JP2003238565A - Condensed ring compound and blood cell-increasing medicine containing the compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new compound having a TOP receptor-operating action, and to obtain a medicinal composition, a blood cell-increasing medicine, especially a platelet-increasing medicine or a thrombocytopenia medicine which contains the compound. <P>SOLUTION: The compound is represented by formula [I] äA<SP>1</SP>is CR<SP>1</SP>[R<SP>1</SP>is SO<SB>m</SB>R<SP>7</SP>(R<SP>7</SP>is an alkyl, amino, or the like; (m) is an integer of 0 to 2), or the like]; A<SP>2</SP>is S; A<SP>3</SP>is CR<SP>4</SP>(R<SP>4</SP>is H, an alkyl, or the like); A<SP>4</SP>is CR<SP>5</SP>R<SP>6</SP>or NR<SP>5</SP>(R<SP>5</SP>and R<SP>6</SP>are each H, an alkyl, a cycloalkyl, or the like); R<SP>2</SP>is H, a halogen, an alkyl, a cycloalkyl, carboxy, an alkoxycarbonyl, a cycloalkyloxycarbonyl, carbamoyl, an acyl, an aryl, a heterocyclic group, or the like; R<SP>3</SP>is amino, OR<SP>8</SP>(R<SP>8</SP>is H, an alkyl, or the like), or the like; (p) is an integer of 0 to 2}. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fused heterocyclic compound having a hemocytosis effect, a pharmaceutical composition containing these compounds, a thrombopoietin (TPO) receptor agonist, and a hemocytosis agent.

[0002]

Blood cells are all made of bone marrow. Bone marrow contains stem cells that are common to all blood cells, including lymphocytes, which differentiate to produce red blood cells, white blood cells, and platelets. The stem cells that are the source of all blood cells are called pluripotent hematopoietic stem cells. Pluripotent hematopoietic stem cells
First, it differentiates into lymphoid stem cells that are the source of lymphocytes and myeloid stem cells that are the source of blood cells other than lymphocytes. The lymphocyte stem cells then differentiate into B cells and T cells via B cell stem cells and T cell stem cells. On the other hand, myeloid stem cells are differentiated into erythroid stem cells, granulocyte-monocytic stem cells, and megakaryocyte stem cells. Furthermore, erythroid stem cells go through preerythroblasts into erythrocytes, and granulocyte-monocytic stem cells are myeloblasts. , Mononuclear lymphocytes to granulocytes and monocytes respectively, and megakaryocyte stem cells proliferate and differentiate into megakaryocyte blasts, promegakaryocytes, and mature megakaryocytes in sequence, and the number of nuclei without cell division increases. It becomes platelets through diploidization (increase in ploidy).

Erythropoietin is required as a hematopoietic promoting factor for the production of proerythroblasts, and G, which is a liquid factor for differentiation of granulocyte-monocytic stem cells, is required.
-CSF is also said to require the involvement of thrombopoietin (TPO) as a stimulating factor in promoting differentiation of megakaryocyte stem cells. TPO is a central humoral factor that stimulates megakaryocyte production. , Acts widely from hematopoietic stem cells to platelets. Its main action points are promotion of proliferation of megakaryocyte progenitor cells and maturation of immature megakaryocytes. Rat T
PO is a signal peptide (SP) consisting of 21 amino acids
It is composed of 326 amino acid residues including, and the molecular weight of the mature protein is about 32,000. Human TPO is composed of 353 amino acid residues including SP consisting of 21 amino acids, and the molecular weight of the mature protein is about 35,000.

In TPO knockout mice and TPO receptor c-Mpl knockout mice, platelets are reduced to about 20%, so that about 80% of platelet production is TP.
It is considered to be regulated by O. SC for TPO
It acts synergistically with F and IL-3 to stimulate pluripotent stem cell colony formation. This is because TPO is IL-6,
It is considered to have an action of inducing pluripotent stem cells in a quiescent phase (G ₀ phase) into the cell cycle (G ₁ phase) like IL-11 and G-CSF.

It has been reported that when TPO was intraperitoneally administered to mice for 5 days, platelets increased 4-fold. IL-3, I
Since L-6 and IL-11 administration increased the platelet count by about 1.5 times, TPO has a strong platelet-increasing action.
2 megakaryocyte progenitor cells in the bone marrow and spleen after TPO administration
Although it increases 0 times or more, granulocyte-type and erythroid-type colonies hardly change. That is, TPO has a platelet-specific increasing effect. In addition, TPO shows a remarkable improving effect on thrombocytopenia associated with myelosuppression.

When TPO binds to the receptor, the receptor is polymerized and JAK kinase, which is a tyrosine kinase lacking the SH2 / SH3 domain, binds to the box1 and box2 regions of the cytoplasmic domain of the receptor and is phosphorylated. JAK kinases are JAK1, JAK2, JAK
Three types of Tyk2 have been identified, but in the case of TPO, JAK2 and Tyk2 are phosphorylated. Activated JAK kinase is believed to first phosphorylate the receptor. A transcription factor, STAT (signal t
ransducers andactivators of transcription) are ST
It is phosphorylated by the JAK kinase, which binds through the SH2 domain of AT itself and is already bound to the receptor. The activated JAK kinase is STAT
There are three types: 1, STAT3, and STAT5. Activated STAT forms a homo- or heterodimer through phosphorylated tyrosine and SH2 domain. Further, other proteins are added to form a complex that translocates into the nucleus, binds to the recognition sequence of the target gene, and induces gene expression. TPO
Is constitutively made up of hepatocytes and renal proximal tubule cells of the kidney, and its receptors are present in platelets, so that when platelets increase, TPO is adsorbed by the platelets and the blood concentration decreases. When the number of platelets decreases, the amount of TPO adsorbed decreases, so that the blood concentration increases. Also, megakaryocytes of bone marrow are TP
When TPO is involved in the adsorption of O and the number of megakaryocytes is small, the value of TPO is remarkably high, but when the number of megakaryocytes is large as in the case of idiopathic thrombocytopenic purpura, the value is not so high. Furthermore, in aplastic anemia, thrombocytopenia after chemotherapy, and thrombocytopenia after bone marrow transplantation, TPO production in bone marrow stromal cells is known to be enhanced.
It is considered that the production of TPO increases or decreases due to sensitization via factors such as factors.

Also, the Japanese Journal of Transfusion
According to Medicine. Vol. 46, No. 3, 46 (3); 311-316, (2000).
Then, the following reports have been made about TPO.
"Megakaryocytic progenitor cells derived from hematopoietic stem cells (colony-f
orming unit of megakaryocyte; CFU-MK)
Immature megakaryocytes that differentiate into immature megakaryocytes during cell division
Spheres increase nuclear ploidy without cell division
(Nucleus from 2n to 4n, 8n, 16n, 32n, 64n
Increase), achieve cytoplasmic maturation. Maturation in vitro
Megakaryocytes are proplatelets with elongated cytoplasm
When the culture is further changed,
telet spontaneously fragmented and platelet-like fragments
It is formed. This fragment is morphologically and functionally
It was proven to resemble platelets in blood. this
In the process of such megakaryopoiesis, TPO is CFU-M
K for megakaryocyte colony stimulating factor and megakaryocyte maturation promotion
Acts as a promoting factor. Soft agar, methyl cellulose, etc.
In the semi-solid culture system of TPO, TPO was a megakaryocyte colony.
-Stimulate CFU-MK as a stimulating factor
-Induce formation. Its activity is interleukin-3
(IL-3) and stem-cell factor; SC
Enhanced in the presence of F). TPO megakaryocyte colony sting
The major factor is mainly the expression level of GPIIb / IIIa (CD41)
CFU-MK (GPIIb / IIIa) in late differentiation⁺CF
U-MK). Rat in liquid medium
GPIIb / IIIa purified from human pelvis⁺CFU-MK to T
Large maturation with increased ploidy when cultured in the presence of PO
Many megakaryocytes were produced (up to 256n megakaryocytes were observed)
Some megakaryocytes are transformed into ploplatelets.
On the other hand, formation of ploplatelets even when TPO was added to mature megakaryocytes
Far from being promoted, it is rather suppressed. Ie blood
The action of TPO that promotes platelet production is at the CFU-MK level
To be demonstrated. Reactivity of human CFU-MK to TPO
Depends on its origin (bone marrow, peripheral blood, cord blood).
CD34⁺Reactive CFU of TPO contained in cell fraction
-The rate of MK is high in cord blood. Is it CFU-MK of cord blood?
Have a large size composed of many megakaryocytes stimulated by TPO.
Colonies are formed. That is, CFU-MK of cord blood
Shows a high proliferative potential for TPO. Meanwhile, bone marrow and peripheral
From blood CFU-MK, small megakaryocytes were stimulated by TPO stimulation.
Ronnie is formed. In addition, in culture in the presence of TPO, umbilical cord
From the CFU-MK of blood, megakaryocytes with relatively low epiloidy
It is generated and ploidy of CFU-MK of bone marrow and peripheral blood
High megakaryocytes are produced. Examine the forming ability of Proplatelet
Then, is CFU-MK of cord blood stimulated by TPO?
CFU-M of peripheral blood before differentiation into proplatelet
A culture period longer than K is required. This phenomenon is cord blood
May explain the delayed platelet recovery after transplantation
Yes. Further on, regarding the effects on other blood cells,
Is reported. "TPO alone is the first term red bud
Burst-forming unit of erythroid; B
FU-E) and late erythroid progenitor cells (colony-forming u)
nit of erythroid; CFU-E)
But in collaboration with EPO, these erythroid progenitor cells
Promote the proliferation and differentiation of. TPO is further undifferentiated before hematopoiesis
It has been revealed that it also acts on carotid cells and hematopoietic stem cells
There is. For example, SCF, IL-3, or flk2 /
In the presence of flt3 ligand (flk2 / flt3 ligand; FL)
TPO is human bone marrow CD34 containing hematopoietic stem cells⁺/ C-
kit^low/ CD38^{neg / low}Various hematopoietic progenitor cells from fractions
Induce vesicles. Also, TPO will cooperate with SCF and IL-3.
And lead the resting hematopoietic stem cells to the cell cycle. like this
In vitro experiments showed that TPO receptor c-Mp
It is suggested that 1 is expressed in hematopoietic stem cells.
In this case, it was separated from the hematopoietic stem cell fraction using an anti-c-Mpl antibody.
C-Mpl ⁺Fraction is c-Mpl^-Higher length than fraction
It has been revealed that it has the ability to construct bone marrow in the phase. In addition
Recently discovered CD38^{neg / low}Of hematopoietic stem cells
In c-Mpl knockout mice, only hematopoietic progenitor cells
Notably, hematopoietic stem cells showing long-term bone marrow reconstitution ability were also significantly reduced.
I have a little. From these results, TPO was found to be a hematopoietic stem cell.
May be deeply involved in the control of
The fact is that TPO receptor agonists simply increase thrombocytosis.
Not only useful as a drug, but also before hematopoietic progenitor cells and undifferentiated hematopoiesis
Induction of carcinogenic cells, that is, differentiation and proliferation of hematopoietic stem cells, or
It is also effective for differentiation and proliferation of erythroid progenitor cells. Also blood
IL-3 (interleukin-
3), combined with stem cell factor (SCF)
EPO (Erythroid) is used for proliferative differentiation of erythroid progenitor cells.
In combination with (popoietin), also hematopoietic progenitor cells and undifferentiated
For induction of hematopoietic progenitor cells, SCF, IL-3 or fl
Its effect when used in combination with k2 / flt3 ligand (FL)
Is expected to be further enhanced. In addition, this
Compounds with such actions are also effective in culturing cord blood.
is there.

Currently, clinical trials of recombinant TPO are in progress, and useful test results have been obtained, but there are problems due to peptides. One of them may cause the production of antibodies against the recombinant TPO preparation in the patient.
In addition, there is a problem that the injection route is obligatory. Therefore, if a low molecular weight compound having an agonistic activity of the TPO receptor can be obtained, a drug that can be administered orally as well as subcutaneously, intramuscularly, and intravenously can be obtained without the risk of causing antibody production. Therefore, it is considered to be an extremely effective drug for treating thrombocytopenia.

As a TPO receptor agonist, Japanese Patent Application Laid-Open No.
-1477 publication, the general formula

[Chemical 9] (R represents a phenyl group or an indolyl group, n is 2 to 6
Represents the integer. ) Are described.

In addition, in International Publication WO 00/35446, the general formula

[Chemical 10] Compounds represented by are described.

Further, in the specification of WO 01/21180, the general formula

[Chemical 11] Compounds represented by are described.

Further, in the specification of WO 01/39773, the general formula

[Chemical 12] Compounds represented by are described. However, each of them has a different structure from the compound of the present invention.

On the other hand, compounds similar to the compound of the present invention include Bull. Soc. Chim. Fr., (1), 322-331 (1970).
To

[Chemical 13] Is listed.

In addition, in the REGISTRY file of STN

[Chemical 14] As CAS registration number 175202-59-2,

[Chemical 15] As CAS registration number 175202-71-8,

[Chemical 16] Is registered under the CAS registration number 289494-15-1.
However, none of the above compounds relates to TPO receptor agonists.

[0015]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a compound having TPO receptor agonistic activity. Compounds having a TPO-like action are not only useful as thrombocytosis agents as described above, but also effective for inducing hematopoietic progenitor cells and undifferentiated hematopoietic progenitor cells, or proliferating and differentiating erythroid progenitor cells. , The present invention is a hemocytosis drug,
It is also an object of the present invention to provide a thrombocytopenic drug which is particularly effective for treating aplastic anemia, thrombocytopenia after chemotherapy, and thrombocytopenia after bone marrow transplantation.

[0016]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that compounds represented by the following general formula have excellent TPO-like action and TPO receptor agonistic activity. Thus, the present invention has been completed by discovering that it has high efficacy as a hemocytosis agent, especially a thrombocytosis agent.

The present invention is a compound represented by the following general formula:
And a TPO receptor agonist and a therapeutic agent for thrombocytopenia containing the compound as an active ingredient. More specifically, it is as shown in the following (1) to (14).

(1) General formula [I]

[Chemical 17] [In the formula, both A ¹ and A ² are

[Chemical 18] Represents; A ³ is

[Chemical 19] Represents; A ⁴ is

[Chemical 20] Represents a double bond. The dotted portions of a, b, c and d are double bonds.
Means that p may be an integer of 0, 1 or 2.
Representation; R¹Is a. Hydrogen atom, b. Halogen atom, c. C_1-6An alkyl group, d. C_1-6An alkoxy group, e. Carboxy group, f. (C_1-6Alkoxy) carbonyl group, g. Carbamoyl group (the carbamoyl group is 1 or 2
C_1-6It may be substituted with an alkyl group. ), h. Cyano group, i. Nitro group, j. Amino group (the amino group is C_1-6Alkyl group, C_1-7
Acyl group and (C_1-6Alkoxy) carbonyl group (the
Alkyl, acyl and alkoxycarbonyl groups are
Mino group, hydroxyl group, carboxy group, -SO₃H, -PO₃H
₂, -OSO₃H, -OPO₃H₂  With a substituent selected from
It may be replaced. 1 or 2 substituents selected from
May be replaced with. }, j. Aryl group (the aryl group is C_1-6Alkyl group
(The alkyl group is substituted with 1 to 3 halogen atoms.
You may ), C_3-7Cycloalkyl group, C_1-6Arco
Xy and amino groups (wherein the amino group is 1 or 2 C
_1-6It may be substituted with an alkyl group. 1) selected from
It may be substituted with 3 to 3 substituents. }, Or k. -SO_mR⁷[Where R⁷Is ・ Hydrogen atom, ・ C_1-6Alkyl group (wherein the alkyl group is a halogen atom,
Hydroxyl group, C_1-6Alkoxy group, carboxy group, (C_1-6A
Lucoxy) carbonyl group and amino group (wherein the amino group is 1
Or two C_1-6It may be substituted with an alkyl group. )
May be substituted with 1 to 3 substituents selected from
Yes. }, ・ Hydroxyl group, .Amino group [wherein the amino group is C_1-6Alkyl group, C_1-7A
Silyl group and (C_1-6Alkoxy) carbonyl group {these
Alkyl, acyl and alkoxycarbonyl groups are
Mino group, hydroxyl group, carboxy group, acyloxy group, -S
O₃H, -PO₃H₂, -OSO₃H, -OPO₃H₂, -O
CO-amino acid residue (the -OCO-amino acid residue is
-OPO₃H₂  Alternatively, it may be substituted with a sugar residue. )as well as
It may be substituted with a substituent selected from sugar residues. } From
It may be substituted with one or two selected substituents. ], -Aryl group (the aryl group is C_1-6Alkyl group (the
Alkyl groups substituted with 1 to 3 halogen atoms
Good. ), C_3-7Cycloalkyl group, C_1-6Alkoxy
Group, an amino group (the amino group is 1 or 2 C_1-6Al
It may be substituted with a kill group. 1) to 3 selected from
It may be substituted with the substituent. }; M is 0-2
Represents an integer. ] Represents R²Is a. Hydrogen atom, b. Halogen atom, c. C_1-6Alkyl group (the alkyl group is a halogen source
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, amino group (the amino group
Is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. May be substituted with a substituent selected from }, d. C_3-7Cycloalkyl group, e. Carboxy group, f. (C_1-6Alkoxy) carbonyl group, g. (C_3-7Cycloalkyl) oxycarbonyl group, h. Carbamoyl group (the carbamoyl group is 1 or 2
C_1-6It may be substituted with an alkyl group. ), i. C_1-7An acyl group, j. An aryl group, or k. 1 selected from nitrogen atom, oxygen atom and sulfur atom
3- to 7-membered heterocycle having up to 4 heteroatoms in the ring
{The heterocycle and the aryl group of j are C_1-6Alkyl
A group (wherein the alkyl group is substituted with 1 to 3 halogen atoms)
You may ), C_3-7Cycloalkyl group, C_1-6Arco
Xy group, amino group (wherein the amino group is 1 or 2 C_1-6A
It may be substituted with a rukyl group. 1 to 3 selected from
May be substituted with one substituent. }; R³Is a. Amino group (the amino group is C_1-6Alkyl group, C_1-7
Acyl group, (C_1-6Alkoxy) carbonyl group and C_1-6
Alkylsulfonyl group, (these alkyl groups, acyl
Group, alkoxycarbonyl group and alkylsulfonyl group
Is an amino group, a hydroxyl group, a carboxy group, -SO₃H,-
PO₃H₂, -OSO₃H, -OPO₃H₂  Chosen from
It may be substituted with a substituent. ) Selected from 1 or 2
It may be substituted with the substituent. }, b. Arylsulfonylamino group {the arylsulfoni
Luamino group is a halogen atom, C_1-6Alkyl group
The alkyl group may be substituted with 1 to 3 halogen atoms
Good. ), An amino group (wherein the amino group is 1 or 2 C_1-6A
It may be substituted with a rukyl group. ) With a substituent selected from
It may be substituted by 1 to 3. }, c. -SO₃H, d. -PO₃H₂  Or e. -OR⁸[Where R⁸Is ・ Hydrogen atom, ・ C_1-6Alkyl group (wherein the alkyl group is a halogen atom,
Hydroxyl group, C_1-6Alkoxy group, carboxy group, (C_1-6A
Lucoxy) carbonyl group, acyloxy group, amino group
(The amino group is 1 or 2 C_1-6Substitute with alkyl group
May be done. ), -OCO-amino acid residue (the -O
CO-amino acid residue is -OPO₃H₂  Or set with sugar residue
It may be replaced. ) And sugar residues selected from 1 to 3
It may be substituted with the substituent. }, ・ Amino acid residues, -CO-amino acid residue (the -CO-amino acid residue and
The amino acid residue is -OPO.₃H₂  Or replaced with sugar residue
May be done. ), -SO₃H, ・ -PO₃H₂Or -X¹-X²-R¹¹ [X here¹Is -CO-, -CO₂-Or * Represents -CONH-; X²Is ・ C_1-6Alkylene, ・ C_1-6Alkenylene, ・ Arylene, .1 to selected from nitrogen atom, oxygen atom and sulfur atom
A 3 to 7 membered heterocycle having 4 heteroatoms in the ring,
Or ・-(OCH₂CH₂)_n-(Where n is an integer from 0 to 8
Represent ) Represents; R¹¹Is ・ Hydrogen atom, ・ Halogen atom, ・ C_1-6Alkyl group (the alkyl group is substituted with an amino group
May be done. ), ・ Hydroxyl group, ・ C_1-6An alkoxy group, ・ Carboxy group, .Amino group (wherein the amino group is 1 or 2 C_1-6Archi
It may be substituted with a group. ), ・ Amino acid residues, -O-amino acid residue {the said -O-amino acid residue and before
The amino acid residue is C_1-7An acyl group (the acyl group is
It may be substituted with a mino group. ) And -OPO₃H₂  Or
It may be substituted with a substituent selected from }, ・ -OSO₃H, or ・ -OPO₃H₂  Represents ] Represents R^FourIs a. Hydrogen atom, b. Halogen atom, c. C_1-6Alkyl group (the alkyl group is a halogen source
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, amino group (the amino group
Is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. ), An aryloxy group and an aralkyloxy group
It may be substituted with 1 to 3 substituents selected. }, d. C_1-6An alkoxy group, e. Carboxy group, f. (C_1-6Alkoxy) carbonyl group, g. C_1-7An acyl group, h. C_1-6An alkylsulfonyl group, i. An aryl group, or j. Aralkyl group {the aralkyl group and the aryl of i above
Ru group is C_1-6Alkyl group (wherein the alkyl group is 1 to 3
It may be substituted with halogen atoms. ), C_3-7Cyclo
Alkyl group, C_1-6An alkoxy group or an amino group (the amino group
No group is 1 or 2 C_1-6Even if it is substituted with an alkyl group
Good. Substituted with 1 to 3 substituents selected from
Good. }; R^Five, R⁶Each independently a. Hydrogen atom, b. C_1-6Alkyl group [wherein the alkyl group is a halogen source]
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, C_1-7An acyloxy group,
Aryloxy group and aralkyloxy group {the aryl
The oxy group and the aralkyloxy group are C_1-6Alkyl group
(The alkyl group is substituted with 1 to 3 halogen atoms.
You may ), C_3-7Cycloalkyl group, C_1-6Arco
A xy group amino group (wherein the amino group is 1 or 2 C_1-6A
It may be substituted with a rukyl group. 1 to 3 selected from
May be substituted with one substituent. } Selected from 1 to
It may be substituted with 3 substituents. ], c. C_3-7Cycloalkyl group, d. Carboxy group, e. C_1-6Alkoxy) carbonyl group, f. C_1-6An alkylsulfonyl group, g. Amino group, h. A carbamoyl group (the carbamoyl group and
Mino group is 1 or 2 C_1-6Substituted with an alkyl group
Good. ), i. C_1-7An acyl group, j. An aryl group, or k. Aralkyl group {the aralkyl group and the aryl of j
Ru group is C_1-6Alkyl group (wherein the alkyl group is 1 to 3
It may be substituted with halogen atoms. ), C_3-7Cyclo
Alkyl group, C_1-6Alkoxy group, amino group (the amino
The group is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. Even if substituted with 1 to 3 substituents selected from
Good. }; R⁹, R^TenEach independently a. Hydrogen atom, b. C_1-6Alkyl group (the alkyl group is a halogen source
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, amino group (the amino group
Is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. Even if substituted with 1 to 3 substituents selected from
Good. }, c. Hydroxyl group, d. C_1-6An alkoxy group, e. C_1-7An acyl group, f. C_1-6An alkylsulfonyl group, g. An aryl group, or h. 1 selected from nitrogen atom, oxygen atom and sulfur atom
3- to 7-membered heterocycle having up to 4 heteroatoms in the ring
{The heterocyclic ring and the aryl group of g are C_1-6Alkyl
A group (the alkyl group is substituted with 1 to 3 halogen atoms)
May be done. ), C_3-7Cycloalkyl group, C_1-6Al
Coxy group, amino group (the amino group is 1 or 2 C
_1-6It may be substituted with an alkyl group. 1) selected from
It may be substituted with 3 to 3 substituents. Represents};

[Chemical 21] Represents Provided that either one of R ⁵ and R ⁶ is a methyl group, and R ¹ and R ² are simultaneously a methyl group, or
Except when R ⁴ , R ⁵ and R ⁶ are simultaneously hydrogen atoms. ]
Or a prodrug thereof, a salt thereof, or a solvate thereof.

(2) General formula [II]

[Chemical formula 22] [In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ ,

[Chemical formula 23] Represents the definition described in (1) above. ] The compound shown by these, its prodrug, its salt, or its solvate.

(3) In the general formula [II],

[Chemical formula 24] And R¹But -SO_mR⁷  (R⁷Is according to claim 1.
Represents a definition. ) Is; R²But (C_1-6Alkoxy)
Rubonyl group or selected from nitrogen atom, oxygen atom and sulfur atom
3 to 7 having 1 to 4 heteroatoms within the ring
Member heterocycle (wherein the heterocycle is C_1-6Alkyl group (the alk
Radicals may be substituted with 1 to 3 halogen atoms
Yes. ), C_3-7Cycloalkyl group, C_1-6An alkoxy group,
An amino group (wherein the amino group is 1 or 2 C_1-6Alkyl
It may be substituted with a group. 1 to 3 units selected from
It may be substituted with a substituent. }; R³But-OR⁸  
(R⁸Represents the definition of claim 1. ) Is; R
^FiveBut C_1-6Alkyl group [wherein the alkyl group is a halogen source]
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, aryloxy group and
Aralkyloxy group {the aryloxy group and aralkyl
The ruoxy group is C _1-6An alkyl group (wherein the alkyl group is 1
It may be substituted with 3 to 3 halogen atoms. ), C_3-7
Cycloalkyl group, C_1-6Alkoxy group, amino group (the
Amino group is 1 or 2 C_1-6Substituted with an alkyl group
May be. Substituted with 1 to 3 substituents selected from
You may Substituted with 1 to 3 substituents selected from
May be done. ] Or C_3-7Is a cycloalkyl group
R; R⁶Is a hydrogen atom or C_1-6The above which is an alkyl group
The compound according to (2) or a prodrug thereof, or
A salt or solvate thereof.

(4) A pharmaceutical composition comprising the compound according to any one of (1) to (3) above, a prodrug thereof, a salt thereof or a solvate thereof as an active ingredient.

(5) A TPO receptor agonist comprising the compound according to any one of (1) to (3) above, a prodrug thereof, a salt thereof or a solvate thereof as an active ingredient.

(6) A hematopoietic drug containing the compound according to any one of (1) to (3) above, a prodrug thereof, a salt thereof or a solvate thereof as an active ingredient.

(7) A hematopoietic stem cell differentiation / proliferation agent comprising the compound according to any one of (1) to (3) above, a prodrug thereof, or a salt thereof or a solvate thereof as an active ingredient. .

(8) The hematopoietic stem cell differentiation / proliferation agent according to (7) above, which is used in combination with stem cell factor (SCL), interleukin-3 (IL-3) or flk2 / flt3 ligand (FL).

(9) A thrombocytosis drug comprising the compound according to any one of (1) to (3) above, a prodrug thereof, a salt thereof or a solvate thereof as an active ingredient.

(10) The thrombocytosis drug according to (9) above, which is used in combination with stem cell factor (SCL) or interleukin-3 (IL-3).

(11) Erythropoietin (EPO) containing the compound according to any one of (1) to (3) above, a prodrug thereof, or a salt thereof or a solvate thereof as an active ingredient. Erythrocytosis drug for concomitant use.

(12) A therapeutic agent for thrombocytopenia, which comprises the compound according to any one of (1) to (3) above, a prodrug thereof, or a salt thereof or a solvate thereof as an active ingredient.

(13) Cord blood is cultured in the presence of the compound according to any one of (1) to (3) above, a prodrug thereof, a salt thereof or a solvate thereof. Cord blood differentiation and proliferation method.

(14) The cord blood differentiation / proliferation method according to (13) above, which comprises culturing the cord blood in the presence of stem cell factor (SCL) or interleukin-3 (IL-3).

The definitions of terms used in the present specification are as follows. The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

The "C _1-6 alkyl group" means a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. , Sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, hexyl group and the like, preferably having 1 carbon atom.
To C ₄ alkyl groups selected from four methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, isobutyl groups, sec-butyl groups and tert-butyl groups.

The "C _3-7 cycloalkyl group" represents a cyclic alkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. And preferably a C _3-5 cycloalkyl group selected from a cyclopropyl group, a cyclobutyl group and a cyclopentyl group.

The term "C _1-6 alkoxy group" means a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec. -Butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy group or hexyloxy group and the like, and preferably methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group or It is a C _1-4 alkoxy group selected from tert-butoxy groups.

[0036] The "(C _1-6 alkoxy) carbonyl group", alkoxycarbonyl group C _1-6 alkoxy portion is indicated by the "C _1-6 alkoxy group" include a methoxycarbonyl group, an ethoxycarbonyl group , Propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group or hexyloxycarbonyl group. Preferably a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,
Isopropoxycarbonyl group, butoxycarbonyl group,
It is a (C _1-4 alkoxy) carbonyl group selected from sec-butoxycarbonyl group or tert-butoxycarbonyl group.

The "(C _3-7 cycloalkyl) oxycarbonyl group" is a cycloalkyloxycarbonyl group whose cycloalkyl moiety is the above-mentioned "C _3-7 cycloalkyl group", for example, a cyclopropyloxycarbonyl group,
Examples thereof include a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group and a cycloheptyloxycarbonyl group. Preferred is a cyclopropyloxycarbonyl group having a cycloalkyl group having 3 to 5 carbon atoms, a cyclobutoxycarbonyl group or a cyclopentyloxycarbonyl group.

The "C _1-7 acyl group" means 1 to 7 carbon atoms.
Represents a single alkanoyl group or aroyl group, and examples thereof include a formyl group, an acetyl group, a propionyl group, a butyryl group, a pivaloyl group and a benzoyl group. It is preferably a formyl group, an acetyl group, a pivaloyl group or a benzoyl group.

The "C _1-7 acyloxy group" has 1 carbon atom.
To 7 alkanoyloxy groups or aroyloxy groups, and examples thereof include a formyloxy group, an acetyloxy group, a propionyloxy group, a butyryloxy group, a pivaloyloxy group and a benzoyloxy group. Preferred is a formyloxy group, an acetyloxy group, a pivaloyloxy group or a benzoyloxy group.

The "C _1-6 alkylsulfonyl group" means a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group. , Sec-butylsulfonyl group, butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, tert-pentylsulfonyl group, hexylsulfonyl group, etc., preferably a methylsulfonyl group having 1 to 4 carbon atoms, an ethylsulfonyl group. , A C _1-4 alkylsulfonyl group selected from a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, a sec-butylsulfonyl group and a tert-butylsulfonyl group.

The "aryl group" is an aromatic hydrocarbon group having 6 to 12 carbon atoms, which may be partially saturated. Examples thereof include a phenyl group, a biphenyl group, an indenyl group, naphthyl group, etc., preferably a phenyl group or a naphthyl group, and particularly preferably a phenyl group.
The position of the bond of these aryl groups and the position of the substituent in the case of having a substituent are not particularly limited as long as they are chemically acceptable.

The "aryloxy group" means a group in which the above "aryl group" is bonded via an oxygen atom, and examples thereof include a phenyloxy group, a biphenyloxy group, an indenyloxy group and a naphthyloxy group, preferably. Is a phenyloxy group or a naphthyloxy group, particularly preferably a phenyloxy group. When these aryloxy groups have a substituent, the position of the substituent is not particularly limited as long as it is chemically acceptable.

The "aralkyl group" means an arylalkyl group in which the above "aryl group" is substituted with the above "C _1-6 alkyl group", and examples thereof include benzyl group, phenethyl group, and 3
Examples include -phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1-naphthylmethyl group and 2-naphthylmethyl group. Preferred is a phenyl C _1-2 alkyl group such as a benzyl group or a phenethyl group in which the “aryl” part is phenyl and the “alkyl” part is methyl or ethyl.

The "aralkyloxy group" is a group in which the above "aryl group" is substituted with the above "C _1-6 alkoxy group", and examples thereof include benzyloxy group, benzhydryloxy group, trityloxy group and phenethyl group. Oxy group, 3-phenylpropoxy group, 2-phenylpropoxy group, 4-
Phenylbutoxy group, indenylmethoxy group, naphthylmethoxy group, 2-naphthylethoxy group, 4-biphenylmethoxy group, 3- (4-biphenyl) propoxy group,
2,3-dihydroindenylmethoxy group or 1,2,
3,4-tetrahydronaphthylmethoxy group and the like can be mentioned. It is preferably an aralkyloxy group selected from a benzyloxy group and a phenethyloxy group.

The "arylsulfonylamino group" represents a group in which the above "aryl group" is bonded to a sulfonylamino group, and examples thereof include a phenylsulfonylamino group, a biphenylsulfonylamino group, an indenylsulfonylamino group and a naphthylsulfonylamino group. Of these, a phenylsulfonylamino group or a naphthylsulfonylamino group is preferable, and a phenylsulfonylamino group is particularly preferable. When these arylsulfonylamino groups have a substituent, the position of the substituent is not particularly limited as long as it is chemically acceptable.

The "3- to 7-membered heterocycle having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in the ring" may be a saturated ring or an unsaturated ring. Well, for example, thiophene, dihydrothiophene, furan, dihydrofuran, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, thiazole, thiazoline, isothiazole, isothiazoline, oxazole, oxazoline, isoxazole, isoxazoline, triazole, triazoline, thiadiazole, Unsaturated 5-membered rings such as thiadiazoline, oxadiazole, oxadiazoline, dithiazole, dithiazoline, dioxazole, dioxazoline; unsaturated 6-membered rings such as pyridine, pyrazine, pyrimidine, pyran; azepine, thiepine, oxepi , Diazepine, thiazepine,
Unsaturated 7-membered rings such as oxazepine, triazepine, thiadiazepine and oxadiazepine; saturated 3-membered rings such as aziridine and oxirane; saturated 4-membered rings such as azetidine and oxetane; pyrrolidine, oxolane, dioxolane, thiolane, dithiolane, pyrazolidine, imidazolidine, Saturated 5-membered rings such as oxazolidine, thiazolidine, isoxazolidine and isothiazolidine; piperidine, oxane,
Examples thereof include saturated 6-membered rings such as thiane, piperazine, morpholine, thiomorpholine, dioxane and dithiane; and saturated 7-membered rings such as hexahydroazepine, tetrahydrooxazepine, tetrahydrothiazepine and hexahydrodiazepine. The position of the hetero atom, the position of the bond and the position of the substituent in the case of having a substituent in the ring of these heterocycles are not particularly limited as long as they are chemically acceptable.

The term "C _1-6 alkylene" means alkylene having 1 to 6 carbon atoms, such as methylene, ethylene,
Examples thereof include propylene, butylene, pentylene, hexylene and the like. Preferably, it is a C _1-4 alkylene group selected from methylene, ethylene, propylene or butylene.

The "C _1-6 alkenylene group" has 2 carbon atoms.
To 6 alkenylene, for example vinylene, 1-
Propenylene, 2-propenylene, 1-butenylene, 2
-Butenylene, 3-butenylene, 1-pentenylene, 2
-Pentenylene, 3-pentenylene, 4-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene and the like can be mentioned. Preferred is a C _1-6 alkynylene group selected from vinylene, 1-propenylene or 2-propenylene.

The "arylene" is a divalent aromatic hydrocarbon group having 6 to 12 carbon atoms, which may be partially saturated. Examples thereof include phenylene, biphenylene, indenylene or naphthylene, preferably phenylene or naphthylene, particularly preferably phenylene. The position of the bond of these arylene and the position of the substituent in the case of having a substituent are not particularly limited as long as they are chemically acceptable.

"Amino acid residue" means alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, phenylglycine, proline, serine, threonine, tryptophan. , Tyrosine, valine and the like. Preferred is alanine, glycine, glutamic acid or lysine. The binding position of the amino acid residue and the position of the substituent in the case of having a substituent are not particularly limited as long as they are chemically acceptable, and may be a side chain,
Bonding with a carboxy group or an amino group is preferred.

The "-O-amino acid residue" refers to a group in which an amino acid is bound via an oxygen atom, and examples of the amino acid include those mentioned in the above "amino acid residue". Preferred is -O-alanine, -O-glutamic acid or -O-lysine. The bonding position between the amino acid residue and the oxygen atom and the position of the substituent when it has a substituent are not particularly limited as long as they are chemically permissible, and may be a side chain. A preferred bond is a bond in which a hydroxyl group of a carboxyl group and an oxygen atom are substituted, and the position of the substituent is another functional group.

The "-CO-amino acid residue" refers to a group in which an amino acid is bound via a carbonyl group, and the amino acid includes those mentioned in the above "amino acid residue". The bonding position between the amino acid residue and the carbonyl group and the position of the substituent in the case of having a substituent are not particularly limited as long as they are chemically acceptable, and may be a side chain. The preferred bonding position is the bond with the amino group, and the position of the substituent is another functional group.

The "-OCO-amino acid residue" refers to a group in which an amino acid is bound via -OC (= O)-, and the amino acid includes those mentioned above in "amino acid residue". The bonding position between the amino acid residue and the oxycarbonyl group and the position of the substituent in the case of having a substituent are not particularly limited as long as they are chemically permissible, and may be a side chain. The preferred bonding position is the bond with the amino group, and the position of the substituent is another functional group.

"Sugar residue" means xylose, ribose,
5-carbon sugar such as arabinose, glucose, galactose,
6-carbon sugars such as glucose, idose, mannose, talose, allose and altrose, amino sugars such as glucosamine, galactosamine, N-acetylglucosamine, N-acetylgalactosamine and derivatives thereof, gluconic acid,
Examples thereof include acidic sugars such as glucuronic acid, galactonic acid, galacturonic acid and sialic acid. The bonding position of these sugar residues is not particularly limited as long as it is chemically acceptable.

The "prodrug" of a compound has a group capable of being chemically or metabolically decomposed, and shows a pharmaceutically active substance by hydrolysis or solvolysis or by decomposition under physiological conditions. It is a derivative of the compound of the present invention. For example, with respect to the hydroxyl group of the compound, -CO-alkyl, -CO
₂ - alkyl, -CONH- alkyl, -CO- alkenyl, -CO ₂ - alkenyl, -CONH- alkenyl, -CO- aryl, -CO ₂ - aryl, -CON
H- aryl, -CO- heterocyclic, -CO ₂ - heterocycle, -
CONH-heterocycle (the alkyl, alkenyl, aryl and heterocycle are halogen atom, alkyl group, hydroxyl group, alkoxy group, carboxy group, amino group, amino acid residue,-
_{PO 3 H 2, -SO 3 H} , -OPO 3 H 2, may be substituted with -OSO ₃ H and the like. ), - CO- polyethylene glycol residue, -CO ₂ - polyethylene glycol residue, -
CO- polyethylene glycol monoalkyl ether residue, -CO ₂ - one polyethylene glycol monoalkyl ether residue or -PO ₃ H ₂ or the like is substituted or, -CO- alkyl the amino group of the compound, -CO ₂ - alkyl, -CO- alkenyl, -CO ₂ - alkenyl, -CO ₂ - aryl, -
CO- aryl, -CO- heterocyclic, -CO ₂ - heterocyclic
(The alkyl, alkenyl, aryl, heterocycle halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, an amino group, an amino acid residue, -PO ₃ H _2, -SO ₃
H, -OPO ₃ H _2, may be substituted with -OSO ₃ H and the like. ), -CO- polyethylene glycol residue, -CO
₂ - polyethylene glycol residue, -CO- polyethylene glycol monoalkyl ether residue, -CO ₂ - polyethylene glycol monoalkyl ether residue or -
PO ₃ as H ₂ or the like has been substituted, or an alkoxy group in the carboxy group of the compound, an aryloxy group (the alkoxy group, aryloxy group halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxy group, an amino group, an amino acid residue _{group, -PO 3 H 2, -SO 3} H, -OPO 3 H 2, -O
It may be replaced with SO ₃ H or the like. ), A polyethylene glycol residue or a polyethylene glycol monoalkyl ether residue and the like are substituted.

The "salt" of a compound or prodrug means an inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate; acetate, propionate, succinate,
Glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate. Organic acid addition salts such as; and amino acid addition salts such as aspartate or glutamate, but are not limited thereto.

The present invention includes solvates,
Here, the "solvate" of the compound or prodrug or a salt thereof means that the compound of the present invention is water, a solvent molecule such as alcohol and van der Waals force, or a solvate, in a solid state such as crystal or amorphous. Electrical interaction,
It means those bonded by relatively weak bonds such as hydrogen bond, charge transfer bond, and coordinate bond. In some cases, the solvent may be incorporated in a solid state such as a water-containing material or an alcohol-containing material.

The compounds represented by the general formulas [I] and [II] according to the present invention include various isomers such as optical isomers,
Stereoisomers, geometric isomers, tautomers and the like may exist.
The scope of the present invention includes all these isomers and mixtures thereof.

[0059]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound represented by the general formula [I] according to the present invention, A ¹ is preferably

[Chemical 25] And A ² is preferably a sulfur atom, A ³ is preferably CH ₂ , and A ⁴ is preferably

[Chemical formula 26] Is. p is preferably 1.

The general formulas [I] and [II] according to the present invention
In the compound represented by, R ¹ is preferably —SO _m R ⁷ , and R ⁷ is preferably a C _1-6 alkyl group or an amino group, and the amino group is unsubstituted or C
_1-7 acyl group substitution is preferable, and the C _1-7 acyl group is preferably amino group substitution. m is preferably 2. R ²
It is preferably a (C _1-6 alkoxy) carbonyl group or a 3- to 7-membered heterocycle having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in the ring. R ³ is preferably —OR ⁸ and R ⁸ is preferably a hydrogen atom or a prodrug residue. R ⁴ is preferably a hydrogen atom or a C _1-6 alkyl group. R ⁵ is preferably C
_1-6 alkyl group or C _3-7 cycloalkyl group, which is preferably unsubstituted, 3-substituted with halogen atom, or 1-substituted with C _1-6 alkoxy group or (C _1-6 alkoxy) carbonyl group . R ⁶ is preferably a hydrogen atom or a C _1-6 alkyl group.

For convenience, the R ³ -N = C site of the compound of the present invention is

[Chemical 27] , But may be in the E form, the Z form, or a mixture thereof.

Next, the method for producing the compound represented by the general formula [I] according to the present invention will be specifically described. However, it goes without saying that the present invention is not limited to these manufacturing methods. When constructing the compound of the present invention, the order of construction may be appropriately selected from a site that is easy to perform. In addition, in each step, when there is a reactive functional group, it may be appropriately protected and deprotected, and reagents other than the exemplified reagents can be appropriately used in order to accelerate the progress of the reaction. All the compounds obtained in each step can be isolated and purified by a conventional method, but in some cases, the compound can proceed to the next step without isolation and purification. Methods for isolation and purification include distillation, crystallization, recrystallization, silica gel column chromatography,
A commonly used method such as thin layer chromatography or preparative HPLC may be appropriately selected and combined.

Process drawing 1

[Chemical 28] (X represents a halogen atom and each of the other symbols has the same meaning as described above.)

Step 1 According to the method described in Synthetic Commun., 25 (16) 2449-2455 (1995), the diketone compound (3) and the compound (4) are
Compound (5-1) is obtained by reacting with carbon disulfide and an alkyl halide.

Second step The compound (5-1) obtained in the first step is treated with m-chlorobenzoic acid, hydrogen peroxide, peracetic acid, periodic acid in a solvent such as dichloromethane, 1,2-dichloroethane or chloroform. Oxidation reaction is carried out using an oxidizing agent such as sodium or potassium permanganate, and trifluoro is carried out in a solvent such as dichloromethane, 1,2-dichloroethane or chloroform in the presence of a base such as pyridine, triethylamine or N, N-diisopropylethylamine. React with acid anhydrides such as acetic anhydride and acetic anhydride. Furthermore, subsequently, by reacting methanol, ethanol, n-propanol, isopropanol, 1,4-dioxane, tetrahydrofuran or the like or a mixed solvent of these and water with an oxidizing agent such as hydrogen peroxide or peracetic acid, Compound (5-
2) is obtained.

Third step The compound (5-2) obtained in the second step is treated with dichloromethane, 1,2-dichloroethane, chloroform, 1,4-
N-chlorosuccinimide, in a mixed solvent of dioxane, tetrahydrofuran, etc. or a mixed solvent of these and water,
By reacting with a halogenating agent such as N-bromosuccinimide, thionyl chloride or oxalyl chloride,
Compound (6) is obtained. In this reaction, the compound (5-
The salt of 2) may be salted with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, and then halogenated.

Fourth Step The compound (6) obtained in the third step is treated with water, methanol, ethanol, n-propanol, isopropanol, 1,4-dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, dichloromethane, 1,2-dichloroethane. The compound (5-3) is obtained by reacting the compound (7) in chloroform, chloroform or a mixed solvent thereof. Sodium carbonate in this reaction,
You may add bases, such as potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate.

Step 5 Compound (5-3) was added to methanol, ethanol, n-
By reacting the compound (8) or a salt thereof in a solvent such as propanol, isopropanol, 1,4-dioxane and tetrahydrofuran, a compound represented by the general formula [I] can be obtained. When a compound having an ═N—R ³ group of ═N—OR ⁸ is desired, first, a compound having an R ³ group of a hydroxyl group is prepared, and then an ether type —OR ⁸ group is formed according to a known method. You may convert. When the substituent R ³ bonded to the nitrogen atom is a stable substituent that does not adversely affect the subsequent reaction, it is replaced with a ═N—R ³ group in advance before the first to fourth steps. Good.

Further, of the compounds represented by the general formula [I], if the compound represented by the compound [I-2] is desired, the following steps can be carried out. Process diagram 2

[Chemical 29] (R ^2A represents an optionally substituted C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _1-6 alkoxy group, an optionally substituted amino group, and the other symbols are respectively the same as defined above. Represents the meaning of.)

Step 6 Compound (9) obtained according to a known method or the method described above in [Step 1] is treated with water, methanol,
Ethanol, n-propanol, isopropanol,
Sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, 1,4-dioxane, tetrahydrofuran or the like or a mixed solvent thereof.
The compound (10) can be obtained by the hydrolysis reaction in the presence of a base such as sodium hydrogen carbonate or potassium hydrogen carbonate.

Step 7 The compound (10) obtained in Step 6 was treated with carboxylic acid such as carbonyldiimidazole, thionyl chloride, oxalyl chloride or isobutyl chlorocarbonate in a solvent such as tetrahydrofuran, 1,4-dioxane or dichloromethane. The compound (11) is reacted in the presence of an agent and a base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine. Then, using a solvent such as benzene, toluene, xylene, etc., acetic acid, propionic acid, p
-The compound (12) is obtained by performing a dehydration reaction under heating in the presence of an acid catalyst such as toluenesulfonic acid or camphorsulfonic acid.

Step 8 The compound (12) obtained in Step 7 is subjected to the method shown in Step 5 to give a compound represented by the general formula [I-2].

When a compound modified with a functional group such as a hydroxyl group or an amino group is desired, it is known by using a reagent such as a halogenated carbonate, an isocyanate, an acid chloride, an acid anhydride, an alkyl halide or an alkyl sulfonate. Can be modified by the method.

When an acid addition salt or base addition salt of the compound represented by the general formula [I] is desired, a known method can be used. For example, the compound represented by the general formula [I] is converted into water, methanol, ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, 1,2-dichloroethane or chloroform, or the like. It may be dissolved in these mixed solvents, the above-mentioned solvent in which a desired acid or base is dissolved is added thereto, and the precipitated crystals are collected by filtration or concentrated under reduced pressure.

When the compound represented by the general formula [I] or its intermediate is a racemate and the optically active substance is desired, it can be separated by a known method. Separation method is optically active 1-
Phenethylamine, optically active alkaloids, optically active camphorsulfonic acid, separation by crystallization of salts using optically active tartaric acid and its derivatives, recrystallization, chiral column chromatography, and appropriately selected conventional methods such as chiral preparative HPLC, It can also be performed in combination.

The compound represented by the general formula [I] according to the present invention thus obtained has an excellent thrombocytosis effect. When the compound of the present invention is used as a TPO receptor agonist, particularly as a therapeutic drug for thrombocytopenia, it is usually administered systemically or locally, orally or parenterally.

The dose varies depending on the age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually within the range of 0.01 mg to 10 g per adult, and is orally or parenterally administered once to several times a day. To be done.

When the compound of the present invention is made into a solid composition for oral administration, it may be in the form of tablets, pills, powders, granules and the like. In such solid compositions, the one or more active substances are at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol,
It is mixed with glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylhydrin, magnesium aluminometasilicate, anhydrous silicic acid powder or the like. Further, the composition may be mixed with an additive other than the diluent according to a conventional method.

In the case of preparing tablets or pills, it may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, if necessary, or with two or more layers. You may. Further, it may be a capsule of a substance such as gelatin or ethyl cellulose.

When the composition is a liquid composition for oral administration, it may be in the form of a pharmaceutically acceptable emulsion, solubilizer, suspension, syrup or elixir. Examples of the diluent to be used include purified water, ethanol, vegetable oil or emulsifier. In addition to the diluent, the composition may be mixed with an auxiliary agent such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent or a preservative.

When preparing a parenteral injection,
Sterile aqueous or non-aqueous solutions, solubilizers, suspensions or emulsifiers are used. Examples of the aqueous solution, solubilizer, and suspension include distilled water for injection, physiological saline cyclodextrin and its derivatives, triethanolamine, diethanolamine, monoethanolamine, triethylamine, and other organic amines or inorganic alkaline solutions. Etc.

In the case of making an aqueous solution, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, etc. may be used. Further, as the solubilizer, for example, polyoxyethylene hydrogenated castor oil, a surfactant (mixed micelle formation) such as sucrose fatty acid ester, or lecithin or hydrogenated lecithin (liposome formation) is used. It is also possible to prepare an emulsion preparation comprising a non-water-soluble solubilizer such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol or the like.

Other compositions for parenteral administration include external preparations containing one or more active substances and formulated by a method known per se, ointments such as ointments, suppositories or pessaries. Etc.

[0084]

EXAMPLES The compound represented by the general formula [I] and the method for producing the same according to the present invention will be specifically described by the following examples. However, it goes without saying that the present invention is not limited to these examples.

Example 1 Step 1 3-Methylsulfanyl-4-oxo-6-propyl-
4,5,6,7-Tetrahydrobenzo [c] thiophene-1-carboxylic acid ethyl ester

[Chemical 30] 5-propylcyclohexane-1,3-dione (20
g, 130 mmol) in N, N-dimethylformamide (120 ml) solution, potassium carbonate (54 g, 390 m)
mol) was added and the mixture was stirred at room temperature for 15 minutes. Carbon disulfide (8.7 ml, 140 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes and then cooled in an ice bath. A solution of ethyl chloroacetate (14 ml, 130 mmol) in N, N-dimethylformamide (128 ml) was added dropwise thereto over 1 hour, and the mixture was further stirred under ice cooling for 1 hour. A solution of methyl iodide (8.1 ml, 130 mmol) in N, N-dimethylformamide (52 ml) was added dropwise thereto under ice cooling, and the mixture was further stirred at room temperature for 2 hours. Water was poured into this suspension until it became a uniform solution, the solution was opened in water (1200 ml), ethanol (500 ml) was further added, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration to give the title compound (2
9 g, yield 73%) was obtained. NMR (δ value, 300 MHz, CDCl ₃ ) 0.88-0.95 (3H, m), 1.34-1.50
(7H, m), 2.05-2.25 (1H, m), 2.25 (1H, dd, J = 16.1, 11.3H
z), 2.55-2.70 (5H, m), 3.58 (1H, ddd, J = 17.4, 4.0, 1.6H
z), 4.34 (2H, q, J = 7.1Hz).

Step 2 3-Methylsulfanyl-4-oxo-6-propyl-
4,5,6,7-Tetrahydrobenzo [c] thiophene-1-carboxylic acid

[Chemical 31] 3-methylsulfanyl-4-oxo-6-propyl-
4,5,6,7-Tetrahydrobenzo [c] thiophene-1-carboxylic acid ethyl ester (58 g, 190 m
2M aqueous sodium hydroxide solution (190 ml, 380 mmol) was added to an ethanol (370 ml) suspension of (mol) and the mixture was reacted under heating under reflux for 2 hours. After cooling, the solvent was distilled off under reduced pressure. Water was added to the concentrated residue, the mixture was acidified with 6M hydrochloric acid and the precipitated solid was collected by filtration and washed with a small amount of ethyl acetate and hexane to give the title compound (50 g, yield 94%). NMR (δ value, 400MHz, DMSO-d ₆ ) 0.85-0.95 (3H, m), 1.30-1.
40 (4H, m), 2.00-2.15 (1H, m), 2.30 (1H, dd, J = 16.6,11.0H
z), 2.45-2.55 (1H, m), 2.55-2.65 (4H, m), 3.20-3.50 (1
H, m).

Step 3 Optically active 3-methylsulfanyl-4-oxo-6-propyl-4,5,6,7-tetrahydrobenzo [c] thiophene-1-carboxylic acid 3-methylsulfanyl-4-oxo-6- Propyl-
After 4,5,6,7-tetrahydrobenzo [c] thiophene-1-carboxylic acid (60 g, 210 mmol) was dissolved in tetrahydrofuran (900 ml) under heating under reflux,
(+)-1-Phenethylamine (27 ml, 210 mm
ol) was added and the mixture was heated under reflux for 1 hour. The solution was allowed to stand overnight at room temperature, the precipitated solid was collected by filtration, and the obtained solid was recrystallized three times using tetrahydrofuran to obtain a crystal. The crystals were suspended in 300 ml of ethyl acetate and tetrahydrofuran and then acidified with 1M hydrochloric acid. The separated organic layer was further washed with 1M hydrochloric acid and saturated saline,
It was dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure to give the title compound (8.1 g, yield 14%). NMR (δ value, 400MHz, DMSO-d ₆ ) 0.85-0.95 (3H, m), 1.30-1.
40 (4H, m), 2.00-2.15 (1H, m), 2.30 (1H, dd, J = 16.6, 11.0
Hz), 2.45-2.55 (1H, m), 2.55-2.65 (4H, m), 3.20-3.50 (1
H, m).

Step 4 1- (3-Methyl- [1,2,4] oxadiazole-
5-yl) -3-methylsulfanyl-6-propyl-
6,7-Dihydro-5H-benzo [c] thiophene-4
-On

[Chemical 32] Optically active 3-methylsulfanyl-4-oxo-6-propyl-4,5,6,7-tetrahydrobenzo [c] thiophene-1-carboxylic acid (8.1 g, 28 mmol)
Carbonyldiimidazole (6.9 g, 43 mmol) was added to a tetrahydrofuran (162 ml) suspension prepared in Step 1.
Heated to reflux for hours. After cooling to room temperature, hydrochloric acid N-
Hydroxyacetamidine (4.1 g, 37 mmol)
And triethylamine (5.2 ml, 37 mmol) were added, and the mixture was reacted with heating under reflux for 2 hours. After cooling, the solvent was distilled off under reduced pressure, the resulting residue was treated with water (200 ml) and a small amount of hexane, and the solid was collected by filtration. This solid was suspended in xylene (200 ml) and 1-heptanol (20 ml), and the reaction was performed for 3 hours while heating while removing water using a Dean Stark apparatus. After allowing to cool, the solvent was evaporated under reduced pressure, the residue was treated with hexane, and the obtained solid was collected by filtration to give the title compound (6.0 g, 65%). NMR (δ value, 300MHz, DMSO-d ₆ ) 0.89 (3H, t, J = 6.8Hz), 1.25
-1.45 (4H, m), 2.05-2.25 (1H, m), 2.30-2.45 (4H, m), 2.4
5-2.65 (1H, m), 2.68 (3H, s), 2.76 (1H, dd, J = 17.0, 10.1H
z), 3.43 (1H, dd, J = 16.8, 3.6Hz).

Step 5 3- (3-Methyl- [1,2,4] oxadiazole-
5-yl) -7-oxo-5-propyl-4,5,6
7-Tetrahydrobenzo [c] thiophene-1-sulfinic acid

[Chemical 33] 1- (3-methyl- [1,2,4] oxadiazole-
5-yl) -3-methylsulfanyl-6-propyl-
6,7-Dihydro-5H-benzo [c] thiophene-4
-On (6.1 g, 19 mmol) chloroform (1
(00 ml) was cooled to -30 ° C, and m-chloroperbenzoic acid (4.6 g, 19 mmol) was added little by little to carry out a reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium sulfite solution were added for liquid separation. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure. The residue obtained is chloroform (34 m
l) and dissolved in trifluoroacetic anhydride (6.8 ml,
48 mmol) and pyridine (1.3 ml, 16 mmo
1) was added, and the mixture was stirred overnight at room temperature. After concentration under reduced pressure, the residue was dissolved in methanol (34 ml) and stirred at room temperature for 1 hour.
After concentrating this solution under reduced pressure, the residue was dissolved in ethyl acetate,
It was washed with 1M hydrochloric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
The obtained residue was treated with ethanol (130 ml) -water (130
ml), and the pH was adjusted to 8 with 1M aqueous sodium hydroxide solution under ice cooling. Hydrogen peroxide solution (3.6m
1, 32 mmol) was slowly added, and the mixture was stirred under ice cooling for 30 minutes and further stirred at room temperature for 1 hour. After acidifying with 1M hydrochloric acid, ethanol was distilled off under reduced pressure. After extraction with ethyl acetate from this solution, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (4.7 g, yield 87%). NMR (δ value, 300MHz, CDCl ₃ ) 0.95 (3H, t, 6.9Hz), 1.30-1.5
5 (4H, m), 2.20-2.55 (5H, m), 2.65-2.95 (2H, m), 3.63 (1
H, dd, J = 17.4, 3.2Hz), 5.10 (1H, br).

Step 6 3- (3-Methyl- [1,2,4] oxadiazole-
5-yl) -7-oxo-5-propyl-4,5,6
7-Tetrahydrobenzo [c] thiophene-1-sulfonic acid amide

[Chemical 34] 3- (3-methyl- [1,2,4] oxadiazole-
5-yl) -7-oxo-5-propyl-4,5,6
7-Tetrahydrobenzo [c] thiophene-1-sulfinic acid (4.7 g, 14 mmol) was added to ethanol (65
ml) -water (15 ml), and 1M aqueous sodium hydroxide solution (14 ml, 14 mmol) was added under ice cooling. The solution was concentrated under reduced pressure, ethanol was added, and the mixture was concentrated again under reduced pressure, and the obtained residue was dried overnight under reduced pressure. Dissolve this solid in methylene chloride (200 ml),
N-chlorosuccinimide under ice cooling (2.6 g, 20 mm
ol) was added, and the mixture was stirred under ice cooling for 30 minutes and further at room temperature for 1 hour. The solution was concentrated under reduced pressure to about 50 ml and then added dropwise to tetrahydrofuran (500 ml) -water (20 ml) containing concentrated aqueous ammonia (20 ml). The solution was stirred at room temperature for 1 hour, neutralized with 1M hydrochloric acid, and extracted with ethyl acetate. After liquid separation, the organic layer was washed with saturated aqueous ammonium chloride and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (0.94
g, yield 20%) was obtained. NMR (δ value, 300MHz, CDCl ₃ ) 0.96 (3H, t, 7.0Hz), 1.35-1.6
0 (4H, m), 2.20-2.50 (5H, m), 2.70-2.95 (2H, m), 3.63 (1
H, dd, J = 17.4, 3.2Hz), 6.04 (2H, s).

Step 7 7-Hydroxyimino-3- (3-methyl- [1,2,
4] oxadiazol-5-yl) -5-propyl-
4,5,6,7-Tetrahydrobenzo [c] thiophene-1-sulfonic acid amide

[Chemical 35] 3- (3-methyl- [1,2,4] oxadiazole-
5-yl) -7-oxo-5-propyl-4,5,6
A solution of 7-tetrahydrobenzo [c] thiophene-1-sulfonic acid amide (0.94 g, 2.7 mmol) in ethanol (20 ml) was added with hydroxylamine hydrochloride (1.1).
g, 16 mmol) and sodium acetate (2.0 g,
24 mmol) was added, and the mixture was reacted under heating under reflux for 3 hours. After completion of the reaction, water was added to the reaction solution and the precipitated solid was collected by filtration to give the title compound (0.92 g, yield 94%). NMR (δ value, 300MHz, DMSO-d ₆ ) 0.75-0.95 (3H, m), 1.25-1.
45 (4H, m), 1.80-2.00 (1H, m), 2.23 (1H, dd, J = 17.4, 10.7
Hz), 2.43 (3H, s), 2.66 (1H, dd, J = 17.0, 10.4Hz), 2.95-
3.15 (1H, m), 3.35-3.45 (1H, m), 7.63 (2H, s), 11.77 (1H,
s).

Example 2 Step 1 3-Methylsulfanyl-4-oxo-6-trifluoromethyl-4,5,6,7-tetrahydrobenzo [c]
Thiophene-1-carboxylic acid isopropyl ester

[Chemical 36] A solution of 5-trifluoromethylcyclohexane-1,3-dione (10 g, 56 mmol) in N, N-dimethylformamide (80 ml) was added with potassium carbonate (23 g, 17
0 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Carbon disulfide (4.0 ml, 67 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour and then cooled to -15 ° C. Isopropyl chloroacetate (6.9 ml, 56 mmol) was added to this,
The mixture was stirred at 0 ° C for 30 minutes and further at room temperature for 1 hour. It was cooled to -15 ° C again and methyl iodide (3.5 ml, 56 m
mol) was added, and the mixture was further stirred at room temperature for 2 hours. After adding water (20 ml) to this suspension and stirring at room temperature for 30 minutes,
The solution was opened in water (200 ml), the precipitated solid was collected by filtration, and the solid was washed with a small amount of ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with diluted saline and saturated saline. After drying over anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was treated with water, and the precipitated solid was collected by filtration, and the solid thus collected was washed with isopropyl ether to give the title compound (8.9 g,
Yield 46%) was obtained. NMR (δ value, 300 MHz, CDCl ₃ ) 1.32-1.41 (6H, m), 2.51-2.67
(4H, m), 2.72-2.99 (3H, m), 3.83-3.95 (1H, m), 5.21 (1H,
sept, J = 6.2Hz).

Step 2 4-oxo-3-sulfamoyl-6-trifluoromethyl-4,5,6,7-tetrahydrobenzo [c] thiophene-1-carboxylic acid isopropyl ester

[Chemical 37] 3-Methylsulfanyl-4-oxo-6-trifluoromethyl-4,5,6,7-tetrahydrobenzo [c]
Thiophene-1-carboxylic acid isopropyl ester (16 g, 44 mmol) in chloroform (470 m)
l) After cooling the solution to -30 ° C, m-chloroperbenzoic acid (11 g, 44 mmol) was added in small portions. Solution-
After slowly warming to 5 ° C, m-chloroperbenzoic acid (0.60 g, 2.4 mmol) was added little by little,
The temperature was slowly raised again to 0 ° C. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium sulfite solution were added for liquid separation. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure. The obtained residue was treated with hexane-ethyl acetate and the precipitated solid was collected by filtration. This solid was converted into methylene chloride (30
0 ml) and trifluoroacetic anhydride (18 m
1, 120 mmol) and pyridine (3.4 ml, 41 m)
mol) was added and the mixture was stirred at room temperature overnight. Further, trifluoroacetic anhydride (8.8 ml, 62 mmol) and pyridine (1.7 ml, 21 mmol) were added, and the mixture was added at room temperature to 2.5.
Stir for hours. After completion of the reaction, the mixture was concentrated under reduced pressure, dissolved in methanol (300 ml), and stirred at room temperature for 0.5 hours.
After concentrating this solution under reduced pressure, the residue was dissolved in ethyl acetate,
It was washed with 1M hydrochloric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
The obtained residue is isopropyl alcohol (300 ml)
Dissolved in 1 M sodium hydroxide aqueous solution (60 m
1, 60 mmol) and isopropyl alcohol (150
ml) was added. Hydrogen peroxide solution (9.4 ml, 8
3 mmol) was added, and the mixture was reacted at room temperature. After completion of the reaction, an aqueous solution of sodium hydrogen sulfite was added and further acidified with 1M hydrochloric acid, and then isopropyl alcohol was distilled off under reduced pressure. After extraction with ethyl acetate from this solution, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in isopropyl alcohol (300 ml), and 1M aqueous sodium hydroxide solution (50 ml, 50 mmol) was added. The solution was concentrated under reduced pressure, toluene was further added, and the mixture was concentrated again under reduced pressure, and the obtained residue was dried under reduced pressure. This solid was dissolved in methylene chloride (300 ml), N-chlorosuccinimide (5.5 g, 41 mmol) was added under ice cooling, and the mixture was stirred under ice cooling. This solution was added to tetrahydrofuran (4000 ml) containing concentrated aqueous ammonia (50 ml) cooled in advance with an ice bath, and the solution was stirred in the ice bath for 1 hour. After completion of the reaction, the mixture was acidified with 1M hydrochloric acid, and the organic solvent was distilled off under reduced pressure. The concentrated residue was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (5.0 g, yield 30%). NMR (δ value, 300MHz, DMSO-d ₆ ) 1.24-1.40 (6H, m), 2.75-2.
97 (2H, m), 3.11 (1H, dd, J = 17.0, 10.7Hz), 3.27-3.55 (1
H, m), 3.69 (1H, dd, J = 17.0, 3.8Hz), 5.15 (1H, sept, J = 6.
3Hz), 7.81 (2H, s).

Step 3 4-Hydroxyimino-3-sulfamoyl-6-trifluoromethyl-4,5,6,7-tetrahydrobenzo [c] thiophene-1-carboxylic acid isopropyl ester

[Chemical 38] 4-oxo-3-sulfamoyl-6-trifluoromethyl-4,5,6,7-tetrahydrobenzo [c] thiophene-1-carboxylic acid isopropyl ester (2.
0 g, 5.2 mmol) of isopropyl alcohol (2
4 ml) solution of hydroxylamine hydrochloride (2.2 g, 3 g
2 mmol) and sodium acetate (3.8 g, 47 m
mol) was added, and the mixture was reacted under heating under reflux for 1 hour. After completion of the reaction, water was added to the reaction solution and the precipitated solid was collected by filtration to obtain the title compound (1.4 g, yield 66%). NMR (δ value, 400MHz, DMSO-d ₆ ) 1.26-1.35 (6H, m), 2.48-2.
65 (1H, m), 2.90 (1H, dd, J = 16.6, 11.3Hz), 3.03 (1H, br),
3.18-3.26 (1H, m), 3.60-3.70 (1H, m), 5.13 (1H, sept, J =
6.2Hz), 7.60 (2H, s), 12.00 (1H, s).

Example 3 Step 1 7- {2- [6-tert-Butoxycarbonylamino-2- (3-tert-butoxycarbonylaminopropanoylamino) hexanoyloxy] ethoxycarbonyloxyimino} -3- (3 -Methyl- [1,2,
4] oxadiazol-5-yl) -5-propyl-
4,5,6,7-Tetrahydrobenzo [c] thiophene-1-sulfonic acid amide

[Chemical Formula 39] Under anhydrous calcium chloride drying, triphosgene (36 mg,
0.12 mmol) in chloroform (1.3 ml) under ice-cooling, dimethylaniline (57 mg, 0.45 m
mol) and [6-tert-butoxycarbonylamino-2- (3-tert-butoxycarbonylaminopropanoylamino) hexanoyloxy] ethanol (1
40 mg, 0.30 mmol) of chloroform (1.3
ml) solution was added, and the mixture was stirred at that temperature for 2 hours and further at room temperature for 3 hours. 7-Hydroxyimino-3- (3
-Methyl- [1,2,4] oxadiazol-5-yl) -5-propyl-4,5,6,7-tetrahydrobenzo [c] thiophene-1-sulfonic acid amide (100
mg, 0.27 mmol) of tetrahydrofuran (2.
7 ml) solution was added. This solution was cooled in an ice bath, a solution of pyridine (76 μl, 0.95 mmol) in chloroform (1 ml) was added, and the mixture was reacted in a refrigerator for 3 days. After completion of the reaction, the solution was poured into diluted hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (silica gel, chloroform / ethyl acetate) to give the title compound (170
mg, yield 72%) was obtained. NMR (δ value, 300MHz, CDCl ₃ ) 0.92-1.00 (3H, m), 1.31-1.63
(26H, m), 1.63-2.08 (3H, m), 2.29-2.50 (6H, m), 2.55-2.
68 (1H, m), 3.03-3.14 (2H, m), 3.20-3.32 (1H, m), 3.33-
3.43 (2H, m), 3.51-3.62 (1H, m), 4.32-4.73 (6H, m), 5.26
(1H, br), 6.43 (1H, br), 6.88 (2H, br).

Step 2 7- {2- [6-amino-2- (3-aminopropanoylamino) hexanoyloxy] ethoxycarbonyloxyimino} -3- (3-methyl- [1,2,4] oxa Diazol-5-yl) -5-propyl-4,5,5
6,7-Tetrahydrobenzo [c] thiophene-1-sulfonic acid amide dihydrochloride

[Chemical 40] 7- {2- [6-tert-butoxycarbonylamino-2- (3-tert-butoxycarbonylaminopropanoylamino) hexanoyloxy] ethoxycarbonyloxyimino} -3- (3-methyl- [1,2,
4] oxadiazol-5-yl) -5-propyl-
4,5,6,7-Tetrahydrobenzo [c] thiophene-1-sulfonic acid amide (170 mg, 0.20 mmo
4M hydrogen chloride / dioxane solution (5 ml) was added to l), and the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue obtained is treated with ethyl ether,
The precipitated solid was collected by filtration to give the title compound (130 m
g, yield 88%) was obtained. NMR (δ value, 300MHz, DMSO-d ₆ ) 0.90 (3H, t, J = 5.1Hz), 1.30
-1.48 (6H, m), 1.49-1.79 (4H, m), 1.93-2.09 (1H, m), 2.4
4 (3H, s), 2.47-2.80 (6H, m), 2.90-3.02 (2H, m), 3.09-3.1
9 (1H, m), 3.39-3.48 (1H, m), 4.20-4.29 (1H, m), 4.29-4.
45 (2H, m), 4.53 (2H, t, J = 3.2Hz), 7.75-8.05 (8H, br), 8.
63 (1H, d, J = 5.3Hz). This compound is useful as a prodrug of the compound of Example 1.

According to the method described above in the general manufacturing method section,
The compounds shown in the following table of Examples were synthesized in the same manner as in Examples 1 to 3.

Test Example Next, the biological activity of the compound of the present invention was tested. Test Example 1 UT-7 / TPO cell proliferation-activating cytokine-free IMDM medium (Iscove's modi
UT-7 / TPO cells starved overnight with fied Dulbecco's medium, containing 10% fetal bovine serum and penicillin / streptomycin) were seeded in a 96-well culture plate at a cell number of 10 ⁴ cells / 100 μl / well. Next, the test compound was treated with dimethyl sulfoxide (DM
SO) to 400 times the final concentration, and a part of it was diluted with IMDM medium to prepare a test compound dilution series. A test compound dilution series (100 μl / well) was added, and the mixture was cultured at 37 ° C. in a CO ₂ incubator.
After 3 days of culture, WST-1 was added at 10 μl / well to continue the culture. Four hours after the addition of WST-1, the absorbance at 450 nm was measured using a microplate reader. A calibration curve was prepared from the measured values and the number of cells was determined. A medium containing 0.5% DMSO was used as a control. Positive control is recombinant human (rh) TPO (Peprotec
(Company h) was diluted with a medium containing 0.5% DMSO. The measurement was carried out in n = 2 wells, and the activity of the test compound was expressed as an EC ₅₀ (concentration of the compound showing the activity corresponding to 50% of the maximum activity of the positive control rhTPO). The results are shown in the following example table.

Test Example 2 Megakaryocyte differentiation and proliferation activity from mouse bone marrow cells Male BALB / c mouse (Charles River Japan, 6
(~ 12 weeks old), the bone marrow cells were aseptically removed from the femur and the tibia, suspended in 5 ml of IMDM medium containing penicillin / streptomycin, and 0.5 mM diisopropyl fluorophosphate (under ice cooling). Wako Pure Chemical Industries, Ltd.) for 20 minutes. The cells were washed twice with IMDM medium and then suspended in 10 ml of IMDM medium to give 10c.
m petri dish. After culturing at 37 ° C. for 90 minutes in a CO ₂ incubator, non-adherent cells were collected. The cells were placed in a 96-well culture plate at 10 ⁵ cells / 100 μl / w.
The cells were seeded at the number of cells. Next, the test compound is added to DMS.
Prepare to 400 times the final concentration with O, and a portion of it to IMD
M medium [Serum alternative protein for 10% serum-free medium (StemCell
technologies) and penicillin / streptomycin (GIBCO)]] to prepare test compound dilution series. 100 μl / of test compound dilution series
Wells were added and cultured in a CO ₂ incubator at 37 ° C., and 6 days later, acetylcholinesterase (Ac
hE) activity was measured. 0.5% DM for control
An SO-containing medium was used. RhTPO was used as a positive control,
It was diluted and prepared in a medium containing 0.5% DMSO. In addition, A
The chE activity was measured by the following method. That is,
1% polyoxyethylene (10) octyl ether [Po
lyoxyethylene (10) Octylphenyl Ether (TritonX-100
(Trade name)]] 5,5′-Dithiobis- (2-nitrobenzoic acid) dissolved in 1M Tris / HCl (pH 8) [5,5′-Dithiobis- (2-nitrobenzoic Acid), DT
NB, 0.21 mg / ml] was added at 50 μl / well, and the absorbance (OD _405-650 ) was measured (pre-value). Then 10
mM acetylthiocholine iodi
d) After adding 20 μl / well of the solution and incubating at room temperature for 30 minutes, the absorbance (OD
_405-650 ) was measured (post value). The activity (%) with respect to the positive control was calculated by the following formula from the value obtained by subtracting the pre value from the post value.

[Equation 1] The measurement was carried out in n = 4 to 6 wells, and the activity of the test compound was expressed as an EC ₅₀ (concentration of compound showing 50% of the maximum activity of the positive control rhTPO). The results are shown in the following example table.

Test Example 3 Mouse X-Ray Irradiation Model Male BALB / c mouse (Charles River Japan, 6
~ 9 weeks old) were grouped into 8 animals / cage using the platelet count as an index before the start of the experiment. X-ray irradiation equipment (M-150WE, SOF
TEX) with an X-ray irradiation dose of 0.25 Gy / min of 20
The mice were exposed for minutes. Vehicle is 30% PEG40
0-containing 7% hydroxypropyl-β-cyclodextrin (HP-β-C
D) The solution was used. 0.15 for test compound in vehicle
It was dissolved at a concentration of 0.45 and 1.5 mg / ml (for 1, 3, 10 mg / kg, respectively). Administration of the test compound was started from the day after the X-ray irradiation (the first day), and was subcutaneously administered to the mice three times a day at 1, 3, 10 mg / 6.67 ml /
It was administered at a dose of kg. On the 9th, 11th, 14th, and 17th days, blood of the mouse was collected from the orbital venous plexus using a hematocrit tube (Terumo) to produce Sysmex F-800.
Various blood cell counts were measured by (Sysmex). Statistical analysis is Du
The significance level determined by the nnett test was set to a risk rate of 5% or less. Changes in the platelet count in the peripheral blood of the mice after administration of the compound of Example 1 are shown in FIG.

[0101]

[Table 1]

[0102]

[Table 2]

[0103]

[Table 3]

[0104]

[Table 4]

[0105]

[Table 5]

[0106]

[Table 6]

[0107]

[Table 7]

[0108]

[Table 8]

[0109]

[Table 9]

[0110]

[Table 10]

[0111]

[Table 11]

[0112]

[Table 12]

[0113]

The compound of the general formula [I] according to the present invention has excellent TPO, as is clear from the above test examples.
It has a receptor agonistic action, a hematopoietic stem cell differentiation / proliferation action, an umbilical cord blood differentiation / proliferation action, and a blood cell proliferating action, particularly a platelet proliferating action. Therefore, these compounds are excellent TPO receptor agonists, hematopoietic stem cell differentiation / proliferation agents, cord blood differentiation / proliferation agents,
Further, it is expected to be a hematopoietic drug, particularly a thrombocytosis drug, an erythrocytosis drug, and a thrombocytopenia therapeutic drug.

[Brief description of drawings]

FIG. 1 is a graph showing changes in the number of platelets in peripheral blood of mice after administration of the compound of Example 1.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4155 A61K 31/4155 31/4196 31/4196 31/422 31/422 31/4245 31/4245 31 / 427 31/427 31/433 31/433 31/4365 31/4365 A61P 7/06 A61P 7/06 43/00 111 43/00 111 C07D 209/44 C07D 209/44 307/87 307/87 333/72 333/72 409/04 409/04 417/04 417/04 495/04 105 495/04 105A (72) Inventor, Koji Inagaki Koji 1-1, Murasakicho, Takatsuki City, Osaka Prefecture Japan Tobacco Inc. Pharmaceutical Research Institute F-Term (reference) 4C063 AA01 BB01 CC94 DD22 DD25 DD41 DD47 DD52 DD58 DD62 DD67 DD81 DD92 EE01 4C071 AA01 BB01 CC01 CC21 DD17 EE13 FF06 HH11 HH23 HH28 LL01 4C086 A02 AA02 AA03 BB03 BC01 BC01 BC62 BC36 BC61 BC02 BC36 MA04 NA14 ZA55 ZC42 4C204 BB01 CB04 D B25 DB29 EB03 FB01 FB03 GB03 GB32

Claims (14)

[Claims] 1. A general formula [I] [Chemical 1] [In the formula, A¹And A²Together, [Chemical 2] Represents; A³Is [Chemical 3] Represents; A^FourIs [Chemical 4] Represents a double bond. The dotted portions of a, b, c and d are double bonds.
Means that p may be an integer of 0, 1 or 2.
Representation; R¹Is a. Hydrogen atom, b. Halogen atom, c. C_1-6An alkyl group, d. C_1-6An alkoxy group, e. Carboxy group, f. (C_1-6Alkoxy) carbonyl group, g. Carbamoyl group (the carbamoyl group is 1 or 2
C_1-6It may be substituted with an alkyl group. ), h. Cyano group, i. Nitro group, j. Amino group (the amino group is C_1-6Alkyl group, C_1-7
Acyl group and (C_1-6Alkoxy) carbonyl group (the
Alkyl, acyl and alkoxycarbonyl groups are
Mino group, hydroxyl group, carboxy group, -SO₃H, -PO₃H
₂, -OSO₃H, -OPO₃H₂  With a substituent selected from
It may be replaced. 1 or 2 substituents selected from
May be replaced with. }, j. Aryl group (the aryl group is C_1-6Alkyl group
(The alkyl group is substituted with 1 to 3 halogen atoms.
You may ), C_3-7Cycloalkyl group, C_1-6Arco
Xy and amino groups (wherein the amino group is 1 or 2 C
_1-6It may be substituted with an alkyl group. 1) selected from
It may be substituted with 3 to 3 substituents. }, Or k. −
SO_mR⁷[Where R⁷Is ・ Hydrogen atom, ・ C_1-6Alkyl group (wherein the alkyl group is a halogen atom,
Hydroxyl group, C_1-6Alkoxy group, carboxy group, (C_1-6A
Lucoxy) carbonyl group and amino group (wherein the amino group is 1
Or two C_1-6It may be substituted with an alkyl group. )
May be substituted with 1 to 3 substituents selected from
Yes. }, ・ Hydroxyl group, .Amino group [wherein the amino group is C_1-6Alkyl group, C_1-7A
Silyl group and (C_1-6Alkoxy) carbonyl group {these
Alkyl, acyl and alkoxycarbonyl groups are
Mino group, hydroxyl group, carboxy group, acyloxy group, -S
O₃H, -PO₃H₂, -OSO₃H, -OPO₃H₂, -O
CO-amino acid residue (the -OCO-amino acid residue is
-OPO₃H₂  Alternatively, it may be substituted with a sugar residue. )as well as
It may be substituted with a substituent selected from sugar residues. } From
It may be substituted with one or two selected substituents. ], -Aryl group (the aryl group is C_1-6Alkyl group (the
Alkyl groups substituted with 1 to 3 halogen atoms
Good. ), C_3-7Cycloalkyl group, C_1-6Alkoxy
Group, an amino group (the amino group is 1 or 2 C_1-6Al
It may be substituted with a kill group. 1) to 3 selected from
It may be substituted with the substituent. }; M is 0-2
Represents an integer. ] Represents R²Is a. Hydrogen atom, b. Halogen atom, c. C_1-6Alkyl group (the alkyl group is a halogen source
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, amino group (the amino group
Is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. May be substituted with a substituent selected from }, d. C_3-7Cycloalkyl group, e. Carboxy group, f. (C_1-6Alkoxy) carbonyl group, g. (C_3-7Cycloalkyl) oxycarbonyl group, h. Carbamoyl group (the carbamoyl group is 1 or 2
C_1-6It may be substituted with an alkyl group. ), i. C_1-7An acyl group, j. An aryl group, or k. 1 selected from nitrogen atom, oxygen atom and sulfur atom
3- to 7-membered heterocycle having up to 4 heteroatoms in the ring
{The heterocycle and the aryl group of j are C_1-6Alkyl
A group (wherein the alkyl group is substituted with 1 to 3 halogen atoms)
You may ), C_3-7Cycloalkyl group, C_1-6Arco
Xy group, amino group (wherein the amino group is 1 or 2 C_1-6A
It may be substituted with a rukyl group. 1 to 3 selected from
May be substituted with one substituent. }; R³Is a. Amino group (the amino group is C_1-6Alkyl group, C_1-7
Acyl group, (C_1-6Alkoxy) carbonyl group and C_1-6
Alkylsulfonyl group, (these alkyl groups, acyl
Group, alkoxycarbonyl group and alkylsulfonyl group
Is an amino group, a hydroxyl group, a carboxy group, -SO₃H,-
PO₃H₂, -OSO₃H, -OPO₃H₂  Chosen from
It may be substituted with a substituent. ) Selected from 1 or 2
It may be substituted with the substituent. }, b. Arylsulfonylamino group {the arylsulfoni
Luamino group is a halogen atom, C_1-6Alkyl group
The alkyl group may be substituted with 1 to 3 halogen atoms
Good. ), An amino group (wherein the amino group is 1 or 2 C_1-6A
It may be substituted with a rukyl group. ) With a substituent selected from
It may be substituted by 1 to 3. }, c. -SO₃H, d. -PO₃H₂  Or e. -OR⁸ [Where R⁸Is ・ Hydrogen atom, ・ C_1-6Alkyl group (wherein the alkyl group is a halogen atom,
Hydroxyl group, C_1-6Alkoxy group, carboxy group, (C_1-6A
Lucoxy) carbonyl group, acyloxy group, amino group
(The amino group is 1 or 2 C_1-6Substitute with alkyl group
May be done. ), -OCO-amino acid residue (the -O
CO-amino acid residue is -OPO₃H₂  Or set with sugar residue
It may be replaced. ) And sugar residues selected from 1 to 3
It may be substituted with the substituent. }, ・ Amino acid residues, -CO-amino acid residue (the -CO-amino acid residue and
The amino acid residue is -OPO.₃H₂  Or replaced with sugar residue
May be done. ), -SO₃H, ・ -PO₃H₂Or -X¹-X²-R¹¹ [X here¹Is -CO-, -CO₂-Or * Represents -CONH-; X²Is ・ C_1-6Alkylene, ・ C_1-6Alkenylene, ・ Arylene, .1 to selected from nitrogen atom, oxygen atom and sulfur atom
A 3 to 7 membered heterocycle having 4 heteroatoms in the ring,
Or ・-(OCH₂CH₂)_n-(Where n is an integer from 0 to 8
Represent ) Represents; R¹¹Is ・ Hydrogen atom, ・ Halogen atom, ・ C_1-6Alkyl group (the alkyl group is substituted with an amino group
May be done. ), ・ Hydroxyl group, ・ C_1-6An alkoxy group, ・ Carboxy group, .Amino group (wherein the amino group is 1 or 2 C_1-6Archi
It may be substituted with a group. ), ・ Amino acid residues, -O-amino acid residue {the said -O-amino acid residue and before
The amino acid residue is C_1-7An acyl group (the acyl group is
It may be substituted with a mino group. ) And -OPO₃H₂  Or
It may be substituted with a substituent selected from }, ・ -OSO₃H, or ・ -OPO₃H₂  Represents ] Represents R^FourIs a. Hydrogen atom, b. Halogen atom, c. C_1-6Alkyl group (the alkyl group is a halogen source
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, amino group (the amino group
Is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. ), An aryloxy group and an aralkyloxy group
It may be substituted with 1 to 3 substituents selected. }, d. C_1-6An alkoxy group, e. Carboxy group, f. (C_1-6Alkoxy) carbonyl group, g. C_1-7An acyl group, h. C_1-6An alkylsulfonyl group, i. An aryl group, or j. Aralkyl group {the aralkyl group and the aryl of i above
Ru group is C_1-6Alkyl group (wherein the alkyl group is 1 to 3
It may be substituted with halogen atoms. ), C_3-7Cyclo
Alkyl group, C_1-6An alkoxy group or an amino group (the amino group
No group is 1 or 2 C_1-6Even if it is substituted with an alkyl group
Good. Substituted with 1 to 3 substituents selected from
Good. }; R^Five, R⁶Each independently a. Hydrogen atom, b. C_1-6Alkyl group [wherein the alkyl group is a halogen source]
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, C_1-7An acyloxy group,
Aryloxy group and aralkyloxy group {the aryl
The oxy group and the aralkyloxy group are C_1-6Alkyl group
(The alkyl group is substituted with 1 to 3 halogen atoms.
You may ), C_3-7Cycloalkyl group, C_1-6Arco
A xy group amino group (wherein the amino group is 1 or 2 C_1-6A
It may be substituted with a rukyl group. 1 to 3 selected from
May be substituted with one substituent. } Selected from 1 to
It may be substituted with 3 substituents. ], c. C_3-7Cycloalkyl group, d. Carboxy group, e. C_1-6Alkoxy) carbonyl group, f. C_1-6An alkylsulfonyl group, g. Amino group, h. A carbamoyl group (the carbamoyl group and
Mino group is 1 or 2 C_1-6Substituted with an alkyl group
Good. ), i. C_1-7An acyl group, j. An aryl group, or k. Aralkyl group {the aralkyl group and the aryl of j
Ru group is C_1-6Alkyl group (wherein the alkyl group is 1 to 3
It may be substituted with halogen atoms. ), C_3-7Cyclo
Alkyl group, C_1-6Alkoxy group, amino group (the amino
The group is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. Even if substituted with 1 to 3 substituents selected from
Good. }; R⁹, R^TenEach independently a. Hydrogen atom, b. C_1-6Alkyl group (the alkyl group is a halogen source
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, amino group (the amino group
Is 1 or 2 C_1-6May be substituted with an alkyl group
Yes. Even if substituted with 1 to 3 substituents selected from
Good. }, c. Hydroxyl group, d. C_1-6An alkoxy group, e. C_1-7An acyl group, f. C_1-6An alkylsulfonyl group, g. An aryl group, or h. 1 selected from nitrogen atom, oxygen atom and sulfur atom
3- to 7-membered heterocycle having up to 4 heteroatoms in the ring
{The heterocyclic ring and the aryl group of g are C_1-6Alkyl
A group (the alkyl group is substituted with 1 to 3 halogen atoms)
May be done. ), C_3-7Cycloalkyl group, C_1-6Al
Coxy group, amino group (the amino group is 1 or 2 C
_1-6It may be substituted with an alkyl group. 1) selected from
It may be substituted with 3 to 3 substituents. Represents}; [Chemical 5] Represents However, R^FiveAnd R⁶One of is a methyl group
And R¹And R²Are simultaneously methyl groups, or R
^Four, R^FiveAnd R⁶Except when are simultaneously hydrogen atoms. ]
Or a prodrug thereof, or
Salt or solvate thereof. 2. A compound represented by the general formula [II]: [In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and Represents the definition of claim 1, respectively. ] The compound shown by these, its prodrug, its salt, or its solvate. 3. In the general formula [II], [Chemical 8] And R¹But -SO_mR⁷  (R⁷Is according to claim 1.
Represents a definition. ) Is; R²But (C_1-6Alkoxy)
Rubonyl group or selected from nitrogen atom, oxygen atom and sulfur atom
3 to 7 having 1 to 4 heteroatoms within the ring
Member heterocycle (wherein the heterocycle is C_1-6Alkyl group (the alk
Radicals may be substituted with 1 to 3 halogen atoms
Yes. ), C_3-7Cycloalkyl group, C_1-6An alkoxy group,
An amino group (wherein the amino group is 1 or 2 C_1-6Alkyl
It may be substituted with a group. 1 to 3 units selected from
It may be substituted with a substituent. }; R³But-OR⁸  
(R⁸Represents the definition of claim 1. ) Is; R
^FiveBut C_1-6Alkyl group [wherein the alkyl group is a halogen source]
Child, hydroxyl group, C_1-6Alkoxy group, carboxy group, (C
_1-6Alkoxy) carbonyl group, aryloxy group and
Aralkyloxy group {the aryloxy group and aralkyl
The ruoxy group is C _1-6An alkyl group (wherein the alkyl group is 1
It may be substituted with 3 to 3 halogen atoms. ), C_3-7
Cycloalkyl group, C_1-6Alkoxy group, amino group (the
Amino group is 1 or 2 C_1-6Substituted with an alkyl group
May be. Substituted with 1 to 3 substituents selected from
You may Substituted with 1 to 3 substituents selected from
May be done. ] Or C_3-7Is a cycloalkyl group
R; R⁶Is a hydrogen atom or C_1-6An alkyl group
2. The compound described in 2 or a prodrug thereof, or
Salt or solvate thereof. 4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, a prodrug thereof, a salt thereof or a solvate thereof as an active ingredient. 5. A TPO receptor agonist comprising the compound according to any one of claims 1 to 3, a prodrug thereof, a salt thereof or a solvate thereof as an active ingredient. 6. A hematopoietic drug containing the compound according to any one of claims 1 to 3, a prodrug thereof, a salt thereof, or a solvate thereof as an active ingredient. 7. A hematopoietic stem cell differentiation / proliferation agent comprising the compound according to any one of claims 1 to 3, a prodrug thereof, a salt thereof, or a solvate thereof as an active ingredient. 8. The hematopoietic stem cell differentiation / proliferation agent according to claim 7, which is used in combination with stem cell factor (SCL), interleukin-3 (IL-3) or flk2 / flt3 ligand (FL). 9. A thrombocytosis drug containing the compound according to any one of claims 1 to 3, a prodrug thereof, a salt thereof, or a solvate thereof as an active ingredient. 10. The thrombocytosis drug according to claim 9, which is used in combination with stem cell factor (SCL) or interleukin-3 (IL-3). 11. A combined use with erythropoietin (EPO), which comprises the compound according to any one of claims 1 to 3, a prodrug thereof, or a salt thereof or a solvate thereof as an active ingredient. Erythrocytosis drug. 12. A therapeutic agent for thrombocytopenia comprising the compound according to any one of claims 1 to 3, a prodrug thereof, a salt thereof or a solvate thereof as an active ingredient. 13. Differentiation of cord blood, which comprises culturing the cord blood in the presence of the compound according to any one of claims 1 to 3, a prodrug thereof, a salt thereof, or a solvate thereof. Propagation method. 14. The cord blood differentiation / proliferation method according to claim 13, wherein the cord blood is cultured in the presence of stem cell factor (SCL) or interleukin-3 (IL-3).