JPH1087490A - Interleukin-6 production inhibitor, bone resorption inhibitor, antiosteoporotic agent, and thiazole compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal agent useful as an interleukin-6 production inhibitor, bone resorption inhibitor or antiosteoporotic agent, containing a thiazole compound having a specific structure as active ingredient. SOLUTION: This medicinal agent contains, as active ingredient, a thiazole compound of the formula (R<1> is H, a (substituted) amino, etc.; R<2> is a (substituted) aryl; R<3> is H, a halogen, etc.) or a pharmaceutically permissible salt thereof, e.g. 2-amino-4-(4-chlorophenyl)-5-methylthiazole. The compound of the formula is obtained, for example, by the following process: bromine is dripped into a 4'-chloropropiophenone's dichloromethane solution to carry out a reaction; after the reaction, the solvent is distilled off the reaction mixture, and ethanol is added to the resultant residuals into a solution, an aqueous thiourea solution is then added to the above solution followed by agitation, and the mixed solution is adjusted to pH7 and the reaction product is purified by silica gel column chromatography.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to interleukin-6 (IL-6) induced by stimulation of various biological substances.
The present invention relates to an IL-6 production inhibitor, a bone resorption inhibitor, and an antiosteoporosis agent capable of controlling the production of osteoporosis.

[0002]

2. Description of the Related Art IL-6 is produced from various cells such as monocytes, T cells, B cells, vascular endothelial cells, fibroblasts, and osteoblasts, and induces differentiation of B cells into antibody-producing cells. It is known to be a substance with various physiological activities such as induction of acute phase protein synthesis from cells, induction of differentiation of brain nervous cells, induction of proliferation and differentiation of hematopoietic cells, induction of differentiation of osteoclasts (experiments Medicine, Vol. 7, No. 1, 1989).

[0003] Regarding the relationship between IL-6 and various diseases,
For example, there are autoimmune diseases in which autoantibody production such as rheumatoid arthritis and Castleman syndrome is considered to be involved in the cause or exacerbation of the disease (European J
ournal of Immunology, 18, 1797, Experimental Medicine, 7, 50, 1989). In the field of cancer, IL-6 is reported to be an autocrine growth factor for multiple myeloma (Nature, 332, 83, 198).
8 years) and as a cancer cachexia (Kakexia) substance (Endocrinology, 128, 2657).
1991). In the area of infectious disease, blood IL-6 concentration of sepsis patients is negatively correlated with survival rate (Journal
of Experimental Medicine, 169, 333, 19
1989, Blood, 74, 1704, 1989). In addition, IL-6 is an acute-phase protein of the inflammatory response, and is considered to be a cause of various symptoms due to inflammation such as fever, chills, and malaise, exhaustion after surgical operations such as organ resection, and delayed recovery. In recent years, the physiological action of IL-6, which has attracted the most attention, is its osteoclast differentiation-inducing activity, and is considered to be one of the causes of osteoporosis caused by enhanced bone resorption by osteoclasts. In addition, Alzheimer's disease, amyloidosis, type I diabetes,
The involvement of IL-6 has also been suspected as a cause of hyperlipidemia, polycythemia vera, thrombocytosis, and myocardial infarction.

[0004] Thus, IL-6 is involved in the onset or exacerbation of various diseases, particularly inflammatory and lymphoproliferative diseases and osteoporosis. It is thought that it is possible to treat this disease. Actually, in a mouse model experiment, IL
In some cases, the therapeutic effect has been confirmed by administering an antibody of -6 to suppress the action of IL-6 or by producing a knockout mouse of the IL-6 gene. For example, in an IL-6 gene knockout mouse, ovariectomy does not cause bone loss (The E
MBO Journal, Volume 13, No. 5, 1189-1196, 1994). In addition, there is a report that administration of an IL-6 antibody suppressed weight loss of cancer-bearing mice due to xylophone (Journal of Clinical Investigation, 89, 16).
81, 1992). By such a model experiment,
Although it is possible to prove the involvement of IL-6 in each disease, in actual medical practice, human-type IL-6
The administration of antibodies has not yet become a reality, and it is more difficult to use the concept of a knockout mouse for humans.

With respect to some thiazole compounds according to the general formula (1) of the present invention, for example, LF Lee, FM S
chleppnik and RK Howe, J. Heterocyclic Chem., 2
2, 1621 (1985) .; W. Ried, L. Kaiser, Justus Liebi
gs Ann. Chem., 1976, 395 .; J. Liebscher, H. Hartma
nn, Z. Chem., 1974, 14, 470 .; M. Muszynski, W. K.
aczmarek, M. Wroblewski, Pol. Pl 147,344; JV M
etzger, The chemistry of heterocyclic compounds, V
ol. 34, Part 1, 337. Part 2, 369. (John Wiley & So
ns, 1978), but its pharmacological action is not described. On the other hand, for the 2,4,5-trisubstituted-thiazole compound, R ¹ is an NH ₂ group and R ²
Is a phenyl or 4-chlorophenyl group and R ¹
Is a morpholino group and the synthesis of an R ² phenyl group is known.

[0006] Regarding the pharmacological action, 2,4-disubstituted-thiazole compounds, for example, antifungal action (SK
Srivastava, KA Gupta, Acta Chim. Hung. 1985, 11
8, 249 (Chem Abstr. 103: 152558W, 1985.)), antibacterial activity (SK Singh, SS Naim, Indian J. Chem. Sect.
B 1989, 28B, 786. (Chem Abstr. 112: 198195q)),
Antiallergic effect (J. Yoshinaga, T. Shogaki, T. Sh
ogaki, T. Takao, H. Ozeki, Y. Kato, Eur. Pat. App
l. EP 321,115) is known. On the other hand, 2,4,5-
In tri-substituted-thiazole compounds, only 2-amino-5-methyl-4-phenylthiazole is
Anesthetic effects of fish (Fr. Demande 2,037,003 (Chem. Abst.
r., 75, 112867t (1971)). That is, there is no report on the IL-6 production inhibitory action, bone resorption inhibitory action, and anti-osteoporosis action as shown in the present invention.

[0007]

An object of the present invention is to provide an IL
An object of the present invention is to provide an agent that suppresses the production of IL-6, a bone resorption inhibitor, and an osteoporosis agent, which are expected as preventive and therapeutic agents for various diseases derived from -6.

[0008]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors conducted a search for a compound inhibiting IL-6 production.
They have found that they have L-6 production inhibitory activity, and have completed the present invention.

That is, the present invention provides the following general formula (1)

[0010]

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(Wherein, R ¹ represents a hydrogen atom, an unsubstituted or substituted amino group, or a lower alkyl group. R ² represents an unsubstituted or substituted aryl group. R ³ represents a hydrogen atom, a halogen atom, Represents a lower alkyl group, an acyl group, an alkoxycarbonyl group, a carboxyl group, a carbamoyl group hydroxymethyl group, a cycloalkyl group, a vinyl group, a cyano group, or an unsubstituted or substituted aryl group.
Or a pharmaceutically acceptable salt thereof as an active ingredient
Provided are a production inhibitor, a bone resorption inhibitor, and an anti-osteoporosis agent. These agents of the present invention include both prophylactic and therapeutic agents.

Further, the present invention provides a compound represented by the general formula (2):

[0013]

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(In the formula, R ^{1 ′} is an amino group, R ^{2 ′} is an unsubstituted or substituted aryl group excluding a phenyl group and a 4-chlorophenyl group, and R ^{3 ′} is a lower alkyl group or an unsubstituted or substituted aryl group. A substituted aryl group), particularly a thiazole compound wherein R ^{2 ′} is a heteroaryl group, and a compound represented by the general formula (3)

[0015]

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Wherein R ^{1 ″} is a pyrrolidyl group or an unsubstituted or substituted piperazinyl group, R ² is an unsubstituted or substituted aryl group, and R ^{3 ″} is an acyl group, an alkoxycarbonyl group, or a carboxyl group. Thiazole compounds are provided.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of the general formula of the present invention, the following means unless otherwise specified. Examples of the substituted amino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, a tert-butylamino group, a dimethylamino group, and a diethylamino group. A lower alkyl-substituted amino group such as ethylmethylamino group or methylpropylamino group; a cycloalkyl-substituted amino group such as cyclopropylamino group, cyclobutylamino group, cyclopentylamino group or cyclohexylamino group; 1-pyrrolidino group, -Piperidyl group,
Lower alkyl-substituted-1-piperazinyl group such as 1-indolyl group, 4-morpholino group, 1-piperazinyl group, 4-methyl-1-piperazinyl group, 4-propyl-1-piperazinyl group, 4-acetyl-1-piperazinyl Group, 4-
(Tert-butoxycarbonyl) -1-piperazinyl group,
A cyclic amino group such as a 4-acyl-1-piperazinyl group can be exemplified.

The lower alkyl group means a C ₁ -C ₆ linear or branched alkyl group. Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, te
rt-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1 -Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group,
2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1
-Methylpropyl group, 1-ethyl-2-methylpropyl group and the like.

The unsubstituted or substituted aryl group also includes a heteroaryl group, and specific examples of the unsubstituted form include a phenyl group, a naphthyl group, a biphenyl group, an anthranyl group, a pyrrolyl group, a furyl group, Thienyl group, imidazolyl group, pyrazoyl group, oxazolyl group,
Thiazolyl group, triazolyl group, thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, quinolyl group, isoquinolyl group, indolyl group, benzofuryl group, benzothienyl group, benzimidazolyl group, benzooxazolyl group, benzothiazolyl group, benzo Examples thereof include a triazolyl group and a phthalanidyl group.

Examples of the substituent which may be present on these aryl groups include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a nitro group, a hydroxyl group, a carboxyl group, a cyano group, a carbamoyl group; Alkyl group such as a group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group; cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group; formyl An acyl group such as a group, acetyl group, propionyl group, butyryl group, trifluoroacetyl group, benzoyl group; phenyl group, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group,
Aryl groups such as thiazolyl group, triazolyl group, thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group and pyridazinyl group; polyfluoroalkyl groups such as trifluoromethyl group and pentafluoroethyl group; methoxycarbonyl group and ethoxycarbonyl group An alkoxycarbonyl group; an amino group such as an amino group, a methylamino group, an ethylamino group, and a propylamino group; an alkoxy group such as a methoxy group and an ethoxy group; an alkylthio group such as a methylthio group, an ethylthio group and a propylthio group; a methanesulfonyl group; Sulfonyl groups such as a benzylsulfonyl group and a benzenesulfonyl group can be exemplified. A plurality of these substituents may be introduced.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the acyl group include a formyl group,
Examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, benzoyl, toluoyl, naphthoyl, nicotinoyl, isonicotinoyl, and the like.

Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group.

Examples of the carbamoyl group include carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N, N-dimethylcarbamoyl, N, N-dipropylcarbamoyl and the like. be able to. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

In the general formula (1), R ¹ is an amino group, R ² is an unsubstituted or substituted aryl group,
A thiazole compound in which R ³ is a group selected from a hydrogen atom, a methyl group, an acetyl group, an ethoxycarbonyl group, a carboxyl group, and a pyridyl group is preferred in that it has high activity.

Specific examples of the thiazole compound according to the present invention are shown in Tables 1 and 2.

[0027]

[Table 1]

[0028]

[Table 2]

The thiazole compounds according to the present invention can be synthesized by reported methods (for example, LF Lee,
FM Schleppnik and RK Howe, J. Heterocyclic
Chem., 22, 1621 (1985) .; W. Ried, L. Kaiser, Just
us Liebigs Ann. Chem., 1976, 395 .; J. Liebscher,
H. Hartmann, Z. Chem., 1974, 14, 470 .; M. Muszyn
ski, W. Kaczmarek, M. Wroblewski, Pol. Pl 147,344
; JV Metzger, Thechemistry of heterocyclic com
pounds, Vol. 34, Part 1, 337.Part 2, 369. (John Wi
ley & Sons, 1978).

The pharmaceutically acceptable salt of the thiazole compound according to the present invention includes salts commonly used in medicine and the like, for example,
Salts with organic acids (acetate, trifluoroacetate, maleate, methanesulfonate, formate, toluenesulfonate, etc.), salts with inorganic acids (hydrochloride, sulfate, phosphate, etc.) Or salts with amino acids (arginyl salt, aspartate, glutamate, etc.). Examples of the thiazole compound having a carboxyl group include alkali metal salts, alkaline earth metal salts, and ethanolamine salts.

In the present invention, the above-mentioned compounds can be used alone or as a mixture, and the agent of the present invention can be administered orally or parenterally for treatment. Oral preparations can be solid preparations such as powders, granules, capsules and tablets, or liquid preparations such as syrups and elixirs. In addition, injections, infusions, mucosal administrations, and external preparations can be used as parenteral administration agents.

These preparations are produced in a conventional manner by adding pharmacologically and pharmaceutically acceptable production auxiliaries to the active ingredient. Furthermore, it is also possible to prepare a sustained-release preparation by a known technique. When the production aid is used, the compounding amount of the thiazole compound in the drug of the present invention is usually 0.1.
It is 1 to 10% by weight, preferably 0.2 to 5% by weight.

As the above-mentioned production aids, oral preparations (oral preparations), injection preparations (injection preparations), mucosal preparations (buccal,
Appropriate ingredients for the formulation depending on the route of administration, such as troches and suppositories, and external preparations (ointments, patches, etc.) are used. For example, in the case of oral preparations and mucosal preparations, excipients (eg:
Starch, lactose, crystalline cellulose, calcium lactate, magnesium aluminate metasilicate, silicic anhydride, mannitol), binders (eg, hydroxypropyl cellulose,
Polyvinylpyrrolidone, etc.), disintegrants (eg, carboxymethylcellulose, carboxymethylcellulose calcium), lubricants (eg, magnesium stearate, talc), coating agents (eg, hydroxyethylcellulose)
Ingredients for pharmaceutical preparations such as sucrose and flavoring agents, and in the case of injections, solubilizers or solubilizers that can constitute aqueous injections (eg, distilled water for injection, physiological saline, propylene glycol-
), Suspensions (eg, surfactants such as polysorbate 80), pH adjusters (eg, organic acids or metal salts thereof), stabilizers, and other ingredients for formulation. Water- or oil-based solubilizers or solubilizers (eg, alcohol-
, Fatty acid esters), adhesives (eg, carboxyvinyl polymers, polysaccharides), emulsifiers (eg, surfactants), and stabilizers.

The preparation having the above constitution can be prepared by a known production method,
For example, it can be produced by the method described in the Japanese Pharmacopoeia 10th Edition General Rules for Preparations or a method with appropriate modifications.

When the active ingredient of the present invention is orally administered, the total amount of the active ingredient is usually 0.1 per day for an adult.
To 300 mg / kg, preferably 0.5 to 30 mg / kg
The dose may be divided into one to three doses of kg. These dosages can be appropriately increased or decreased depending on the compound used, age, symptoms, and the like.

When the active ingredient of the present invention is administered parenterally, the dose may be reduced to about one tenth of that in the case of oral administration in consideration of the blood concentration of the active ingredient. As a total of components, usually 0.005 to 10 per adult per day
mg / kg, preferably 0.01 to 3 mg / kg
The dose may be administered once to three times a day, and these doses can be appropriately increased or decreased depending on the compound used, age, symptoms, and the like.

[0037]

The present invention will be described below in more detail with reference to Synthesis Examples and Test Examples. However, the present invention is not limited to these.

(Synthesis Example 1) 4′-chloropropiophenone (0.3 g, 1.8 mmol) in dichloromethane (1
0 ml) solution was cooled to 0 ° C. and bromine (92 μl, 1.8
mmol) was added dropwise. The reaction mixture was returned to room temperature,
Stirred for minutes. After the reaction, the solvent was distilled off, and ethanol (10 ml) was added to the residue to form a solution.
16 g, 2.1 mmol) in water (5 ml).
Stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water.
After adjusting to H7, the mixture was extracted with ethyl acetate and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give 2-amino-
4- (4-Chlorophenyl) -5-methylthiazole (65 mg) was obtained. (Compounds in Table 1-5) ¹ H NMR (CDCl ₃ , δ, ppm): 2.37 (s, 3H), 4.93 (bs, 2
H), 7.35 (d, J = 8.6Hz, 2H), 7.49 (d, J = 8.6Hz, 2
H) .; Mass (m / e): 224 (M ⁺ ).

(Synthesis Example 2) 4'-Hydroxypyropiophenone (0.3 g, 2.0 mmol) was added to chloroform-
It was dissolved in a mixed solvent of ethyl acetate (10 ml-10 ml), copper bromide (0.9 g, 4.0 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethanol (15 ml), a solution of thiourea (0.23 g, 3.0 mmol) in water (5 ml) was added, and the mixture was stirred at room temperature for 16 hours and further at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, adjusted to pH 7 with an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography, and 2-amino-4- (4-hydroxyphenyl) -5-methylthiazole (0.2
g) was obtained. (Compounds in Table 1-6) ¹ H NMR (CDCl ₃ , δ, ppm): 2.26 (s, 3H), 6.68 (s, 2
H), 6.76 (d, J = 8.7Hz, 2H), 7.36 (d, J = 8.7Hz, 2
H), 9.45 (s, 1H) .; Mass (m / e) 206 (M ⁺ ).

The reaction was carried out in the same manner as in Synthesis Example 1 or 2, and the compounds shown in Tables 1 and 2 were synthesized. The ¹ H NMR (CDCl ₃ , δ, ppm) spectrum and the mass spectrum of the synthesized compound are shown below. Compounds in Table 1-1: 2.38 (s, 3H), 5.05 (bs, 2H), 7.
20-7.45 (m, 3H), 7.55 (d, J = 6.8Hz, 2H).
(m / e) 190 (M ⁺ ). Compounds in Tables 1-3: 2.16 (s, 3H), 4.90 (bs, 2H), 7.
25-7.5 (m, 4H).; Mass (m / e): 224 (M ⁺ ). Compounds in Table 1-4: 2.39 (s, 3H), 5.04 (bs, 2H), 7.
24-7.36 (m, 2H), 7.41-7.46 (m, 1H), 7.56 (m, 1
H).; Mass (m / e) 224 (M ⁺ ). Compounds in Tables 1-7: 2.45 (s, 3H), 4.88 (bs, 2H), 7.
56 (t, J = 8.0Hz, 1H), 7.93 (d, J = 8.0Hz, 1H), 8.1
5 (d, J = 8.0Hz, 1H), 8.46 (s, 1H) .; Mass (m / e) 235
(M ⁺ ). Compounds in Tables 1-8: 2.44 (s, 3H), 4.94 (bs, 2H), 7.
30-7.50 (m, 3H), 7.60-7.70 (m, 6H).; Mass (m /
e) 266 (M ⁺ ). Compounds in Tables 1-9: 2.42 (s, 3H), 4.89 (bs, 2H), 7.
62-7.72 (m, 4H).; Mass (m / e) 258 (M ⁺ ). Compounds in Table 1-10: 2.15 (s, 3H), 4.91 (bs, 2H),
7.26 (dd, J = 1.8Hz, J = 8.0Hz, 1H), 7.32 (d, J = 8.0H
z, 1H), 7.46 (d, J = 1.8Hz, 1H) .; Mass (m / e) 258
(M ⁺ ). Compounds in Table 1-11: 2.40 (s, 3H), 6.91 (bs, 2H),
7.55 (d, J = 6.0Hz, 2H), 8.56 (d, J = 6.0Hz, 2H).
Mass (m / e) 191 (M ⁺ ). Compounds in Tables 1-12: 2.44 (s, 3H), 5.19 (bs, 2H),
7.03-7.07 (m, 1H), 7.20-7.26 (m, 2H) .; Mass (m
/ e) 196 (M +). Compounds in Table 1-13: 6.44 (bs, 2H), 7.00-7.08
(m, 2H), 7.25-7.35 (m, 4H), 8.43 (m, 2H) .; Mass
(m / e) 271 (M ⁺ ). Compound in Table 1-14: 1.26 (t, J = 7.1 Hz, 3H), 4.20
(q, J = 7.1 Hz, 2H), 5.63 (bs, 2H), 7.37 (d, J = 8.6
Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H) .; Mass (m / e) 282
(M ⁺ ). Compounds in Table 1-15: 1.22 (t, J = 7.1 Hz, 3H), 4.20
(q, J = 7.1 Hz, 2H), 5.97 (bs, 2H), 7.34-7.42 (m,
3H), 7.60-7.70 (m, 2H). Compounds in Table 1-18: 2.02 (s, 3H), 5.55 (m, 2H),
7.4-7.5 (m, 5H).; Mass (m / e) 218 (M ⁺ ). Compounds in Table 1-21: 5.07 (ds, 2H), 7.2-7.5 (m,
3H), 6.73 (s, 1H), 7.77 (d, J = 8.4Hz, 2H).
(m / e) 176 (M ⁺ ). Compounds in Table 1-23: 5.17 (ds, 2H), 6.63 (s, 1H),
7.05 (m, 2H), 7.73 (m, 2H).; Mass (m / e) 194 (M ⁺ ). Compounds in Table 2-3: 1.22 (t, J = 7.2 Hz, 3H), 2.69
(d, J = 4.8Hz, 3H), 4.18 (q, J = 7.2Hz, 2H), 7.36-
7.42 (m, 4H), 7.63-7.68 (m, 2H) .; Mass (m / e) 26
2 (M ⁺ ). Compound in Table 2-4: 1.25 (t, J = 7.2 Hz, 3H), 2.86
(d, J = 5.0Hz, 3H), 4.20 (q, J = 7.2Hz, 2H), 6.56
(m, 1H), 7.36 (d, J = 8.6Hz, 2H), 7.64 (d, J = 8.6H
; Mass (m / e) 296 (M ⁺ ). Compounds in Table 2-7: 1.68 (bs, 6H), 1.97 (s, 3H),
3.58 (bs, 4H), 7.40 -7.45 (m, 3H), 7.45-7.55 (m,
2H).; Mass (m / e) 286 (M ⁺ ). Compounds in Table 2-8: 3.58 (m, 4H), 3.85 (m, 4H), 7.
30-7.40 (m, 3H), 7.65-7.75 (m, 2H).; Mass (m /
e) 290 (M ⁺ ). Compounds in Table 2-10: 2.00 (s, 1H), 3.60 (m, 4H),
3.81 (m, 4H), 7.40 -7.55 (m, 5H) .; Mass (m / e) 288
(M ⁺ ). Compounds in Table 2-11: 2.06 (s, 3H), 2.16 (s, 3H),
3.55-3.85 (m, 8H), 7.40-7.51 (m, 4H).; Mass (m
/ e) 363 (M ⁺ ). Compounds in Table 2-12: 1.48 (s, 9H), 1.99 (s, 3H),
3.50-3.68 (m, 8H), 7.40-7.55 (m, 5H).
(m / e) 387 (M ⁺ ). Compounds in Table 2-13: 1.48 (s, 9H), 2.05 (s, 3H),
3.50-3.65 (m, 8H), 7.40-7.50 (m, 4H).
(m / e) 421 (M ⁺ ). Compound in Table 2-14: 1.24 (t, J = 7.2Hz, 3H), 3.3
0-3.45 (m, 4H), 3.90-4.05 (m, 4H), 4.21 (q, J
= 7.2Hz, 2H), 7.39-7.42 (m, 3H), 7.68 -7.73 (m,
2H).; Mass (m / e) 317 (M ⁺ ). Compounds in Table 2-15: 1.26 (t, J = 7.0 Hz, 3H), 2.9
6-3.01 (m, 4H), 3.54-3.59 (m, 4H), 4.20 (q, J
= 7.0Hz, 2H), 7.35 (d, J = 8.6Hz, 2H), 7.70 (d, J
= 8.6 Hz, 2H).; Mass (m / e) 351 (M ⁺ ). Compounds in Table 2-16: 1.29 (t, J = 7.1 Hz, 3H), 4.29
(q, J = 7.1Hz, 3H), 7.40-7.47 (m, 2H), 7.73-7.
78 (m, 3H), 8.89 (s, 1H). Compounds in Table 2-17: 7.43-7.60 (m, 3H), 7.65-
7.78 (m, 2H), 9.08 (d, J = 0.8Hz, 1H), 10.05 (d, J
= 0.8Hz, 1H). Compounds in Table 2-18: 4.95 (s, 2H), 7.37-7.58 (m,
3H), 7.63-7.78 (m, 2H). Compounds in Table 2-19: 2.50 (s, 3H), 2.67 (s, 3H),
7.38 (d, J = 8.6Hz, 2H), 7.5 (d, J = 8.6Hz, 2H).; Mas
s (m / e) 223 (M ⁺ ). Compound in Table 2-20: 1.26 (t, J = 7.2 Hz, 3H), 4.00
(s, 3H), 4.22 (q, J = 7.2Hz, 2H), 7.45-7.55 (m, 3
H), 7.90-8.00 (m, 2H) .; Mass (m / e) 247 (M ⁺ ).

(Synthesis Example 3) 2-amino-4- (4-chlorophenyl) -5-ethoxycarbonylthiazole (2
5 mg, 0.088 mmol) in ethanol (3 ml)
And dissolved in sodium hydroxide (18 mg, 0.45 mm
ol) in water (1 ml) and stirred at 50 ° C. for 1 hour. The reaction mixture was adjusted to pH 7.0 with 0.1 M hydrochloric acid, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. After drying over magnesium sulfate, the solvent was distilled off to obtain 2-amino-4- (4-chlorophenyl) -thiazole-5-carboxylic acid (20 mg). (Table 1-1
6) ¹ H NMR (CDCl ₃ , δ, ppm): 7.41 (d, J = 8.5 Hz, 2H),
7.68 (d, J = 8.5Hz, 2H), 7.77 (bs, 2H) .; Mass (m /
e) 254 (M ⁺ ).

The reaction was carried out in the same manner as in Synthesis Example 3;
5 and the compounds shown in Table 2-6 were obtained. The ¹ H NMR (CDCl ₃ , δ, ppm) spectrum and the mass spectrum of the synthesized compound are shown below. Compounds in Table 2-5: 2.85 (d, J = 4.8 Hz, 3H), 7.35-
7.38 (m, 3H), 7.63 -7.70 (m, 2H), 8.22- 8.32 (m,
1H).; Mass (m / e) 234 (M ⁺ ). Compound in Table 2-6: 2.85 (d, J = 4.8 Hz, 3H), 7.43
(d, J = 8.8Hz, 2H), 7.70 (d, J = 8.8Hz, 2H), 8.25-
8.35 (m, 1H) .; Mass (m / e) 268 (M ⁺ ).

Synthesis Example 4 2-Formylamino-4-phenylthiazole-5-carboxylic acid (80 mg, 0.3
2 mmol) in a DMF solution, dicyclohexylcarbodiimide (100 mg, 0.48 mmol) and N-hydroxybenzotriazole (49 mg, 032 mmol)
And then add propylamine (50 μl, 0.61
mmol) and stirred at room temperature for 1.5 hours. The precipitate in the reaction solution was filtered, and the filtrate was washed with ethyl acetate.
The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 2-formylamino-4-phenyl-5-
60 mg of propylcarbamoylthiazole was obtained. This compound (45 mg, 0.16 mmol) was dissolved in methanol (2 ml), and phosphorus oxychloride (29 μl, 0.1 μm) was dissolved.
31 mmol) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was extracted with ethyl acetate, washed with sodium hydrogen carbonate and water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain 2-amino-4-phenyl-5-propylcarbamoylthiazole (26 mg). (Table 1-1
9 compound) ¹ H NMR (CDCl ₃ , δ, ppm): 0.73 (t, J = 7.4 Hz, 3H),
1.32 (m, 2H), 3.15 (m, 2H), 5.51 (bs, 3H), 7.40
-7.50 (m, 3H), 7.50-7.60 (m, 2H).; Mass (m / e)
261 (M ⁺ ).

The reaction was carried out in the same manner as in Synthesis Example 4;
20 compounds were obtained. Below, ¹ H NMR (C
(DCl ₃ , δ, ppm) spectrum and mass spectrum are shown. Compounds in Table 2-20: 0.82 (t, J = 6.2 Hz, 6H), 1.00
-1.40 (m, 8H), 3.80-4.00 (m, 1H), 5.21 (d, J =
9.0Hz, 1H), 5.44 (bs, 2H), 7.40-7.60 (m, 5H) .; M
ass (m / e) 317 (M ⁺ ).

(Test Example 1) IL-6 Production Inhibition Activity Test 1 × 10 ⁴ / mL mouse preosteoblast MC3T3E1 (medium; alpha MEM containing 10% fetal bovine serum) was placed in a 96-well multiwell plate. , CO _{2 for} 3 days according to the standard method
The cells were cultured in an incubator. Confirm that the cells are confluent, and confirm that parathyroid hormone (PTH) 2
The medium was replaced with 0 ng / mL or the medium containing both PTH and test compounds at various concentrations according to the dilution sequence. After further culturing for one day, the concentration of IL-6 produced in the culture supernatant was quantified by a bioassay. Quantitation of IL-6 was determined using mouse hybridoma M that proliferated in an IL-6-dependent manner.
This was performed according to a standard method using H60. The concentration of the inhibitor required to suppress the amount of IL-6 produced by PTH stimulation by 50% was defined as the IC ₅₀ value. Tables 3 and 4 show the IL-6 production inhibitory activity of the compounds according to the present invention.

[0046]

[Table 3]

[0047]

[Table 4]

Test Example 2 Bone Resorption Inhibitory Activity Test The ovary of a 4-week-old ddY mouse (female) was excised under ketamine hydrochloride anesthesia. From the day after ovariectomy, the compounds in Tables 1-5
The doses of 0.4, 2, and 10 mg / kg / day were intraperitoneally administered for 4 consecutive weeks, and sacrificed 4 weeks later, and the femur dry weight was measured. Uterine weight was also measured. Bone hardness tester TK-252C
The femoral strength was measured by a three-point bending test using (Muromachi Kikai Co., Ltd.). As a control, there were prepared a group to which a sham operation was performed without ovariectomy and only a solvent (5% DMSO) was administered, and a group to which ovariectomy was performed and only the solvent was administered. Each group 5
One mouse was used. The following table shows the dry weight of the femur of each group,
Ultimate load (ultimat) which is an index of uterine weight and bone strength
e load) and yield energy were shown as mean ± standard error. The same test was performed for the compounds in Tables 1-17 and 2-9, and the results are shown in Tables 5, 6, and 7, respectively.

[0049]

[Table 5] Table 5. Bone resorption inhibitory activity of compounds in Table 1-5 Compound dose Thigh Bone dry weight / body weight (mg / g) Uterine weight (mg) ─────────────────────────────────── 0 mg / kg / day (solvent only) 1.33 ± 0.03 20.7 ± 2.6 0.4 mg / kg / day 1.39 ± 0.03 20.7 ± 1.3 2 mg / kg / day 1.47 ± 0.04 21.3 ± 1.6 10 mg / kg / day 1.37 ± 0.03 19.0 ± 1.4 Sham operation 1.51 ± 0.06 117.2 ± 10.7 ─────────────────────────────────── (Table 5 continued)投 与 Compound dose Ultimate load (N) Breaking energy (mJ) ─ ────────────────────────────────── 0 mg / kg / day (solvent only) 14.7 ± 0.3 3.2 ± 0.1 0.4 mg kg / day 15.4 ± 0.9 3.0 ± 0.3 2 mg / kg / day 17.6 ± 0.7 4.2 ± 0.1 10 mg / kg / day 15.9 ± 0.3 3.6 ± 0.2 Sham operation 17.2 ± 1.2 3.6 ± 0.6 ───────── ──────────────────────────

[0050]

[Table 6] Table 6. Bone resorption inhibitory activity of compounds in Table 1-17 Compound dose Thigh Bone dry weight / body weight (mg / g) Uterine weight (mg) ─────────────────────────────────── 0 mg / kg / day (solvent only) 1.30 ± 0.07 16.7 ± 1.4 0.4 mg / kg / day 1.32 ± 0.04 15.4 ± 1.4 2 mg / kg / day 1.32 ± 0.04 17.0 ± 1.2 10 mg / kg / day 1.36 ± 0.03 13.3 ± 0.4 Sham operation 1.48 ± 0.02 122.0 ± 14.4 ─────────────────────────────────── (Table 6 continued)投 与 Compound dose Ultimate load (N) Breaking energy (mJ) ─ ────────────────────────────────── 0 mg / kg / day (solvent only) 12.6 ± 0.4 3.3 ± 0.5 0.4 m g / kg / day 14.0 ± 0.6 3.7 ± 0.3 2 mg / kg / day 13.6 ± 0.7 4.1 ± 0.3 10 mg / kg / day 12.8 ± 0.5 3.6 ± 0.2 Sham operation 16.3 ± 1.1 4.2 ± 0.6 ─────── ────────────────────────────

[0051]

[Table 7] Table 7. Bone resorption inhibitory activity of compounds in Table 2-9 Compound dose Thigh Bone dry weight / body weight (mg / g) Uterine weight (mg) ─────────────────────────────────── 0 mg / kg / day (solvent only) 1.30 ± 0.03 19.3 ± 2.1 0.4 mg / kg / day 1.34 ± 0.02 17.6 ± 0.9 2 mg / kg / day 1.35 ± 0.02 16.3 ± 0.7 10 mg / kg / day 1.35 ± 0.01 13.9 ± 0.4 Sham operation 1.50 ± 0.04 105.4 ± 8.0 ─────────────────────────────────── (Table 7 continued)投 与 Compound dose Ultimate load (N) Breaking energy (mJ) ─ ────────────────────────────────── 0 mg / kg / day (solvent only) 13.1 ± 0.7 3.7 ± 0.5 0.4 mg / kg / day 13.6 ± 0.5 3.1 ± 0.4 2 mg / kg / day 14.3 ± 0.8 3.8 ± 0.2 10 mg / kg / day 15.0 ± 0.1 3.8 ± 0.6 Sham operation 16.0 ± 0.5 3.9 ± 0.3 ───────── ──────────────────────────

From Tables 5, 6, and 7, the compounds in Tables 1-5, 1-17, and 2-9 show that the compounds shown in Table 1-5, in the ovariectomized mouse, which is an animal model of postmenopausal osteoporosis, It has been found that the compound has an activity of suppressing a decrease in bone weight and bone strength without increasing the weight.

[0053]

Industrial Applicability The thiazole compound according to the present invention has an activity of suppressing a decrease in bone weight and bone strength without increasing uterine weight in an ovariectomized mouse, which is an animal model of postmenopausal osteoporosis, and (6) It has uses as a production inhibitor, a bone resorption inhibitor, and an anti-osteoporosis agent.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 277/40 C07D 277/40 // C07D 277/22 277/22 (72) Inventor Mina Yada 1 Unomori 1 Sagamihara City, Kanagawa Prefecture −18−10

Claims (6)

[Claims] 1. The following general formula (1): (Wherein, R ¹ represents a hydrogen atom, an unsubstituted or substituted amino group, or a lower alkyl group. R ² represents an unsubstituted or substituted aryl group. R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group. , An acyl group, an alkoxycarbonyl group, a carboxyl group, a carbamoyl group, a hydroxymethyl group, a cycloalkyl group, a vinyl group, a cyano group, or an unsubstituted or substituted aryl group). 6. An interleukin-6 production inhibitor comprising a salt acceptable to a plant as an active ingredient. 2. The following general formula (1): (Wherein, R ¹ represents a hydrogen atom, an unsubstituted or substituted amino group, or a lower alkyl group. R ² represents an unsubstituted or substituted aryl group. R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group. , An acyl group, an alkoxycarbonyl group, a carboxyl group, a carbamoyl group, a hydroxymethyl group, a cycloalkyl group, a vinyl group, a cyano group, or an unsubstituted or substituted aryl group). A bone resorption inhibitor comprising a salt acceptable to a human as an active ingredient. 3. The following general formula (1): (Wherein, R ¹ represents a hydrogen atom, an unsubstituted or substituted amino group, or a lower alkyl group. R ² represents an unsubstituted or substituted aryl group. R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group. , An acyl group, an alkoxycarbonyl group, a carboxyl group, a carbamoyl group, a hydroxymethyl group, a cycloalkyl group, a vinyl group, a cyano group, or an unsubstituted or substituted aryl group). An anti-osteoporosis agent comprising, as an active ingredient, a salt acceptable for osteoporosis. 4. A compound of the general formula (2) (Wherein R ^{1 ′} is an amino group, R ^{2 ′} is an unsubstituted or substituted aryl group excluding a phenyl group and a 4-chlorophenyl group, and R ^{3 ′} is a lower alkyl group or an unsubstituted or substituted aryl group. A thiazole compound. 5. The thiazole compound according to claim 4, wherein R ^{2 ′} is a heteroaryl group. 6. A compound of the general formula (3) (Wherein, R ^{1 ″} is a pyrrolidinyl group or an unsubstituted or substituted piperazinyl group, R ² is an unsubstituted or substituted aryl group, and R ^{3 ″} is an acyl group, an alkoxycarbonyl group, or a carboxyl group. ).