WO2022080346A1

WO2022080346A1 - Novel nitrogen-containing cyclic compound and application thereof

Info

Publication number: WO2022080346A1
Application number: PCT/JP2021/037662
Authority: WO
Inventors: 真一川口; 忠志辻田
Original assignee: 国立大学法人佐賀大学
Priority date: 2020-10-16
Filing date: 2021-10-12
Publication date: 2022-04-21
Also published as: JP2022066061A; JP6904528B1

Abstract

Provided is a novel pyrazoline derivative that can be used as a research reagent, a drug, and the like and can be synthesized at low cost by a simple reaction process. The novel pyrazoline derivative or a salt thereof is represented by General Formula (I), General Formula (II), or General Formula (III). (R1 is a substituted or unsubstituted monocyclic, fused cyclic, or polycyclic aryl group having one or two 5- or 6-membered aromatic ring(s) or a substituted or unsubstituted cyclic alkyl group, R2 is a hydrogen atom or a substituted or unsubstituted alkyl group, and each R3 is independently a substituted or unsubstituted linear or cyclic alkyl group. Here, in the general formula (III), the combination (R1, R2, R3) is not (phenyl group, methyl group, hydrogen atom), (phenyl group, methyl group, methyl group), and (phenyl group, ethyl group, ethyl group).)

Description

New nitrogen-containing cyclic compounds and their uses

The present invention relates to a novel nitrogen-containing cyclic compound, and more particularly to a nitrogen-containing cyclic compound that can be used as a research reagent, a drug, or the like, and its use.

The nitrogen-containing cyclic compound is regarded as an important compound in the fields of pharmaceuticals and pesticides, and is widely used in various applications such as pharmaceuticals and plant disease control agents.

Since, for example, a pyrazoline derivative as a nitrogen-containing cyclic compound has high utility value in a wide range, many researchers are working on its novel synthesis. For example, in the pharmaceutical field, certain pyrazoline derivatives have been confirmed to have anticonvulsant activity (see Non-Patent Document 1).
Further, for example, the 2,3-diaryl-pyrazolidine derivative, which is one of the pyrazoline derivatives, has been confirmed to have an inhibitory activity against an enzyme that decomposes a neuropeptide / neurotensin (see Patent Document 1).

In recent years, in the pharmaceutical field, hypoxia inducible factor (HIF) activator (hereinafter referred to as HIF activator) has been revealed by Dr. William Kaelin, who won the 2019 Nobel Prize in Physiology or Medicine. Has been attracting attention due to its useful properties.

This hypoxia-inducible factor (HIF) is a protein that is expressed when cells or tissues fall into a hypoxic state, and has a function of promoting angiogenesis and eliminating the hypoxic state. Furthermore, hypoxia-inducing factor (HIF) is a "master transcription factor" that promotes transcription of many genes such as erythrocyte-producing hormone and vascular endothelial growth factor, and plays an important role in eliminating hypoxia.

However, hypoxia-inducible factor (HIF) is hydroxylated by the action of iron atoms in prolyl-hydroxylase (PHD), followed by ubiquitin by the von Hippel-Lindau (VHL) protein. It undergoes chemical modification and is degraded by the proteasome. In other words, hypoxia-inducible factor (HIF) is negatively controlled because it is always decomposed and its abundance is kept low under normal conditions.

Therefore, if hypoxia-inducible factor (HIF) can be activated by inhibiting the function (activity) of prolyl hydroxylase (PHD), it is considered that the resistance of the tissue to the hypoxic state can be enhanced.

It has been noted that hypoxia in peripheral tissues, that is, ischemia, is a predisposing factor for lifestyle-related diseases such as kidney disease, chronic kidney disease, ischemic disease, hypertension, diabetes, and arteriosclerosis. The use of HIF activators has been considered as a treatment for such ischemia-related diseases, and clinical trials are actually progressing.

In particular, blood transfusions and intravenous injections of erythropoietin protein are applied in the current treatment of chronic renal diseases, but since it affects the financial burden on patients and the decrease in QOL due to the increased frequency of hospital visits, a lighter oral therapeutic drug is required. It is being done.

As a HIF activator as a therapeutic agent for chronic kidney disease, a compound having a 2-oxoglutarate (2-OG: 2-oxoglutarate) skeleton (2-OG analog compound) is used as a main component. Since the 2-OG-like compound coordinates with the active center of prolyl hydroxylase (PHD) and acts as a cofactor, it acts to inactivate prolyl hydroxylase (PHD) by its competitive inhibitory action. It is a mechanism.

Compounds conventionally known as HIF activators include dimethyloxaloylglycine (DMOG: Dimethyloxaloylglycine) and IOX2 (N-[[1,2-dihydro-4-hydroxy-2-oxo-1-(phenylmethyl)). -3-quinolyl] carbonyl] glycine) and the like, all of which are 2-OG analogs having a 2-oxoglutaric acid (2-OG) skeleton.

Further, as a HIF activator currently under development, for example, roxadustat (FG-4592) jointly developed by Fibrogen and Astellas Pharma can be mentioned (see Non-Patent Document 2). In addition, Vadadustat (MT-6548) developed by Mitsubishi Tanabe Pharma / Akebia (see Patent Document 2) and Enarodustat (JTZ-951) developed by Japan Tobacco / Torii Pharmaceutical (non-JTZ-951). (See Patent Document 3), Daprodustat (GSK-1278863) developed by GlaxoSmithKline (see Patent Document 3), and the like. In each case, a 2-OG analog compound having a 2-oxoglutaric acid (2-OG) skeleton is used.

International Publication WO2003 / 078400 Gazette U.S. Patent Publication No. 20040254215 International Publication WO 2007/150011

However, the pyrazoline derivative, which is a conventional nitrogen-containing cyclic compound exemplified in Non-Patent Document 1 and Patent Document 1, is an expensive compound because its synthetic reaction is complicated, and for example, a drug in the pharmaceutical field can be used. It cannot be said that it is fully utilized for various purposes including.

In addition, the above-mentioned conventional HIF activator is also an expensive drug. This is partly due to the complexity of the synthetic reaction of 2-OG analogs, which are the main components of conventional HIF activators, and inexpensive drugs and reagents are desired. I can't find any drugs or reagents.

An object of the present invention is to provide a novel nitrogen-containing cyclic compound that can be used in a wide range of applications such as research reagents and drugs and can be synthesized at low cost by a simple reaction step. One of its uses is to provide an inexpensive and highly safe composition that exerts an inhibitory action on prolyl hydroxylase (PHD) and exhibits HIF activation ability. For example, it is an object of the present invention to provide a composition that can also be used as an oral therapeutic agent for chronic kidney disease.

As a result of diligent research on a novel compound that can be applied to pharmaceuticals, the present inventors have found a novel nitrogen-containing cyclic compound. Furthermore, they have found that the compound can be prepared by an extremely simple reaction step, and have completed the present invention.

Thus, according to the present invention, a nitrogen-containing cyclic compound represented by the following general formula (I), general formula (II), or general formula (III) or a salt thereof is provided as a solution to the above-mentioned problems. To. (However, R ¹ is an aryl group having a monocyclic structure, a fused ring structure, or a polycyclic structure having an aromatic ring number of 1 to 2 consisting of a substituted or unsubstituted 5-membered ring or 6-membered ring, or a substituted or unsubstituted ring. R ² is a hydrogen atom or a substituted or unsubstituted alkyl group, and R ³ is an independently substituted or unsubstituted linear or cyclic alkyl group, respectively. However, the general formula (III). In), the combinations of (R ¹ , R ² , R ³ ) are (phenyl group, methyl group, hydrogen atom), (phenyl group, methyl group, methyl group), and (phenyl group, ethyl group, respectively. Ethyl group) except when it is.)

Further, according to the present invention, a pharmaceutical composition containing the nitrogen-containing cyclic compound represented by the general formula (I), the general formula (II), or the general formula (III) or a salt thereof is also provided. (However, R ¹ is an aryl group having a monocyclic structure, a fused ring structure, or a polycyclic structure having an aromatic ring number of 1 to 2 consisting of a substituted or unsubstituted 5-membered ring or 6-membered ring, or a substituted or unsubstituted ring. R ² is a hydrogen atom or a substituted or unsubstituted alkyl group, and R ³ is an independently substituted or unsubstituted linear or cyclic alkyl group.)

The NMR chart of the compound 5a which concerns on the Example of this invention is shown. The NMR chart of the compound 5a'according to the Example of this invention is shown. The NMR chart of the compound 5a "according to the Example of this invention is shown. The measurement results of the HIF transcription activity of the

compounds

5c and 5e according to the examples of the present invention are shown. The measurement result of the HIF transcription activity of the

compound

5f, 5g which concerns on the Example of this invention is shown. The measurement results of the HIF transcription activity of the

compounds

5b and 5k according to the examples of the present invention are shown. The measurement results of the HIF transcription activity of the compounds 5j and 5i according to the examples of the present invention are shown. The measurement results of the HIF transcription activity of the compounds 5ab and 5ac according to the examples of the present invention are shown. The measurement result of the HIF transcription activity of the compound 5fb which concerns on the Example of this invention is shown. The measurement results of the HIF transcription activity of the compounds 5a, 5a'according to the examples of the present invention are shown. The results of the HIF-stabilized cell-cell comparison between the compound 5a according to the embodiment of the present invention and the conventional HIF inhibitor are shown.

The nitrogen-containing cyclic compound of the present invention or a salt thereof is represented by the following general formula (I), general formula (II), or general formula (III). (However, R ¹ is an aryl group having a monocyclic structure, a fused ring structure, or a polycyclic structure having an aromatic ring number of 1 to 2 consisting of a substituted or unsubstituted 5-membered ring or 6-membered ring, or a substituted or unsubstituted ring. R ³ is an independently substituted or unsubstituted linear or cyclic alkyl group. However, in the general formula (III), the combination of (R ¹ , R ² , R ³ ) is , (Phenyl group, methyl group, hydrogen atom), (phenyl group, methyl group, methyl group), and (phenyl group, ethyl group, ethyl group), respectively.)

The present inventors use the nitrogen-containing cyclic compound or a salt thereof according to the present invention as separate and independent compounds represented by the above general formula (I), general formula (II), or general formula (III). We have succeeded in synthesizing a pyrazoline derivative or a pyrazoline derivative to derive the present invention. That is, each of the above general formulas (I), general formula (II), or general formula (III) represents a tautomer of the same compound (keto-enol tautomer, enamine-imine tautomer) for convenience. It represents a nitrogen-containing cyclic compound synthesized separately as an independent pyrazoline derivative or a pyrazoline derivative.

The above-mentioned "salt" is the biological and pharmaceutical effect of the free acid or free base of the nitrogen-containing cyclic compound represented by the above general formula (I), general formula (II), or general formula (III). Refers to the salt that holds. For example, examples of the salt derived from the base include salts containing cations of alkali metal or alkaline earth metal, and examples thereof include sodium salt, potassium salt, lithium salt, cesium salt, calcium salt, magnesium salt and the like. can. The nitrogen-containing cyclic compound according to the present invention can be in salt form, more preferably a salt containing an alkaline earth metal, for example, a sodium salt, a potassium salt, a lithium salt, or a cesium salt because of its ease of handling. The sodium salt form is preferable because of the ease of use.

Since the nitrogen-containing cyclic compound according to the present invention contains a carbon atom serving as an asymmetric center, an optically pure enantiomer, a mixed enantiomer such as a racemate, an optically pure diastereomer, and the like thereof. It can also exist in the form of a mixed mixed diastereomer, a racemate composed of diastereomers, or the like.

R ¹ is preferably an aryl group having a monocyclic structure, a fused ring structure, or a polycyclic structure having an aromatic ring number of 1 to 2 consisting of a substituted or unsubstituted 6-membered ring, or a substituted or unsubstituted cyclic alkyl group. Among them, the monocyclic structure and the fused ring structure having an aromatic ring number of 1 to 2 composed of a substituted or unsubstituted 6-membered ring include, for example, (1) an unsubstituted phenyl group, a naphthyl group, a biphenyl group, and a thienyl group. , Pyridine group, aryl group such as anthranyl group; (2) Trill group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group , 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 3,6-dimethylphenyl group, 2,3,4-trimethylphenyl group , 2,3,5-trimethylphenyl group, 2,3,6-trimethylphenyl group, 2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group, 3,4,5-trimethylphenyl group , 2-Ethylphenyl group, propylphenyl group, butylphenyl group, hexylphenyl group, cyclohexylphenyl group, octylphenyl group, 2-methyl-1-naphthyl group, 3-methyl-1-naphthyl group, 4-methyl-1 -Naphenyl group, 5-methyl-1-naphthyl group, 6-methyl-1-naphthyl group, 7-methyl-1-naphthyl group, 8-methyl-1-naphthyl group, 1-methyl-2-naphthyl group, 3 -Methyl-2-naphthyl group, 4-methyl-2-naphthyl group 5-methyl-2-naphthyl group, 6-methyl-2-naphthyl group, 7-methyl-2-naphthyl group, 8-methyl-2-naphthyl group An aryl group substituted with a lower alkyl group such as a group or a 2-ethyl-1-naphthyl group; (3) an aryl group substituted with a lower haloalkyl group such as a trifluoromethylphenyl group or a trifluoroethylphenyl group; (4). 3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl Group, 3,5-dimethoxyphenyl group, 3,6-dimethoxyphenyl group, 2,3,4-trimethoxyphenyl group, 2,3,5-trimethoxyphenyl group, 2,3,6-trimethoxyphenyl group , 2,4,5-Trimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 3,4,5-to Limethoxyphenyl group, 2-ethoxyphenyl group, propoxyphenyl group, 2-methoxy-1-naphthyl group, 3-methoxy-1-naphthyl group, 4-methoxy-1-naphthyl group, 5-methoxy-1-naphthyl group , 6-methoxy-1-naphthyl group, 7-methoxy-1-naphthyl group, 8-methoxy-1-naphthyl group, 1-methoxy-2-naphthyl group, 3-methoxy-2-naphthyl group, 4-methoxy- 2-naphthyl group, 5-methoxy-2-naphthyl group, 6-methoxy-2-naphthyl group, 7-methoxy-2-naphthyl group, 8-methoxy-2-naphthyl group, 2-ethoxy-1-naphthyl group, etc. An aryl group substituted with a lower alkoxy group of; (5) an aryl group substituted with a phenoxy group such as a phenoxybenzyl group; (6) an aryl group substituted with a hydroxyl group such as a phenol group, a naphthol group, or a cresol group; 7) Halogen atoms such as chlorophenyl group, dichlorophenyl group, trichlorophenyl group, fluorophenyl group, difluorophenyl group, trifluorophenyl group, tetrafluorophenyl group, pentafluorophenyl group, bromophenyl group, dibromophenyl group and iodophenyl group. Examples thereof include, but are not limited to, an aryl group substituted with.

Further, R ¹ also includes those in which a plurality of types of the substituents mentioned above are substituted at a plurality of substitutable positions of the aryl group. For example, it is substituted with a methoxy group and a halogen atom such as 2-chloro-3-methoxyphenyl group, 2-chloro-4-methoxyphenyl group, 2-chloro-5-methoxyphenyl group, 2-chloro-6-methoxyphenyl group and the like. Examples thereof include, but are not limited to, aryl groups.

More preferably, this R ¹ is composed of an aryl group containing ^one or two substituted or unsubstituted benzene rings or naphthalene rings, or a substituted or unsubstituted cyclic alkyl group having 3 to 10 carbon atoms. .. When R ¹ is composed of a substituted or unsubstituted aryl group, for example, an aryl group which may be substituted with an alkyl group, an alkoxy group or a halogen atom can be mentioned, and the monocyclic structure includes a phenyl group. The fused ring structure is preferably a naphthyl group, and the polycyclic structure is preferably a biphenyl group or a phenoxybenzyl group, more preferably R ¹ is composed of one or two benzene rings, and more preferably. It is composed of a substituted or unsubstituted phenyl group or a biphenyl group, and is composed of, for example, a phenyl group or a biphenyl group.

When R ¹ is composed of a substituted or unsubstituted cyclic alkyl group having 3 to 10 carbon atoms, it is not particularly limited, but for example, a cyclohexyl group, a 4-ethylcyclohexyl group, a 4-propylcyclohexyl group, 4, 4-Dimethylcyclohexyl group, 2,6-dimethylcyclohexyl group, 3,5-dimethylcyclohexyl group, cyclohexylmethyl group, cyclopropyl group, 2,3-dimethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2,5- Examples thereof include a dimethylcyclopentyl group, a 3-ethylcyclopentyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecanyl group, etc. Among them, the cyclic compound has less angular distortion of the bond angle and is excellent in chemical stability. A 5-membered ring compound to an 8-membered ring compound are suitable, and examples thereof include a substituted or unsubstituted cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, and a 6-membered ring compound and a 6-membered ring compound because they have less angular distortion. A 7-membered ring compound is suitable, and examples thereof include a substituted or unsubstituted cyclohexyl group and a cycloheptyl group, and among these, a cyclohexyl group is mentioned, for example.

R ² is preferably a substituted or unsubstituted alkyl group, preferably a linear or branched methyl group in which R ² is a linear or branched lower alkyl group having 1 to 10 carbon atoms. Examples thereof include an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group. Of these, a lower alkyl group having 1 to 5 carbon atoms, which has a relatively low carbon number, is suitable because of its ease of handling. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or isobutyl. Group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3 -Dimethylbutyl group and the like can be mentioned, and examples thereof include a methyl group, an ethyl group, a propyl group and an isopropyl group. Further, R ² is not limited to these, and for example, in the case of an application in which it is desired to contain a longer chain functional group, a lower alkyl group having 6 to 10 carbon atoms is also suitable depending on various applications. For example, a linear or branched nonyl group can be preferably used.

R ³ is a substituted or unsubstituted linear or cyclic alkyl group, preferably composed of a linear or cyclic alkyl group having 1 to 6 carbon atoms, and is more preferable as the linear alkyl group. Is composed of a lower alkyl group having 1 to 5 carbon atoms, more preferably composed of a lower alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, and a propyl group. Further, R ³ is preferably a cyclic alkyl group having 3 to 10 carbon atoms as the cyclic alkyl group, and is not particularly limited, but for example, a cyclohexyl group, a 4-ethylcyclohexyl group, a 4-propylcyclohexyl group, 4 , 4-Dimethylcyclohexyl group, 2,6-dimethylcyclohexyl group, 3,5-dimethylcyclohexyl group, cyclohexylmethyl group, cyclopropyl group, 2,3-dimethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2,5 -Dimethylcyclopentyl group, 3-ethylcyclopentyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecanyl group, etc., among which the cyclic compound has less angular distortion of the bond angle and is excellent in chemical stability. A 5-membered ring compound to an 8-membered ring compound is suitable, and examples thereof include a substituted or unsubstituted cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, and the 6-membered ring compound has further less angular distortion. And a 7-membered ring compound are suitable, and examples thereof include a substituted or unsubstituted cyclohexyl group and a cycloheptyl group, and among these, a cyclohexyl group is mentioned, for example.

The pyrazolidine derivative or a salt thereof as the nitrogen-containing cyclic compound of the present invention represented by the general formula (I) can be produced by using a three-step reaction represented by the following reaction formula (A).

The reaction steps of these three-step reactions (1) to (3) will be described in more detail below. The same applies to the reaction steps of the general formulas (II) and (III) as follows.

(1) As shown in the reaction formula (A-1) of the first step or lower, first, compound 2 having a pyrimidine skeleton containing R ³ is added to compound 1 in which R ¹ is added to an aldehyde group under a piperidine catalyst. Compound 3 is obtained by heating and undergoing an aldol condensation reaction. A known method can be used for this aldol condensation reaction (for example, Gorovoy, A. et al. Synth. Commun. 2014, 44, 1296-1300.).

(2nd stage)
Next, as shown in the following reaction formula (A-2), hydrazine monohydrate is added to the obtained compound 3 and refluxed under ethanol to obtain compound 4 having a pyrazolidine skeleton. The reflux time is not particularly limited, but may be 1 hour to several hours, for example, 1 hour. Known methods can be used for this pyrazolidine formation reaction (eg, Abdel Latif, N. et al. Bioorg. Chem. 2016, 67, 116.).

(3rd stage)
Next, as shown in the following reaction formula (A-3), the obtained compound 4 is heated in the presence of a carbonate ester (acid anhydride) containing R ² and a carboxylic acid containing R ² to alkanoyl. The pyrazolidine derivative 5 according to the present invention can be obtained by subjecting it to an acylation reaction, and production has been confirmed by this reaction (see Examples described later). The heating temperature is not particularly limited, but can be 100 ° C to 200 ° C, for example, 125 ° C. The heating time is not particularly limited, but can be 1 hour to 10 hours, for example, 2 hours. A known method can be used for this alkanoylation (acyllation) reaction.

Further, the nitrogen-containing cyclic compound of the present invention or a salt thereof can also be produced by using the reaction represented by the following reaction formula (B) for the general formula (II), and is actually produced by this reaction. Production has been confirmed in (see Examples below).

That is, the heating performed in the third step of the general formula (I) is in the presence of the carboxylic acid containing R ² and the carbonic acid ester containing R ² , instead of the third step of the general formula (II). Then, heating is carried out in the same manner in the presence of the carboxylic acid containing R ² .

Further, the nitrogen-containing cyclic compound of the present invention or a salt thereof can also be produced by using the reaction represented by the following reaction formula (C) for the general formula (III), and is actually produced by this reaction. Production has been confirmed in (see Examples below).

That is, in the third-step reaction of the reaction formula (C) to the general formula (III), the carboxylic acid containing R ² and the carbonic acid ester containing R ² in the above reaction formula (A-3) to the general formula (I). Instead of heating in the presence of, it is heated in the presence of a carboxylic acid containing R ² .

The nitrogen-containing cyclic compound of the present invention is an extremely simple three-step reaction (1) to (3) for any of the general formulas (I), (II) and (III) as a pyrazoline derivative, a pyrazoline derivative or a salt thereof. ) Can be obtained.

As described above, the nitrogen-containing cyclic compound according to the present invention can be obtained as a separate and independent compound represented by the above general formula (I), general formula (II), or general formula (III). That is, each of the above general formulas (I), general formula (II), or general formula (III) represents a tautomer of the same compound (keto-enol tautomer, enamine-imine tautomer) for convenience. It represents a compound synthesized separately as an independent pyrazoline derivative or a pyrazoline derivative (see Examples below).

With respect to the nitrogen-containing cyclic compound represented by the general formula (I), the general formula (II), or the general formula (III) thus obtained, the biological and pharmaceutical effects of the free acid or the free base can be obtained. It is possible to form a retained salt form. The following is an example of the salt.

(However, M ⁺ represents a cation of an alkali metal or an alkaline earth metal.)

As described above, the salt derived from the base can be a sodium salt, a potassium salt, a lithium salt, a cesium salt, a calcium salt, a magnesium salt or the like. The nitrogen-containing cyclic compound according to the present invention can be in salt form, more preferably a salt containing an alkaline earth metal, for example, a sodium salt, a potassium salt, a lithium salt, or a cesium salt because of its ease of handling. The sodium salt form is preferable because of the ease of use.

As described above, the novel nitrogen-containing cyclic compound or a salt thereof according to the present invention can be synthesized as a pyrazoline derivative or a pyrazoline derivative or a salt thereof by a simple three-step reaction step, and can be produced at a lower cost than before. can.

The novel nitrogen-containing cyclic compound or salt thereof thus obtained has a wide range of uses.

For example, as an example thereof, a composition containing a novel nitrogen-containing cyclic compound represented by the following general formula (I), general formula (II), or general formula (III) and a salt thereof can be mentioned. (However, R ¹ is composed of a monocyclic structure, a fused ring structure, or a polycyclic structure having an aromatic ring number of 1 to 2 consisting of a substituted or unsubstituted 5-membered ring or a 6-membered ring, and R ² is a hydrogen atom or a substituted ring. Alternatively, it is an unsubstituted alkyl group, and R ³ is an independently substituted or unsubstituted linear or cyclic alkyl group.)

As for the nitrogen-containing cyclic compound represented by the general formula (I), the general formula (II), or the general formula (III) contained in the present composition, as described above, the biological of the free acid or the free base thereof. And it is possible to form a salt form that retains its pharmaceutical effect. The following is an example of the salt.

As described above, as the salt derived from the base, for example, sodium salt, potassium salt, lithium salt, cesium salt, calcium salt, magnesium salt and the like can be used. The nitrogen-containing cyclic compound according to the present invention can be in salt form, more preferably a salt containing an alkaline earth metal, for example, a sodium salt, a potassium salt, a lithium salt, or a cesium salt because of its ease of handling. The sodium salt form is preferable because of the ease of use.

The composition according to the present invention contains the above-mentioned novel nitrogen-containing cyclic compound or a salt thereof, and can be used for various purposes.

For example, in the pharmaceutical field, if there is a composition that can be produced inexpensively and exerts an inhibitory effect on prolyl hydroxylase (PHD), HIF is cheaper than before due to its hypoxia-inducing factor (HIF) activating effect. It is considered possible to provide an activator and its reagent. This has the potential to realize an excellent therapeutic agent for chronic kidney disease that is inexpensive and easy to use, but such an excellent composition has not existed in the past.

In this regard, the present inventors have also found that the above-mentioned composition according to the present invention surprisingly exhibits an excellent ability to inhibit the activity of proline hydroxylase (PHD). This ability to inhibit the activity of proline hydroxylase (PHD) makes it possible to activate hypoxia-inducible factor (HIF), and a HIF activator having a new basic structure will be realized.

In fact, the composition according to the present invention has certainly been confirmed to be more active than conventional HIF activators as exhibiting the active action of hypoxia-inducible factor (HIF) (see Examples below). ..

Considering the suitability for such applications, more preferably, R ¹ is composed of one or two phenyl groups and / or R ² is composed of a lower alkyl group having 1 to 5 carbon atoms. It is preferably composed and / or composed of a linear or cyclic alkyl group having 1 to ⁶ carbon atoms in R3.

As described above, R ¹ is preferably an aryl group having a monocyclic structure, a fused ring structure, or a polycyclic structure having 1 to 2 aromatic rings composed of substituted or unsubstituted 6-membered rings, for example. , (1) aryl groups such as unsubstituted phenyl group, naphthyl group, biphenyl group, thienyl group, pyridine group, anthranyl group; (2) trill group, 2-methylphenyl group, 3-methylphenyl group, 4-methyl Phenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group , 3,6-dimethylphenyl group, 2,3,4-trimethylphenyl group, 2,3,5-trimethylphenyl group, 2,3,6-trimethylphenyl group, 2,4,5-trimethylphenyl group, 2 , 4,6-trimethylphenyl group, 3,4,5-trimethylphenyl group, 2-ethylphenyl group, propylphenyl group, butylphenyl group, hexylphenyl group, cyclohexylphenyl group, octylphenyl group, 2-methyl-1 -Naphenyl group, 3-methyl-1-naphthyl group, 4-methyl-1-naphthyl group, 5-methyl-1-naphthyl group, 6-methyl-1-naphthyl group, 7-methyl-1-naphthyl group, 8 -Methyl-1-naphthyl group, 1-methyl-2-naphthyl group, 3-methyl-2-naphthyl group, 4-methyl-2-naphthyl group, 5-methyl-2-naphthyl group, 6-methyl-2- An aryl group substituted with a lower alkyl group such as a naphthyl group, 7-methyl-2-naphthyl group, 8-methyl-2-naphthyl group, 2-ethyl-1-naphthyl group; (3) trifluoromethylphenyl group, An aryl group substituted with a lower haloalkyl group such as a trifluoroethylphenyl group; (4) 3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4-dimethoxyphenyl group, 2,5 -Dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 3,6-dimethoxyphenyl group, 2,3,4-trimethoxyphenyl group, 2, 3,5-Trimethoxyphenyl group, 2,3,6-trimethoxyphenyl group, 2,4,5-trimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 3,4,5-trimethoxy Phenyl group, 2-ethoxyphenyl group, propoxyphenyl group, 2-methoxy-1-naphthyl group, 3-Methone-1-naphthyl group, 4-methoxy-1-naphthyl group, 5-methoxy-1-naphthyl group, 6-methoxy-1-naphthyl group, 7-methoxy-1-naphthyl group, 8-methoxy-1 -Naphenyl group, 1-methoxy-2-naphthyl group, 3-methoxy-2-naphthyl group, 4-methoxy-2-naphthyl group, 5-methoxy-2-naphthyl group, 6-methoxy-2-naphthyl group, 7 Aryl groups substituted with lower alkoxy groups such as -methoxy-2-naphthyl group, 8-methoxy-2-naphthyl group, 2-ethoxy-1-naphthyl group; (5) substituted with phenoxy groups such as phenoxybenzyl group. Aryl group; (6) Aryl group substituted with hydroxyl group such as phenol group, naphthol group, cresol group; (7) Chlorophenyl group, dichlorophenyl group, trichlorophenyl group, fluorophenyl group, difluorophenyl group, trifluorophenyl group , Tetrafluorophenyl group, pentafluorophenyl group, bromophenyl group, dibromophenyl group, aryl group substituted with halogen atom such as iodophenyl group, and the like, more preferably alkyl group, alkoxy group or halogen atom. It is an aryl group that may be substituted, and more preferably a phenyl group as a monocyclic structure, a naphthyl group as a condensed ring structure, and a biphenyl group or a phenoxybenzyl group as a polycyclic structure.

Further, R ¹ is more preferably composed of a phenyl group or a biphenyl group from the viewpoint that it can exhibit excellent efficacy as a composition.

In addition to this, R ¹ can also be composed of a substituted or unsubstituted linear or cyclic alkyl group, in which case R ¹ is preferably a linear chain having 1 to 6 carbon atoms. Alternatively, it is composed of a cyclic alkyl group, and the linear alkyl group is more preferably composed of a lower alkyl group having 1 to 5 carbon atoms, and more preferably composed of a lower alkyl group having 1 to 3 carbon atoms. It is composed and includes, for example, a methyl group, an ethyl group, and a propyl group. Further, R ³ is preferably a cyclic alkyl group having 3 to 10 carbon atoms as the cyclic alkyl group, and is not particularly limited, but for example, a cyclohexyl group, a 4-ethylcyclohexyl group, a 4-propylcyclohexyl group, 4 , 4-Dimethylcyclohexyl group, 2,6-dimethylcyclohexyl group, 3,5-dimethylcyclohexyl group, cyclohexylmethyl group, cyclopropyl group, 2,3-dimethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2,5 -Includes dimethylcyclopentyl group, 3-ethylcyclopentyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecanyl group, etc., and cyclohexyl group is preferable from the viewpoint of ease of handling.

As described above, R ² is preferably a substituted or unsubstituted alkyl group, preferably composed of a lower alkyl group having 1 to 5 carbon atoms, and more preferably 1 to 3 carbon atoms. It is composed of a lower alkyl group of the above, and examples thereof include a methyl group, an ethyl group, and a propyl group.

As described above, R ³ is preferably a substituted or unsubstituted linear or cyclic alkyl group, and the linear alkyl group is preferably composed of a lower alkyl group having 1 to 5 carbon atoms. It is more preferably composed of a lower alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group and a propyl group. Further, R ³ is preferably a cyclic alkyl group having 3 to 10 carbon atoms as the cyclic alkyl group, and is not particularly limited, but for example, a cyclohexyl group, a 4-ethylcyclohexyl group, a 4-propylcyclohexyl group, 4 , 4-Dimethylcyclohexyl group, 2,6-dimethylcyclohexyl group, 3,5-dimethylcyclohexyl group, cyclohexylmethyl group, cyclopropyl group, 2,3-dimethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2,5 -Includes dimethylcyclopentyl group, 3-ethylcyclopentyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecanyl group and the like.

R ³ is a linear alkyl group having a small molecular weight such as a methyl group, an ethyl group, or a propyl group, or a cyclopropyl group, a cyclopentyl group, or a cyclohexyl group because it can exhibit excellent effects as a composition. It is preferably a cyclic alkyl group having a molecular weight of about the same, and more preferably a methyl group, an ethyl group, a propyl group, or a cyclohexyl group, for example.

The aspect of the composition according to the present invention is not particularly limited, but can be used as a drug, a quasi drug, or a reagent.

When the composition according to the present invention is used as a drug or a quasi-drug (that is, as a quasi-drug), it causes various human or animal diseases by the action of inhibiting the proline hydroxylase activity as described above. It can be used as a treatable drug (therapeutic drug).

Examples of such diseases include kidney disease, chronic kidney disease, ischemic disease, hypertension, diabetes, and arteriosclerosis, and examples thereof include drugs for improving ischemic symptoms due to chronic kidney disease (chronic nephritis). ..

Further, since the composition according to the present invention is a small molecule compound, it can be orally administered, and can be used, for example, as a hypoxia-inducing factor (HIF) activator for oral administration. The hypoxia-inducible factor (HIF) activator for oral administration according to the present invention can reduce the burden on the patient because it can avoid invasion such as subcutaneous injection. For example, HIF for oral administration for the treatment of kidney disease. It can be used as an activator. Recently, although a subcutaneous injection route that continuously reduces pain with a patch or the like has been developed, there is still a certain burden on the patient, and in any case, the hypoxia-inducing factor (HIF) for oral administration according to the present invention. The activator makes it possible to reduce the burden on the patient.

In this regard, in the conventional HIF activator, as described above, a compound having a 2-oxoglutaric acid (2-OG) skeleton (2-OG-like compound) is generally used, but the composition according to the present invention is used. The structure is completely different from that of conventional HIF activators, and the mechanism of action of HIF activity is also completely different, because it is understood from its structural formula as a compound that is not based on the 2-oxoglutaric acid (2-OG) skeleton. Therefore, when the composition according to the present invention is used as a HIF activator, it becomes a novel HIF activator that has never existed in the past. In addition, the composition according to the present invention is synthesized by the simple reaction of the above three steps, and can be produced at a lower cost than the conventional HIF activator using a 2-OG analog. Furthermore, it has been confirmed that the composition according to the present invention has higher HIF activity selectivity than conventional HIF activators (see Examples described later).

The composition according to the present invention can contain the above nitrogen-containing cyclic compound or a salt thereof at an arbitrary concentration depending on the purpose. In addition, the concentration can be freely designed according to the age and weight of the patient, the type and degree of the disease, and the route of administration.

Further, since the composition according to the present invention can be introduced with various functional groups due to its chemical structure, it is also possible to improve the water solubility or to make it fat-soluble in terms of its solvent characteristics. Due to this property of the composition according to the present invention, the action / administration route can be freely changed and easily controlled.

Since the composition according to the present invention exhibits an excellent activity of hypoxia-inducible factor (HIF), it can also be used as a research reagent (that is, as a reagent composition).

The active action of this hypoxia-inducible factor (HIF) is highly topical and is being researched by many researchers all over the world, and there is a high need for it as a research reagent, and a cheaper and simpler research reagent is desired. It's being rare. The composition according to the present invention can be provided as an excellent research reagent satisfying such needs.

(Example)
Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.
The analysis was carried out with the following equipment.
¹ H-NMR, ¹³ C-NMR: Varian NMR 400 MHz system
Gel Permeation Chromatography (GPC): LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.

Production of Pyrazoline Derivative (Example 1)
Preparation of 5- (1-Acetyl-5-Phenylpyrazolidine-3-iriden) -1,3-dimethylbarbituric acid (Compound 5a)

The following synthetic reaction was carried out according to the above general formula (A) (R ¹ = C ₆ H ₅ , R ² = CH ₃ , R ³ = CH ₃ ).

After frame-drying a 25 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of benzaldehyde (manufactured by Nacalai Tesque) and 5-acetyl-1,3-dimethylbarbituric acid (Tokyo Chemical Industry) (Industrial) 5 mmol was added and stirred. After heating to 170 degrees, 2 drops of piperidine (manufactured by Nacalai Tesque) were dropped. After 7 minutes, the reaction was stopped heating and cooled to obtain a white solid. Filter with ethanol and vacuum dry the filter to enone (6-hydroxy-1,3-dimethyl-5-[(2E) -3-phenylprop-2-enoyl] -1,2,3,4- (Tetrahydropyrimidine-2,4-dione) was obtained in 84% yield.

The previously synthesized intermediate enone compound 6-hydroxy-1,3-dimethyl-5-[(2E) -3-phenylprop-2-enoyl] -1,2,3,4-tetrahydropyrimidine-2,4-dione) 1 mmol, 2 eq hydrazine monohydrate (manufactured by Nacalai Tesque) and ethanol were added and stirred. After completion of the reaction, filtration was carried out with ethanol, and the filtrate was vacuum dried to obtain compound 4. The structure was determined by ¹ H NMR and ¹³ C NMR.

Next, frame dry a 25 mL two-necked flask under an argon atmosphere, and then add 0.3 mmol of compound 4, acetic acid (manufactured by Nacalai Tesque) 0.5 mL, and acetic anhydride (manufactured by Tokyo Kasei) 0.5 mL, 125 ^o . Stir in C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) and whitened as pure compound 5 5- (1-acetyl-5-phenylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (compound 5a). A solid (yield 80%) was obtained. The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.
5- (1-acetyl-5-phenylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5a): white solid; ¹ HNMR (400 MHz, CDCl ₃ ) δ1.94 (s, 3H), 3.27 (s) , 3H), 3.37 (s, 3H), 3.99 (dd, J = 2.5, 19.5 Hz, 1H), 4.3 (dd, J = 10.9, 19.5 Hz, 1H), 5.4 (d, J = 8.16 Hz, 1H) , 7.2 (d, J = 7.2 Hz, 2H), 7.31-7.47 (m, 3H), 13.19 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.6, 27.7, 45.1, 58.6, 86.3 , 125.0, 129.0, 129.7, 139.3, 151.6, 157.7, 162.1, 163.6, 164.3.

(Example 2)
Preparation of 1,3-dimethyl-5- (5-phenyl-1-propanoylpyrazolidine-3-ylidene) barbituric acid (Compound 5ab) (general formula (A): R ¹ = C ₆ H ₅ , R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask under an argon atmosphere, add 0.3 mmol of compound 4, 0.5 mL of propionic acid (manufactured by Nakarai), and 0.5 mL of propionic anhydride (manufactured by Tokyo Kasei), and add 2 at 125 ^o C. Stirred for hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) and given as pure compound 5 1,3-dimethyl-5- (5-phenyl-1-propanoylpyrazolidine-3-iriden) barbituric acid (compound 5ab). A white solid (yield 80%) was obtained. The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

1,3-dimethyl-5- (5-phenyl-1-propanoylpyrazolidin-3-ylidene) barbituric acid (5ab): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.02-1.08 (m, 3H) , 1.95-2.11 (m, 1H), 2.15-2.38 (m, 1H), 3.27 (s, 3H), 3.37 (s, 3H), 3.99 (d, J = 19.1 Hz, 1H), 4.29 (dd, J) = 11.0, 18.6 Hz, 1H), 5.40 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 7.1 Hz, 2H), 7.31-7.48 (m, 3H), 13.70 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ8.5, 26.3, 27.7 (2C), 45.1, 58.2, 86.3, 125.0, 129.0, 129.7, 139.5, 151.6, 157.5, 162.2, 164.3, 167.2.

(Example 3)
Preparation of 5- (1-n-butanoyl-5-phenylpyrazolidine-3-iriden) -1,3-dimethylbarbituric acid (Compound 5ac) (general formula (A): R ¹ = C ₆ H ₅ , R ² = CH ₂ CH ₂ CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask under an argon atmosphere, add 0.3 mmol of compound 4, butyric acid (manufactured by Nakarai) 0.5 mL, and anhydrous butyric acid (manufactured by Tokyo Kasei) 0.5 mL, and stir at 125 ^o C for 2 hours. bottom. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. Then, it was separated by gel permeation chromatography (GPC) (LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.) and 5- (1-n-butanoyl-5-phenylpyrazolidine-3-ylidene) -1 as pure compound 5. , 3-Dimethylbarbituric acid (Compound 5ac) was obtained as a white solid (yield 86%). The structure was determined by 1H NMR and 13C NMR with TMS as the 0ppm standard, respectively.

5- (1-n-butanoyl-5-phenylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5ac): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ0.80 (s, 3H), 1.41-1.73 (m, 2H), 1.89-2.08 (m, 1H), 2.10-2.28 (m, 1H), 3.27 (s, 3H), 3.36 (s, 3H), 4.0 (d, J = 19.0 Hz, 1H), 4.29 (dd, J = 10.9, 19.2 Hz, 1H), 5.41 (d, J = 9.2 Hz, 1H), 7.23 (d, J = 7.0 Hz, 2H), 7.30-7.45 (m, 3H), 02 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ13.6, 17.9, 27.7, 34.7, 45.1, 58.2, 86.3, 125.0, 129.0, 129.7, 139.6, 151.6, 157.6, 162.2, 164.3, 166.5 ..

(Example 4)
Preparation of 5- (1-Acetyl-5- (4-Fluorophenyl) Pyrazolidine-3-Ilidene) -1,3-dimethylbarbituric acid (Compound 5b) (general formula (A): R ¹ = C ₆ H ₄ F, R ² = CH ₂ CH ₂ CH ₃ , R ³ = CH ₃ )

A 25 mL two-necked flask equipped with a reflux tube was frame-dried in an argon atmosphere, and then 4 equal volumes of 4-fluorobenzaldehyde (manufactured by Aldrich Sigma) and 5-acetyl-1,3-dimethylbarbituric acid (manufactured by Aldrich Sigma). Tokyo Chemical Industry Co., Ltd.) 5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, the reaction is stopped heating and cooled to obtain a white solid. Filtrate with ethanol and vacuum dry the filter to enone 5-[(2E) -3- (4-fluorophenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene- 1,2,3,4-tetrahydropyrimidin-4-one is obtained in 35% yield. Intermediate Enon compound 5-[(2E) -3- (4-fluorophenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1 synthesized in a 25 mL two-necked flask , 2,3,4-tetrahydropyrimidin-4-one 1 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, the mixture was filtered through ethanol, and the filtrate was vacuum dried to obtain compound 4b (5- (5- (4-fluorophenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid) in a yield of 79%. I got it in. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

5- (5- (4-fluorophenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (4b): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ3.29 (s, 3H), 3.32 (s, 3H) 3.67-3.77 (m, 1H), 4.10 (dd, J = 18.5, 9.1 Hz, 1H), 4.85 (ddd, J = 7.8, 7.8, 7.8 Hz, 1H), 5.22 (d, J = 7.3 Hz, 1H), 7.06 (t, J = 8.6 Hz, 2H), 7.31-7.39 (m, 2H), 12.01 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.6, 27.8, 43.1, 58.8, 86.3, 115.9 (d, J _CF = 21.5 Hz), 128.0 (d, J _CF = 8.1 Hz) 135.1 (d, J _CF = 3.18 Hz), 151.8, 162.3, 162.5 (d, J _CF = 245.8) Hz), 164.9, 165.8.

5b composition
After frame-drying a 25 mL two-necked flask under an argon atmosphere, add 0.3 mmol of compound 4b, 0.5 mL of acetic acid (manufactured by Nakarai), and 0.5 mL of acetic anhydride (manufactured by Tokyo Kasei), and stir at 125 ^o C for 2 hours. bottom. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and as a pure compound 5- (1-acetyl-5- (4-fluorophenyl) pyrazolidine-3-ylidene) -1. , 3-Dimethylbarbituric acid (Compound 5b) was obtained as a white solid (yield 79%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5- (4-fluorophenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5b): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.94 (s, 3H), 3.27 (s, 3H), 3.36 (s, 3H), 3.96 (d, J = 19.2 Hz, 1H), 4.31 (dd, J = 10.9, 19.4 Hz, 1H), 5.39 (d, J = 8.8) Hz, 1H), 7.12 (t, J = 7.5 Hz, 2H), 7.24 (m, 2H), 13.7 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.6, 27.7, 45.1, 58.0 , 86.4, 116.8 (d, J _CF = 21.5 Hz), 127.0 (d, J _CF = 8.0 Hz), 135.2, 151.6, 157.5, 162.1, 162.7 (d, J _CF = 247.9 Hz) 163.5, 164.3.

(Example 5)
Preparation of 5- (1-Acetyl-5- (4-Fluorophenyl) Pyrazolidine-3-Ilidene) -1,3-dimethylbarbituric acid (Compound 5c) (general formula (A): R ¹ = C ₆ H ₄ Cl, R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 4-chlorobenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) and 5-acetyl-1,3-dimethylbarbituric acid (Manufactured by Tokyo Chemical Industry Co., Ltd.) 2.5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, the reaction is stopped heating and cooled to obtain a white solid. Filtrate with ethanol and vacuum dry the filter to enone 5-[(2E) -3- (4-chlorophenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene- 1,2,3,4-tetrahydropyrimidin-4-one is obtained in 52% yield. Intermediate Enon compound 5-[(2E) -3- (4-chlorophenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1 synthesized in a 25 mL two-necked flask , 2,3,4-tetrahydropyrimidin-4-one 1 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, filtration is performed with ethanol, and the filtrate is vacuum dried to obtain compound 4c (5- (5- (4-chlorophenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid) in a yield of 80%. I got it in. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

5- (5- (4-chlorophenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (4c): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ3.30 (s, 3H), 3.34 (s, 3H), 3.75 (dd, J = 6.5, 18.7 Hz, 1H), 4.10 (dd, J = 8.9, 18.7 Hz, 1H), 4.81-4.91 (m, 1H), 5.06 (d, J = 6.6) Hz, 1H), 7.29-7.39 (m, 4H), 12.00 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.6, 27.7, 43.0, 58.7, 86.4, 111.6, 127.6, 129.2, 134.2 , 137.8, 151.8, 156.4, 162.2, 165.0, 166.1.

Synthesis of 5c A 25 mL two-necked flask was frame-dried under an argon atmosphere, then 0.3 mmol of compound 4c, acetic acid (manufactured by Nakarai) 0.5 mL, and acetic anhydride (manufactured by Tokyo Kasei) 0.5 mL were added at 125 ^o C. Stirred for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. After that, it was separated by gel permeation chromatography (GPC) (LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.), and 5- (1-acetyl-5- (4-chlorophenyl) pyrazolidine-3-ylidene) -1, as a pure compound. 3-Dimethylbarbituric acid (Compound 5c) was obtained as a white solid (yield 98%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5- (4-chlorophenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5c): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.94 (s, 3H), 3.25 (s, 3H), 3.34 (s, 3H), 3.93 (d, J = 19.0 Hz, 1H), 4.33 (dd, J = 10.8, 19.4 Hz, 1H), 5.41 (d, J = 8.5) Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H) 13.63 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.6, 27.7 , 45.0, 58.0, 86.3, 126.6, 129.9, 135.0, 137.8, 151.5, 157.5, 162.0, 163.6, 164.3.

(Example 6)
Preparation of 5- (1-Acetyl-5- (4-Methylphenyl) Pyrazolidine-3-Ilidene) -1,3-dimethylbarbituric acid (Compound 5e) (general formula (A): R ¹ = C ₆ H ₄ CH ₃ , R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 4-methylbenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) and 5-acetyl-1,3-dimethylbarbituric acid (Manufactured by Tokyo Chemical Industry) 2.5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, the reaction was stopped from heating and cooled to obtain a white solid. Filter with ethanol and vacuum dry the filter to enone 5-[(2E) -3- (4-methylphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene- 1,2,3,4-tetrahydropyrimidin-4-one was obtained in 85% yield. Intermediate Enon compound 5-[(2E) -3- (4-methylphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1 synthesized in a 25 mL two-necked flask , 2,3,4-tetrahydropyrimidin-4-one 0.5 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, filtration was performed with ethanol, and the filtrate was vacuum dried to obtain compound 4e (5- (5- (4-methylphenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid) in a yield of 82%. I got it in. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

1,3-dimethyl-5- (5- (4-methylphenyl) pyrazolidin-3-ylidene) barbituric acid (4e): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ2.34 (s, 3H), 3.29 (s, 3H), 3.32 (s, 3H), 3.87-3.77 (m, 1H), 4.09 (dd, J = 9.1, 18.9 Hz, 1H), 4.81 (ddd, J = 8.0, 8.1, 8.1 Hz, 1H), 5.09 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 11.00 (s, 1H); ¹³ C NMR ( 100 MHz, CDCl ₃ ) δ 21.1, 27.6, 27.7, 42.8, 59.5, 86.2, 126.2, 129.7, 136.0, 138.3, 151.9, 162.3, 165.0, 166.2.

5e composition
After frame-drying a 25 mL two-necked flask under an argon atmosphere, add 0.3 mmol of compound 4e, 0.5 mL of acetic acid (manufactured by Nakarai), and 0.5 mL of acetic anhydride (manufactured by Tokyo Kasei), and stir at 125 ^o C for 2 hours. bottom. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and as a pure compound 5- (1-acetyl-5- (4-methylphenyl) pyrazolidine-3-ylidene) -1. , 3-Dimethylbarbituric acid (Compound 5e) was obtained as a white solid (yield 87%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5- (4-methylphenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5e): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.93 (s, 3H), 2.35 (s, 3H), 3.26 (s, 3H), 3.35 (s, 3H), 3.95 (dd, J = 3.1, 19.5 Hz, 1H), 4.31 (dd, J = 10.8, 19.5, 1H) , 5.37 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 13.66 (br, 1H); ¹³ C NMR (100 MHz) , CDCl ₃ ) δ 20.7, 21.2, 27.7, 45.2, 58.6, 86.3, 125.1, 130.3, 136.4, 139.0, 151.6, 157.8, 162.1, 163.7, 164.4.

(Example 7)
Preparation of 5- (1-Acetyl-5- ([1,1'-biphenyl] -4-yl) pyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5f) (general formula (A)) : R ¹ = C ₆ H ₄ C ₆ H ₅ , R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 4-phenylbenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) and 5-acetyl-1,3-dimethylbarbituric acid (Made by Tokyo Chemical Industry) 5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, the reaction was stopped from heating and cooled to obtain a white solid. Filtrate with ethanol and vacuum dry the filter to enone 5-[(2E) -3- (4-biphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene- 1,2,3,4-tetrahydropyrimidin-4-one was obtained in 49% yield. Intermediate Enon compound 5-[(2E) -3- (4-biphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1 synthesized in a 25 mL two-necked flask , 2,3,4-tetrahydropyrimidin-4-one 0.5 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, filtration was performed with ethanol, and the filtrate was vacuum dried to obtain compound 4f (5- (5- (4-biphenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid) in a yield of 87%. I got it in. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

5- (5-([1,1'-biphenyl] -4-yl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (4f): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ3 .29 (s, 3H), 3.33 (s, 3H), 3.79 (dd, J = 7.6, 18.9 Hz, 1H), 4.12 (dd, J = 9.2, 18.9 Hz, 1H), 4.88 (ddd, J = 7.9) , 7.9, 8.3 Hz, 1H), 5.13 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.40-7.47 (m, 4H), 7.53-7.82 (m, 4H) , 12.02 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.6, 27.7, 42.9, 59.3, 86.3, 126.7, 127.0, 127.6, 127.7, 128.8, 138.1, 140.2, 141.3, 151.8, 162.2, 165.0, 166.1.

5f composition
A 25 mL two-necked flask was frame-dried under an argon atmosphere, 0.3 mmol of compound 4f, 0.5 mL of acetic acid (manufactured by Nakarai), and 0.5 mL of acetic anhydride (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. .. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and separated as a pure compound 5- (1-acetyl-5- ([1,1'-biphenyl] -4-yl)). Pyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5f) was obtained as a white solid (yield 96%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5-([1,1'-biphenyl] -4-yl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5f): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.99 (s, 3H), 3.26 (s, 3H), 3.35 (s, 3H), 4.02 (dd, J = 1.9, 19.2 Hz, 1H), 4,34 (dd, J = 10.9, 19.4 Hz, 1H), 5.45 (d, J = 8.3 Hz, 1H), 7.29-7.40 (m, 3H), 7.45 (t, J = 7.5 Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H) , 7.62 (d, J = 7.7 Hz, 2H), 13.68 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ20.7, 27.7, 45.1, 58.4, 86.3, 125.5, 127.0, 127.8, 128.3, 128.9, 138.1, 139.8, 142.0, 151.5, 157.7, 162.1, 163.7, 164.3.

(Example 8)
Preparation of 5- (5-([1,1'-biphenyl] -4-yl) -1-propanoylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (compound 5fb) (general formula) (A): R ¹ = C ₆ H ₄ C ₆ H ₅ , R ² = CH ₂ CH ₃ , R ³ = CH ₃ )

5- (5-([1,1'-biphenyl] -4-yl) -1-propanoylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5fb): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.09 (s, 3H), 2.00-2.19 (m, 1H), 2.20-2.40 (m, 1H), 3.27 (s, 3H), 3.37 (s, 3H), 4.02 (d, J = 19.1) Hz, 1H), 4.20-4.40 (m, 1H), 5.45 (d, J = 7.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.8 Hz, 2H), 13.65 (br, 1H); ¹³ C NMR (100 MHz, 100 MHz, CDCl ₃ ) δ8.6, 26.4, 26.4, 27.7, 45.1, 58.0, 86.4, 125.5, 127.0, 127.8, 128.3, 128.9, 138.4, 139.9, 141.9, 151.6, 157.6, 162.1, 164.3, 167.3.

(Example 9)
Preparation of 5- (1-Acetyl-5- (4-Methoxyphenyl) Pyrazolidine-3-Ilidene) -1,3-dimethylbarbituric acid (Compound 5g) (general formula (A): R ¹ = C ₆ H ₄ OCH ₃ , R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 4-methoxybenzaldehyde (manufactured by Tokyo Chemical Industry) and 5-acetyl-1,3-dimethylbarbituric acid (manufactured by Tokyo Chemical Industry Co., Ltd.) (Made by Tokyo Chemical Industry) 5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, the reaction was stopped from heating and cooled to obtain a white solid. Filtrate with ethanol and vacuum dry the filter to enone 5-[(2E) -3- (4-methoxyphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene- 1,2,3,4-tetrahydropyrimidin-4-one was obtained in 89% yield. Intermediate Enon compound 5-[(2E) -3- (4-methoxyphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1 synthesized in a 25 mL two-necked flask , 2,3,4-tetrahydropyrimidin-4-one 0.5 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, the mixture was filtered through ethanol, and the filtrate was vacuum dried to obtain 4 g of the compound (5- (5- (4-methoxyphenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid) in a yield of 78%. I got it in. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

5- (5- (4-methoxyphenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (4g): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ3.29 (s, 3H), 3.32 (s, 3H), 3.71 (dd, J = 7.9, 18.8 Hz, 1H), 3.80 (s, 3H), 4.08 (dd, J = 8.9, 18.8 Hz, 1H), 4.80 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 11.98 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.7, 27.8, 42.8, 55.5, 59.4, 86.3, 114.5, 127.7, 131.0, 152.0, 159.7, 162.4, 165.1, 166.4.

5g synthesis
After frame-drying a 25 mL two-necked flask under an argon atmosphere, 4 g of a 0.3 mmol compound, 0.5 mL of acetic acid (manufactured by Nakarai) and 0.5 mL of acetic anhydride (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. .. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. After that, it was separated by gel permeation chromatography (GPC) (LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.), and 5- (1-acetyl-5- (4-methoxyphenyl) pyrazolidine-3-ylidene) -1, as a pure compound. 3-Dimethylbarbituric acid (Compound 59) was obtained as a white solid (yield 78%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5- (4-methoxyphenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5g): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.93 (s, 3H), 3.26 (s, 3H), 3.35 (s, 3H), 3.81 (s, 3H), 3.95 (dd, J = 2.6, 19.5 Hz, 1H), 4.29 (dd, J = 10.8, 19.5 Hz, 1H) ), 5.35 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 13.64 (br, 1H); ¹³ C NMR (100) MHz, CDCl ₃ ) δ 20.6, 21.5, 27.7, 45.2, 55.4, 58.3, 86.2, 115.0, 125.3, 126.5, 128.2, 129.0, 131.2, 151.6, 157.7, 159.9, 162.1, 163.7, 164.3.

(Example 10)
Preparation of 5- (1-Acetyl-5-Phenylpyrazolidine-3-iriden) -1,3-dicyclohexylbarbituric acid (Compound 5i) (general formula (A): R ¹ = C ₆ H ₅ , R ² = CH ₃ , R ³ = C ₆ H ₅ (c-Hex))

A 25 mL two-necked flask equipped with a reflux tube was frame-dried in an argon atmosphere, and then 4 equal volumes of benzaldehyde (manufactured by Nakarai) and 5-acetyl-1,3-bizcyclohexylbarbituric acid (Reference: Tetrahedron). (Prepared by the method described in Lett. 2001, 42, 8435) 1.5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 74 minutes, the reaction was stopped heating and cooled to obtain a white solid. Filter with ethanol and vacuum dry the filter to enone 5-[(2E) -3-phenylprop-2-enoyl] -6-hydroxy-1,3-biscyclohexyl-2-methylidene-1,2,3. , 4-tetrahydropyrimidin-4-one was obtained in 55% yield. Intermediate Enon compound 5-[(2E) -3-phenylprop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1,2,3, synthesized in a 25 mL two-necked flask 4-tetrahydropyrimidin-4-one 0.5 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, the mixture was filtered through ethanol, and the filtrate was vacuum dried to give compound 4i (5- (5-phenylpyrazolidin-3-ylidene) -1,3-biscyclohexylbarbituric acid) in a yield of 97%. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

1,3-biscyclohexyl-5- (5-phenylpyrazolidin-3-ylidene) barbituric acid (4i) :: green oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.12-1.26 (m, 2H), 1.26- 1.39 (m, 4H), 1.52-1.66 (m, 6H), 1.72-1.86 (m, 4H), 2.24-2.42 (m, 4H), 3.71 (dd, J = 18.9, 7.6 Hz, 1H), 4.02- 4.14 (m, 1H), 4.62-4.75 (m, 2H), 4.81 (ddd, J = 8.0, 8.0, 8.0 Hz, 1H), 4.99 (d, J = 7.6 Hz, 1H), 7.25-7.38 (m, 5H), 12.08 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 25.4, 26.6, 29.3, 43.3, 53.8, 59.4, 76.7, 77.1, 77.4, 87.1, 126.3, 128.3, 129.0, 139.4, 151.1, 162.6, 165.4, 166.5.

5i composition
A 25 mL two-necked flask was frame-dried under an argon atmosphere, 0.3 mmol of compound 4i, 0.5 mL of acetic acid (manufactured by Nakarai), and 0.5 mL of acetic anhydride (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. .. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and as a pure compound 5- (1-acetyl-5-phenylpyrazolidine-3-iriden) -1,3-dicyclohexyl. Barbituric acid (Compound 5i) was obtained as a brown liquid (yield 99%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5-phenylpyrazolidin-3-ylidene) -1,3-dicyclohexylbarbituric acid (5i): brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.10-1.45 (m, 6H), 1.53-1.72 (m, 6H), 1.75-1.90 (m, 4H), 1.94 (s, 3H), 2.20-2.50 (m, 4H), 3.98 (d, J = 17.6 Hz, 1H), 4.28 (dd, J = 19.4, 10.8 Hz, 1H), 4.60-4.84 (m, 2H), 5.37 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 7.2 Hz, 2H), 7.32-7.48 (m, 3H) ), 13.94 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.6, 25.3, 26.5, 29.2, 45.4, 53.9, 58.5, 76.8, 77.1, 77.3, 77.4, 87.2, 124.9, 128.9, 129.7 , 139.5, 150.9, 157.8, 162.6, 163.4, 164.6.

(Example 11)
Preparation of 5- (1-Acetyl-5-naphthylpyrazolidine-3-iriden) -1,3-dimethylbarbituric acid (Compound 5j) (general formula (A): R ¹ = C ₁₀ H ₈ , R ² ) = CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 3-naphthylaldehyde (manufactured by Tokyo Chemical Industry) and 5-acetyl-1,3-dimethylbarbituric acid (manufactured by Tokyo Chemical Industry Co., Ltd.) Tokyo Chemical Industry Co., Ltd.) 2.5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, the reaction was stopped from heating and cooled to obtain a white solid. Filter with ethanol and vacuum dry the filter to enone 5-[(2E) -3-naphthylprop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1,2,3. , 4-tetrahydropyrimidin-4-one was obtained in 73% yield. Intermediate Enon compound 5-[(2E) -3-naphthylprop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1,2,3,4 synthesized in a 25 mL two-necked flask -Tetrahydropyrimidin-4-one 0.5 mmol, 2eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, the mixture was filtered through ethanol, and the filtrate was vacuum dried to give compound 4j (1,3-dimethylpyrazolidin-3-ylidene) barbituric acid in a yield of 76%. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400MHz system).

1,3-dimethyl-5- (5-naphthylpyrazolidin-3-ylidene) barbituric acid (4j): green solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ3.29 (s, 3H), 3.32 (s, 3H ), 3.85 (d, J = 18.7 Hz, 1H), 4.18 (d, J = 18.7 Hz, 1H), 5.00 (s, 1H), 5.10 (s, 1H), 7.39-7.54 (m, 3H), 7.75 -7.89 (m, 4H), 12.03 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.7, 27.8, 43.0, 60.1, 86.6, 124.0, 125.5, 126.6, 126.8, 127.9, 128.1, 129.3 , 133.4, 133.5, 136.6, 152.0, 162.5, 165.3, 166.5.

5j composition
A 25 mL two-necked flask was frame-dried under an argon atmosphere, 0.3 mmol of compound 4j, 0.5 mL of acetic acid (manufactured by Nakarai), and 0.5 mL of acetic anhydride (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. .. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and as a pure compound 5- (1-acetyl-5-naphthylpyrazolidine-3-iriden) -1,3-dimethyl. Barbituric acid (Compound 5j) was obtained as a white solid (yield 76%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5-naphthylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5j): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.96 (s, 3H), 3.26 ( s, 3H), 3.37 (s, 3H), 4.06 (dd, J = 2.7, 19.5 Hz, 1H), 4.38 (dd, J = 10.9, 19.5 Hz), 5.56 (d, J = 8.2 Hz, 1H), 7.33 (dd, J = 1.2, 8.5 Hz, 1H), 7.54 (t, J = 3.6 Hz, 2H), 7.69 (s, 1H), 7.84 (t, J = 8.1 Hz, 2H), 7.91 (d, J) = 8.5 Hz, 1H), 13.75 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.7, 27.7, 27.8, 45.0, 58.8, 86.4, 122.2, 124.2, 127.0, 127.2, 127.85, 127.93, 130.3, 133.1, 133.2, 136.3, 151.6, 157.7, 162.1, 163.7, 164.4.

(Example 12)
Preparation of 5- (1-Acetyl-5-4 (Phenoxyphenyl) Pyrazolidine-3-Ilidene) -1,3-dimethylbarbituric acid (Compound 5k) (general formula (A): R ¹ = C ₆ H ₄ OC ₆ H ₅ , R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 25 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 4-phenoxybenzaldehyde (manufactured by Tokyo Chemical Industry) and 5-acetyl-1,3-dimethylbarbituric acid (manufactured by Tokyo Chemical Industry Co., Ltd.) (Made by Tokyo Chemical Industry) 2.5 mmol was added and stirred. After heating to 180 degrees, 2 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, the reaction was stopped from heating and cooled to obtain a white solid. Filtrate with ethanol and vacuum dry the filter to enone 5-[(2E) -3- (4-phenoxyphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene- 1,2,3,4-tetrahydropyrimidin-4-one was obtained in 70% yield. Intermediate Enon compound 5-[(2E) -3- (4-phenoxyphenyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1, synthesized in a 25 mL two-

necked flask

2,3,4-tetrahydropyrimidin-4-one 0.5 mmol, 2eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, filtration was performed with ethanol, and the filtrate was vacuum dried to obtain compound 4k (1,3-dimethyl-5-(5- (4-phenoxyphenyl) pyrazolidin-3-ylidene) barbituric acid) in a yield of 76%. I got it in. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400MHz system).

(1,3-dimethyl-5- (5- (4-phenoxyphenyl) pyrazolidin-3-ylidene) barbituric acid (4k): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ3.27 (s, 3H) , 3.29 (s, 3H), 3.72 (dd, J = 7.6, 18.8 Hz, 1H), 4.07 (dd, J = 9.1, 18.8), 4.81 (ddd, J = 8.0, 8.0, 8.3 Hz, 1H), 5.09 (d, J = 7.5 Hz, 1H), 8.93-7.00 (m, 4H), 7.10 (t, J = 7.4, 1H), 7.28-7.35 (m, 4H), 11.97 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.7, 27.8, 43.0, 59.2, 86.4, 119.1, 119.2, 123.8, 127.9, 129.9, 133.8, 151.9, 156.8, 157.6, 162.4, 165.0, 166.2.

5k composition
After frame-drying a 25 mL two-necked flask in an argon atmosphere, 0.3 mmol of compound 4 k, acetic acid (manufactured by Nakarai) 0.5 mL, and acetic anhydride (manufactured by Tokyo Kasei) 0.5 mL were added, and the mixture was stirred at 125 ^o C for 2 hours. .. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. After that, it was separated by gel permeation chromatography (GPC) (LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.), and as a pure compound, 5- (1-acetyl-5- (4-phenoxyphenyl) pyrazolidine-3-ylidene) -1, 3-Dimethylbarbituric acid (Compound 5k) was obtained as a white solid (yield 76%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5-4 (phenoxyphenyl) pyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5k): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.97 (s, 3H ), 3.28 (s, 3H), 3.36 (s, 3H), 3.99 (m, 1H), 4.3 (dd, J = 10.8, 19.5 Hz, 1H), 5.37 (d, J = 8.5, 1H), 7.01 ( d, J = 8.0 Hz, 4H), 7.15 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 13.64 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.7, 27.7, 45.2, 58.2, 86.4, 119.4, 124.0, 126.6, 129.9, 133.6, 151.6, 156.2, 157.6, 158.1, 162.2, 163.6, 164.3.

(Example 13)
Preparation of 5- (1-i-butyroyl-5-phenylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5l) (general formula (A): R ¹ = C ₆ H ₅ , R ² = CH (CH ₃ ) ₂ , R ³ = CH ₃ )

After frame-drying a 10 mL two-necked flask under an argon atmosphere, 0.3 mmol of compound 4a (5- (5-phenylpyrazolidin-3-ylidene) pyrimidine-1,3-dimethylbarbituric acid) and isobutyric acid (manufactured by Nakarai) ) 0.6 mL and 0.6 mL of anhydrous isobutyric acid (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. After that, it is recrystallized from ethanol and filtered to form 5l of pure compound 5- (1- i-butyroyl-5-phenylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (compound 5l). ) Was obtained as a white solid (yield 59%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-i-propyl-5-phenylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5l): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ7.40 (s, 3H), 7.24 (d, J = 6.7 Hz, 2H), 5.48 (s, 1H), 4.26 (s, 1H), 4.01 (d, J = 18.3 Hz, 1H), 3.36 (s, 3H), 3.27 (s, 3H) ), 2.41 (s, 1H), 1.19 (d, J = 5.6 Hz, 3H), 0.82 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.9, 164.3, 162.1, 157.7, 151.6, 140.0 , 129.6, 128.9, 124.9, 86.4, 58.2, 45.0, 31.7, 27.7, 19.3, 18.5

(Example 14)
Preparation of 5- (1-n-decanoyl-5-phenylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5m) (general formula (A): R ¹ = C ₆ H ₅ , R ² = ⁿ C ₉ H ₁₉ , R ³ = CH ₃ )

After frame-drying a 10 mL two-necked flask under an argon atmosphere, 0.3 mmol of compound 4a (5- (5-phenylpyrazolidin-3-ylidene) pyrimidine-1,3-dimethylbarbituric acid) and decanoic acid (manufactured by Nakarai) ) 0.6 mL and 0.6 mL of decanoic acid anhydride (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. Then, by filtering with hexane, 5- (1- n-decanoyl-5-phenylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (compound 5 m) as a pure compound 5 m is made into a white solid (compound 5 m). The yield was 63%). The structure was determined by 1H NMR and 13C NMR with TMS as the 0ppm standard, respectively.

5- (1-i-decanoyl-5-phenylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5m): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ7.41-7.35 (m, 3H ), 7.24-7.22 (m, 2H), 5.39 (d, J = 8.4 Hz, 1H), 4.28 (dd, J = 19.1, 10.5 Hz, 1H), 3.99 (d, J = 18.6 Hz, 1H), 2.17 (s, 1H), 2.01 (s, 1H), 1.52 (d, J = 42.1 Hz, 2H), 1.08-1.32 (13H), 0.87 (t, J = 6.9 Hz, 3H); ¹³ C NMR (100 MHz) , CDCl ₃ ) δ166.8, 164.3, 162.2, 157.6, 151.6, 139.7, 129.6, 128.9, 125.0, 86.3, 77.4, 77.0, 76.7, 58.3, 45.1, 35.3, 33.9, 31.8, 29.3, 28.8, 27.7, 24.7, 24.4, 22.6, 14.0

(Example 15)
Preparation of 5- (1-n-hexanoyl-5-phenylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5n) (general formula (A): R ¹ = C ₆ H ₅ , R ² = ⁿ C ₅ H ₁₁ , R ³ = CH ₃ )

After frame-drying a 10 mL two-necked flask under an argon atmosphere, 0.2 mmol of compound 4a (5- (5-phenylpyrazolidin-3-ylidene) pyrimidine-1,3-dimethylbarbituric acid) and hexane acid (manufactured by Nakarai) ) 0.4 mL and 0.4 mL of hexanoic acid anhydride (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. Then, by filtering with hexane, 5- (1-n-hexanoyl-5-phenylpyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5n) was added as a pure compound 5n to a white solid (Compound 5n). The yield was 34%). The structure was determined by 1H NMR and 13C NMR with TMS as the 0ppm standard, respectively.

5- (1-i-hexanoyl-5-phenylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5m): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.35 (m, 3H) , 7.24-7.22 (m, 2H), 5.26-5.51 (1H), 4.32-4.24 (m, 1H), 3.99 (d, J = 19.0 Hz, 1H), 3.37 (s, 3H), 3.27 (s, 3H) ), 2.09 (d, J = 72.4 Hz, 1H), 1.52 (d, J = 41.3 Hz, 2H), 1.15 (s, 4H), 0.82-0.79 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.7, 164.3, 162.2, 157.5, 151.6, 139.7, 129.6, 129.0, 125.0, 86.3, 58.3, 45.1, 32.8, 31.2, 27.5, 24.1, 22.2, 13.8

(Example 16)
Preparation of 5- (1-Acetyl-5-Cyclohexyl) Pyrazolidine-3-Ilidene) -1,3-dimethylbarbituric acid (Compound 5o) (general formula (A): R ¹ = ^c C ₆ H ₁₁ , R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 10 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of cyclohexanecarbaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.), 5-acetyl-1,3-dimethylbarbituric acid ( (Made by Tokyo Chemical Industry) 2.5 mmol was added and stirred. After heating to 180 degrees, 3 drops of piperidine (manufactured by Nakarai) were dropped. After 1 hour, stop heating and cool to obtain a yellow solid. Filter through ethanol, vacuum dry the filtrate, and isolate the filtrate by silica gel column chromatography to isolate the intermediate enone (3o) 5-[(2E) -3- (cyclohexyl) prop-2-enoyl]. -6-hydroxy-1,3-dimethyl-2-methylidene-1,2,3,4-tetrahydropyrimidin-4-one is obtained in a yield of 25%. The structure was confirmed by 1H NMR.

5-[(2E) -3- (cyclohexyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1,2,3,4-tetrahydropyrimidin-4-one (3o): yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 16.96 (s, 1H), 7.80 (d, J = 15.6 Hz, 1H), 7.28 (dd, J = 15.6, 6.7 Hz, 1H), 3.34 (d) , J = 15.6 Hz, 6H), 2.30 (d, J = 6.7 Hz, 1H), 1.86-1.78 (m, 4H), 1.70 (d, J = 12.4 Hz, 1H), 1.38-1.19 (m, 5H)

Intermediate Enon compound 5-[(2E) -3- (cyclohexyl) prop-2-enoyl] -6-hydroxy-1,3-dimethyl-2-methylidene-1,2 synthesized in a 20 mL two-necked flask , 3,4-tetrahydropyrimidin-4-one (3o) 0.4 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai), and ethanol were added and stirred. After completion of the reaction, the mixture was concentrated under reduced pressure and dried under vacuum to give compound 4c (5- (5-cyclohexylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid) in a yield of 80%. The structure was determined by ¹ H NMR (Varian NMR 400 MHz system).

5- (5-cyclohexylpyrazolidin-3-ylidene) -1,3-dimethylpyrimidine-2,4,6 (1H, 3H, 5H) -trione (4o): yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ4 .29 (s, 1H), 3.99-3.94 (d, 1H), 3.62 (s, 1H), 3.32 (s, 6H) 2.22 (s, 3H), 1.45 (dd, J = 18.8, 10.7 Hz, 1H) , 1.27-1.14 (m, 4H), 1.04 (q, J = 11.7 Hz, 2H)

5o composition
After frame-drying a 10 mL two-necked flask under an argon atmosphere, 0.2 mmol of compound 4o (5- (5-cyclohexylpyrazolidin-3-ylidene) -1,3-dimethylpyrimidine-2,4,6 (1H,) 3H, 5H) -trione), acetic acid (manufactured by Nakarai) 0.5 mL, and acetic anhydride (manufactured by Tokyo Kasei) 0.5 mL were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and as a pure compound 5- (1-acetyl-5-hexylpyrazolidine-3-iriden) -1,3- Dimethylbarbituric acid (Compound 5o) was obtained as a yellow oily substance (yield 57%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5-cyclohexylpyrazolidin-3-ylidene) -1,3-dimethylbarbituric acid (5o): yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.94 (s, 3H), 3.25 ( s, 3H), 3.34 (s, 3H), 3.93 (d, J = 19.0 Hz, 1H), 4.33 (dd, J = 10.8, 19.4 Hz, 1H), 5.41 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H) 13.63 (br, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.6, 27.7, 45.0, 58.0, 86.3, 126.6, 129.9, 135.0, 137.8, 151.5, 157.5, 162.0, 163.6, 164.3.

(Example 17)
Preparation of 5- (1-Acetyl-5- (2-Chloro-3-methoxyphenyl) Pyrazolidine-3-Ilidene) -1,3-dimethylbarbituric acid (Compound 5p) (general formula (A): R ¹ = C ₆ H ₄ ClOCH ₃ , R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 10 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 2-chloro-3-methoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.), 5-acetyl-1,3- 2.5 mmol of dimethylbarbituric acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred. After heating to 180 degrees, 3 drops of piperidine (manufactured by Nakarai) were dropped. After 7 minutes, stop heating and let cool to obtain a yellow solid. After filtering with ethanol and vacuum-drying the filter, intermediate enone ((E) -5-(3- (2-chloro-3-methoxyphenyl) acryloyl) -6-hydroxy-1,3-dimethylpyrimidine- 2,4 (1H, 3H) -dione) is obtained in a yield of 85%. The structure was determined by ¹ H NMR.

(E) -5- (3- (2-chloro-3-methoxyphenyl) acryloyl) -6-hydroxy-1,3-dimethylpyrimidine-2,4 (1H, 3H) -dione (3p): yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 17.04 (s, 1H), 8.55-8.45 (m, 2H), 7.48-6.99 (m, 4H), 3.93 (s, 4H), 3.38 (d, J = 13.7 Hz, 6H)

4p composition
Intermediate enone compound synthesized in a 50 mL two-necked flask (E) -5-(3- (2-chloro-3-methoxyphenyl) acryloyl) -6-hydroxy-1,3-dimethylpyrimidine-2,4 (1H) , 3H) -dione (3p) 1 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai) and ethanol were added and stirred. After completion of the reaction, filter with ethanol. The filtrate was vacuum dried to give compound 4p in 80% yield. The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

5- (1-acetyl-5-4- (2-chrolo-3-metoxy) pyrazolidin-3-ylidene) 5- (5- (2-chloro-3-methoxyphenyl) pyrazolidin-3-ylidene) -1,3 -dimethylpyrimidine-2,4,6 (1H, 3H, 5H)-trione (4p): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.08 (s, 1H), 7.24 (t, J = 7.6 Hz) , 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 5.27 (s, 2H), 4.13-4.09 (m, 2H), 3.91 (s, 3H) , 3.80 (d, J = 18.9 Hz, 1H), 3.34 (s, 3H), 3.28 (s, 3H)

5p composition
After frame-drying a 10 mL two-necked flask under an argon atmosphere, 0.2 mmol of compound 4p (5- (1-acetyl-5-4- (2-chrolo-3-metoxy) pyrazolidin-3-ylidene) 5- (5- (2-chloro-3-methoxyphenyl) pyrazolidin-3-ylidene) -1,3-dimethylpyrimidine-2,4,6 (1H, 3H, 5H) -trione), acetic anhydride (manufactured by Nakarai) 0.5 mL , 0.5 mL of acetic anhydride (manufactured by Tokyo Kasei) was added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and as a pure compound 5- (1-acetyl-5- (2-chloro-3-methoxyphenyl) pyrazolidin-3-ylidene). ) -1,3-dimethylpyrimidine-2,4,6 (1H, 3H, 5H) -trione (Compound 5p) was obtained as a white solid (yield 75%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

5- (1-acetyl-5- (2-chloro-3-methoxyphenyl) pyrazolidin-3-ylidene) -1,3-dimethylpyrimidine-2,4,6 (1H, 3H, 5H)-trione (5p): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29-7.26 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 5.82 (d, J = 8.0 Hz, 1H), 4.35 (dd, J = 19.3, 10.9 Hz, 1H), 3.94 (s + m, 3 + 1H), 3.35 (s, 3H), 3.26 (s, 3H), 1.95 (s) , 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.3, 163.5, 162.0, 158.0, 155.9, 151.5, 138.1, 128.5, 119.9, 116.8, 112.1, 86.4, 56.4, 55.9, 43.9, 29.6, 27.7, 20.3

(Example 18)
Preparation of 5- (1-acetyl-5- (4-n-octylphenyl) pyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5q) (general formula (A): R ¹ = C ₆ H ₅ (C ₈ H ₁₇ ), R ² = CH ₃ , R ³ = CH ₃ )

After frame-drying a 10 mL two-necked flask equipped with a reflux tube in an argon atmosphere, 4 equal volumes of 4-octylbenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) and 5-acetyl-1,3-dimethylbarbituric acid (Made by Tokyo Chemical Industry) 2.5 mmol was added and stirred. After heating to 180 degrees, 3 drops of piperidine (manufactured by Nakarai) were dropped. After 1 hour, the heating is stopped and the mixture is cooled to obtain a yellow solid. After filtering with ethanol and vacuum drying the filter, intermediate enone (3q) (E) -6-hydroxy-1,3-dimethyl-5- (3- (4-octylphenyl) acryloyl) pyrimidine-2 , 4 (1H, 3H) -dione is obtained in 48% yield. The structure was determined by 1H NMR.

(E) -6-hydroxy-1,3-dimethyl-5- (3- (4-octylphenyl) acryloyl) pyrimidine-2,4 (1H, 3H) -dione (3q): yellow solid; ¹ H NMR (400) MHz, CDCl ₃ ) δ 16.96 (s, 1H), 8.52 (d, J = 15.8 Hz, 1H), 7.98 (d, J = 15.8 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 2.63 (t, J = 7.7 Hz, 2H), 1.65-1.58 (m, 2H), 1.32-1.27 ( m, 13H), 0.88 (t, J = 6.9 Hz, 4H)

4q composition
Intermediate enone compound (E) -6-hydroxy-1,3-dimethyl-5- (3- (4-octylphenyl) acryloyl) pyrimidine-2,4 (1H, 3H) synthesized in a 50 mL two-necked flask -Dione (3q), 1 mmol, 2 eq hydrazine monohydrate (manufactured by Nakarai) and ethanol were added and stirred. After completion of the reaction, filter with ethanol. The filtrate was vacuum dried to give compound 4q in 56% yield. The structure was determined by ¹ H NMR (Varian NMR 400 MHz system).

1,3-dimethyl-5-(5- (4-octylphenyl) pyrazolidin-3-ylidene) pyrimidine-2,4,6 (1H, 3H, 5H) -trione (4q): white solid; ¹ H NMR (400) MHz, CDCl ₃ ) δ 7.22-7.14 (m, 4H), 5.40 (d, J = 7.4 Hz, 1H), 4.32 (dd, J = 19.5, 10.9 Hz, 1H), 3.96 (dd, J = 19.4, 3.7) Hz, 1H), 3.34 (s, 3H), 3.25 (s, 3H), 2.60 (t, J = 7.7 Hz, 2H), 1.94-1.91 (m, 2H), 1.59-1.57 (m, 2H), 1.30 -1.23 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H)

5q composition
After frame-drying a 10 mL two-necked flask under an argon atmosphere, 0.3 mmol of compound 1,3-dimethyl-5-(5- (4-octylphenyl) pyrazolidin-3-ylidene) pyrimidine-2,4, 6 (1H, 3H, 5H) -trione (4q), acetic acid (manufactured by Nakarai) 0.6 mL, and acetic anhydride (manufactured by Tokyo Kasei) 0.6 mL were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. As a pure compound 1,3-dimethyl-5-(5- (4-octylphenyl) -1- (prop-1-en-2-yl) pyrazolidin-3-ylidene) pyrimidine-2,4,6 (1H, 3H, 5H) -trione (compound 5q) was obtained as a white solid (yield 96%). The structure was determined by ¹ H NMR and ¹³ C NMR with TMS as the 0 ppm standard, respectively.

1,3-dimethyl-5- (5- (4-octylphenyl) -1- (prop-1-en-2-yl) pyrazolidin-3-ylidene) pyrimidine-2,4,6 (1H, 3H, 5H) -trione (5q): white solid; ¹ H NMR (400 MHz, CDCl ₃ ) δ12.00 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H) ), 5.08 (brs, 1H), 4.83-4.78 (m, 1H), 4.13-4.05 (m, 1H), 3.76-3.69 (m, 1H), 3.31 (s, 3H), 3.28 (s, 3H), 2.58 (t, J = 7.6 Hz, 2H), 2.08 (s, 3H), 1.59-1.56 (m, 2H), 1.30-1.24 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.1, 164.9, 162.3, 151.8, 144.3, 136.2, 129.0, 126.2, 86.1, 59.5, 42.7, 35.5, 31.8, 31.4, 29.4, 29.24, 29.21, 27.7, 27.6, 22.6, 21.4, 14.1

(Example 19)
Preparation of 5- (1-propinoyl-5-phenylpyrazolidine-3-iriden) -1,3-dicyclohexylbarbituric acid (Compound 5r) (general formula (A): R ¹ = C ₆ H ₅ , R ² ) = CH ₂ CH ₃ , R ³ = C ₆ H ₅ (c-Hex))

5r composition
After frame-drying a 10 mL two-necked flask in an argon atmosphere, 4i (1,3-biscyclohexyl-5- (5-phenylpyrazolidin-3-ylidene) barbituric acid) synthesized in Example 10 and propionic acid ( Nakarai) 0.6 mL and propionic anhydride (Tokyo Kasei) 0.6 mL were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. It is then separated by gel permeation chromatography (GPC) (LaboACE LC-5060, manufactured by Nippon Analytical Industry Co., Ltd.) and as a pure compound 5- (1-propinoyl-5-phenylpyrazolidine-3-ylidene) -1,3- Dicyclohexylbarbituric acid (Compound 5r) was obtained as yellow candy (yield 51%). The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

5- (1-propynoyl-5-phenylpyrazolidin-3-ylidene) -1,3-dicyclohexylbarbituric acid (5r): yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.25 (m, 3H), 7.22 (d, J = 7.0 Hz, 2H), 5.39 (brs, 1H), 4.74-4.61 (m, 2H), 4.25-4.15 (m, 1H), 4.02-3.92 (m, 1H), 2.39-2.22 (m) , 5H), 1.99-1.92 (m, 1H), 1.85-1.72 (m, 4H), 1.71-1.52 (m, 6H), 1.37-1.10 (m, 6H), 1.20-0.98 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.1, 164.6, 162.5, 157.7, 150.8, 139.7, 129.6, 128.8, 124.9, 87.1, 58.1, 53.9, 45.3, 29.2, 26.5, 26.3, 25.3, 8.5

(Example 20)
Preparation of 5- (1-n-butyroyl-5-phenylpyrazolidine-3-ylidene) -1,3-dicyclohexylbarbituric acid (Compound 5s) (general formula (A): R ¹ = C ₆ H ₅ , R ² = CH ₂ CH ₂ CH ₃ , R ³ = C ₆ H ₅ (c-Hex))

5s composition
After frame-drying a 10 mL two-necked flask in an argon atmosphere, 4i (1,3-biscyclohexyl-5- (5-phenylpyrazolidin-3-ylidene) barbituric acid) 0.3 mmol synthesized in Example 10, butyric acid (Nakarai) 0.6 mL and anhydrous butyric acid (Tokyo Kasei) 0.6 mL were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. After that, it was separated by gel permeation chromatography (GPC) (LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.), and 5- (1-n-butyroyl-5-phenylpyrazolidine-3-ylidene) -1, as a pure compound. 3-Dicyclohexylbarbituric acid (Compound 5r) was obtained as a yellow oil (yield 71%). The structure was determined by ¹ H NMR and ¹³ C NMR (Varian NMR 400 MHz system).

5- (1-n-butyloyl-5-phenylpyrazolidin-3-ylidene) -1,3-dicyclohexylbarbituric acid (5s): yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.36 (m, 3H) , 7.22 (d, J = 7.2 Hz, 2H), 5.38 (d, J = 6.7 Hz, 1H), 4.79-4.65 (m, 2H), 4.29-4.22 (m, 1H), 3.98 (d, J = 18.8) Hz, 1H), 2.44-2.27 (m, 4H), 2.25-2.17 (m, 1H), 2.05-1.94 (m, 1H), 1.80-0.75 (m, 21H); ¹³ C NMR (100 MHz, CDCl ₃ ) ) δ 166.3, 164.6, 162.6, 157.7, 150.8, 139.8, 129.6, 128.8, 125.0, 87.1, 58.1, 53.9, 45.4, 34.7, 29.2, 26.5, 25.3, 18.0, 13.6

(Example 21)
Preparation of 5- (1-i-butyroyl-5-phenylpyrazolidine-3-ylidene) -1,3-dicyclohexylbarbituric acid (compound 5t) (general formula (A): R ¹ = C ₆ H ₅ , R ² = CH ₂ CH ₃ , R ³ = C ₆ H ₅ (c-Hex))

5t composition
After frame-drying a 10 mL two-necked flask in an argon atmosphere, 4i (1,3-biscyclohexyl-5- (5-phenylpyrazolidin-3-ylidene) barbituric acid) 0.3 mmol synthesized in Example 10, iso 0.6 mL of butyric acid (manufactured by Nakarai) and 0.6 mL of anhydrous isobutyric acid (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. After that, it was separated by gel permeation chromatography (GPC) (LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.), and 5- (1-i-butyroyl-5-phenylpyrazolidine-3-ylidene) -1, as a pure compound. 3-Dicyclohexylbarbituric acid (Compound 5t) was obtained as a yellow oil (yield 82%). The structure was determined by 1H NMR and 13C NMR (Varian NMR 400 MHz system).

5- (1-i-butyloyl-5-phenylpyrazolidin-3-ylidene) -1,3-dicyclohexylbarbituric acid (5t): yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ); δ 7.39-7.36 (m, 3H) ), 7.22 (d, J = 7.3 Hz, 2H), 5.44 (d, J = 7.3 Hz, 1H), 4.79-4.66 (m, 2H), 4.29-4.22 (m, 1H), 4.00 (d, J = 17.2 Hz, 1H), 2.48-2.30 (m, 5H), 1.88-1.74 (m, 4H), 1.70-1.55 (m, 6H), 1.45-1.20 (m, 9H), 0.85-0.78 (m, 3H) ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.6, 164.6, 162.6, 157.8, 150.9, 140.2, 129.6, 128.9, 124.9, 87.2, 58.0, 53.9, 45.3, 31.7, 29.2, 26.5, 25.3, 19.4, 18.5

(Example 22)
Preparation of 5- (1-n-hexanoyl-5-phenylpyrazolidine-3-iriden) -1,3-dicyclohexylbarbituric acid (Compound 5u) (general formula (A): R ¹ = C ₆ H ₅ , R ² = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , R ³ = C ₆ H ₅ (c-Hex))

5u composition
After frame-drying a 10 mL two-necked flask in an argon atmosphere, 4i (1,3-biscyclohexyl-5- (5-phenylpyrazolidin-3-ylidene) barbituric acid) 0.3 mmol and hexane synthesized in Example 10 0.6 mL of acid (manufactured by Nakarai) and 0.6 mL of anhydrous caproic acid (manufactured by Tokyo Kasei) were added, and the mixture was stirred at 125 ^o C for 2 hours. After completion of the reaction, toluene was added, the mixture was concentrated on an evaporator, and the mixture was vacuum dried. After that, it was separated by gel permeation chromatography (GPC) (LaboACE LC-5060 manufactured by Nippon Analytical Industry Co., Ltd.), and 5- (1-i-butyroyl-5-phenylpyrazolidine-3-ylidene) -1, as a pure compound. 3-Dicyclohexylbarbituric acid (Compound 5t) was obtained as a yellow oil (yield 51%). The structure was determined by 1H NMR and 13C NMR (Varian NMR 400 MHz system).

5- (1-n-hexanoyl-5-phenylpyrazolidin-3-ylidene) -1,3-dicyclohexylbarbituric acid (5u): yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ); δ 7.39-7.36 (m, 3H) ), 7.22 (d, J = 7.3 Hz, 2H), 5.44 (d, J = 7.3 Hz, 1H), 4.79-4.66 (m, 2H), 4.29-4.22 (m, 1H), 4.05-3.99 (m, 1H), 2.48-2.30 (m, 5H), 2.24-2.15 (m, 1H), 1.88-1.74 (m, 4H), 1.70-1.55 (m, 8H), 1.45-1.20 (m, 10H), 0.84 ( t, J = 7.2 Hz 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.6, 164.6, 162.6, 157.8, 150.9, 140.2, 129.6, 128.9, 124.9, 87.2, 58.0, 53.9, 45.3, 31.2, 29.2, 27.5, 26.5, 25.3, 24.1, 22.3, 13.9

(Example 23)
Preparation of 5- (1-Acetyl-5-Phenyl-2-pyrazolin-3-iriden) -1,3-dimethylbarbituric acid (Compound 5a'(keto-imine form))

A 25 mL two-necked flask was frame-dried under an argon atmosphere, and then the intermediate enone compound 6-hydroxy-1,3-dimethyl-5-[(2E) -3-phenylprop-2) synthesized in Example 1 above was used. -enoyl] -1,2,3,4-tetrahydropyrimidine-2,4-dione 0.5 mmol, hydrazine monohydrate (manufactured by Nakarai) 2 mmol, glacial acetic acid (manufactured by Nakarai) 1 mL were added, and the mixture was stirred at 125 ^o C for 2 hours. .. After completion of the reaction, filtration was carried out with ethanol (EtOH), and the filtrate was vacuum dried to obtain compound 5'a. The structure was determined by ¹ H NMR and ¹³ C NMR. A white solid 5- (1-acetyl-5-4 (phenoxyphenyl) pyrazolidine-3-ylidene) -1,3-dimethylbarbituric acid (Compound 5a') was obtained (yield 80%).

(5a'): white solid; ¹ HNMR (400 MHz, CDCl ₃ ) δ1.94 (s, 3H), 3.31 (s, 6H), 3.90-4.02 (m, 1H), 4.28-4.36 (m, 1H) , 5.40 (d, J = 8.4 Hz, 1H), 7.22-7.42 (m, 5H); ¹³ CNMR (100 MHz, CDCl ₃ ) δ20.6, 27.7, 45.1, 58.6, 86.3, 125.0, 129.0, 129.7, 139.2 , 139.3, 151.6, 157.7, 163.6.

(Example 24)
5- (1-acetyl-5-phenyl-4-4,5-dihydro-1H-pyrazol-3-yl) -6-hydroxy-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4- Preparation of dione (compound 5a ”(enol form))

After frame-drying a 25 mL two-necked flask in an argon atmosphere, the intermediate enone compound 6-hydroxy-1,3-dimethyl-5-[(2E) -3-phenylprop-2-enoyl] -1,2 , 3,4-tetrahydropyrimidine-2,4-dione) 0.6 mmol, acetylhydrazine Tokyo Chemical Industry 0.6 mmol, and 3 mL of methanol were added, and the mixture was stirred at a bath temperature of 80 ^o C for 18 hours. After completion of the reaction, filtration was carried out with methanol (MeOH), and the filtrate was vacuum dried to obtain compound 5a "as a white solid. The structure was determined by ¹ HNMR (DMSO).

(5a ”): white solid; ¹ HNMR (400 MHz, DMSO) δ3.16 (s, 3H), 3.18 (s, 3H), 3.33 (s, 3H), 3.60-3.70 (m, 1H), 3.82- 3.98 (m, 1H), 4.62 (s, 1H), 7.02-7.28 (m, 3H). 13C is thin and has not been observed.

(Comparison of NMR charts)
The NMR charts of Compound 5a, Compound 5a'and Compound 5a "obtained in each of the above Examples are shown in FIGS. 1, 2 and 3. The NMR charts were compared.

From the results of the above NMR chart, 3.31 (s, 6H) was observed equivalently in compound 5a'(protons corresponding to H1 and H2). Since the carbonyls corresponding to C3 and C4 of ¹³ C are equivalent in compound 5a', it was confirmed that the number of ¹³ C is one less than that of compound 5a.

Compound 5a ”has a completely different shape of the multiplet (multiplex line) in the region of 4.0 to 5.5 ppm indicating H of the 5-membered ring from the compound 5a and compound 5a'of the above-mentioned examples. In the vicinity of 4.6 ppm. OH-derived singlet (single line) was observed.

(Comparison of solubility)
Compound 5a and compound 5a'of the above example were easily soluble in chloroform, but compound 5a "of this example was sparingly soluble in chloroform.

From the above results, it was confirmed that compound 5a, compound 5a'and compound 5a "of each example were synthesized separately and independently as compounds having different structures at room temperature. Similarly, each of the other implementations. Compounds having different structures represented by the general formula (I), the general formula (II), or the general formula (III), which are related to all the compounds of the example, can also be synthesized separately and independently.

(Yield for each reaction process)
The yields for each reaction step in each of the above examples are summarized below.

(1) First stage (aldol condensation reaction)

(2) Second stage (pyrazolidine formation reaction)

(3) Third step (alkanoylation (acylation) reaction)

(Example 25)
The HRE luciferase assay system (Tsujita, T .; Kawaguchi, Si .; Dan, T .; Baird, L .; Miyata, T .; Yamamoto, M., Hypoxia-Sensitive Reporter System for High) previously developed by the present inventors. -Throughput Screening. Tohoku J. Exp. Med. 2015, 235 (2), 151-159) was used to measure whether the compounds of each of the above examples show HIF-activated signals and HIF activity. The chemical ability (HIF transcription activity ability) was measured. As a comparative example, the HIF activation ability (HIF transcription activity ability) of dimethyloxaloylglycine (DMOG; Dimethyloxaloylglycine), which is known as the above-mentioned conventional HIF activator, was also measured.

The HRE luciferase assay system is a SK-N-BE (2) -C cell (SKN: HER-NLuc) that stably introduces a structure that expresses nano-Luc (Promega) under the regulation of the transcriptional regulatory region of HIF. Was used. SKN: HRE-N Luc was seeded on a 384-well plate (Corning) at 7.0 × 10 ³ cell / well and precultured at 37 ° C for 16 hours at 5% CO ₂ . The next day, the cells were replaced with a medium containing various drugs serially diluted from 100 μM, and cultured for 24 hours. After adding 1/3 of the luciferase assay (NanoGlo Luciferase Assay, manufactured by Promega) after stimulation, the emission intensity is measured with a multimode microplate reader (SpectraMax i3x, manufactured by Molecular Device) for measuring absorption, fluorescence, and emission spectra. Was measured. The luciferase activity based on the HIF transcription activity was determined as the relative activity of various drugs when 1% DMSO stimulation was set to 1.

SKN: HRE-N Luc was seeded on a 384-well plate (Corning) at 7.0 × 10 ³ cell / well and precultured at 37 ° C for 16 hours at 5% CO ₂ . The next day, the cells were replaced with a medium containing various drugs serially diluted from 100 μM, and cultured for 24 hours. After stimulation, 1/10 of the medium was added with Cell Counting Kit-8 (manufactured by Dojin Kagaku Kenkyusho), and the color reaction was carried out in the incubator for 30 minutes to 1 hour. After that, the absorbance at 450 nm was measured with a multimode microplate reader (SpectraMax i3x, manufactured by Molecular Devices) for measuring absorbance, fluorescence, and emission spectra. Finally, the survival rate for each stimulus was calculated when the cells treated with 1% DMSO were 100%.

The obtained results are shown in FIGS. 4 to 9 and summarized in the following table. The 5-fold activity ratio in the table indicates the ratio of (5-fold activity concentration of commercially available roxadustat (FG-4592, Astellas Pharma / Fibrogen)) / (5-fold activity concentration of each compound). .. The HIF transcription activity in the table is as follows.
+ Compound 5a (standard) or higher
++ 5 times activity ratio 1 or more
+++ 5 times activity ratio 10 or more

Furthermore, the measurement results of the HIF transcription activity obtained for the 5a (keto-enamine form) obtained in Example 1 and the 5a'(keto-imine form) obtained in Example 13 are shown in FIG. show.

From the obtained results, it was confirmed that all the compounds according to each example exhibited high HIF activation ability. It was confirmed that all of the independently synthesized compounds, keto-enamine, keto-imine, and enol-imine, exert high HIF activation ability. Compound 5a of Example 1 exhibited excellent HIF activating ability almost equivalent to that of DMOG of Comparative Example, which has been conventionally known as a HIF activator. Furthermore, all of the compounds according to each of the other examples showed a HIF activation ability that greatly exceeded that of the DMOG of the comparative example. In particular, very high HIF activation ability was confirmed for compound 5i.

Regarding cytotoxicity, some weak cytotoxicity was observed in compound 5i, but the value of this cytotoxicity is about 100 times that of LC ₅₀ , which is about 24 μM, compared to the active action region of 0.3 μM or more. Since there is a difference, it is a fairly weak cytotoxicity, and a certain level of safety has been confirmed. No cytotoxicity was detected for the compounds according to each of the other examples, and high safety was confirmed.

The compound 5a of Example 1 was immunocombined with the commercially available roxadustat (FG-4592, manufactured by Astellas Pharma / Fibrogen) and dimethyloxaloylglycine (DMOG) known as a conventional HIF activator. FIG. 11 shows the results of comparison between HIF-stabilized cells using a blot (immunoblot; IB) (also known as Western Blotting (WB)). The protein separated by electrophoresis was transferred to a hydrophobic membrane, and the band was detected from the antibody reaction to detect the target proteins HIF-1α, HIF-2α, and α-tubulin. From the obtained results, it was confirmed that the compound 5a of Example 1 showed superior stability to the commercially available roxadustat and the known HIF activator (DMOG).

Claims

A pyrazoline derivative represented by the following general formula (I), general formula (II), or general formula (III) or a salt thereof.
(However, R 1 is an aryl group having a monocyclic structure, a fused ring structure, or a polycyclic structure having an aromatic ring number of 1 to 2 consisting of a substituted or unsubstituted 5-membered ring or a 6-membered ring, or a substituted or unsubstituted aryl group. A cyclic alkyl group, R 2 is a hydrogen atom or a substituted or unsubstituted alkyl group, and R 3 is an independently substituted or unsubstituted linear or cyclic alkyl group, provided with the general formula (III). In, the combinations of (R 1 , R 2 , R 3 ) are (phenyl group, methyl group, hydrogen atom), (phenyl group, methyl group, methyl group), and (phenyl group, ethyl group, ethyl, respectively). Except when it is based on).
R1 is composed of an aryl group containing one or two substituted or unsubstituted benzene rings or naphthalene rings, or a substituted or unsubstituted cyclic alkyl group having 3 to 10 carbon atoms.
The pyrazoline derivative according to claim 1 or a salt thereof.
R 2 is composed of a linear or branched lower alkyl group having 1 to 10 carbon atoms.
The pyrazoline derivative or a salt thereof according to claim 1 or 2.
R 3 is composed of a linear or cyclic alkyl group having 1 to 6 carbon atoms.
The pyrazoline derivative or a salt thereof according to any one of claims 1 to 3.
Racemic, enantiomer, diastereomer, or meso,
The pyrazoline derivative or a salt thereof according to any one of claims 1 to 4.
A composition containing a pyrazoline derivative represented by the following general formula (I), general formula (II), or general formula (III) or a salt thereof.
(However, R 1 is an aryl group having a monocyclic structure, a fused ring structure, or a polycyclic structure having an aromatic ring number of 1 to 2 consisting of a substituted or unsubstituted 5-membered ring or a 6-membered ring, or a substituted or unsubstituted aryl group. A cyclic alkyl group, R 2 is a hydrogen atom or a substituted or unsubstituted alkyl group, and R 3 is an independently substituted or unsubstituted linear or cyclic alkyl group.)
R1 is composed of an aryl group containing one or two substituted or unsubstituted benzene rings or naphthalene rings, or a substituted or unsubstituted cyclic alkyl group having 3 to 10 carbon atoms.
The composition according to claim 6.
R 2 is composed of a lower alkyl group having 1 to 5 carbon atoms.
The composition according to claim 6 or 7.
R 3 is composed of a linear or cyclic alkyl group having 1 to 6 carbon atoms.
The composition according to any one of claims 6 to 8.
Racemic, enantiomer, diastereomer, or meso,
The composition according to any one of claims 6 to 9.
The composition according to any one of claims 6 to 10, which is used for inhibiting the activity of proline hydroxylase.
The composition according to claim 11, for use in a disease that can be treated by inhibiting the activity of proline hydroxylase.
The composition according to claim 12, wherein the disease is selected from the group consisting of kidney disease, chronic kidney disease, ischemic disease, hypertension, diabetes, and arteriosclerosis.
The composition according to any one of claims 6 to 13, wherein the embodiment is a drug, a quasi drug, or a reagent.
The composition according to claim 14, which is for oral administration.
A hypoxia-inducible factor activator for oral administration containing the composition according to claim 15.