JP2002356484A - Thiophene derivative and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new thiophene derivative useful as a prophylactic, a therapeutic agents, etc., for arthropathy represented by chondropathy. SOLUTION: This compound is represented by the general formula (I) [wherein, R<1> is a hydrocarbon residue, a heterocyclic group, hydroxy group, an acyl group or amino group which may respectively be substituted; R<2> is cyano group, formyl group, thioformyl group, a heterocyclic group which may be substituted or a group represented by the formula Z<1> -Z<2> (wherein, Z<1> is CO, CS, SO or SO2 ; Z<2> is a hydrocarbon residue, a heterocyclic group, hydroxy group or amino group which may respectively be substituted); R<3> is hydrogen atom, a halogen atom, cyano group or amino group, an acyl group, a hydrocarbon residue or a heterocyclic group which may respectively be substituted; and ring-A is a 5- or a 7-membered ring which may be substituted] or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a thiophene derivative and a use thereof, and more particularly, to a thiophene derivative or a salt thereof having an activity of inducing differentiation of undifferentiated cells such as osteoblasts and chondrocytes, and a use thereof. .

[0002]

2. Description of the Related Art Bone diseases include non-metabolic bone diseases such as bone fractures, bone deformity / osteomyelosis, osteosarcoma, myeloma, osteogenesis imperfecta, scoliosis, and osteoporosis, osteomalacia, rickets, fibrosis. There are metabolic bone diseases such as osteomyelitis, renal osteodystrophy and osteochet's disease, but metabolic bone diseases have recently become a problem. For example, osteoporosis, a metabolic bone disease, is a systemic disease characterized by low bone mass and increased bone fragility and osteofractures caused by changes in the microstructure of bone tissue, and its main clinical Symptoms are kyphosis, lumbar spine and fractures of the vertebral body, femoral neck, lower radius, ribs, upper humerus, and the like.
In bone tissue, bone formation and bone destruction due to bone resorption are always repeated while maintaining a balance, and osteoblasts including progenitor osteoblasts play a central role in bone formation, and osteoclasts play a central role in bone resorption. When the balance between bone formation and bone destruction due to bone resorption is lost, the amount of bone is reduced. Heretofore, bone resorption inhibiting substances such as estrogen, calcitonin, bisphosphonate and the like have been mainly used as prophylactic / therapeutic agents for osteoporosis.

[0003] A joint disease is a disease in which degeneration of articular cartilage is the main lesion (for example, rheumatoid arthritis or osteoarthritis). Cartilage is a tissue composed of collagen and proteoglycans.
Proteoglycan release from the cartilage tissue is promoted, and the ability of the tissue to synthesize proteoglycan begins to decrease. At the same time, the release and activation of matrix metalloproteases such as collagenase-3 are enhanced, and collagen of cartilage tissue is degraded. A series of these reactions promotes hardening and destruction of cartilage tissue, and then progression of the lesion causes synovial hyperplasia, destruction of subchondral bone, cartilage hypertrophy or osteogenesis at the margins of the joint, and deformation of the joint. In severe cases, it can lead to dysfunction. Joint disease is most common in knee joints, but also in elbows, hips, feet, and finger joints. Among the joint diseases, osteoarthritis is the disease with the largest number of patients, but aging is considered as one of the causes of this disease. You. As a treatment method, an analgesic antiphlogistic or a hyaluronic acid preparation has been used for the purpose of removing pain associated with cartilage degeneration / subchondral bone sclerosis and destruction. However, all of them are only used as symptomatic treatments and have not been sufficiently effective. Promoting chondrogenesis, suppressing cartilage destruction, and promoting differentiation induction of chondrocytes including precursor chondrocytes are considered to be effective for prevention and treatment of cartilage diseases.

As thiophene derivatives, JP-A-12-16
No. 9470-2 describes a thiophene derivative which enhances the action of a cell differentiation inducing factor. However, these thiophene derivatives have a substituent containing a sulfur atom, and are easily oxidized in a living body, and there is a concern that the activity may be reduced.

[0005]

In the clinical practice of bone or joint diseases (eg, cartilage disease), drugs that are excellent in prevention and treatment of bone or joint diseases are still desired. In particular, drugs that are excellent in prevention and treatment of joint diseases represented by cartilage diseases are desired.

[0006]

The present inventors have SUMMARY OF THE INVENTION may, made various studies in view of the above situation, new thiophene derivative or a salt thereof of the formula shown below having features in R ¹ (I) Have a strong differentiation-inducing activity of undifferentiated cells such as precursor osteoblasts and precursor chondrocytes, and are found to be useful as preventive and therapeutic agents for bone or joint diseases.
As a result of further research based on this, the present invention was completed.

That is, the present invention provides: 1) a general formula (I):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group, an optionally substituted Good heterocyclic group or formula: -Z ¹ -Z
² (wherein, Z ¹ represents —CO—, —CS—, —SO—, or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, R ³ represents a hydrogen atom, a halogen atom, a cyano group or an amino group which may be substituted,
An acyl group, a hydrocarbon residue or a heterocyclic group;
Represents an optionally substituted 5- to 7-membered ring. 2) The compound according to 1) above, wherein ring A is an optionally substituted aromatic 5-membered ring; 3) The above-mentioned, wherein ring A is an azole optionally substituted 1) the compound according to 1), 4) ring A is

Embedded image [Wherein, R ⁴ , R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom or an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group or an amino group. . 5) The compound according to 1) above, wherein ring A is

Embedded image [Wherein, R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group or an amino group; Represents a group. 6) R ² is a cyano group or a compound of the formula: —Z ¹ -Z ^2
1 represents -CO-, and Z ² represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group, each of which may be substituted. 7) The compound according to 1) above, wherein ring A is

Embedded image [Wherein R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group; A group or an amino group. And R ² is a cyano group, or a formula: -Z ¹
-Z ² (wherein, ^{Z 1} represents a -CO-, ^{Z 2} is substituted optionally substituted hydrocarbon residue which may each heterocyclic group, a hydroxyl group or an amino group.) The 1 is) 8) The compound of the above 1), wherein R ¹ is an optionally substituted hydrocarbon residue; 9) The compound of the above 1), wherein R ¹ is an optionally substituted heterocyclic group. 10) The compound of the above 1), wherein R ¹ is an optionally substituted hydroxyl group; 11) the compound of the above 1), wherein R ¹ is an optionally substituted amino group; 12) Ring A is

Embedded image [Wherein R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group; A group or an amino group. Wherein R ¹ is a hydroxyl group which may be substituted; and 13) ring A is

Embedded image [Wherein, R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group or an amino group; Represents a group. ]
And 1) wherein R ¹ is an optionally substituted hydroxyl group
14) The compound according to the above 1), wherein R ³ is a hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, respectively. 15) The prodrug of the compound according to the above 1) or a salt thereof. , 16) Formula:

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group, an optionally substituted Good heterocyclic group or formula: -Z ¹ -Z
² (wherein, Z ¹ represents —CO—, —CS—, —SO—, or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, R ³ represents a hydrogen atom, a halogen atom, a cyano group or an amino group which may be substituted,
An acyl group, a hydrocarbon residue or heterocyclic group, R ⁶
Is a hydrogen atom, a halogen atom, a cyano group or an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group,
It represents an acyl group, a sulfonyl group or an amino group. A) reacting with a trialkyl orthoformate and a boron trifluoride-diethyl ether complex in the presence of a base,
formula:

Embedded image [In the formula, R ¹⁰ represents a hydrogen atom or a hydrocarbon residue which may be substituted, and other symbols have the same meanings as described above. Or a salt thereof, or b) reacting with N, N-dimethylalumamidodialkylacetal or trisdialkylaminomethane,
formula:

Embedded image [Wherein, R ¹¹ represents a hydrogen atom or a hydrocarbon residue which may be substituted, and other symbols have the same meanings as described above. A compound represented by the formula: H ₂ N—Q′H wherein Q ′ represents an oxygen atom or NA ¹ , and A ¹ represents A hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, respectively. A hydrazine derivative or a hydroxylamine derivative represented by the formula:

Embedded image Wherein each symbol is as defined above. 17) a method for producing a compound represented by the general formula (I):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group, an optionally substituted Good heterocyclic group or formula: -Z ¹ -Z
² (wherein, Z ¹ represents —CO—, —CS—, —SO—, or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, R ³ represents a hydrogen atom, a halogen atom, a cyano group or an amino group which may be substituted,
An acyl group, a hydrocarbon residue or a heterocyclic group;
Represents an optionally substituted 5- to 7-membered ring. Or a pharmaceutically acceptable salt thereof or a prodrug thereof; 18) The above-mentioned 17) which is a preventive or therapeutic agent for bone or joint disease.
19) The pharmaceutical composition according to the above 17), wherein the bone or joint disease is osteoporosis, fracture, osteoarthritis or rheumatoid arthritis; 20) the pharmaceutical composition according to the above 17), which is an agent for inducing cell differentiation. 21) a method for preventing or treating bone or joint disease, which comprises administering an effective amount of the compound according to claim 1 or a prodrug thereof to a mammal; and 22) an agent for preventing or treating bone or joint disease. And a prodrug thereof according to 1) above.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group or an amino group. Examples of the hydrocarbon residue in the optionally substituted hydrocarbon residue in R ¹ include an optionally substituted aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, and an alicyclic- Examples thereof include an aliphatic hydrocarbon residue, an aromatic hydrocarbon residue, and an aromatic-aliphatic hydrocarbon residue (aralkyl group).

The aliphatic hydrocarbon residue includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, A saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms such as octyl (eg, an alkyl group), for example, vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-
Butenyl, 3-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4
-Pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-
Heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
-Butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadynyl, 1-heptynyl, 1 −
An unsaturated aliphatic hydrocarbon residue having 2 to 8 carbon atoms such as octynyl (eg, an alkenyl group, an alkynyl group, an alkadienyl group, an alkadiynyl group) is exemplified.

The alicyclic hydrocarbon residue is, for example, a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl (eg, cycloalkyl group). , 1-
Cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,
2-cycloheptenyl, 3-cycloheptenyl, 2,4
-An unsaturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cycloheptadienyl (e.g., cycloalkenyl group, cycloalkadienyl group, etc.), 1-indenyl, 2-indenyl, 1-indanyl, -Indanyl, 1,2,3,4-
Tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,
4-dihydro-1-naphthyl, 3,4-dihydro-2-
Partially saturated condensed bicyclic hydrocarbon residue such as naphthyl [preferably C _9-10 partially saturated condensed bicyclic hydrocarbon residue or the like (a benzene ring is bonded to a 5- to 6-membered non-aromatic cyclic hydrocarbon group) And the like))].

The alicyclic-aliphatic hydrocarbon residue includes:
Those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3
-Cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3
-Cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2-
(3,4-dihydro-2-naphthyl) ethyl, 2- (1,
2,3,4-tetrahydro-2-naphthyl) ethyl, 2-
Those having 4 to 14 carbon atoms such as (3,4-dihydro-2-naphthyl) ethenyl (eg, C _3-7 cycloalkyl-C _1-4)
Alkyl group, C _3-7 cycloalkenyl-C _1-4 alkyl group, C _3-7 cycloalkyl-C _2-4 alkenyl group, C _3-7
Cycloalkenyl-C _2-4 alkenyl group, C _9-10 partially saturated condensed bicyclic hydrocarbon-C _1-4 alkyl group, C _9-10 partially saturated condensed bicyclic hydrocarbon-C _2-4 alkenyl group, etc. ).

Examples of the aromatic hydrocarbon residue include phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro- 1-naphthyl, 5,
6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4- And aryl groups having 6 to 10 carbon atoms (including those in which a 5- to 6-membered non-aromatic hydrocarbon ring is fused to a phenyl group) such as naphthyl.

The aromatic-aliphatic hydrocarbon residue includes:
For example, benzyl, phenethyl, 1-phenylethyl, 1
-Phenylpropyl, 2-phenylpropyl, 3-phenyl
Phenyl-C such as nilpropyl_1-4Alkyl group, for example
Α-naphthylmethyl, α-naphthylethyl, β-naphthyl
Naphthyl-C such as tylmethyl and β-naphthylethyl
_1-4C 7-14 aralkyl groups such as alkyl groups
(C_6-10Aryl-C_1-4Alkyl group), for example, still
Phenyl-C such as cinnamyl_2-4Alkenyl group
Which C_6-10Aryl-C_2-4Alkenyl groups, etc.
It is.

The heterocyclic group of the optionally substituted heterocyclic group for R ¹ includes, for example, (i) one sulfur atom,
A 5- to 7-membered heterocyclic group containing one nitrogen atom or one oxygen atom, (ii) a 5- to 7-membered heterocyclic group containing 2 to 4 nitrogen atoms, or (iii) 1 to 2 A 5- to 7-membered heterocyclic group containing a nitrogen atom and one sulfur or oxygen atom, and (iv) a 5- to 7-membered ring containing 2 or less nitrogen atoms, a benzene ring Alternatively, it may be condensed with a 5-membered ring containing one sulfur atom. The heterocyclic groups exemplified in (i) to (iv) may each be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be any of aromatic and non-aromatic. Is also good.

Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ include an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group and a non-aromatic heterocyclic group. Specific examples of the heterocyclic group in the optionally substituted heterocyclic group for R ¹ include (i) an aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.), (ii) aromatic Group fused heterocyclic groups (eg, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl Thiantrenyl, phenanthrinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl,
Pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4- Triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,
3-b] pyridazinyl) and (iii) a non-aromatic heterocyclic group (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
Thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like).

R¹Optionally substituted hydroxyl
As the group, a hydroxyl group and a suitable substituent for this hydroxyl group,
For example, R¹"They may be substituted
Hydroxyl group substituted with a `` hydrocarbon residue or heterocyclic group ''
No. Preferably, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopen
Chill, tert-pentyl, hexyl, isohexyl,
C such as heptyl and octyl _1-8Substituted with alkyl
C_1-8Alkyloxy; phenyl, α-naphthy
, Β-naphthyl, 4-indenyl, 5-indenyl,
4-indanyl, 5-indanyl, 5,6,7,8-tetra
Lahydro-1-naphthyl, 5,6,7,8-tetrahydro
-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,
6-dihydro-2-naphthyl, 5,6-dihydro-3-
C such as naphthyl, 5,6-dihydro-4-naphthyl
_6-10C substituted with an aryl group_6-10Arlio
Xy; aromatic monocyclic heterocyclic group (eg, furyl, thienyl
, Pyrrolyl, oxazolyl, isoxazolyl, thia
Zolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazo
Ryl, 1,3,4-oxadiazolyl, furanil, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, pi
Limidinyl, pyridazinyl, pyrazinyl, triazinyl
A) substituted aromatic group; fused aromatic heterocyclic group
(Eg, benzofuranyl, isobenzofuranyl, benzo
[b] thienyl, indolyl, isoindolyl, 1H-a
Ndazolyl, benzimidazolyl, benzoxazoly
1,2-benzoisothiazolyl, 1H-benzotri
Azolyl, quinolyl, isoquinolyl, cinnolinyl,
Nazolinyl, quinoxalinyl, phthalazinyl, naphthyl
Dinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenanthrinil, phenanthrolinyl, indolizy
Nil, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5]
-A] pyridyl, imidazo [1,2-a] pyridyl, imidazo
[1,5-a] pyridyl, imidazo [1,2-b] pyridazini
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyrida
And a hydroxyl group substituted with dilinyl or the like. More preferred
Or C_6-10Aryloxy (particularly preferably
Enyloxy) or an aromatic monocyclic heterocyclic group (particularly preferred).
Preferably pyridyl) or an aromatic fused heterocyclic group (especially
Preferably a hydroxyl group substituted with quinolyl).
You. As a substituent of the substituted hydroxyl group exemplified here
The “hydrocarbon residue” or “heterocyclic group” is a group represented by R¹
As the "optionally substituted hydrocarbon residue"
Or heterocyclic group ''
May have the same substituents as the “ring group”.
R¹In the optionally substituted acyl group
As the acyl group, the aforementioned R¹As each
An optionally substituted hydrocarbon residue or heterocyclic group ''
"Hydrocarbon residue" or "Heterocyclic group" and carbonyl
And those bonded to a group. Preferably, meth
, Ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, tert-pentyl, f
C such as xyl, isohexyl, heptyl, octyl, etc.
_1-8C with alkyl and carbonyl groups bonded_1-8Al
Kill carbonyl; phenyl, α-naphthyl, β-naph
Chill, 4-indenyl, 5-indenyl, 4-indani
5-Indanyl, 5,6,7,8-tetrahydro-1
-Naphthyl, 5,6,7,8-tetrahydro-2-naphthy
5,6-dihydro-1-naphthyl, 5,6-dihydro
-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,
C such as 6-dihydro-4-naphthyl_6-10Aryl
Group in which a carbonyl group and a carbonyl group are bonded_{6-1 0}Aryl carb
Nyl; an aromatic monocyclic heterocyclic group (eg, furyl, thienyl)
, Pyrrolyl, oxazolyl, isoxazolyl, thia
Zolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazo
Ryl, 1,3,4-oxadiazolyl, furanil, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, pi
Limidinyl, pyridazinyl, pyrazinyl, triazinyl
Group) and a carbonyl group; aromatic condensed hetero
Ring groups (eg, benzofuranyl, isobenzofuranyl,
Zo [b] thienyl, indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazoly
1,2-benzoisothiazolyl, 1H-benzotri
Azolyl, quinolyl, isoquinolyl, cinnolinyl,
Nazolinyl, quinoxalinyl, phthalazinyl, naphthyl
Dinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenanthrinil, phenanthrolinyl, indolizy
Nil, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5]
-A] pyridyl, imidazo [1,2-a] pyridyl, imidazo
[1,5-a] pyridyl, imidazo [1,2-b] pyridazini
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyrida
And a carbonyl group.
More preferably, methyl, ethyl, propyl, isopropyl
Pill, butyl, isobutyl, sec-butyl, tert
-Butyl, pentyl, isopentyl, neopentyl, t
ert-pentyl, hexyl, isohexyl, hepti
C, such as le and octyl_1-8Alkyl and carbonyl groups
Combined C_1-8And alkylcarbonyl.

The optionally substituted amino group in R ¹ includes an amino group, an N-monosubstituted amino group and an N, N-disubstituted amino group. Examples of the substituted amino group include, for example, an optionally substituted hydrocarbon residue (for example, the same as the optionally substituted hydrocarbon residue represented by R ¹ , more specifically, C _{1 -8} alkyl group, C _3-7 cycloalkyl group, C _2-8 alkenyl group, C
_2-8 alkynyl group, C _3-7 cycloalkenyl group, C _6-10 aryl group which may have a C _1-4 alkyl group, etc.),
An optionally substituted heterocyclic group (for example, the same as the optionally substituted heterocyclic group represented by R ¹ ), or a compound of the formula: —COR ′ (where R ′ is a hydrogen atom or And a hydrocarbon residue or a heterocyclic group which may be substituted, wherein the “hydrocarbon residue or heterocyclic group which may be substituted” as R ′ is the above “each of R ′” substituted "hydrocarbon residue in even optionally substituted hydrocarbon group or heterocyclic group" optionally "or" heterocyclic group "similar to substituents which may have, respectively.), preferably C _1-10 An amino group having one or two acyl groups (eg, C _2-7 alkanoyl, benzoyl, nicotinoyl, etc.) as a substituent (eg, methylamino, dimethylamino, ethylamino, diethylamino,
Dipropylamino, dibutylamino, diallylamino,
Cyclohexylamino, phenylamino, N-methyl-
N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino and the like). Further, two groups in the substituted amino group may be bonded to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, piperazino, morpholino, thiomorpholino, and the like).

R¹"
Good hydrocarbon residues, heterocyclic groups, acyl groups "
"Hydrocarbon residue", "heterocyclic group" and "acyl group"
May be each substituted with 1 to 3 substituents
And the substituent is, for example, lower (C_1-6) Alkyl
Groups (eg, methyl, ethyl, propyl, isopropyl,
Chill, isobutyl, sec-butyl, tert-butyl
, Pentyl, isopentyl, neopentyl, hexyl
), Low grade (C_2-6) Alkenyl group [eg, vinyl, ant
Allyl, 1-propenyl, 2-methyl-1-propene
Nil, 1-butenyl, 2-butenyl, 3-butenyl, 3
-Methyl-2-butenyl, 1-pentenyl, 2-pentene
Nil, 3-pentenyl, 4-pentenyl, 4-methyl-
3-pentenyl, 1-hexenyl, 2-hexenyl, 3
-Hexenyl, 4-hexenyl, 5-hexenyl
Etc.], low grade (C_2-6) Alkynyl group (eg, ethynyl, 1-
Propynyl, 2-propynyl, 1-butynyl, 2-butyi
Nil, 3-butynyl, 1-pentynyl, 2-pentini
, 3-pentynyl, 4-pentynyl, 1-hexynyl
, 2-hexynyl, 3-hexynyl, 4-hexynyl
, 5-hexynyl, etc.), C_3-7Cycloalkyl group
(Eg, cyclopropyl, cyclobutyl, cyclopent
, Cyclohexyl, cycloheptyl, etc.), C_6-10A
Reel group (eg, phenyl, α-naphthyl, β-naphthyl
), Aromatic heterocyclic groups [eg, furyl, thienyl, pyro
Ryl, oxazolyl, isoxazolyl, thiazolyl, i
Sothiazolyl, imidazolyl, pyrazolyl, 1,2,3-
Oxadiazolyl, 1,2,4-oxadiazolyl, 1,
3,4-oxadiazolyl, furazanyl, 1,2,3-thio
Asiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
Triazolyl, tetrazolyl, pyridyl, pyridazini
, Pyrimidinyl, pyrazinyl, triazinyl, benzo
Furanyl, isobenzofuranyl, benzo [b] thieni
, Indolyl, isoindolyl, 1H-indazoly
, Benzimidazolyl, benzoxazolyl, 1,2-
Benzisoxazolyl, benzothiazolyl, 1,2-
Isothiazolyl, 1H-benzotriazolyl, quino
Ryl, isoquinolyl, cinnolinyl, quinazolinyl,
Noxalinyl, phthalazinyl, naphthyridinyl, purini
, Pteridinyl, carbazolyl, α-carbolinyl,
β-carbolinyl, γ-carbolinyl, acridinyl,
Phenoxazinyl, phenothiazinyl, phenazinyl,
Phenoxathiinyl, thianthrenyl, phenathridini
Le, phenatrolinyl, indolizinyl, pyrrolo [1,
2-b] pyridazinyl, pyrazolo [1,5-a] pyridi
, Imidazo [1,2-a] pyridyl, imidazo [1,5
-A] pyridyl, imidazo [1,2-b] pyridazini
, Imidazo [1,2-a] pyrimidinyl, 1,2,4-
Triazolo [4,3-a] pyridyl, 1,2,4-tria
(I) a nitrogen source such as zolo [4,3-b] pyridazinyl;
1 to a hetero atom selected from an oxygen atom and a sulfur atom
An aromatic 5- or 6-membered heterocyclic group having four, (ii)
Hetero atom selected from nitrogen atom, oxygen atom and sulfur atom
5- or 6-membered heterocyclic ring having 1 to 3
Selected from a zen ring or a nitrogen, oxygen, or sulfur atom
5- or 6-membered aromatic having 1-3 heteroatoms
A fused bicyclic heterocyclic group formed by condensing a heterocyclic ring, (ii.
i) Hete selected from nitrogen, oxygen and sulfur
Aromatic 5- or 6-membered complex having 1 to 3 carbon atoms
Ring, benzene ring and nitrogen atom, oxygen atom, sulfur atom
5-membered aromatic having 1-3 heteroatoms selected from the group consisting of
Or a 6-membered heterocyclic or benzene ring condensed to form
Fused tricyclic heterocyclic group], (i), (ii) and
(Iii) formed by bonding each heterocyclic group and an oxy group
Heterocyclic-oxy group, non-aromatic heterocyclic group (eg, oxirani
, Azetidinyl, oxetanyl, thietanyl, pylori
Dinyl, tetrahydrofuryl, thiolanyl, piperidini
, Tetrahydropyranyl, morpholinyl, thiomorpho
Nitrogen atom, oxygen atom, sulfur such as linyl and piperazinyl
4-7 members having 1-3 heteroatoms selected from atoms
A non-aromatic heterocyclic group), C_{7 -14}Aralkyl groups (eg,
Benzyl, phenethyl, 1-phenylethyl, 1-fe
Nylpropyl, 2-phenylpropyl, 3-phenylp
Ropyl, α-naphthylmethyl, α-naphthylethyl, β
C such as naphthylmethyl, β-naphthylethyl, etc. _6-10A
Reel-C_1-4Alkyl group, etc.), amino group, N-mono
Substituted amino group [eg, methylamino, ethylamino, allyl
(Allyl) amino, cyclohexylamino, phenyla
N- (C_1-6Alkyl) amino group, N- (C
_2-6Alkenyl) amino group, N- (C_3-7Cycloalkyl
Ru) amino group, N- (C_6-10Aryl) amino group
And N, N-disubstituted amino groups [eg, dimethylamino,
Diethylamino, dibutylamino, diallyl (allyl)
C, such as amino, N-methyl-N-phenylamino,
_1-6Alkyl group, C_2-6Alkenyl group, C_3-7Cycloal
Kill group and C_6-10Two substitutions selected from aryl groups
Such as amino group substituted with a group], amidino group, acyl group
(E.g., formyl, acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
Hexanoyl, heptanoyl, octanoyl, cyclop
Lopancarbonyl, cyclobutanecarbonyl, cyclope
Carbonyl, cyclohexanecarbonyl, croto
Noyl, 2-cyclohexenecarbonyl, benzoyl,
C such as nicotinoyl_2-8Alkanoyl group, C_3-8Arche
Noyl group, C_3-7Cycloalkyl-carbonyl group, C_3-7
Cycloalkenyl-carbonyl group, C_6-10Aryl-ka
Selected from a rubonyl group, a nitrogen atom, an oxygen atom, and a sulfur atom
-Or 6-membered fragrance having 1 to 3 heteroatoms
Is formed by bonding an aromatic or non-aromatic heterocycle to a carbonyl group.
A carbamoyl group,
N-monosubstituted carbamoyl group [eg, methylcarbamoy
, Ethylcarbamoyl, cyclohexylcarbamoy
N- (C) such as phenylcarbamoyl, etc._1-6Al
Kill) carbamoyl group, N- (C_2-6Alkenyl) cal
Bamoyl group, N- (C_3-7Cycloalkyl) carbamoy
Group, N- (C_6-10Aryl) carbamoyl group],
N, N-disubstituted carbamoyl group [eg, dimethylcarbamo
Yl, diethylcarbamoyl, dibutylcarbamoyl,
Diallyl carbamoyl, N-methyl-N-phenyl
C, such as phenylcarbamoyl_1-6Alkyl group, C_2-6A
Lucenyl group, C_3-7Cycloalkyl group and C_6-10Ants
Substituted with two substituents selected from a carbonyl group
Yl group, etc.], sulfamoyl group, N-monosubstituted sulf
Amoyl group [eg, methylsulfamoyl, ethylsulfur
Amoyl, cyclohexylsulfamoyl, phenyls
N- (C such as rufamoyl_1-6Alkyl) sulfamo
Yl group, N- (C_2-6Alkenyl) sulfamoyl group,
N- (C_3-7Cycloalkyl) sulfamoyl group, N-
(C_6-10Aryl) sulfamoyl group], N, N-
Disubstituted sulfamoyl group [eg, dimethyl sulfamoi
, Diethylsulfamoyl, dibutylsulfamoy
, Diallyl (allyl) sulfamoyl, N-methyl-
C, such as N-phenylsulfamoyl_1-6Alkyl
Group, C_2-6Alkenyl group, C_3-7A cycloalkyl group and
C_6-10Substituted with two substituents selected from an aryl group
Sulfamoyl group, etc.), carboxyl group, lower (C
_1-6) Alkoxy-carbonyl group (eg, methoxycarbo)
Nil, ethoxycarbonyl, propoxycarbonyl, i
Sopropoxycarbonyl, butoxycarbonyl, isobu
Toxycarbonyl, sec-butoxycarbonyl, te
rt-butoxycarbonyl, pentyloxycarboni
, Hexyloxycarbonyl, etc.), hydroxyl, lower
(C_1-6) Alkoxy groups (eg, methoxy, ethoxy,
Loxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentyloxy
, Hexyloxy, etc.), lower (C_2-6) Alkenylo
A xy group [eg, allyloxy, 2-butenylo
Xy, 2-pentenyloxy, 3-hexenyloxy
Do], C_3-7Cycloalkyloxy group (eg, cyclopropyl
Ruoxy, cyclobutyloxy, cyclopentyloxy
, Cyclohexyloxy, cycloheptyloxy
Etc.), C_6-10Aryloxy group (eg, phenoxy, naph
Cyloxy), C_7-14Aralkyloxy groups (eg,
Enyl-C_{1- Four}Alkyloxy, naphthyl-C_1-4Archi
C such as ruoxy_6-10Aryl-C_{1- Four}Alkyloxy
Group), mercapto group, lower (C_1-6) Alkylthio
Groups (eg, methylthio, ethylthio, propylthio, iso
Propylthio, butylthio, isobutylthio, sec-
Butylthio, tert-butylthio, pentylthio, i
Sopentylthio, neopentylthio, hexylthio
Etc.), C_7-14An aralkylthio group (eg, phenyl-C_1-4A
Luquilthio, Naphthyl-C_1-4C such as alkylthio
_6-10Aryl-C_1-4Alkylthio group), C_6-10A
Reelthio group (eg, phenylthio, naphthylthio
Etc.), low grade (C_1-6) Alkylsulfinyl group (eg,
Tylsulfinyl, ethylsulfinyl, propylsulfinyl
Finyl, isopropylsulfinyl, butylsulfy
Nil, isobutylsulfinyl, sec-butylsulfur
Inyl, tert-butylsulfinyl, pentylsulfur
Finyl, isopentylsulfinyl, neopentyls
Rufinyl, hexylsulfinyl, etc.), C_7-14Ara
Rukylsulfinyl group (eg, phenyl-C_1-4Alkyl
Sulfinyl, naphthyl-C_1-4Alkylsulfinyl
Such as C_6-10Aryl-C_1-4Alkylsulfinyl group
Etc.), C_6-10Arylsulfinyl group (eg, phenyl
Sulfinyl, naphthylsulfinyl, etc.), lower (C
_1-6) Alkylsulfonyl group (eg, methylsulfonyl,
Ethyl sulfonyl, propyl sulfonyl, isopropyl
Sulfonyl, butylsulfonyl, isobutylsulfonyl
, Sec-butylsulfonyl, tert-butylsulfur
Honyl, pentylsulfonyl, isopentylsulfonyl
, Neopentylsulfonyl, hexylsulfonyl
Etc.), C_7-14An aralkylsulfonyl group (eg, phenyl-
C_1-4Alkylsulfonyl, naphthyl-C_1-4Alkyls
C such as rufonyl_6-10Aryl-C_1-4Alkylsulfo
), C_{6 -Ten}Arylsulfonyl group (eg,
Nylsulfonyl, naphthylsulfonyl, etc.), sulfo
Group, cyano group, azide group, halogen atom (eg, fluorine,
Chlorine, bromine, iodine, etc.), nitro group, nitroso group,
Phosphono group which may be stelated [eg, phosphono
Group, ethoxyphosphoryl and the like (C_1-6Alkoxy) ho
Di (C) such as a sphoryl group and diethoxyphosphoryl_1-6A
Lucoxy) phosphoryl group, etc.
(C) substituted with a good phosphono group_1-6) Alkyl
Groups (eg, phosphono-C_1-6Alkyl group, C_1-6Alkoxy
Phosphoryl-C_1-6Alkyl group, diethoxyphosphoryl
Di (C) such as methyl_1-6Alkoxy) phosphoryl-C_1-6
Alkyl group), C_1-6Haloalkyl group (eg, tri
C substituted with 1 to 4 halogens such as fluoromethyl
_1-6Alkyl group), C_1-6Haloalkoxy group
(Eg, 1-4 halogens such as trifluoromethoxy)
Is substituted C_{1 -6}Alkoxy group etc.)
You. Among the above substituents, a hydroxyl group and a lower (C
_1-6) When the alkoxy group is adjacent as a substituent,
C such as methylenedioxy and ethylenedioxy_1
-6An alkylenedioxy may be formed.

The above C _6-10 aryl group, aromatic heterocyclic group,
A C _6-10 aryl group as a substituent of an N-monosubstituted amino group, a C _6-10 aryl group as a substituent of an N, N-disubstituted amino group, and a C _6-10 aryl group as a substituent of an N-monosubstituted carbamoyl group _6-10 aryl group, N, N- C _6-10 aryl group as a substituent of di-substituted carbamoyl group, C _6-10 aryl as a substituent of the N- mono-substituted sulfamoyl group, N, N-
A C _6-10 aryl group as a substituent of a disubstituted sulfamoyl group, a C _6-10 aryl group in a C _6-10 aryloxy group,
A C _6-10 aryl group in a C _7-14 aralkyloxy group,
_7-14 aralkylthio C _6-10 aryl group in the group, C _6-10 aryl groups in C _6-10 arylthio group, C _{7- 14} aralkyl sulfinyl C _6-10 aryl group in the Le group, C _6-10 C _6-10 aryl groups in the aryl sulfinyl group, C _6-10 aryl groups C _6-10 aryl groups, and C _6-10 during arylsulfonyl groups in C _7-14 aralkylsulfonyl groups, further 1
May be substituted with up to 3 substituents, such as a lower (C _1-6 ) alkyl group, an amino group,
N- (C _1-6 alkyl) amino group, N, N-di (C _1-6 alkyl) amino group, amidino group, carbamoyl group, N-
(C _1-6 alkyl) carbamoyl group, N, N-di (C _1-6
Alkyl) carbamoyl group, sulfamoyl group, N-
(C _1-6 alkyl) sulfamoyl group, N, N-di (C
_1-6 alkyl) sulfamoyl group, carboxyl group, lower (C _2-7 ) alkoxycarbonyl group, hydroxyl group, lower (C _1-6 ) alkoxy group, mercapto group, lower (C _1-6 )
Alkylthio group, sulfo group, cyano group, azide group, halogen atom, nitro group, nitroso group, phosphono group which may be esterified [eg, phosphono group, C _1-6 alkoxyphosphoryl group, di (C _1-6 Alkoxy) phosphoryl group, etc., and a lower (C _1-6 ) alkyl group substituted with an optionally esterified phosphono group [eg, phosphono-C _1-6
Alkyl group, C _1-6 alkoxy phosphoryl -C _1-6 alkyl group, such as di (C _1-6 alkoxy) phosphoryl -C _1-6 alkyl group such as diethoxyphosphorylmethyl] and the like. Among the above substituents, when hydroxyl group and lower the (C _1-6) alkoxy groups are adjacent as substituents form a C _1-6 alkylenedioxy, such as methylenedioxy and ethylenedioxy Is also good. R ¹
Is preferably an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group, particularly an optionally substituted hydroxyl group.

R ² represents a cyano group, a formyl group, a thioformyl group, an optionally substituted heterocyclic group or a group represented by the formula: -Z ¹
-Z ² (wherein, Z ¹ represents -CO-, -CS-, -SO-
Or -SO 2 _- indicates, Z ² represents a hydrocarbon residue which may be substituted respectively, a heterocyclic group, an amino group or a hydroxyl group. ). Examples of the optionally substituted heterocyclic group for R ² include the same as the optionally substituted heterocyclic group for R 1. Z ¹ in R ² represents —CO— or —CS—
Is preferable, and -CO- is more preferable. As R ² ,
A group represented by —CO—Z ^{2 ′} (wherein, Z ^{2 ′} represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group) is preferable. Examples of the optionally substituted hydrocarbon residue for Z ² include, for example, the same as the optionally substituted hydrocarbon residue for R ¹ . The optionally substituted hydrocarbon residue in Z ² is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
ec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,
1-8 carbon atoms such as isohexyl, heptyl and octyl
Saturated aliphatic hydrocarbon residues (eg, alkyl). Examples of the optionally substituted heterocyclic group for Z ² include the same as the optionally substituted heterocyclic group for R ¹ .

Examples of the optionally substituted amino group for Z ² include the same as the optionally substituted amino group for R ¹ , as well as —NHOR and —NHNH
R or —NHNRR ′ (wherein, R is as defined above,
R ′ represents an optionally substituted hydrocarbon residue or a heterocyclic group. ). R '
Examples of the “optionally substituted hydrocarbon residue or heterocyclic group” represented by R include those similar to those represented by R. The optionally substituted amino group for Z ² is preferably an amino group,
Examples include an amino group having one or two _1-8 alkyl groups as a substituent (eg, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, etc.). Examples of the optionally substituted hydroxyl group for Z ² include, for example, the same as the optionally substituted hydroxyl group for R ¹ . The optionally substituted hydroxyl group for Z ² is preferably a hydroxyl group, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, _{C 1-8} alkyloxy substituted with _{C 1-8} alkyl such as octyl. In R ² Z ² a hydroxyl group which may be the amino group or substituted or optionally substituted it is preferable. In R ² Z ² is amino group which may be substituted more preferred. Especially, Z ² in R ² is an amino group or an amino group having a C _1-8 alkyl group as a one or two substituents, (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, etc.) is preferred . R ² is particularly preferably a cyano group or a formula —Z ¹ —Z ² (wherein Z ¹ represents —CO—).

R ³ represents a hydrogen atom, a halogen, a cyano group or an amino group, an acyl group, a hydrocarbon residue or a heterocyclic group which may be substituted. Examples of the halogen for R ³ include fluorine, chlorine, bromine, iodine and the like. Examples of the optionally substituted amino group for R ³ include the same as the optionally substituted amino group for R ¹ . As the optionally substituted acyl group for R ³ , for example, those in which the “hydrocarbon residue or heterocyclic group optionally substituted” represented by R ¹ and a carbonyl group are preferable, A hydrocarbon residue represented by R ¹ ,
The same substituents as the acyl group as the substituent of the heterocyclic group are exemplified. Examples of the optionally substituted hydrocarbon residue for R ³ include the same as the optionally substituted hydrocarbon residue for R ¹ . As the optionally substituted hydrocarbon residue for R ³ , preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Examples thereof include saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl groups) such as pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, and octyl. Examples of the optionally substituted heterocyclic group for R ³ include the same as the optionally substituted heterocyclic group for R ¹ . Examples of the optionally substituted hydroxyl group for R ³ include, for example,
Those similar to the hydroxy group which may be substituted in R ¹ can be mentioned.

R⁴, R⁵And R⁶Are the same or different
Represents a hydrogen atom or a carbon which may be substituted
Hydride residue, heterocyclic group, hydroxyl group, acyl group, sulfonyl
A group or an amino group. R⁴, R⁵And R⁶In
Hydrocarbon residues, each of which may be substituted,
The ring group, hydroxyl group, acyl group or amino group is represented by R¹As
Each optionally substituted hydrocarbon residue, heterocyclic ring
Groups similar to groups, hydroxyl groups, acyl groups or amino groups
I can do it. R⁴, R⁵And R⁶In, replaced
As the sulfonyl group in the sulfonyl group which may be present,
R mentioned above¹As "each may be substituted
"Hydrocarbon residue" or "hydrocarbon residue"
Is a "heterocyclic group" and -SO₂And-are combined.
It is. Preferably, methyl, ethyl, propyl, isop
Propyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl,
tert-pentyl, hexyl, isohexyl, hepti
C, such as le and octyl _1-8Alkyl and sulfonyl groups
Combined C_1-8Alkylsulfonyl; phenyl, α
-Naphthyl, β-naphthyl, 4-indenyl, 5-in
Denenyl, 4-Indanyl, 5-Indanyl, 5,6,7,
8-tetrahydro-1-naphthyl, 5,6,7,8-tet
Lahydro-2-naphthyl, 5,6-dihydro-1-naph
Tyl, 5,6-dihydro-2-naphthyl, 5,6-dihydride
B-3-naphthyl, 5,6-dihydro-4-naphthyl
Which C_6-10C having an aryl group and a sulfonyl group bonded
_{6-1 0}Arylsulfonyl; aromatic monocyclic heterocyclic group
(E.g., furyl, thienyl, pyrrolyl, oxazolyl, i
Soxazolyl, thiazolyl, isothiazolyl, imida
Zolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazo
Ryl, Frazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tet
Lazolyl, pyridyl, pyrimidinyl, pyridazinyl, pi
Radinyl, triazinyl, etc.) and sulfonyl group
Aromatic fused heterocyclic group (eg, benzofuranyl,
Sobenzofuranyl, benzo [b] thienyl, indolyl,
Isoindolyl, 1H-indazolyl, benzimidazo
Ryl, benzoxazolyl, 1,2-benzoisothiazo
Ryl, 1H-benzotriazolyl, quinolyl, isoquino
Ril, cinnolinyl, quinazolinyl, quinoxalinyl,
Phthalazinyl, naphthyridinyl, purinyl, pteridini
, Carbazolyl, α-carbolinyl, β-carbolinyl
, Γ-carbolinyl, acridinyl, phenoxazini
Phenothiazinyl, phenazinyl, phenoxathii
Nil, thianthrenyl, phenanthrinil, phenan
Tolorinyl, indolizinyl, pyrrolo [1,2-b] pyrida
Dinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2
-A] pyridyl, imidazo [1,5-a] pyridyl, imidazo
[1,2-b] pyridazinyl, imidazo [1,2-a] pyridin
Le, imidazo [1,5-a] pyridyl, imidazo [1,2-b]
Pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,
2,4-triazolo [4,3-a] pyridyl, 1,2,4-to
Liazolo [4,3-b] pyridazinyl) and sulfonyl group
Attached groups. More preferably, methyl, d
Chill, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isope
Pentyl, neopentyl, tert-pentyl, hexyl
C such as octyl, isohexyl, heptyl and octyl_1-8
C with alkyl and sulfonyl groups bonded_1-8Alkyls
And rufonyl. As a substituent of a sulfonyl group
Is the above R¹Each of which may be substituted
The same as a substituent in a residue, heterocyclic group or acyl group
Things.

The “optionally substituted 5” represented by ring A
The "7-membered ring" includes, for example, (i) one sulfur atom, 1
A 5- to 7-membered heterocyclic group containing one nitrogen atom or one oxygen atom, (ii) a 5- to 7-membered heterocyclic group containing 2 to 4 nitrogen atoms, or (iii) a 1 to 2 nitrogen atom Examples thereof include a 5- to 7-membered heterocyclic group containing an atom and one sulfur or oxygen atom, and specific examples thereof include the same as the specific examples of the heterocyclic group in the optionally substituted heterocyclic group in R ¹ . No. Ring A is preferably a 5-membered aromatic ring, particularly an optionally substituted azole group (eg, pyrazole, isoxazole, isothiazole, etc.), more preferably
The above formula:

Embedded image (Wherein each symbol has the same meaning as described above.), And an aromatic 5-membered heterocyclic ring is preferable. And the group represented by

The compound of the present invention represented by the formula (I) [hereinafter referred to as compound (I)]. Or a salt of a raw material compound for producing the salt thereof, is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a base And salts with acidic or acidic amino acids. Preferred examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
Salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like are included. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
Salts with citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, etc., and preferred examples of the salt with an acidic amino acid include
For example, salts with aspartic acid, glutamic acid and the like can be mentioned.

Compound (I) or a salt thereof may be a prodrug thereof. A prodrug of the compound (I) or a salt thereof is a compound which is converted into the compound (I) or a salt thereof by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, oxidation, reduction, hydrolysis or the like enzymatically. And a compound which is converted to the compound (I) or a salt thereof by causing hydrolysis or the like by stomach acid or the like. As a prodrug of the compound (I) or a salt thereof, a compound in which the hydroxyl group of the compound (I) or a salt thereof is acylated, alkylated, phosphorylated or borated or a salt thereof (for example, the compound (I) or a salt thereof) The hydroxyl group of the salt is acetylated, palmitoylated, propanoylated, pivaloyylated,
A succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compound or a salt thereof), the carboxyl group of compound (I) or a salt thereof is
Esterified, amidated compounds (for example, when the carboxyl group of compound (I) or a salt thereof is ethylesterified, phenylesterified, carboxyoxymethylesterified, dimethylaminomethylesterified, pivaloyloxymethylesterified, Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound or salt thereof Etc.) are used. These prodrugs can be produced according to a method known per se or a method analogous thereto. The prodrug of compound (I) or a salt thereof can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pp. 163-198. May be changed.

The compounds of the present invention (I) or a salt thereof isotope ^{(eg, 2 H, 3 H, 14} C, 3 5 S, etc. ¹²⁵ I) may be labeled with a. When the compound obtained in the present invention or a salt thereof has a double bond in the molecule and has a Z or E configuration, each of them or a mixture thereof is also included in the present invention.
When the compound obtained in the present invention or a salt thereof has a stereoisomer such as having an asymmetric carbon in the molecule,
Either each of them or a mixture thereof is included in the present invention.

Hereinafter, a method for producing the compound of the present invention will be described. Compound (I) or a salt thereof can be produced, for example, by the following Method A to Method L or a method analogous thereto. [Method A]

Embedded image [Wherein, R ⁷ represents an optionally substituted hydrocarbon residue corresponding to R ³ , and R ⁸ and R ⁹ are each independently a hydrogen atom or a substituted same as exemplified for R ^1. A hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group, and A ¹ and A ² are each a hydrogen atom or R ¹
And Hal represents a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), Q represents a sulfur atom,
Indicates an oxygen atom or an NH group. Other symbols are as defined above. In this method, first, compound (1) is halogenated by a method known per se to give compound (2), and then compound (4) is produced by reacting compound (3) with amide, thioamide or amidine. The reaction between compound (2) and compound (3) is performed in a suitable solvent in the presence or absence of a base. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,
Halogenated hydrocarbons such as 1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol , N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, ethyl acetate or a mixed solvent thereof. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide and potassium te.
alkali metal alkoxides such as rt-butoxide; alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate; alkali metal hydrogens such as disodium hydrogen phosphate and dipotassium hydrogen phosphate Phosphates, sodium hydride, alkali metal hydrides such as potassium hydride, trimethylamine, triethylamine, pyridine,
Bases such as amines such as picoline, N-methylpyrrolidine, N-methylmorpholine and N, N-dimethylaniline are appropriately selected and used, and the amount of these bases is about 1 to about 5 based on the compound (2). The molar equivalent is preferred, and the amount of amide, thioamide or amidine (3) used is preferably about 1 to about 5 molar equivalents relative to compound (2). This reaction is generally carried out at about 0 ° C to about + 180 ° C, preferably at about + 30 ° C to
The reaction is performed at about + 120 ° C. for about 30 minutes to about 50 hours. The compound (4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The corresponding carboxylic acid (5) can be produced by subjecting compound (4) in which R ² is —COOR ⁷ [that is, compound (4 ′)] to an acid or alkali hydrolysis reaction known per se, By subjecting compound (5) to an amidation reaction [reaction with compound (6)] known per se, compound (7) can be produced. The amidation reaction can be performed, for example, by introducing the compound (5) into an acid halide with a halogenating agent such as oxalyl chloride or thionyl chloride, and then reacting the compound with the compound (6). The reaction between the compound (5) and the halogenating agent is usually performed in a solvent, and examples of the solvent include aromatic hydrocarbons such as benzene and toluene, and ethers such as diethyl ether and tetrahydrofuran. For example, pyridine, N, N-dimethylformamide or the like may be used as the reaction accelerator. This reaction is generally performed at about 0 ° C. to about + 120 ° C. for about 30 minutes to about 24 hours. The amount of the halogenating agent to be used is preferably about 1 to 2 molar equivalents relative to compound (5). The obtained acid halide may be subjected to the reaction with the compound (6) after being separated by a usual separation and purification means, or the reaction mixture containing the acid halide may be subjected to the reaction with the compound (6) without separation. It can also be attached. The reaction between the acid halide and the compound (6) is usually performed in a solvent. Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, dioxane and tetrahydrofuran, acetone, acetonitrile, ethyl acetate, N, N -Dimethylformamide and the like.
The reaction can also be carried out using an excess amount of compound (6) as a solvent. This reaction can be carried out in the presence or absence of a base. Examples of the base include organic bases such as trimethylamine, triethylamine, pyridine and N, N-dimethylaniline, and inorganic bases such as sodium hydrogencarbonate and potassium carbonate. Bases and the like. The amount of compound (6) to be used is preferably about 1 to 2 molar equivalents relative to the acid halide, but an excessive amount of compound (6) can be used as a solvent. This reaction is generally carried out at about 0 ° C. to about +120.
C. for about 30 minutes to about 24 hours. Compound (4) wherein Q is an NH group is compound (4)
-1) can be isomerized like compound (4-2), but these are subjected to a reaction of compound (8) with a halogenated hydrocarbon to produce compounds (9-1) and (9-2). I do. This reaction is carried out in a suitable solvent in the presence or absence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. Is mentioned. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide. Alkali metal alkoxides, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal salts such as sodium acetate and potassium acetate, and alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate , Sodium hydride,
Alkali metal hydrides such as potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N
-Methylpyrrolidine, N-methylmorpholine, N, N-
Bases such as amines such as dimethylaniline are appropriately selected and used, and the amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound (4). The amount of halogenated hydrocarbon (8) used is About 1 to about 5 molar equivalents relative to compound (4) are preferred. This reaction is carried out usually at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 30 minutes to about 50 hours. Compounds (9-1) and (9-2) thus obtained can be obtained by known separation and purification means,
For example, they can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[Method B]

Embedded image (In the formula, each symbol has the same meaning as described above.) In this method, after the above compound (2) is azido-formed by a method known per se to give compound (10), carboxylic acid anhydride (11) (Eg, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, etc.) to produce compound (12) by reduction. As the reduction reaction, catalytic reduction using a transition metal catalyst (eg, palladium, platinum, rhodium, etc.) and hydrogen is preferable, and this reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N, N-dimethylformamide, ethyl acetate, and acid anhydrides (11 )) (For example, acetic acid, propionic acid, butyric acid, isobutyric acid, etc.) or a mixed solvent thereof. The reaction temperature is usually about -2.
Preferred is 0 ° C to about + 150 ° C, especially about 0 ° C to about + 100 ° C, and the reaction time is about 1 hour to about 24 hours. The compound (12) thus obtained is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like. Compound (13) is produced by subjecting compound (12) to a reaction with phosphorus oxychloride in an appropriate solvent or without a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. And ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. The amount of phosphorus oxychloride to be used is preferably about 1 to about 5 molar equivalents relative to compound (12). The reaction temperature is generally about 0 ° C. to about + 150 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours. The compound (13) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. R ² is -C
OOR ^7, compound (13) can ^{be R 2} to produce a compound (13) is -COOH by subjecting the known acid or alkali hydrolysis and also, ^{R 2}
Is subjected to an amidation reaction [reaction with compound (6)] known per se to compound (13) wherein
² can also be prepared compounds is -CONR ⁸ R ⁹ (13). This reaction can be carried out under the same conditions as those for the reaction for deriving compound (5) from compound (4 ′) and the reaction for deriving compound (7) from compound (5).

[Method C]

Embedded image (In the formula, R ¹⁰ represents a methyl group or an ethyl group. Other symbols have the same meanings as described above.) In this method, compound (14) is produced by reducing compound (10) described above. . As the reduction reaction, catalytic reduction using a transition metal catalyst (eg, palladium, platinum, rhodium, etc.) and hydrogen is preferable, and this reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane,
Examples thereof include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol, N, N-dimethylformamide, ethyl acetate, and a mixed solvent thereof. The reaction temperature is usually about -20 ° C to about +150.
C., especially from about 0.degree. C. to about + 100.degree. C., and the reaction time is from about 1 hour to about 24 hours. The compound (14) thus obtained is separated and purified by a known means, for example, concentration,
It can be isolated and purified by concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (14) was converted to a compound of the formula (1) in an appropriate solvent or without solvent.
Compound (16) is produced by subjecting it to the reaction with the dithioester represented by 5). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like A mixed solvent and the like can be mentioned. The amount of the dithioester (15) to be used is preferably about 1 to about 5 molar equivalents relative to the compound (14). The reaction temperature is generally about 0 ° C. to about + 150 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours. The compound (16) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (1
Compound (17) is produced by reacting 6) with phosphorus oxychloride in the same manner as in Method B. R ² is -COOR
^The compound (17) wherein R ² is —COOH can be produced by subjecting the compound (17) which is ⁷ to an acid or alkali hydrolysis reaction known per se, and the compound (where R ² is —COOH ( 17) is subjected to an amidation reaction [reaction with compound (6)] known per se to give R ²
There may also be prepared compound is -CONR ⁸ R ⁹ (17). This reaction can be carried out under the same conditions as those for the reaction for deriving compound (5) from compound (4 ′) and the reaction for deriving compound (7) from compound (5).

[Method D]

Embedded image (In the formula, Q ′ represents an oxygen atom or NA ^{1. The} other symbols have the same meanings as described above.) In the present method, the above compound (1) is treated with oxynitride in the presence of N, N-dimethylformamide. Compound (18) is produced by subjecting it to a reaction with phosphorus chloride. As the solvent, for example, halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or the like; A mixed solvent may be used. N, N-
The amount of dimethylformamide and phosphorus oxychloride to be used is preferably about 1 to about 5 molar equivalents relative to compound (1). The reaction temperature is usually about -20 ° C to about + 180 ° C, particularly about 0 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 24 hours. The compound (18) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (1
8) is reacted with a hydroxylamine derivative or hydrazine derivative of compound (19) to give compound (2)
0) is manufactured. This reaction is advantageously performed in a solvent that does not adversely influence the reaction, in the presence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. , Diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane, N, N-dimethylformamide,
Examples thereof include dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. Examples of the base include sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, magnesium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, sodium methoxide,
Sodium ethoxide, alkali metal alkoxides such as potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Alkali metal salts such as sodium acetate and potassium acetate,
Alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as sodium hydride and potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methyl Bases such as amines such as morpholine and N, N-dimethylaniline are appropriately selected and used, and the amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound (18), such as hydroxylamine or hydrazine ( The use amount of 19) is preferably about 1 to about 5 molar equivalents relative to compound (18). This reaction is usually performed at about 0 ° C.
To about + 180 ° C, preferably from about + 30 ° C to about + 120 ° C
For about 30 minutes to about 50 hours. Compound (20) thus obtained can be obtained by a known separation and purification means,
For example, they can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (2) wherein R ² is —COOR ⁷
0) can ^{be R 2} to produce a compound (20) in which is -COOH by a subjected to per se known acid or alkali hydrolysis reaction, also known per se to compounds wherein ^{R 2} is -COOH (20) Amidation reaction [Compound (6)
With R2], R ² is -CONR ⁸ R ⁹
Can also be produced. This reaction can be carried out under the same conditions as those for the reaction for deriving compound (5) from compound (4 ′) and the reaction for deriving compound (7) from compound (5).

[Method E]

Embedded image (In the formula, each symbol has the same meaning as described above.) In this method, the compound (18) is subjected to a reaction with sulfur and sodium sulfide in an appropriate solvent, and then treated with sulfuryl chloride. Thus, compound (21) is produced. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol;
Examples thereof include dimethylformamide, dimethylsulfoxide, acetonitrile, and a mixed solvent thereof.
The amount of sulfur and sodium sulfide used is determined by the amount of compound (18)
About 1 to about 3 molar equivalents are preferred. The reaction temperature is usually about 0 ° C to about + 180 ° C, especially about + 30 ° C to about +
120 ° C is preferred and the reaction time is from about 1 hour to about 24 hours. The sulfuryl chloride treatment of the intermediate thus obtained is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,
Examples include halogenated hydrocarbons such as 2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, and a mixed solvent thereof. The amount of sulfuryl chloride to be used is preferably about 1 to about 3 molar equivalents relative to compound (18). The reaction temperature is usually about -20 ° C to about + 150 ° C, particularly about 0 ° C to about + 100 ° C, and the reaction time is about 1 hour to about 24 hours. The compound (21) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (2
By reacting 1) with a large excess of ammonia, compound (2)
2) is manufactured. This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol; and mixed solvents thereof. . This reaction is generally carried out at about -20 ° C to about + 180 ° C, preferably at about 0 ° C to
The reaction is performed at about + 120 ° C. for about 1 hour to about 50 hours. The compound (22) thus obtained is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like. R ² is able ^{to R 2} to produce a compound (22) is -COOH by subjecting the compound is a -COOR ⁷ (22) per se known acid or alkali hydrolysis reaction, also, ^{R 2} is - COO
By subjecting compound (22) which is H to an amidation reaction [reaction with compound (6)] known per se, R ² is -CO
Compound (22) which is NR ⁸ R ⁹ can also be produced. This reaction can be carried out under the same conditions as those for the reaction for deriving compound (5) from compound (4 ′) and the reaction for deriving compound (7) from compound (5).

[Method F]

Embedded image (In the formula, R ¹¹ represents an ethoxycarbonyl group or a p-toluenesulfonyl group. Other symbols have the same meanings as described above.) In the present method, the compound (1) is prepared by compounding the compound (1) in an appropriate solvent Reaction of (23) with ethyl carbazate or p-toluenesulfonyl hydrazide gives compound (24)
To manufacture. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. , Diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane,
Examples thereof include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate, and a mixed solvent thereof.
The amount of ethyl carbazate or p-toluenesulfonyl hydrazide (23) to be used is preferably about 1 to about 2 molar equivalents relative to compound (1). The reaction temperature is usually about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours.
The compound (24) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (25) is produced by treating compound (24) with thionyl chloride. The reaction is
It is performed in an appropriate solvent or without solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. And ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, and a mixed solvent thereof. This reaction is carried out usually at about -20C to about + 180C, preferably at about 0C to about + 120C, for about 1 hour to about 50 hours. The compound (2) thus obtained
5) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. R ² is -C
The compound (25) which is OOR ⁷ is subjected to an acid or alkali hydrolysis reaction known per se, whereby R ² is -COO.
H, a compound (25) can be produced,
Compound (25) wherein R ² is --CONR ⁸ R ⁹ may be produced by subjecting compound (25) wherein R ² is --COOH to an amidation reaction [reaction with compound (6)] known per se. it can. This reaction can be carried out under the same conditions as those for the reaction for deriving compound (5) from compound (4 ′) and the reaction for deriving compound (7) from compound (5).

[Method G]

Embedded image (Each symbol in the formula has the same meaning as described above.) In this method, the compound (18) is subjected to the reaction of the compound (26) with a thiol in an appropriate solvent in the presence of a base. Then, compound (27) is produced. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate Alternatively, a mixed solvent thereof may be used. As the base,
For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Alkali metal salts such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium hydride;
Alkali metal hydrides such as potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N
-Methylpyrrolidine, N-methylmorpholine, N, N-
Bases such as amines such as dimethylaniline are appropriately selected and used, and the amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound (18), and thiol (26)
Is preferably about 1 to about 3 molar equivalents relative to compound (18). This reaction is carried out usually at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 1 hour to about 50 hours. The compound (2) thus obtained
7) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In the above reaction, the compound (28) may be partially produced, but usually the compound (27) is subjected to an aldol-type dehydration condensation reaction to produce the compound (28). This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene;
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbons such as dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, ethylene Examples thereof include alcohols such as glycol, acetonitrile, ethyl acetate, and a mixed solvent thereof. Examples of the dehydration reagent include lower carboxylic anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, and isobutyric anhydride; sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; and amines ( A mixture of pyrrolidine, piperidine, etc.) and carboxylic acids (acetic acid, benzoic acid, etc.) is appropriately selected and used. The amount of the dehydrating reagent to be used is a catalytic amount or a large excess with respect to compound (27). 1 hour to about 50 hours. The compound (28) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
Compound (28) in which R ² is —COOR ⁷ is subjected to a known acid or alkali hydrolysis reaction to give R ^2.
Can be produced by subjecting the compound (28) wherein R ² is --COOH to an amidation reaction known per se [reaction with the compound (6)]. ² is -CONR ⁸ R ⁹ (2
8) can also be manufactured. This reaction can be carried out under the same conditions as those for the reaction for deriving compound (5) from compound (4 ′) and the reaction for deriving compound (7) from compound (5).

[Method H]

Embedded image (Each symbol in the formula has the same meaning as described above.) In this method, the compound (2) is subjected to a reaction of the compound (29) with an imine in an appropriate solvent in the presence of a base. And
Compound (30) is produced. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene;
Diethyl ether, tetrahydrofuran, dioxane,
Examples thereof include ethers such as dimethoxyethane, and a mixed solvent thereof. As the base, for example, a base such as lithium diethylamide or lithium diisopropylamide is appropriately selected and used, and the amount of the base to be used is preferably about 1 to about 2 molar equivalents relative to compound (2),
The amount of imine (29) to be used is preferably about 1 to about 2 molar equivalents relative to compound (2). In this reaction, first, imine (29)
Is advantageously treated by adding compound (2) after treatment with a base. The reaction temperature is usually about -80 ° C to about +10
At 0 ° C, preferably from about -80 ° C to about + 30 ° C, the reaction time is from about 30 minutes to about 24 hours. The compound (30) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. R
Compound (30) in which R ² is —COOH can be produced by subjecting compound (30) in which ² is —COOR ⁷ to an acid or alkali hydrolysis reaction known per se, and R ² is —COOH Is subjected to an amidation reaction [reaction with compound (6)] known per se to give compound (3) wherein R ² is —CONR ⁸ R ⁹
0) can also be produced. This reaction can be carried out under the same conditions as those for the reaction for deriving compound (5) from compound (4 ′) and the reaction for deriving compound (7) from compound (5).

For example, the compound represented by the general formula (I) can be produced according to the following method I. [Method I]

Embedded image (In the formula, n represents 1 or 2, and other symbols have the same meanings as described above.) In this method, first, 1,3-diketone is converted to a base, carbon disulfide, and a halogenated hydrocarbon (31). To produce the dithioester of compound (32). This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane,
Examples thereof include N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. Examples of the base include sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, carbonate Alkali metal salts such as potassium, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium hydride and potassium hydride Alkali metal hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-
Bases such as amines such as methylmorpholine and N, N-dimethylaniline are appropriately selected and used. The amount of these bases used is preferably about 1 to about 2 molar equivalents based on 1,3-diketone, and the amount of carbon disulfide used is preferably about 1 to about 2 molar equivalents based on 1,3-diketone. The amount of hydrogen (31) used is about 1 to 1,3-diketone.
About 2 molar equivalents, especially about 1 molar equivalent, are preferred. This reaction is usually carried out at about -80 ° C to about + 150 ° C, preferably at about -20 ° C.
To about + 100 ° C. for about 1 hour to about 24 hours. The compound (32) thus obtained is separated and purified by known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like. Compound (32) was dissolved in a suitable solvent,
Compound (34) is produced by reacting with a halogenated hydrocarbon represented by the general formula (33) in the presence of a base. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, diethyl ether,
Ethers such as tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, N, N-dimethylformamide, dimethyl sulfoxide , Acetonitrile, ethyl acetate or a mixed solvent thereof. Examples of the base include sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, carbonate Alkali metal salts such as potassium, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium hydride and potassium hydride Alkali metal hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-
Bases such as amines such as methylmorpholine and N, N-dimethylaniline are appropriately selected and used, and the amount of these bases to be used is about 1 to about 10 molar equivalents, particularly about 1 to about 5 molar equivalents to compound (32). The molar equivalent is preferable, and the amount of the halogenated hydrocarbon (33) to be used is about 1 to about the compound (32).
About 2 molar equivalents are preferred. The reaction temperature is usually about 0 ° C. to about +
180 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours. The compound (1) thus obtained is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like. Compound (35) is produced by subjecting compound (34) to an oxidation reaction. As the oxidizing agent used in this reaction, peracids such as peracetic acid, pertrifluoroacetic acid and m-chloroperbenzoic acid, metal oxides such as potassium permanganate and chromium oxide, hydrogen peroxide and the like are used. In this reaction, 1 to 10 molar equivalents of the oxidizing agent with respect to compound (34),
Preferably, 1 to 3 molar equivalents are used. As the solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction. Examples thereof include hydrocarbons such as n-hexane, n-heptane, benzene, toluene and xylene; and halogens such as dichloromethane chloroform and carbon tetrachloride. Hydrocarbons, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, acetic acid Esters such as methyl, acetone, 2-butanone, 4-methyl-2
Ketones such as pentanone and cyclohexone; and halogenated hydrocarbons such as dichloromethane chloroform and carbon tetrachloride, and ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, and dioxane are preferable. These solvents are used alone or as a mixture of two or more. The reaction is carried out at a reaction temperature of 0 ° C to 120 ° C.
C., preferably at 20 to 80.degree. C., for 1 to 24 hours, preferably 2 to 6 hours. Compound (35) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like.

Next, the compound (35) is reacted with various nucleophilic reagents to produce the compound (1). As the nucleophilic reagent, for example, metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents, aryl metal reagents, thioalcoholates, amines and the like are used. In this reaction, it is preferable to add a base in some cases. As the base to be used, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, magnesium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, sodium carbonate, potassium carbonate,
Alkali metal salts such as sodium bicarbonate, cesium fluoride, sodium acetate and potassium acetate; metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; metal hydroxides such as sodium hydroxide and potassium hydroxide And amines such as triethylamine, pyridine and N-methylmorpholine. The amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (35). When a base is used, it is preferably about 1 to about 5 molar equivalents relative to compound (35). This reaction is generally performed in a solvent that does not adversely influence the reaction. Examples of the solvent which does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as dimethylformamide and 1-methylpyrrolidone, and sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -70 to about 150C, preferably about -20 to about 100C. The reaction time is usually about 0.
5 to about 24 hours. The compound (1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. R ² is -COO
A R ⁷ is compound (1) compound wherein R ² is -COOH by a subjected to per se known acid or alkali hydrolysis reaction (1) can be produced, also, R ² is -
By subjecting compound (1), which is COOH, to an amidation reaction [reaction with compound (6)] known per se, R ² is-
Compound (1) which is CONR ⁸ R ⁹ can also be produced.

[Method J] Compound (20) can also be synthesized by the following method.

Embedded image [Wherein, R ¹⁰ and R ¹¹ each represent a hydrogen atom or an optionally substituted hydrocarbon residue as exemplified for R ¹ , and each of the other symbols has the same meaning as described above. . In this method, compound (31) is produced by subjecting compound (1) to a reaction with trialkyl orthoformate and boron trifluoride-diethyl ether complex in the presence of a base. As the base, an organic base such as triethylamine and diisopropylethylamine is used. As the solvent, for example, halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride are preferable. The amount of the trialkyl orthoformate, boron trifluoride-diethyl ether complex and base to be used is preferably about 1 to about 10 molar equivalents relative to compound (1). The reaction temperature is usually about -70 ° C to about 60
C., especially −50 ° C. to 30 ° C., and the reaction time is about
1 hour to about 24 hours. The compound (31) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (32) is produced by reacting compound (1) with N, N-dimethylformamide dialkyl acetal or trisdialkylaminomethane. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
As the solvent, aromatic hydrocarbons such as benzene, toluene and xylene, and amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone are preferable. Compound (20) is produced by reacting compound (31) and compound (32) thus obtained with a hydroxylamine derivative or hydrazine derivative of compound (19). The reaction may be promoted by adding an acid to the reaction system. As the acid used, the above-mentioned inorganic acids and organic acids are used. This reaction is performed in a solvent that does not adversely influence the reaction.
As the solvent, alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide, N, N-dimethylacetamide, and amides such as N-methylpyrrolidone are preferable. . The amount of the acid to be used is about 0.1 to about 1 based on the compound (1).
0 molar equivalents are preferred. The reaction temperature is usually about 0 ° C to about 12 ° C.
0 ° C., especially 50 ° C. to 100 ° C., is suitable, and the reaction time is about 1 hour to about 24 hours. The compound (20) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound represented by formula (I) can also be synthesized by the following method. [K method]

Embedded image [The symbols in the formula are as defined above. Y represents boronic acid, boronic ester, zinc halide, copper halide, trialkyltin or triflate. The starting compound (36) of this method is described in the literature [WO2000047578, EP6
76395 and Monash Eft Für Chemich (Mo
natshefte fur Chemie), Vol. 120, p. 65 (1987)]. Known compounds can be used as they are, or can be produced by the method described therein or a method analogous thereto. Compound (3
6) is reacted with a compound (37) in which Y (boronic acid, boronic ester or triflate) is bonded to a 5- to 7-membered ring in the presence of a metal catalyst to give compound (3).
8) is manufactured. As the metal catalyst used in this reaction,
Metal catalysts generally used in aryl coupling are exemplified. For example, tetrakis (triphenylphosphine) palladium (0), dichloropalladium (II), diacetoxypalladium (II), tetrakis (triphenylphosphine) nickel (0), dichloronickel (II), diacetoxynickel (II), Copper (II) chloride, copper (II) chloride and the like are used. In some cases, it is preferable to further add phosphine (for example, triphenylphosphine, tributylphosphine, or the like). This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N-dimethylformamide;
Amides such as dimethylacetamide and N-methylpyrrolidone are preferred. The amount of compound (37) to be used is preferably about 1 to about 5 molar equivalents relative to compound (36). The amount of the metal catalyst to be used is preferably about 0.1 to about 1 molar equivalent with respect to compound (36). The reaction temperature is usually about -70 ° C to about 150 ° C, preferably 20 ° C to 80 ° C, and the reaction time is about 1 hour to about 24 hours. The compound (38) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

Further, the R of the compound represented by the general formula (I)
The conversion of ¹ can also be performed by the following method. [Method L] In the general formula (I), the compound of R ¹ optionally substituted with a hydrocarbon residue, a heterocyclic group, a hydroxyl group, or an amino group is produced by the following method.

Embedded image [Wherein, R ^{1 ′} represents an optionally substituted hydrocarbon residue, and other symbols have the same meanings as described above. That is, the sulfinyl compound or the sulfonyl compound (40) is produced by subjecting the sulfanyl group of the compound (39) which can be produced from the compound (34) by the method A to the method K to oxidation conditions. As the oxidizing agent used in the present oxidation reaction, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, pertrifluoroacetic acid, potassium permanganate, chromium oxide and the like are used. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent. As the solvent,
For example, diethyl ether, tetrahydrofuran, ethers such as dioxane, dichloromethane, chloroform,
Halogenated carbons such as carbon tetrachloride are preferred. The amount of the oxidizing agent to be used is preferably about 1 to about 10 molar equivalents relative to compound (39). The reaction temperature is usually about 0 ° C. to about 100 ° C., preferably 0 ° C. to 50 ° C., and the reaction time is about 1 hour to about 2 hours.
4 hours. Compound (40) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Next, the compound (1) is produced by reacting the compound (40) with a nucleophile in the presence of a base as necessary. As nucleophiles,
Organic metal reagents such as Grignard reagents and organic lithium reagents, alcohols such as aromatic alcohols and aliphatic alcohols, and amines such as aromatic amines and aliphatic amines can be used. As the base, the above-mentioned inorganic bases and organic bases can be used. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated carbons such as dichloromethane, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene;
Dimethylformamide, N, N-dimethylacetamide, N
Amides such as methylpyrrolidone are preferred. The nucleophile and the base are preferably used in an amount of about 1 to about 10 molar equivalents relative to compound (39). The reaction temperature is usually about -7
0 ° C. to about 100 ° C., especially −20 ° C. to 50 ° C., is suitable, and the reaction time is about 1 hour to about 24 hours. The compound (1) thus obtained is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like.

The compound (I) of the present invention or a salt thereof induces osteoblast differentiation including progenitor osteoblasts and promotes differentiation induction, and induces chondrocyte differentiation including precursor chondrocytes and promotes differentiation induction. Is expected to have a BMP action-enhancing effect. Therefore, a prophylactic / therapeutic agent for a bone or joint disease containing the compound (I) of the present invention or a salt thereof is used, for example, an osteogenesis promoting agent, a prophylactic / therapeutic agent for a bone disease, a prophylactic / therapeutic bone fracture Agents, cartilage formation promoters and cartilage disease preventive / treatment agents, specifically, non-metabolism such as fracture, refracture, bone deformity / osteomyeloma, osteosarcoma, myeloma, osteogenesis imperfections, scoliosis etc. in the orthopedic field Bone deficiency, osteoporosis, osteomalacia, rickets, fibrous osteomyelitis, renal osteodystrophy, metabolic bone disease such as bone Petchet's disease, ankylosing myelitis; or osteoarthritis or chronic Such as rheumatoid arthritis It can be used as a prophylactic / therapeutic agent for joint diseases typified by cartilage diseases, as a bone tissue repair agent after surgery for multiple myeloma, lung cancer, breast cancer and the like. In the field of dentistry, it can be expected to be applied to treatment of periodontal disease, repair of periodontal tissue defects in periodontal disease, stabilization of artificial dental roots, repair of ridges and cleft palate. Further, the compound (I) of the present invention or a salt thereof is expected to have an activity enhancing activity of a neurotrophic factor. Further, the compound (I) of the present invention or a salt thereof may be an anti-matrix metalloprotease (anti-M
MP) activity is expected. In addition, it has excellent clinically useful properties such as stability, absorbability (particularly, oral absorbability), and bioavailability. Moreover, its toxicity is low. Therefore, the compound (I) or a salt thereof of the present invention can be safely administered to mammals (eg, human, rat, mouse, dog, rabbit, cat, cow, horse, pig, etc.).

The dose of the compound (I) of the present invention or a salt thereof can be variously selected depending on the administration route and the condition of the patient to be treated. For oral administration per person, for example, about 0.1 mg to about 500 mg, preferably about 1 mg to
About 100 mg, for parenteral administration, about 0.01 mg to about 100 mg, more preferably about 0.1 mg to about 10 m
g can be selected from the range of 1 to 3 times a day.

The target compound (I) of the present invention or a salt thereof is mixed with a pharmaceutically acceptable carrier to prepare a solid preparation such as tablets, capsules, granules and powders; or a syrup,
It can be administered orally or parenterally as a liquid preparation such as an injection. Transdermal preparations such as patches, cataplasms, ointments (including creams), plasters, tapes, lotions, solutions, suspensions, emulsions and sprays can also be made. As a pharmaceutically acceptable carrier,
Various conventional organic or inorganic carrier substances are used as the drug substance, and excipients, lubricants, binders, and
Disintegrant: incorporated as a solvent, dissolution aid, suspending agent, tonicity agent, buffer, soothing agent and the like in liquid preparations. Also, if necessary, preservatives, antioxidants, stabilizers,
Pharmaceutical additives such as coloring agents and sweetening agents can also be used.

Preferred examples of excipients include, for example, lactose,
Sucrose, D-mannitol, starch, crystalline cellulose,
And light anhydrous silicic acid. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, pregelatinized starch, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferred examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium,
Sodium carboxymethyl starch; low-substituted hydroxypropylcellulose; Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

If necessary, oral preparations can be prepared by coating with a method known per se for the purpose of taste masking, enteric coating or sustainability.
Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bruronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (ROHM) And methacrylic acid / acrylic acid copolymer).

Preferred examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include, for example, stearyltriethanolamine,
Surfactants such as sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate;
For example, polyvinyl alcohol, polyvinyl pyrrolidone,
Examples include hydrophilic polymer substances such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the preservative include, for example, p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

Further, the compound (I) or a salt thereof may be, for example, a cyclooxygenase inhibitor (Cox-I, C
ox-II inhibitors), disease-modifying antirheumatic drugs and immunosuppressants, biologics, analgesics and anti-inflammatory drugs or other prophylactic / therapeutic drugs for bone or joint diseases, etc., as a single preparation or simultaneously or simultaneously It can be administered at intervals. Cyclooxygenase inhibitors (Cox-I, Cox-
Examples of the (II inhibitor) include salicylic acid derivatives such as celecoxib, rofecoxib, and aspirin, diclofenac, indomethacin, loxoprofen and the like. The dosage of these oral preparations is, for example, about 100 to 200 mg / day for celecoxib, about 10 to 30 mg / day for rofecoxib, about 1000 to 4500 mg / day for salicylic acid derivatives such as aspirin, and about 25 to 75 mg / day for diclofenac. Sun, indomethacin is about 50 ~
150mg / day, loxoprofen about 60-180m
g / day. As disease-modifying antirheumatic drugs and immunosuppressants,
Examples include methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, and oral gold preparations. The dosage of these oral preparations is, for example, about 2.5 to 7.5 mg / week for methotrexate, about 20 to 100 mg / day for leflunomide, about 1 to 5 mg / day for prograf, and about 500 to 200 mg for sulfasalazine.
0 mg / day, D-penicillamine is about 100-600 mg / day
The daily oral dose is about 3-6 mg / day. Examples of the biological agent include monoclonal antibodies (eg, anti-TNF-α antibody, anti-IL-12 antibody, anti-IL-
6 antibodies, anti-ICAM-I antibodies, anti-CD4 antibodies, etc.), soluble receptors (eg, soluble TNF-α receptors, etc.),
And proteinaceous ligands (such as IL-I receptor antagonists). The dose of these oral preparations is, for example, about 0.1 to 50 mg / kg / day, preferably 0.5 to 20 mg / kg / day. Examples of analgesics and anti-inflammatory agents include central analgesics (eg, morphine, codeine, pentadisine, etc.), steroids (eg, prednisolone, dexamethasone, betamethasone, etc.), anti-inflammatory enzyme agents (eg, bromercin, lysozyme, proctase, etc.) ). The dosage of these oral preparations is, for example, about 1 to 10 for central analgesics.
00 mg / day, preferably about 5-300 mg / day, for steroids about 0.1-400 mg / day, preferably about 0.
5-100 mg / day, about 1-100 mg /
Days, preferably about 5 to 40 mg / day. Destruction of joint tissue in other bone or joint diseases [eg, fracture, refracture, bone defect, osteoporosis, osteomalacia, bone Pechet disease, ankylosing myelitis, rheumatoid arthritis, osteoarthritis and similar diseases] For bone tissue repair after surgery for multiple myeloma, lung cancer, breast cancer, etc.], for example, calcium preparations (eg, calcium carbonate), calcitonin preparations (eg, eel calcitonin, salmon) calcitonin, porcine calcitonin, Abikatonin etc.), vitamin _{D 3} compounds (e.g., 1.alpha.-hydroxy vitamin _D 3, l [alpha], 25-dihydroxyvitamin _D 3,
Flocalcitriol, Secarciferol, etc.), sex hormone-related compounds (eg, tibolone, estrogen, estradiol, osaterone, raloxifene, droloxifene, olmeloxifen, tamoxifen, mifebristone, etc.), prostaglandin A ₁ , bisphosphonic acids ( Examples: etidronate, simidronate, alendronate, tiludronate, risedronate, clodronate, etc.), ipriflavones, fluorine compounds (eg, sodium fluoride, etc.), vitamin K ₂ , osteogenic protein (BMP), fibroblast growth factor (FGF) ), Platelet-derived growth factor (PDGF), transforming growth factor (TGF-β), insulin-like growth factors-1 and 2 (IGF-1,2), parathyroid hormone (PT
H) (eg, PTH (1-34), PTH (1-8
4), PTH (1-36), etc.).

[0048]

The present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples, but the present invention is not limited thereto. In the following, Me indicates methyl and Et indicates ethyl.

Reference Example 1

Embedded image 4-[(2E) -3- (dimethylamino) -2-propenoyl] -3-methyl-5- (methylsulfonyl) -2-thiophenecarboxylic acid ethyl ester 4-acetyl-3-methyl-5-methylsulfonyl- A mixed solution of 2-thiophenecarboxylic acid ethyl ester (10 g), tris (dimethylamino) methane (14 ml) and DMF (50 ml) is heated to 55 ° C.
After stirring for 3 hours, the mixture was concentrated and the residue was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried (MgSO ₄ ), and evaporated under reduced pressure to give the title compound as yellow crystals. Melting point: 130-131
° C.

Reference Example 2

Embedded image Methanesulfonic acid (1.7 g) was added to the compound (3 g) obtained in Reference Example 1.
ml) and the mixture was stirred at room temperature for 30 minutes. Add ethanol to this solution
(20 ml) and methylhydrazine monohydrate (0.5 ml),
Stirred at C for 1 hour. After cooling, the precipitated crystals were collected by filtration and washed with cold ethanol to give the title compound (89%) as colorless needles. _{^{1 H NMR (CDCl 3 in ppm}} ) d: 1.41 (3H, t, J = 7.4Hz),
2.28 (3H, s), 2.97 (3H, s), 3.67 (3H, s), 4.41 (2H, q, J = 7.
2Hz), 6.30 (1H, d, J = 2.2Hz), 7.62 (1H, d, J = 2.2Hz).

Embodiment 1

Embedded image 5- (1,3-benzodioxole) -3-methyl-4- (1-methyl-1H
-Pyrazol-5-yl) -2-thiophenecarboxylic acid ethyl ester sesamol (1.39 g) was dissolved in N-methylpyrrolidone (50 ml), and potassium t-butoxide (1.08 g) was added. 2 at room temperature
After stirring for 0 minutes, the compound (3.00 g) obtained in Reference Example 2 was added, and the mixture was stirred at 90 ° C. for 12 hours. The mixture was returned to room temperature, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The residual oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate: hexane (1: 4), 0.58 g of the title compound (32
%) As a yellow oil. Melting point: 95-97 ° C.

Embodiment 2

Embedded image 5- (1,3-benzodioxole) -3-methyl-4- (1-methyl-1H
-Pyrazol-5-yl) -2-thiophenecarboxylic acid A mixed solution of the compound (0.58 g) obtained in Example 1, an aqueous potassium hydroxide solution (30 ml) and tetrahydrofuran (40 ml) was stirred at room temperature for 48 hours, and then treated with 2N Hydrochloric acid was added and extracted with a mixed solution of ethyl acetate-THF. The extract was washed with water and saturated saline. After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain 0.43 g (82%) of the title compound as colorless prism crystals. Melting point: 203-205 ° C.

Embodiment 3

Embedded image 5- (1,3-benzodioxole) -3-methyl-4- (1-methyl-1H
-Pyrazol-5-yl) -2-thiophencarboxamide The compound obtained in Example 2 (0.35 g), WSC (0.21 g), HOBt-
After stirring a DMF solution (10 ml) of NH ₃ (0.17 g) at room temperature for 5 hours,
Concentrated under reduced pressure. Water was poured into the residue and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous sodium hydroxide solution and saturated saline, dried (MgSO ₄ ), and evaporated to give 0.34 g (97%) of the title compound as colorless prism crystals. Melting point: 143-145 ° C.

Embodiment 4

Embedded image 3-methyl-4- (1-methyl-1H-pyrazol-5-yl) -5-phenoxy-2-thiophenecarboxylic acid ethyl ester phenol (0.86 g) was dissolved in N-methylpyrrolidone (50 ml),
Potassium t-butoxide (0.98 g) was added. The mixture was stirred at room temperature for 20 minutes, and the compound (2.74 g) obtained in Reference Example 2 was added.
Stirred at 0 ° C. for 12 hours. The mixture was returned to room temperature, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline and then dried (M
gSO ₄ ) and the solvent were concentrated under reduced pressure. The residual oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate: hexane (1: 4), 0.91 g (32%) of the title compound was obtained.
Was obtained as a yellow oil. ¹ H NMR (ppm in CDCl ₃ ) δ:
1.33 (3H, t, J = 7.4Hz), 2.37 (3H, s), 3.78 (3H, s), 4.30 (2
H, q, J = 7.4Hz), 6.22 (1H, d, J = 2.2Hz), 7.07-7.40 (5H, m),
7.54 (1H, d, J = 2.2Hz).

Embodiment 5

Embedded image 3-methyl-4- (1-methyl-1H-pyrazol-5-yl) -5-phenoxy-2-thiophenecarboxylic acid The compound obtained in Example 4 (0.90 g), potassium hydroxide (0.35 g), A mixed solution of water (20 ml) and ethanol (50 ml) was stirred at 50 ° C. for 5 hours.
The reaction solution was concentrated, diluted with water, made acidic by adding 4N hydrochloric acid, and extracted with a mixed solution of ethyl acetate-THF. The extract was washed with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure to give 0.72 g (87%) of the title compound as prism crystals.

Embodiment 6

Embedded image 3-methyl-4- (1-methyl-1H-pyrazol-5-yl) -5-phenoxy-2-thiophenecarboxamide The compound obtained in Example 5 (0.64 g), WSC (0.43 g), HOBt-
A DMF solution (10 ml) of NH ₃ (0.34 g) was stirred at room temperature for 12 hours, and then concentrated under reduced pressure. Water was poured into the residue and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous sodium hydroxide solution and a saturated saline solution, dried (MgSO ₄ ), and evaporated to give 0.58 g (91%) of the title compound as colorless prism crystals. Melting point: 165-166 ° C.

Reference Example 3

Embedded image 3-Acetyl-5-cyano-4-methyl-2-methylsulfonylthiophene A solution of 3-acetyl-5-cyano-4-methyl-2-methylsulfanylthiophene (5.71 g) in dichloromethane (200 ml) was m-
After adding chloroperbenzoic acid (20 g) and stirring at room temperature for 12 hours, the mixture was poured into water and extracted with dichloromethane. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure to give the title compound 5.4.
1 g (82%) was obtained as colorless prisms. ¹ H NMR (ppm in
CDCl ₃ ) δ: 2.45 (3H, s), 2.60 (3H, s), 3.28 (3H, s).

Reference Example 4

Embedded image 3-Acetyl-5-cyano-2-butyl-3-methylthiophene 2.0M butylmagnesium chloride solution in a THF (250ml) solution of the compound obtained in Reference Example 3 (16.99g) under cooling at -70 ° C
(35 ml) was added dropwise. After stirring for 3 hours while gradually returning to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 2N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residual oil was subjected to silica gel column chromatography, and the title compound was eluted with ethyl acetate: hexane (1:10) to give 7.31 g (47%) of the title compound as a colorless liquid. ¹ H NMR (ppm
in CDCl ₃ ) δ: 0.95 (3H, t, J = 7.2Hz), 1.32-1.51 (2H, m),
1.59-1.74 (2H, m), 2.48 (3H, s), 2.51 (3H, s), 2.97 (2H,
t, J = 7.2Hz).

Reference Example 5

Embedded image 4-acetyl-5-butyl-3-methyl-2-thiophenecarboxylic acid ethyl ester The compound obtained in Reference Example 4 (7.31 g), concentrated hydrochloric acid (3 ml), 36%
A mixed solution of hydrochloric acid-ethanol solution (80 ml) and ethanol (100 ml) was heated under reflux for one week. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, and then dried (MgSO ₄ ). The obtained residue was subjected to silica gel column chromatography. Ethyl acetate: hexane (1:19)
3.98 g of the title compound was obtained as an oil from the portion eluted with. _{^{1 H NMR (ppm in CDCl 3}} ) δ: 0.93 (3H, t, J = 7.2Hz),
1.37 (3H, t, J = 7.0Hz), 1.58-1.74 (2H, m), 2.48 (3H, s),
2.57 (3H, s), 2.87 (2H, t, J = 7.2HZ), 4.32 (2H, q, J = 7.0H
z).

Embodiment 7

Embedded image 5-butyl-3-methyl-4- (1-methyl-1H-pyrazol-5-yl) -2-thiophenecarboxylic acid ethyl ester Boron trifluoride ether complex (4.6ml) in dichloromethane
(30 ml) triethyl orthoformate (5.
04 ml). The solution was stirred under ice cooling for 15 minutes,
Cooled to ° C. The compound obtained in Reference Example 5 was added to the solution.
(3.98 g) in dichloromethane (25 ml) and then diisopropylethylamine (5.76 g) were added dropwise. After stirring at -70 ° C for 1 hour, the reaction solution was poured into aqueous sodium hydrogen carbonate solution,
Extracted with chloroform. The organic layer was washed successively with water, diluted hydrochloric acid, and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure to give 5-butyl-4- (3,3-diethoxypropanoyl) -3- as an oil.
Methylthiophene-2-carboxylic acid ethyl ester (5.52
g) was obtained. This is methylhydrazine (1.72 g), 2N hydrochloric acid (2
6 ml) and ethanol (100 ml), heated under reflux for 3 hours, and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate.
The extract was washed successively with water and saturated saline and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the residual oil obtained was subjected to column chromatography. From the portion eluted with ethyl acetate: hexane (1: 8), 3.5 g of the title compound was obtained as an oil. ¹ HN
MR (ppm in CDCl ₃ ) d: 0.85 (3H, t, J = 7.4Hz), 1.20-1.38
(2H, m), 1.38 (3H, t, J = 7.0Hz), 1.52 (2H, sext, J = 7.0Hz),
2.25 (3H, s), 2.59 (2H, td, J = 7.4,4.6Hz), 3.61 (3H, s),
4.34 (2H, q, J = 7.4Hz), 6.18 (1H, d, J = 1.8Hz), 7.57 (1H, d,
J = 1.8Hz).

Embodiment 8

Embedded image 5-butyl-3-methyl-4- (1-methyl-1H-pyrazol-5-yl) -2-thiophenecarboxylic acid The compound (2.20 g) obtained in Example 7, potassium hydroxide (1,
A mixed solution of 54 g), water (20 ml), methanol (20 ml) and THF (5 ml) was stirred at room temperature for 12 hours. After concentrating the reaction solution, dilute with water, acidify with 4N hydrochloric acid, and add ethyl acetate-THF
Was extracted with a mixed solution of The extract was washed with water and saturated saline and dried (MgSO ₄ ) .The solvent was concentrated under reduced pressure, and 1.73 g (87
%) Were obtained as prism crystals. ¹ H NMR (ppm in CDCl ₃ )
δ: 0.86 (3H, t, J = 7.2Hz), 1.20-1.39 (2H, m), 1.49-1.64
(2H, m), 2.28 (3H, s), 2.62 (2H, td, J = 7.4,4.8Hz), 3.65
(3H, s), 6.20 (1H, d, J = 1.8Hz), 7.61 (1H, d, J = 1.8Hz).

Embodiment 9

Embedded image 5-butyl-3-methyl-4- (1-methyl-1H-pyrazol-5-yl) -2-thiophencarboxamide The compound obtained in Example 8 (1.00 g), WSC (0.76 g), HOBt-
A DMF solution (15 ml) of NH ₃ (0.60 g) was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. Water was poured into the residue and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried (MgSO ₄ ) and evaporated to give 0.88 g (88%) of the title compound as colorless prism crystals. Melting point: 115-117 ° C.

Test Example 1 Bone formation promoting action: Alkaline phosphatase activity was measured as an indicator of bone formation using stromal cells prepared from bone marrow of the femur of normal rats. That is, the method of Maniatopoulos et al. [Cell Tissue Research
arch), 254, 317 Tribute (1988)], according to Sprague-Dawle, a 7-week-old male.
y) To prepare stromal cells from rat femur bone marrow and form dexamethasone (10
^-7 M) and β-glycerophosphate (10 ⁻² M) in an α-MEM (minimum essential medium) solution. One week later, the confluent primary cells are treated with 0.25% trypsin-0.2% EDTA solution,
The cells were collected and subcultured in culture dishes at a cell density of 1.6 × 10 ⁻⁴ cells / cm ² (day 0 of culture). From the second day of the culture, a test compound (10 ⁻⁵ M) was added to the above culture solution, and further 5
Cultured for days. After washing the cells with phosphate buffer, 0.2% N
Add onidet P-40 and homogenize, 3000 rpm
The supernatant obtained after centrifugation at 10 m for 10 minutes was used and the method of Lowry et al. [Journa of Biological Chemistry (Journa
l of Biological Chemistry), Volume 207, 19 Tribute (1
954)], and alkaline phosphatase activity was measured. The measured values are shown in Table 1 as mean ± standard deviation (mean ±
SE). Statistical processing was performed by Student's t-test.

[0064]

[Table 1] Mean ± SE (n = 4), ** p (0.01 vs control) Student's t
-test

[0065]

The compound of the present invention represented by the general formula (I) or a salt thereof has an activity of inducing differentiation of undifferentiated cells such as osteoblasts and chondrocytes, and an activity of promoting differentiation induction. In addition, since BMP action enhancing action is expected, it is useful as a preventive and therapeutic agent for metabolic bone diseases including osteoporosis. In addition, cell differentiation inducing agents having such an action include, for example, bone or cartilage formation promoting agents, bone diseases such as fractures, bone defects and osteoarthritis in the field of orthopedics, or joint diseases typified by cartilage diseases. (Eg, osteoarthritis). Further, in the dental field, effects such as repair of periodontal tissue defects due to periodontal disease, stabilization of artificial dental roots, repair of ridges and cleft palate can be expected. In addition, since the compound of the present invention represented by the general formula (I) or a salt thereof is expected to have a neurotrophic factor action-enhancing activity, Alzheimer-type dementia, general senile dementia, motor neuron disorders (muscle neurons) It is expected to be useful for the treatment and prevention of various neurodegenerative diseases such as amyotrophic lateral sclerosis) and diabetic peripheral neuropathy. Further, since the compound represented by the general formula (I) or a salt thereof of the present invention is expected to have anti-MMP activity, it is involved in MMP such as osteoarthritis, rheumatoid arthritis, arteriosclerosis, and cancer metastasis. It is expected to be useful for treating and preventing diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 19/10 A61P 19/10 29/00 101 29/00 101 43/00 105 43/00 105 C07D 409 / 14 C07D 409/14 F term (reference) 4C063 AA01 AA03 BB01 CC92 DD22 EE01 4C086 BC36 GA02 GA04 MA01 NA14 ZA96 ZA97 ZB15 ZC19

Claims (22)

[Claims] 1. A compound of the general formula (I): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group, an optionally substituted Good heterocyclic group or formula: -Z ¹ -Z
² (wherein, Z ¹ represents —CO—, —CS—, —SO—, or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, R ³ represents a hydrogen atom, a halogen atom, a cyano group or an amino group which may be substituted,
An acyl group, a hydrocarbon residue or a heterocyclic group;
Represents an optionally substituted 5- to 7-membered ring. Or a salt thereof. 2. The compound according to claim 1, wherein ring A is an optionally substituted aromatic 5-membered ring. 3. The compound according to claim 1, wherein ring A is an azole which may be substituted. (4) ring A is [Wherein, R ⁴ , R ⁵ And R ⁶ Are the same or different
A hydrogen atom or a carbon atom which may be substituted
Hydrogen residue, heterocyclic group, hydroxyl group, acyl group, sulfonyl group
Alternatively, it represents an amino group. The compound according to claim 1,
object. (5) ring A is [Wherein, R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group or an amino group; Represents a group. The compound according to claim 1, wherein 6. R ² is a cyano group or a formula: —Z ¹ -Z ²
(Wherein Z ¹ represents -CO-, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group). . (7) ring A is [Wherein R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group; A group or an amino group. And R ² is a cyano group, or a formula: -Z ¹
-Z ² (wherein, ^{Z 1} represents a -CO-, ^{Z 2} is optionally substituted hydrocarbon group which may be substituted respectively, a heterocyclic group, a hydroxyl group or an amino group.) Claim 1 is A compound as described. 8. The compound according to claim 1, wherein R ¹ is an optionally substituted hydrocarbon residue. 9. The compound according to claim 1, wherein R ¹ is an optionally substituted heterocyclic group. 10. The compound according to claim 1, wherein R ¹ is an optionally substituted hydroxyl group. 11. The compound according to claim 1, wherein R ¹ is an amino group which may be substituted. 12. The ring A is [Wherein R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group; A group or an amino group. The compound according to claim ¹ , wherein R ¹ is a hydroxyl group which may be substituted. 13. Ring A is [Wherein, R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a halogen atom, a cyano group or a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group or an amino group; Represents a group. ]
And R ¹ is a hydroxyl group which may be substituted.
A compound as described. 14. The compound according to claim 1, wherein R ³ is a hydrogen atom or an optionally substituted hydrocarbon residue or heterocyclic group. 15. A prodrug of the compound of claim 1 or a salt thereof. 16. The formula: embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group, an optionally substituted Good heterocyclic group or formula: -Z ¹ -Z
² (wherein, Z ¹ represents —CO—, —CS—, —SO—, or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, R ³ represents a hydrogen atom, a halogen atom, a cyano group or an amino group which may be substituted,
An acyl group, a hydrocarbon residue or heterocyclic group, R ⁶
Is a hydrogen atom, a halogen atom, a cyano group or an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group,
It represents an acyl group, a sulfonyl group or an amino group. A) reacting with a trialkyl orthoformate and a boron trifluoride-diethyl ether complex in the presence of a base,
Formula: [In the formula, R ¹⁰ represents a hydrogen atom or a hydrocarbon residue which may be substituted, and other symbols have the same meanings as described above. Or a salt thereof, or b) reacting with N, N-dimethylalumamidodialkylacetal or trisdialkylaminomethane,
Formula: [Wherein, R ¹¹ represents a hydrogen atom or a hydrocarbon residue which may be substituted, and other symbols have the same meanings as described above. A compound represented by the formula: H ₂ N—Q′H wherein Q ′ represents an oxygen atom or NA ¹ , and A ¹ represents A hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, respectively. And reacting with a hydrazine derivative or a hydroxylamine derivative represented by the following formula: Wherein each symbol is as defined above. ] Or a salt thereof. 17. Formula (I): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group, an optionally substituted Good heterocyclic group or formula: -Z ¹ -Z
² (wherein, Z ¹ represents —CO—, —CS—, —SO—, or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, R ³ represents a hydrogen atom, a halogen atom, a cyano group or an amino group which may be substituted,
An acyl group, a hydrocarbon residue or a heterocyclic group;
Represents an optionally substituted 5- to 7-membered ring. Or a pharmaceutically acceptable salt thereof or a prodrug thereof. 18. The pharmaceutical composition according to claim 17, which is a preventive or therapeutic agent for a bone or joint disease. 19. The bone or joint disease is osteoporosis, fracture,
18. It is osteoarthritis or rheumatoid arthritis.
A pharmaceutical composition according to claim 1. 20. The pharmaceutical composition according to claim 17, which is a cell differentiation inducer. 21. A method for preventing or treating a bone or joint disease, comprising administering an effective amount of the compound according to claim 1 or a prodrug thereof to a mammal. 22. Use of the compound according to claim 1 or a prodrug thereof for producing a prophylactic / therapeutic agent for a bone or joint disease.