3.96 (3H, s), 6.11-6.40 (2H, m), 6.77, and
7.03 (total 1H, d, J = 7.8Hz), 7.18-7.37 (5H, m), 7.39
(1H, s). Melting point: 179-182 ° C.

Production Example 2 6,7-Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N-phenylamide (Exemplary Compound No.
1-977) (2a) 2-[(N- (3,4-dimethoxyphenyl)
-N- (4-Methoxyphenyl) amino) methylene] malonate Diethyl N- (3,4-dimethoxyphenyl) -N- (4-methoxyphenyl) amine 5.74 g and diethyl ethoxymethylenemalonate 4.92 ml Was heated and stirred at 250 ° C. for 4 hours. After cooling, the reaction solution was separated and purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/4) to obtain 8.78 g of the title compound as a red oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.07 (3H, t, J = 7.3H)
z), 1.26 (3H, t, J = 7.2Hz), 3.55 (2H, q, J = 7.2Hz), 3.
81 (6H, s), 3.87 (3H, s), 4.2 (2H, q, J = 7.2Hz), 6.63
6.65 (2H, m), 6.80 (1H, d, J = 8.7Hz), 6.86 (2H, d, J =
8.8Hz), 7.04 (2H, d, J = 8.8Hz), 7.87 (1H, s).

(2b) 6,7-dimethoxy-1- (4-
Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 2-[(N- (3,4-dimethoxyphenyl) -N- (4- A mixture of 8.38 g of diethyl methoxyphenyl) amino) methylene] malonate and 60 g of polyphosphoric acid was heated and stirred at 100 ° C. for 2 hours. After the reaction solution was poured on ice to dissolve the polyphosphoric acid in water, the insolubles were collected by filtration. The solid collected by filtration was dissolved in methylene chloride, the methylene chloride layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: acetone / methylene chloride = 1 / 9-1 /
The compound was separated and purified in 4) to give the title compound 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4.
1.51 g of -dihydroquinoline-3-carboxylic acid ethyl ester as a white solid and 1- (3,4-dimethoxyphenyl) -6-methoxy-4-oxo-1,4
1.16 g of -dihydroquinoline-3-carboxylic acid ethyl ester was obtained as a gray solid. 6,7-dimethoxy-1- (4-methoxyphenyl) -4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, t, J = 7.2H)
z), 3.71 (3H, s), 3.93 (3H, s), 4.00 (3H, s), 4.39 (2
H, q, J = 7.2Hz), 6.33 (1H, s), 7.10 (2H, d, J = 8.8Hz),
7.35 (2H, d, J = 8.8 Hz), 7.93 (1H, s), 8.41 (1H, s). Melting point: 194-195 ° C 1- (3,4-dimethoxyphenyl) -6-methoxy-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester NMR spectrum (CDCl ₃ ) δ ppm: 1.42 (3H, t, J = 7.3H)
z), 3.90 (3H, s), 3.92 (3H, s), 3.99 (3H, s), 4.40 (2
H, q, J = 7.3Hz), 6.88 (1H, d, J = 2.2Hz), 6.95-7.04 (3
H, m), 7.13 (1H, dd, J = 2.9, 9.4Hz), 7.96 (1H, d, J =
3.0Hz), 8.45 (1H, s). Melting point: 207-209 ° C.

(2c) 6,7-dimethoxy-1- (4-
Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6,7-dimethoxy-1- obtained in Production Example (2b)
(4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 1.3
30 g of a 10% aqueous potassium hydroxide solution was added to 0 g, and 1 g
The mixture was heated and stirred at 00 ° C. for 1 hour. After cooling, the reaction solution was neutralized with concentrated hydrochloric acid, and the precipitated solid was collected by filtration. The solid collected by filtration was dissolved in methylene chloride, the methylene chloride layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The precipitated solid was suspended in ether and collected by filtration to obtain 1.12 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.76 (3H, s), 3.94 (3
H, s), 4.05 (3H, s), 6.46 (1H, s), 7.12 (2H, d, J = 9.0
Hz), 7.35 (2H, d, J = 9.0Hz), 7.86 (1H, s), 8.69 (1H,
s). Melting point: 238-241 ° C.

(2d) 6,7-dimethoxy-1- (4-
Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide 6,7-dimethoxy-1- obtained in Production Example (2c)
5 ml of anhydrous methylene chloride solution of 250 mg of (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 0.26 ml of triethylamine
To the mixture was added 0.12 ml of isobutyl chloroformate at 0 ° C. After stirring at 0 ° C. for 15 minutes, N-methylaniline 0.1.
06 ml was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: methanol / methylene chloride = 1/19) to obtain 124 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.49 (3H, s), 3.67 (3
H, s), 3.91 (3H, s), 3.95 (3H, s), 6.25 (1H, br.s),
7.04 (2H, d, J = 8.8Hz), 7.09-7.36 (7H, m), 7.69 (2H, b
rs). Melting point: 180-182 ° C.

Production Example 3 6,7-Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N- (3-chlorophenyl) amide
(Exemplified Compound No. 1-1372) 6,7-dimethoxy-1- obtained in Production Example 2 (c)
(4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 150 mg, triethylamine 0.15 ml, isobutyl chloroformate 0.07 m
l and 3-chloro-N-methylaniline 0.06 ml
Was used in the same manner as in Production Example (2d) to give 99 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.47 (3H, s), 3.69 (3
H, s), 3.92 (3H, s), 3.96 (3H, s), 6.29 (1H, s), 7.06
-7.37 (8H, m), 7.69 (1H, s), 7.79 (1H, s). Melting point: 165-168C.

Production Example 4 6,7-Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N- (4-chlorophenyl) amide
(Exemplified Compound No. 1-980) 6,7-Dimethoxy-1- obtained in Production Example 2 (c)
(4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 150 mg, triethylamine 0.15 ml, isobutyl chloroformate 0.07 m
1 and 0.06 ml of 4-chloro-N-methylaniline
Was used in the same manner as in Production Example (2d) to give 164 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.46 (3H, s), 3.68 (3
H, s), 3.92 (3H, s), 3.96 (3H, s), 6.28 (1H, s), 7.06
(2H, d, J = 9.1Hz), 7.08-7.38 (6H, m), 7.66 (1H, br),
7.79 (1H, br). Melting point: 146-149 ° C.

Production Example 5 6,7-Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-ethyl-N-phenylamide (exemplified compound number
1-978) 6,7-Dimethoxy-1- obtained in Production Example 2 (c)
(4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 200 mg, triethylamine 0.19 ml, isobutyl chloroformate 0.09 m
The reaction was carried out in the same manner as in Production Example (2d) using 1 and 0.07 ml of N-ethylaniline to obtain 213 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 1.22 (3H, t, J = 7.1H)
z), 3.66 (3H, s), 3.84-4.00 (2H, m), 3.91 (3H, s), 3.
94 (3H, s), 6.22 (1H, br), 7.04 (2H, d, J = 8.8Hz), 7.0
9-7.37 (6H, m), 7.53-7.67 (2H, m). Melting point: 150-152 ° C.

Production Example 6 6,7-Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N- (4-methoxyphenyl) amide
(Exemplified Compound No. 1-981) 6,7-dimethoxy-1- obtained in Production Example 2 (c)
(4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 200 mg, triethylamine 0.19 ml, isobutyl chloroformate 0.09 m
The reaction was carried out in the same manner as in Production Example (2d) using 1 and 73 mg of N-methyl-p-anisidine to obtain 377 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.44 (3H, s), 3.67 (3
H, s), 3.74 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 6.23
(1H, br.s), 6.72-6.92 (2H, br), 7.00-7.40 (6H, m), 7.
52-7.72 (2H, m). Melting point: 166-167 ° C.

Production Example 7 7-Methoxy-1- (3-methoxyphenyl) -4-o
Xo-1,4-dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide (Exemplary Compound No. 1-1
368) (7a) Diethyl 2-{[bis- (3-methoxyphenyl) -amino] methylene} malonate Using 4.0 g of bis- (3-methoxyphenyl) -amine and 4.15 g of diethyl ethoxymethylenemalonate. The reaction was carried out in the same manner as in Production Example (2a) and purified to obtain 5.73 g of the title compound as an orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.06 (3H, t, J = 7.3H)
z), 1.27 (3H, t, J = 7.3Hz), 3.51 (2H, q, J = 7.2Hz), 3.
77 (6H, s), 4.22 (2H, q, J = 7.3Hz), 6.65 (2H, s), 6.69
(2H, d, J = 7.9Hz), 6.77 (2H, d, J = 8.5Hz), 7.22-7.26
(2H, m), 7.93 (1H, s).

(7b) 7-methoxy-1- (3-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 2-{[bis] obtained in Production Example (7a) Production Example (2b) using 5.59 g of diethyl-(3-methoxyphenyl) -amino] methylene dimalonate and 40 g of polyphosphoric acid
And purified to give the title compound, 7-methoxy-1- (3-methoxyphenyl) -4-oxo-.
1.84 g of 1,4-dihydroquinoline-3-carboxylic acid ethyl ester as a white solid and 5-methoxy-1- (3-methoxyphenyl) -4-oxo-1,4
350 mg of -dihydroquinoline-3-carboxylic acid ethyl ester was obtained as a yellow solid. 7-Methoxy-1- (3-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester NMR spectrum (CDCl ₃ ) δ ppm: 1.40 (3H, t, J = 6.9H)
z), 3.75 (3H, s), 3.88 (3H, s), 4.39 (2H, q, J = 6.9H
z), 6.39 (1H, d, J = 2.3Hz), 6.94 (1H, dd, J = 2.1, 2.2H
z), 6.99-7.02 (2H, m), 7.10-7.13 (1H, m), 7.51 (1H,
t, J = 8.2Hz), 8.45-8.49 (2H, m). Melting point: 211-212 ° C 5-methoxy-1- (3-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid Acid ethyl ester NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, t, J = 7.3H)
z), 3.86 (3H, s), 3.98 (3H, s), 4.37 (2H, q, J = 7.3H
z), 6.50 (1H, d, J = 7.8Hz), 6.81 (1H, d, J = 8.4Hz), 6.9
0 (1H, dd, J = 2.2, 2.3Hz), 6.97 (1H, dd, J = 2.2, 8.3H
z), 7.08-7.11 (1H, m), 7.36 (1H, dd, J = 8.2, 8.7Hz),
7.49 (1H, dd, J = 8.0, 8.1 Hz), 8.32 (1H, s). Melting point: 189-191 ° C. (7c) 7-methoxy-1- (3-methoxyphenyl)
4-oxo-1,4-dihydroquinoline-3-carboxylic acid 7-methoxy-1- (3-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3 obtained in Production Example (7b) -Carboxylic acid ethyl ester (500 mg) was suspended in ethanol (10 ml), water (1 ml) and sodium hydroxide (500 mg) were added, and the reaction solution was heated to reflux for 30 minutes. After the solvent of the reaction solution was concentrated under reduced pressure, the aqueous layer was acidified with diluted hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was suspended in diisopropyl ether and collected by filtration to obtain 486 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.78 (3H, s), 3.88 (3
H, s), 6.52 (1H, d, J = 2.4Hz), 6.93-7.24 (4H, m), 7.5
4 (1H, t, J = 8.1Hz), 8.48 (1H, d, J = 8.9Hz), 8.74 (1H,
s). Melting point: 165-168 ° C (7d) 7-methoxy-1- (3-methoxyphenyl)
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide 7-methoxy-1- (3-methoxyphenyl) -4-oxo- obtained in Production Example (7c) Production Example (2) using 200 mg of 1,4-dihydroquinoline-3-carboxylic acid, 0.2 ml of triethylamine, 0.09 ml of isobutyl chloroformate and 0.06 ml of N-methylaniline.
The reaction was carried out in the same manner as in d) to obtain 118 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.48 (3H, s), 3.69 (3
H, s), 3.84 (3H, s), 6.31 (1H, s), 6.72-7.41 (9H, m),
7.45 (1H, t, J = 8.1Hz), 7.61-7.76 (1H, br), 8.24-8.2
6 (1H, m). Melting point: 150-152 ° C.

Production Example 8 6-methoxy-1- (3,4-dimethoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N-phenylamide (Exemplary Compound No.
1-538) (8a) 6-methoxy-1- (3,4-dimethoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid 6-methoxy-1- (3,4-dimethoxyphenyl)-
500 mg of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester and 500 mg of sodium hydroxide
The reaction and post-treatment were carried out in the same manner as in Production Example (2c) using mg to obtain 391 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.90 (3H, s), 3.97 (3
H, s), 4.00 (3H, s), 6.87 (1H, d, J = 2.5Hz), 6.98-7.3
4 (6H, m), 7.90 (1H, d, J = 2.9 Hz), 8.76 (1H, s). Melting point: 165-168 ° C (8b) 6-methoxy-1-
(3,4-dimethoxyphenyl) -4-oxo-1,4
-Dihydroquinoline-3-carboxylic acid N-methyl-N
-Phenylamide 6-methoxy-1- (3,4-dimethoxyphenyl)-
The reaction was carried out in the same manner as in Production Example (2d) using 200 mg of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 0.19 ml of triethylamine, 0.09 ml of isobutyl chloroformate and 0.06 ml of N-methylaniline. This gave 231 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.50 (3H, s), 3.87 (3
H, s), 3.88 (3H, s), 3.97 (3H, s), 6.61-7.37 (7H, m),
7.65-7.84 (2H, m). Melting point: 193-195C.

Production Example 9 7-Methoxy-1-phenyl-4-oxo-1,4-di
Hydroquinoline-3-carboxylic acid N-methyl-N-phenyl
Enylamide (Exemplified Compound No. 1-646) (9a) 2-{[N-phenyl-N-phenylamino]
Methylene diethyl malonate N- (3-methoxyphenyl) -N-phenylamine 1
The reaction was carried out in the same manner as in Production Example (2a) using 0 g and 10.5 g of diethyl ethoxymethylenemalonate, and purified to obtain 16.6 g of the title compound as an orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.05 (3H, t, J = 7.1H)
z), 1.27 (3H, t, J = 6.9Hz), 3.48 (2H, q, J = 7.2Hz), 3.
77 (3H, s), 4.21 (2H, q, J = 7.1Hz), 6.62-6.68 (2H, m),
6.77 (1H, dd, J = 8.3, 2.4Hz), 7.12 (2H, d, J = 7.8Hz),
7.20-7.30 (1H, m), 7.35 (2H, t, J = 7.9Hz), 7.93 (1H, m
s). (9b) 7-methoxy-1-phenyl-4-oxo-
Production Example (2b) using 16.6 g of diethyl 1,4-dihydroquinoline-3-carboxylate 2-ethyl [N- (3-methoxyphenyl) -N-phenylamino] methylene} malonate and 120 g of polyphosphoric acid ), Purified and purified by the title compound, 7-methoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-3-.
750m as carboxylic acid ethyl ester as white solid
g and 1- (3-methoxyphenyl) -4-oxo-
4.0 g of 1,4-dihydroquinoline-3-carboxylic acid ethyl ester was obtained as a yellow solid. 7-methoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester NMR spectrum (DMSO-d6) δ ppm: 1.25 (3H, t, J = 7.2)
Hz), 3.69 (3H, s), 4.20 (2H, q, J = 7.2Hz), 6.26 (1H,
d, J = 2.5Hz), 7.12 (1H, dd, J = 2.2, 8.8Hz), 7.60-7.72
(5H, m), 8.22 (1H, d, J = 9.1 Hz), 8.39 (1H, s). Melting point: 150 ° C. 1- (3-methoxyphenyl) -4-oxo-1,4-
Dihydroquinoline-3-carboxylic acid ethyl ester NMR spectrum (DMSO-d6) δ ppm: 1.26 (3H, t, J = 7.2
Hz), 3.82 (3H, s), 4.22 (2H, q, J = 7.2Hz), 7.02 (1H,
d, J = 8.5Hz), 7.20-7.24 (2H, m), 7.31 (1H, t, J = 2.1H
z), 7.49 (1H, t, J = 7.1Hz), 7.58 (1H, t, J = 8.2Hz), 7.
66 (1H, dt, J = 1.4,8.7Hz), 8.28 (1H, dd, J = 8.0, 1.2H
z), 8.45 (1H, s). Melting point: 228 ° C. (9c) 7-methoxy-1-phenyl-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 7-methoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 595
Preparation Example (2) using 500 mg of sodium hydroxide and 500 mg of sodium hydroxide.
The reaction and post-treatment were carried out in the same manner as in c) to obtain 391 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.77 (3H, s), 6.46 (1
H, d, J = 2.3Hz), 7.15 (1H, dd, J = 2.4,9.1Hz), 7.40-7.
46 (2H, m), 7.62-7.69 (3H, m), 8.49 (1H, d, J = 9.3Hz),
8.74 (1H, s). Melting point: 165-168 ° C (9d) 7-methoxy-1-phenyl-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide 7-methoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 200 mg, triethylamine 0.2 ml, chloro 0.09m of isobutyl formate
The reaction was carried out in the same manner as in Production Example (2d) using 1 and 0.06 ml of N-methylaniline to obtain 118 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.48 (3H, s), 3.68 (3
H, s), 6.24 (1H, s), 6.90 (1H, d, J = 8.5Hz), 7.09-7.7
8 (11H, m), 8.25-8.27 (1H, m). Melting point: 143-145 ° C. Production Example 10 6,7-dimethoxy-1- (3,4-dimethoxyphenyl)
L) -4-oxo-1,4-dihydroquinoline-3-ca
Rubonic acid N-methyl-N-phenylamide (exemplified compound
Product No. 1-1134) (10a) 2-[(bis- (3,4-dimethoxyphenyl) amino) methylene] malonic acid diethyl ester bis- (3,4-dimethoxyphenyl) amine 15.0
g and 12.3 g of diethyl ethoxymethylenemalonate, followed by purification in the same manner as in Production Example (2a).
3.6 g of the title compound were obtained as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.07 (3H, t, J = 7.0H
z), 1.23-1.28 (3H, m), 3.57 (2H, q, J = 7.1Hz), 3.82 (6
H, s), 3.88 (6H, s), 4.21 (2H, q, J = 7.1Hz), 6.65 (2H,
m), 6.67 (1H, d, J = 2.4Hz), 6.81 (2H, d, J = 8.3Hz),
7.87 (1H, s).

(10b) 1- (3,4-Dimethoxy-phenyl) -6,7-dimethoxy-4-oxo-1,4-
Dihydro-quinoline-3-carboxylic acid ethyl ester 2-[(bis- (3,4-) obtained in Production Example (10a).
The reaction was carried out and purified using 23.6 g of diethyl dimethoxyphenyl) amino) methylene] malonate and 150 g of polyphosphoric acid in the same manner as in Production Example (2b) to obtain 17.1 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, t, J = 7.2H)
z), 3.72 (3H, s), 3.92 (3H, s), 4.000 (3H, s), 4.002
(3H, s), 4.39 (2H, q, J = 7.2Hz), 6.34 (1H, s), 6.91 (1
H, d, J = 2.0Hz), 7.03 (1H, d, J = 2.1Hz), 7.04 (1H, s),
7.93 (1H, s), 8.43 (1H, s). Melting point: 243-247 ° C.

(10c) 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1- (1) obtained in Production Example (10b) 3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4
The reaction was carried out and purified using 3.50 g of -dihydroquinoline-3-carboxylic acid ethyl ester and 14 ml of a 10% aqueous potassium hydroxide solution in the same manner as in Production Example (2c).
38 g of the title compound were obtained as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.77 (3H, s), 3.92 (3
H, s), 4.01 (3H, s), 4.04 (3H, s), 6.50 (1H, s), 6.91
(1H, d, J = 2.2Hz), 7.00-7.14 (2H, m), 7.85 (1H, s), 8.
71 (1H, s). Melting point: 235-240 ° C.

(10d) 6,7-dimethoxy-1-
(3,4-dimethoxyphenyl) -4-oxo-1,4
-Dihydroquinoline-3-carboxylic acid N-methyl-N
-Phenylamide 6,7-dimethoxy-1- obtained in Production Example (10c)
(3,4-dimethoxyphenyl) -4-oxo-1,4
-Dihydroquinoline-3-carboxylic acid 200 mg, triethylamine 0.18 ml, isobutyl chloroformate 0.1 mg.
The reaction was carried out in the same manner as in Production Example (2d) using 08 ml and N-methylaniline 0.05 ml to obtain 118 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.49 (3H, s), 3.68 (3
H, s), 3.88 (3H, s), 3.96 (3H, s), 3.98 (3H, s), 6.29
(1H, s), 6.73-6.92 (2H, m), 6.99 (1H, d, J = 8.6Hz),
7.11-7.38 (5H, m), 7.69 (2H, br). Melting point: 242-243 ° C.

Production Example 11 1- (3,4-Dimethoxyphenyl) -4-oxo-
1,4-dihydroquinoline-3-carboxylic acid N-methyl
Ru-N-phenylamide (Exemplified Compound No. 1-57) (11a) 2-[(N- (3,4-dimethoxyphenyl) -N-phenylamino) methylene] malonate N- (3,4-dimethoxy) (Phenyl) -N-phenylamine 5.0 g and diethyl ethoxymethylenemalonate 4.
The reaction was carried out and purified in the same manner as in Production Example (2a) using 85 ml to obtain 8.10 g of the title compound as an orange oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.06 (3H, t, J = 7.3H)
z), 1.27 (3H, t, J = 7.2Hz), 3.53 (2H, q, J = 7.2Hz), 3.
82 (3H, s), 3.89 (3H, s), 4.21 (2H, q, J = 7.3Hz), 6.67-
6.71 (2H, m), 6.83 (1H, d, J = 8.5Hz), 7.07 (2H, d, J =
7.7Hz), 7.19 (1H, t, J = 7.7Hz), 7.31-7.35 (2H, m), 7.9
3 (1H, s).

(11b) 1- (3,4-dimethoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid ethyl ester 2-[(N- (3,4-dimethoxyphenyl) -N-phenylamino) methylene] malonic acid diethyl (7.9 g) and polyphosphoric acid (60 g) were reacted in the same manner as in Production Example (2b). After purification, 910 mg of the title compound, 6,7-dimethoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester, was obtained as a white solid and 1- (3,4-dimethoxyphenyl). )
195 mg of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was obtained as a yellow solid. 6,7-dimethoxy-4-oxo-1-phenyl-1,
4-dihydroquinoline-3-carboxylic acid ethyl ester NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, t, J = 7.3H)
z), 6.70 (3H, s), 4.01 (3H, s), 4.39 (2H, q, J = 7.3H
z), 6.33 (1H, s), 7.45 (2H, dd, J = 2.1, 8.0Hz), 7.61-
7.67 (3H, m), 7.94 (1H, s), 8.43 (1H, s). Melting point: 191-192 ° C 1- (3,4-dimethoxyphenyl) -4-oxo-
1,4-dihydroquinoline-3-carboxylic acid ethyl ester NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, t, J = 7.3H)
z), 3.91 (3H, s), 4.00 (3H, s),, 4.41 (2H, q, J = 7.3H
z), 6.90 (1H, d, J = 2.2Hz), 6.99-7.05 (3H, m), 7.43 (1
H, t, J = 7.8Hz), 7.51-7.55 (1H, m), 8.53-8.56 (2H,
m). Melting point: 207-209 ° C.

(11c) 1- (3,4-dimethoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid 1- (3,4-dimethoxyphenyl) -4-oxo-
Using 580 mg of 1,4-dihydroquinoline-3-carboxylic acid ethyl ester and 3.0 g of sodium hydroxide, the reaction and post-treatment were carried out in the same manner as in Production Example (2c) to obtain 510 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.91 (3H, s), 4.01 (3
H, s), 6.89 (1H, d, J = 2.3Hz), 6.99-7.07 (2H, m), 7.2
0 (1H, d, J = 8.6Hz), 7.58 (1H, t, J = 7.5Hz), 7.70 (1H,
t, J = 8.0Hz), 8.57 (1H, dd, J = 1.3, 8.1Hz), 8.83 (1H,
s). (11d) 1- (3,4-dimethoxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-methyl-N-phenylamide 1- (3,4-dimethoxyphenyl) -4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 300 m
g, 505 mg of triethylamine, 200 mg of isobutyl chloroformate and 321 mg of N-methylaniline were reacted in the same manner as in Production Example (2d) to obtain 336 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.49 (3H, s), 3.87 (3
H, s), 3.98 (3H, s), 6.72 (1H, s), 6.84 (1H, br), 6.9
0-7.00 (7H, m), 7.12-7.20 (1H, m), 7.21-7.35 (5H, m),
7.45 (1H, t, J = 7.5 Hz), 7.79 (1H, br), 8.33 (1H, br).

Production Example 12 6-Methoxy-1- (4-methoxyphenyl) -4-o
Xo-1,4-dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide (Exemplary Compound No. 1-3
81) (12a) 2-[(bis- (4-methoxyphenyl) amino) methylene] malonic acid diethyl ester Produced using 10.6 g of bis- (4-dimethoxyphenyl) amine and 11.0 g of diethyl ethoxymethylenemalonate. The reaction was carried out and purified in the same manner as in Example (2a) to give 17.4.
g of the title compound were obtained as white crystals. NMR spectrum (CDCl ₃ ) δ ppm: 1.07 (3H, t, J = 7.2H)
z), 1.26 (3H, t, J = 7.2Hz), 3.53 (2H, q, J = 7.2Hz), 3.
80 (6H, s), 4.21 (2H, q, J = 7.2Hz), 6.85 (4H, d, J = 8.9H
z), 7.03 (4H, d, J = 8.9 Hz), 7.88 (1H, s). Melting point: 199-200 ° C.

(12b) 6-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester 2-[(bis- (4-methoxyphenyl) amino 1) g of diethyl methylene] malonate and 120 of polyphosphoric acid
Using g, the reaction was carried out and purified in the same manner as in Production Example (2b) to obtain 6.86 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 1.41 (3H, t, J = 7.2H)
z), 3.91 (3H, s), 3.92 (3H, s), 4.39 (2H, q, J = 7.2H
z), 6.94 (1H, d, J = 9.0Hz), 7.07-7.13 (3H, m), 7.27-
7.35 (2H, m), 7.96 (1H, d, J = 3.0 Hz), 8.45 (1H, s). Melting point: 196-199 ° C.

(12c) 6-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6-methoxy-1- (4-methoxyphenyl) -4-oxo The reaction was carried out in the same manner as in Production Example (2c) using 6.20 g of -1,4-dihydroquinoline-3-carboxylic acid ethyl ester and 30 ml of a 10% aqueous solution of potassium hydroxide to purify the compound, thereby obtaining 2.98 g of the title compound. Obtained as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.93 (3H, s), 3.97 (3
H, s), 7.07-7.14 (3H, m), 7.27 (1H, dd, J = 9.46, 2.9H
z), 7.33 (2H, dd, J = 7.04-1.98m), 7.90 (1H, d, J = 3.0H
z), 8.74 (1H, s). Melting point: 221-223 ° C.

(12d) 6-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide Obtained in Production Example (12c). 6-methoxy-1- (4-
(Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 300 mg, triethylamine 505 mg, isobutyl chloroformate 200 mg and N
Using 321 mg of -methylaniline, the reaction was carried out in the same manner as in Production Example (2d) to give the title compound as a white solid in 364 mg.
mg. NMR spectrum (CDCl ₃ ) δ ppm: 3.49 (3H, s), 3.87 (3
H, s), 3.90 (3H, s), 6.85 (1H, d, J = 9.1Hz), 7.00-7.3
5 (10H, m), 7.65-7.85 (2H, m). Melting point: 200 ° C.

Production Example 13 6,7-Dimethoxy-1-phenyl-4-oxo-1,
N-methyl 4-dihydroquinoline-3-carboxylate
N-phenylamide (Exemplary Compound No. 1-770) (13a) 6,7-dimethoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid 6 obtained in Production Example (11b) , 7-Dimethoxy-4-
Oxo-1-phenyl-1,4-dihydroquinoline-3
-5 ml of 3N hydrochloric acid was added to 3 ml of an ethanol solution of 770 mg of carboxylic acid ethyl ester, and the mixture was heated under reflux for 2 hours. After diluting the reaction solution with methylene chloride, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated solid was suspended in diisopropyl ether and collected by filtration to obtain 620 mg of the title compound. NMR spectrum (CDCl ₃ ) δ ppm: 3.74 (3H, s), 4.05 (3
H, s), 6.44 (1H, s), 7.44-7.47 (2H, m), 7.66-7.68 (3
H, m), 7.86 (1H, s), 8.70 (1H, s).

(13b) 6,7-Dimethoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide 7-dimethoxy-1-
Phenyl-4-oxo-1,4-dihydroquinoline-3
Carboxylic acid 250 mg, triethylamine 404 m
g, 137 mg of isobutyl chloroformate and 321 mg of N-methylaniline were reacted in the same manner as in Production Example (2d) to obtain 290 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.49 (3H, s), 3.65 (3
H, s), 3.96 (3H, s), 6.25 (1H, s), 7.14-7.35 (8H, m),
7.51-7.62 (4H, m), 7.69 (1H, br).

Production Example 14 6,7-Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N- (3-fluorophenyl) amide
(Exemplified Compound No. 1-1373) (14a) 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N- (3-fluorophenyl) amide 6,7-dimethoxy-1- obtained in Production Example (2c)
The reaction was carried out in the same manner as in Production Example (2d) using (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg), triethylamine (404 mg), isobutyl chloroformate (137 mg) and 3-fluoroaniline (333 mg). This gave 368 mg of the title compound as a white solid. NMR spectrum (DMSO-d6) δ ppm: 3.65 (3H, s), 3.89
(3H, s), 3.92 (3H, s), 6.45 (1H, s), 6.92 (1H, dt, J =
1.9, 7.8Hz), 7.23 (2H, d, J = 8.8Hz), 7.33-7.43 (2H,
m), 7.65 (2H, d, J = 8.8Hz), 7.72-7.82 (2H, m), 8.56 (1
H, s). (14b) 6,7-Dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N- (3-fluorophenyl) amide 6,7-dimethoxy-1- obtained in Production Example (14a)
(4-Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid A solution of 330 mg of N- (3-fluorophenyl) amide in 10 ml of N, N-dimethylformamide at room temperature with sodium hydride (55% 60 mg) and stirred at room temperature for 30 minutes, 426 mg of methyl iodide was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (methanol / methylene chloride = 5%)
The title compound was converted to a white solid by 305m.
g was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 3.48 (3H, s), 3.69 (3
H, s), 3.92 (3H, s), 3.96 (3H, s), 6.29 (1H, s), 6.87
(1H, dt, J = 2.1, 8.2Hz), 7.00-7.30 (7H, m), 7.68 (1H,
s). Melting point: 152 ° C.

Production Example 15 6,7-Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N- (3,5-difluorophenyl)
Amide (Exemplified Compound No. 1-983) (15a) 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N- (3,5-difluorophenyl) amide 6,7-dimethoxy-1- obtained in Production Example (2c)
(4-Methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 300 mg, triethylamine 404 mg, isobutyl chloroformate 137 mg and 3,5-difluoroaniline 387 mg were used in the same manner as in Production Example (2d). The reaction was performed to obtain 378 mg of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.67 (3H, s), 3.94 (3
H, s), 4.05 (3H, s), 6.44 (1H, s), 6.50-6.57 (1H, m),
7.12 (2H, d, J = 9.0Hz), 7.34-7.42 (4H, m), 7.89 (1H,
s), 8.76 (1H, s). (15b) 6,7-dimethoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide 6,7-dimethoxy-1- obtained in Production Example (15a)
A solution of 355 mg of (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N- (3,5-difluorophenyl) amide in 10 ml of N, N-dimethylformamide at room temperature with sodium hydride ( 5
(Containing 5%) and stirred at room temperature for 30 minutes.
426 mg of methyl iodide was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / methylene chloride = 5).
%) And the title compound was converted to a white solid by 31%.
4 mg were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 3.47 (3H, s), 3.70 (3
H, s), 3.92 (3H, s), 3.97 (3H, s), 6.32 (1H, s), 6.63
(1H, tt, J = 2.2, 8.9Hz), 6.90 (2H, dd, J = 1.9,8.0Hz),
7.08 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz), 7.69
(1H, s), 7.90 (1H, s). Melting point: 213 ° C.

Production Example 166-hydroxy-7-methoxy-1- (4-methoxyphenyl)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N-phenylamide (exemplary)
Compound No. 1-1354) (16a) 2-{[(3-methoxy-4-methoxymeth
[Xyphenyl)-(4-methoxyphenyl) amino] me
N- (3-methoxy-4-methoxymethoxyphenyl) diethylenedimalonate
-N- (4-methoxyphenyl) amine 2.0 g and eth
1.54 ml of a mixture of diethyl xymethylenemalonate
The mixture was stirred at 200 ° C. for 2.5 hours. The reaction mixture is
Ricagel column chromatography (elution solvent: cyclo
Hexane / ethyl acetate = 5/1 to 5/2)
This gave 2.57 g of the title compound as a red solid. NMR spectrum (CDCl_Three) δppm: 1.07 (3H, t, J = 7.3H
z), 1.26 (3H, t, J = 7.3Hz), 3.51 (3H, s), 3.55 (2H, q,
 J = 7.2Hz), 3.81 (6H, s), 4.21 (2H, q, J = 7.3Hz), 5.20
(2H, s), 6.59 (1H, dd, J = 2.5, 8.7Hz), 6.64 (1H, s),
6.86 (2H, d, J = 8.8Hz), 7.05-7.09 (3H, m), 7.87 (1H,
s). Melting point: 88-90 ° C (16b) 6- (t-butyldimethylsilyloxy)-
7-methoxy-1- (4-methoxyphenyl) -4-o
Oxo-1,4-dihydroquinoline-3-carboxylic acid 2-{[(3-methoxy-) obtained in Production Example (16a).
4-methoxymethoxyphenyl)-(4-methoxyfe
Nil) amino] methylene dimalonate
A mixture of 20 ml of water acetic acid and 10 ml of concentrated sulfuric acid was added, and 50
Stirred at C for 4 hours. Pour the reaction mixture into ice water and add ethyl acetate
Extracted. The ethyl acetate layer was washed with saturated saline and dried
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Remaining
The residue is mixed with 100ml of ethanol and 100ml of water
After suspending and adding 10 g of sodium hydroxide, 1 hour
Heated to reflux. Ethanol is distilled off under reduced pressure.
The aqueous solution was adjusted to pH 1 with dilute hydrochloric acid, and the precipitated solid was collected by filtration.
And washed with water and diethyl ether. The resulting solid
Dissolve in 100 ml of anhydrous N, N-dimethylformamide
And 17.6 g of imidazole and t-butyldimethyl
Add 17.3 g of silyl chloride and stir at 50 ° C for 2 hours
did. Dilute the reaction solution with aqueous citric acid solution and extract with ethyl acetate.
Issued. The ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate.
After drying with urea, the solvent was concentrated under reduced pressure. Silica gel residue
Column chromatography (elution solvent: n-hexane /
(Ethyl acetate = 2/1-0/1)
And 1- (4- (t-butyldimethylsilyloxy)-
3-methoxyphenyl) -6-methoxy-4-oxo-
The mixture of 1,4-dihydroquinoline-3-carboxylic acids is
5.2 g were obtained as a pale orange solid. NMR spectrum (CDCl_Three) δppm: 0.21, 0.23 and 0.25
(total 6H, each s), 1.02 and 1.04 (total 9H, each
s), 3.69, 3.83, 3.94 and 3.97 (total 6H, eachs), 6.
42-7.37 (5H, m), 7.88-7.90 (1H, m), 8.67 and 8.76 (to
tal 1H, each s). Melting point: 192 to 193 ° C. (16c) 6- (t-butyldimethylsilyloxy)-
7-methoxy-1- (4-methoxyphenyl) -4-o
Xo-1,4-dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide 6- (t-butyldimethyl) obtained in Production Example (16b)
Silyloxy) -7-methoxy-1- (4-methoxyphenyl)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid and 1- (4- (t-butyldimethylsilyl)
Oxy) -3-methoxyphenyl) -6-methoxy-4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid
5.2 g of a mixture of 2.47 ml of N-methylaniline,
3.18 ml of triethylamine and isobu chloroformate
Reaction in the same manner as in Production Example (2d) using 1.80 ml of chill
Was done. The obtained crude product was subjected to reverse phase HPLC (elution
Agent: acetonitrile / buffer = 65 / 35-80
/ 20 (buffer: water / acetic acid / triethylamine =
1000/2/2)) to give the title compound
1.87 g of 1- (4- (t-butyldimethyl) as a color solid
Tylsilyloxy) -3-methoxyphenyl) -6-meth
Toxi-4-oxo-1,4-dihydroquinoline-3-
Carboxylic acid N-methyl-N-phenylamide with yellow foam
3.61 g was obtained as a product. 6- (t-butyldimethylsilyloxy) -7-methoxy
C-1- (4-methoxyphenyl) -4-oxo-1,
4-dihydroquinoline-3-carboxylic acid N-methyl-
N-phenylamide NMR spectrum (CDCl_Three) δppm: 0.15 (6H, s), 0.98 (9
H, s), 3.48 (3H, s), 3.60 (3H, s), 3.90 (3H, s), 6.21
(1H, br s), 7.04 (2H, d, J = 9.0Hz), 7.14-7.29 (7H,
m), 7.60-7.80 (2H, br). Melting point: 196-201 ° C 1- (4- (t-butyldimethylsilyloxy) -3-
Methoxyphenyl) -6-methoxy-4-oxo-1,
4-dihydroquinoline-3-carboxylic acid N-methyl-
N-phenylamide NMR spectrum (CDCl_Three) δppm: 0.22 (6H, s), 1.03 (9
H, s), 3.50 (3H, s), 3.79 (3H, s), 3.88 (3H, s), 6.65
-6.80 (2H, br), 6.90 (1H, d, J = 9.2Hz), 6.96 (1H, d, J
= 8.1Hz), 7.06-7.09 (1H, m), 7.14-7.17 (1H, m), 7.23-
7.30 (4H, m), 7.70-7.85 (2H, br). (16d) 6-hydroxy-7-methoxy-1- (4-
Methoxyphenyl) -4-oxo-1,4-dihydroxy
Norin-3-carboxylic acid N-methyl-N-phenyla
Mid 6- (t-butyldimethyl) obtained in Production Example (16c)
Silyloxy) -7-methoxy-1- (4-methoxyphenyl)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N-phenylamide 900
mg of anhydrous tetrahydrofuran in 10 ml of suspension.
M-tetrabutylammonium fluoride-tetrahydride
4.96 ml of a lofuran solution was added dropwise under ice cooling. At room temperature
After stirring for 1 hour, the reaction was diluted with ethyl acetate. Organic layer
Was washed with aqueous citric acid solution and saturated saline solution,
After drying over magnesium, the solvent was distilled off under reduced pressure. From the residue
The precipitated solid was suspended in ethyl acetate and collected by filtration.
This was obtained as a white solid (540 mg). NMR spectrum (CDCl_Three) δppm: 3.48 (3H, s), 3.70 (3
H, s), 3.91 (3H, s), 6.23 (1H, s), 7.04 (2H, d, J = 8.8
Hz), 7.15-7.30 (7H, m), 7.67 (1H, br), 7.81 (1H, s). Melting point: 240 ° C Production Example 171- (4-hydroxy-3-methoxyphenyl) -6
Methoxy-4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N-phenylamide (exemplary)
Compound No. 1-1374) 1- (4- (t-Butyldi) obtained in Production Example (16c)
Methylsilyloxy) -3-methoxyphenyl) -6
Methoxy-4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N-phenylamide 1.0
g and 1.0 M tetrabutylammonium fluoride-
Production example using 5.51 ml of tetrahydrofuran solution
The reaction and purification were carried out in the same manner as (16d) to give the title compound as pale
647 mg were obtained as a yellow solid. NMR spectrum (CDCl_Three) δppm: 3.50 (3H, s), 3.87 (3
H, s), 3.88 (3H, s), 6.69-6.79 (2H, m), 6.90 (1H, d,
J = 9.1 Hz), 7.04-7.30 (7H, m), 7.70-7.85 (2H, br). Melting point: 235-237 ° C Production Example 187-methoxy-1- (4-methoxyphenyl) -4-o
Xo-1,4-dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide (Exemplary Compound No. 1-1
375) (18a) 2-{[(4-methoxyphenyl)-(3-
Methoxyphenyl) -amino] -methylene dimalonic acid
Diethyl ester (4-methoxyphenyl)-(3-methoxyphenyl)
7.50 g of amine and diethyl ethoxymethylenemalonate
The reaction was carried out in the same manner as in Production Example (2a) using 7.78 g of toluene.
12.6 g of the title compound were obtained as a colorless oil. NMR spectrum (CDCl_Three) δppm: 1.07 (3H, t, J = 7.3H
z), 1.26 (3H, t, J = 7.3Hz), 3.53 (2H, q, J = 7.3Hz), 3.
76 (3H, s), 3.82 (3H, s), 4.21 (2H, q, J = 7.3Hz), 6.58
(1H, s), 6.62 (1H, d, J = 8.1Hz), 6.70-6.74 (1H, m),
6.88 (2H, d, J = 8.8Hz), 7.08 (2H, d, J = 8.8Hz), 7.21 (1
H, dd, J = 8.1, 8.8 Hz), 7.92 (1H, s). (18b) 7-methoxy-1- (4-methoxyphenyl)
L) -4-oxo-1,4-dihydroquinoline-3-ca
Rubonic acid ethyl ester 2-{[(4-methoxyphenyl) obtained in Production Example (18a)
Enyl)-(3-methoxyphenyl) -amino] -methyl
11.7 g of lendemalonic acid diethyl ester
The reaction was carried out in the same manner as in Production Example (2b) using
Purification afforded 0.83 g of the title compound as a white solid.
Was. NMR spectrum (CDCl_Three) δppm: 1.40 (3H, t, J = 7.3H
z), 3.73 (3H, s), 3.92 (3H, s), 4.38 (2H, q, J = 7.3H
z), 6.34 (1H, d, J = 2.2Hz), 6.99 (1H, dd, J = 2.4, 8.8H
z), 7.09 (2H, d, J = 8.7Hz), 7.34 (2H, d, J = 8.4Hz), 8.
43 (1H, s), 8.47 (1H, d, J = 8.8Hz). Melting point: 146 ° C (18c) 7-methoxy-1- (4-methoxyphenyl)
L) -4-oxo-1,4-dihydroquinoline-3-ca
Rubonic acid 7-methoxy-1- (4-) obtained in Production Example (18d)
Methoxyphenyl) -4-oxo-1,4-dihydroxy
660 mg of noline-3-carboxylic acid ethyl ester,
4.0 g of potassium hydroxide, 10 ml of ethanol and water
The reaction was carried out in the same manner as in Production Example (2c) using 10 ml,
504 mg of the title compound were obtained as a white solid. NMR spectrum (CDCl_Three) δppm: 3.78 (3H, s), 3.93 (3H
H, s), 6.47 (1H, s), 7.09-7.16 (3H, m), 7.33 (2H, d,
J = 8.8Hz), 8.48 (1H, d, J = 8.8Hz), 8.73 (1H, s). Melting point: 220-223 ° C (decomposition) (18d) 7-methoxy-1- (4-methoxyphenyl)
L) -4-oxo-1,4-dihydroquinoline-3-ca
Rubonic acid N-methyl-N-phenylamide 7-methoxy-1- (4-
Methoxyphenyl) -4-oxo-1,4-dihydroxy
303 mg of noline-3-carboxylic acid, triethylamine
0.33 ml, anhydrous methylene chloride 5 ml, chloroformate
0.15 ml of sodium butyl and 1.0 of N-methylaniline
Using 1 ml, the reaction was carried out in the same manner as in Production Example (2d).
37 mg of the title compound were obtained as a white solid. NMR spectrum (DMSO-d₆) δppm: 3.32 (3H, s), 3.64
(3H, s), 3.86 (3H, s), 6.21 (1H, s), 6.98 (1H, dd, J =
1.5, 8.1Hz), 7.12-7.18 (3H, m), 7.22-7.34 (6H, m),
7.90 (1H, s), 8.03 (1H, d, J = 8.8Hz). Melting point: 149-150 ° C Production Example 193-{[6,7-dimethoxy-1- (4-methoxy
Nil) -4-oxo-1,4-dihydroquinoline-3-
Carbonyl] -methyl-amino} -thiophen-2-ca
Rubonic acid methyl ester (Exemplary Compound No. 1-137
6) (19a) 3-{[6,7-dimethoxy-1- (4-me
Toxiphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carbonyl] -amino} -thiophen-2-
Carboxylic acid methyl ester 6,7-dimethoxy-1- obtained in Production Example (2c)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid 425 mg, triethyl
Amine 0.42 ml, isobutyl chloroformate 0.19 m
1- and 3-aminothiophene-2-carboxylic acid methyl
As in Production Example (2d) using 1.88 g of
Reaction was carried out to obtain 516 mg of the title compound as a white solid.
Was. NMR spectrum (CDCl_Three) δppm: 3.74 (3H, s), 3.93 (3
H, s), 4.02 (3H, s), 4.04 (3H, s), 6.41 (1H, s), 7.1
1 (2H, d, J = 8.8Hz), 7.37 (2H, d, J = 8.8Hz), 7.47 (1H,
d, J = 5.9Hz), 8.11 (1H, s), 8.38 (1H, d, J = 5.9Hz), 8.
78 (1H, s). Melting point: 263-264 ° C. (19b) 3-{[6,7-dimethoxy-1- (4-meth
Toxiphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carbonyl] -methyl-amino} -thiophene
2-Carboxylic acid methyl ester 3-{[6,7-dimethoxy] obtained in Production Example (19a)
C-1- (4-methoxyphenyl) -4-oxo-1,
4-dihydroquinoline-3-carbonyl] -amino}-
Thiophene-2-carboxylic acid methyl ester 100m
g, DMF 2.5 ml, sodium hydride (containing 55%
Yes) using 16 mg and 0.038 ml of methyl iodide
And the reaction was carried out in the same manner as in Production Example (14b).
92 mg were obtained as a white solid. NMR spectrum (CDCl_Three) δppm: 3.41 (3H, s), 3.67 (3
H, s), 3.75 (3H, s), 3.91 (3H, s), 3.94 (3H, s), 6.
24 (1H, s), 7.00-7.42 (6H, m), 7.59 (1H, s), 7.77 (1H,
 s). Melting point: 199-201 ° C Production Example 203-{[6,7-dimethoxy-1- (4-methoxy
Nil) -4-oxo-1,4-dihydroquinoline-3-
Carbonyl] -ethyl-amino} -thiophen-2-ca
Rubonic acid methyl ester (Exemplary Compound No. 1-137
7) 3-{[6,7-dimethoxy] obtained in Production Example (19a)
C-1- (4-methoxyphenyl) -4-oxo-1,
4-dihydroquinoline-3-carbonyl] -amino}-
Thiophene-2-carboxylic acid methyl ester 155m
g, DMF 4 ml, sodium hydride (containing 55%) 2
Made using 5 mg and 0.075 ml of ethyl iodide
The reaction was carried out in the same manner as in Example (14b), and the title compound was converted into a white solid.
124 mg were obtained as a body. NMR spectrum (CDCl_Three) δppm: 1.21 and 1.27 (total
 3H, each t, J = 7.3Hz), 3.51 and 3.63 (total 3H, each
 s), 3.78-4.24 (8H, m), 6.23 (1H, s), 7.00-7.16 (3H,
m), 7.25-7.42 (3H, m), 7.56-7.62 (1H, m), 7.79 and
7.82 (total 1H, each s). Melting point: 151-152 ° C Production Example 216,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N- (pyridin-2-yl) amide
(Exemplified Compound No. 1-1378) (21a) 6,7-dimethoxy-1- (4-methoxyphenyl)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N- (pyridin-2-yl) amide 6,7-dimethoxy-1- obtained in Production Example (2c)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid 414mg, triethyl
Amine 0.41 ml, isobutyl chloroformate 0.20 m
Production example using l and 2-aminopyridine 1.10 g
The reaction was carried out in the same manner as in (2d), and the title compound was converted into a white solid.
313 mg were obtained. NMR spectrum (CDCl_Three) δppm: 3.74 (3H, s), 3.94 (3
H, s), 4.04 (3H, s), 6.42 (1H, s), 7.01 (1H, dd, J = 5.
1, 8.3Hz), 7.09-7.13 (2H, m), 7.35-7.39 (2H, m), 7.6
6-7.71 (1H, m), 7.96 (1H, s), 8.31 (1H, d, J = 8.1Hz),
8.37-8.39 (1H, m), 8.76 (1H, s). Melting point: 260-262 ° C (21b) 6,7-dimethoxy-1- (4-methoxyphenyl)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N- (pyridine-2-i
B) 6,7-Dimethoxy-1- obtained in Production Example (21a)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid N- (pyridine-2-
Yl) amide 120mg, DMF2ml, hydrogenated sodium
22% (containing 55%) and methyl iodide 0.0
The reaction was carried out in the same manner as in Production Example (175b) using 52 ml.
Thus, 41 mg of the title compound was obtained as a pale yellow-white solid. NMR spectrum (CDCl_Three) δppm: 3.78 (3H, s), 3.96 (3H
H, s), 4.10 (3H, s), 4.73 (3H, s), 6.47 (1H, s), 7.16
(2H, d, J = 8.8Hz), 7.40 (2H, d, J = 8.8Hz), 7.59 (1H,
t, J = 6.6Hz), 7.90 (1H, s), 8.23 (1H, dd, J = 8.1, 8.8H
z), 8.76 (1H, s), 9.03 (1H, d, J = 8.8Hz), 9.92 (1H, d,
J = 6.6Hz). Melting point: 175-177 ° C Production Example 226,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
N-ethyl-N- (pyridin-2-yl) amide acid
(Exemplified Compound No. 1-1379) 6,7-Dimethoxy-1- obtained in Production Example (21a)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid N- (pyridine-2-
Yl) amide 100mg, DMF2.5ml, hydrogenated
22 mg of thorium (containing 55%) and ethyl iodide
Reaction in the same manner as in Production Example (14b) using 0.067 ml
Was performed to obtain 36 mg of the title compound as a white solid. NMR spectrum (CDCl_Three) δppm: 1.26 (3H, t, J = 7.3H
z), 3.67 (3H, s), 3.91 (3H, s), 3.92 (3H, s), 4.12 (2
(H, q, J = 7.3Hz), 6.29 (1H, s), 7.03-7.06 (3H, m), 7.21
-7.25 (2H, m), 7.41 (1H, d, J = 8.1Hz), 7.60-7.65 (2H,
m), 7.91 (1H, d, J = 8.8Hz), 8.30 (1H, dd, J = 2.2, 5.9H
z). Melting point: 153-156 ° C Production Example 236,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
N-ethyl-N- (pyridin-3-yl) amide acid
(Exemplary Compound No. 1-1381) (23a) 6,7-dimethoxy-1- (4-methoxyphenyl)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N- (pyridin-3-yl) amide 6,7-dimethoxy-1- obtained in Production Example (2c)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid 300 mg, triethyl
Amine 0.29 ml, isobutyl chloroformate 0.13 m
Production example using l and 3-aminopyridine 794 mg
The reaction was carried out in the same manner as in (2d), and the title compound was converted into a white solid.
123 mg were obtained. NMR spectrum (CDCl_Three) δppm: 3.76 (3H, s), 3.94 (3H
H, s), 4.06 (3H, s), 6.45 (1H, s), 7.12 (2H, d, J = 8.8
Hz), 7.27-7.30 (1H, m), 7.31-7.38 (2H, m), 7.91 (1H, m
s), 8.28-8.37 (2H, m), 8.79 (1H, m), 8.91 (1H, d, J =
Melting point: 249-250 ° C (23b) 6,7-dimethoxy-1- (4-methoxyph)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-ethyl-N- (pyridine-3-i
B) Amide 6,7-dimethoxy-1- obtained in Production Example (23a)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid N- (pyridine-3-
Yl) amide 70mg, DMF2.5ml, hydrogenated nato
13 mg of lithium (containing 55%) and 0.1% of ethyl iodide.
The reaction was carried out in the same manner as in Production Example (175b) using 039 ml.
This gave 25 mg of the title compound as a pale yellow-white solid. NMR spectrum (CDCl_Three) δppm: 1.22 (3H, t, J = 7.3H
z), 3.67 (3H, s), 3.91 (3H, s), 3.92 (3H, s), 3.98 (2
H, q, J = 7.3Hz), 6.26 (1H, s), 6.70 (1H, s), 7.07 (2H,
 d, J = 8.8Hz), 7.26-7.32 (2H, m), 7.53 (1H, br), 7.83
(1H, dd, J = 1.5, 8.1Hz), 7.92 (1H, s), 8.37 (2H, br). Melting point: 204-207 ° C Production Example 246,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Acid N-methyl-N- (pyridin-4-yl) amide
(Exemplary Compound No. 1-1382) (24a) 6,7-dimethoxy-1- (4-methoxyphenyl)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N- (pyridin-4-yl) amide 6,7-dimethoxy-1- obtained in Production Example (2c)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid 300 mg, triethyl
Amine 0.29 ml, isobutyl chloroformate 0.13 m
Production example using l and 4-aminopyridine 794 mg
The reaction was carried out in the same manner as in (2d), and the title compound was converted into a white solid.
306 mg were obtained. NMR spectrum (CDCl_Three) δppm: 3.76 (3H, s), 3.95 (3
H, s), 4.06 (3H, s), 6.45 (1H, s), 7.10-7.16 (2H, m),
 7.34-7.40 (2H, m), 7.68-7.72 (2H, m), 7.90 (1H, s),
8.51-8.53 (2H, m), 8.78 (1H, s). Melting point: 261-263 ° C (24b) 6,7-dimethoxy-1- (4-methoxyph)
Enyl) -4-oxo-1,4-dihydroquinoline-3
-Carboxylic acid N-methyl-N- (pyridine-4-i
B) 6,7-Dimethoxy-1- obtained in Production Example (24a)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid N- (pyridine-4-
Yl) amide 70mg, DMF1ml, sodium hydride
(Containing 55%) and methyl iodide 0.03
The reaction was carried out in the same manner as in Production Example (14b) using 0 ml,
42 mg of the title compound were obtained as a white solid. NMR spectrum (CD_ThreeOD) δppm: 3.71 (3H, s), 3.94 (3
H, s), 3.99 (3H, s), 4.23 (3H, s), 6.53 (1H, s), 7.24
(2H, d, J = 8.8Hz), 7.54 (2H, d, J = 8.8Hz), 7.87 (1H,
s), 8.26 (2H, d, J = 7.3Hz), 8.63 (2H, d, J = 7.3Hz), 8.
77 (1H, s). Melting point: 214-217 ° C (decomposition) Production Example 256,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid
N-ethyl-N- (pyridin-4-yl) amide acid
(Exemplary Compound No. 1-1383) 6,7-Dimethoxy-1- obtained in Production Example (24a)
(4-methoxyphenyl) -4-oxo-1,4-dihi
Droquinoline-3-carboxylic acid N- (pyridine-4-
Yl) amide 70mg, DMF1ml, sodium hydride
(Containing 55%) 13mg, ethyl iodide 0.039m
The reaction was carried out in the same manner as in Production Example (14b) using
21 mg of the compound was obtained as a white solid. NMR spectrum (CD_ThreeOD) δppm: 1.22 (3H, t, J = 7.3H
z), 3.66 (3H, s), 3.87 (3H, s), 3.91 (3H, s), 4.04 (2
H, q, J = 7.3Hz), 6.42 (1H, s), 7.19 (2H, d, J = 7.3Hz),
 7.36-7.41 (4H, m), 7.55 (1H, s), 8.12 (1H, s), 8.41
(2H, d, J = 6.6Hz). Melting point: 165-169 ° C Production Example 261- (4-hydroxyphenyl) -6,7-dimethoxy
-4-oxo-1,4-dihydroquinoline-3-carbo
Acid N-methyl-N-phenylamide (exemplified compound number
No. 1-827) (26a) 2-{[(3,4-dimethoxyphenyl)-
(4-methoxymethoxyphenyl) -amino] -methyl
Dimethyl dimalonate (3,4-dimethoxyphenyl)-(4-methoxymethoate)
5.79 g of (xyphenyl) -amine and ethoxymethylene
Production Example (2a) using 4.44 ml of diethyl malonate
And purify the title compound as a white solid.
8.60 g was obtained. NMR spectrum (CDCl_Three) δppm: 1.07 (3H, t, J = 7.1H
z), 1.26 (3H, t, J = 7.1Hz), 3.48 (3H, s), 3.55 (2H, q,
 J = 7.2Hz), 3.82 (3H, s), 3.88 (3H, s), 4.21 (2H, q, J =
7.1Hz), 5.16 (2H, s), 6.64-6.68 (2H, m), 6.81 (1H, d,
 J = 9.4Hz), 6.95-7.06 (4H, m), 7.87 (1H, s). Melting point: 94-96 ° C (26b) 1- (4-acetoxyphenyl) -6,7-
Dimethoxy-4-oxo-1,4-dihydroquinoline-
3-Carboxylic acid ethyl ester 2-{[(3,4-dimethoate) obtained in Production Example (26a)
(Xyphenyl)-(4-methoxymethoxyphenyl)-
Amino] -methylene dimalonate in 8.60 g
A mixture of 20 ml of water acetic acid and 10 ml of concentrated sulfuric acid was added, and 50
Stirred at C for 4 hours. Pour the reaction mixture into ice water and add ethyl acetate
Extracted. The ethyl acetate layer was washed with saturated saline and dried
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Remaining
The residue is subjected to silica gel column chromatography (eluent:
(Dichloromethane / ethyl acetate = 1/1)
1- (4-acetoxyphenyl)-which is the title compound
6,7-dimethoxy-4-oxo-1,4-dihydroxy
Norin-3-carboxylic acid ethyl ester was converted to a white solid.
4.69 g, and 6-acetoxy-1- (3,4
-Dimethoxyphenyl) -4-oxo-1,4-dihydrido
Roquinoline-3-carboxylic acid ethyl ester
320 mg were obtained as a body. 1- (4-acetoxyphenyl) -6,7-dimethoxy
-4-oxo-1,4-dihydroquinoline-3-carbo
Acid ethyl ester NMR spectrum (CDCl_Three) δppm: 1.41 (3H, t, J = 7.1H
z), 2.38 (3H, s), 3.72 (3H, s), 4.00 (3H, s), 4.39 (2
H, q, J = 7.1Hz), 6.33 (1H, s), 7.38 (2H, d, J = 8.8Hz),
 7.48 (2H, d, J = 8.8Hz), 7.93 (1H, s), 8.42 (1H, s). Melting point: 188-189 ° C 6-acetoxy-1- (3,4-dimethoxyphenyl)
-4-oxo-1,4-dihydroquinoline-3-carbo
Acid ethyl ester NMR spectrum ((CDCl_Three) δppm: 1.40 (3H, t, J = 7.1H
z), 2.34 (3H, s), 3.90 (3H, s), 4.00 (3H, s), 4.40 (2
H, q, J = 7.1Hz), 6.87-7.35 (5H, m), 8.20 (1H, s), 8.
52 (1H, s). Melting point: 72-75 ° C. (26c) 1- (4-hydroxyphenyl) -6,7-
Dimethoxy-4-oxo-1,4-dihydroquinoline-
3-Carboxylic acid ethyl ester 1- (4-acetoxyphen) obtained in Production Example (26b)
Nyl) -6,7-dimethoxy-4-oxo-1,4-di
Hydroquinoline-3-carboxylic acid ethyl ester
To a 44 g ethanol solution 20 ml at room temperature
715 mg of toxide was added and the mixture was stirred for 2 hours. Reaction solution
After concentration under reduced pressure, the residue was dissolved in methylene chloride. Organic layer
Wash with diluted hydrochloric acid and saturated saline, and dry with sodium sulfate
After drying, the solvent was concentrated under reduced pressure to give the title compound as a white solid.
1.29 g were obtained. NMR spectrum (DMSO-d6) δ ppm: 1.25 (3H, t, J = 7.1)
Hz), 3.62 (3H, s), 3.87 (3H, s), 4.20 (2H, q, J = 7.0H
z), 6.37 (1H, s), 7.00 (2H, d, J = 8.7Hz), 7.43 (2H, d,
 J = 8.7Hz), 7.65 (1H, s), 8.30 (1H, s). Melting point: 133-135 ° C (26d) 6,7-dimethoxy-1- (4-methoxymeth
Toxiphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carboxylic acid methyl ester 1- (4-hydroxyphene) obtained in Production Example (26c)
Nyl) -6,7-dimethoxy-4-oxo-1,4-di
Hydroquinoline-3-carboxylic acid ethyl ester
20 g of DMF solution in 29 g of sodium hydride was added at 0 ° C.
168 mg and stirred for 10 minutes.
0.44 ml of methyl ether was added, and the temperature was raised to room temperature to obtain 2
Stirred for hours. Add methanol to the reaction mixture and stir for a while.
After stirring, the solvent was concentrated under reduced pressure, and the residue was diluted with methylene chloride.
I shouted. Wash the organic layer with saturated aqueous sodium bicarbonate and saturated saline
After drying over sodium sulfate, the solvent was concentrated under reduced pressure.
Was. The residue was purified by silica gel column chromatography (Ace
Ton / dichloromethane = 1/2)
845 mg of the compound was obtained as a white solid. NMR spectrum (CDCl_Three) δppm: 3.55 (3H, s), 3.73 (3
H, s), 3.92 (3H, s), 4.01 (3H, s), 5.28 (2H, s), 6.36
(1H, s), 7.25 (2H, d, J = 8.8Hz), 7.35 (2H, d, J = 8.8H
z), 7.93 (1H, s), 8.43 (1H, s). Melting point: 205-208 ° C (26e) 6,7-dimethoxy-1- (4-methoxymeth)
Toxiphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carboxylic acid 6,7-dimethoxy-1- obtained in Production Example (26d)
(4-methoxymethoxyphenyl) -4-oxo-1,
4-dihydroquinoline-3-carboxylic acid methyl ester
Sodium hydroxide in 10 ml of 845 mg ethanol solution
20 mg of an aqueous solution of 200 mg of
Stirred for hours. Cool the reaction to 0 ° C. until pH 3
Hydrochloric acid was added thereto, and this was extracted with methylene chloride. Organic layer
Was dried over sodium sulfate and concentrated under reduced pressure to give the title compound.
Was obtained as a yellow solid. NMR spectrum (CDCl_Three) δppm: 3.56 (3H, s), 3.77 (3
H, s), 4.05 (3H, s), 5.30 (2H, s), 6.48 (1H, s), 7.26
(2H, d, J = 8.8Hz), 7.35 (2H, d, J = 8,8Hz), 7.86 (1H,
s), 8.68 (1H, s). Melting point: 174-178 ° C (26f) 6,7-dimethoxy-1- (4-methoxymeth)
Toxiphenyl) -4-oxo-1,4-dihydroquino
Phosphorus-3-carboxylic acid N-methyl-N-phenyl-a
Mido 6,7-dimethoxy-1- obtained in Production Example (26d)
(4-methoxymethoxyphenyl) -4-oxo-1,
814 mg of 4-dihydroquinoline-3-carboxylic acid,
0.74 ml of triethylamine, isobutyl chloroformate
0.33 ml and 2.29 ml of N-methylaniline
The reaction was carried out in the same manner as in Production Example (2d) using the title compound
Was obtained as a yellow solid. NMR spectrum (CDCl_Three) δppm: 3.49 (3H, s), 3.54 (3
H, s), 3.68 (3H, s), 3.96 (3H, s), 5.26 (2H, s), 6.27
(1H, s), 7.10-7.30 (9H, m), 7.60-7.73 (2H, m). Melting point: 71-73 ° C (26 g) 1- (4-hydroxyphenyl) -6,7-
Dimethoxy-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid N-methyl-N-phenylamide 6,7-dimethoxy-1- obtained in Production Example (26f)
(4-methoxymethoxyphenyl) -4-oxo-1,
4-dihydroquinoline-3-carboxylic acid N-methyl-
1.00 g of N-phenylamide, 10 ml of concentrated hydrochloric acid, TH
F10ml was mixed and stirred at 60 ° C for 30 minutes. reaction
Dilute the solution with methylene chloride and dilute the organic layer with water and saturated
After washing with brine, it was dried over sodium sulfate. Reduce solvent
Concentration under pressure gave 789 mg of the title compound as a yellow solid.
Was. NMR spectrum (CDCl_Three) δppm: 3.52 (3H, s), 3.68 (3
H, s), 3.94 (3H, s), 6.34 (1H, s), 6.93-7.40 (9H, m),
 7.60-7.80 (2H, m). Melting point: 149-152 ° C Example 1 Measurement of Bile Acid Transporter Inhibitory Activity Male Syrian golden hamster was used for the experiment.
Animals are kept in metal cages with free access to food and water.
Was. Compound of the present invention is 0.5% carboxymethyl cellulose
Oral administration (100 mg / 10 ml / kg) as a suspension in
Was. 1.5 hours after administration, [^ThreeH] -Tauroko
Luic acid (37 KBq) was administered orally. [^ThreeH] -Taurocholic acid
Dissection of the hamster 24 hours after oral administration of gallbladder
Juice was collected and the radioactivity in gallbladder bile was determined. Invention of the present application
Radioactivity of the control determined without using the compound
Inhibition from radioactivity when using a constant concentration of the compound of the present invention
The rate (%) was determined. As a result, the compound of the present invention was excellent.
Ileal bile acid transporter inhibitory activity.

Example 2 Hamster everted ileal ri
Measurement of ileal bile acid transporter inhibitory activity using ngs) The measurement of ileal bile acid transporter inhibitory activity in this test example is described in [Pharm. Res., 12, 693-699 (1995)]. This was performed according to the method of Stewart et al.

That is, a hamster inverted intestinal ring was used as a material for the ileal bile acid transporter. A 5-7 week old male Syrian hamster was anesthetized with ether, and the ileum was extirpated about 10 cm from the blind end and inverted. One rat inverted intestinal ring was obtained. In order to correct the difference in the expression level of the bile acid transporter depending on the site of the ileum, rings were appropriately selected from the upper and lower parts of the ileum, and three rings were used as a group to make a total of five groups. One of the five groups was a control group to which no sample was added.
One group (background group) to which 0-fold higher concentration of non-radiolabeled taurocholic acid was added was provided. The remaining three groups were groups to which various samples were added. Each ring was loaded with radioactive taurocholic acid by an ileal bile acid transporter while shaking each ring in 1 ml of a radioactive taurocholic acid solution at 37 ° C. for 5 minutes at a speed of 90 rpm. The composition of the radioactive taurocholic acid solution is composed of 1.0 μCi radioactive taurocholic acid, 0.037 mM non-radioactive taurocholic acid (however, the background group is 37 mM), various samples at appropriate concentrations, and Ringer's buffer. After the ring was washed three times with Ringer's buffer, the wet weight was measured, placed in a vial, and the tissue lysing agent NCS-II (AMERSH) was used.
AM) (0.5 ml) and left at 50 ° C. overnight to completely dissolve. 2.5 ml of liquid scintillation cocktail was added and the radioactivity was measured on a liquid scintillation counter.

The ileal bile acid transporter activity was determined by correcting the radioactivity incorporated in each ring by wet weight,
After expressing the activity in m / mg (radioactivity per 1 mg), the average value of the background group was subtracted from the average value of each group to determine the activity, and the concentration of the compound of the present invention was 30 μg /
The inhibition rate of the ileal bile acid transporter activity when the amount was set to ml was determined. As a result, the compound of the present invention exhibited excellent ileal bile acid transporter inhibitory activity. [Table 3] ---------------------------------------------- ------ Production example Compound number Inhibition rate (%) ----------------------------------- ----------------- 548.3 155.5 ------------------------- ---------------------------.

Formulation Example 1 Tablet Compound of Preparation Example 15 10 mg Lactose 68.5 Crystalline Cellulose 20 Carboxymethyl starch Sodium 5 Light Silicic Anhydride 0.5 Magnesium Stearate 1 105 mg

[0382]

The compounds having general formulas (I) and (II) of the present invention are useful as ileal bile acid transporter inhibitors.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Keita Kono, inventor, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Ken Kitayama 1-2-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Toru Hasegawa 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term (reference) 4C031 PA06 4C086 AA01 AA02 BC29 MA01 MA04 NA14 ZA45 ZC20 ZC33

Claims (44)

[Claims] 1. A compound of the general formula (Ia) [Wherein, R ¹ , R ² , R ³ and R ⁴ are the same or different and are each a hydrogen atom,
A hydroxy group or a lower alkoxy group; R ⁵ represents an aryl group or an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups; R ⁶ represents a group having the formula —CONR ⁷ R ⁸ (Wherein, R ⁷ represents a C ₁ -C ₁₀ alkyl group or a C ₂ -C ₁₀ alkenyl group, and R ⁸ is a group selected from an aryl group, an aromatic heterocyclic group, and a substituent group a. To 5 to 5 substituted aryl groups or an aromatic heterocyclic group substituted by 1 to 5 groups selected from a substituent group a), provided that R ² is a hydrogen atom and R ³ is When it is a lower alkoxy group, R ⁵ represents a hydroxy group or an aryl group substituted with 1 to 5 lower alkoxy groups. A nitrogen-containing heterocyclic derivative having the formula:
A medicament containing its pharmacologically acceptable salt, its ester or other derivative. <Substituent group a> halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group,
A lower alkylthio group, a lower aliphatic acyloxy group, an aromatic acyloxy group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a carboxy group and a lower alkoxycarbonyl group. 2. The pharmaceutical composition according to claim 1, wherein R ¹ and R ⁴ are each a hydrogen atom or a pharmaceutically acceptable salt thereof. 3. The medicament according to claim 1, wherein R ² is a hydrogen atom or a pharmacologically acceptable salt thereof. 4. A medicament comprising the compound according to claim 1 or 2, wherein R ² is a hydroxy group or a lower alkoxy group, or a pharmaceutically acceptable salt thereof. 5. A medicament comprising the compound according to any one of claims 1 to 4, wherein R ³ is a hydroxy group or a lower alkoxy group, or a pharmaceutically acceptable salt thereof. 6. The pharmaceutical composition according to claim 1, wherein R ⁵ is an aryl group or a pharmacologically acceptable salt thereof. 7. The compound according to claim 1, wherein R ⁵ is an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups, or a pharmaceutically acceptable compound thereof. Pharmaceuticals containing salts. 8. The compound according to claim 1, wherein R ⁵ is an aryl group substituted with one or two hydroxy groups or lower alkoxy groups, or a pharmaceutically acceptable compound thereof. Pharmaceuticals containing salts. 9. The method according to claim 1, wherein R ⁵ is 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl. Or a pharmacologically acceptable salt thereof. 10. A medicament comprising a compound according to any one of claims 1 to 9 wherein R ⁷ is a C ₁ -C ₁₀ alkyl group or a pharmaceutically acceptable salt thereof. 11. A medicament comprising the compound according to any one of claims 1 to 9, wherein R ⁷ is a C ₁ -C ₆ alkyl group, or a pharmaceutically acceptable salt thereof. 12. A medicament comprising the compound according to any one of claims 1 to 9, wherein R ⁷ is a C ₁ -C ₄ alkyl group, or a pharmaceutically acceptable salt thereof. 13. A medicament comprising the compound according to any one of claims 1 to 9, wherein R ⁷ is a methyl group or an ethyl group, or a pharmacologically acceptable salt thereof. 14. The aromatic heterocyclic group according to any one of claims 1 to 13, wherein R ⁸ is substituted with 1 to 5 aromatic heterocyclic groups or a group selected from substituent group a. A medicament comprising a compound which is a cyclic group or a pharmacologically acceptable salt thereof. 15. The compound according to any one of claims 1 to 13, wherein R ⁸ is an aryl group or an aryl group substituted with 1 to 5 aryl groups or a group selected from substituent group a. A medicament containing its pharmacologically acceptable salt. 16. The compound according to any one of claims 1 to 13, wherein R ⁸ is an aryl group or an aryl group substituted by one or two aryl groups or a group selected from substituent group a. A medicament containing its pharmacologically acceptable salt. 17. The method according to claim 1, wherein R ⁸ is an aryl group or an aryl group having 1 or 2 substituents, wherein the substituent is a halogen atom, a hydroxy group, A lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group) or a pharmacologically acceptable salt thereof. 18. The method according to any one of claims 1 to 13, wherein R ⁸ is an aryl group or an aryl group having 1 or 2 substituents (the substituent is a halogen atom, a hydroxy group, Or a pharmacologically acceptable salt thereof. 19. The method of claim 1, wherein R ⁸ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, -Methoxyphenyl,
A medicament containing a compound which is a 3,4-difluorophenyl, 3,5-difluorophenyl or 3,5-dichlorophenyl group or a pharmacologically acceptable salt thereof. 20. The medicament according to claim 1, comprising any one compound selected from the following or a pharmacologically acceptable salt thereof. 1- (4-hydroxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 1- (4-hydroxyphenyl) -6 7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-hydroxyphenyl) -6,7-dimethoxy-4-oxo-1,4 -Dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-methoxyphenyl) -6,7-dimethoxy-
4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-methoxyphenyl) -6,7-dimethoxy-
4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl)
Amide, 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (4-methoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-methoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid Acid N-methyl-N- (4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4- Dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl)
Amide, 6,7-dimethoxy-1- (4-hydroxyphenyl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4- Dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N
-Ethyl-N- (3,5-difluorophenyl) amide, 1- (4-methoxyphenyl) -7-dimethoxy-4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-ethyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N
-Methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-hydroxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-methyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-ethyl-N- (3,5-difluorophenyl) amide, 1- (4-hydroxyphenyl) -7-dimethoxy-4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-methyl-N-phenylamide, and 7-methoxy-
1- (4-hydroxyphenyl) -4-oxo-1,4
-Dihydroquinoline-3-carboxylic acid N-methyl-N
-(3-fluorophenyl) amide. 21. A compound of the general formula (I) Or the general formula (II): [Wherein, R ¹ , R ² , R ³ , and R ⁴ are the same or different and are each a hydrogen atom,
A hydroxy group or a lower alkoxy group; R ⁵ represents an aryl group or an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups; R ⁶ represents a group having the formula —CONR ⁷ R ⁸ (Wherein, R ⁷ represents a C ₁ -C ₁₀ alkyl group or a C ₂ -C ₁₀ alkenyl group, and R ⁸ is a group selected from an aryl group, an aromatic heterocyclic group, and a substituent group a. To 5-substituted aryl groups or aromatic heterocyclic groups substituted with 1 to 5 substituents selected from a group selected from substituent group a.). ], A pharmacologically acceptable salt thereof, an ester or other derivative thereof, and an ileal bile acid transporter inhibitor. <Substituent group a> halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group,
A lower alkylthio group, a lower aliphatic acyloxy group, an aromatic acyloxy group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a carboxy group and a lower alkoxycarbonyl group. 22. The ileal bile acid transporter inhibitor according to claim 21, which comprises the compound having the general formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof. 23. The ileal bile acid transporter inhibitor according to claim 21, which comprises a compound having the general formula (II), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof. 24. The ileal bile acid transporter inhibitor according to any one of claims 21 to 23, which comprises a compound wherein R ¹ and R ⁴ are hydrogen atoms or a pharmacologically acceptable salt thereof. Agent. 25. The ileal bile acid transporter inhibitor according to any one of claims 21 to 24, comprising a compound wherein R ² is a hydrogen atom or a pharmaceutically acceptable salt thereof. 26. The ileal bile acid transporter according to any one of claims 21 to 24, which comprises a compound wherein R ² is a hydroxy group or a lower alkoxy group, or a pharmacologically acceptable salt thereof. Inhibitors. 27. The ileal bile acid transporter according to any one of claims 21 to 26, comprising a compound wherein R ³ is a hydroxy group or a lower alkoxy group, or a pharmacologically acceptable salt thereof. Inhibitors. 28. The ileal bile acid transporter inhibitor according to any one of claims 21 to 27, comprising a compound wherein R ⁵ is an aryl group or a pharmacologically acceptable salt thereof. 29. The compound according to any one of claims 21 to 27, wherein R ⁵ is an aryl group substituted with 1 to 5 hydroxy groups or lower alkoxy groups, or a pharmaceutically acceptable compound thereof. An ileal bile acid transporter inhibitor containing a salt. 30. A compound according to any one of claims 21 to 27, wherein R ⁵ is an aryl group substituted with one or two hydroxy groups or lower alkoxy groups, or a pharmaceutically acceptable compound thereof. An ileal bile acid transporter inhibitor containing a salt. 31. The method according to any one of claims 21 to 27, wherein R ⁵ is 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl An ileal bile acid transporter inhibitor comprising a compound as a group or a pharmacologically acceptable salt thereof. 32. The ileal bile acid trans-compound according to any one of claims 21 to 31, comprising a compound wherein R ⁷ is a C ₁ -C ₁₀ alkyl group or a pharmaceutically acceptable salt thereof. Porter inhibitor. 33. The ileal bile acid trans-compound according to any one of claims 2 to 31, comprising a compound wherein R ⁷ is a C ₁ -C ₆ alkyl group or a pharmacologically acceptable salt thereof. Porter inhibitor. 34. The ileal bile acid trans-compound according to any one of claims 21 to 31, comprising a compound wherein R ⁷ is a C ₁ -C ₄ alkyl group or a pharmacologically acceptable salt thereof. Porter inhibitor. 35. The ileal bile acid transporter inhibitor according to any one of claims 2 to 31, wherein the compound is a compound wherein R ⁷ is a methyl group or an ethyl group, or a pharmacologically acceptable salt thereof. Agent. 36. The aromatic heterocyclic group according to any one of claims 21 to 35, wherein R ⁸ is substituted with 1 to 5 aromatic heterocyclic groups or a group selected from substituent group a. An ileal bile acid transporter inhibitor comprising a compound that is a cyclic group or a pharmacologically acceptable salt thereof. 37. The compound according to any one of claims 21 to 35, wherein R ⁸ is an aryl group or an aryl group substituted with 1 to 5 groups selected from a substituent group a, or An ileal bile acid transporter inhibitor comprising a pharmacologically acceptable salt thereof. 38. The compound according to any one of claims 21 to 35, wherein R ⁸ is an aryl group or an aryl group substituted by one or two groups selected from a substituent group a, or An ileal bile acid transporter inhibitor comprising a pharmacologically acceptable salt thereof. 39. The method according to any one of claims 21 to 35, wherein R ⁸ is an aryl group or an aryl group having 1 or 2 substituents (the substituent is a halogen atom, a hydroxy group, An ileal bile acid transporter inhibitor comprising a compound selected from a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group) or a pharmaceutically acceptable salt thereof. 40. The method according to any one of claims 21 to 35, wherein R ⁸ is an aryl group or an aryl group having 1 or 2 substituents (the substituent is a halogen atom, a hydroxy group, Or a pharmacologically acceptable salt thereof, which is a group selected from lower alkoxy groups). 41. The method according to any one of claims 21 to 35, wherein R ⁸ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, -Methoxyphenyl,
An ileal bile acid transporter inhibitor comprising a compound that is a 3,5-difluorophenyl or 3,5-dichlorophenyl group or a pharmacologically acceptable salt thereof. 42. The ileal bile acid transporter inhibitor according to claim 21, comprising any one compound selected from the following or a pharmacologically acceptable salt thereof. 1- (4-hydroxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 1- (4-hydroxyphenyl) -6 7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-hydroxyphenyl) -6,7-dimethoxy-4-oxo-1,4 -Dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl) -4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-methoxyphenyl) -6,7-dimethoxy-
4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-methoxyphenyl) -6,7-dimethoxy-
4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl)
Amide, 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (4-methoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-methoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid Acid N-methyl-N- (4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -6,7,8-trimethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 7-methoxy-1-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 6,7- Dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4- Dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide, 6,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl)
Amide, 6,7-dimethoxy-1- (4-hydroxyphenyl)
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, 6,7-dimethoxy-1- (4-methoxyphenyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4- Dihydroquinoline-3-carboxylic acid N
-Methyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N
-Ethyl-N- (3,5-difluorophenyl) amide, 1- (4-methoxyphenyl) -7-dimethoxy-4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-ethyl-N-phenylamide, 7-methoxy-1- (4-methoxyphenyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid N
-Methyl-N- (3-fluorophenyl) amide, 7-methoxy-1- (4-hydroxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-methyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-ethyl-N- (3,5-difluorophenyl) amide, 1- (4-hydroxyphenyl) -7-dimethoxy-4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-methyl-N-phenylamide, 7-methoxy-1- (4-hydroxyphenyl) -4-
Oxo-1,4-dihydroquinoline-3-carboxylic acid
N-methyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6, 7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6, 7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7,8-Trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7,8-Trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (4-methoxyphenyl) amide, 1- (3,4-dimethoxyphenyl) -4-hydroxy- 6,7,8-Trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7 , 8-Trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-
(4-fluorophenyl) amide, 1- (3,4-dimethoxyphenyl) -4-hydroxy-6,7,8-trimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl- N-
(4-methoxyphenyl) amide, 1- (4-hydroxyphenyl) -4-hydroxy-7
-Methoxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid N-methyl-N-phenylamide, 1- (4-hydroxyphenyl) -4-hydroxy-7
-Methoxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-hydroxyphenyl) -4-hydroxy-7
-Methoxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 1- (4-hydroxyphenyl) -4-hydroxy-7
-Methoxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid N-ethyl-N- (3-fluorophenyl) amide, 1- (4-hydroxyphenyl) -4-hydroxy-7
-Methoxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 1- (4-hydroxyphenyl) -4-hydroxy-7
-Methoxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-7-
Methoxy-2-oxo-1,2-dihydroquinoline-3
-Carboxylic acid N-methyl-N-phenylamide, 1- (4-methoxyphenyl) -4-hydroxy-7-
Methoxy-2-oxo-1,2-dihydroquinoline-3
-Carboxylic acid N-ethyl-N-phenylamide, 1- (4-methoxyphenyl) -4-hydroxy-7-
Methoxy-2-oxo-1,2-dihydroquinoline-3
-Carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-7-
Methoxy-2-oxo-1,2-dihydroquinoline-3
-Carboxylic acid N-ethyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-7-
Methoxy-2-oxo-1,2-dihydroquinoline-3
-Carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-7-
Methoxy-2-oxo-1,2-dihydroquinoline-3
-Carboxylic acid N-ethyl-N- (3,5-difluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N-phenylamide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-ethyl-N- (3-fluorophenyl) amide, 1- (4-methoxyphenyl) -4-hydroxy-6,
7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N- (3,5-difluorophenyl) amide and 1- (4-methoxyphenyl) -4-hydroxy-6 , 7-Dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N
-Ethyl-N- (3,5-difluorophenyl) amide. (43) an agent for treating hyperlipidemia, comprising as an active ingredient the compound according to any one of (21) to (42), a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof; Or prophylactic agents. 44. A therapeutic or prophylactic agent for arteriosclerosis, comprising as an active ingredient the compound according to any one of claims 21 to 42, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof. Agent.