JP2002316985A - Benzothiophene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a benzothiophene derivative having low toxicity and excellent immunosuppressive action and its pharmacologically permissible salt, ester and other derivative. SOLUTION: The present invention relates to a benzothiophene derivative expressed by general formula (I) [R<1> and R<2> are each H or an amino-protecting group; R<3> is H or a hydroxy-protecting group; R<4> is a lower alkyl; (n) is an integer of 1-6; X is ethylene group or the like; Y is a 1-10C alkylene or the like; R<5> is an aryl or the like; and R<6> and R<7> are each H or the like] and its pharmacologically permissible salt, ester and other derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a benzothiophene derivative having an excellent immunosuppressive action, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof, and a medicament containing them (preferably, Immunosuppressants).

[0002]

2. Description of the Related Art Conventionally, in the treatment of immune-related diseases such as rheumatism and other autoimmune diseases, anti-inflammatory drugs such as steroids have been used for inflammatory reactions caused by abnormal immune responses. It is a symptomatic treatment, not a radical treatment.

It has been reported that abnormalities in the immune system are also involved in the onset of diabetes and nephritis [Kidney I
nternational, 51, 94 (1997); Journal of Immunology,
157,4691 (1996)], and no drug has been developed to improve the abnormality.

On the other hand, the development of a method for suppressing the immune response has
It is also extremely important in preventing rejection in organ and cell transplantation and in treating and / or preventing various autoimmune diseases. Conventionally known immunosuppressants include the following. (1) WO94 / 08943 (EP62740)
6) has the following general formula (a)

[0005]

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[In the above compound (a), R is a linear or branched carbon chain which may have a substituent. In the chain, a double bond, a triple bond, oxygen, sulfur, -N ( R ⁶ ) −
(Wherein R ⁶ is hydrogen), an arylene which may have a substituent, a heteroarylene which may have a substituent, and a substituent may be provided at the chain end. It may have aryl, cycloalkyl which may have a substituent, and heteroaryl which may have a substituent. 、 And R ² ,
R ³ , R ⁴ and R ⁵ are the same or different and are hydrogen or alkyl. Are disclosed as immunosuppressants, and the following compounds are disclosed.

[0007]

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(2) WO 96/06068 (EP
778263) has the following general formula (b)

[0009]

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[In the above compound (b), R ¹ , R ² and R ³ are a hydrogen atom and the like, W is a hydrogen atom and an alkyl group, Z is a single bond or an alkylene group,
X represents a hydrogen atom or an alkoxy group, and Y represents a hydrogen atom, an alkyl, an alkoxy, an acyl, an acyloxy, an amino, an acylamino group or the like. Has the following formula:
It is disclosed as an immunosuppressant, and the following compounds are disclosed.

[0011]

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(3) WO 98/45249 (EP
10000272) has the following general formula (c)

[0013]

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[In the above compound (c), R ¹ , R ² ,
R ³ and R ⁴ are the same or different and are hydrogen or an acyl group. Are disclosed as immunosuppressants, and the following compounds are disclosed.

[0015]

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[0016]

It is known that conventionally known immunosuppressive agents are toxic to the kidney and liver, and against such a background, they have low toxicity and excellent immunosuppressive activity. It has been attempted to find a compound having

The present inventors have conducted intensive studies on derivatives having an immunosuppressive effect. As a result, it has been found that benzothiophene derivatives have an excellent immunosuppressive activity with lower toxicity than conventionally known immunosuppressants. And completed the present invention.

[0018]

Means for Solving the Problems (1) The benzothiophene derivative of the present invention has the following general formula (I).

Formula (I)

[0020]

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Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom or an amino-protecting group, R ³ represents a hydrogen atom or a hydroxy-protecting group, and R ⁴ represents a lower group; An alkyl group; n represents an integer of 1 to 6;
Is an ethylene group, a vinylene group, an ethynylene group, a formula -D-
A group having CH ₂ — (where D is a carbonyl group,
A group having CH (OH)-, an oxygen atom, a sulfur atom or a nitrogen atom. ), An aryl group or an aryl group substituted with at least one group selected from substituent group a, wherein Y is a single bond, a C ₁ -C ₁₀ alkylene group, or a substituent group a or b at least one C ₁ -C ₁₀ alkylene group substituted with a group selected, C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or chain end, or from substituent group a and b At least one selected
Represents a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end substituted with a plurality of groups, wherein R ⁵ is a hydrogen atom, a cycloalkyl group, an aryl group, a heterocyclic group; Group, cycloalkyl group substituted with at least one group selected from substituent groups a and b, aryl group substituted with at least one group selected from substituent groups a and b, or A heterocyclic group substituted with at least one group selected from substituent groups a and b, wherein R ⁶ and R ⁷ are the same or different and are each a hydrogen atom or a substituent group a
Represents a group selected from

However, when R ⁵ is a hydrogen atom, Y represents a group other than a single bond or a linear C ₁ -C ₁₀ alkylene group. ], A pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. <Substituent group a> halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, carboxyl group, lower alkoxycarbonyl group,
Hydroxy group, lower aliphatic acyl group, amino group, mono-
Lower alkylamino group, di-lower alkylamino group, lower aliphatic acylamino group, cyano group and nitro group <Substituent group b> selected from cycloalkyl group, aryl group, heterocyclic group and substituent group a A cycloalkyl group substituted with at least one group, an aryl group substituted with at least one group selected from substituent group a, and at least one group selected from substituent group a A substituted heterocyclic group.

Preferred compounds include the following compounds. (2) In (1), the formula (Ia)

[0024]

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A compound having the formula (Ib):

[0026]

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(4) In any one selected from (1) to (3), R ¹ and R ² are the same or different and each is a hydrogen atom, a lower alkoxycarbonyl group, an aralkyloxycarbonyl A compound which is an aralkyloxycarbonyl group substituted by 1 to 3 groups or groups selected from a substituent group a, (5) (1)
In any one selected from (3) to (3), R ¹
And (6) a compound in which R ² is a hydrogen atom, (6) in any one selected from (1) to (5),
^A compound in which ³ is a hydrogen atom, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted by 1 to 3 groups selected from a substituent group a, (7) (1) to ( In any one selected from 5), R ³ is
A compound which is a hydrogen atom, (8) a compound wherein in any one selected from (1) to (7), R ⁴ is a C ₁ -C ₄ alkyl group, (9) (1) to (7) Wherein R ⁴ is a C ₁ -C ₂ alkyl group, (10) wherein R ⁴ is any one selected from (1) to (7) A compound which is a methyl group, (11) a compound wherein n is 2 or 3 in any one selected from (1) to (10), (12) a compound selected from (1) to (10) (13) The compound according to any one of the above, wherein n is 2.
(14) The compound according to any one of (1) to (12), wherein X is an ethylene group,
(15) The compound according to any one of (1) to (12), wherein X is an ethynylene group,
(16) The compound according to any one of (1) to (12), wherein X is an aryl group or an aryl group substituted with at least one group selected from substituent group a, ) (in any one selected from 1) to (15), Y is, C ₁ -C ₁₀ C ₁ substituted with at least one group selected from an alkylene group, or a substituent group a and b A compound which is a —C ₁₀ alkylene group, (1
7) In any one selected from (1) to (15), Y is a C ₁ -C ₆ alkylene group or a substituent group a
A compound which is a C ₁ -C ₆ alkylene group substituted with at least one group selected from and b, (18) (1)
In any one selected from (15) to (15), Y
Is an ethylene group, a trimethylene group, a tetramethylene group,
Or a compound which is an ethylene, trimethylene, tetramethylene or pentamethylene group substituted with at least one group selected from substituent groups a and b, (1
9) In any one selected from (1) to (15), a compound wherein Y is an ethylene group, trimethylene group or tetramethylene group, (20) any one selected from (1) to (15) Or 1 in which Y is
A compound which is an ethylene group or a trimethylene group, (2
1) In any one selected from (1) to (15), Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in a carbon chain or at a chain end, or a substituent group a and a compound which is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in a carbon chain or at a chain end substituted with at least one group selected from b.
(22) The compound according to any one of (1) to (15), wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in a carbon chain or at a chain end, (23) (24) The compound according to any one of (1) to (15), wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom in a carbon chain or at a chain end. In any one selected from (15), compounds wherein Y is a C ₁ -C ₆ alkylene group having an oxygen atom in a carbon chain or at a chain end, (2
5) (in any one selected from 1) to (15), Y _{is, -O-CH 2 -, -} O- (CH 2)
_{2 -, - O- (CH 2} ) 3 -, - CH 2 -O -, - (C
_{H 2) 2 -O -, -} (CH 2) 3 -O- or -CH ₂ -O-
A compound which is a group having CH ₂ —, (26) in any one selected from (1) to (15),
_{There, -CH 2 -O -, - (} CH 2) 2 -O- or -CH ₂ -
O-CH ₂ - compound is a group having the (27)
In any one selected from (1) to (26), R ⁵ is at least one group selected from a cycloalkyl group, an aryl group, a heterocyclic group, and substituent groups a and b. Substituted cycloalkyl group or substituent groups a and b
Ali substituted with at least one group selected from
(28) In any one selected from (1) to (26), R ⁵ is at least selected from a cycloalkyl group, an aryl group, and substituent groups a and b. (29) (1) a compound which is a cycloalkyl group substituted with one group or an aryl group substituted with at least one group selected from substituent groups a and b;
In any one selected from (26) to (26), R
^A compound in which ⁵ is an aryl group substituted with at least one group selected from the group consisting of a cycloalkyl group, an aryl group, and a substituent group a and b, (30) from (1) to (26); In any one of the selected ones, R ⁵ is a cycloalkyl group, an aryl group, or an aryl group having 1 to 3 substituted groups.
(31) wherein the substituent is a group selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group. In any one selected from (26), R ⁵ is a cycloalkyl group,
A compound which is an aryl group or an aryl group substituted by 1 to 3 groups (the substituent is a halogen atom, a lower alkyl group or a lower alkoxy group); (32) (1) to (26) In any one selected from
⁽⁵ ) a compound in which ⁵ is a cyclohexyl group, a phenyl group or a p-tolyl group; (33) In any one selected from (1) to (32), R ⁶ and R ⁷ are the same or different, and Atom, halogen atom, lower alkyl group,
A compound which is a halogeno lower alkyl group, a lower alkoxy group or a lower alkylthio group, (34) (1) to (3)
In any one selected from 2), R ⁶ and R ⁷
Is a hydrogen atom.

In the above formula, "aryl group" in the definition of X, R ⁵ and substituent group b, "aryl group substituted by at least one group selected from substituent group a", and The aryl part of the "aryl group substituted with at least one group selected from the substituent groups a and b" is, for example, a C6-C10 aryl group such as phenyl, indenyl and naphthyl.
Aromatic hydrocarbon groups, preferably a phenyl or naphthyl group, and most preferably a phenyl group.

In the above formula, "C" in the definition of Y₁-C_Ten
Alkylene group "and" substituent groups a and b
C substituted with at least one group₁-C_TenAlkylene
Group ”C₁-C_TenAlkylene moiety is methylene, methyl
Methylene, ethylene, propylene, trimethylene, 1-
Methyl ethylene, tetramethylene, 1-methyltrimethyl
Len, 2-methyltrimethylene, 3-methyltrimethyle
1-methylpropylene, 1,1-dimethylethylene
Pentamethylene, 1-methyltetramethylene, 2-
Methyltetramethylene, 3-methyltetramethylene, 4
-Methyltetramethylene, 1,1-dimethyltrimethyl
2,2-dimethyltrimethylene, 3,3-dimethyl
Trimethylene, hexamethylene, 1-methylpentamethyl
Len, 2-methylpentamethylene, 3-methylpentame
Tylene, 4-methylpentamethylene, 5-methylpentane
Methylene, 1,1-dimethyltetramethylene, 2,2-
Dimethyltetramethylene, 3,3-dimethyltetramethyl
Len, 4,4-dimethyltetramethylene, heptamethyle
, 1-methylhexamethylene, 2-methylhexamethyl
Len, 5-methylhexamethylene, 3-ethylpentame
Tylene, octamethylene, 2-methylheptamethylene,
5-methylheptamethylene, 2-ethylhexamethyl
2-ethyl-3-methylpentamethylene, 3-ethyl
2-methylpentamethylene, nonamethylene, 2-meth
Tyloctamethylene, 7-methyloctamethylene, 4-
Ethyl heptamethylene, 3-ethyl-2-methylhexa
Methylene, 2-ethyl-1-methylhexamethylene, de
A straight or branched chain having 1 to 10 carbon atoms such as a camethylene group
A branched alkylene group, preferably C₁-C₆Alkylene
And more preferably C₁-C_FiveAn alkylene group,
More preferably, ethylene, trimethylene or tetramethyl
An ethylene group or a trimethylene group.
Group.

In the above formula, “carbon chain middle” in the definition of Y
Or C having an oxygen or sulfur atom at the chain end₁−
C_TenAlkylene group "and" substituent groups a and b.
A carbon chain substituted with at least one group
Is C having an oxygen atom or a sulfur atom at the chain end.₁-C_Ten
Oxygen atom in the carbon chain or at the chain end of the alkylene group
Or C having a sulfur atom₁-C_TenAlkylene "moiety
Is "C₁-C_TenEnd or chain of "alkylene group"
A group having an oxygen or sulfur atom in it, such as
For example, -O-CH_Two-, -O- (CH_Two)_Two-, -O- (C
H_Two)_Three-, -O- (CH_Two)_Four-, -O- (CH_Two)_Five−,
-O- (CH_Two)₆-, -O- (CH_Two)₇-, -O- (C
H_Two)₈-, -O- (CH_Two)₉-, -O- (CH_Two)
_Ten-, -CH_Two-O-CH_Two-, -CH_Two-O- (CH_Two)
_Two-, -CH_Two-O- (CH_Two)_Three-, -CH_Two-O- (C
H_Two)_Four-,-(CH_Two)_Two-O-CH_Two-,-(CH_Two)_Two
-O- (CH_Two)_Two-,-(CH_Two)_Two-O- (CH_Two)
_Three-,-(CH_Two)_Two-O- (CH_Two)_Four-,-(CH_Two)_Three
-O-CH_Two-,-(CH_Two)_Three-O- (CH_Two)_Two−, −
(CH_Two) _Three-O- (CH_Two)_Three-,-(CH_Two)_Four-OC
H_Two-,-(CH_Two)_Four-O- (CH _Two)_Two-,-(CH_Two)
_Five-O-CH_Two-, -CH_Two-O-,-(CH_Two)_Two-O
-,-(CH_Two)_Three-O-,-(CH_Two)_Four-O-,-(C
H_Two)_Five-O-,-(CH_Two)₆-O-,-(CH_Two)₇-O
-,-(CH_Two)₈-O-,-(CH_Two)₉-O-,-(C
H_Two)_Ten-O-, -S-CH_Two-, -S- (CH_Two)_Two−,
-S- (CH_Two)_Three-, -S- (CH_Two)_Four-, -S- (C
H_Two)_Five-, -S- (CH_Two)₆-, -S- (CH_Two)₇−,
-S- (CH_Two)₈-, -S- (CH_Two)₉-, -S- (C
H_Two)_Ten-, -CH_Two-S-CH_Two-, -CH_Two-S- (C
H_Two)_Two-, -CH_Two-S- (CH_Two)_Three-, -CH_Two-S-
(CH_Two)_Four-,-(CH_Two)_Two-S-CH_Two-,-(C
H_Two)_Two-S- (CH_Two)_Two-,-(CH_Two)_Two-S- (CH
_Two)_Three-,-(CH_Two)_Two-S- (CH_Two)_Four-,-(C
H_Two)_Three-S-CH_Two-,-(CH_Two)_Three-S- (CH_Two)_Two
-,-(CH_Two)_Three-S- (CH_Two)_Three-,-(CH_Two)_Four−
S-CH_Two-,-(CH_Two)_Four-S- (CH_Two)_Two−, −
(CH_Two)_Five-S-CH_Two-, -CH_Two-S-,-(C
H_Two)_Two-S-,-(CH_Two)_Three-S-,-(CH_Two)_Four-S
-,-(CH_Two)_Five-S-,-(CH _Two)₆-S-,-(C
H_Two)₇-S-,-(CH_Two)₈-S-,-(CH_Two)₉-S
-,-(CH_Two)_TenA group having -S-, preferably
Is a C having an oxygen atom in a carbon chain or at a chain end.₁-C
_TenAn alkylene group, more preferably a carbon chain.
Is C having an oxygen atom at the chain end₁-C_FourAn alkylene group
And more preferably -O-CH_Two-, -O- (CH_Two)_Two
-, -O- (CH_Two)_Three-, -CH_Two-O-,-(CH _Two)
_Two-O-,-(CH_Two)_Three-O- or -CH_Two-O-CH_Two
And most preferably -CH_Two-O-,
− (CH_Two)_Two-O- or -CH_Two-O-CH_TwoHaving
Group.

In the above formula, “cycloalkyl group” in the definition of R ⁵ and the substituent group b, “cycloalkyl group substituted with at least one group selected from the substituent group a”
And the cycloalkyl moiety of the "cycloalkyl group substituted with at least one group selected from substituent groups a and b" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, indanyl And a saturated carbocyclic group having 3 to 10 carbon atoms, and may be condensed with another cyclic group such as a benzene ring. Such cycloalkyl groups, preferably a C ₅ -C ₆ cycloalkyl group, most preferably a cyclohexyl group.

In the above formula, "heterocyclic group", "heterocyclic group substituted with at least one group selected from substituent group a" in the definition of R ⁵ and substituent group b, and "substituent group" a
And a heterocyclic group substituted with at least one group selected from b), a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms. For example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-
Oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, aromatic heterocyclic groups such as pyrazinyl, and tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, isoprazinyl, isoprazinyl, isoprazinyl Examples include partially or completely reduced saturated heterocyclic groups corresponding to these groups such as xazolidinyl, thiazolidinyl, and pyrazolidinyl. Further, the heterocyclic group may be condensed with another cyclic group such as a benzene ring. Inil,
Groups such as indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl. It is preferably a 5- to 6-membered aromatic heterocyclic group, most preferably a furyl, thienyl, pyrrolyl or imidazolyl group.

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 R ⁴ and the substituent group a is, 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-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 1
1-carbon group such as ethylbutyl and 2-ethylbutyl groups
From 6 to 6 linear or branched alkyl groups, preferably C ₁ -C ₄ alkyl groups, more preferably C ₁ -C ₂ alkyl groups, most preferably methyl group .

In the above formula, the “halogeno lower alkyl group” in the definition of the substituent group “a” is a group in which the above “lower alkyl group” is substituted by a halogen atom, such as 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-yo- Dohexyl, 2,2
A halogeno C ₁ -C ₆ alkyl group, 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, the “lower alkoxy group” in the definition of the substituent group “a” indicates 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, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methyl Pentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy 1 carbon such as a group
From 6 to 6 linear or branched alkoxy groups, preferably C ₁ -C ₄ alkoxy groups, more preferably C ₁ -C ₂ alkoxy groups.
An 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 alkoxycarbonyl group" in the definition of the substituent group a indicates a group in which the above "lower alkoxy group" is bonded to a carbonyl group, for example, 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 straight-chain or branched-chain alkoxycarbonyl group having 2 to 7 carbon atoms, such as 1,3-dimethylbutoxycarbonyl and 2,3-dimethylbutoxycarbonyl;
Suitable a C ₂ -C ₅ alkoxycarbonyl group, more preferably a C ₂ -C ₃ alkoxycarbonyl group, most preferably a methoxycarbonyl group.

In the above formula, the term "lower aliphatic acyl 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 carbonyl group. Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl,
It is a linear or branched lower aliphatic acyl group having 1 to 7 carbon atoms such as a crotonoyl group, preferably a C ₁ -C ₅ lower aliphatic acyl group, more preferably an acetyl or propionyl group. And most preferably an acetyl group.

In the above formula, the “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 term "lower aliphatic acylamino group" in the definition of the substituent group "a" refers to a group in which the above "lower aliphatic acyl group" is bonded to an amino group, for example, formylamino, acetylamino, propionyl C1-C7 linear or branched lower fats such as amino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonoylamino groups Group, preferably an acetylamino or propionylamino group, and most preferably an acetylamino group.

In the above formula, R ¹ And R ^Two "A" in the definition of
"Protecting group for amino group" is generally used in the field of synthetic organic chemistry.
Means the protecting group of the amino group used, for example,
“Lower alkyl group”; the above “lower aliphatic acyl group”,
Loroacetyl, dichloroacetyl, trichloroacetyl
Halogen, lower aliphatic such as trifluoroacetyl
Acyl group, lower alkoxy such as methoxyacetyl
“Aliphatic acyl” such as a substituted lower aliphatic acyl group
Benzoyl, 1-indancarbonyl, 2-yne
Like dancarbonyl, 1- or 2-naphthoyl
Arylcarbonyl group, 4-chlorobenzoyl, 4-phenyl
Halogenoarylcarbonyl such as fluorobenzoyl
Group, 2,4,6-trimethylbenzoyl, 4-toluoi
Arylcarbonyl substituted with lower alkyl such as
Substituted with a lower alkoxy group such as 4-anisoyl.
Arylcarbonyl group, 4-nitrobenzoyl, 2
Aryl substituted with nitro, such as nitrobenzoyl
Carbonyl group, 2- (methoxycarbonyl) benzoy
Ants substituted with lower alkoxycarbonyl such as
Carbonyl groups, 4-phenylbenzoyl
"Aromatic" such as arylcarbonyl group substituted by reel
Group acyls "; the above-mentioned" lower alkoxycarbonyl group ",
2,2,2-trichloroethoxycarbonyl, 2-tri
Halogen such as methylsilylethoxycarbonyl
Is lower alkoxy substituted with tri-lower alkylsilyl
"Alkoxycarbonyls" such as carbonyl groups; vinyl
Such as ruoxycarbonyl, allyloxycarbonyl
“Alkenyloxycarbonyls”; benzyloxyca
An aralkyloxycarbonyl group such as rubonyl,
Methoxybenzyloxycarbonyl, 3,4-dimethoxy
Cibenzyloxycarbonyl, 2-nitrobenzyloxy
Of cyclocarbonyl, 4-nitrobenzyloxycarbonyl
1 to 3 substituted with a group selected from such a substituent group a.
Aralkyloxycarbonyl groups such as
Oxycarbonyls "; trimethylsilyl, triethyl
Silyl, isopropyldimethylsilyl, t-butyldimethyl
Tylsilyl, methyldiisopropylsilyl, methyldi-
tors such as t-butylsilyl and triisopropylsilyl;
Lower alkylsilyl group, diphenylmethylsilyl, di
Phenylbutylsilyl, diphenylisopropylsilyl
Aryl or phenyldiisopropylsilyl
Or tri-substituted silyl with lower alkyl
“Silyls” such as a group; benzyl, phenethyl, 3-phenyl
Phenyl, α-naphthylmethyl, β-naphthylme
Tyl, diphenylmethyl, triphenylmethyl, α-na
Like phthyldiphenylmethyl, 9-anthrylmethyl
Lower alkyl substituted with 1 to 3 aryl groups
Group, 4-methylbenzyl, 2,4,6-trimethylben
Jill, 3,4,5-trimethylbenzyl, 4-methoxy
Benzyl, 4-methoxyphenyldiphenylmethyl, 2
-Nitrobenzyl, 4-nitrobenzyl, 4-chlorobe
Benzyl, 4-bromobenzyl, 4-cyanobenzyl, 4
-Cyanobenzyldiphenylmethyl, bis (2-nitro
Phenyl) methyl, lower alkyl such as piperonyl,
Ali with lower alkoxy, nitro, halogen or cyano
Wherein the aryl ring is substituted with one to three substituted aryl groups
"Aralkyls" such as lower alkyl groups; and
N, N-dimethylaminomethylene, benzylidene, 4-
Methoxybenzylidene, 4-nitrobenzylidene, sari
Silidene, 5-chlorosalicylidene, diphenylmethyle
, (5-chloro-2-hydroxyphenyl) phenyl
Substituted methods that form "Schiff bases" such as methylene
And a lower alkoxy carboxy group.
Bonyl group, aralkyloxycarbonyl group or substituent group
aralkyl substituted with 1 to 3 groups selected from a
It is an oxycarbonyl group.

The term "protecting group for hydroxy group" in the definition of R ³ includes "protecting group in the reaction" which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis. "Protecting groups that can be cleaved in vivo by biological methods such as hydrolysis".

Examples of such “protecting group in the reaction” include the above “lower alkyl group”; the above “aliphatic acyls”; the above “aromatic acyls”; tetrahydropyran-2-yl, 3-bromo "Tetrahydropyranyl or tetrahydrothiopyranyls" such as tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; “Tetrahydrofuranyl or tetrahydrothiofuranyls” such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl; the above “silyls”; 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 ethyls” such as halogenated ethyl groups such as 2,2,2-trichloroethyl; the “aralkyls”; the “alkoxycarbonyls”; the “alkenyloxycarbonyls”; the “aralkyloxycarbonyl groups” ].

On the other hand, the "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" includes, for example, ethylcarbonyloxymethyl, pivaloyloxymethyl, dimethylaminoacetyloxymethyl, 1-acetoxy Acyloxyalkyls such as ethyl; 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl,
1- (t-butoxycarbonyloxy) ethyl, 1-
1- such as (ethoxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) ethyl
(Alkoxycarbonyloxy) alkyls; phthalidyl group; 4-methyl-oxodioxoenylmethyl, 4-
"Carbonyloxyalkyls" such as oxodioxorenylmethyl groups such as phenyl-oxodioxorenylmethyl and oxodioxorenylmethyl; the "aliphatic acyls"; the "aromatic acyls";"Half ester salt residue of succinic acid";"phosphateresidue";"ester forming residue such as amino acid"; carbamoyl group; aralkylidene group such as benzylidene; alkoxyethylidene group such as methoxyethylidene and ethoxyethylidene. Oxomethylene; "two hydroxyl protecting groups" such as thioxomethylene; and "carbonyloxyalkyloxycarbonyl group" such as pivaloyloxymethyloxycarbonyl. Whether or not administered by intravenous injection to experimental animals such as rats and mice, Examining body fluids of the animal, after, it can be determined by detectable compound or a pharmacologically acceptable salt thereof underlying.

As such a protecting group for a hydroxy group,
Preferably, it is a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted by 1 to 3 groups selected from a substituent group a.

In the above, specific examples of “cycloalkyl group substituted with at least one group selected from substituent groups a and b” in the definition of R ⁵ include, for example,
2-fluorocyclopropyl, 2-chlorocyclopropyl, 2- or 3-fluorocyclopentyl, 2- or 3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or 4-
Chlorocyclohexyl, 2-, 3- or 4-bromocyclohexyl, 2-, 3- or 4-iodocyclohexyl, 2-methylcyclopropyl, 2-methylcyclobutyl, 2- or 3-methylcyclopentyl, 2
-Or 3-ethylcyclopentyl, 2-, 3- or 4-methylcyclohexyl, 2-, 3- or 4
-Ethylcyclohexyl, 2-trifluoromethylcyclopropyl, 2- or 3-trifluoromethylcyclopentyl, 2-, 3- or 4-trifluoromethylcyclohexyl, 2-methoxycyclopropyl, 2-
Or 3-methoxycyclopentyl, 2- or 3
-Ethoxycyclopentyl, 2-, 3- or 4-methoxycyclohexyl, 2-, 3- or 4-ethoxycyclohexyl, 2-, 3- or 4-propoxycyclohexyl, 2-, 3- or 4-isopropoxycyclohexyl, 2 -, 3- or 4- (1-ethylpropoxy) cyclohexyl, 2-, 3- or 4
-(2-ethylpropoxy) cyclohexyl, 2-carboxylcyclopropyl, 2- or 3-carboxylcyclopentyl, 2-, 3- or 4-carboxylcyclohexyl, 2-methoxycarbonylcyclopropyl, 2- or 3-methoxycarbonylcyclopentyl, 2-, 3- or 4-methoxycarbonylcyclohexyl, 2-hydroxycyclopropyl, 2- or 3-hydroxycyclopentyl, 2-, 3- or 4-hydroxycyclohexyl, 2-formylcyclopropyl, 2- or 3-formylcyclopentyl ,
2-, 3- or 4-formylcyclohexyl, 2-
Acetylcyclopropyl, 2- or 3-acetylcyclopentyl, 2-, 3- or 4-acetylcyclohexyl, 2-aminocyclopropyl, 2- or 3
-Aminocyclopentyl, 2-, 3- or 4-aminocyclohexyl, 2-methylaminocyclopropyl,
2- or 3-methylaminocyclopentyl, 2- or 3-ethylaminocyclopentyl, 2-, 3- or 4-methylaminocyclohexyl, 2-dimethylaminocyclopropyl, 2- or 3-dimethylaminocyclopentyl, 2- or 3 -Diethylaminocyclopentyl, 2-, 3- or 4-dimethylaminocyclohexyl, 2-cyanocyclopropyl, 2- or 3-cyanocyclopentyl, 2-, 3- or 4
-Cyanocyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- or 4-cyclohexylcyclohexyl, 2-phenylcyclopropyl,
2- or 3-phenylcyclopentyl, 2-, 3-
Or 4-phenylcyclohexyl, 3,4-difluorocyclohexyl, 3,4-dichlorocyclohexyl, 2,3-dimethoxycyclohexyl, 3,4-dimethoxycyclohexyl, 3,5-dimethoxycyclohexyl, 3,4,5-trimethoxycyclohexyl And preferably a group selected from substituent groups a and b.
A cycloalkyl group substituted with 1 to 3 substituents, and more preferably a cycloalkyl group substituted with 1 to 3 substituents (the substituent is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkoxy group). And more preferably a cycloalkyl group substituted with 1 to 3 substituents, wherein the substituent comprises a halogen atom, a lower alkyl group and a lower alkoxy group. And most preferably a monosubstituted cyclohexyl group (the substituent is a halogen atom, a lower alkyl group or a lower alkoxy group).

In the above, specific examples of the "aryl group substituted with at least one group selected from substituent groups a and b" in the definition of R ⁵ include, for example, 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-propylphenyl, 2-, 3- or 4-butylphenyl, 2-, 3- or 4 -Pentylphenyl, 2-,
3- or 4-trifluoromethylphenyl, 2-,
3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-propoxyphenyl, 2-, 3- or 4-isopropoxyphenyl, 2-, 3- or 4- Butoxyphenyl, 2-, 3- or 4- (1-ethylpropoxy)
Phenyl, 2-, 3- or 4- (2-ethylpropoxy) phenyl, 2-, 3- or 4-methylthiophenyl, 2-, 3- or 4-ethylthiophenyl,
2-, 3- or 4-carboxylphenyl, 2-,
3- or 4-methoxycarbonylphenyl, 2-,
3- or 4-ethoxycarbonylphenyl, 2-,
3- or 4-hydroxyphenyl, 2-, 3- or 4-formylphenyl, 2-, 3- or 4-acetylphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methyl Aminophenyl, 2
-, 3- or 4-dimethylaminophenyl, 2-,
3- or 4-cyanophenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or 4-
Cyclohexylphenyl, 2-, 3- or 4-biphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-
Dichlorophenyl, 3,4-dichlorophenyl, 3,5
-Dichlorophenyl, 3,4-dibromophenyl, 2,
3-dimethylphenyl, 3,4-dimethylphenyl,
3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl -2-methoxyphenyl, 6-fluoro-4-methyl-2-methoxyphenyl, 5-fluoroinden-3-yl, 5-fluoroinden-3-yl, 5-methylinden-3-
Yl, 5-methoxyinden-3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl,
5-methylinden-2-yl, 5-methoxyinden-2-yl, 5-hydroxyinden-3-yl, 5-
Nitroinden-3-yl, 5-cyclohexylinden-3-yl, 5-phenylinden-3-yl, 5-
Phenoxyinden-3-yl, 5-benzyloxyinden-3-yl, 5-phenylthioinden-3-yl, 5-hydroxyinden-2-yl, 5-nitroinden-2-yl, 5-cyclohexylindene- 2-
Yl, 5-phenylinden-2-yl, 5-fluoronaphthalen-2-yl, 5-fluoronaphthalen-2-
Yl, 5-methylnaphthalen-2-yl, 5-methoxynaphthalen-2-yl, 5-fluoronaphthalen-1-
Yl, 5-fluoronaphthalen-1-yl, 5-methylnaphthalen-1-yl, 5-methoxynaphthalene-1-
Yl, 5-hydroxynaphthalen-2-yl, 5-nitronaphthalen-2-yl, 5-cyclohexylnaphthalen-2-yl, 5-phenylnaphthalen-2-yl,
-Phenoxynaphthalen-2-yl, 5-benzyloxynaphthalen-2-yl, 5-phenylthionaphthalen-2-yl, 5-hydroxynaphthalen-1-yl,
-Nitronaphthalen-1-yl, 5-cyclohexylnaphthalen-1-yl and 5-phenylnaphthalen-1-yl groups, preferably substituted by 1 to 3 groups selected from substituent groups a and b. And more preferably a substituted or unsubstituted aryl group having 1 to 3 substituents such as a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group. And more preferably an aryl group substituted with 1 to 3 substituents (the substituent is a group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group). A group selected from the group consisting of
A monosubstituted aryl group (the substituent is a halogen atom,
It is a lower alkyl group or a lower alkoxy group. ), And most preferably a p-tolyl group.

In the above, specific examples of “heterocyclic group substituted by at least one group selected from substituent groups a and b” in the definition of R ⁵ include, for example, 3-, 4
-Or 5-methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-fluorothiophen-2-yl, 2-, 4- or 5-fluoro Furan-3-yl, 3-, 4- or 5-bromothiophen-2-yl, 2-, 4- or 5-bromofuran-3-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- or 4-
Methylthiazol-5-yl, 3-, 4- or 5-
Fluorobenzothiophen-2-yl, 3-, 4- or 5-bromobenzothiophen-2-yl, 3-, 4
-Or 5-methylbenzothiophen-2-yl, 3
-, 4- or 5-methoxybenzothiophene-2-
Yl, 2-, 4- or 5-fluorobenzothiophen-3-yl, 2-, 4- or 5-bromobenzothiophen-3-yl, 2-, 4- or 5-methylbenzothiophen-3-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl, 4-, 5-, 6-
Or 7-methylbenzothiophen-2-yl, 3
-, 4- or 5-hydroxyfuran-2-yl, 2
-, 4- or 5-hydroxyfuran-3-yl, 3
-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or 5-nitrothiophen-2-yl, 3-, 4- or 5-phenylthiophen-2-
Yl, 2-, 4- or 5-hydroxythiophene
3-yl, 2-, 4- or 5-cyanothiophene-
3-yl, 1-, 2- or 3-hydroxypyridin-4-yl, 1-, 2- or 3-cyanopyridine-
4-yl, 1-, 2- or 3-phenylpyridine-
4-yl group, preferably a heterocyclic group substituted by 1 to 3 groups selected from substituent groups a and b, more preferably a heterocyclic group selected from substituent groups a and b. A furyl, thienyl, pyrrolyl or imidazolyl group substituted with 1 to 3 substituents, more preferably a furyl, thienyl, pyrrolyl or imidazolyl group substituted with 1 to 3 substituents (the substituent is a halogen atom, A lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group and a lower alkylthio group), and still more preferably 1 to 3 substituted furyl, thienyl, pyrrolyl or An imidazolyl group (the substituent is a group selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group), most preferably
1-substituted furyl, thienyl, pyrrolyl or imidazolyl group (the substituent is a group selected from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups).

"Pharmacologically acceptable salt" means that the compound having the general formula (I) of the present invention is reacted with an acid when the compound has a basic group such as an amino group.
When the compound has an acidic group such as a carboxyl group, it can be converted to a salt by reacting with a base.

The salt based on a basic group is preferably
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 salts based on acidic groups are preferably alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, iron salt and the like. 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 A) amine salts such as organic salts such as aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates and aspartates.

The compound of the present invention having the general formula (I), its pharmacologically acceptable salt, its ester or other derivative absorbs moisture by being left in the air or recrystallized. However, in some cases, hydrates are formed with adsorbed water, and such hydrates are also included in the salts of the present invention.

The compound of the present invention having the general formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof may have an asymmetric carbon atom in the molecule, and thus may have various isomerisms. May have body. In the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all these isomers and mixtures of these isomers in any proportion.

The compound of formula (I-1) of the present invention having the general formula (I)

[0057]

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NR ¹ R ² group, OR ³
Group and the R ⁴ group are substituted with an asymmetric carbon atom, so that the formula (I)
The group having -1) is the following (I-1a) or (I-1)
b)

[0059]

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[0060]

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Compounds having the configuration (I-1b) are particularly preferable.

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

"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", there is consensus as described above.

On the other hand, as the “general protecting group” for the “ester of a carboxy group”, preferably the above “lower alkyl group”; ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2- Propenyl, 1-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-hexenyl, 4-
Lower alkenyl groups such as hexenyl and 5-hexenyl; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2
-Propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-
Methyl-3-butynyl, 1-ethyl-3-butynyl, 2
-Pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3
-Pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4
-Pentynyl, 2-hexynyl, 3-hexynyl, 4-
Lower alkynyl groups such as hexynyl and 5-hexynyl; the aforementioned "halogeno lower alkyl"; such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl Hydroxy "lower alkyl group";"lower aliphatic acyl" such as acetylmethyl- "lower alkyl group";"aralkylgroup"; and "silyl group".

The term "protecting group which 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. It refers to a protecting group, and 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 ''
I agree with the above.

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 above-mentioned "pharmacologically acceptable salt" and the above-mentioned "ester thereof" when the compound having the general formula (I) of the present invention has an amino group. Derivatives are shown below.
Examples of such a derivative include an amide derivative having an acyl group.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in the following Tables 1 and 2. However, the present invention is not limited to these compounds. is not.

The abbreviations in the table are as follows. Bu: butyl group iBu: isobutyl group Bz: benzyl group Et: ethyl group cHx: cyclohexyl group Me: methyl group Np (1): naphthalen-1-yl group Np (2): naphthalen-2-yl group Ph: phenyl group cPn: cyclopentyl group Pr: propyl group iPr: isopropyl group.

[0071]

[Table 1]

[0072]

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[0073]  Compd. R¹ R^Two R^Three R^Four n -X-Y-R^Five R⁶ R⁷  1-1 H H H Me 1-(CH_Two)_Five-cHx H H 1-2 H H H Me 1-(CH_Two)₆-cHx H H 1-3 H H H Me 1 -CH = CH- (CH_Two)_Three-cHx H H 1-4 H H H Me 1 -CH = CH- (CH_Two)_Four-cHx H H 1-5 H H H Me 1 -C≡C- (CH_Two)_Three-cHx H H 1-6 H H H Me 1 -C≡C- (CH_Two)_Four-cHx H H 1-7 H H H Me 1 -CO- (CH_Two)_Four-cHx H H 1-8 H H H Me 1 -CO- (CH_Two)_Five-cHx H H 1-9 H H H Me 1 -CH (OH)-(CH_Two)_Four-cHx H H 1-10 H H H Me 1 -CH (OH)-(CH_Two)_Five-cHx H H 1-11 H H H Me 1-[4- (cHx-CH_TwoO) -Ph] H H 1-12 H H H Me 1-(4-BzO-Ph) H H 1-13 H H H Me 1 -C≡C-CH_TwoO-cPn H H 1-14 H H H Me 1 -C≡C- (CH_Two)_TwoO-cPn H H 1-15 H H H Me 1 -C≡C-CH_TwoO-cHx H H 1-16 H H H Me 1 -C≡C- (CH_Two)_TwoO-cHx H H 1-17 H H H Me 1 -C≡C-CH_TwoO-Ph H H 1-18 H H H Me 1 -C≡C- (CH_Two)_TwoO-Ph H H 1-19 H H H Me 2-(CH_Two)_Two-cHx H H 1-20 H H H Me 2-(CH_Two)_Two-Ph H H 1-21 H H H Me 2-(CH_Two)_Two-(4-F-Ph) H H 1-22 H H H Me 2-(CH_Two)_Two-(4-Me-Ph) H H 1-23 H H H Me 2-(CH_Two)_Two-(4-Et-Ph) H H 1-24 H H H Me 2-(CH_Two)_Two-(4-CF_Three-Ph) H H 1-25 H H H Me 2-(CH_Two)_Two-(4-MeO-Ph) H H 1-26 H H H Me 2-(CH_Two)_Two-(4-EtO-Ph) H H 1-27 H H H Me 2-(CH_Two)_Two-(4-MeS-Ph) H H 1-28 H H H Me 2-(CH_Two)_Two-(4-cHx-Ph) H H 1-29 H H H Me 2-(CH_Two)_Two-(4-Ph-Ph) H H 1-30 H H H Me 2-(CH_Two)_Three-cHx H H 1-31 H H Me Me 2-(CH_Two)_Three-cHx H H 1-32 Me H H Me 2-(CH_Two)_Three-cHx H H 1-33 CO_TwoMe H H Me 2-(CH_Two)_Three-cHx H H 1-34 H H H Me 2-(CH_Two)_Three-(4-F-cHx) H H 1-35 H H H Me 2-(CH_Two)_Three-(4-Me-cHx) H H 1-36 H H H Me 2-(CH_Two)_Three-(4-MeO-cHx) H H 1-37 H H H Me 2-(CH_Two)_Three-Ph H H 1-38 H H Me Me 2-(CH_Two)_Three-Ph H H 1-39 Me H H Me 2-(CH_Two)_Three-Ph H H 1-40 CO_TwoMe H H Me 2-(CH_Two)_Three-Ph H H 1-41 H H H Me 2-(CH_Two)_Three-(4-F-Ph) H H 1-42 H H H Me 2-(CH_Two)_Three-(4-Me-Ph) H H 1-43 H H H Me 2-(CH_Two)_Three-(4-Et-Ph) H H 1-44 H H H Me 2-(CH_Two)_Three-(4-CF_Three-Ph) H H 1-45 H H H Me 2-(CH_Two)_Three-(4-MeO-Ph) H H 1-46 H H H Me 2-(CH_Two)_Three-(4-EtO-Ph) H H 1-47 H H H Me 2-(CH_Two)_Three-(4-MeS-Ph) H H 1-48 H H H Me 2-(CH_Two)_Three-(4-cHx-Ph) H H 1-49 H H H Me 2-(CH_Two)_Three-(4-Ph-Ph) H H 1-50 H H H Me 2-(CH_Two)_Four-cHx H H 1-51 H H Me Me 2-(CH_Two)_Four-cHx H H 1-52 Me H H Me 2-(CH_Two)_Four-cHx H H 1-53 CO_TwoMe H H Me 2-(CH_Two)_Four-cHx H H 1-54 H H H Me 2-(CH_Two)_Four-(4-F-cHx) H H 1-55 H H H Me 2-(CH_Two)_Four-(4-Me-cHx) H H 1-56 H H H Me 2-(CH_Two)_Four-(4-MeO-cHx) H H 1-57 H H H Me 2-(CH_Two)_Four-Ph H H 1-58 H H Me Me 2-(CH_Two)_Four-Ph H H 1-59 Me H H Me 2-(CH_Two)_Four-Ph H H 1-60 CO_TwoMe H H Me 2-(CH_Two)_Four-Ph H H 1-61 H H H Me 2-(CH_Two)_Four-(4-F-Ph) H H 1-62 H H H Me 2-(CH_Two)_Four-(4-Me-Ph) H H 1-63 H H H Me 2-(CH_Two)_Four-(4-Et-Ph) H H 1-64 H H H Me 2-(CH_Two)_Four-(4-CF_Three-Ph) H H 1-65 H H H Me 2-(CH_Two)_Four-(4-MeO-Ph) H H 1-66 H H H Me 2-(CH_Two)_Four-(4-EtO-Ph) H H 1-67 H H H Me 2-(CH_Two)_Four-(4-MeS-Ph) H H 1-68 H H H Me 2-(CH_Two)_Four-(4-cHx-Ph) H H 1-69 H H H Me 2-(CH_Two)_Four-(4-Ph-Ph) H H 1-70 H H H Me 2-(CH_Two)_Five-cPn H H 1-71 H H H Me 2-(CH_Two)_Five-cHx H H 1-72 H H Me Me 2-(CH_Two)_Five-cHx H H 1-73 Me H H Me 2-(CH_Two)_Five-cHx H H 1-74 CO_TwoMe H H Me 2-(CH_Two)_Five-cHx H H 1-75 H H H Me 2-(CH_Two)_Five-(4-F-cHx) H H 1-76 H H H Me 2-(CH_Two)_Five-(4-Me-cHx) H H 1-77 H H H Me 2-(CH_Two)_Five-(4-MeO-cHx) H H 1-78 H H H Me 2-(CH_Two)_Five-Ph H H 1-79 H H Me Me 2-(CH_Two)_Five-Ph H H 1-80 Me H H Me 2-(CH_Two)_Five-Ph H H 1-81 CO_TwoMe H H Me 2-(CH_Two)_Five-Ph H H 1-82 H H H Me 2-(CH_Two)_Five-(3-F-Ph) H H 1-83 H H H Me 2-(CH_Two)_Five-(4-F-Ph) H H 1-84 H H H Me 2-(CH_Two)_Five-(4-Cl-Ph) H H 1-85 H H H Me 2-(CH_Two)_Five-(4-Br-Ph) H H 1-86 H H H Me 2-(CH_Two)_Five-(3-Me-Ph) H H 1-87 H H H Me 2-(CH_Two)_Five-(4-Me-Ph) H H 1-88 H H H Me 2-(CH_Two)_Five-(3-Et-Ph) H H 1-89 H H H Me 2-(CH_Two)_Five-(4-Et-Ph) H H 1-90 H H H Me 2-(CH_Two)_Five-(3-Pr-Ph) H H 1-91 H H H Me 2-(CH_Two)_Five-(4-Pr-Ph) H H 1-92 H H H Me 2-(CH_Two)_Five-(3-iPr-Ph) H H 1-93 H H H Me 2-(CH_Two)_Five-(4-iPr-Ph) H H 1-94 H H H Me 2-(CH_Two)_Five-(3-Bu-Ph) H H 1-95 H H H Me 2-(CH_Two)_Five-(4-Bu-Ph) H H 1-96 H H H Me 2-(CH_Two)_Five-(3-CF_Three-Ph) H H 1-97 H H H Me 2-(CH_Two)_Five-(4-CF_Three-Ph) H H 1-98 H H H Me 2-(CH_Two)_Five-(3-MeO-Ph) H H 1-99 H H H Me 2-(CH_Two)_Five-(4-MeO-Ph) H H 1-100 H H H Me 2-(CH_Two)_Five-(3-EtO-Ph) H H 1-101 H H H Me 2-(CH_Two)_Five-(4-EtO-Ph) H H 1-102 H H H Me 2-(CH_Two)_Five-(3-PrO-Ph) H H 1-103 H H H Me 2-(CH_Two)_Five-(4-PrO-Ph) H H 1-104 H H H Me 2-(CH_Two)_Five-(3-iPrO-Ph) H H 1-105 H H H Me 2-(CH_Two)_Five-(4-iPrO-Ph) H H 1-106 H H H Me 2-(CH_Two)_Five-[3- (2-Et-PrO) -Ph] H H 1-107 H H H Me 2-(CH_Two)_Five-[4- (2-Et-PrO) -Ph] H H 1-108 H H H Me 2-(CH_Two)_Five-(3-iBuO-Ph) H H 1-109 H H H Me 2-(CH_Two)_Five-(4-iBuO-Ph) H H 1-110 H H H Me 2-(CH_Two)_Five-(3-MeS-Ph) H H 1-111 H H H Me 2-(CH_Two)_Five-(4-MeS-Ph) H H 1-112 H H H Me 2-(CH_Two)_Five-(3-EtS-Ph) H H 1-113 H H H Me 2-(CH_Two)_Five-(4-EtS-Ph) H H 1-114 H H H Me 2-(CH_Two)_Five-(3-PrS-Ph) H H 1-115 H H H Me 2-(CH_Two)_Five-(4-PrS-Ph) H H 1-116 H H H Me 2-(CH_Two)_Five-(3-iPrS-Ph) H H 1-117 H H H Me 2-(CH_Two)_Five-(4-iPrS-Ph) H H 1-118 H H H Me 2-(CH_Two)_Five-[3- (2-Et-PrS) -Ph] H H 1-119 H H H Me 2-(CH_Two)_Five-[4- (2-Et-PrS) -Ph] H H 1-120 H H H Me 2-(CH_Two)_Five-(3-iBuS-Ph) H H 1-121 H H H Me 2-(CH_Two)_Five-(4-iBuS-Ph) H H 1-122 H H H Me 2-(CH_Two)_Five-(3-cHx-Ph) H H 1-123 H H H Me 2-(CH_Two)_Five-(4-cHx-Ph) H H 1-124 H H H Me 2-(CH_Two)_Five-(3-Ph-Ph) H H 1-125 H H H Me 2-(CH_Two)_Five-(4-Ph-Ph) H H 1-126 H H H Me 2-(CH_Two)_Five-(2,4-diMe-Ph) H H 1-127 H H H Me 2-(CH_Two)_Five-(3,4-diMe-Ph) H H 1-128 H H H Me 2-(CH_Two)_Five-(3,5-diMe-Ph) H H 1-129 H H H Me 2-(CH_Two)_Five-Np (1) H H 1-130 H H H Me 2-(CH_Two)_Five-Np (2) H H 1-131 H H H Me 2-(CH_Two)₆-cPn H H 1-132 H H H Me 2-(CH_Two)₆-cHx H H 1-133 H H Me Me 2-(CH_Two)₆-cHx H H 1-134 Me H H Me 2-(CH_Two)₆-cHx H H 1-135 CO_TwoMe H H Me 2-(CH_Two)₆-cHx H H 1-136 H H H Me 2-(CH_Two)₆-(4-F-cHx) H H 1-137 H H H Me 2-(CH_Two)₆-(4-Me-cHx) H H 1-138 H H H Me 2-(CH_Two)₆-(4-MeO-cHx) H H 1-139 H H H Me 2-(CH_Two)₆-Ph H H 1-140 H H Me Me 2-(CH_Two)₆-Ph H H 1-141 Me H H Me 2-(CH_Two)₆-Ph H H 1-142 CO_TwoMe H H Me 2-(CH_Two)₆-Ph H H 1-143 H H H Me 2-(CH_Two)₆-(3-F-Ph) H H 1-144 H H H Me 2-(CH_Two)₆-(4-F-Ph) H H 1-145 H H H Me 2-(CH_Two)₆-(4-Cl-Ph) H H 1-146 H H H Me 2-(CH_Two)₆-(4-Br-Ph) H H 1-147 H H H Me 2-(CH_Two)₆-(3-Me-Ph) H H 1-148 H H H Me 2-(CH_Two)₆-(4-Me-Ph) H H 1-149 H H H Me 2-(CH_Two)₆-(3-Et-Ph) H H 1-150 H H H Me 2-(CH_Two)₆-(4-Et-Ph) H H 1-151 H H H Me 2-(CH_Two)₆-(3-Pr-Ph) H H 1-152 H H H Me 2-(CH_Two)₆-(4-Pr-Ph) H H 1-153 H H H Me 2-(CH_Two)₆-(3-iPr-Ph) H H 1-154 H H H Me 2-(CH_Two)₆-(4-iPr-Ph) H H 1-155 H H H Me 2-(CH_Two)₆-(3-Bu-Ph) H H 1-156 H H H Me 2-(CH_Two)₆-(4-Bu-Ph) H H 1-157 H H H Me 2-(CH_Two)₆-(3-CF_Three-Ph) H H 1-158 H H H Me 2-(CH_Two)₆-(4-CF_Three-Ph) H H 1-159 H H H Me 2-(CH_Two)₆-(3-MeO-Ph) H H 1-160 H H H Me 2-(CH_Two)₆-(4-MeO-Ph) H H 1-161 H H H Me 2-(CH_Two)₆-(3-EtO-Ph) H H 1-162 H H H Me 2-(CH_Two)₆-(4-EtO-Ph) H H 1-163 H H H Me 2-(CH_Two)₆-(3-PrO-Ph) H H 1-164 H H H Me 2-(CH_Two)₆-(4-PrO-Ph) H H 1-165 H H H Me 2-(CH_Two)₆-(3-iPrO-Ph) H H 1-166 H H H Me 2-(CH_Two)₆-(4-iPrO-Ph) H H 1-167 H H H Me 2-(CH_Two)₆-[3- (2-Et-PrO) -Ph] H H 1-168 H H H Me 2-(CH_Two)₆-[4- (2-Et-PrO) -Ph] H H 1-169 H H H Me 2-(CH_Two)₆-(3-iBuO-Ph) H H 1-170 H H H Me 2-(CH_Two)₆-(4-iBuO-Ph) H H 1-171 H H H Me 2-(CH_Two)₆-(3-MeS-Ph) H H 1-172 H H H Me 2-(CH_Two)₆-(4-MeS-Ph) H H 1-173 H H H Me 2-(CH_Two)₆-(3-EtS-Ph) H H 1-174 H H H Me 2-(CH_Two)₆-(4-EtS-Ph) H H 1-175 H H H Me 2-(CH_Two)₆-(3-PrS-Ph) H H 1-176 H H H Me 2-(CH_Two)₆-(4-PrS-Ph) H H 1-177 H H H Me 2-(CH_Two)₆-(3-iPrS-Ph) H H 1-178 H H H Me 2-(CH_Two)₆-(4-iPrS-Ph) H H 1-179 H H H Me 2-(CH_Two)₆-[3- (2-Et-PrS) -Ph] H H 1-180 H H H Me 2-(CH_Two)₆-[4- (2-Et-PrS) -Ph] H H 1-181 H H H Me 2-(CH_Two)₆-(3-iBuS-Ph) H H 1-182 H H H Me 2-(CH_Two)₆-(4-iBuS-Ph) H H 1-183 H H H Me 2-(CH_Two)₆-(3-cHx-Ph) H H 1-184 H H H Me 2-(CH_Two)₆-(4-cHx-Ph) H H 1-185 H H H Me 2-(CH_Two)₆-(3-Ph-Ph) H H 1-186 H H H Me 2-(CH_Two)₆-(4-Ph-Ph) H H 1-187 H H H Me 2-(CH_Two)₆-(2,4-diMe-Ph) H H 1-188 H H H Me 2-(CH_Two)₆-(3,4-diMe-Ph) H H 1-189 H H H Me 2-(CH_Two)₆-(3,5-diMe-Ph) H H 1-190 H H H Me 2-(CH_Two)₆-Np (1) H H 1-191 H H H Me 2-(CH_Two)₆-Np (2) H H 1-192 H H H Me 2-(CH_Two)₇-cHx H H 1-193 H H Me Me 2-(CH_Two)₇-cHx H H 1-194 Me H H Me 2-(CH_Two)₇-cHx H H 1-195 CO_TwoMe H H Me 2-(CH_Two)₇-cHx H H 1-196 H H H Me 2-(CH_Two)₇-(4-F-cHx) H H 1-197 H H H Me 2-(CH_Two)₇-(4-Me-cHx) H H 1-198 H H H Me 2-(CH_Two)₇-(4-MeO-cHx) H H 1-199 H H H Me 2-(CH_Two)₇-Ph H H 1-200 H H Me Me 2-(CH_Two)₇-Ph H H 1-201 Me H H Me 2-(CH_Two)₇-Ph H H 1-202 CO_TwoMe H H Me 2-(CH_Two)₇-Ph H H 1-203 H H H Me 2-(CH_Two)₇-(4-F-Ph) H H 1-204 H H H Me 2-(CH_Two)₇-(4-Me-Ph) H H 1-205 H H H Me 2-(CH_Two)₇-(4-Et-Ph) H H 1-206 H H H Me 2-(CH_Two)₇-(4-CF_Three-Ph) H H 1-207 H H H Me 2-(CH_Two)₇-(4-MeO-Ph) H H 1-208 H H H Me 2-(CH_Two)₇-(4-EtO-Ph) H H 1-209 H H H Me 2-(CH_Two)₇-(4-MeS-Ph) H H 1-210 H H H Me 2-(CH_Two)₇-(4-cHx-Ph) H H 1-211 H H H Me 2-(CH_Two)₇-(4-Ph-Ph) H H 1-212 H H H Me 2-(CH_Two)₈-cHx H H 1-213 H H H Me 2-(CH_Two)₈-(4-F-cHx) H H 1-214 H H H Me 2-(CH_Two)₈-(4-Me-cHx) H H 1-215 H H H Me 2-(CH_Two)₈-(4-MeO-cHx) H H 1-216 H H H Me 2-(CH_Two)₈-Ph H H 1-217 H H H Me 2-(CH_Two)₈-(4-F-Ph) H H 1-218 H H H Me 2-(CH_Two)₈-(4-Me-Ph) H H 1-219 H H H Me 2-(CH_Two)₈-(4-Et-Ph) H H 1-220 H H H Me 2-(CH_Two)₈-(4-CF_Three-Ph) H H 1-221 H H H Me 2-(CH_Two)₈-(4-MeO-Ph) H H 1-222 H H H Me 2-(CH_Two)₈-(4-EtO-Ph) H H 1-223 H H H Me 2-(CH_Two)₈-(4-MeS-Ph) H H 1-224 H H H Me 2-(CH_Two)₈-(4-cHx-Ph) H H 1-225 H H H Me 2-(CH_Two)₈-(4-Ph-Ph) H H 1-226 H H H Me 2-(CH_Two)_Three-O-cHx H H 1-227 H H Me Me 2-(CH_Two)_Three-O-cHx H H 1-228 Me H H Me 2-(CH_Two)_Three-O-cHx H H 1-229 CO_TwoMe H H Me 2-(CH_Two)_Three-O-cHx H H 1-230 H H H Me 2-(CH_Two)_Three-O- (4-F-cHx) H H 1-231 H H H Me 2-(CH_Two)_Three-O- (4-Me-cHx) H H 1-232 H H H Me 2-(CH_Two)_Three-O- (4-MeO-cHx) H H 1-233 H H H Me 2-(CH_Two)_Three-O-Ph H H 1-234 H H Me Me 2-(CH_Two)_Three-O-Ph H H 1-235 Me H H Me 2-(CH_Two)_Three-O-Ph H H 1-236 CO_TwoMe H H Me 2-(CH_Two)_Three-O-Ph H H 1-237 H H H Me 2-(CH_Two)_Three-O- (4-F-Ph) H H 1-238 H H H Me 2-(CH_Two)_Three-O- (4-Me-Ph) H H 1-239 H H H Me 2-(CH_Two)_Three-O- (4-Et-Ph) H H 1-240 H H H Me 2-(CH_Two)_Three-O- (4-CF_Three-Ph) H H 1-241 H H H Me 2-(CH_Two)_Three-O- (4-MeO-Ph) H H 1-242 H H H Me 2-(CH_Two)_Three-O- (4-EtO-Ph) H H 1-243 H H H Me 2-(CH_Two)_Three-O- (4-MeS-Ph) H H 1-244 H H H Me 2-(CH_Two)_Three-O- (4-cHx-Ph) H H 1-245 H H H Me 2-(CH_Two)_Three-O- (4-Ph-Ph) H H 1-246 H H H Me 2-(CH_Two)_Four-O-cPn H H 1-247 H H H Me 2-(CH_Two)_Four-O-cHx H H 1-248 H H Me Me 2-(CH_Two)_Four-O-cHx H H 1-249 Me H H Me 2-(CH_Two)_Four-O-cHx H H 1-250 CO_TwoMe H H Me 2-(CH_Two)_Four-O-cHx H H 1-251 Me H H Me 2-(CH_Two)_Four-O-cHx 5-Me H 1-252 Me H H Me 2-(CH_Two)_Four-O-cHx 5-F H 1-253 H H H Me 2-(CH_Two)_Four-O- (4-F-cHx) H H 1-254 H H H Me 2-(CH_Two)_Four-O- (4-Me-cHx) H H 1-255 H H H Me 2-(CH_Two)_Four-O- (4-MeO-cHx) H H 1-256 H H H Me 2-(CH_Two)_Four-O-Ph H H 1-257 H H Me Me 2-(CH_Two)_Four-O-Ph H H 1-258 Me H H Me 2-(CH_Two)_Four-O-Ph H H 1-259 CO_TwoMe H H Me 2-(CH_Two)_Four-O-Ph H H 1-260 H H H Me 2-(CH_Two)_Four-O- (3-F-Ph) H H 1-261 H H H Me 2-(CH_Two)_Four-O- (4-F-Ph) H H 1-262 H H H Me 2-(CH_Two)_Four-O- (4-Cl-Ph) H H 1-263 H H H Me 2-(CH_Two)_Four-O- (4-Br-Ph) H H 1-264 H H H Me 2-(CH_Two)_Four-O- (3-Me-Ph) H H 1-265 H H H Me 2-(CH_Two)_Four-O- (4-Me-Ph) H H 1-266 H H H Me 2-(CH_Two)_Four-O- (3-Et-Ph) H H 1-267 H H H Me 2-(CH_Two)_Four-O- (4-Et-Ph) H H 1-268 H H H Me 2-(CH_Two)_Four-O- (3-Pr-Ph) H H 1-269 H H H Me 2-(CH_Two)_Four-O- (4-Pr-Ph) H H 1-270 H H H Me 2-(CH_Two)_Four-O- (3-iPr-Ph) H H 1-271 H H H Me 2-(CH_Two)_Four-O- (4-iPr-Ph) H H 1-272 H H H Me 2-(CH_Two)_Four-O- (3-Bu-Ph) H H 1-273 H H H Me 2-(CH_Two)_Four-O- (4-Bu-Ph) H H 1-274 H H H Me 2-(CH_Two)_Four-O- (3-Pn-Ph) H H 1-275 H H H Me 2-(CH_Two)_Four-O- (4-Pn-Ph) H H 1-276 H H H Me 2-(CH_Two)_Four-O- (3-CF_Three-Ph) H H 1-277 H H H Me 2-(CH_Two)_Four-O- (4-CF_Three-Ph) H H 1-278 H H H Me 2-(CH_Two)_Four-O- (3-MeO-Ph) H H 1-279 H H H Me 2-(CH_Two)_Four-O- (4-MeO-Ph) H H 1-280 H H H Me 2-(CH_Two)_Four-O- (3-EtO-Ph) H H 1-281 H H H Me 2-(CH_Two)_Four-O- (4-EtO-Ph) H H 1-282 H H H Me 2-(CH_Two)_Four-O- (3-PrO-Ph) H H 1-283 H H H Me 2-(CH_Two)_Four-O- (4-PrO-Ph) H H 1-284 H H H Me 2-(CH_Two)_Four-O- (3-iPrO-Ph) H H 1-285 H H H Me 2-(CH_Two)_Four-O- (4-iPrO-Ph) H H 1-286 H H H Me 2-(CH_Two)_Four-O- [3- (2-Et-PrO) -Ph] H H 1-287 H H H Me 2-(CH_Two)_Four-O- [4- (2-Et-PrO) -Ph] H H 1-288 H H H Me 2-(CH_Two)_Four-O- (3-iBuO-Ph) H H 1-289 H H H Me 2-(CH_Two)_Four-O- (4-iBuO-Ph) H H 1-290 H H H Me 2-(CH_Two)_Four-O- (3-MeS-Ph) H H 1-291 H H H Me 2-(CH_Two)_Four-O- (4-MeS-Ph) H H 1-292 H H H Me 2-(CH_Two)_Four-O- (3-EtS-Ph) H H 1-293 H H H Me 2-(CH_Two)_Four-O- (4-EtS-Ph) H H 1-294 H H H Me 2-(CH_Two)_Four-O- (3-PrS-Ph) H H 1-295 H H H Me 2-(CH_Two)_Four-O- (4-PrS-Ph) H H 1-296 H H H Me 2-(CH_Two)_Four-O- (3-iPrS-Ph) H H 1-297 H H H Me 2-(CH_Two)_Four-O- (4-iPrS-Ph) H H 1-298 H H H Me 2-(CH_Two)_Four-O- [3- (2-Et-PrS) -Ph] H H 1-299 H H H Me 2-(CH_Two)_Four-O- [4- (2-Et-PrS) -Ph] H H 1-300 H H H Me 2-(CH_Two)_Four-O- (3-iBuS-Ph) H H 1-301 H H H Me 2-(CH_Two)_Four-O- (4-iBuS-Ph) H H 1-302 H H H Me 2-(CH_Two)_Four-O- (3-cHx-Ph) H H 1-303 H H H Me 2-(CH_Two)_Four-O- (4-cHx-Ph) H H 1-304 H H H Me 2-(CH_Two)_Four-O- (3-Ph-Ph) H H 1-305 H H H Me 2-(CH_Two)_Four-O- (4-Ph-Ph) H H 1-306 H H H Me 2-(CH_Two)_Four-O- (2,4-diMe-Ph) H H 1-307 H H H Me 2-(CH_Two)_Four-O- (3,4-diMe-Ph) H H 1-308 H H H Me 2-(CH_Two)_Four-O- (3,5-diMe-Ph) H H 1-309 H H H Me 2-(CH_Two)_Five-O-cHx H H 1-310 H H H Me 2-(CH_Two)_Five-O-Ph H H 1-311 H H H Me 2-(CH_Two)₆-O-cHx H H 1-312 H H H Me 2-(CH_Two)₆-O-Ph H H 1-313 H H H Me 2-(CH_Two)_Three-OCH_Two-cHx H H 1-314 H H H Me 2-(CH_Two)_Three-OCH_Two-(4-F-cHx) H H 1-315 H H H Me 2-(CH_Two)_Three-OCH_Two-(4-Me-cHx) H H 1-316 H H H Me 2-(CH_Two)_Three-OCH_Two-(4-MeO-cHx) H H 1-317 H H H Me 2-(CH_Two)_Three-OCH_Two-Ph H H 1-318 H H H Me 2-(CH_Two)_Four-OCH_Two-cPn H H 1-319 H H H Me 2-(CH_Two)_Four-OCH_Two-cHx H H 1-320 H H Me Me 2-(CH_Two)_Four-OCH_Two-cHx H H 1-321 Me H H Me 2-(CH_Two)_Four-OCH_Two-cHx H H 1-322 CO_TwoMe H H Me 2-(CH_Two)_Four-OCH_Two-cHx H H 1-323 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-F-cHx) H H 1-324 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Me-cHx) H H 1-325 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-MeO-cHx) H H 1-326 H H H Me 2-(CH_Two)_Four-OCH_Two-Ph H H 1-327 H H Me Me 2-(CH_Two)_Four-OCH_Two-Ph H H 1-328 Me H H Me 2-(CH_Two)_Four-OCH_Two-Ph H H 1-329 CO_TwoMe H H Me 2-(CH_Two)_Four-OCH_Two-Ph H H 1-330 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-F-Ph) H H 1-331 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Cl-Ph) H H 1-332 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Br-Ph) H H 1-333 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Me-Ph) H H 1-334 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Et-Ph) H H 1-335 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Pr-Ph) H H 1-336 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-iPr-Ph) H H 1-337 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Bu-Ph) H H 1-338 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-CF_Three-Ph) H H 1-339 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-MeO-Ph) H H 1-340 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-EtO-Ph) H H 1-341 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-PrO-Ph) H H 1-342 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-iPrO-Ph) H H 1-343 H H H Me 2-(CH_Two)_Four-OCH_Two-[4- (2-Et-PrO) -Ph] H H 1-344 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-iBuO-Ph) H H 1-345 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-MeS-Ph) H H 1-346 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-EtS-Ph) H H 1-347 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-PrS-Ph) H H 1-348 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-iPrS-Ph) H H 1-349 H H H Me 2-(CH_Two)_Four-OCH_Two-[4- (2-Et-PrS) -Ph] H H 1-350 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-iBuS-Ph) H H 1-351 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-cHx-Ph) H H 1-352 H H H Me 2-(CH_Two)_Four-OCH_Two-(4-Ph-Ph) H H 1-353 H H H Me 2-(CH_Two)_Four-OCH_Two-(2,4-diMe-Ph) H H 1-354 H H H Me 2-(CH_Two)_Four-OCH_Two-(3,4-diMe-Ph) H H 1-355 H H H Me 2-(CH_Two)_Four-OCH_Two-(3,5-diMe-Ph) H H 1-356 H H H Me 2-(CH_Two)_Five-OCH_Two-cHx H H 1-357 H H H Me 2-(CH_Two)_Five-OCH_Two-Ph H H 1-358 H H H Me 2-(CH_Two)₆-OCH_Two-cHx H H 1-359 H H H Me 2-(CH_Two)₆-OCH_Two-Ph H H 1-360 H H H Me 2 -CH = CH-cHx H H 1-361 H H H Me 2 -CH = CH-Ph H H 1-362 H H H Me 2 -CH = CH- (CH_Two)_Two-cHx H H 1-363 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-F-cHx) H H 1-364 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-Me-cHx) H H 1-365 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-MeO-cHx) H H 1-366 H H H Me 2 -CH = CH- (CH_Two)_Two-Ph H H 1-367 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-F-Ph) H H 1-368 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-Me-Ph) H H 1-369 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-Et-Ph) H H 1-370 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-CF_Three-Ph) H H 1-371 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-MeO-Ph) H H 1-372 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-EtO-Ph) H H 1-373 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-MeS-Ph) H H 1-374 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-cHx-Ph) H H 1-375 H H H Me 2 -CH = CH- (CH_Two)_Two-(4-Ph-Ph) H H 1-376 H H H Me 2 -CH = CH- (CH_Two)_Three-cHx H H 1-377 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-F-cHx) H H 1-378 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-Me-cHx) H H 1-379 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-MeO-cHx) H H 1-380 H H H Me 2 -CH = CH- (CH_Two)_Three-Ph H H 1-381 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-F-Ph) H H 1-382 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-Me-Ph) H H 1-383 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-Et-Ph) H H 1-384 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-CF_Three-Ph) H H 1-385 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-MeO-Ph) H H 1-386 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-EtO-Ph) H H 1-387 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-MeS-Ph) H H 1-388 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-cHx-Ph) H H 1-389 H H H Me 2 -CH = CH- (CH_Two)_Three-(4-Ph-Ph) H H 1-390 H H H Me 2 -CH = CH- (CH_Two)_Four-cHx H H 1-391 H H H Me 2 -CH = CH- (CH_Two)_Four-Ph H H 1-392 H H H Me 2 -CH = CH- (CH_Two)_Five-cHx H H 1-393 H H H Me 2 -CH = CH-CH_TwoO-cHx H H 1-394 H H H Me 2 -CH = CH-CH_TwoO-Ph H H 1-395 H H H Me 2 -CH = CH-CH_TwoO- (4-Me-Ph) H H 1-396 H H H Me 2 -CH = CH- (CH_Two)_TwoO-cHx H H 1-397 H H H Me 2 -CH = CH- (CH_Two)_TwoO-Ph HH 1-398 HHH Me 2 -C≡C-cHx HH 1-399 HHH Me 2 -C≡C- (4-F-cHx) HH 1-400 HHH Me 2 -C≡C- (4- Me-cHx) HH 1-401 HHH Me 2 -C≡C- (4-MeO-cHx) HH 1-402 HHH Me 2 -C≡C-Ph HH 1-403 HHH Me 2 -C≡C- (4 -F-Ph) HH 1-404 HHH Me 2 -C≡C- (4-Me-Ph) HH 1-405 HHH Me 2 -C≡C- (4-Pr-Ph) HH 1-406 HHH Me 2 -C≡C- (4-Bu-Ph) HH 1-407 HHH Me 2 -C≡C- (4-MeO-Ph) HH 1-408 HHH Me 2 -C≡C- (4-EtO-Ph) HH 1-409 HHH Me 2 -C≡C- (4-PrO-Ph) HH 1-410 HHH Me 2 -C≡C- (4-cHx-Ph) HH 1-411 HHH Me 2 -C≡C- (4-Ph-Ph) HH 1-412 HHH Me 2 -C≡C- (CH_Two)_Two-cHx H H 1-413 H H H Me 2 -C≡C- (CH_Two)_Two-(4-F-cHx) H H 1-414 H H H Me 2 -C≡C- (CH_Two)_Two-(4-Me-cHx) H H 1-415 H H H Me 2 -C≡C- (CH_Two)_Two-(4-MeO-cHx) H H 1-416 H H H Me 2 -C≡C- (CH_Two)_Two-Ph H H 1-417 H H H Me 2 -C≡C- (CH_Two)_Two-(4-F-Ph) H H 1-418 H H H Me 2 -C≡C- (CH_Two)_Two-(4-Me-Ph) H H 1-419 H H H Me 2 -C≡C- (CH_Two)_Three-cPn H H 1-420 H H H Me 2 -C≡C- (CH_Two)_Three-cHx 5-F H 1-421 H H H Me 2 -C≡C- (CH_Two)_Three-cHx 5-Me H 1-422 H H H Me 2 -C≡C- (CH_Two)_Three-cHx H H 1-423 H H Me Me 2 -C≡C- (CH_Two)_Three-cHx H H 1-424 Me H H Me 2 -C≡C- (CH_Two)_Three-cHx H H 1-425 CO_TwoMe H H Me 2 -C≡C- (CH_Two)_Three-cHx H H 1-426 H H H Me 2 -C≡C- (CH_Two)_Three-(4-F-cHx) H H 1-427 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Me-cHx) H H 1-428 H H H Me 2 -C≡C- (CH_Two)_Three-(4-MeO-cHx) H H 1-429 H H H Me 2 -C≡C- (CH_Two)_Three-Ph H H 1-430 H H Me Me 2 -C≡C- (CH_Two)_Three-Ph H H 1-431 Me H H Me 2 -C≡C- (CH_Two)_Three-Ph H H 1-432 CO_TwoMe H H Me 2 -C≡C- (CH_Two)_Three-Ph H H 1-433 H H H Me 2 -C≡C- (CH_Two)_Three-(3-F-Ph) H H 1-434 H H H Me 2 -C≡C- (CH_Two)_Three-(4-F-Ph) H H 1-435 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Cl-Ph) H H 1-436 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Br-Ph) H H 1-437 H H H Me 2 -C≡C- (CH_Two)_Three-(3-Me-Ph) H H 1-438 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Me-Ph) H H 1-439 H H H Me 2 -C≡C- (CH_Two)_Three-(3-Et-Ph) H H 1-440 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Et-Ph) H H 1-441 H H H Me 2 -C≡C- (CH_Two)_Three-(3-Pr-Ph) H H 1-442 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Pr-Ph) H H 1-443 H H H Me 2 -C≡C- (CH_Two)_Three-(3-iPr-Ph) H H 1-444 H H H Me 2 -C≡C- (CH_Two)_Three-(4-iPr-Ph) H H 1-445 H H H Me 2 -C≡C- (CH_Two)_Three-(3-Bu-Ph) H H 1-446 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Bu-Ph) H H 1-447 H H H Me 2 -C≡C- (CH_Two)_Three-(3-CF_Three-Ph) H H 1-448 H H H Me 2 -C≡C- (CH_Two)_Three-(4-CF_Three-Ph) H H 1-449 H H H Me 2 -C≡C- (CH_Two)_Three-(3-MeO-Ph) H H 1-450 H H H Me 2 -C≡C- (CH_Two)_Three-(4-MeO-Ph) H H 1-451 H H H Me 2 -C≡C- (CH_Two)_Three-(3-EtO-Ph) H H 1-452 H H H Me 2 -C≡C- (CH_Two)_Three-(4-EtO-Ph) H H 1-453 H H H Me 2 -C≡C- (CH_Two)_Three-(3-PrO-Ph) H H 1-454 H H H Me 2 -C≡C- (CH_Two)_Three-(4-PrO-Ph) H H 1-455 H H H Me 2 -C≡C- (CH_Two)_Three-(3-iPrO-Ph) H H 1-456 H H H Me 2 -C≡C- (CH_Two)_Three-(4-iPrO-Ph) H H 1-457 H H H Me 2 -C≡C- (CH_Two)_Three-[3- (2-Et-PrO) -Ph] H H 1-458 H H H Me 2 -C≡C- (CH_Two)_Three-[4- (2-Et-PrO) -Ph] H H 1-459 H H H Me 2 -C≡C- (CH_Two)_Three-(3-iBuO-Ph) H H 1-460 H H H Me 2 -C≡C- (CH_Two)_Three-(4-iBuO-Ph) H H 1-461 H H H Me 2 -C≡C- (CH_Two)_Three-(3-MeS-Ph) H H 1-462 H H H Me 2 -C≡C- (CH_Two)_Three-(4-MeS-Ph) H H 1-463 H H H Me 2 -C≡C- (CH_Two)_Three-(3-EtS-Ph) H H 1-464 H H H Me 2 -C≡C- (CH_Two)_Three-(4-EtS-Ph) H H 1-465 H H H Me 2 -C≡C- (CH_Two)_Three-(3-PrS-Ph) H H 1-466 H H H Me 2 -C≡C- (CH_Two)_Three-(4-PrS-Ph) H H 1-467 H H H Me 2 -C≡C- (CH_Two)_Three-(3-iPrS-Ph) H H 1-468 H H H Me 2 -C≡C- (CH_Two)_Three-(4-iPrS-Ph) H H 1-469 H H H Me 2 -C≡C- (CH_Two)_Three-[3- (2-Et-PrS) -Ph] H H 1-470 H H H Me 2 -C≡C- (CH_Two)_Three-[4- (2-Et-PrS) -Ph] H H 1-471 H H H Me 2 -C≡C- (CH_Two)_Three-(3-iBuS-Ph) H H 1-472 H H H Me 2 -C≡C- (CH_Two)_Three-(4-iBuS-Ph) H H 1-473 H H H Me 2 -C≡C- (CH_Two)_Three-(3-cHx-Ph) H H 1-474 H H H Me 2 -C≡C- (CH_Two)_Three-(4-cHx-Ph) H H 1-475 H H H Me 2 -C≡C- (CH_Two)_Three-(3-Ph-Ph) H H 1-476 H H H Me 2 -C≡C- (CH_Two)_Three-(4-Ph-Ph) H H 1-477 H H H Me 2 -C≡C- (CH_Two)_Three-(2,4-diMe-Ph) H H 1-478 H H H Me 2 -C≡C- (CH_Two)_Three-(3,4-diMe-Ph) H H 1-479 H H H Me 2 -C≡C- (CH_Two)_Three-(3,5-diMe-Ph) H H 1-480 H H H Me 2 -C≡C- (CH_Two)_Three-Np (1) H H 1-481 H H H Me 2 -C≡C- (CH_Two)_Three-Np (2) H H 1-482 H H H Me 2 -C≡C- (CH_Two)_Four-cHx H H 1-483 H H H Me 2 -C≡C- (CH_Two)_Four-(4-F-cHx) H H 1-484 H H H Me 2 -C≡C- (CH_Two)_Four-(4-Me-cHx) H H 1-485 H H H Me 2 -C≡C- (CH_Two)_Four-(4-MeO-cHx) H H 1-486 H H H Me 2 -C≡C- (CH_Two)_Four-Ph H H 1-487 H H H Me 2 -C≡C- (CH_Two)_Four-(4-F-Ph) H H 1-488 H H H Me 2 -C≡C- (CH_Two)_Four-(4-Cl-Ph) H H 1-489 H H H Me 2 -C≡C- (CH_Two)_Four-(4-Br-Ph) H H 1-490 H H H Me 2 -C≡C- (CH_Two)_Four-(4-Me-Ph) H H 1-491 H H H Me 2 -C≡C- (CH_Two)_Four-(4-Et-Ph) H H 1-492 H H H Me 2 -C≡C- (CH_Two)_Four-(4-iPr-Ph) H H 1-493 H H H Me 2 -C≡C- (CH_Two)_Four-(4-Bu-Ph) H H 1-494 H H H Me 2 -C≡C- (CH_Two)_Four-(4-CF_Three-Ph) H H 1-495 H H H Me 2 -C≡C- (CH_Two)_Four-(4-MeO-Ph) H H 1-496 H H H Me 2 -C≡C- (CH_Two)_Four-(4-EtO-Ph) H H 1-497 H H H Me 2 -C≡C- (CH_Two)_Four-(4-PrO-Ph) H H 1-498 H H H Me 2 -C≡C- (CH_Two)_Four-(4-iPrO-Ph) H H 1-499 H H H Me 2 -C≡C- (CH_Two)_Four-[4- (2-Et-PrO) -Ph] H H 1-500 H H H Me 2 -C≡C- (CH_Two)_Four-(4-iBuO-Ph) H H 1 -501 H H H Me 2 -C≡C- (CH_Two)_Four-(4-MeS-Ph) H H 1 -502 H H H Me 2 -C≡C- (CH_Two)_Four-(4-EtS-Ph) H H 1-503 H H H Me 2 -C≡C- (CH_Two)_Four-(4-PrS-Ph) H H 1-504 H H H Me 2 -C≡C- (CH_Two)_Four-(4-iPrS-Ph) H H 1 -505 H H H Me 2 -C≡C- (CH_Two)_Four-[4- (2-Et-PrS) -Ph] H H 1-506 H H H Me 2 -C≡C- (CH_Two)_Four-(4-iBuS-Ph) H H 1 -507 H H H Me 2 -C≡C- (CH_Two)_Four-(4-cHx-Ph) H H 1 -508 H H H Me 2 -C≡C- (CH_Two)_Four-(4-Ph-Ph) H H 1-509 H H H Me 2 -C≡C- (CH_Two)_Four-(2,4-diMe-Ph) H H 1-510 H H H Me 2 -C≡C- (CH_Two)_Four-(3,4-diMe-Ph) H H 1-511 H H H Me 2 -C≡C- (CH_Two)_Four-(3,5-diMe-Ph) H H 1-512 H H H Me 2 -C≡C- (CH_Two)_Five-cHx H H 1-513 H H H Me 2 -C≡C- (CH_Two)_Five-(4-F-cHx) H H 1 -514 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Me-cHx) H H 1 -515 H H H Me 2 -C≡C- (CH_Two)_Five-(4-MeO-cHx) H H 1-516 H H H Me 2 -C≡C- (CH_Two)_Five-Ph H H 1-517 H H H Me 2 -C≡C- (CH_Two)_Five-(4-F-Ph) H H 1-518 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Cl-Ph) H H 1-519 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Br-Ph) H H 1-520 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Me-Ph) H H 1-521 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Et-Ph) H H 1-522 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Pr-Ph) H H 1-523 H H H Me 2 -C≡C- (CH_Two)_Five-(4-iPr-Ph) H H 1-524 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Bu-Ph) H H 1-525 H H H Me 2 -C≡C- (CH_Two)_Five-(4-CF_Three-Ph) H H 1 -526 H H H Me 2 -C≡C- (CH_Two)_Five-(4-MeO-Ph) H H 1-527 H H H Me 2 -C≡C- (CH_Two)_Five-(4-EtO-Ph) H H 1-528 H H H Me 2 -C≡C- (CH_Two)_Five-(4-PrO-Ph) H H 1-529 H H H Me 2 -C≡C- (CH_Two)_Five-(4-iPrO-Ph) H H 1-530 H H H Me 2 -C≡C- (CH_Two)_Five-[4- (2-Et-PrO) -Ph] H H 1-531 H H H Me 2 -C≡C- (CH_Two)_Five-(4-iBuO-Ph) H H 1-532 H H H Me 2 -C≡C- (CH_Two)_Five-(4-MeS-Ph) H H 1 -533 H H H Me 2 -C≡C- (CH_Two)_Five-(4-EtS-Ph) H H 1 -534 H H H Me 2 -C≡C- (CH_Two)_Five-(4-PrS-Ph) H H 1-535 H H H Me 2 -C≡C- (CH_Two)_Five-(4-iPrS-Ph) H H 1-536 H H H Me 2 -C≡C- (CH_Two)_Five-[4- (2-Et-PrS) -Ph] H H 1-537 H H H Me 2 -C≡C- (CH_Two)_Five-(4-iBuS-Ph) H H 1-538 H H H Me 2 -C≡C- (CH_Two)_Five-(4-cHx-Ph) H H 1-539 H H H Me 2 -C≡C- (CH_Two)_Five-(4-Ph-Ph) H H 1-540 H H H Me 2 -C≡C- (CH_Two)_Five-(2,4-diMe-Ph) H H 1-541 H H H Me 2 -C≡C- (CH_Two)_Five-(3,4-diMe-Ph) H H 1-542 H H H Me 2 -C≡C- (CH_Two)_Five-(3,5-diMe-Ph) H H 1-543 H H H Me 2 -C≡C-CH_TwoO-cHx H H 1-544 H H Me Me 2 -C≡C-CH_TwoO-cHx H H 1-545 Me H H Me 2 -C≡C-CH_TwoO-cHx H H 1-546 CO_TwoMe H H Me 2 -C≡C-CH_TwoO-cHx H H 1-547 H H H Me 2 -C≡C-CH_TwoO- (4-F-cHx) H H 1-548 H H H Me 2 -C≡C-CH_TwoO- (4-Me-cHx) H H 1-549 H H H Me 2 -C≡C-CH_TwoO- (4-MeO-cHx) H H 1-550 H H H Me 2 -C≡C-CH_TwoO-Ph H H 1-551 H H Me Me 2 -C≡C-CH_TwoO-Ph H H 1-552 Me H H Me 2 -C≡C-CH_TwoO-Ph H H 1-553 CO_TwoMe H H Me 2 -C≡C-CH_TwoO-Ph H H 1-554 H H H Me 2 -C≡C-CH_TwoO- (4-F-Ph) H H 1-555 H H H Me 2 -C≡C-CH_TwoO- (4-Me-Ph) H H 1-556 H H H Me 2 -C≡C-CH_TwoO- (4-Me-Ph) 5-F H 1-557 H H H Me 2 -C≡C-CH_TwoO- (4-Me-Ph) 5-Me H 1-558 H H H Me 2 -C≡C-CH_TwoO- (4-Et-Ph) H H 1-559 H H H Me 2 -C≡C-CH_TwoO- (4-CF_Three-Ph) H H 1 -560 H H H Me 2 -C≡C-CH_TwoO- (4-MeO-Ph) H H 1-561 H H H Me 2 -C≡C-CH_TwoO- (4-EtO-Ph) H H 1 -562 H H H Me 2 -C≡C-CH_TwoO- (4-MeS-Ph) H H 1-563 H H H Me 2 -C≡C-CH_TwoO- (4-cHx-Ph) H H 1-564 H H H Me 2 -C≡C-CH_TwoO- (4-Ph-Ph) H H 1-565 H H H Me 2 -C≡C- (CH_Two)_TwoO-cPn H H 1-566 H H H Me 2 -C≡C- (CH_Two)_TwoO-cHx H H 1-567 H H H Me 2 -C≡C- (CH_Two)_TwoO-cHx 5-F H 1-568 H H H Me 2 -C≡C- (CH_Two)_TwoO-cHx 5-Me H 1-569 H H Me Me 2 -C≡C- (CH_Two)_TwoO-cHx H H 1-570 Me H H Me 2 -C≡C- (CH_Two)_TwoO-cHx H H 1-571 CO_TwoMe H H Me 2 -C≡C- (CH_Two)_TwoO-cHx H H 1 -572 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-F-cHx) H H 1-573 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Me-cHx) H H 1-574 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-MeO-cHx) H H 1 -575 H H H Me 2 -C≡C- (CH_Two)_TwoO-Ph H H 1-576 H H Me Me 2 -C≡C- (CH_Two)_TwoO-Ph H H 1-577 Me H H Me 2 -C≡C- (CH_Two)_TwoO-Ph H H 1-578 CO_TwoMe H H Me 2 -C≡C- (CH_Two)_TwoO-Ph H H 1-579 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-F-Ph) H H 1-580 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-F-Ph) H H 1-581 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Cl-Ph) H H 1-582 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Br-Ph) H H 1-583 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-Me-Ph) H H 1-584 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Me-Ph) H H 1-585 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-Et-Ph) H H 1-586 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Et-Ph) H H 1-587 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-Pr-Ph) H H 1-588 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Pr-Ph) H H 1-589 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-iPr-Ph) H H 1-590 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-iPr-Ph) H H 1-591 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-Bu-Ph) H H 1-592 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Bu-Ph) H H 1-593 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-CF_Three-Ph) H H 1 -594 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-CF_Three-Ph) H H 1-595 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-MeO-Ph) H H 1-596 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-MeO-Ph) H H 1-597 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-EtO-Ph) H H 1-598 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-EtO-Ph) H H 1-599 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-PrO-Ph) H H 1-600 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-PrO-Ph) H H 1-601 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-iPrO-Ph) H H 1-602 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-iPrO-Ph) H H 1-603 H H H Me 2 -C≡C- (CH_Two)_TwoO- [3- (2-Et-PrO) -Ph] H H 1-604 H H H Me 2 -C≡C- (CH_Two)_TwoO- [4- (2-Et-PrO) -Ph] H H 1-605 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-iBuO-Ph) H H 1-606 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-iBuO-Ph) H H 1-607 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-MeS-Ph) H H 1-608 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-MeS-Ph) H H 1-609 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-EtS-Ph) H H 1-610 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-EtS-Ph) H H 1-611 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-PrS-Ph) H H 1-612 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-PrS-Ph) H H 1-613 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-iPrS-Ph) H H 1-614 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-iPrS-Ph) H H 1-615 H H H Me 2 -C≡C- (CH_Two)_TwoO- [3- (2-Et-PrS) -Ph] H H 1-616 H H H Me 2 -C≡C- (CH_Two)_TwoO- [4- (2-Et-PrS) -Ph] H H 1-617 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-iBuS-Ph) H H 1-618 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-iBuS-Ph) H H 1-619 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-cHx-Ph) H H 1 -620 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-cHx-Ph) H H 1-621 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3-Ph-Ph) H H 1-622 H H H Me 2 -C≡C- (CH_Two)_TwoO- (4-Ph-Ph) H H 1-623 H H H Me 2 -C≡C- (CH_Two)_TwoO- (2,4-diMe-Ph) H H 1-624 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3,4-diMe-Ph) H H 1-625 H H H Me 2 -C≡C- (CH_Two)_TwoO- (3,5-diMe-Ph) H H 1-626 H H H Me 2 -C≡C- (CH_Two)_ThreeO-cHx H H 1-627 H H H Me 2 -C≡C- (CH_Two)_ThreeO-Ph H H 1-628 H H H Me 2 -C≡C- (CH_Two)_FourO-cHx H H 1-629 H H H Me 2 -C≡C- (CH_Two)_FourO-Ph H H 1-630 H H H Me 2 -C≡C-CH_TwoOCH_Two-cHx H H 1-631 H H Me Me 2 -C≡C-CH_TwoOCH_Two-cHx H H 1-632 Me H H Me 2 -C≡C-CH_TwoOCH_Two-cHx H H 1 -633 CO_TwoMe H H Me 2 -C≡C-CH_TwoOCH_Two-cHx H H 1 -634 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-F-cHx) H H 1-635 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-Me-cHx) H H 1-636 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-MeO-cHx) H H 1-637 H H H Me 2 -C≡C-CH_TwoOCH_Two-Ph H H 1-638 H H Me Me 2 -C≡C-CH_TwoOCH_Two-Ph H H 1-639 Me H H Me 2 -C≡C-CH_TwoOCH_Two-Ph H H 1-640 CO_TwoMe H H Me 2 -C≡C-CH_TwoOCH_Two-Ph H H 1-641 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-F-Ph) H H 1-642 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-Me-Ph) H H 1-643 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-Et-Ph) H H 1-644 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-CF_Three-Ph) H H 1 -645 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-MeO-Ph) H H 1-646 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-EtO-Ph) H H 1-647 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-MeS-Ph) H H 1-648 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-cHx-Ph) H H 1-649 H H H Me 2 -C≡C-CH_TwoOCH_Two-(4-Ph-Ph) H H 1-650 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-cPn H H 1-651 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-cHx H H 1 -652 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-F-cHx) H H 1-653 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Me-cHx) H H 1-654 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-MeO-cHx) H H 1-655 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-Ph H H 1-656 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-F-Ph) H H 1-657 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Cl-Ph) H H 1-658 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Br-Ph) H H 1-659 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Me-Ph) H H 1-660 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Me-Ph) 5-F H 1-661 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Me-Ph) 5-Me H 1-662 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Et-Ph) H H 1-663 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Pr-Ph) H H 1-664 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-iPr-Ph) H H 1-665 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Bu-Ph) H H 1-666 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-CF_Three-Ph) H H 1-667 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-MeO-Ph) H H 1-668 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-EtO-Ph) H H 1-669 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-PrO-Ph) H H 1-670 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-iPrO-Ph) H H 1-671 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-[4- (2-Et-PrO) Ph] H H 1-672 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-iBuO-Ph) H H 1-673 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-MeS-Ph) H H 1-674 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-EtS-Ph) H H 1-675 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-PrS-Ph) H H 1-676 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-iPrS-Ph) H H 1-677 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-[4- (2-Et-PrS) Ph] H H 1-678 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-iBuS-Ph) H H 1-679 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-cHx-Ph) H H 1-680 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(4-Ph-Ph) H H 1-681 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(2,4-diMe-Ph) H H 1-682 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(3,4-diMe-Ph) H H 1-683 H H H Me 2 -C≡C- (CH_Two)_TwoOCH_Two-(3,5-diMe-Ph) H H 1-684 H H H Me 2 -C≡C- (CH_Two)_ThreeOCH_Two-cHx H H 1-685 H H H Me 2 -C≡C- (CH_Two)_ThreeOCH_Two-Ph H H 1-686 H H H Me 2 -C≡C- (CH_Two)_FourOCH_Two-cHx H H 1 -687 H H H Me 2 -C≡C- (CH_Two)_FourOCH_Two-Ph H H 1 -688 H H H Me 2 -CO-CH_Two-(4-cHx-Ph) H H 1-689 H H H Me 2 -CO-CH_Two-(4-Ph-Ph) H H 1-690 H H H Me 2 -CO- (CH_Two)_Two-cHx H H 1-691 H H H Me 2 -CO- (CH_Two)_Two-Ph H H 1-692 H H H Me 2 -CO- (CH_Two)_Three-cHx H H 1-693 H H H Me 2 -CO- (CH_Two)_Three-Ph H H 1 -694 H H H Me 2 -CO- (CH_Two)_Four-cHx H H 1-695 H H H Me 2 -CO- (CH_Two)_Four-(4-F-cHx) H H 1-696 H H H Me 2 -CO- (CH_Two)_Four-(4-Me-cHx) H H 1-697 H H H Me 2 -CO- (CH_Two)_Four-(4-MeO-cHx) H H 1-698 H H H Me 2 -CO- (CH_Two)_Four-Ph H H 1-699 H H H Me 2 -CO- (CH_Two)_Four-(4-F-Ph) H H 1-700 H H H Me 2 -CO- (CH_Two)_Four-(4-Me-Ph) H H 1-701 H H H Me 2 -CO- (CH_Two)_Four-(4-Et-Ph) H H 1-702 H H H Me 2 -CO- (CH_Two)_Four-(4-CF_Three-Ph) H H 1-703 H H H Me 2 -CO- (CH_Two)_Four-(4-MeO-Ph) H H 1-704 H H H Me 2 -CO- (CH_Two)_Four-(4-EtO-Ph) H H 1-705 H H H Me 2 -CO- (CH_Two)_Four-(4-MeS-Ph) H H 1-706 H H H Me 2 -CO- (CH_Two)_Four-(4-cHx-Ph) H H 1-707 H H H Me 2 -CO- (CH_Two)_Four-(4-Ph-Ph) H H 1-708 H H H Me 2 -CO- (CH_Two)_Five-cHx H H 1 -709 H H H Me 2 -CO- (CH_Two)_Five-(4-F-cHx) H H 1-710 H H H Me 2 -CO- (CH_Two)_Five-(4-Me-cHx) H H 1-711 H H H Me 2 -CO- (CH_Two)_Five-(4-MeO-cHx) H H 1-712 H H H Me 2 -CO- (CH_Two)_Five-Ph H H 1-713 H H H Me 2 -CO- (CH_Two)_Five-(4-F-Ph) H H 1 -714 H H H Me 2 -CO- (CH_Two)_Five-(4-Me-Ph) H H 1-715 H H H Me 2 -CO- (CH_Two)_Five-(4-Et-Ph) H H 1-716 H H H Me 2 -CO- (CH_Two)_Five-(4-CF_Three-Ph) H H 1 -717 H H H Me 2 -CO- (CH_Two)_Five-(4-MeO-Ph) H H 1-718 H H H Me 2 -CO- (CH_Two)_Five-(4-EtO-Ph) H H 1-719 H H H Me 2 -CO- (CH_Two)_Five-(4-MeS-Ph) H H 1 -720 H H H Me 2 -CO- (CH_Two)_Five-(4-EtS-Ph) H H 1-721 H H H Me 2 -CO- (CH_Two)_Five-(4-cHx-Ph) H H 1-722 H H H Me 2 -CO- (CH_Two)_Five-(4-Ph-Ph) H H 1-723 H H H Me 2 -CO- (CH_Two)₆-cHx H H 1 -724 H H H Me 2 -CO- (CH_Two)₆-Ph H H 1-725 H H H Me 2 -CO- (CH_Two)₇-cHx H H 1-726 H H H Me 2 -CO- (CH_Two)₇-Ph H H 1 -727 H H H Me 2 -CO- (CH_Two)_TwoO-cHx H H 1 -728 H H H Me 2 -CO- (CH_Two)_TwoO- (4-F-cHx) H H 1-729 H H H Me 2 -CO- (CH_Two)_TwoO- (4-Me-cHx) H H 1-730 H H H Me 2 -CO- (CH_Two)_TwoO- (4-MeO-cHx) H H 1-731 H H H Me 2 -CO- (CH_Two)_TwoO-Ph H H 1-732 H H H Me 2 -CO- (CH_Two)_TwoO- (4-F-Ph) H H 1-733 H H H Me 2 -CO- (CH_Two)_TwoO- (4-Me-Ph) H H 1-734 H H H Me 2 -CO- (CH_Two)_TwoO- (4-Et-Ph) H H 1-735 H H H Me 2 -CO- (CH_Two)_TwoO- (4-CF_Three-Ph) H H 1-736 H H H Me 2 -CO- (CH_Two)_TwoO- (4-MeO-Ph) H H 1-737 H H H Me 2 -CO- (CH_Two)_TwoO- (4-EtO-Ph) H H 1-738 H H H Me 2 -CO- (CH_Two)_TwoO- (4-MeS-Ph) H H 1-739 H H H Me 2 -CO- (CH_Two)_TwoO- (4-cHx-Ph) H H 1-740 H H H Me 2 -CO- (CH_Two)_TwoO- (4-Ph-Ph) H H 1-741 H H H Me 2 -CO- (CH_Two)_ThreeO-cPn H H 1-742 H H H Me 2 -CO- (CH_Two)_ThreeO-cHx H H 1-743 H H Me Me 2 -CO- (CH_Two)_ThreeO-cHx H H 1-744 Me H H Me 2 -CO- (CH_Two)_ThreeO-cHx H H 1-745 CO_TwoMe H H Me 2 -CO- (CH_Two)_ThreeO-cHx H H 1-746 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-F-cHx) H H 1 -747 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Me-cHx) H H 1-748 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-MeO-cHx) H H 1-749 H H H Me 2 -CO- (CH_Two)_ThreeO-Ph H H 1-750 H H Me Me 2 -CO- (CH_Two)_ThreeO-Ph H H 1-751 Me H H Me 2 -CO- (CH_Two)_ThreeO-Ph H H 1-752 CO_TwoMe H H Me 2 -CO- (CH_Two)_ThreeO-Ph H H 1-753 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-F-Ph) H H 1-754 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Cl-Ph) H H 1-755 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Br-Ph) H H 1-756 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Me-Ph) H H 1-757 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Et-Ph) H H 1-758 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Pr-Ph) H H 1-759 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-iPr-Ph) H H 1-760 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Bu-Ph) H H 1-761 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-CF_Three-Ph) H H 1 -762 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-MeO-Ph) H H 1-763 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-EtO-Ph) H H 1-764 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-PrO-Ph) H H 1-765 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-iPrO-Ph) H H 1-766 H H H Me 2 -CO- (CH_Two)_ThreeO- [4- (2-Et-PrO) -Ph] H H 1-767 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-iBuO-Ph) H H 1-768 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-MeS-Ph) H H 1-769 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-EtS-Ph) H H 1-770 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-PrS-Ph) H H 1-771 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-iPrS-Ph) H H 1-772 H H H Me 2 -CO- (CH_Two)_ThreeO- [4- (2-Et-PrS) -Ph] H H 1-773 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-iBuS-Ph) H H 1-774 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-cHx-Ph) H H 1-775 H H H Me 2 -CO- (CH_Two)_ThreeO- (4-Ph-Ph) H H 1-776 H H H Me 2 -CO- (CH_Two)_ThreeO- (2,4-diMe-Ph) H H 1-777 H H H Me 2 -CO- (CH_Two)_ThreeO- (3,4-diMe-Ph) H H 1-778 H H H Me 2 -CO- (CH_Two)_ThreeO- (3,5-diMe-Ph) H H 1-779 H H H Me 2 -CO- (CH_Two)_FourO-cHx H H 1 -780 H H H Me 2 -CO- (CH_Two)_FourO-Ph H H 1-781 H H H Me 2 -CO- (CH_Two)_FiveO-cHx H H 1-782 H H H Me 2 -CO- (CH_Two)_FiveO-Ph H H 1-783 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-cHx H H 1 -784 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-F-cHx) H H 1-785 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-Me-cHx) H H 1-786 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-MeO-cHx) H H 1-787 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-Ph H H 1 -788 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-F-Ph) H H 1-789 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-Me-Ph) H H 1-790 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-Et-Ph) H H 1-791 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-CF_Three-Ph) H H 1 -792 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-MeO-Ph) H H 1-793 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-EtO-Ph) H H 1-794 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-MeS-Ph) H H 1-795 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-cHx-Ph) H H 1-796 H H H Me 2 -CO- (CH_Two)_TwoOCH_Two-(4-Ph-Ph) H H 1-797 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-cHx H H 1 -798 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-F-cHx) H H 1-799 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Me-cHx) H H 1-800 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-MeO-cHx) H H 1-801 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-Ph H H 1-802 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-F-Ph) H H 1-803 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Cl-Ph) H H 1-804 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Br-Ph) H H 1-805 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Me-Ph) H H 1-806 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Et-Ph) H H 1-807 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Pr-Ph) H H 1-808 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-iPr-Ph) H H 1-809 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Bu-Ph) H H 1-810 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-CF_Three-Ph) H H 1-811 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-MeO-Ph) H H 1-812 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-EtO-Ph) H H 1-813 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-PrO-Ph) H H 1-814 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-iPrO-Ph) H H 1-815 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-[4- (2-Et-PrO) Ph] H H 1-816 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-iBuO-Ph) H H 1-817 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-MeS-Ph) H H 1-818 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-EtS-Ph) H H 1-819 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-PrS-Ph) H H 1-820 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-iPrS-Ph) H H 1-821 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-[4- (2-Et-PrS) Ph] H H 1-822 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-iBuS-Ph) H H 1-823 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-cHx-Ph) H H 1-824 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(4-Ph-Ph) H H 1-825 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(2,4-diMe-Ph) H H 1-826 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(3,4-diMe-Ph) H H 1-827 H H H Me 2 -CO- (CH_Two)_ThreeOCH_Two-(3,5-diMe-Ph) H H 1-828 H H H Me 2 -CO- (CH_Two)_FourOCH_Two-cHx H H 1 -829 H H H Me 2 -CO- (CH_Two)_FourOCH_Two-Ph H H 1 -830 H H H Me 2 -CO- (CH_Two)_FiveOCH_Two-cHx H H 1-831 H H H Me 2 -CO- (CH_Two)_FiveOCH_Two-Ph H H 1-832 H H H Me 2 -CH (OH) -CH_Two-cHx H H 1 -833 H H H Me 2 -CH (OH) -CH_Two-Ph H H 1 -834 H H H Me 2 -CH (OH)-(CH_Two)_Two-cHx H H 1 -835 H H H Me 2 -CH (OH)-(CH_Two)_Two-Ph H H 1-836 H H H Me 2 -CH (OH)-(CH_Two)_Three-cHx H H 1-837 H H H Me 2 -CH (OH)-(CH_Two)_Three-Ph H H 1-838 H H H Me 2 -CH (OH)-(CH_Two)_Four-cHx H H 1-839 H H H Me 2 -CH (OH)-(CH_Two)_Four-Ph H H 1-840 H H H Me 2 -CH (OH)-(CH_Two)_Five-cHx H H 1-841 H H H Me 2 -CH (OH)-(CH_Two)_Five-Ph H H 1-842 H H H Me 2 -CH (OH)-(CH_Two)₆-cHx H H 1-843 H H H Me 2 -CH (OH)-(CH_Two)₆-Ph H H 1-844 H H H Me 2 -CH (OH)-(CH_Two)₇-cHx H H 1-845 H H H Me 2 -CH (OH)-(CH_Two)₇-Ph H H 1-846 H H H Me 2-[4- (cHx-CH_TwoO) -Ph] H H 1-847 H H H Me 2-[4- (cHx- (CH_Two)_TwoO) Ph] H H 1-848 H H H Me 2-[4- (cHx- (CH_Two)_ThreeO) Ph] H H 1-849 H H H Me 2-(4-BzO-Ph) H H 1-850 H H H Me 2-[4- (Ph- (CH_Two)_TwoO) -Ph] H H 1-851 H H H Me 2-[4- (Ph- (CH_Two)_ThreeO) -Ph] H H 1-852 H H H Et 2-(CH_Two)_Three-cHx H H 1-853 H H H Et 2-(CH_Two)_Three-Ph H H 1-854 H H H Et 2-(CH_Two)_Four-cHx H H 1-855 H H H Et 2-(CH_Two)_Four-Ph H H 1-856 H H H Et 2-(CH_Two)_Five-cPn H H 1-857 H H H Et 2-(CH_Two)_Five-cHx H H 1-858 H H H Et 2-(CH_Two)_Five-Ph H H 1-859 H H H Et 2-(CH_Two)_Five-(4-F-Ph) H H 1-860 H H H Et 2-(CH_Two)_Five-(4-Me-Ph) H H 1-861 H H H Et 2-(CH_Two)_Five-(4-Et-Ph) H H 1-862 H H H Et 2-(CH_Two)_Five-(4-CF_Three-Ph) H H 1-863 H H H Et 2-(CH_Two)_Five-(4-MeO-Ph) H H 1-864 H H H Et 2-(CH_Two)_Five-(4-EtO-Ph) H H 1-865 H H H Et 2-(CH_Two)_Five-(4-MeS-Ph) H H 1-866 H H H Et 2-(CH_Two)_Five-(4-cHx-Ph) H H 1-867 H H H Et 2-(CH_Two)_Five-(4-Ph-Ph) H H 1-868 H H H Et 2-(CH_Two)₆-cPn H H 1 -869 H H H Et 2-(CH_Two)₆-cHx H H 1 -870 H H H Et 2-(CH_Two)₆-Ph H H 1-871 H H H Et 2-(CH_Two)₆-(4-F-Ph) H H 1-872 H H H Et 2-(CH_Two)₆-(4-Me-Ph) H H 1-873 H H H Et 2-(CH_Two)₆-(4-Et-Ph) H H 1-874 H H H Et 2-(CH_Two)₆-(4-CF_Three-Ph) H H 1-875 H H H Et 2-(CH_Two)₆-(4-MeO-Ph) H H 1-876 H H H Et 2-(CH_Two)₆-(4-EtO-Ph) H H 1-877 H H H Et 2-(CH_Two)₆-(4-MeS-Ph) H H 1-878 H H H Et 2-(CH_Two)₆-(4-cHx-Ph) H H 1-879 H H H Et 2-(CH_Two)₆-(4-Ph-Ph) H H 1-880 H H H Et 2-(CH_Two)₇-cHx H H 1-881 H H H Et 2-(CH_Two)₇-Ph H H 1-882 H H H Et 2 -CH = CH-cHx H H 1-883 H H H Et 2 -CH = CH-Ph H H 1-884 H H H Et 2 -CH = CH- (CH_Two)_Three-cHx H H 1-885 H H H Et 2 -CH = CH- (CH_Two)_Three-Ph H H 1-886 H H H Et 2 -CH = CH- (CH_Two)_Four-cHx H H 1-887 H H H Et 2 -CH = CH- (CH_Two)_Four-Ph H H 1-888 H H H Et 2 -CH = CH-CH_TwoO-cHx H H 1-889 H H H Et 2 -CH = CH-CH_TwoO-Ph H H 1-890 H H H Et 2 -CH = CH- (CH_Two)_TwoO-cHx H H 1-891 H H H Et 2 -CH = CH- (CH_Two)_TwoO-Ph H H 1-892 H H H Et 2 -C≡C-CH_Two-cHx H H 1-893 H H H Et 2 -C≡C-CH_Two-Ph H H 1-894 H H H Et 2 -C≡C- (CH_Two)_Two-cHx H H 1-895 H H H Et 2 -C≡C- (CH_Two)_Two-Ph H H 1-896 H H H Et 2 -C≡C- (CH_Two)_Three-cPn H H 1-897 H H H Et 2 -C≡C- (CH_Two)_Three-cHx H H 1-898 H H H Et 2 -C≡C- (CH_Two)_Three-(4-F-cHx) H H 1-899 H H H Et 2 -C≡C- (CH_Two)_Three-(4-Me-cHx) H H 1-900 H H H Et 2 -C≡C- (CH_Two)_Three-(4-MeO-cHx) H H 1-901 H H H Et 2 -C≡C- (CH_Two)_Three-Ph H H 1-902 H H H Et 2 -C≡C- (CH_Two)_Three-(4-F-Ph) H H 1-903 H H H Et 2 -C≡C- (CH_Two)_Three-(4-Me-Ph) H H 1-904 H H H Et 2 -C≡C- (CH_Two)_Three-(4-Et-Ph) H H 1-905 H H H Et 2 -C≡C- (CH_Two)_Three-(4-CF_Three-Ph) H H 1-906 H H H Et 2 -C≡C- (CH_Two)_Three-(4-MeO-Ph) H H 1-907 H H H Et 2 -C≡C- (CH_Two)_Three-(4-EtO-Ph) H H 1-908 H H H Et 2 -C≡C- (CH_Two)_Three-(4-MeS-Ph) H H 1-909 H H H Et 2 -C≡C- (CH_Two)_Three-(4-cHx-Ph) H H 1-910 H H H Et 2 -C≡C- (CH_Two)_Three-(4-Ph-Ph) H H 1-911 H H H Et 2 -C≡C- (CH_Two)_Four-cPn H H 1-912 H H H Et 2 -C≡C- (CH_Two)_Four-cHx H H 1-913 H H H Et 2 -C≡C- (CH_Two)_Four-(4-F-cHx) H H 1-914 H H H Et 2 -C≡C- (CH_Two)_Four-(4-Me-cHx) H H 1-915 H H H Et 2 -C≡C- (CH_Two)_Four-(4-MeO-cHx) H H 1-916 H H H Et 2 -C≡C- (CH_Two)_Four-Ph H H 1-917 H H H Et 2 -C≡C- (CH_Two)_Four-(4-F-Ph) H H 1-918 H H H Et 2 -C≡C- (CH_Two)_Four-(4-Me-Ph) H H 1-919 H H H Et 2 -C≡C- (CH_Two)_Four-(4-Et-Ph) H H 1-920 H H H Et 2 -C≡C- (CH_Two)_Four-(4-CF_Three-Ph) H H 1-921 H H H Et 2 -C≡C- (CH_Two)_Four-(4-MeO-Ph) H H 1-922 H H H Et 2 -C≡C- (CH_Two)_Four-(4-EtO-Ph) H H 1-923 H H H Et 2 -C≡C- (CH_Two)_Four-(4-MeS-Ph) H H 1-924 H H H Et 2 -C≡C- (CH_Two)_Four-(4-cHx-Ph) H H 1-925 H H H Et 2 -C≡C- (CH_Two)_Four-(4-Ph-Ph) H H 1-926 H H H Et 2 -C≡C- (CH_Two)_Five-cHx H H 1-927 H H H Et 2 -C≡C- (CH_Two)_Five-Ph H H 1-928 H H H Et 2 -C≡C- (CH_Two)₆-cHx H H 1-929 H H H Et 2 -C≡C- (CH_Two)₆-Ph H H 1-930 H H H Et 2 -C≡C-CH_TwoO-cHx H H 1-931 H H H Et 2 -C≡C-CH_TwoO-Ph H H 1-932 H H H Et 2 -C≡C- (CH_Two)_TwoO-cPn H H 1-933 H H H Et 2 -C≡C- (CH_Two)_TwoO-cHx H H 1-934 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-F-cHx) H H 1-935 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-Me-cHx) H H 1-936 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-MeO-cHx) H H 1-937 H H H Et 2 -C≡C- (CH_Two)_TwoO-Ph H H 1-938 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-F-Ph) H H 1-939 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-Me-Ph) H H 1-940 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-Et-Ph) H H 1-941 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-CF_Three-Ph) H H 1-942 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-MeO-Ph) H H 1-943 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-EtO-Ph) H H 1-944 H H H Et 2 -C≡C- (CH_Two)_TwoO- (4-MeS-Ph) H H 1-945 H H H Et 2 -CO- (CH_Two)_Three-cHx H H 1-946 H H H Et 2 -CO- (CH_Two)_Three-Ph H H 1-947 H H H Et 2 -CO- (CH_Two)_Four-cHx H H 1 -948 H H H Et 2 -CO- (CH_Two)_Four-Ph H H 1-949 H H H Et 2 -CO- (CH_Two)_Five-cHx H H 1-950 H H H Et 2 -CO- (CH_Two)_Five-Ph H H 1-951 H H H Et 2 -CH (OH)-(CH_Two)_Four-cHx H H 1-952 H H H Et 2 -CH (OH)-(CH_Two)_Four-Ph H H 1-953 H H H Et 2 -CH (OH)-(CH_Two)_Five-cHx H H 1-954 H H H Et 2 -CH (OH)-(CH_Two)_Five-Ph H H 1-955 H H H Et 2-[4- (cHx-CH_TwoO) -Ph] H H 1-956 H H H Et 2-[4- (cHx- (CH_Two)_TwoO) Ph] H H 1-957 H H H Et 2-[4- (cHx- (CH_Two)_ThreeO) Ph] H H 1-958 H H H Et 2-(4-BzO-Ph) H H 1-959 H H H Et 2-[4- (Ph- (CH_Two)_TwoO) -Ph] H H 1-960 H H H Et 2-[4- (Ph- (CH_Two)_ThreeO) -Ph] H H 1-961 H H H Pr 2-(CH_Two)_Five-cHx H H 1-962 H H H Pr 2-(CH_Two)_Five-Ph H H 1-963 H H H Pr 2-(CH_Two)₆-cHx H H 1 -964 H H H Pr 2-(CH_Two)₆-Ph H H 1-965 H H H Pr 2 -C≡C-CH_Two-cHx H H 1 -966 H H H Pr 2 -C≡C- (CH_Two)_Three-cHx H H 1-967 H H H Pr 2 -C≡C- (CH_Two)_Three-Ph H H 1-968 H H H Pr 2 -C≡C- (CH_Two)_Four-cHx H H 1-969 H H H Pr 2 -C≡C- (CH_Two)_Four-Ph H H 1-970 H H H Pr 2 -C≡C- (CH_Two)_TwoO-cHx H H 1-971 H H H Pr 2 -C≡C- (CH_Two)_TwoO-Ph H H 1-972 H H H Pr 2-[4- (cHx-CH_TwoO) -Ph] H H 1-973 H H H Pr 2-(4-BzO-Ph) H H 1-974 H H H Me 3-(CH_Two)_Five-cHx H H 1-975 H H H Me 3-(CH_Two)₆-cHx H H 1-976 H H H Me 3 -CH = CH- (CH_Two)_Three-cHx H H 1-977 H H H Me 3 -CH = CH- (CH_Two)_Four-cHx H H 1-978 H H H Me 3 -C≡C- (CH_Two)_Three-cHx H H 1-979 H H H Me 3 -C≡C- (CH_Two)_Four-cHx H H 1 -980 H H H Me 3 -CO- (CH_Two)_Four-cHx H H 1-981 H H H Me 3 -CO- (CH_Two)_Five-cHx H H 1-982 H H H Me 3 -CO- (CH_Two)_Four-Ph H H 1-983 H H H Me 3 -CO- (CH_Two)_Five-Ph H H 1-984 H H H Me 3 -CH (OH)-(CH_Two)_Four-cHx H H 1-985 H H H Me 3 -CH (OH)-(CH_Two)_Five-cHx H H 1-986 H H H Me 3-[4- (cHx-CH_TwoO) -Ph] H H 1-987 H H H Me 3-(4-BzO-Ph) H H 1-988 H H H Me 3 -C≡C-CH_TwoO-cPn H H 1-989 H H H Me 3 -C≡C- (CH_Two)_TwoO-cPn H H 1-990 H H H Me 3 -C≡C-CH_TwoO-cHx H H 1-991 H H H Me 3 -C≡C- (CH_Two)_TwoO-cHx H H 1-992 H H H Me 3 -C≡C-CH_TwoO-Ph H H 1-993 H H H Me 3 -C≡C- (CH_Two)_TwoO-Ph H H  .

[0074]

[Table 2]

[0075]

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[0076] Compd. R ¹ R ² R ³ R ⁴ n -XYR ⁵ R ⁶ R ⁷ 2-1 HHH Me 2-(CH ₂ ) ₃ -cHx HH 2-2 HHH Me 2-(CH ₂ ) ₃ -Ph HH 2-3 HHH Me 2-(CH ₂ ) ₄ -cHx HH 2-4 HHH Me 2-(CH ₂ ) ₄ -Ph HH 2-5 HHH Me 2-(CH ₂ ) ₅ -cPn HH 2-6 HHH Me 2-(CH ₂ ) ₅ -cHx HH 2-7 HHH Me 2-(CH ₂ ) _5- (4-F-cHx) HH 2-8 HHH Me 2-(CH ₂ ) _5- (4-Me-cHx) HH 2-9 HHH Me 2-(CH ₂ ) _5- (4-MeO- cHx) HH 2-10 HHH Me 2-(CH ₂ ) ₅ -Ph HH 2-11 HHH Me 2-(CH ₂ ) _5- (4-F-Ph) HH 2-12 HHH Me 2-(CH ₂ ) _5- (4-Me-Ph) HH 2-13 HHH Me 2-(CH ₂ ) _5- (4-Et-Ph) HH 2-14 HHH Me 2-(CH ₂ ) _5- (4-MeO-Ph ) HH 2-15 HHH Me 2-(CH ₂ ) _5- (4-EtO-Ph) HH 2-16 HHH Me 2-(CH ₂ ) _5- (4-MeS-Ph) HH 2-17 HHH Me 2 -(CH ₂ ) ₆ -cPn HH 2-18 HHH Me 2-(CH ₂ ) ₆ -cHx HH 2-19 HHH Me 2-(CH ₂ ) _6- (4-F-cHx) HH 2-20 HHH Me 2-(CH ₂ ) _6- (4-Me-cHx) HH 2-21 HHH Me 2-(CH ₂ ) _6- (4-MeO-cHx) HH 2-22 HHH Me 2-(CH ₂ ) _6- Ph HH 2-23 HHH Me 2-(CH ₂ ) _6- (4-F-Ph) HH 2-24 HHH Me 2-(CH ₂ ) _6- (4-Me-Ph) HH 2-25 HHH Me 2 -(CH ₂ ) _6- (4-Et-Ph) HH 2-26 HHH Me 2-(CH ₂ ) _6- (4-MeO-Ph) HH 2-27 HHH Me 2-(CH ₂ ) _6- ( 4-EtO-Ph) HH 2-28 HHH Me 2-(CH ₂ ) ₇ -cHx HH 2-29 HHH Me 2-(CH ₂ ) ₇ -Ph HH 2-30 HHH Me 2-(CH ₂ ) ₅ -cPn HH 2-31 HHH Me 2-(CH ₂ ) ₄ -cHx HH 2-32 HHH Me 2-(CH ₂ ) ₄ -O- (4-F-cHx) HH 2-33 HHH Me 2-(CH ₂ ) ₄ -O- (4-Me-cHx) HH 2-34 HHH Me 2-(CH ₂ ) ₄ -O- (4-MeO-cHx) HH 2-35 HHH Me 2-(CH ₂ ) ₄ -O-Ph HH 2-36 HHH Me 2-(CH _{2) 4 -O- (4-F} -Ph) HH 2-37 HHH Me 2 - (CH 2) 4 -O- (4-Me-Ph) HH 2-38 HHH Me 2 - (CH 2) 4 - O- (4-MeO-Ph) HH 2-39 HHH Me 2-(CH ₂ ) ₄ -O- (4-EtO-Ph) HH 2-40 HHH Me 2 -CH = CH-CH ₂ -cHx HH 2 -41 HHH Me 2 -CH = CH-CH ₂ -Ph HH 2-42 HHH Me 2 -CH = CH- (CH ₂ ) ₂ -cHx HH 2-43 HHH Me 2 -CH = CH- (CH ₂ ) ₂ -Ph HH 2-44 HHH Me 2 -CH = CH- (CH ₂ ) ₃ -cHx HH 2-45 HHH Me 2 -CH = CH- (CH ₂ ) ₃ -Ph HH 2-46 HHH Me 2 -CH = CH- (CH ₂ ) _3- (4-F-Ph) HH 2-47 HHH Me 2 -CH = CH- (CH ₂ ) _3- (4-Me-Ph) HH 2-48 HHH Me 2 -CH = CH- (CH ₂ ) _3- (4-MeO-Ph) HH 2-49 HHH Me 2 -CH = CH- (CH ₂ ) ₄ -cHx HH 2-50 HHH Me 2 -CH = CH- (CH ₂ ) _{4 -Ph HH 2-51 HHH Me 2 -CH} = CH- (CH 2) 4 - (4-F-Ph) HH 2-52 HHH Me 2 -CH = CH- (CH 2) 4 - (4-Me -Ph) HH 2-53 HHH Me 2 -CH = CH- (CH 2) 4 - ( 4-MeO-Ph) HH 2-54 HHH Me 2 -CH = CH- (CH ₂ ) ₅ -cHx HH 2-55 HHH Me 2 -CH = CH- (CH ₂ ) ₅ -Ph HH 2-56 HHH Me 2 -CH = CH- (CH ₂ ) ₆ -cHx HH 2-57 HHH Me 2 -CH = CH- (CH ₂ ) ₆ -Ph HH 2-58 HHH Me 2 -CH = CH-CH ₂ O-cHx HH 2-59 HHH Me 2 -CH = CH-CH ₂ O-Ph HH 2-60 HHH Me 2 -CH = CH-CH ₂ O- (4-F-Ph) HH 2-61 HHH Me 2 -CH = CH -CH ₂ O- (4-Me-Ph) HH 2-62 HHH Me 2 -CH = CH-CH ₂ O- (4-MeO-Ph) HH 2-63 HHH Me 2 -CH = CH- (CH ₂ ) ₂ O-cHx HH 2-64 HHH Me 2 -CH = CH- (CH ₂ ) ₂ O-Ph HH 2-65 HHH Me 2 -CH = CH- (CH ₂ ) ₂ O- (4-F-Ph ) HH 2-66 HHH Me 2 -CH = CH- (CH ₂ ) ₂ O- (4-Me-Ph) HH 2-67 HHH Me 2 -CH = CH- (CH ₂ ) ₂ O- (4-MeO -Ph) HH 2-68 HHH Me 2 -CH = CH-CH ₂ OCH ₂ -cHx HH 2-69 HHH Me 2 -CH = CH-CH ₂ OCH ₂ -Ph HH 2-70 HHH Me 2 -CH = CH -CH ₂ OCH _2- (4-F-Ph) HH 2-71 HHH Me 2 -CH = CH-CH ₂ OCH _2- (4-Me-Ph) HH 2-72 HHH Me 2 -CH = CH-CH ₂ OCH _2- (4-MeO-Ph) HH 2-73 HHH Me 2 -C≡C-CH ₂ -cHx HH 2-74 HHH Me 2 -C≡C-CH ₂ -Ph HH 2-75 HHH Me 2 -C≡C- (CH ₂ ) ₂ -cHx HH 2-76 HHH Me 2 -C≡C- (CH ₂ ) ₂ -Ph HH 2-77 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cPn HH 2-78 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-79 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-F-cHx) HH 2-80 HHH Me 2 -C≡C- (CH ₂ ) _3- (4 -Me-cHx) HH 2-81 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-MeO-cHx) HH 2-82 HHH Me 2 -C≡C- (CH ₂ ) ₃ -Ph HH 2-83 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-F-Ph) HH 2-84 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Me-Ph) HH 2-85 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Et-Ph) HH 2-86 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-MeO-Ph) HH 2-87 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-EtO-Ph) HH 2-88 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-MeS-Ph) HH 2-89 HHH Me 2 -C≡C- (CH ₂ ) ₄ -cPn HH 2-90 HHH Me 2 -C≡C- (CH ₂ ) ₄ -cHx HH 2-91 HHH Me 2 -C≡C- ( _{CH 2) 4 - (4-} F-cHx) HH 2-92 HHH Me 2 -C≡C- (CH 2) 4 - (4-Me-cHx) HH 2-93 HHH Me 2 -C≡C- ( _{CH 2) 4 - (4-} MeO-cHx) HH 2-94 HHH Me 2 -C≡C- (CH 2) 4 -Ph HH 2-95 HHH Me 2 -C≡C- (CH 2) 4 - ( 4-F-Ph) HH 2-96 HHH Me 2 -C≡C- (CH 2) 4 - (4-Me-Ph) HH 2-97 HHH Me 2 -C≡C- (CH 2) 4 - ( 4-Et-Ph) HH 2-98 HHH Me 2 -C≡C- (CH 2) 4 - (4-MeO-Ph) HH 2-99 HHH Me 2 -C≡C- (CH 2) 4 - ( 4-EtO-Ph) HH 2-100 HHH Me 2 -C≡C- (CH ₂ ) ₅ -cHx HH 2-101 HHH Me 2 -C _{≡C- (CH 2) 5 -Ph HH} 2-102 HHH Me 2 -C≡C- (CH 2) 6 -cHx HH 2-103 HHH Me 2 -C≡C- (CH 2) 6 -Ph HH 2 -104 HHH Me 2 -C≡C-CH ₂ O-cPn HH 2-105 HHH Me 2 -C≡C-CH ₂ O-cHx HH 2-106 HHH Me 2 -C≡C-CH ₂ O- (4 -F-cHx) HH 2-107 HHH Me 2 -C≡C-CH ₂ O- (4-Me-cHx) HH 2-108 HHH Me 2 -C≡C-CH ₂ O- (4-MeO-cHx ) HH 2-109 HHH Me 2 -C≡C-CH ₂ O-Ph HH 2-110 HHH Me 2 -C≡C-CH ₂ O- (4-F-Ph) HH 2-111 HHH Me 2 -C ≡C-CH ₂ O- (4-Me-Ph) HH 2-112 HHH Me 2 -C≡C-CH ₂ O- (4-Et-Ph) HH 2-113 HHH Me 2 -C≡C-CH ₂ O- (4-MeO-Ph) HH 2-114 HHH Me 2 -C≡C-CH ₂ O- (4-EtO-Ph) HH 2-115 HHH Me 2 -C≡C-CH ₂ O- ( 4-MeS-Ph) HH 2-116 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cPn HH 2-117 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-118 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-F-cHx) HH 2-119 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Me-cHx) HH 2 -120 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-MeO-cHx) HH 2-121 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-Ph HH 2-122 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-F-Ph) HH 2-123 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Me-Ph) HH 2-124 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Et-Ph) HH 2-1 25 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-MeO-Ph) HH 2-126 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-EtO-Ph) HH 2-127 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-MeS-Ph) HH 2-128 HHH Me 2 -C≡C-CH ₂ OCH ₂ -cPn HH 2-129 HHH Me 2 -C≡C-CH ₂ OCH ₂ -cHx HH 2-130 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-F-cHx) HH 2-131 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-Me-cHx) HH 2-132 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-MeO-cHx) HH 2-133 HHH Me 2 -C≡C-CH ₂ OCH _2- Ph HH 2-134 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-F-Ph) HH 2-135 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-Me-Ph) HH 2-136 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-Et-Ph) HH 2-137 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-MeO-Ph) HH 2- 138 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-EtO-Ph) HH 2-139 HHH Me 2 -C≡C-CH ₂ OCH _2- (4-MeS-Ph) HH 2-140 HHH Me 2 -CO- (CH ₂ ) ₄ -cHx HH 2-141 HHH Me 2 -CO- (CH ₂ ) ₄ -Ph HH 2-142 HHH Me 2 -CO- (CH ₂ ) ₅ -cHx HH 2-143 HHH Me 2 -CO- (CH ₂ ) ₅ -Ph HH 2-144 HHH Me 2-[4- (cHx-CH ₂ O) -Ph] HH 2-145 HHH Me 2-[4- (cHx- (CH ₂ ) ₂ O) Ph] HH 2-146 HHH Me 2-[4- (cHx- (CH ₂ ) ₃ O) Ph] HH 2-147 HHH Me 2-(4-BzO-Ph) HH 2-148 HH H Me 2-[4- (Ph- (CH ₂ ) ₂ O) -Ph] HH 2-149 HHH Me 2-[4- (Ph- (CH ₂ ) ₃ O) -Ph] HH 2-150 HHH Et 2-(CH ₂ ) ₅ -cHx HH 2-151 HHH Et 2-(CH ₂ ) ₆ -cHx HH 2-152 HHH Et 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-153 HHH Et 2 -C≡C- (CH ₂ ) ₄ -cHx HH 2-154 HHH Et 2-[4- (cHx-CH ₂ O) -Ph] HH 2-155 HHH Et 2-(4-BzO-Ph) HH 2 -156 HHH Et 2 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-157 HHH Et 2 -C≡C- (CH ₂ ) ₂ O-Ph HH 2-158 HHH Pr 2-(CH ₂ ) ₅ -cHx HH 2-159 HHH Pr 2-(CH ₂ ) ₆ -cHx HH 2-160 HHH Pr 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-161 HHH Pr 2 -C≡C- ( CH ₂ ) ₄ -cHx HH 2-162 HHH Pr 2-[4- (cHx-CH ₂ O) -Ph] HH 2-163 HHH Pr 2-(4-BzO-Ph) HH 2-164 HHH Pr 2- C≡C- (CH ₂ ) ₂ O-cHx HH 2-165 HHH Pr 2 -C≡C- (CH ₂ ) ₂ O-Ph HH .

In Tables 1 and 2 above, suitable compounds include, for example, compound numbers: 1-19 to 1-31, 1-34 to 1-37, 1-41 to 1-5
0, 1-54 to 1-57, 1-61 to 1-71, 1-75 to 1-78, 1-82 to 1-13
2, 1-136 to 1-139, 1-143 to 1-192, 1-226, 1-230 to 1-23
3, 1-237-1-247, 1-253-1-256, 1-260-1-319, 1-323
~ 1-326, 1-330 ~ 1-359, 1-398, 1-402, 1-412 ~ 1-422,
1-426 ~ 1-429, 1-433 ~ 1-516, 1-547 ~ 1-550, 1-554 ~
1-568, 1-572 to 1-575, 1-579 to 1-630, 1-634 to 1-637, 1
-641 to 1-708, 1-712 to 1-724, 1-731 to 1-742, 1-746 to 1-7
49, 1-753〜1-831, 1-852〜1-881, 1-891〜1-960, 2-1
To 2-27, 2-31 to 2-39, 2-73 to 2-101, 2-104 to 2-153, and more preferably, Exemplified Compound No .: 1-226, 1-230 ~ 1-233, 1-237 ~ 1-247,
1-253〜1-256, 1-260〜1-319, 1-323〜1-326, 1-330〜
1-359, 1-412 ~ 1-422, 1-426 ~ 1-429, 1-433 ~ 1-511, 1
-547 to 1-550, 1-554 to 1-568, 1-572 to 1-575, 1-579 to 1-
630, 1-634〜1-637, 1-641〜1-651, 1-659〜1-687, 1-6
90 ~ 1-694, 1-698 ~ 1-708, 1-731 ~ 1-1-742, 1-749, 1-
753-1-780, 1-783, 1-787-1-797, 1-801-1-827, 2-1
~ 2-27, 2-31 ~ 2-39, 2-73 ~ 2-101, 2-104, 2-105, 2-1
09 to 2-117, 2-121 to 2-129, 2-133 to 2-139, 2-140 to 2-14
3 and more preferably, Exemplified Compound No .: 1-226, 1-233, 1-237-1-247, 1-260
~ 1-285, 1-309 ~ 1-313,1-317 ~ 1-319, 1-326, 1-330,
1-333〜1-336, 1-338, 1-412〜1-422, 1-429, 1-433〜1
-481, 1-550, 1-554〜1-568, 1-575, 1-579〜1-627, 1-
630, 1-690, 1-691, 1-698, 1-708, 1-731, 1-742, 2-1
04, 2-105, 2-109 to 2-117.

[0078]

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

In the method A, the compound (Ic) wherein X is an ethynylene group, the compound (Id) wherein X is an ethylene group, and the compound (I) wherein X is a vinylene group
e), compound (If) in which X is a group having —CO—CH ₂ —, compound (Ig) in which X is a group having —CH (OH) —CH ₂ —, and X is an aryl group or a group of substituents a
This is a method for producing a compound (Ih) which is an aryl group substituted by 1 to 3 groups selected from the group consisting of:

[0080]

Embedded image

[0081]

Embedded image

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , Y and n are as defined above,
R ^5a , R ^6a and R ^7a each represents an amino, hydroxy and / or carboxyl group in which an amino, hydroxy and / or carboxyl group contained as a substituent in the R ⁵ , R ⁶ and R ⁷ groups may be protected; Some others R ⁵ , R ⁶ and R ⁷
And the same groups as defined in the definition of the group, and R ⁸ and R
^8a represents a hydrogen atom or a lower alkyl group together, and ring Ar represents an aryl group or an aryl group substituted with at least one group selected from substituent group a.

In the above, the “protecting group” of the “optionally protected amino group” in the definition of R ^5a , R ^6a and R ^7a
Is not particularly limited as long as it is a protecting group for an amino group used in the field of synthetic organic chemistry, but shows the same consent as described above, and is preferably a lower alkoxycarbonyl group or a lower aliphatic acyl group. , Most preferably a t-butoxycarbonyl group or an acetyl group.

In the above, the “protecting group” of the “optionally protected hydroxy group” in the definition of R ^5a , R ^6a and R ^7a is a protecting group for a hydroxy group used in the field of organic synthetic chemistry. Although not particularly limited, for example, the same meaning as the protecting group of the hydroxy group "in a reaction that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis", and preferably shows the same meaning. It is a lower aliphatic acyl group, an 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 acetyl. Or a methoxymethyl group.

In the above, the “protecting group” of the “optionally protected carboxyl group” in the definition of R ^5a , R ^6a and R ^7a is a carboxyl protecting group used in the field of synthetic organic chemistry. Although not particularly limited, for example, the lower alkyl group, benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, diphenylmethyl,
1 to 1 which may be substituted with lower alkyl, lower alkoxy, nitro, halogen or cyano such as triphenylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4-fluorobenzyl, 4-cyanobenzyl. It is a lower alkyl group substituted with three aryls, preferably a lower alkyl group, and most preferably a methyl group.

Step A1 is a step for producing a compound having the general formula (IV). The compound having the general formula (II) is prepared by reacting the compound having the general formula (II) in an inert solvent under a nitrogen atmosphere in the presence of a base and a palladium catalyst. A compound having the general formula (III)
It is performed by Sonogashira coupling 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 hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride;
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether; Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone,
Ketones such as cyclohexanone; acetonitrile,
Nitriles such as isobutylbitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide and sulfolane;
And preferably ethers, amides or sulfoxides (most preferably amides or ethers). Further, the addition of a small amount of water to the reaction solvent may accelerate the progress of the reaction.

The base used in the above reaction is usually
There is no particular limitation as long as it is a base used for the Sonogashira coupling reaction. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkalis such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate Metal bicarbonates; lithium hydride,
Alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide, sodium ethoxide, potassium alkali metal alkoxides such as t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethyl Aniline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.
Organic amines such as [0] -7-undecene (DBU); preferably organic amines (most preferably triethylamine).

The palladium catalyst used in the above reaction is not particularly limited as long as it is usually used in the Sonogashira coupling reaction. For example, palladium salts such as palladium acetate, palladium chloride and palladium carbonate; And palladium salt complexes such as dichlorobis (triphenylphosphine) palladium complex which forms a complex with a child.

The yield can be improved by using copper (I) iodide and benzyltriethylammonium chloride as additives.

The reaction temperature varies depending on the type of the starting compound, base, solvent and the like, but is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 120 ° C.).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 15 minutes to 24 hours).

If necessary, the target compound (IV) in this step can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of an organic compound, for example, silica gel, alumina, magnesium oxide. Adsorption column chromatography using a silica gel-based carrier such as Florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (Rohm and & Co.)
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step.

In the step A2, a compound having the general formula (Ic)
A step of preparing a compound (I) in an inert solvent.
V) is reacted with a base and hydrolyzed, if desired
R^5a, R ^6aAnd R^7aAmino, hydroxy and / or
Or removal of the carboxyl protecting group, R¹
And R^TwoProtecting the amino group in and / or
Is R^ThreeBy protecting the hydroxy group in
Is

The inert solvent used when reacting compound (IV) with a base is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane,
Aliphatic hydrocarbons such as ligroin and petroleum ether;
Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol;
Alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; water; or a mixed solvent of the above solvents, preferably a mixed solvent of alcohols and ethers (Most preferably, a mixed solvent of methanol and tetrahydrofuran).

Examples of the base used when reacting compound (IV) with a base include those similar to the base used in the above-mentioned Method A, Step A1. Hydroxides (most preferably potassium hydroxide, lithium hydroxide or sodium hydroxide).

The reaction temperature varies depending on the type of the starting compound, base, solvent and the like, but is usually from -20 ° C to 250 ° C.
(Preferably 0 ° C. to 150 ° C.).

The reaction time varies depending on the starting compound, the base, the type of solvent, the reaction temperature and the like, but is usually from 30 minutes to 7 minutes.
2 hours (preferably 1 hour to 48 hours).

The removal of the amino, hydroxy and / or carboxy group protecting group, which is a desired step, varies depending on its type, but is generally carried out by methods well known in the art of synthetic organic chemistry, for example, TWGreen, (Protective Groups in
Organic Synthesis), John Wiley & Sons: JFWMcOmi
s, (Protective Groups in OrganicChemistry), Plenu
m Press can be performed by the method described in, for example,
It can be performed as follows.

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

The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction.
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether are preferred.

The reaction temperature and 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 to be used in the above reaction is not particularly limited as long as it is usually used as a base and does not inhibit the reaction. Preferably, the base is, for example, lithium carbonate, sodium carbonate or potassium carbonate. Alkali metal 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, and the like.

The inert solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction. For example, methanol, ethanol, n-
Propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol
Alcohols such as toluene, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; water; A mixed solvent with a solvent; 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 used, and are not particularly limited. However, in order to suppress a side reaction, the reaction is usually performed at 0 ° C. to 150 ° C. for 1 hour. Let react for ~ 10 hours.

When the amino-protecting group is an aralkyl or an 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). ) A method of removing or using an oxidizing agent is preferred.

The inert solvent used for the removal by catalytic reduction is not particularly limited as long as it does not inhibit the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as toluene, benzene and xylene; esters such as methyl acetate, 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, n-
Propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol
Alcohols such as diethylene glycol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; organic acids such as acetic acid; 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 usually 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 the 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 inert solvent used in the removal by oxidation is not particularly limited as long as it does not inhibit the reaction. For example, chloroform, dichloromethane,
Halogenated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; Ketones; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide; sulfolane; Ters or sulfoxides (most preferably halogenated hydrocarbons or sulfoxides).

The oxidizing agent to be used is not particularly limited as long as it does not hinder the reaction and is usually used as an oxidizing agent, but is preferably potassium persulfate, sodium persulfate, or ammonium cerium nitrate. (CA
N), 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 protecting group for the amino 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. Examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and the like.
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 above reaction is not particularly limited as long as it does not inhibit the reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated carbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride Hydrogens; esters such as methyl acetate, 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, isopropanol, n-butanol, isobutanol, t -Butanol, isoamyl alcohol, diethylene glycol,
Alcohols such as glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; water; or water or a mixed solvent of the above solvents; , Preferably ethers, alcohols or water (most preferably 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.

When the protecting group for the amino group is an allyloxycarbonyl group, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions. it can.

When a silyl is used as a protecting group for the hydroxy group, a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or 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.

The inert solvent used for removing the protecting group with a fluorine anion is not particularly limited as long as it does not inhibit the reaction.
Ter, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water;

When the protecting group is removed by fluorine anion, the reaction may be accelerated by adding an organic acid such as formic acid, acetic acid or propionic acid.

The reaction temperature and reaction time when the protecting group is removed by fluorine anion vary depending on the starting compound, catalyst, solvent and the like, but are usually 0 ° C. to 100 ° C. (preferably
(10 ° C. to 50 ° C.) for 1 hour to 24 hours.

When the protecting group is removed with an inorganic acid or an organic acid, treatment with an inorganic acid or an organic acid is carried out in the same manner as in the removal reaction when the protecting group for an amino group or an imino group is an aralkyl. Achieved.

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

The inert solvent used for removal by catalytic reduction is not particularly limited as long as it does not inhibit the reaction. For example, an inert group such as an aralkyl group or an aralkyloxycarbonyl group having an amino- or imino-protecting group may be used. In the case of, there may be mentioned the same inert solvents as used for the removal by contacting with a reducing agent, preferably alcohols (most preferably methanol).

As the catalyst to be used for the removal by the catalytic reduction, if it is usually used for the catalytic reduction reaction,
Although not particularly limited, for example, when the protecting group for the amino group or the imino group is an aralkyl or an aralkyloxycarbonyl, the same as the inert catalyst used when the protective group is removed by contact with a reducing agent. And palladium-carbon is preferred.

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 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 inhibit the reaction. For example, when the protecting group for the amino group is an aralkyl or aralkyloxycarbonyl, And the same inert solvent as used in the removal by contact with the solvent.

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. For example, when the protecting group for the amino group is an aralkyl or aralkyloxycarbonyl, the oxidizing agent is in contact with the oxidizing agent. The same oxidizing agents as those used for removal by removal can be 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.

In liquid ammonia or methanol
, 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, when the protecting group for the hydroxy group is an aralkyl or aralkyloxycarbonyl, aluminum chloride-sodium iodide or
By using an alkylsilyl halide such as trimethylsilyl iodide, the protecting group can be removed.

The inert solvent used when removing the protecting group using aluminum chloride-sodium iodide or an alkylsilyl halide is not particularly limited as long as it does not participate in the present reaction. Halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; mixed solvents of the above solvents.

The reaction temperature and reaction time when the protecting group is removed using aluminum chloride-sodium iodide or alkylsilyl halides vary depending on the starting compound, solvent and the like, but is usually 0 ° C. to 50 ° C. for 5 minutes. Up to 72 hours.

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

When the hydroxy-protecting 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 is usually used as a base and does not affect the other parts of the compound. Examples thereof include lithium carbonate, sodium carbonate, and carbonate. Alkali metal carbonates such as potassium; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium-t-butoxide; ammonia such as aqueous ammonia and concentrated ammonia-methanol; Substances, metal alkoxides or ammonia (most preferably alkali It is a genus hydroxides or metal alkoxides).

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

The reaction temperature and reaction time vary depending on the starting compound, base used, 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, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or substituted ethyl, it is usually used in a solvent. , By treatment with an acid.

The acid used in the above reaction is usually
There is no particular limitation as long as it is used as a Bronsted acid or Lewis acid, and preferably, hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid; or acetic acid, trifluoroacetic acid, methanesulfonic acid, or p- Bronsted acids such as organic acids such as toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cation exchange resins such as Dowex 50W can also be used.

The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction.
For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride;
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether; Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol Alcohols such as, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; acetone, methyl ethyl ketone,
Ketones such as 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 -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 aforementioned 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 by one to three aryls which may be substituted by 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 protecting group for the hydroxy group is an aliphatic acyl, an aromatic acyl or an alkoxycarbonyl.

The method for protecting the amino and hydroxy groups depends on the type of the protecting group, but is generally a method well known in the art of synthetic organic chemistry, for example, Protective.
Groups in Organic Synthesis (Third Edition, 1999, Jo
hn Wiley & Sons, Inc.), for example, as follows.

As a method for protecting the amino group, for example, in the compound (Ic), a compound in which R ¹ and R ² are hydrogen atoms is treated in an inert solvent (preferably, diethyl ether
Ter, 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; ), In the presence or absence of a base (organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine), the following compounds R ^1a -Q (VIII) [wherein R ^1a is An amino-protecting group (synonymous with that described above) is shown, and Q is a halogen atom. ]
With 0 ° C. to 50 ° C. (preferably around room temperature) for 30 minutes to 10 hours (preferably 1 hour to 5 hours).

Examples of the method for protecting the hydroxy group include the following.
For example, in compound (Ic), R ^ThreeIs a hydrogen atom
The compound is dissolved in an inert solvent (preferably chloroform,
Of chloromethane, 1,2-dichloroethane, carbon tetrachloride
Such as halogenated hydrocarbons; formamide, dimethyl
Formamide, dimethylacetamide, hexamethylli
Amides such as triamide acid; dimethyl sulfoxy
Sulfoxides such as chloride) in the presence of a base (preferably
Means lithium hydride, sodium hydride, potassium hydride
Alkali metal hydrides such as triethylamido
, Tributylamine, diisopropylethylamine,
Organic amines such as N-methylmorpholine and pyridine
), The following compounds R^3a-Q (IX) [in the above formula, R^3aIs a hydroxyl protecting group (as described above)
Show willingness. ), And Q indicates consent as described above.
You. ] At 0 to 50 ° C (preferably around room temperature).
Minutes to 24 hours (preferably 1 hour to 24 hours)
This is done by letting

The removal of the protecting group for the amino group, the hydroxy group and / or the carboxy group, and the protection of the amino group and / or the hydroxy group can be carried out in any order and in any order.

If desired, the target compound (Ic) in this step can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of an organic compound, for example, silica gel, alumina, magnesium oxide. Adsorption column chromatography using a silica gel-based carrier such as Florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (Rohm and & Co.)
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step.

Step A3 is a step for producing a compound having the general formula (Id), and the compound (I) is prepared in an inert solvent.
c) after reduction (preferably catalytic reduction in a hydrogen atmosphere), optionally protecting groups for amino, hydroxy and / or carboxyl groups in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a By protecting the amino group at R ¹ and R ² and / or protecting the hydroxy group at R ³ .

The inert solvent used for 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; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as chlorobenzene and dichlorobenzene; methyl acetate, ethyl acetate, propyl acetate;
Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; methano-
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
Alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; organic acids such as acetic acid and hydrochloric acid; water; a mixed solvent of the above solvent and water; Include alcohols or ethers (most preferably,
Methanol).

The catalyst used for the catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction, but is preferably palladium-carbon, Raney-nickel, platinum oxide, platinum black. , Rhodium-aluminum oxide,
Triphenylphosphine-rhodium chloride, palladium-
Barium sulfate is used.

The reaction temperature varies depending on the type of the starting compound, the catalyst and the solvent, but is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 100 ° C.).

The reaction time varies depending on the starting compound, catalyst, solvent, reaction temperature and the like, but is usually 5 minutes to 96 hours (preferably 15 minutes to 72 hours).

R ¹ , R ² , R ³ ,
Amino, hydroxy and / or R ^5a , R ^6a and R ^7a
Or removal of the carboxyl protecting group, R ¹
And protecting the amino group in R ² , and / or protecting the hydroxy group in R ³ , by removing the protecting group for the amino, hydroxy and / or carboxyl group in Step A2 of Method A; Protecting the amino group at ¹ and R ² and / or protecting the hydroxy group at R ³ is performed in the same manner.

If desired, the target compound (Id) in this step can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, silica gel, alumina, magnesium oxide. Adsorption column chromatography using a silica gel-based carrier such as Florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (Rohm and & Co.)
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

When it is necessary to separate the isomers, the separation can be carried out by the above separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step.

Step A4 is a step of producing a compound having the general formula (V). After reacting compound (III) with catecholborane, compound (II) and Suzuki co
This is performed by performing an upling reaction.

The reaction temperature for reacting compound (III) with catechol borane varies depending on the starting compound, the type of solvent and the like, but is usually 0 ° C. to 150 ° C. (preferably 1 ° C.).
0 ° C to 100 ° C).

The reaction time for reacting compound (III) with catecholborane varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours). .

Thereafter, the Suzuki coupling reaction is performed in the same manner as the Sonogashira coupling reaction in the first step A1 of Method A.

Examples of the solvent, base and palladium catalyst used in the above reaction include those similar to those used in the above-mentioned Method A, Step A1.

The desired compound (V) in this step is, if necessary,
Conventional methods, for example, recrystallization, reprecipitation, or methods commonly used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel adsorption column chromatography using a carrier such as florisil ; Sephadex LH-20 (manufactured by Pharmacia),
A method using a synthetic adsorbent such as distribution column chromatography using a carrier such as Amberlite XAD-11 (manufactured by Rohm and Haas) and Diaion HP-20 (manufactured by Mitsubishi Kasei), ion exchange chromatography. Separation and purification by appropriate combination of the method to be used or the normal phase / reverse phase column chromatography method (preferably high performance liquid chromatography) using silica gel or alkylated silica gel and eluting with a suitable eluent. can do.

When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step.

Step A5 is a step of reacting a compound having the general formula (Ie)
A process for producing a compound, in an inert solvent,
After reacting (V) with a base to hydrolyze, if desired, R
^5a, R^6aAnd R^7aAmino, hydroxy and / or young
Or removing the protecting group of the carboxyl group, R¹Passing
And R^TwoProtecting the amino group in and / or
Is R ^ThreeBy protecting the hydroxy group in
This step is performed in the same manner as the above-mentioned Method A, Step A2.

Step A6 is a step for producing a compound having the general formula (If), wherein the compound (Ic) is subjected to an addition reaction of water using an acid catalyst in an inert solvent,
Then, if desired, R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a
By removing the protecting groups for the amino, hydroxy and / or carboxyl groups in, protecting the amino group in R ¹ and R ² , and / or protecting the hydroxy group in R ³ .

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, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride;
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether; Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol Alcohols such as, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; acetone, methyl ethyl ketone,
Ketones such as methyl isobutyl ketone, isophorone and cyclohexanone; water; a mixed solvent of the above solvents; and preferably alcohols.

The acid catalyst used in the above reaction is not particularly limited as long as it can be 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 or acetic acid, formic acid, oxalic acid,
Bronsted acids such as organic acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid, or zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron trifluoride A Lewis acid such as bromide or an acidic ion exchange resin can be mentioned, and an inorganic acid is preferable.

The reaction temperature varies depending on the type of the starting compound, catalyst, solvent and the like, but is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 100 ° C.).

The reaction time varies depending on the starting compound, catalyst, solvent, reaction temperature and the like, but is usually from 5 minutes to 96 hours (preferably from 15 minutes to 72 hours).

R ¹ , R ² , R ³ ,
Amino, hydroxy and / or R ^5a , R ^6a and R ^7a
Or removal of the carboxyl protecting group, R ¹
And protecting the amino group in R ² , and / or protecting the hydroxy group in R ³ , by removing the protecting group for the amino, hydroxy and / or carboxyl group in Step A2 of Method A; Protecting the amino group at ¹ and R ² and / or protecting the hydroxy group at R ³ is performed in the same manner.

Step A7 is a step for producing a compound having the general formula (Ig), and the compound (Ig) is prepared in an inert solvent.
f) by reducing the CO group to a -CH (OH)-group, followed by R ¹ , R ² , R, R ^5a , R
^{It is performed} by removing the protecting group of the amino, hydroxy and / or carboxyl group in ^6a and R ^7a , protecting the amino group in R ¹ and R ² , and / or protecting the hydroxy group in R ³ . .

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; aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; halogenated hydrocarbons such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Or a mixed solvent of the above solvents, preferably ethers or alcohols (most preferably methanol or ethanol).

As the reducing agent used in the above reaction, C
The reducing agent is not particularly limited as long as it is a reducing agent that can reduce the O group to a —CH (OH) — group. For example, alkali metal borohydrides such as sodium borohydride, lithium borohydride, and sodium cyanoborohydride Diisobutylaluminum hydride, lithium aluminum hydride,
Aluminum hydride compounds such as lithium triethoxyaluminum hydride; and preferably alkali metal borohydrides (sodium cyanoborohydride).

The reaction temperature varies depending on the type of the starting compound, the reducing agent, the solvent and the like, but is usually from -10 ° C to 100 ° C.
(Preferably −20 ° C. to 20 ° C.).

The reaction time depends on the starting compound, reducing agent, solvent,
Although it depends on the reaction temperature and the like, it is usually from 10 minutes to 48 hours (preferably from 30 minutes to 12 hours).

R ¹ , R ² , R ³ ,
Amino, hydroxy and / or R ^5a , R ^6a and R ^7a
Or removing the protecting group of a carboxyl group, R ¹
And protecting the amino group in R ² , and / or protecting the hydroxy group in R ³ , by removing the protecting group for the amino, hydroxy and / or carboxyl group in Step A2 of Method A; Protecting the amino group at ¹ and R ² and / or protecting the hydroxy group at R ³ is performed in the same manner.

Step A8 is a step of producing a compound having the general formula (VII), which is carried out by subjecting the compound having the general formula (VI) to a Suzuki coupling reaction with the compound (II). The method is carried out in the same manner as in the above-mentioned Method A, Step A4, in which the compound (III) reacted with catecholborane is subjected to a Suzuki coupling reaction with the compound (II).

Step A9 is a step for producing a compound having the general formula (Ih), and the compound (V) is prepared in an inert solvent.
II) is reacted with a base and hydrolyzed, if desired
Removing amino, hydroxy and / or carboxyl protecting groups on ^5a , R ^6a and R ^7a , protecting amino groups on R ¹ and R ² , and / or protecting hydroxy groups on R ³ This step is performed in the same manner as in Method A, Step A2.

In the compound (II), the following (I
I-1) Group

[0190]

Embedded image

[Wherein R ⁴ has the same meaning as described above. In place of the following (II-2)

[0192]

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[Wherein R ^1a and R ^2a represent R ¹ and R ²
Group represents the same groups in the other R ¹ and the definition of R ² groups which do not exhibit hydrogen atoms at the same time, R ³ and R ⁴ is a consent discussions with those described above. (X) having the formula

[0194]

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Using as a starting material for Method A, reacting with Compound (III) or (VI), if desired, R
Removing amino, hydroxy and / or carboxyl protecting groups on R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group on R ¹ and R ² , and / or By protecting the hydroxy group in R ^3, the target compounds (Ic) to (Ih) can also be directly produced by omitting the step of opening the group (II-1).

Method B is a method for producing compound (XI) which is compound (II) or (X).

[0197]

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In the above formula, R ^6a , R ^7a and n have the same meanings as described above, and Z represents the group (II-1) or (I
I-2) represents a group.

Step B1 is a step for producing a compound (XI), which is carried out by reacting a compound having the general formula (X) with a brominating agent in an inert solvent.

The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and preferably amides (most preferably dimethylformamide).

As the brominating agent used in the above reaction,
Although not particularly limited, for example, “Comprehensive Organic
Transformations "(Larock, VCH, p316-317).
N-bromosuccinimide or bromine.

The reaction temperature varies depending on the type of the starting compound, the brominating agent, the solvent and the like.
° C (preferably -20 ° C to 100 ° C).

The reaction time varies depending on the starting compound, the brominating agent, the solvent, the reaction temperature and the like, but is usually from 5 minutes to 48 minutes.
Time (preferably 30 minutes to 24 hours).

If desired, the target compound (XI) in this step can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separating and purifying an organic compound, for example, silica gel, alumina, magnesium compound. Adsorption column chromatography using a carrier such as silica gel-based florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (ROHM &
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step. Method C is as follows. In compound (X), Z is a compound of the formula (I)
I-2), wherein R ¹ is a hydrogen atom, R ²
Is a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, or a group selected from substituent group a,
An aralkyloxycarbonyl group which is monosubstituted;
A compound (Xa) wherein ³ is a hydrogen atom, and Z is a compound represented by the formula (II-
Compounds (Xb) and Z, which are groups having 1), have the formula (II)
This is a method for producing a compound (Xc) which is a group having -2).

[0206]

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In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ^6a , R
^7a and n are as defined above, and R ⁹ is
A formyl group, a carboxy group or a lower alkoxycarbonyl group; R ¹⁰ represents a hydrogen atom or a lower alkyl group; R ^10a represents a lower alkyl group; R ¹¹ represents a lower alkyl group, an aralkyl group, or a substituent And an aralkyl group substituted by 1 to 3 groups selected from group a.

Step C1 is a step of producing a compound having the general formula (XIII). The compound having the general formula (XII) is prepared in an inert solvent in the presence or absence of a base (preferably (In the presence), by reaction with a reducing agent.

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; aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; acetic acid, 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
Alcohols such as toluene, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide Water; or water or a mixed solvent of the above solvents; and preferably ethers.

The reducing agent used in the above reaction is, for example,
The same reducing agents as those used in the method A, step A7 can be used.

As the base used in the above reaction, for example, those similar to the reducing agent used in the aforementioned Method A, Step A1 can be mentioned.

The reaction temperature varies depending on the type of the starting compound, the reducing agent used, the base, the solvent and the like.
It is 0 ° C to 100 ° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the reducing agent used, the base, the solvent, the reaction temperature and the like.
5 minutes to 150 hours (preferably 1 hour to 100 hours)
It is.

Step C2 is a step of producing a compound having the general formula (XIV). In the step of converting the hydroxy group of the compound (XIII) to a leaving group in an inert solvent in the presence of a base, iodine is added. The reaction is carried out by reacting with an agent to iodate the leaving group.

The reagent forming a leaving group includes, for example,
Sulfonyl halides such as methanesulfonyl chloride and P-toluenesulfonyl chloride; thionyl halides such as thionyl chloride, thionyl bromide and thionyl iodide; sulfuryl halides such as sulfuryl chloride, sulfuryl bromide and sulfuryl iodide; phosphorus trichloride Phosphorus trihalides, such as phosphorus tribromide; phosphorus pentahalides, such as phosphorus pentachloride and phosphorus pentabromide;
Phosphorous oxyhalides such as phosphorus oxychloride and phosphorus oxybromide; rhenium reagents such as methyltrioxorhenium (VII);

As the base used when converting a hydroxy group to a leaving group, it is usually used in the field of synthetic organic chemistry as a base used when converting a hydroxy group to a leaving group. The base is not particularly limited, as long as it is the same as the base used in the above-mentioned Method A, Step A1.

The inert solvent used for converting the hydroxy group to the leaving group is not particularly limited as long as it is inert to the reaction. For example, hexane, heptane,
Aliphatic hydrocarbons such as ligroin and petroleum ether;
Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; ketones such as acetone and 2-butanone; formamide;
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane; and preferably halogenated hydrocarbons.

The reaction temperature for converting the hydroxy group to a leaving group varies depending on the starting compound, the reagent used, the type of the solvent, and the like, but is usually -50 ° C to 200 ° C (preferably -10 ° C to 150 ° C.).

The reaction time for converting the hydroxy group to a leaving group varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours). Time).

The iodinating agent used in the above reaction is usually
The iodination agent used in the field of organic synthetic chemistry is not particularly limited, and examples thereof include sodium iodide and potassium iodide.

The reaction temperature for the iodination of the leaving group varies depending on the starting compound, the reagent used, the type of the solvent and the like, but is usually 0 ° C. to 200 ° C. (preferably 10 ° C. to 15 ° C.).
0 ° C).

The reaction time for iodination of the leaving group varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours). It is.

Step C3 is a step of preparing a compound having the general formula (XVI), and reacting the compound (XIV) with a compound having the general formula (XV) in an inert solvent in the presence of a base. It is done by doing.

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 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; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; water;
Or water or a mixed solvent of the above-mentioned solvents; preferably, alcohols or amides.

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned Method A, Step A1. Or alkali metal alkoxides.

The reaction temperature varies depending on the type of the starting compound, base, solvent and the like, but is usually from -78 ° C to 100 ° C.
(Preferably 0 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).

Step C4 is a step of preparing a compound having the general formula (XVII), which is carried out by reacting the compound (XVI) with a base in an inert solvent and hydrolyzing an ester group to a carboxy group. Will be

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 Or water or a mixed solvent of the above solvents; and preferably alcohols.

The base used in the above reaction is not particularly limited as long as it is a base usually used in hydrolyzing an ester group to a carboxy group in the field of synthetic organic chemistry. The same ones as used in the step A1 can be mentioned, and preferred are alkali metal hydroxides.

The reaction temperature varies depending on the type of the starting compound, base, solvent and the like, but is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 30 minutes to 120 hours (preferably 1 hour to 80 hours).

Step C5 is a step of producing a compound having the general formula (XIX), wherein the carboxy group of the compound (XVII) is subjected to a Curtius rearrangement reaction to convert the compound into a carbamate, and the compound (XVII) In an inert solvent in the presence of a base in the presence of a base, followed by a heat reaction with a compound having the general formula (XVIII).

The inert solvent used when reacting compound (XVII) with the diarylphosphoric acid azide derivative and the inert solvent used when reacting with compound (XVIII) are those which are inert to this reaction. Although not particularly limited, for example, hexane, heptane, ligroin, aliphatic hydrocarbons such as petroleum ether; benzene, toluene, aromatic hydrocarbons such as xylene; chloroform, dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or water or a mixed solvent of the above solvents; Group hydrocarbons (most preferably, ) It is.

The base used for reacting the compound (XVII) with the diarylphosphate azide derivative is not particularly limited as long as it is a base usually used in Curtius rearrangement in the field of organic synthetic chemistry. The same ones as used in the above-mentioned Method A, Step A1 can be mentioned, and preferred are organic amines.

The reaction temperature when reacting compound (XVII) with a diarylphosphoric azide derivative and compound (XVI)
Both the reaction temperature when reacting with II) and the starting compound,
The temperature is usually 0 ° C to 200 ° C (preferably 20 ° C to 150 ° C) depending on the type of the base and the solvent.

The reaction temperature when reacting compound (XVII) with a diarylphosphorus azide derivative and compound (XVI)
Both the reaction temperature when reacting with II) and the starting compound,
The time is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours), depending on the base, solvent, reaction temperature and the like.

The compound (XVIII), which hardly reacts directly with the diarylphosphate azide derivative, is reacted together when the compound (XVII) is reacted with the diarylphosphate azide derivative, so that the carboxyl group can be formed at a stroke. Can be converted to

Step C6 is a step of preparing a compound having the general formula (Xa), which is carried out by reducing the ester group of compound (XIX). The reaction is performed by reacting with an agent.

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; aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Or a mixed solvent of the above solvents, preferably a mixed solvent of alcohols and ethers.

The reducing agent used in the above reaction is not particularly limited as long as it is a reducing agent that is usually used in reducing synthetic ester groups in the field of synthetic organic chemistry.
For example, the same ones as those used in the above-mentioned Method A, Step A7 can be mentioned, and preferred are alkali metal borohydrides.

The reaction temperature varies depending on the starting compound, the kind of the solvent and the like, but is usually from -78 ° C to 150 ° C (preferably from -20 ° C to 50 ° C).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 30 minutes to 24 hours).

Step C7 is a step of producing compound (Xb), which is carried out by reacting compound (Xa) with a base in an inert solvent and closing the ring to an oxazolidine ring.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present 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; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; water;
Or water or a mixed solvent of the above-mentioned solvents; preferably, alcohols or amides.

As the base used in the above reaction, for example, the same bases as those used in the above-mentioned Method A, Step A1 can be mentioned, and preferred are alkali metal alkoxides.

The reaction temperature varies depending on the type of the starting compound, the base, the solvent and the like, but is usually from -78 ° C to 100 ° C.
(Preferably −50 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).

Step C8 is a step of producing compound (Xc). After reacting compound (Xb) with a base in an inert solvent and hydrolyzing it, R ¹ , R ² , R ³ , R ³
Removing amino, hydroxy and / or carboxyl protecting groups on ^5a , R ^6a and R ^7a , protecting amino groups on R ¹ and R ² , and / or protecting hydroxy groups on R ³ Is performed by

The inert solvent used when reacting compound (Xb) with a base is not particularly limited as long as it is inert to the present reaction. For example, hexane, heptane,
Aliphatic hydrocarbons such as ligroin and petroleum ether;
Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol;
Alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; water; or a mixed solvent of the above solvents, preferably a mixed solvent of alcohols and ethers It is.

Examples of the base used when reacting compound (Xb) with a base include those similar to the ones used in the above-mentioned Method A, Step A1. These are hydroxides.

The reaction temperature varies depending on the type of the starting compound, the base, the solvent and the like, but is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 100 ° C.).

The reaction time varies depending on the starting compound, the base, the type of the solvent, the reaction temperature and the like, but is usually from 30 minutes to 4 minutes.
8 hours (preferably 1 hour to 24 hours).

R ¹ , R ² , R ³ ,
Amino, hydroxy and / or R ^5a , R ^6a and R ^7a
Or removing the protecting group of a carboxyl group, R ¹
And protecting the amino group in R ² , and / or protecting the hydroxy group in R ³ , by removing the protecting group for the amino, hydroxy and / or carboxyl group in Step A2 of Method A; Protecting the amino group at ¹ and R ² and / or protecting the hydroxy group at R ³ is performed in the same manner.

If necessary, the target compound in each step of the method C is, if necessary, a conventional method, for example, recrystallization, reprecipitation, or a method commonly used for separating and purifying an organic compound, for example, silica gel, alumina, magnesium, and the like. Adsorption column chromatography using a carrier such as musilica gel type Florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm &
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step.

The compound (XI) can be obtained separately from the method B by inserting a bromination step (consensus with the method B) after any of the steps C1 to C5 of the method C. ) Can be manufactured.

Method D is a compound (Xd) in which n is an integer of 2 or more, Z is a group (II-2), and R ³ is a hydrogen atom. A compound (Xe), which is an integer, wherein W is a group (II-1); and
This is a method for producing a compound (Xf) in which n is an integer of 2 or more and W is a group (II-2).

[0259]

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In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ^6a , R
^7a and Ph are as defined above, and R ¹² is
C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ with a heteroatom interposed
A C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkynyl group substituted with an alkyl group, an aryl group or an aromatic heterocyclic group, a C ₃ -C ₂₀ alkynyl group interposed by a hetero atom, an aryl group or an aromatic heterocyclic group; C ₂ -C ₂₀ alkynyl group substituted with cyclic group, C ₂ -C ₂₀ alkenyl group, C ₃ heteroatoms are mediated
-C _{20 alkenyl,} group, C ₂ an aryl group or an aromatic heterocyclic C ₂ -C _{20 alkenyl,} groups substituted with one, heteroatom substituted with an aryl group or an aromatic heterocyclic group interposed -
C ₂₀ alkyl group, or indicates a C ₃ -C ₁₀ cycloalkyl group, m is an integer of 0 to 4.

In the above, “C ₁ ” in the definition of R ¹²
-C ₂₀ alkyl group ", for example, the" lower alkyl group ", heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-
Methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propyl Pentyl, 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,
3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl,
Tridecyl, tetradecyl, pentadecyl, 3,7,1
1-trimethyldodecyl, hexadecyl, 4,8,12
-Trimethyltridecyl, 1-methylpentadecyl, 1
4-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosyl, and 3,7,11,15-tetramethylhexadecyl group It is a linear or branched alkyl group having 1 to 20 carbon atoms, preferably a C ₁ -C ₁₀ alkyl group.

In the above, the “C ₂ -C ₂₀ alkyl group in which a hetero atom is present” in the definition of R ¹² is the same as the aforementioned “C ₁ -C ₂₀ alkyl group”.
“-C ₂₀ alkyl group” in which “alkyl group having 2 to 20 carbon atoms” is the same or different and is a group in which one or two sulfur atoms, oxygen atoms, or nitrogen atoms are interposed. For example, methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, ethylthiomethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 2-ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methylthiobutyl, 2-methylthiobutyl, 3-methylthiobutyl, 2-ethylthiopropyl, 3-methyl-3-methylthiopropyl,
-Methylthiopentyl, 3-methylthiopentyl, 2-
Methylthiopentyl, 1-methylthiopentyl, 3,3
-Dimethylthiobutyl, 2,2-dimethylthiobutyl,
1,1-dimethylthiobutyl, 1-methyl-2-methylthiobutyl, 1,3-dimethylthiobutyl, 2,3-dimethylthiobutyl, 2-ethylthiobutyl, 1-methylthiohexyl, 2-methylthiohexyl, 3 -Methylthiohexyl, 4-methylthiohexyl, 5-methylthiohexyl, 1-propylthiobutyl, 4-methyl-4-
Methylthiopentyl, 1-methylthioheptyl, 2-methylthioheptyl, 3-methylthioheptyl, 4-methylthioheptyl, 5-methylthioheptyl, 6-methylthioheptyl, 1-propylthiopentyl, 2-ethylthiohexyl, 5-methyl-5 -Methylthiohexyl,
3-methylthiooctyl, 4-methylthiooctyl, 5
-Methylthiooctyl, 6-methylthiooctyl, 1-
Propylthiohexyl, 2-ethylthioheptyl, 6-
Methyl-6-methylthioheptyl, 1-methylthiononyl, 3-methylthiononyl, 8-methylthiononyl,
-Ethylthiooctyl, 3-methyl-7-methylthiooctyl, 7,7-dimethylthiooctyl, 4-methyl-
8-methylthiononyl, 3,7-dimethyl-11-methylthiododecyl, 4,8-dimethyl-12-methylthiotridecyl, 1-methylthiopentadecyl, 14-methylthiopentadecyl, 13-methyl-13-methylthiotetradecyl, Alkyl having 2 to 20 carbon atoms interposed by 1 or 2 sulfur atoms such as 15-methylthiohexadecyl, 1-methylthioheptadecyl and 3,7,11-trimethyl-15-methylthiohexadecyl Groups: methyloxymethyl, 1-methyloxyethyl, 2-methyloxyethyl, ethyloxymethyl,
-Methyloxypropyl, 2-methyloxypropyl,
3-methyloxypropyl, 2-ethyloxyethyl,
2-methyl-2-methyloxyethyl, 1-methyloxybutyl, 2-methyloxybutyl, 3-methyloxybutyl, 2-ethyloxypropyl, 3-methyl-3-
Methyloxypropyl, 4-methyloxypentyl, 3
-Methyloxypentyl, 2-methyloxypentyl,
1-methyloxypentyl, 3,3-dimethyloxybutyl, 2,2-dimethyloxybutyl, 1,1-dimethyloxybutyl, 1-methyl-2-methyloxybutyl, 1,3-dimethyloxybutyl, 3-dimethyloxybutyl, 2-ethyloxybutyl, 1-methyloxyhexyl, 2-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl, 5-methyloxyhexyl, 1-propyloxybutyl, 4- Methyl-4-methyloxypentyl, 1-methyloxyheptyl, 2-methyloxyheptyl, 3-methyloxyheptyl, 4-methyloxyheptyl, 5-methyloxyheptyl, 6-methyloxyheptyl, 1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl-5-methyloxy Hexyl, 3-methyloxy-octyl, 4-methyl-oxy-octyl, 5-methyloxy-octyl, 6-methyloxy-octyl, 1-propyloxy-hexyl, 2-ethyl-oxy-heptyl, 6-methyl -
6-methyloxyheptyl, 1-methyloxynonyl,
3-methyloxynonyl, 8-methyloxynonyl, 3
-Ethyloxyoctyl, 3-methyl-7-methyloxyoctyl, 7,7-dimethyloxyoctyl, 4-methyl-8-methyloxynonyl, 3,7-dimethyl-1
1-methyloxidedecyl, 4,8-dimethyl-12-
Methyloxytridecyl, 1-methyloxypentadecyl, 14-methyloxypentadecyl, 13-methyl-
13-methyloxytetradecyl, 15-methyloxyhexadecyl, 1-methyloxyheptadecyl, and
An alkyl group having 2 to 20 carbon atoms interposed by one or two oxygen atoms such as 3,7,11-trimethyl-15-methyloxyhexadecyl; N-methylaminomethyl, 1- (N- Methylamino) ethyl, 2- (N-methylamino) ethyl, N-ethylaminomethyl, 1-
(N-methylamino) propyl, 2- (N-methylamino) propyl, 3- (N-methylamino) propyl,
-(N-ethylamino) ethyl, 2- (N, N-dimethylamino) ethyl, 1- (N-methylamino) butyl,
2- (N-methylamino) butyl, 3- (N-methylamino) butyl, 2- (N-ethylamino) propyl,
-(N, N-dimethylamino) propyl, 4- (N-methylamino) pentyl, 3- (N-methylamino) pentyl, 2- (N-methylamino) pentyl, 1- (N-
Methyl (amino) pentyl, 3- (N, N-dimethylamino) butyl, 2- (N, N-dimethylamino) butyl,
1- (N, N-dimethylamino) butyl, 1-methyl-
2- (N-methylamino) butyl, 1,3-di (N-methylamino) butyl, 2,3-di (N-methylamino)
Butyl, 2- (N-ethylamino) butyl, 1- (N-
Methylamino) hexyl, 2- (N-methylamino) hexyl, 3- (N-methylamino) hexyl, 4- (N
-Methylamino) hexyl, 5- (N-methylamino)
Hexyl, 1- (N-propylamino) butyl, 4-methyl-4- (N-methylamino) pentyl, 1- (N-
Methylamino) heptyl, 2- (N-methylamino) heptyl, 3- (N-methylamino) heptyl, 4- (N
-Methylamino) heptyl, 5- (N-methylamino)
Heptyl, 6- (N-methylamino) heptyl, 1-
(N-propylamino) pentyl, 2- (N-ethylamino) hexyl, 5-methyl-5- (N-methylamino) hexyl, 3- (N-methylamino) octyl,
-(N-methylamino) octyl, 5- (N-methylamino) octyl, 6- (N-methylamino) octyl,
1- (N-propylamino) hexyl, 2- (N-ethylamino) heptyl, 6-methyl-6- (N-methylamino) heptyl, 1- (N-methylamino) nonyl,
-(N-methylamino) nonyl, 8- (N-methylamino) nonyl, 3- (N-ethylamino) octyl, 3-
Methyl-7- (N-methylamino) octyl, 7,7-
Di (N-methylamino) octyl, 4-methyl-8-
(N-methylamino) nonyl, 3,7-dimethyl-11
-(N-methylamino) dodecyl, 4,8-dimethyl-
12- (N-methylamino) tridecyl, 1- (N-methylamino) pentadecyl, 14- (N-methylamino) pentadecyl, 13-methyl-13- (N-methylamino) tetradecyl, 15- (N-methyl Amino) hexadecyl, 1- (N-methylamino) heptadecyl,
And an alkyl group having 2 to 20 carbon atoms interposed by one or two nitrogen atoms, such as 3,7,11-trimethyl-15- (N-methylamino) hexadecyl. Has a C _2-
It is a C ₁₀ alkyl group.

In the above, the “C ₁ -C ₂₀ alkyl group substituted with an aryl group or an aromatic heterocyclic group” in the definition of R ¹² is the above-mentioned “C ₁ -C ₂₀ alkyl group”
The same or different, and represents a group substituted by one or three aryl groups or aromatic heterocyclic groups;
And "aromatic heterocyclic group" are in agreement with those described above. In the above, “C ₂ -C ₂₀ ” in the definition of R ¹²
“Alkynyl group” includes, for example, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, -Methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-
Methyl-3-butynyl, 2-methyl-3-butynyl, 1
-Ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-
Pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-
Pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, heptynyl, 1-methylhexynyl, 2-methylhexynyl, 3-methylhexynyl, 4-methylhexynyl, 5-methylhexynyl, 1- Propylbutynyl,
4,4-dimethylpentynyl, octynyl, 1-methylheptynyl, 2-methylheptynyl, 3-methylheptynyl, 4-methylheptynyl, 5-methylheptynyl,
6-methylheptynyl, 1-propylpentynyl, 2-
Ethylhexynyl, 5,5-dimethylhexynyl, noninyl, 3-methyloctynyl, 4-methyloctynyl,
5-methyloctynyl, 6-methyloctynyl, 1-propylhexynyl, 2-ethylheptynyl, 6,6-dimethylheptynyl, decynyl, 1-methylnoninyl, 3
-Methylnoninyl, 8-methylnoninyl, 3-ethyloctynyl, 3,7-dimethyloctynyl, 7,7-dimethyloctynyl, undecinyl, 4,8-dimethylnoninyl, dodecinyl, tridecinyl, tetradecynyl, pentadecynyl, 3,7,11 -Trimethyldodecynyl,
Hexadecynyl, 4,8,12-trimethyltridecynyl, 1-methylpentadecynyl, 14-methylpentadecynyl, 13,13-dimethyltetradecynyl, heptadecynyl, 15-methylhexadecynyl, octadecynyl, 1-methylhepta decynyl, Nonadeshiniru, Aikoshiniru, and, 3,7,11,15 a-tetramethyl hexadecylcarbamoyl sulfonyl straight or branched alkynyl group having 2 to 20 carbon atoms, such as radicals, preferably C ₁ - It is a C ₁₀ alkynyl group.

[0264] In the above, "C ₃ -C ₂₀ alkynyl heteroatoms are mediated" in the definition of R ^12, the "C ₃ -C ₂₀ alkynyl group" of the "C ₁ -C ₂₀ alkynyl group" The same or different, and represents one or two groups interposed by a sulfur atom, an oxygen atom, or a nitrogen atom, for example, 1-methylthioethynyl, 2-methylthioethynyl, 1-methylthiopropynyl, Methylthiopropynyl, 3-methylthiopropynyl, 2-ethylthioethynyl, 2-methyl-2-methylthioethynyl, 1
-Methylthiobutynyl, 2-methylthiobutynyl, 3-
Methylthiobutynyl, 2-ethylthiopropynyl, 3-
Methyl-3-methylthiopropynyl, 4-methylthiopentynyl, 3-methylthiopentynyl, 2-methylthiopentynyl, 1-methylthiopentynyl, 3,3-dimethylthiobutynyl, 2,2-dimethylthiobutynyl,
1,1-dimethylthiobutynyl, 1-methyl-2-methylthiobutynyl, 1,3-dimethylthiobutynyl, 2,
3-dimethylthiobutynyl, 2-ethylthiobutynyl,
1-methylthiohexynyl, 2-methylthiohexynyl, 3-methylthiohexynyl, 4-methylthiohexynyl, 5-methylthiohexynyl, 1-propylthiobutynyl, 4-methyl-4-methylthiopentynyl, 1-
Methylthioheptynyl, 2-methylthioheptynyl, 3
-Methylthioheptynyl, 4-methylthioheptynyl,
5-methylthioheptynyl, 6-methylthioheptynyl, 1-propylthiopentynyl, 2-ethylthiohexynyl, 5-methyl-5-methylthiohexynyl, 3-
Methylthiooctynyl, 4-methylthiooctynyl, 5
-Methylthiooctynyl, 6-methylthiooctynyl,
1-propylthiohexynyl, 2-ethylthioheptynyl, 6-methyl-6-methylthioheptynyl, 1-methylthiononinyl, 3-methylthiononinyl, 8-methylthiononinyl, 3-ethylthiooctynyl , 3-methyl-7-methylthiooctynyl, 7,7-dimethylthiooctynyl, 4-methyl-8-methylthiononinyl, 3,
7-dimethyl-11-methylthiododecynyl, 4,8-
Dimethyl-12-methylthiotridecynyl, 1-methylthiopentadecynyl, 14-methylthiopentadecynyl, 13-methyl-13-methylthiotetradecynyl,
15-methylthiohexadecynyl, 1-methylthioheptadecynyl and 3,7,11-trimethyl-15-
An alkynyl group having 3 to 20 carbon atoms interposed by one or two sulfur atoms, such as methylthiohexadecynyl; 1-methyloxyethynyl, 2-methyloxyethynyl, 1-methyloxypropynyl, 2-methyl Oxypropynyl, 3-methyloxypropynyl, 2-ethyloxyethynyl, 2-methyl-2-methyloxyethynyl, 1-methyloxybutynyl, 2-methyloxybutynyl, 3-methyloxybutynyl, 2-ethyloxypropynyl , 3-methyl-3-methyloxypropynyl,
4-methyloxypentynyl, 3-methyloxypentynyl, 2-methyloxypentynyl, 1-methyloxypentynyl, 3,3-dimethyloxybutynyl, 2,2
-Dimethyloxybutynyl, 1,1-dimethyloxybutynyl, 1-methyl-2-methyloxybutynyl, 1,
3-dimethyloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyloxybutynyl, 1-methyloxyhexynyl, 2-methyloxyhexynyl, 3-methyloxyhexynyl, 4-methyloxyhexynyl , 5
-Methyloxyhexynyl, 1-propyloxybutynyl, 4-methyl-4-methyloxypentynyl, 1-methyloxyheptynyl, 2-methyloxyheptynyl,
3-methyloxyheptynyl, 4-methyloxyheptynyl, 5-methyloxyheptynyl, 6-methyloxyheptynyl, 1-propyloxypentynyl, 2-ethyloxyhexynyl, 5-methyl- 5-methyloxyhexynyl, 3-methyloxyoctynyl, 4-methyloxyoctynyl, 5-methyloxyoctynyl, 6-methyloxyoctynyl, 1-propyloxyhexynyl, 2-ethyloxyheptynyl, 6-methyl-6-methyloxyheptynyl, 1-methyloxynoninyl, 3
-Methyloxynoninyl, 8-methyloxynoninyl,
3-ethyloxyoctynyl, 3-methyl-7-methyloxyoctynyl, 7,7-dimethyloxyoctynyl, 4-methyl-8-methyloxynoninyl, 3,7-
Dimethyl-11-methyloxidedecynyl, 4,8-dimethyl-12-methyloxytridecynyl, 1-methyloxypentadecynyl, 14-methyloxypentadecynyl, 13-methyl-13-methyloxytetradecynyl, 1 or 2 such as 15-methyloxyhexadecynyl, 1-methyloxyheptadecynyl and 3,7,11-trimethyl-15-methyloxyhexadecynyl
An alkynyl group having 3 to 20 carbon atoms interposed by two oxygen atoms; 1- (N-methylamino) ethynyl, 2-
(N-methylamino) ethynyl, 1- (N-methylamino) propynyl, 2- (N-methylamino) propynyl, 3- (N-methylamino) propynyl, 2- (N-
Ethylamino) ethynyl, 2- (N, N-dimethylamino) ethynyl, 1- (N-methylamino) butynyl,
-(N-methylamino) butynyl, 3- (N-methylamino) butynyl, 2- (N-ethylamino) propynyl, 3- (N, N-dimethylamino) propynyl, 4-
(N-methylamino) pentynyl, 3- (N-methylamino) pentynyl, 2- (N-methylamino) pentynyl, 1- (N-methylamino) pentynyl, 3- (N,
N-dimethylamino) butynyl, 2- (N, N-dimethylamino) butynyl, 1- (N, N-dimethylamino)
Butynyl, 1-methyl-2- (N-methylamino) butynyl, 1,3-di (N-methylamino) butynyl, 2,
3-di (N-methylamino) butynyl, 2- (N-ethylamino) butynyl, 1- (N-methylamino) hexynyl, 2- (N-methylamino) hexynyl, 3- (N
-Methylamino) hexynyl, 4- (N-methylamino) hexynyl, 5- (N-methylamino) hexynyl, 1- (N-propylamino) butynyl, 4-methyl-4- (N-methylamino) pentynyl, 1- (N-methylamino) heptynyl, 2- (N-methylamino) heptynyl, 3- (N-methylamino) heptynyl, 4-
(N-methylamino) heptynyl, 5- (N-methylamino) heptynyl, 6- (N-methylamino) heptynyl, 1- (N-propylamino) pentynyl, 2- (N
-Ethylamino) hexynyl, 5-methyl-5- (N-
Methylamino) hexynyl, 3- (N-methylamino)
Octynyl, 4- (N-methylamino) octynyl, 5
-(N-methylamino) octynyl, 6- (N-methylamino) octynyl, 1- (N-propylamino) hexynyl, 2- (N-ethylamino) heptynyl, 6-methyl-6- (N-methylamino ) Heptinyl, 1- (N
-Methylamino) noninyl, 3- (N-methylamino)
Noninyl, 8- (N-methylamino) noninyl, 3-
(N-ethylamino) octynyl, 3-methyl-7-
(N-methylamino) octynyl, 7,7-di (N-methylamino) octynyl, 4-methyl-8- (N-methylamino) noninyl, 3,7-dimethyl-11- (N-
Methylamino) dodecinyl, 4,8-dimethyl-12-
(N-methylamino) tridecinyl, 1- (N-methylamino) pentadecinyl, 14- (N-methylamino)
Pentadecynyl, 13-methyl-13- (N-methylamino) tetradecynyl, 15- (N-methylamino) hexadecynyl, 1- (N-methylamino) heptadecynyl, and 3,7,11-trimethyl-15- (N -Methylamino) hexadecynyl, an alkynyl group having 3 to 20 carbon atoms interposed by 1 or 2 nitrogen atoms, preferably C ₃ -C ₁₀ intervening by a hetero atom.
Alkynyl group.

In the above, the “C ₂ -C ₂₀ alkynyl group substituted with an aryl group or an aromatic heterocyclic group” in the definition of R ¹² is the same as or different from the above “C ₂ -C ₂₀ alkynyl group”. And 1 or 3 groups substituted with the above “aryl group” or the above “aromatic heterocyclic group”.

In the above, “C ₂ ” in the definition of R ¹²
—C ₂₀ alkenyl group ”is, for example, ethenyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2
-Propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1
-Methyl-3-butenyl, 2-methyl-3-butenyl,
1-ethyl-3-butenyl, 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, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, heptenyl, 1-methylhexenyl, 2-methylhexenyl, 3-methylhexenyl, 4-methylhexenyl, 5 -Methylhexenyl, 1-propylbutenyl,
4,4-dimethylpentenyl, octenyl, 1-methylheptenyl, 2-methylheptenyl, 3-methylheptenyl, 4-methylheptenyl, 5-methylheptenyl,
6-methylheptenyl, 1-propylpentenyl, 2-
Ethylhexenyl, 5,5-dimethylhexenyl, nonenyl, 3-methyloctenyl, 4-methyloctenyl,
5-methyloctenyl, 6-methyloctenyl, 1-propylhexenyl, 2-ethylheptenyl, 6,6-dimethylheptenyl, decenyl, 1-methylnonenyl, 3
-Methylnonenyl, 8-methylnonenyl, 3-ethyloctenyl, 3,7-dimethyloctenyl, 7,7-dimethyloctenyl, undecenyl, 4,8-dimethylnonenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, 3,7,11-trimethyl Dodecenyl,
Hexadecenyl, 4,8,12-trimethyltridecenyl, 1-methylpentadecenyl, 14-methylpentadecenyl, 13,13-dimethyltetradecenyl, heptadecenyl, 15-methylhexadecenyl, octadecenyl And straight-chain or branched alkenyl groups having 2 to 20 carbon atoms, such as 1,1-methylheptadecenyl, nonadecenyl, eicosenyl and 3,7,11,15-tetramethylhexadecenyl group. And preferably C ₂ -C
₁₀ alkenyl groups.

[0267] In the above, "C ₃ -C ₂₀ alkenyl group which heteroatoms are mediated" in the definition of R ^12, the "C ₃ -C ₂₀ alkenyl group" of the "C ₂ -C ₂₀ alkenyl group" The same or different, and represents one or two groups interposed by a sulfur atom, an oxygen atom, or a nitrogen atom, for example, 1-methylthioethenyl, 2-methylthioethenyl, 1-methylthiopropenyl, 2-methylthiopropenyl, 3-methylthiopropenyl, 2-ethylthioethenyl, 2-methyl-2-methylthioethenyl, 1
-Methylthiobutenyl, 2-methylthiobutenyl, 3-
Methylthiobutenyl, 2-ethylthiopropenyl, 3-
Methyl-3-methylthiopropenyl, 4-methylthiopentenyl, 3-methylthiopentenyl, 2-methylthiopentenyl, 1-methylthiopentenyl, 3,3-dimethylthiobutenyl, 2,2-dimethylthiobutenyl,
1,1-dimethylthiobutenyl, 1-methyl-2-methylthiobutenyl, 1,3-dimethylthiobutenyl, 2,
3-dimethylthiobutenyl, 2-ethylthiobutenyl,
1-methylthiohexenyl, 2-methylthiohexenyl, 3-methylthiohexenyl, 4-methylthiohexenyl, 5-methylthiohexenyl, 1-propylthiobutenyl, 4-methyl-4-methylthiopentenyl, 1-
Methylthioheptenyl, 2-methylthioheptenyl, 3
-Methylthioheptenyl, 4-methylthioheptenyl,
5-methylthioheptenyl, 6-methylthioheptenyl, 1-propylthiopentenyl, 2-ethylthiohexenyl, 5-methyl-5-methylthiohexenyl, 3-
Methylthiooctenyl, 4-methylthiooctenyl, 5
-Methylthiooctenyl, 6-methylthiooctenyl,
1-propylthiohexenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl, 1-methylthiononenyl, 3-methylthiononenyl, 8-methylthiononenyl, 3-ethylthiooctenyl, 3- Methyl-7-methylthiooctenyl, 7,7-dimethylthiooctenyl, 4-methyl-8-methylthiononenyl, 3,
7-dimethyl-11-methylthiododecenyl, 4,8-
Dimethyl-12-methylthiotridecenyl, 1-methylthiopentadecenyl, 14-methylthiopentadecenyl, 13-methyl-13-methylthiotetradecenyl,
15-methylthiohexadecenyl, 1-methylthioheptadecenyl and 3,7,11-trimethyl-15-
An alkenyl group having 3 to 20 carbon atoms and interposed by one or two sulfur atoms such as methylthiohexadecenyl; 1-methyloxyethenyl, 2-methyloxyethenyl, 1-methyloxypropenyl, 2-methyloxypropenyl, 3-methyloxypropenyl, 2-ethyloxyethenyl, 2-methyl-2-methyloxyethenyl, 1-methyloxybutenyl, 2-methyloxybutenyl, 3-methyloxybutenyl, 2-ethyloxypropenyl, 3-methyl-3-methyloxypropenyl,
4-methyloxypentenyl, 3-methyloxypentenyl, 2-methyloxypentenyl, 1-methyloxypentenyl, 3,3-dimethyloxybutenyl, 2,2
-Dimethyloxybutenyl, 1,1-dimethyloxybutenyl, 1-methyl-2-methyloxybutenyl, 1,
3-dimethyloxybutenyl, 2,3-dimethyloxybutenyl, 2-ethyloxybutenyl, 1-methyloxyhexenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl, 4-methyloxyhexenyl, 5
-Methyloxyhexenyl, 1-propyloxybutenyl, 4-methyl-4-methyloxypentenyl, 1-methyloxyheptenyl, 2-methyloxyheptenyl,
3-methyloxyheptenyl, 4-methyloxyheptenyl, 5-methyloxyheptenyl, 6-methyloxyheptenyl, 1-propyloxypentenyl, 2-ethyloxyhexenyl, 5-methyl-5-methyloxyhexenyl, 3-methyloxyoctenyl, 4-methyloxyoctenyl, 5-methyloxyoctenyl, 6-methyloxyoctenyl, 1-propyloxyhexenyl, 2-ethyloxyheptenyl, 6-methyl-6-methyloxyhept Thenyl, 1-methyloxynonenyl, 3
-Methyloxynonenyl, 8-methyloxynonenyl,
3-ethyloxyoctenyl, 3-methyl-7-methyloxyoctenyl, 7,7-dimethyloxyoctenyl, 4-methyl-8-methyloxynonenyl, 3,7-
Dimethyl-11-methyloxidedecenyl, 4,8-dimethyl-12-methyloxytridecenyl, 1-methyloxypentadecenyl, 14-methyloxypentadecenyl, 13-methyl-13-methyloxy 1 or 2 such as tetradecenyl, 15-methyloxyhexadecenyl, 1-methyloxyheptadecenyl and 3,7,11-trimethyl-15-methyloxyhexadecenyl
An alkenyl group having 3 to 20 carbon atoms interposed by two oxygen atoms; 1- (N-methylamino) ethenyl, 2-
(N-methylamino) ethenyl, 1- (N-methylamino) propenyl, 2- (N-methylamino) propenyl, 3- (N-methylamino) propenyl, 2- (N-
Ethylamino) ethenyl, 2- (N, N-dimethylamino) ethenyl, 1- (N-methylamino) butenyl,
-(N-methylamino) butenyl, 3- (N-methylamino) butenyl, 2- (N-ethylamino) propenyl, 3- (N, N-dimethylamino) propenyl, 4-
(N-methylamino) pentenyl, 3- (N-methylamino) pentenyl, 2- (N-methylamino) pentenyl, 1- (N-methylamino) pentenyl, 3- (N,
N-dimethylamino) butenyl, 2- (N, N-dimethylamino) butenyl, 1- (N, N-dimethylamino)
Butenyl, 1-methyl-2- (N-methylamino) butenyl, 1,3-di (N-methylamino) butenyl, 2,
3-di (N-methylamino) butenyl, 2- (N-ethylamino) butenyl, 1- (N-methylamino) hexenyl, 2- (N-methylamino) hexenyl, 3- (N
-Methylamino) hexenyl, 4- (N-methylamino) hexenyl, 5- (N-methylamino) hexenyl, 1- (N-propylamino) butenyl, 4-methyl-4- (N-methylamino) pentenyl, 1- (N-methylamino) heptenyl, 2- (N-methylamino) heptenyl, 3- (N-methylamino) heptenyl, 4-
(N-methylamino) heptenyl, 5- (N-methylamino) heptenyl, 6- (N-methylamino) heptenyl, 1- (N-propylamino) pentenyl, 2- (N
-Ethylamino) hexenyl, 5-methyl-5- (N-
Methylamino) hexenyl, 3- (N-methylamino)
Octenyl, 4- (N-methylamino) octenyl, 5
-(N-methylamino) octenyl, 6- (N-methylamino) octenyl, 1- (N-propylamino) hexenyl, 2- (N-ethylamino) heptenyl, 6-methyl-6- (N-methylamino ) Heptenyl, 1- (N
-Methylamino) nonenyl, 3- (N-methylamino)
Nonenyl, 8- (N-methylamino) nonenyl, 3-
(N-ethylamino) octenyl, 3-methyl-7-
(N-methylamino) octenyl, 7,7-di (N-methylamino) octenyl, 4-methyl-8- (N-methylamino) nonenyl, 3,7-dimethyl-11- (N-
Methylamino) dodecenyl, 4,8-dimethyl-12-
(N-methylamino) tridecenyl, 1- (N-methylamino) pentadecenyl, 14- (N-methylamino)
Pentadecenyl, 13-methyl-13- (N-methylamino) tetradecenyl, 15- (N-methylamino) hexadecenyl, 1- (N-methylamino) heptadecenyl, and 3,7,11-trimethyl-15- (N Examples thereof include an alkenyl group having 3 to 20 carbon atoms interposed by one or two nitrogen atoms such as -methylamino) hexadecenyl, and preferably a C ₃ -C ₁₀ alkenyl interposed by a hetero atom. Group.

In the above, the “C ₂ -C ₂₀ alkenyl group substituted with an aryl group or an aromatic heterocyclic group” in the definition of R ¹² is the same as or different from the above “C ₂ -C ₂₀ alkenyl group”. And 1 or 3 groups substituted with the above “aryl group” or the above “aromatic heterocyclic group”.

[0269] In the above, "C ₂ -C ₂₀ alkyl group hetero atom substituted by an aryl group or an aromatic heterocyclic group is interposed" in the definition of R ¹² is, C ₂ -C said that "heteroatom-mediated " ₂₀ alkyl groups" represents the same or different groups substituted by 1 or 3 of the above "aryl groups" or the above "aromatic heterocyclic groups".

In the above, “C ₃ ” in the definition of R ¹²
“—C ₁₀ cycloalkyl group” has the same consensus as the above “cycloalkyl group”.

The step D1 is a step for producing a compound having the general formula (XXII), wherein only one hydroxyl group of the compound having the general formula (XX) is carried out in the presence or absence of an inert solvent (preferably Is carried out) in the presence of a lipase in the presence of a compound having the general formula (XXI).

"Lipase" used in the above reaction
Is not particularly limited and the optimal one varies depending on the type of the starting compound, but preferably Pseudomonas sp., Pseudom
onasfluorescens, Pseudomonas cepacia, Chromobacter
ium viscosum, Aspergillusniger, Aspergillus oryza
e, Candida antarctica, Candida cylindracea, Candid
a lipolytica, Candida rugosa, Candida utilis, Peni
cillium roqueforti, Rhizopus arrhizus, Rhizopus de
lemar, Rhizopus javanicus, Rhizomucor miehei, Rhiz
opus niveus, Humicola lanuginosa, Mucor javanicus,
Mucor miehei, Thermus aquaticus, Thermus flavus, Ther
mus thermophilus, human pancreas, hog pancreas,
porcine pancreas, a lipase from wheat germ,
The enzyme can be used not only partially or completely after purification, but also in an immobilized form.

Most preferably, Pseudomonas sp. Immobilized (for example, immobilized lipase from Pseudomo
nas sp. (TOYOBO).

The compound (XX) used in the above reaction
As the suitable compound in I), the most suitable compound varies depending on the type of the raw material compound. Vinyl esters of aliphatic carboxylic acids, most preferably vinyl esters of n-hexanoic acid.

The inert solvent used in the above reaction is not particularly limited, and may be only the compound (XXI), or the most suitable one varies depending on the type of the starting compound. Preferably, ethers such as diisopropyl ether, t-butyl methyl ether, diethyl ether, and tetrahydrofuran; aliphatic hydrocarbons such as n-hexane and n-pentane; and aromatics such as benzene and toluene Group hydrocarbons; and halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, more preferably ethers, and most preferably diisopropyl ether.

The reaction temperature varies depending on the starting compound, the solvent used, the type of lipase used and the like, but is usually -50 to 50 ° C, preferably 0 to 40 ° C.

The reaction time varies depending on the starting compound, the solvent used, the lipase used, the reaction temperature and the like, but is usually 15 minutes to 150 hours, preferably 30 minutes to 24 hours.

Step D2 is a step of producing a compound having the general formula (XXIII), which is carried out by oxidizing an alcohol moiety of the compound (XXII) to an aldehyde in an inert solvent in the presence of an oxidizing agent.

The oxidation reaction in the above reaction is not particularly limited as long as it is an oxidation reaction for producing an aldehyde from a primary alcohol. For example, Collins oxidation carried out using pyridine and chromic acid in methylene chloride; methylene chloride PCC oxidation performed using pyridinium chloride chromate (PCC) in methylene chloride; PDC oxidation performed using pyridinium dichromate (PDC) in methylene chloride; electrophilic agents (eg, acetic anhydride, trianhydride Fluoroacetic acid, thionyl chloride, sulfuryl chloride, oxalyl chloride,
Dicyclohexylcarbodiimide, diphenylketene-
DMSO, such as Swern oxidation, performed using p-tolylimine, N, N-diethylaminoacetylene, sulfur trioxide / pyridine complex) and dimethyl sulfoxide (DMSO).
Oxidation; and manganese dioxide oxidation performed using manganese dioxide in methylene chloride or benzene, and preferably performed in methylene chloride.
PCC oxidation or Swern oxidation.

The reaction temperature varies depending on the type of the starting compound, the solvent, the oxidizing agent and the like, but is usually from -50 ° C to 50 ° C, preferably from -10 ° C to 30 ° C.

The reaction time varies depending on the starting compound, the solvent, the kind of the oxidizing agent, the reaction temperature and the like, but is usually from 10 minutes to 24 hours, preferably from 30 minutes to 24 hours.

Step D3 is a step of producing a compound having the general formula (XXV), in which an aldehyde of the compound (XXIII) is reacted with an aldehyde of the compound (XXIII) in an inert solvent in the presence of a base. It is performed by

The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphorotriamide; And ethers (most preferably tetrahydrofuran).

The base used in the above reaction is not particularly limited, as long as it is used as a base in a usual reaction. Preferred are alkali metal alkoxides (most preferably potassium t-butoxide).

The reaction temperature varies depending on the type of the starting compound, solvent, base and the like, but is usually from -78 ° C to 200 ° C, preferably from -50 ° C to 150 ° C.

The reaction time varies depending on the starting compound, solvent, type of base, reaction temperature and the like, but is usually from 10 minutes to 4 minutes.
8 hours, preferably 15 minutes to 12 hours.

Step D4 is a step of producing a compound having the general formula (XXVI), which is carried out by converting the compound (XXV) into a compound (XXVI) in an inert solvent in the presence of a reducing agent. This step is performed in the same manner as in the catalytic conversion performed in the above-mentioned Method A, Step A3.

Step D5 is a step for producing a compound (Xd) in an inert solvent in the presence of a base.
XVI) is carried out by hydrolysis.

The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, alcohols such as methanol and ethanol, benzene, Toluene, aromatic hydrocarbons such as xylene, methylene chloride, chloroform, carbon tetrachloride, halogenated hydrocarbons such as dichloroethane, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether, or And a mixed solvent of these solvents, or a mixed solvent of these solvents and water. Preferred are alcohols and ethers.

The base used in the above reaction is not particularly limited as long as it is used as a base in a usual reaction. For example, the same bases as used in the above-mentioned Method A, step A1 can be mentioned. Preferably, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like can be mentioned.

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

The reaction time varies depending on the starting compound, reaction temperature, inert solvent, type of base, reaction temperature and the like, but is usually 30 minutes to 48 hours, and preferably 1 hour to 24 hours.

Step D6 is a step of producing compound (Xe), which is carried out by reacting compound (Xd) with a base in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Ethers such as diethylene glycol dimethyl ether; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; benzene, toluene, Aromatic hydrocarbons such as xylene, preferably ethers and amides.

The base used in the above reaction is not particularly limited as long as it is used as a base in a usual reaction. For example, an alkali such as lithium hydride, sodium hydride or potassium hydride may be used. Metal hydrides; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium methoxide And alkali metal alkoxides such as butyllithium, lithium diisopropylamide, and lithium bis (trimethylsilyl) amide. Preferred are alkali metal alkoxides and alkali metal hydrides. is there.

The reaction temperature varies depending on the type of the starting compound, the inert solvent, the base and the like, but is usually from -80 ° C to 10 ° C.
0 ° C., preferably 0 ° C. to 50 ° C.

The reaction time varies depending on the starting compound, reaction temperature, inert solvent, type of base, reaction temperature and the like, but is usually from 5 minutes to 48 hours.

Step D7 is a step for producing a compound having the general formula (Xf), which is carried out by protecting the hydroxyl group of compound (Xd).
It is carried out in the same manner as the method for protecting the hydroxyl group in the step.

If necessary, the target compound in each step of the present Method D may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of an organic compound, for example, silica gel, alumina, magnesium, and the like. Adsorption column chromatography using a carrier such as musilica gel type Florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm &
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step.

In the above description regarding the production of the target compounds (Xd), (Xe) and (Xf), only the structural formula of one of the optical isomers is described, but in the step D1, the type of the lipase is changed. The process is not limited to the absolute configuration described, as optical isomers having the opposite absolute configuration are also obtained.

Also, a bromination step (which is in agreement with the above-mentioned Method B) is inserted after any one of Steps D1 to D5 of the present method, whereby Compound (XI) is obtained separately from Method B. Can be manufactured.

Method E is a method for producing compound (XXIV).

[0304]

Embedded image

In the above formula, R ^6a , R ^7a , m, Q and Ph
Has the same meaning as described above.

Step E1 is a step for producing a compound (XXIV), wherein the compound of the formula (XXVII)
By reacting a compound having the formula with triphenylphosphine.

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, petroleum ether; aromatic hydrocarbons such as toluene, benzene, xylene; methylene chloride;
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether, preferably aromatic Hydrocarbons (most preferably benzene).

The reaction temperature varies depending on the starting compound, the kind of the solvent and the like, but is usually from room temperature to 200 ° C., preferably from 0 ° C. to 150 ° C. (most preferably 110 ° C.).

The reaction time mainly depends on the reaction temperature, the starting compound,
Although it varies depending on the type of the solvent used, it is usually 5 minutes to 96 hours, preferably 15 minutes to 48 hours (most preferably 24 hours).

If necessary, the target compound in each step of the present Method E may be a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium, and the like. Adsorption column chromatography using a carrier such as musilica gel type Florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm &
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned means for separation and purification after completion of the reaction in each of the above steps or at an appropriate time after completion of the desired step.

Starting compounds (III), (VI) and (VI
II), (IX), (XV), (XVIII), (X
X) and (XXI) are known or are easily produced according to known methods or methods analogous thereto [for example, compound (III) can be prepared according to J. Med. Chem., 35, 2253 (1992);
Org. Chem., 59, 3368 (1994) or a method analogous thereto, which is easily prepared to give compound (VI)
Can be easily produced according to the method described in J. Org. Chem., 60, 7508 (1995) or a method analogous thereto, and the compound (X
V) is easily prepared according to the method described in J. Am. Chem. Soc., 68, 1934 (1946) or a method analogous thereto, and compound (XX) is prepared according to J. Med. Chem., 39, 4451 ( 1996) or a method analogous thereto. ].

The compound of the present invention having the above general formula (I), its pharmaceutically acceptable salt, its ester or other derivative has an excellent immunosuppressive action.

When the compound having the above general formula (I), its pharmaceutically acceptable salt or its ester or other derivative of the present invention is used as the above-mentioned therapeutic or prophylactic agent, it may be used alone or appropriately. Pharmacologically acceptable, mixed with excipients, diluents, etc., for example, tablets, capsules,
It can be administered orally with granules, powders or syrups or parenterally with injections or suppositories.

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 and 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, acidulants, flavors) Can be mentioned.), It is prepared in a known manner by using additives such as diluents.

The dosage varies depending on symptoms, age and the like.
g (preferably 5 mg), upper limit 200 mg (preferably,
In the case of intravenous administration, the lower limit is 0.005 mg (preferably 1 mg) per day and the upper limit is 100 m
g (preferably 10 mg) per adult per day
It is desirable to administer from 6 to 6 times depending on the symptoms.

[0317]

The present invention will be described in more detail with reference to the following examples and test examples, but the scope of the present invention is not limited to these examples.

Example 1 (2R) -amino-4- [3- (4-cyclohexylo)
Xibut-1-ynyl) benzo [b] thiophen-6-
Yl] -2-methylbutan-1-ol (Exemplary Compound No. 1-566) (1a) Bromide (benzo [b] thiophen-6-yl)
Methyltriphenylphosphonium salt 6-bromomethylbenzo [b] thiophene 42.9 g
(189 mmol) and triphenylphosphine
5 g (189 mmol) was dissolved in 300 ml of benzene and stirred at 100 degrees for 16 hours. After filtering the reaction solution,
The desired compound 8 is obtained by drying the residue under reduced pressure.
7.0 g (94.2% yield) was obtained.

(1b) (2R) -t-butoxycarboni
Lumin-3-n-hexanoyloxy-2-methyl-
1-propanol 2-t-butoxycarbonylamino-2-methyl-1,
20.0 g (97.4 mmol) of 3-propanediol was suspended in 200 ml of diisopropyl ether, and 16.3 ml (0.10 mol) of n-hexanoic acid vinyl ester and lipase [Immobilized
lipase from Pseudomonas sp. (TOYOBO; 0.67U / mg)]
0.8 g was added, followed by vigorous stirring at room temperature for 2 hours. After filtering the reaction solution, the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 2: 1) to give 25.0 g (85%) of the title compound as a colorless oil.

The obtained (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol was analyzed using an optically active HPLC column for analysis (ChiralCel OF (Daicel), (0.46 cm × 25 cm), elution solvent: n-hexane: 2-
The optical purity was determined by propanol = 70: 30, flow rate; 0.5 ml / min).

The eluted first (8.2 minutes) was the 2S form and the later eluted (10.5 minutes) was the 2R form, and it was confirmed that the optical purity in this reaction was 85% ee.

[Α] ^D ₂₅ -8.5 (c 1.86, CHCl ₃ ) Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δppm: 4.86
(s, 1H), 4.25 (d, 1H, J = 11.2 Hz), 4.19 (d, 1H, J
= 11.2 Hz), 3.86 (brs, 1H), 3.70-3.55 (m, 2H), 2.3
6 (t, 2H, J = 7.4 Hz), 1.68-1.58 (m, 2H), 1.44 (s,
9H), 1.40-1.30 (m, 4H), 1.25 (s, 3H), 0.90 (t, 3
(H, J = 7.0 Hz) Infrared absorption spectrum νmax cm ^-1 (Liquid Film): 3415,
3380, 2961, 2935, 2874, 1721, 1505, 1458, 1392, 1
368, 1293, 1248, 1168, 1076 Mass spectrum (FAB) m / z: 304 ((M + H) ⁺ ).

(1c) (2R) -t-butoxycarboni
Lumin-3-n-hexanoyloxy-2-methyl-
1-propanal (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl- obtained in Example 1b.
30.7 g (0.10 mol) of 1-propanol was added to methylene chloride 600
The resulting solution was dissolved in ice-cold water, and 4Å220 g of molecular sieve and 43.6 g (0.20 mol) of pyridinium chloride chromate were added under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with ether and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 10: 1 to 5: 1),
This gave 28.8 g (95%) of the title compound as a colorless oil.

Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ )
δppm: 9.45 (s, 1H), 5.26 (brs, 1H), 4.44 (d, 1H,
J = 11.2 Hz), 4.32 (d, 1H, J = 11.2 Hz), 2.32 (t,
2H, J = 7.6 Hz), 1.70-1.55 (m, 2H), 1.45 (s, 9H),
1.38 (s, 3H), 1.40-1.25 (m, 4H), 0.90 (t, 3H, J =
7.0 Hz) Infrared absorption spectrum νmax cm ^-1 (Liquid Film): 3367,
2961, 2935, 2874, 1742, 1707, 1509, 1458, 1392, 1
369, 1290, 1274, 1254, 1166, 1100, 1078 Mass spectrum (FAB) m / z: 302 ((M + H) ⁺ ) (1d) (2R) -t-butoxycarbonylamino-1
-N-hexanoyloxy-2-methyl-4- (benzo
[B] thiophen-6-yl) -3-butene (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl- obtained in Example 1c.
28.2 g (93.6 mmol) of 1-propanal and bromide (benzo [b] thiophene-synthesized in Example 1a)
6-yl) methyltriphenylphosphonium salt 45.8
g (93.6 mmol) in tetrahydrofuran 700
10. Suspension in potassium tert-butoxide.
6 g (0.103 mol) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, water was added to the reaction solution, and extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated saline. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 10: 1) to obtain 28.0 g (yield 69.3%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.82
(d, 1H, J = 9.7 Hz), 7.75 (d, 1H, J = 8.2 Hz), 7.4
4-7.39 (m, 1H), 7.32-7.26 (m, 2H), 6.74, 5.73 (d,
1H, J = 12.6Hz), 6.61, 6.34 (d, 1H, J = 16.2H
z), 4.87, 4.69 (br s, 1H in total), 4.34-4.16, (m, 2H), 2.
37-2.32 (m, 2H), 1.67-1.15 (m, 20H), 0.91-0.84 (m,
3H). Infrared absorption spectrum ν _max cm ^-1 (Liquid Film): 3440,
3373, 2961, 2932, 2872, 1724, 1597, 1498, 1457, 1
390, 1367, 1247, 1167, 1099, 1073. Mass spectrum (FAB) m / z: 431 (M ⁺ ) (1e) (2R) -t-butoxycarbonylamino-1
-N-hexanoyloxy-2-methyl-4- (benzo
[B] thiophen-6-yl) butane (2R) -t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl- obtained in Example 1d
28.0 g (64.9 mmol) of 4- (benzo [b] thiophen-6-yl) -3-butene was added to methanol 7
Dissolved in 100 ml of 10% palladium-carbon 14.0
g, and the mixture was stirred at room temperature for 6 days under a hydrogen atmosphere. After palladium-carbon was filtered through celite, the filtrate was distilled off under reduced pressure.
The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 15: 1 to 10: 1) to obtain 24.30 g (yield: 86.6%) of the title compound. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.73
(d, 1H, J = 8.2 Hz), 7.69 (s, 1H), 7.36 (d, 1H, J
= 5.2 Hz), 7.28 (d, 1H, J = 5.6 Hz), 7.19 (d, 1H,
J = 8.1 Hz), 4.56 (br s, 1H), 4.28 (d, 1H, J = 11.
0 Hz), 4.14 (d, 1H, J = 11.0 Hz), 2.73 (t, 2H, J =
8.7 Hz), 2.34 (t, 2H, J = 7.5 Hz), 1.68-1.61 (m, 2
H), 1.45 (s, 9H), 1.41-1.38 (m, 8H), 0.89 (t, 3H,
J = 6.7Hz). Infrared absorption spectrum ν _max cm ^-1 (Liquid Film): 3371,
2960, 2933, 2870, 1720, 1604, 1501, 1466, 1392, 1
367, 1248, 1167, 1074. Mass spectrum (FAB) m / z: 456 ((M + Na) ⁺ ) (1f) (4R)-[2- (benzo [b] thiophene-
6-yl) ethyl] -4-methyloxazolidine-2-
On (2R) -t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl- obtained in Example 1e.
4- (benzo [b] thiophen-6-yl) butane 2
4.3 g (56.0 mmol) in tetrahydrofuran
After dissolving in 220 ml and methanol 110 ml, 1N aqueous sodium hydroxide solution 110 ml was added thereto under ice cooling, and the mixture was stirred under ice cooling for 15 minutes and at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated saline. After the methylene chloride layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 18.8 g (yield 100%) of the desired alcohol. 18.8 g (56.0 mmol) of this alcohol compound was dissolved in 380 ml of dimethylformamide, and 9.43 g (84.1 mmol) of potassium t-butoxide was added under ice-cooling. Stirred for hours. Water was added to the reaction solution, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (elution solvent: hexane /
Purification by ethyl acetate (3: 2 to 2: 1) gave 13.8 g (yield 94.2%) of the title compound. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.73
(d, 1H, J = 8.2 Hz), 7.68 (s, 1H), 7.38 (d, 1H, J
= 5.7 Hz), 7.29 (d, 1H, J = 13.0 Hz), 7.18 (d, 1H,
J = 13.6 Hz), 5.91 (br s, 1H), 4.21 (d, 1H, J = 8.
7 Hz), 4.09 (d, 1H, J = 8.7 Hz), 2.84-2.76 (m, 2H),
1.97 (t, J = 8.5 Hz, 3H). Infrared absorption spectrum ν _max cm ^-1 (KBr): 3292, 2970, 2
930, 1749, 1722, 1601,1479, 1461, 1397, 1277, 104
5. Mass spectrum (EI) m / z: 261 (M ⁺ ) (1 g) (4R)-[2- (3-bromobenzo [b] thi)
Offen-6-yl) ethyl] -4-methyloxazoly
Gin-2-one (4R)-[2- (benzo [b] obtained in Example 1f.
Thiophen-6-yl) ethyl] -4-methyloxazolidine-2-one (12.8 g, 49.0 mmol) was dissolved in dimethylformamide (250 ml), and N-bromosuccinimide (10.5 g, 58.8 mmol) was ice-cooled. The mixture was stirred under ice cooling for 10 minutes and at room temperature for 4.5 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 3: 2-1: 1) to obtain 12.2 g (yield: 62.2%) of the title compound. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.73
(d, 1H, J = 8.3 Hz), 7.64 (s, 1H), 7.37 (s, 1H),
7.28 (d, 1H, J = 1.3 Hz), 6.12 (br s, 1H), 4.21,
(d, J = 8.6 Hz), 4.10 (d, 1H, J = 8.6 Hz), 2.88-2.
75, (m, 2H), 1.96 (t, 2H, J = 8.4 Hz), 1.66 (s, 3
H). Infrared absorption spectrum ν _max cm ^-1 (KBr): 3269, 3109, 2
972, 2916, 1749, 1602,1555, 1481, 1462, 1401, 131
9, 1272, 1220, 1165, 1043, 937, 817, 758. Mass spectrum (FAB) m / z: 340 ((M + H) ⁺ ) (1h) (4R)-[2- (3- (4-cyclohexyl)
Oxybut-1-ynyl) benzo [b] thiophene-6
-Yl) ethyl] -4-methyloxazolidine-2-o
Emissions obtained in Example 1 g (4R) - [2- (3-bromobenzo [b] thiophen-6-yl) ethyl] -4-methyl-oxazolidine-2-one 1.00 g (2.95 mmol) dimethyl Dissolved in 8.0 ml of formamide,
1.12 g of 4-cyclohexyloxy-1-butyne
(7.37 mmol), 4.11 ml of triethylamine
(29.5 mmol), copper (I) iodide 112 mg
(0.059 mmol) dichlorobis (triphenylphosphine) palladium 414 mg (0.59 mmol)
Was added and stirred at 80 ° C. for 16 hours under a nitrogen atmosphere. After evaporating the reaction solution under reduced pressure, the residue was subjected to reverse phase HPLC [TSKgel ODS
-80 Ts (2.0 mm ID × 25 cm), elution solvent: acetonitrile / water = 7: 3] to obtain 0.55 g (yield: 45.3%) of the title compound.

(1i) (2R) -amino-4- [3-
(4-cyclohexyloxybut-1-ynyl) benzo
[B] thiophen-6-yl] -2-methylbutane-1
- (4R)-[2- (3- (4-Cyclohexyloxybut-1-ynyl) benzo [b] thiophen-6-yl) ethyl] -4-methyloxazolidine-2- obtained in Example 1h. ON is tetrahydrofuran / methanol = 2
The mixture was dissolved in 12 ml of a 1: 1 mixed solvent, 4 ml of a 10 N aqueous potassium hydroxide solution was added, and the mixture was stirred at 100 ° C. for 16 hours. Thereafter, the reaction solution was added to a 1N aqueous sodium hydroxide solution, extracted with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel chromatography (elution solvent: methylene chloride / methanol / aqueous ammonia solution = 100: 10:
1) to give 548 mg of the title compound (yield 10
0%). Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.83
(d, 1H, J = 9.0 Hz), 7.75 (s, 1H), 7.57 (s, 1H),
7.33 (d, 1H, J = 9.0 Hz), 3.72 (t, 2H, J = 6.8 H
z), 3.61, (d, 1H, J = 11.6 Hz), 3.56 (d, 1H, J = 1
1.6 Hz), 3.45-3.38 (m, 1H), 3.31 (s, 1H), 2.88-2.77
(m, 2H), 2.73 (t, 1H, J = 6.7 Hz), 2.07-1.90 (m,
4H), 1.77-1.74 (m, 2H), 1.57-1.52 (m, 1H), 1.40-1.
21 (m, 10H) mass spectrum (FAB) m / z: 386 (M + H ⁺ ) Example 2 (2R) -amino-4- [3- (3-cyclohexylme)
Tyloxypropyn-1-ynyl) benzo [b] thiof
[ En -6-yl] -2-methylbutan-1-ol (Exemplified Compound No. 1-630) 1.12 g of 4-cyclohexyloxy-1-butyne
In the same manner as in Example 1 except that 0.88 g of 3-cyclohexylmethyloxy-1-propyne was used instead of (7.37 mmol), 311 mg of the title compound was obtained. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.8
3 (d. 1H, J = 8.7 Hz), 7.78 (s, 1H), 7.72 (s, 1H),
7.36 (d, 1H, J = 8.7 Hz), 4.43 (s, 2H), 3.67, (d,
1H, J = 11.5 Hz), 3.56 (d, 1H, J = 11.5 Hz), 3.31
(s, 1H), 2.86-2.78 (m, 2H), 2.08-1.90 (m, 2H), 1.
83-1.60 (m, 7H), 1.37 (s, 1H), 1.40-1.18 (m, 5H), 1.0
6-0.97 (m, 2H) Mass spectrum (FAB) m / z: 386 (MH ^<+> ).

Example 3 (2R) -Amino -4- [3- (5-cyclohexyl-
1-pentynyl) benzo [b] thiophen-6-yl]
-2-methylbutan-1-ol (Exemplary Compound No. 1-42
2) 4-Cyclohexyloxy-1-butyne 1.12 g
(7.37 mmol) instead of 5-cyclohexyl-
In the same manner as in Example 1 using 1.30 g of 1-pentyne, 381 mg of the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.79
(d. 1H, J = 9.1 Hz), 7.75 (s, 1H), 7.55 (s, 1H),
7.32 (d, 1H, J = 9.1 Hz), 6.27 (s, 2H), 3.66, (d,
1H, J = 11.5 Hz), 3.56 (d, 1H, J = 11.5 Hz), 2.86-
2.78 (m, 2H), 2.48 (m, 2H), 2.08-1.90 (m, 2H), 1.8
6-1.60 (m, 8H), 1.45-1.14 (m, 8H), 1.00-0.91 (m, 2
H) Mass spectrum (FAB) m / z: 384 (M + H ⁺ ).

Example 4 (2R) -amino-4- [3- (3-p-tolyloxy-
1-propynyl) benzo [b] thiophen-6-yl]
-2-methylbutan-1-ol (Exemplary Compound No. 1-55
5) 1.12 g of 4-cyclohexyloxy-1-butyne
(7.37 mmol) instead of 3-p-tolyloxy-
In the same manner as in Example 1 using 1.30 mg of 1-propyne, 185 mg of the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 7.76
(s, 1H), 7.71 (s, 1H), 7.70 (d, 1H, J = 7.9 Hz),
7.30 (d, 1H, J = 7.9 Hz), 7.12 (d, 2H, J = 8.5 H
z), 6.97 (d, 1H, J = 8.5 Hz), 5.00 (s, 2H), 3.66,
(d, 1H, J = 11.6 Hz), 3.56 (d, 1H, J = 11.6 Hz),
3.31 (S, 2H), 2.87-2.75 (m, 2H), 2.29 (s, 3H), 2.07
-1.89 (m, 2H) 1.36 (s, 3H), 1.41-1.17 (m, 3H) Mass spectrum (FAB) m / z: 380 (M + H ⁺ ).

Example 5 (2R) -Amino -4- [3- (4-cyclohexylio)
Xybutan-1-yl) benzo [b] thiophen-6-
Il] -2-methylbutan-1-ol (Exemplary Compound No. 1-247) (2R) -amino-4- [3- (4) obtained in Example 1
-Cyclohexyloxybut-1-ynyl) benzo [b] thiophen-6-yl] -2-methylbutane-1
-250 mg (6.48 mmol) of all are dissolved in 10 ml of methanol, and 10% palladium-carbon 250
mg, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. After palladium-carbon was filtered through celite, the filtrate was distilled off under reduced pressure. The residue is subjected to silica gel chromatography (elution solvent:
Methylene chloride / methanol / ammonia aqueous solution = 10
0: 10: 1) to give 236 m of the title compound.
g (93.3% yield). Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 7.73
(d. 1H, J = 8.7 Hz), 7.71 (s, 1H), 7.26 (d, 1H, J
= 8.7 Hz), 7.16 (s, 1H), 4.88 (s, 2H), 3.66, (d, 1
H, J = 11.6 Hz), 3.57-3.49 (m, 3H, 3.31-3.39 (m,
1H), 3.30-3.20 (m, 1H), 2.88-2.74 (m, 4H), 2.07-1.52
(m, 2H), 1.37 (s, 3H), 1.36-1.19 (m, 4H) Mass spectrum (FAB) m / z: 390 (M + H ⁺ ).

Test Example 1Inhibition against rat HvGR (Host versus Graft Reaction)
Measurement of activity (1) Two strains of rats [Lewis (male, 6 weeks old, Japanese char
Russ River Co., Ltd.) and WKAH / Hkm (male, 7 weeks old Japan
SLC Corporation)]. 5 rats per group
(Host) was used. (2) Induction of HvGR Spleen cells from spleen of WKAH / Hkm rat or Lewis rat
Was isolated and RPMI1640 medium (LIFE TECHNOLOGIES, Rockvill
e MD U.S.A.)⁸The cells were suspended at a concentration of cells / ml. Lewis Lat
WKAH / Hkm rat or Le
Wis rat spleen cell suspension (100 μl each)
1x10⁷) Was injected. (3) Administration of Compound The compound was suspended in 0.5% tragacanth solution. Suspended compound
In the compound administration group (WKAH / Hkm rat spleen cells were injected)
5 ml / kg of Lewis rats)
Once a day for 4 consecutive days from the day of spleen cell injection
Was orally administered. The syngeneic group (Lewis rat spleen cells)
Group injected with Lewis rats) and control group (WKAH / Hkm
Lewis rat injected with spleen cells
G), a 0.5% tragacanth solution is orally administered instead of the sample.
Gave. (4) Method of measuring inhibitory activity against HvGR Average popli of syngeneic group from popliteal lymph node weight of each individual
subtract teal lymph node weight ("popliteal phosphorus by HvGR"
Pavement weight ”), average of control group“ popliteal
HvGR of each individual in the compound administration group with respect to
The inhibition rate was calculated from the "popliteal lymph node weight due to".
The inhibitory activity of the compound is minimal due to the dose of the compound and the inhibition rate.
It was indicated by the ID50 value (mg / kg) calculated using the square method.

As a result of this test, the compound of the present invention was found to be FTY-
720 [WO94 / 08943 (EP62740)
Compound of Example 29 of 6)].

[0331]

The compound of the present invention having the general formula (I) has low toxicity and excellent immunosuppressive activity.
Useful as an immunosuppressant.

Continuing from the front page (72) Inventor Ryuichi Shimozato 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Futa Nara 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term in the formula company (reference) 4C086 AA03 BB03 ZB08

Claims (34)

[Claims] 1. A compound of the general formula (I) [Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or an amino-protecting group, R ³ represents a hydrogen atom or a hydroxy-protecting group, and R ⁴ represents a lower alkyl group. And n represents an integer of 1 to 6; X represents an ethylene group, a vinylene group, an ethynylene group, a formula -D
A group having —CH ₂ — (wherein D represents a carbonyl group, a group having the formula —CH (OH) —, an oxygen atom, a sulfur atom or a nitrogen atom), an aryl group or a substituent group a. And Y represents a single bond, a C ₁ -C ₁₀ alkylene group, or a group substituted with at least one group selected from substituent groups a and b. C
₁ -C ₁₀ alkylene group, C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or the chain ends,
Or substituted with at least one group selected from substituent group a and b, shows a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or the chain ends, R ⁵ is hydrogen At least one selected from an atom, a cycloalkyl group, an aryl group, a heterocyclic group, and substituent groups a and b
Cycloalkyl groups substituted with at least one group, aryl groups substituted with at least one group selected from substituent groups a and b, or at least one group selected from substituent groups a and b A heterocyclic group substituted with R ⁶ and R ^6
7 is the same or different and represents a hydrogen atom or a group selected from substituent group a. Provided that when R ⁵ is a hydrogen atom, Y represents a group other than C ₁ -C ₁₀ alkylene group a single bond and linear. ], A pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. <Substituent group a> halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, carboxyl group, lower alkoxycarbonyl group,
Hydroxy group, lower aliphatic acyl group, amino group, mono-
Lower alkylamino group, di-lower alkylamino group, lower aliphatic acylamino group, cyano group and nitro group <Substituent group b> selected from cycloalkyl group, aryl group, heterocyclic group and substituent group a A cycloalkyl group substituted with at least one group, an aryl group substituted with at least one group selected from substituent group a, and at least one group selected from substituent group a A substituted heterocyclic group. 2. The method according to claim 1, wherein the compound of formula (Ia) Or a pharmacologically acceptable salt thereof, an ester or other derivative thereof. 3. The method of claim 1, wherein the compound of formula (Ib) Or a pharmacologically acceptable salt thereof, an ester or other derivative thereof. 4. One of the first to third aspects
In the above item, R ¹ and R ² are the same or different and each are a hydrogen atom, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or an aralkyloxycarbonyl group substituted by 1 to 3 groups selected from a substituent group a. A compound or a pharmacologically acceptable salt thereof. 5. One of the first to third aspects
In the above item, the compound or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are a hydrogen atom. 6. One of the first to fifth aspects
In the above item, R ³ is a hydrogen atom, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted by 1 to 3 groups selected from substituent group a, or a pharmaceutically acceptable compound thereof. Salt. 7. One of the first to fifth aspects selected from the above.
In the above item, the compound wherein R ³ is a hydrogen atom, or a pharmacologically acceptable salt thereof. 8. One of the first to seventh aspects selected from the above.
In the above item, the compound or a pharmacologically acceptable salt thereof, wherein R ⁴ is a C ₁ -C ₄ alkyl group. 9. Any one selected from claims 1 to 7
In the above item, the compound or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C ₁ -C ₂ alkyl group. 10. The compound according to any one of claims 1 to 7, wherein R ⁴ is a methyl group, or a pharmaceutically acceptable salt thereof. 11. The compound according to any one of claims 1 to 10, wherein n is 2 or 3, or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 1, wherein n is 2, or a pharmacologically acceptable salt thereof. 13. The compound according to any one of claims 1 to 12, wherein X is an ethylene group, or a pharmaceutically acceptable salt thereof. 14. The compound according to any one of claims 1 to 12, wherein X is an ethynylene group, or a pharmacologically acceptable salt thereof. 15. The compound according to any one of claims 1 to 12, wherein X is an aryl group or an aryl group substituted with at least one group selected from substituent group a. Or a pharmacologically acceptable salt thereof. 16. The method according to claim 1, wherein Y is substituted with a C ₁ -C ₁₀ alkylene group or at least one group selected from substituent groups a and b. C ₁ -C
_A compound having ₁₀ alkylene groups or a pharmacologically acceptable salt thereof. 17. The method according to claim 1, wherein Y is substituted with a C ₁ -C ₆ alkylene group or at least one group selected from substituent groups a and b. A compound which is a C ₁ -C ₆ alkylene group or a pharmacologically acceptable salt thereof. 18. The method according to claim 1, wherein Y is an ethylene group, a trimethylene group, a tetramethylene group, or at least one group selected from substituent groups a and b. Or a pharmacologically acceptable salt thereof, which is an ethylene, trimethylene, tetramethylene or pentamethylene group substituted with 19. The compound according to any one of claims 1 to 15, wherein Y is an ethylene group, a trimethylene group or a tetramethylene group, or a pharmaceutically acceptable salt thereof. 20. The compound according to claim 1, wherein Y is an ethylene group or a trimethylene group, or a pharmaceutically acceptable salt thereof. 21. The method according to claim 1, wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in a carbon chain or at a chain end, or a substituent group a And substituted with at least one group selected from b.
A compound which is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in a carbon chain or at a chain end, or a pharmacologically acceptable salt thereof. 22. The compound according to any one of claims 1 to 15, wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in a carbon chain or at a chain end, or a pharmacological compound thereof. Above acceptable salts. 23. The method according to any one of claims 1 to 15, wherein Y is C _1- having an oxygen atom in a carbon chain or at a chain end.
A compound which is a C ₁₀ alkylene group or a pharmacologically acceptable salt thereof. 24. The method according to claim 1, wherein Y is C ₁ -C having an oxygen atom in a carbon chain or at a chain end.
A compound which is a C ₆ alkylene group or a pharmacologically acceptable salt thereof. 25. The method according to any one of claims 1 to 15, wherein Y is —O—CH ₂ —, —O— (CH ₂ ) ₂ —, —O—
(CH ₂ ) ₃ —, —CH ₂ —O—, — (CH ₂ ) ₂ —O—,
A compound which is a group having — (CH ₂ ) ₃ —O— or —CH ₂ —O—CH ₂ —, or a pharmaceutically acceptable salt thereof. 26. The method according to claim 1, wherein Y is —CH ₂ —O—, — (CH ₂ ) ₂ —O— or —CH ₂
A compound which is a group having —O—CH ₂ — or a pharmacologically acceptable salt thereof. 27. The method according to claim 1, wherein R ⁵ is at least one selected from a cycloalkyl group, an aryl group, a heterocyclic group, and substituent groups a and b. Or a pharmacologically acceptable salt thereof, which is a cycloalkyl group substituted with a group or an aryl group substituted with at least one group selected from substituent groups a and b. 28. The method according to claim 1, wherein R ⁵ is substituted with at least one group selected from a cycloalkyl group, an aryl group, and substituent groups a and b. Or a pharmacologically acceptable salt thereof, which is a cycloalkyl group or an aryl group substituted with at least one group selected from substituent groups a and b. 29. The method according to claim 1, wherein R ⁵ is substituted by at least one group selected from the group consisting of a cycloalkyl group, an aryl group and substituent groups a and b. Or a pharmacologically acceptable salt thereof. 30. The method according to any one of claims 1 to 26, wherein R ⁵ is a cycloalkyl group, an aryl group, or an aryl group having 1 to 3 substituents, wherein the substituent is A halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower alkylthio group) or a pharmaceutically acceptable salt thereof. 31. The method according to any one of claims 1 to 26, wherein R ⁵ is a cycloalkyl group, an aryl group, or an aryl group having 1 to 3 substituents, wherein the substituent is A halogen atom, a lower alkyl group or a lower alkoxy group), or a pharmaceutically acceptable salt thereof. 32. The compound according to any one of claims 1 to 26, wherein R ⁵ is a cyclohexyl group, a phenyl group or a p-tolyl group, or a pharmaceutically acceptable salt thereof. 33. The method according to any one of claims 1 to 32, wherein R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group. Or a compound having a lower alkylthio group or a pharmacologically acceptable salt thereof. 34. The compound according to any one of claims 1 to 32, wherein R ⁶ and R ⁷ are a hydrogen atom, or a pharmaceutically acceptable salt thereof.