WO2000076980A1 - Novel nitrogen-contaiing heterocyclic derivatives or salts thereof - Google Patents

Abstract

Compounds which are useful as preventives or remedies for complications of diabetes based on protein kinase C inhibition. Nitrogen-containing heterocyclic derivatives characterized by the chemical structure in that a nitrogen-containing heterocycle having carbamoyl is bonded to aryl, cycloalkyl or heteroaryl via a nitrogen atom, and to optionally substituted alkylene, etc. via another nitrogen atom, for example, 4-benzyloxy-2-[(2-dimethylaminoethyl)amino]-6-(3-methylanilino)pyrimidine-5-carboxamide. These compounds well inhibit PKC activity and exert a favorable effect of ameliorating complications of diabetes.

Description

 Specification

 辦 Mineral nitrogen-containing heterocyclic derivative or its salt

Technical field

 The present invention relates to a gfm nitrogen-containing heterocyclic derivative useful as a drug, particularly a protein kinase c (PKOp and a harmful agent), and a material thereof.

 Protein kinase c (PKC) is a serine that is characterized by its lipids

It is a Z threonine kinase. PKC plays an important role in regulating cell expression and cell differentiation and proliferation in cells. Currently, it is classified into 10 isozymes based on its molecular structure and transformation (Biochem J 291: 329-343 (1993)). PKC is a single polypeptide composed of 592-737 amino acids in length, consisting of a regulatory domain and a catalytic domain. These domains can be further divided into well-preserved areas and areas that separate them. Although the catalytic domain of PKC is very similar to the catalytic domain found in other protein kinases, the regulatory domain is unique to PKC. PKC isozymes are known to have 40-80% homology at the amino acid level.

PKCI *. Enzyme regulated by a number of factors, including membrane phospholipids, calcium, and certain umami substances (diasylglycerol generated by phospholipase activation). (Science 258: 607- 61 4 (1 992)). PKC isozymes, such as 1, 2, and _r, refer to membrane phospholipids, calcium and diaglycerol Z phorbol ester for complete remodeling. PKC <5, ε, η, and 0 types; ¾ † iification is calcium-independent. The ^ and λ forms of PKC are also independent of both calcium and diacylglycerol, and it is believed that only membrane phospholipids are involved in the formation.

It has been known that specific PKC isozymes are involved in the onset of disease and its disease. For example, elevated blood glucose levels seen in diabetes can 11 ± 1 and 2 isozymes in the retina (Am J Physiol 265: E783-793 (1993)). In diabetic renal fibers, one isozyme is also deteriorated (JClin Invest 100: 115-126 (1997)). Also vascular fibers heart However, activation of the S2 isozyme has been reported (Proc Natl Accad Sc USA 89: 11059-1 1063 (1992)). The yS2 isozyme has also been shown to be involved in leukocyte differentiation / proliferation (JBiol Chem 269: 23 230-23235 (1994)).

 As described above, PKC plays an important role in the development and development of specific diseases, and PKC-specific inhibitors may be effective therapeutic agents. In diabetes, the formation of lysozyme may lead to increased production of extracellular matrix and cytokines, phosphorylase A2 formation and inhibition of Na / K-ATPase, leading to various complications. (Dia betes 47: 859-866 (1 998)).薬 剤, Drugs showing a strong inhibitory effect on lysozyme have been shown to improve diabetic nephropathy and retinopathy as well as improve the above abnormalities (Science 272: 728-731). (1 996). JC lin Invest 100: 1 15—126 (1 997)).

 As a PKCP harmful agent, staurosporine, an alkaloid produced by a substance, is known as a potent inhibitor (BB och em Biophys Res Commun 135: 397-402 (1 986)). However, the usefulness of this agent and related compounds as therapeutic agents for diseases is limited by the lack of specificity of inhibition against other protein kinases (J Med Chem 39: 2664-2671 (1996)). In other words, staurosporine is concerned about its lack of selectivity.

 In addition, a compound having a structure similar to staurosporine, bisindolylmaleimide, is known to be a compound that it it is not selective for other protein kinases and is not selective for PKC (J Med Chem 35: 994-1001 (1992) )).

 As bisindolylmaleimide, it is described in JP-A-7-215977 that a compound represented by the following general formula is effective for diabetic compounds.

(Refer to the above publication for the symbols in the formula.)

 WO 97/19065 also states that compounds represented by the following general formula are useful as proteinase inhibitors, but they are effective for diabetic complications That is not suggested or disclosed.

 (Refer to the gazette in the formula ί * ±.) Disclosure of the Invention

The present inventors have considered that a nitrogen-containing heterocyclic ring having carbamoyl US may be bonded to aryl, cycloalkyl, or heteroaryl via an N atom and further have a substituent via another N atom. A nitrogen-containing heterocyclic derivative represented by the following general formula (I) or a salt thereof, which is characterized by being chemically bonded to a lower alkylene or the like, is an excellent protein kinase CP. Thus, the present invention has been completed. That is, the present invention relates to a nitrogen-containing complex ring derivative represented by the following general formula (I) or a salt thereof, and an additive containing them as an active ingredient, particularly diabetic healing agent j.

(The symbols in the above formula have the following meanings,

X

R ⁴

 D: aryl which may have a substituent, cycloalkyl which may have a substituent, or heteroaryl which may have a substituent

^{R 1: -N (R 5)} R 6, - good even have a substituent, a lower alkylene ^{- N (R 5) R 6} , OH, addition to which may have a substituent亍Roariru,

AA ² : same or different, may have a substituent, lower alkylene, bond,

 Ring E: cycloalkylene optionally having a substituent, arylene optionally having a substituent, tt heteroarylene optionally having a substituent,

A ³ : NR ⁷ , CO, 0, S, which may have a substituent, lower alkylene, or a bond,

R ² , R ³ , RR ⁵ , R ⁶ and R ⁷ : identical or different, having a hydrogen atom, halogen, OH, NH ₂ , CN, one CHO, -C (= NH) -NH ₂ , having a substituent Lower alkyl, may have one C (= 〇) -substituent, M may have lower alkyl, one c (= o) -o-substituent may have lower alkyl, -so _2- lower alkyl optionally having a substituent, -c (= o) -heteroaryl optionally having a substituent, cycloalkyl optionally having a substituent, optionally having a substituent Aryl, may have a substituent Heteroaryl, may have a substituent, may be a lower alkino uo-substituent, may have a lower alkyl,

However, R ¹ and R ³ may be taken together with adjacent A ² and N to represent a heteroaryl which may have a substituent, and when R ⁵ is a hydrogen atom, R ⁶ (and Hereinafter, the compound (I) of the present invention will be described in detail.

 In the definition of the general formula in this specification, the term “lower” means a linear or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Thus, "lower alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, Examples include 2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, and 3-methylpentyl. Of these, those having 1 to 3 carbon atoms are preferred, and methyl and ethyl are particularly preferred.

 The “lower alkylene” may be a branched lower alkylene such as fit methyl methylene such as methylene, ethylene, propylene and butylene.

 “Cycloalkyl” means cycloalkynole having 3 to 8 carbon atoms. Particularly preferred are 5- and 6-membered alkyls.

 Parisole J includes phenyl, naphchilile, antrizole, fenantrisole, indanile, and fluoreniz.

 "Heteroaryl j includes furyl, chenisole, pyrrolizole, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazyl, thiadiazolyl, triazolyl, triazolyl, triazolyl, indoleyl, triazolyl, and tetrazolino H Pyrimidinyl, 2,3-methylenedioxyphenyl, 2,3-dihydroindolyl, 1,3-dihydroisoindolinylyl, 1,3-dihydroisobenzofuranyl, 3-oxoisoindolyl, 2-oxo Examples thereof include 1,2-dihydroquinolinyl, 1,1-dioxobenzothiophenyl, and 9-oxofluoreniso bicyclic or tricyclic heteroaryl.

“Cycloalkylene”, “arylene”, and “heteroarylene” mean that the above-mentioned cycloalkyl J, “aryl”, and “heteroaryl” each have two bonds. -In the general formula (I), the bond between Y and X may be a double bond or a single bond,

0

 But

N

N ¹ , or

 R

In the case of, a nitrogen-containing heterocyclic ring

 Represents c

"Optionally substituted aryl J," optionally substituted cycloalkyl "," optionally substituted heteroaryl "," optionally substituted M 有 し -class alkylene "," Cycloalkylene optionally having substituent (s) "," arylene optionally having substituent (s) "," heteroarylene optionally having substituent (s) ", and" optionally having substituent (s) ". good, as the "substituent j lower Arirekiru j, COOH, OH, halogen _{atom, N0 2, CN, NH 2} , S0 2 NH 2, COOHS loweralkyl, CO NH- (lower alkyl), NH- (lower Arirekiru ), N- (lower alkyl) _2, lower alkyl, -CH氐級Anorekiru, halogeno-lower alkyl, -O- halogeno lower alkyl, -si & loweralkyl, -SO氐級alkyl, - S0 ₂ NH- (lower alkyl) , - SO ₂ N-(lower alkyl) _2, cycloalkyl, § Li Le, Heteroariru, = 0, = CH _2, lower Arukiso aryl, although lower alkylene U ~ CH氐級alkylene J aryl and the like, but the invention is not limited thereto, as long as conventional substituents in the art chair Also, "! ~ Can take up to 3 substituents. “Halogen atom” includes a fluorine atom, a chlorine atom, an iodine atom and a bromine atom.

 The compounds of the present invention include, in addition to the above-mentioned tautomers, mixtures of various isomers such as geometric isomers and optical isomers, and isolated ones.

 The compound (I) of the present invention may form an acid addition salt. Further, depending on the type of the substituent, a salt with a base may be formed. Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, m-acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid. Acid, maleic acid, fumaric acid, linco, tartaric acid, citrate, methanesulfonate, ethanesulfonic acid, etc., aspartic acid, glutamic acid, etc., acid addition salts with hidden amino acids, sodium, potassium, magnesium, calcium, Examples include inorganic bases such as aluminum, organic bases such as methylamine, ethylamine and ethanolamine, salts with basic amino acids such as lysine and ornithine, and ammonium salts.

 Furthermore, the present invention also includes hydrates of compound (I), various pharmaceutically acceptable solvates, and polymorphs. It should be noted that the present invention is not limited to the compounds described in the Examples below, but the nitrogen-containing heterocyclic derivative represented by the general formula (I) or a pharmaceutically acceptable derivative thereof. It includes all salts.

 The compounds of the present invention include all compounds that are metabolized in vivo and converted into the compound having the general formula (I) or a salt thereof, and all prodrugs. It is a thing. The group that forms the prodrug of the compound of the present invention includes Prog.Med.5: 2 15 7 -2 16 1

And the groups mentioned in Hirokawa Shoten, 1990, Developing Custom Products, Vol. 7, Molecular Design, pp. 163-198. .

(Removal)

The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the type of the skeleton or the substituent. At that time, depending on the type of the functional group, it may be technically effective to replace the functional group with an appropriate protecting group, that is, a group which can be easily converted to the functional group at the stage of a raw material or an intermediate. is there. Thereafter, the desired compound can be obtained by removing the protecting group according to the formula. Such functional as a group such as amino group, hydroxyl group, can be exemplified Karubokishino US etc., as their protecting groups such green (Greene) and Wuts (Wuts) _{Author, rp ro tective Grotps in Organic Synthesis} ( third 2nd edition) ”). It may be used as appropriate.

 Hereinafter, a typical production method of the compound of the present invention will be described.

Manufacturing method 1

(L ¹ in the formula denotes a leaving group, D ^{ring,,,, 1¾ 2, 1¾} 3, wherein the symbols丫similar) compounds from the preparation of the compound (II) or compound (IV) (I ). The elimination ¾L ^1, for example Ii, androgenic atom, methylsulfanyl, methanesulfonyl O carboxymethyl, toluene sulfonyl Ruokishi, triflumizole Ruo b methanesulfonyl O carboxymethyl, 1 [Eta] "benzotriazole source ΙΗ -. Iruokishi like compound (II ), Compound (I) can be obtained by using an equimolar amount of nucleophile (III) in excess of Si. When compound (IV) is used, triarylbismucin, aryl The compound (I) can be obtained by reacting an alkylating agent such as halide, aryltriflate, arylpropoic acid, etc. In addition, the obtained compound (I) is treated with "chlorosuccinic acid imid b "Halogenation of the nitrogen-containing heterocycle can be effected by the action of a halogenating agent such as bromosuccinimide or xenon difluoride. The reaction can also be performed without solvent or with benzene, toluene, or xylene. Aromatic hydrocarbons such as acetyl ether, tetrahydrofuran, dioxane, etc., halogenated hydrocarbons such as dichloromethane, 1,2 "dichloroethane, and chloroform, etc., h dimethylformamide (DMF), The reaction can be carried out in a solvent that is insensitive to the reaction of dimethylsulfoxide (DMSO), dimethylacetamide, methylpyrrolidone, acetonitrile (MeCN), and ethizoacetate. It can be set appropriately depending on the compound. Depending on the compound (organic base (preferably diisopropylethylamine, methylmorpholine, pyridine, 4-(, N-dimethylamino) pyridine) or metal salt base (preferably carbonated sodium hydroxide, sodium hydroxide) Or under a metal salt base and an inclusion compound such as 18 "crown" 6. In addition, the compound obtained by this production method is used for protecting a hydroxyl group or an amino group {carboxyzo U} -protected functional group (specifically, the above-mentioned rprotective Grotps in Organic Synthesis (second example), such as the benzyl in the benzylamine moiety and the alkoxy in the alkoxy ester moiety. If the J) has the protecting group (word B) in J), the compound having an amino group {hydroxyl group or carboxiso U} can be produced by removing the M protecting group moiety according to a conventional method.

 Last 2

 (Same as the symbol in the formula)

This production method is a method for obtaining (I) by hydrolyzing a nitrile compound (V) under various conditions. The reaction is conducted without solvent or in solvents inert to the reaction of ethers, halogenated hydrocarbons, methanol, alcohols of ethanolo H, DMF, DMSO, pyridine, water, etc., sulfuric acid, hydrochloric acid, hydrogen bromide Acid, mineral acid such as polyphosphoric acid, organic acid such as m-acetic acid or I]] under a base such as sodium oxide, hydroxide hydroxide, potassium carbonate, charcoal, thorium or ammonia. In some cases, it is advantageous to carry out the reaction in the presence of hydrogen peroxide, etc., in order for the reaction to proceed smoothly.

Manufacturing method 3

(R ⁵ , R ⁶ and other symbols in the formula are the same as I)

This method is a method for obtaining a compound (lb) from a compound (la, lc) having an amino group or an I * ^ acid group. When the compound (la) is used, it may be reacted with an organic halide such as an acid halide or a symmetrical acid anhydride or a mixed acid anhydride, or may be used as an aldehyde, sodium borohydride, or triacetoxy hydrogen. The compound (lb) can be obtained by reductive amination using a metal hydride complex compound such as sodium borohydride, sodium cyanoborohydride, or hydrogenation using a metal catalyst such as radium-activated carbon. When a compound (lc) having a hydroxyl group is used, the hydroxyl group is converted into a leaving group such as a halogen atom by a conventional method, and then the compound (lb) is prepared by using an equimolar excess amount of an amine compound as a nucleophilic agent. Obtainable. Can be carried out without solvent or in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, MeCN, etc., with cooling or cooling. The reaction ¾ ^ can be appropriately set depending on the compound. For some compounds it may be advantageous to work in the presence of a Lewis acid. Further, when R ³ of the obtained compound is a hydrogen atom, the acyl can be introduced into R ³ by the same method as described above. Manufacturing method 4

(In the formula, ZI * 0, S or I or W means A ³ , R ⁴ and other symbols are the same as I5)

In this production method, compound (Id) is obtained by using compound (VI) and nucleophile (VI I) in the same manner as in knitting production method 1. In the case of A ³ force, the reaction is preferably performed in an organic base in a solvent, and in the case of A ³ force of 0 or S, the reaction is preferably performed in a metal salt base: j. When the compound obtained by this production method has a hetero atom (Z) protected by penzino US, the compound (le) can be obtained by removing benzyl according to a conventional method like knitting. Further, the compound (le) is reacted with the compound (VI II) to obtain (If). The reaction is carried out without solvent or in a solvent inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, MeCN, etc., in a solvent inert to sodium, potassium "^-butoxide, butyllithium The reaction can be carried out under the flow of ^ 7¾ under a base such as sodium amide, etc. Reaction S can be appropriately set depending on the compound.

Manufacturing method 5

 (lh)

(R ⁹ and R ¹ ° in the formula may each have a substituent, and mean lower alkyl or arylsole, and other symbols are the same as those in the compilation)

In this production method, a compound (Ig, lh, li, U) is obtained by converting a functional group of a compound by a conventional method. The compounds (l & lh, li) can be converted into each other by subjecting them to an oxidation or reduction reaction. When the compound (lg) is used, a 1, M-dimension (I j) to carbonino can be obtained by performing a reaction using phosphorus ylide {organometallic fiber. The reaction can be carried out without solvent or in a solvent that is insensitive to reactions such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, MeCN, etc. The reaction can be appropriately set depending on the compound. it can.

Hereinafter, a typical method for producing a starting compound of the compound (I) of the present invention will be described.

Manufacturing method 6

 (XI)

(Wherein L ¹ , L ² , and L ³ each represent a leaving group, R "represents cyano or carbamoyl, and the other symbols are the same as ¾ίΓΐ 自)

The starting compound 00 can be obtained via an intermediate (VI II, IX) by repeatedly performing the same reaction as in Method 1 of Sukki's method 1 on the compound (VI I). Starting compound (XI) can be obtained by subjecting an intermediate having R "to cyano to a hydrolysis reaction in the same manner as in jf self-production method 2. Manufacturing method 7

 (XII)

 (XVI) (XVII)

(In the formula, R ¹² i * 7K element, means carboxy or carbamoyl, R ¹³ means formyl, cyano, carpamoyl, and R ⁴ , and other symbols are the same as those of the editor.)

The starting compound (XVI I) can be subjected to the same substitution reaction as for compound (XIV) and the hydrolysis reaction of compound (XVI) to compound (XIV, XV) as in method (I5) Can be. Intermediate (XV) can be obtained by subjecting compound (XIV) having a pyrazine ring to trifluoromethylation using the same method as in Knitting Method 8 or using xenon difluoride and trifluoroacetic acid. it can. Compound (XI) can be subjected to a conventional radiocassole reaction using formamide, sulfuric acid and hydrogen peroxide, or lithium 2.2,6,6-tetramethylpiこ と After the action of an organic metal salt such as a ligide, the compound is treated with carbon dioxide or the like to generate a carboxylate on the nitrogen-containing heterocycle, and then amidated by a conventional method. It can be manufactured at When (XI II) of formino US is used as R ¹³ , it can be oxidized by a conventional method to form a carboxy group, and then amidated in the same manner as described above to obtain an intermediate compound (XIV). Intermediate (XI II) is prepared by reacting compound (XI I) with an organic alkali metal salt base in the same manner as described above. Power demand ^: can be obtained by using ^. Further, (XI II) having an ester or cyano at R ¹³ can be obtained by subjecting a compound (XI I) having a carboxy group or a valmoizole group at R ¹² to a condensation reaction or dehydration reaction by a conventional method. it can. Intermediate (XVI) can be produced by subjecting compound ( ^XIII ) in which R ¹³ is cyano to the same substitution reaction as in Production method 1 described above. Usually, the self-organization reaction is carried out in a solvent inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, pyridine, and the like, with cooling under a reduced amount.

Manufacturing method 8

 (The symbols in the formula are the same as it itself)

 The starting compound (IV) can be obtained by subjecting the cyano of the compound (XIX) to a hydrolysis reaction in the same manner as in Production Method 2. Intermediate (XIX) can be obtained by subjecting compound (XVI I I) to a substitution reaction similar to that of self-produced method 1.

 The compound of the present invention obtained by each of the above production methods can be purified by known methods, for example, extraction, 1, fractional chromatography, fractional crystallization, recrystallization and the like. In addition, the salt of the compound of the present invention can be converted into a desired salt by a usual salt formation reaction.

Various isomers can be used in a conventional manner by utilizing physicochemical differences between the isomers. For example, an optically active substance can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. The optical body can be produced from an appropriate optically active compound. Industrial applicability

 The compound of the present invention is useful as an activity of a rice preparation. In particular, since it has PKC activity inhibitory activity, it is useful for the prevention and control of diabetic complications, ischemia, inflammation and cancer-related pathologies involving PKC. Here, diabetic complications include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, and skin disease.

 The effects of the compound of the present invention were confirmed by the following test methods.

 (ΙίΙ ^ method)

 1. PKC inhibition! Ii ^ (Measurement of PKC¾½ by SPA)

 PKCP and harmful ISIt was determined by a method according to (J. Bio. Chem, 260: 10039-10043, 1985).

 Scintillation occurs when a molecule having radioactive activity approaches (binds) to the surface of a plastic bead containing a scintillator, developed by SPA (Sc intillation Proximity As say) and Amersham. This is a system that uses. The beads are pre-coated with streptavidin, to which the biotin moiety of the substrate peptide binds.

Anti-J heart fluid (Composition: 2.5mUnit PKC isozymes (Calbioc), 50mM-HEPES (pH 7.5), 0.25mM EDTA, 0.125mM DTT, 12.5mM MgC I _2> 0.5 mM EGT A, 0.75 mM Ca CI ₂ , 0.25% Triton X—100, 0.2 μΜ biotin-ε-peptide (Β ί ο ti η— Ε RMRPRKRQGSVRRRV, peptide synthesizer synthetically), 0. 2 μΜ ATP, 0. 2 At C i [- 33 p] -AT P (1 OmC i

I, Amersham ne ±), 50 ngZml Forpol 12,3,13-dibutyrate (WAKO), 184 g / ml phosphatidylserine (WAKO) 50 μI, DMSO solution of test compound Was added to “I 2 I (final concentration of DMSO is 4%). This was prepared in Opti PIate ™ (PACKARD), and then ^^ (20 ~ 25 ° C). After standing for 1 hour, serine phosphorylation was performed Reaction stop solution (0.1 mg SPA beads, 136 MAT P, 5 Om HE PES (pH 7.5), 0.25 mM EDTA, 0.125 mM DTT. 1 The reaction was stopped by adding 1.5 mM MgCl ₂ , 0.5 mM EGTA, 0.75 mM CaCI ₂ ) per 150 μl per well.

Seal the plate, stir and let stand for 15 minutes at room temperature. After centrifugation for 3 minutes, the SPA beads were sedimented. The dimension activity of each well was measured using TOP COUNT (PACKARD), and the serine phosphorylation activity by PKC was calculated.

 As a result, the compound of the present invention successfully inhibited the activity of PKC. Table A below shows the PKC2P and toxicity values of representative compounds of the present invention.

Table A

2. PKCyS 2 | S¾ | i ^

 〇 2 ^ & harm | ^ is determined by the method according to (J. Biol. Chem, 268: 9122-9129, 1993 and Eur. J. Biochem, 194: 89-94, 1990)! I did.

 1) Creation of activated human PKCyS 2 expression vector

 For the human wild-type PKCyS2 gene, human spleen cDNA was transformed into type III, recloned by PCR, and inserted into a pcDNA3.1 expression vector. Using this vector and the modified MS input primer, a modified PKCyS2 expression vector in which amino acids 22 to 28 (7 amino acids) had been deleted was constructed. Amino acids 22-28 are a pseudosubstrate region and function to reverse PKC¾½. Deletion of this portion enables expression of ¾1 ± -modified PKC / S.

 2) Measurement of PKC / S 2 inhibitory activity

COS 7 cells were cultured in a 24-well plate, and the activated ΡΚΟβ expression vector and pAΡ1 — I uc I ferase † T †, ノ ノ ノ S (Stratameme エ ¾ · fugene (Roche D As a control, the pcDNA3.1 vector and the plasmid were transfected as a control.3 hours after transfection! 〃I was added (final concentration of DMSO was 0.1%) and cultured for 24 hours.Cell lysate (25 mM TrisC I (pH 7.8), 2 mM DTT, 2 mM CDTA, 10% glycerol) was added to each well. , 1% Triton X-100) was added to the tube with 100 I. 回収 The collected cell lysate (20〃 I) was dispensed into a tube, and Pitka Gene (Toyo Ink) was added to emit light. The luminometer (L u ma LB9501, Berthold). Inhibitory effect of fiber compounds on the enhancement of I uciferase activity by PKCyS activity (the value of I uciferase; Sti of cells transfected with pcDNA3.1 reduced from the activity of I uciferase transfected with activated PKC 2) Was regarded as PKCS 2 P and harmful action.

 As a result, the compound of the present invention successfully inhibited the PKC) S2 activity. Table B below shows the activity values of representative compounds of the present invention.

Table B

3. Improvement of diabetic complications! ^

 1) Improvement effect of diabetic nephropathy

 The effect of improving diabetic nephropathy was confirmed by a method according to (Science, 272: 728-731, 1996).

 An 8-week-old male Wistar rat is intravenously administered with streptozotocin (Sigma) at 60 mgZkg under pentobarbital anesthesia to develop diabetes. The test compound is orally administered once a day for 8 consecutive weeks from the day after the administration of streptozotocin. Collect urine at 2, 4, 6, and 8 weeks after administration, and measure total protein and albumin in urine. The inhibitory effect of the compound on total protein and albumin leakage due to diabetes was defined as diabetic nephropathy ameliorating effect.

 As a result, the compound of Example 17-1 showed a tendency to increase urinary albumin excretion »j after 8 weeks of oral administration of 1Q に お い て kg in the above difficulties.

 2) Improvement effect of diabetic neurosis

 The effect of ameliorating diabetic neurosis was measured by a method according to (Eur. J. Endcrinol. 134: 467-473, 1996).

A 13-week-old male Wistar rat is intravenously administered with streptozotocin (Sigma) at a dose of 50 mgZkg under penton-rubbital anesthesia to develop diabetes. From the day after the administration of streptozotocin, the compound (2) is orally administered once a day for 8 consecutive weeks. After continuous injection, the motor sigmoid i¾ in the sciatic nerve is measured using an experiment ruler (Synax 1200, NEC Corporation). The compound's に 対 す る effect on the delay of boats with diabetes due to diabetes is considered to be a diabetic neuropathy ameliorating effect. I do.

As a result, it has been clarified that the compound of the present invention has a favorable effect of improving diabetic neuropathy. Table C shows the results of Example 17-1 of the compound of the present invention. (Table C: Sciatic god tree after 6 weeks of drug administration il ^ ^ sec)

Significant difference test: normal group vs diabetic group: p <0.001, diabetic group vs 20H administration group: p <0.05 Based on the above results, the compound of the present invention successfully inhibits PKC yS 2¾11 and is effective in improving diabetic complications. It was clarified to show a certain diabetic nephropathy improvement effect and a diabetic neuropathy improvement effect. Pharmaceuticals containing, as an active ingredient, one or two of the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof can be used as a carrier or excipient for commonly used pharmaceutical preparations Tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc., using other additives, orally or parenterally Is administered.

 The clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, body weight, age, etc. of the patient to which the compound is applied. The parenteral dose is 0-01 to 100 mg, which is administered once or in several divided doses.The dose varies under various conditions. It may be enough.

Tablets, powders, granules and the like are used as the solid fibers for oral administration according to the present invention. In such solids, one or more of the 14 substances may comprise at least one inactive diluent, such as Ιί¾, mannitol, glucose, hydroxypropylcellulose, sprinkled crystalline cellulose, starch, polyvinylpyrrolidone, Mixed with magnesium aluminate metasilicate. In accordance with the usual methods, the textile is made of additives other than diluents, such as lubricants such as magnesium stearate, disintegrators such as calcium diglycolate, stabilizers such as lactose, A solubilizing or solubilizing agent such as glutamic acid or aspartic acid may be contained. Tablets or pills are coated with sugar such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc. ¾JiI may be used with a film of a soluble substance.

 Liquid compositions for oral administration include pharmaceutically acceptable solutions, solutions, syrups, syrups, elixirs, etc., and commonly used inert diluents such as iim Includes water and ethyl alcohol. This product may contain solubilizing or solubilizing agents, humectants, auxiliaries such as MM agents, sweeteners, I ^ agents, fragrances, and preservatives in addition to the diluent.

 Injections for parenteral administration include sterile aqueous or non-aqueous solutions, syrups, and syrups. Examples of aqueous solutions and diluents for diluents include distilled water for sizing agents and hydraulics for sanitary facilities. Examples of water-insoluble solution agents and diluents for foaming agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and sorbitol 80 (trade name). is there.

 Such foods may further include additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. These are sterilized by, for example, passing through a bacteria retaining filter, blending a bactericide or irradiation. They can also be used by dissolving sterile solid fibers and dissolving them in sterile water or a sterile ait solvent before use. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the method of the compound of the present invention will be specifically described with reference to at examples of the compound of the present invention. However, the present invention is not limited to these examples. Note that the starting compound of the compound of the present invention also includes a nominal compound, and a method for producing these compounds will be described as a reference example. Reference example 1

 2,4,6 ~ Triclomouth pyrimidine "5" Carbonitrile 16.0g is dissolved in 320nl of tetrahydrofuran, and at € 5 ° C, N, N "Disopropylethylamine 10.4g and / 7Γtoluidine 8 .5 g was added. The mixture was stirred for 1 hour under ice cooling, and the solvent was removed. 00nl of water was added to the system, extracted with 500ml of ethyl acetate, and the organic layer was saturated: washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crystals were recrystallized with 300 ml of acetonitrile to obtain 15.0 g of 2,4-dichloro ^ "(3-methylanilino) pyrimidi / ~ 5" carbonitrile from the mother liquor. Was.

Reference Example 2-1

Dissolve 9.6 g of 2,4-dichloro "6" (3-methylanilino) pyrimidi ~ 5 "carbonitrile in 15 Qnl of tetrahydrofuran and add 15 Ng of N, N-dimethylethylenediamine at 65 ° C. Added mixture After stirring at 120 ° C. for 1 hour, 750 ml of water was added, and the mixture was extracted with 500 ml of chloroform. After the aqueous layer was extracted again with 500 ml of chloroform, the organic layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The crystals obtained by evaporating the solvent under reduced pressure are washed with 120 ml of methanol, and dried, and then dried. 4-chloro-2 "[(2-dimethylaminoethyl) amino] (3-methylanilino) pyrimidine" 5 "force rubonitrile 5. 5 g were obtained.

Reference Examples 2 to 2 to Reference Example 2-12, Reference Examples 8 to 25 to Reference Example 8-28, Reference Examples 20 to 1 and Reference Example 20-2 in the same manner as Reference Example 2-1. I got

Reference example 3-1

 4-Cross-mouth 2 "[(2" dimethylaminoethyl) amino "" (3-methylanilino) pyrimidine-5-carbonitrile 2.92 g was dissolved in Ν, dimethylformamide 5Qnl, and benzyl alcohol 9.54 g and 60 2.83 g of sodium k-iodide was added and the mixture was heated for 3 hours at 100 ° C. 20 ml of a saturated aqueous solution of ammonium chloride and 200 ml of water were added to the reaction mixture, and the precipitated crystals were dissolved in 10 m of water to give 2-propanol. 15m, further washed with ether 1Qnl, dried and dried to give 4-benzyloxy, "2-[(2-dimethylaminoethyl) amino" "6" (3-methylalanilino) pyrimidi: -5 "carbonitrile 3.13g The compounds described in Reference Examples 3-2 to 3-12 were obtained in the same manner as in Reference Example 3-1.

Reference Example 4-1

 4-chloro-2 "[(2-dimethylaminoethyl) amino] ~ 6 ~ (3-methylanilino) pyrimidine-5" carbonitrile 136η¾, add 2ml of m "triluidine and heat at 130 ° C for 8 hours The reaction mixture was purified by silica gel column chromatography (eluent; chloroform: methanol: aqueous ammonia = 200: 10: 1), and [[(2-dimethylaminoethyl) amino] "4, 6" bis- ( 3-methylyanilino) pyrimidine · 5 "carbonitrile 7 & τ¾ was obtained.

In the same manner as in Reference Italian J-1, a compound of Reference Italian J4-2 word EE was obtained.

Reference example 5

 4,6 "Dichloro-2-Methylsulfanisopyrimidine" 5-Carboxylealdehyde 9.3g in 2 ・ Methino-2-propanol 30Qnl, Water 80ml, 2 "Metiso U ~ 2" Butene 18ml phosphoric acid 5.07 g of dihydrate ^ "thorium and 5.74 g of chlorine ^" trim were added, and the mixture was stirred under water cooling for 4 hours. To the reaction solution, 120 ml of 1N hydrochloric acid and 70 Qnl of chloroform were added, and the mixture was stirred in a room volume. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 9.94 g of 4,6 "cyclohexane-2" methylsulfanipyrimidine "5-carboxylic acid.

Reference example 6 4,6 "Dichloro-2" methylsulfanazopyrimidine "5" carboxylic acid 7.71g was added with 100ml of thionyl chloride and added for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 1,2-dichloromethane 10Onl, and thereto was added 19% of 28% aqueous ammonia under ice-cooling, followed by stirring for 2 hours. After distilling off the solvent under reduced pressure, 200 ml of water was added, and the mixture was collected by filtration, washed with water, dried at 60 ° C under reduced pressure, and dried at 4,6 to 2-methylsulfanizopyrimidine. "6.70 g of carboxamide were obtained.

In the same manner as in Reference Example 6, a compound of Reference Example 10 was obtained.

Reference example 7-1

 4, & "Dic-mouth-2" Methylsulfanazo ^ pyrimidine "5" Carboxamide 595π¾ in 25 ml of 1,4-dioxane solution N, N "Diisopropylethylamine 0.4 ml, 3-Promorediline The reaction solution was added with 80 ml of ethyl acetate, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Filtration gave 4- (3-promorenirino) -6-chloro-2 "methylsulfanazopyrimidine" 5 "carboxamide 93Q¾.

In the same manner as in Reference Example 7-1, compounds of Reference Examples 7-2 to 7-24 and Reference Examples 18-1 to 18-24 were obtained.

Reference Example 8-1

 4-(3-promorenirino)-6 "black mouth-2" methylsulfanizo U-pyrimidine "5-potassium lipoxamide A solution of 65% dimethyl sulfoxide in 10 ml of water-cooled lime 32 rg, 31% hydrogen peroxide in water Add 0.71 ml and stir with the same ^ for 5 hours Add 200 ml of water to the JgJt mixture, stir with ^, collect the precipitated solid by filtration, wash with water, and dry under reduced pressure at 60 ° C. This gave 4-(3-promorenirino) -2-methylsulfani U-6-pyrimidone "5" canoleboxamide 330 mg.

The compounds of Reference Examples 8 to 2 to 8-24, Reference Example 21-1, and Reference Example 21-2 were obtained in the same manner as in Reference Example 8-1.

Reference Example 9-1

2,2,6,6 "tetramethizolebiperidine 2.65 ml of butyllithium was added dropwise to a solution of 2.7 ml of tetrahydrofuran in 80 ml of ice under ice cooling, and the mixture was stirred for 10 minutes. After stirring at −78 ° C. for 30 minutes, A solution of 2.0 g of 2,6-dichlorovirazine in 10 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 30 minutes, 2 g of dry ice was added to the reaction solution, and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was mixed with chloroform, washed with 1ΝHCl, saturated: ^ water, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure, and acetone was added to the residue. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by reversed-phase ram chromatography (eluent; water: methanolic U = 1: 1) to obtain 1.2 g of 3,5-dic-mouth virazine-2-carboxylic acid.

The compounds of Reference Examples 9 to 2 to Reference Example 9-6 were obtained in the same manner as in Reference Example 9-1.

Reference Example 11

3, 5 "dichloro Vila Jin -. 2-Kasorebon acid in ethanol 10ml solution 75Qrg, under ice-cooling chloride Chioni Le 693rtg was added and after 4 hours pressurizing ^ not a _L, and the solvent was evaporated under reduced pressure resulting The residue was purified by silica gel column chromatography Of effluent: hexane / IFETHIOS U = 7/3) to obtain 3,5-dichloropyrazine-2-ethyl carboxylate 82 & Tg.

Reference Example 12

 To 1 g of 3,5 "dichlorovirazine-2" carboxamide was added 7.3 ml of phosphorus oxychloride and 2 to 3 g of getylaniline, and the mixture was stirred at 50 ° C for 3 hours, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed with water, 0.5 hydrochloric acid, and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography Of effluent: hexane / ^ acid acid U = 8/1) to obtain 770 mg of 2-cyano-3,5-dig mouth virazine.

Reference Example 13-1

 To a solution of 2,6 "pyrazine, 10.7 g of 10-acid / methanol in 30 ml, was added 5.68 g of pentanone, 6.75 g of 31% i-hydrogen oxide solution and 20 ml of acid, and 20 ml of sulfuric acid. 9.4 g was added, and the mixture was stirred for 1 hour in a room.The solvent was distilled off; 30 ΟτιΙ of water was added, and the mixture was extracted with 50 Qnl of ether.The organic layer was washed with water and then with saturated water. The extract was dried over magnesium sulfate, and the solvent was distilled off.The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to give 5 "(3,5" dichloric acid). Oral pyrazine-2-yl) Valeric acid methyl ester 1 · Qg was obtained in the same manner as in Reference example 13-1.

Reference Example 14-1

 3-Benzoi U-2, 6 "dichlorovirazine 502 ^ formamide 15m 50% acetic acid 2 3 1 31 hydrogen peroxide 1.5 ml, sulfuric acid heptahydrate 27Q 加 え, the mixture is 显 for 18 hours The reaction mixture was added with 300 ml of water and extracted with 300 ml of ethyl acetate The organic layer was saturated: washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by column chromatography (eluent; hexane: ethyl acetate = 2: 1) gave 6-benzoizole_3,5 "dichlorovirazine-2" carboxamide 18 & rg.

In the same manner as in Reference Example 14-1, the compounds of Reference Example 141-2 to Reference Example 14-9 were obtained. Reference Example 15

 1.2 g of trifluoroacetic acid was added to a solution of 570 mg of 2,6 "dioctyl pyrazine-3-carboxamide in 6 ml of dichloromethane. Further, 1 g of xenon difluoride was added so that the reaction did not exceed 35 ° C. The reaction mixture was added with water (300 ml), extracted with dichloromethane, the organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by chromatography (eluent; hexane: ethyl acetate = 4: 1) gave 6-trifluo-methine JU-3,5 "Dic-mouth virazine-" carboxamide 10Q¾.

Reference Example 16-1

 3,5-Dichloro mouth Hydroxymethylpyrazine-2 "carboxamide 88Q¾, 950ul of methanesulfonyl chloride and 15ml of pyridine were added, and the mixture was stirred for 1.5 hours with S. After the solvent was distilled off under reduced pressure, 150ml of water was added, and ethyl acetate was added. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6 "chloromethino 3,5" dichlorovirazine-2 ~ carboxamide 51 & ¾. .

The compounds of Reference Example 16-2 and Reference Example 16-3 were obtained in the same manner as in Reference Example 16-1.

Reference Example 17-1

 6 "(1-chloroethyl) -3,5-dichlorovirazine-1-carboxamide 2_ 24 g of a solution of 70 g of ethanol and 35 ml of tetrahydrofuran are added with 750o of Wo ° radium activated carbon, and 4 atmospheres of hydrogen at 4 atmospheres for 18 hours. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. The resulting residue was dried to obtain 1.92 g of 3,5 "dichloro-&-ethylpyrazine-2-carboxamide.

In the same manner as in Reference Example 17-1, the compound of Reference Example 17-2 and Reference Example 17-3 was obtained.

Reference Example 19

After stirring a mixture of 7.35 g of diphosphorus pentoxide and 5.15 ml of phosphoric acid at 10 ° C. for 2 hours, 5- (3-methylanilino) -3-methylsulfanine [1, 2, 4] 257 n¾ of triazine “6” carbonitrile was added, and the mixture was stirred at 90 ° C for 2 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was separated. The extract was washed with saturated ^ water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent; chloroform: methanol = 75: 1) to give 5- (3-methylanilino) -3-methylsulfani [1, 2, 4] Triazine "6" cadrepoxamide 20 mg was obtained as an achromatic crystal. Example 1

 4-benzyloxy-2-[(2 "dimethylaminoethyl) amino" -6 "(3-methylanilino) pyrimidine" 5 "Carbonitrile 680ng dissolved in 7ml dimethyl sulfoxide, carbonic acid rim 700 η 700 and 31% 1.2 ml of aqueous hydrogen peroxide was added, and the mixture was stirred at 60 ° C for 3.5 hours. 70 ml of water was added to the reaction mixture, and the precipitated crystals were washed with 10 ml of water and dried. The resulting crude crystals were purified by silica gel column chromatography (eluent; chloroform: methanol: aqueous ammonia = 400: 10: 1) to give 4-benzyloxy-2-[(2-dimethylamino). Tyl) amino] "6" (3-methylarilino) pyrimidine "5" carboxamide 30% was obtained.

Example 2 to Example 14 and Example 11 to Example 18-3 were obtained in the same manner as in Example 1.

 4-Benzylamino-2 "[(2-dimethylaminoethyl) amino]" & · (3-Methylanilino) pyrimidine "5" Dissolve 300 n¾ of carboxamide in 30 nl of acetic acid, and add K / o palladium on charcoal 30 Qr¾. In addition, the mixture was stirred at 4 atm under a hydrogen atmosphere for 30 hours. The catalyst was removed by filtration, the solvent was removed, and the residue obtained by evaporation was purified by silica gel column chromatography (eluent; chloroform: methanol: ammonia water = 50: 10: 1) to give 4-amino-ethanol. · [(2 "Dimethylaminoethyl) amino" "6" (3-Methylanilino) pyrimidine "5- ~ casoleboxamide 155% was obtained.

Example 16

 4-Amino-2-[(2-dimethylaminoethyl) amino] —6- (3-Methylanilino) pyrimidine-1 5-carboxamide 55¾ is dissolved in 1.5 ml of pyridine, and 23ul of acetic anhydride is added under ice-cooling. For 2.5 hours and then at 50 ° C for 15 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent; chloroform: methanol: aqueous ammonia = 100: 10: 1), and 2- [acetyl- (2-dimethylaminoethyl) was purified. ) Amino] -1-4-amino-6- (3-methylanilino) pyrimidine-1-carpoxamide (50%) was obtained.

 The compounds of Example 23-1 and Example 23-2 were obtained in the same manner as in Mie.

Example 17-1

4-benzyloxy-2 "[(2-dimethylaminoethyl) amino] -6" (3-methylanilino) pyrimidine "5" Dissolve 1.0 g of carboxamide in 5 ml of a tetrahydrofuran-ethanol mixed solvent (2: 1), and add 10% Palladium-activated carbon 200π 活性 was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the solvent was removed;: ΐ¾Ε, and distilled off to give 2-[(2 "dimethylaminoethyl) amino""to (3-methylanilino)- 4-pyrimidone "5" carboxamide 69 (^ was obtained.

 Example 17-2 to Example 17 to 9, Example 2 (H to Example 20 to 3, Example 35 to 1 and Example 35-2) Was.

 Examples 19-1

 0.93 ml of Ν, ~ dimethylaminoethylamine was added to 4- (3-bromoanilino) -2 "methylsulfanizo-6-pyrimidone" 5-carboxamide 301π¾, and the mixture was stirred at 90 ° C. for 4 hours. 2 ml of acetonitrile was added to the residue obtained by concentrating the reaction solution, and the mixture was stirred in a room, and the precipitated solid I was collected by filtration and washed with acetonitrile to obtain 285 rr of crude crystals. This was recrystallized from a mixed solvent of 24m of methanol, 6m of water, and 10ml of 1,4 dioxane to give 6 ~ (3-promolinerino) -2 "[(2-dimethylaminoethyl) amino] -pyrimidone" 5 " 180 n¾ of carboxamide was obtained.

 Example 1 ^ 2 to Example 19 "29, Example 25 to 1 to Example 2, Example 26 to 1 to Example 26-25. Example 38 and Example 39 in the same manner as Examples 19 to 1. The compound of the word Btfc was obtained.

 Example 21-1

 [2- [5-Carbamoy U "6" (3-methylanilino) -4-pyrimidone-2-ylamino] ethyl] methyl carbamic acid t-butyl ester 90Qre is dissolved in 1 ml of methanol, and 4 hydrogen chloride and vinegar 50 ml of acid chill solution was added. After the mixture was stirred with ^ for 30 minutes, the solvent was distilled off, and 100 ml of ethanol was added to the obtained residue. The solvent was again distilled off under reduced pressure, 50 ml of water was added to the obtained residue, and the precipitated crystals were dried and dried to give 2 "[(2-methylaminoethyl) amino" -6 "(3-methylanilino) -4-pyrimidone + carboxamide. 0% of the hydrochloride were obtained.

 In the same manner as in Example 21-1, a compound having the composition described in Example 21-2 (5 |) was obtained.

 Example 22-1

Dissolve 2-[(2-methylaminoethyl) amino] (3-methylanilino) -pyrimidone "5- ~ carboxamide hydrochloride 671 ^ in 30 ml of ^" dimethylformamide-chloroform (1: 1) and add 3-phenylpropionaldehyde 200¾ and triacetoxyborohydride 840¾ were added, and the mixture was stirred for 1 hour. The solvent was distilled off, and the residue was added with 10Onl of water, and ethyl acetate was added. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; Purification with form: methanol: aqueous ammonia = 200: 10: 1), 2 "[2- [methyl- (3-phenylpropyl) amino] ethylamino] -6- (3-methylanilino)" 4-pyrimidone-1 ~ 38 ng of carboxamide was obtained. The compounds of Examples 22 to 2 to Example 22-7 were obtained in the same manner as in Example 22-1.

Example 24

 2-[(2-Methylaminoethyl) amino] -1-6- (3-Methylanilino) -14-Pyrimidone-15-Carboxamide hydrochloride {3}, Ν, Ν-dimethylglycine 6Qrg, 1-ethyl-13--1-dimethylaminopropyl 6) Dimethylformamide (6 ml) was added to a mixture of carbodiimide hydrochloride (120 n¾), 1-hydroxybenzotriazole (85τ¾) and lium carbonate (1 mg), and the mixture was stirred at room temperature for 18 hours. The solvent was removed by evaporation of mm; 30 ml of water was added to the residue obtained by washing with water, and the precipitated crystals were washed with 5 ml of water, dried and dried. 2-[[2- (Dimethisoleaminoacetylmethylamino) ethylisoamino] One 6- (3-methylanilino) -pyrimidone-5-carboxamide 150 ^ was obtained.

Example 27-1

 3-amino-5-[(2-Dimethylaminoethyl) amino] —6-methyl virazine 1-2-carboxamide 420 n¾ is dissolved in dichloromethane 2Qnl, and 1.15 g of trifrenirubismucin and 32Qrg of vinegar ^ (II) are added. The mixture was stirred at 显 for 1 hour and at 50 ° C. for 3.5 hours. 20 ml of dichloromethane was added to the reaction mixture, and the insoluble matter was removed by filtration using Celite. The solvent is distilled off, and the residue is purified by silica gel column chromatography (eluent; chloroform: methanol: aqueous ammonia = 200: 10: 1) to give 5-[(2-dimethylaminoethyl) amino] — 6-Methyl-3-phenylaminopyrazine-1-carboxamide 10C was obtained.

The compound of Example 27-2 was obtained in the same manner as in Example 27-1.

Example 28

 5 — [(2-Dimethylaminoethyl) amino] -1-3- (3-methylanilino) -pyrazine-12-carboxamide 200 n «is dissolved in 2 ml of chloroform, and Ν · chlorosuccinimide 101n¾ is added. Stirred for hours. After completion of the reaction, the reaction solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol: aqueous ammonia = 500: 10: 1), and 6 "clothe" 5 — [(2-dimethylamino) Ethyl) amino-1-3- (3-methylanilino) -pyrazine-12-potassium lipoxamide was obtained.

Example 29

5 — [(2-Dimethylaminoethyl) amino] —3— (3-methylanilino) -pyrazine-1-carboxamide Dissolve 20 Otg in 6 ml of dichloromethane and 3 ml of acetonitrile, add xenon difluoride 41Qrg under ice cooling, and then add Q. For 18 hours. After the reaction is completed, add water and add ethyl acetate. Extracted. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol: ammonia water = 200: 10: 1) to give 6 "fluoro" 5 — [(2-dimethylamino) Ethyl) amino-1-3- (3-methylanilino) -pyrazine-12-carboxamide 17π¾ was obtained.

Example 30

 5-[(2-Dimethylaminoethyl) amino] -6-hydroxymethyl-3- (3-methylanilino) pyrazine- 223iTg of 223iTg in a 100 ml solution of chloroform in manganese dioxide 2.3 was added, and the mixture was added. ^ Stirred for 16 hours. The residue obtained by evaporating the insolubles and evaporating the solvent under reduced pressure was purified by silica gel gel chromatography (eluent; chloroform: methanol = 20: 1), and the residue was purified with 5— [(2— Dimethylaminoethyl) amino-6-formyl-3- (3-methylanilino) pyrazine-12-carboxamide 181n¾ was obtained.

Example 31

 5-[(2-Dimethylaminoethyl) amino] -1-6-formyl-3- (3-methylanilino) pyrazine-2-hydroxylupoxamide To a solution of 55 rrg of 55 rrg of ethanol in 5 ml of ethanol ethizole fofoacetoacetate Qig and 55 mg of carbonic acid realm The mixture was stirred at 70 ° C. for 13 hours. The solvent was distilled off under reduced pressure, 15 ml of water was added to the residue obtained, and the crystallized solid was collected by filtration and dried. The obtained crystals were dissolved in 5 ml of methanol and 5 ml of tetrahydrofuran, 15 rrg of 10% radium charcoal was added, and the mixture was stirred under a hydrogen atmosphere for 20 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent; chromate form: methanol solution = 30: 1) and purified.

[(2-Dimethylaminoethyl) amino] -1-5- (3-methylanilino) pyrazine-12-yl] 2 rg of engineered propionate was obtained.

Examples 32 to 1

 3- [6—Solebamoyl-1--3-((2-dimethylaminoethyl) amino] —5- (3-methylanilino) pyrazine-1-yl] ethyl propionate 62η¾ in a solution of 3 ml of methanol and 3 ml of tetrahydrofuran 2 Sodium hydroxide 6 ml was added and the mixture was stirred at M¾ for 1 hour. 1N hydrochloric acid was added to the reaction mixture to adjust the volume of the solution to 5. The residue obtained by distilling off the solvent from the solvent was purified by reversed-phase column chromatography (eluent; water: methanol solution = 1: 1), and the residue was purified using 3- [6-virubamoyl 3-[(2-dimethizoleamino). [Echizore) amino] -1- (3-methylethirino) pyrazine-12-isole] propionic acid 6tig was obtained.

In the same manner as in Example 32-1, the compounds of Examples 32 and 2 were obtained. Example 33

 6-Benzoyl-5-[(2-dimethylaminoethyl) amino] —3- (3-Methylanilino) pyrazine-1-carboxamide To a solution of 26Qrg of 5 ml of ethanol and 5 ml of tetrahydrofuran was added 120 mg of sodium borohydride. And stirred for 1.5 hours. The solvent was evaporated under reduced pressure, 50 ml of water was added to the residue obtained, and the mixture was extracted with 150 ml of chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 5-[(2-dimethylaminoethyl) amino] -16-hydroxyphenylmethyl-3- (3-methylanilino. ) Pyrazine-1-carboxamide 8Qrg was obtained.

Example 34

 5 — [(2-Dimethylaminoethyl) amino] 16- (1-hydroxy-1-methylethyl) 1-3- (3-methylanilino) pyrazine-12-force Lupoxamide 5 ml of acetic acid was added to 21Qrg, and the mixture was heated at 120 ° C. for 45 minutes. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; quenched form: methanol: aqueous ammonia = 300: 10: 1), and the obtained crystals were washed with ethanol-ether. Thus, 5-[(2-dimethylaminoethyl) amino] -3- (3-methylanilino) -1-6- (2-propynyl) pyrazine-1-carboxamide 122n ミ ド was obtained.

Example 36

 2- (2-Hydroxyethylamino) 16- (3-Methylanilino) 14-Pyrimidone-15-force Ruboxamide 430¾ is dissolved in ml, Ν-dimethylformamide 30ml, methyl iodide 110ul and cesium carbonate 93Qng And stirred at 60 ° C for 0 hour. The solvent was distilled off under reduced pressure, 50 ml of water was added to the residue obtained, and the mixture was extracted with ethyl acetate 150τιΙ. After the aqueous layer was extracted with ethyl acetate again, the organic layer was combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (eluent; chloroform-form) to give 2- (2-hydroxyshetylamino) -1-methyl-4- (3-methylanilino) -16-pyrimidone-5 — Obtained 193 ng of carboxamide.

Example 37

2-[(2-Hydroxyethyl) amino] -1-methyl-4-1 (3-methylanilino) -1-6-pyrimidone-5-caproloxamide 5Qi¾ is dissolved in 5 ml of pyridine, and 30 ul of methanesulfonic acid chloride is added thereto. For 7.5 hours. To the reaction mixture was added 5 ml of an aqueous solution of dimethylamine, and the mixture was stirred for 14 hours. The solvent was distilled off, and 15 ml of water was added to the residue, and the mixture was extracted with 3Qnl of chloroform. After the aqueous layer was extracted again with chloroform, the organic layers were combined, washed with brine, and dried. Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol: aqueous ammonia = 100: 10: 1) to give 2-[(2-dimethylaminoethyl) amino] — 1-Methyl-41- (3-methylanilino) -1-6-pyrimidone-5-carboxamide a¾ was obtained.

Tables 1 to 12 show the structural formulas and physicochemical properties of the self-reference example compounds and the example compounds. Further, the compounds in Tables 13 and 14 can be easily produced in the same manner as described in Examples or Production Methods, or by applying modifications obvious to those skilled in the art. The symbols in the table have the following meanings.

R f: Reference example number, EX: Example number, S tructure: Structural formula, Data: Physical property data (F: FAB-MS (M + H) +, FN: F AB-MS (MH) \ E: EI- MS, ND: nuclear magnetic resonance scan Bae spectrum (TMS internal standard, solvent DMSO- d _6), NC: nuclear magnetic resonance scan Bae spectrum (TMS internal standard, solvent CDC I _3), M: mp (° C) ), Ph: phenyl, Bn: benzyl, Me: methyl, Et: ethyl, nPr: propyl, iPr: 2-propyl, nBu: butyl, tBu: tert-butyl, cHex : Hexyl hexyl, Ac: acetyl, Boc: t BuO—CO—, To I: 3—methizolefenizole

SOS: d HO ^S WQ 'ε 10 3W-9' ε 01-L

HO Ongu-6-8 10 6-L εεε: d HO ngi-8-8 10 ng d-L

99C ^: d HO LQ ε: 10 L-Dimension O

HO o ³ w-ε 9-8 10 o ^a we 9-

HO ι-ε ο S-8 ΙΖ Δ10 ε 9-L

HO 8 00 10 r-L

HO ³ 0Ν-ε ε-8 10 ZL

LLZ-A HO Η 2-8 10 H Z-L

998: J HO-ε u 8 fr: J 10 l-L ε 0

89m eO / OOdfALOd 0869Z./00 OfA W / 7 Table 3 (continued)

Or its tautomer

 Table 4

Rf ArNH R ^b Data Rf ArNH R ^b Data

7-21 CI F-.301 8-21 OH FN.281

7-22 C CI F: 335 8-22 OH F: 317

7-23 <° X CI F: 339 & -23 OH F: 321

7-24 CI F: 383 8-24 OH F: 365

Table 5

Table 6

Rf R ^d R ^e R ^f Data

9-1 CI COOH H E: 191

9-2 CI O ^ Ph H FN: 251

9-3 CI CH ₂ 0H HF: 179

9-4 CI Me OH H F: 193

9-5 CI H F: 207

9-6 CI Et ^ OH H F 207

10 CI C0NH ₂ HF 192

11 CI COOEt H F 221

12 CI CN H E 173

13-1 CI (CH ₂ ) ₄ C00Me HF 263

13-2 CI 0 0 H F: 235

14-1 CI O ^ Ph CONH ₂ F: 296

14-2 CI CH ₂ 0H C0NH ₂ F: 222

14-3 CI Me ^ OH C0NH ₂ F: 236

14-4 CI M ^H CONH ₂ F: 250

6 (continued)

89m εθ / OOdf / J t! 0869Z./00 OAV

89Z.e0 / 00dT / XDd 0869/00 ΟΛ \

( ^SJC 1 H

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89, e0 / 00df / lDd 0869./00 ΟΛ

89, £ 0 / 00df / 13d 0869./00 OW

89Z.e0 / 00dT / 13d 0869L / 00 OAV

(s'H 00

 2 · "'Ηε) 99 -9 B' (ΖΗ9 · ^ = Γ'Ρ 'W \ LZ

 L 'Η3) 9 ZHH' '(zHCI = f' P'Hl) 9Z.'9

 JH 1 HN 1 θ |

 '(ZH6' 9 = Γ 'b' Η2) C9ε '(W 9 = Γ' ^ s Ή 1) N

9) 61 τ '(^ »39 = Γ' ^ 'H9) ^ L ^: S> CM 9S: J

 (s'H 83 U '' HQS

DSO'Z.

'9' ( ^S 'H3) 96 S HNI ^G丄

'( ^Z H € = Γ' b 'Η¾ 8fr ε' (ZH6 = Γ 'Η2) W 9ΙΛΙ

( ^s

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-

frL Z. Ή HNI ^G 1

1) 6 9 '(s'Hl) S' (s'HDQe'Q '(W9

= f'b 'Η2) 6 ^ ε' (^ ΉΖ) 09 ・ ΖΖ '(s'HOOG

1 ^'(s' H9) 8l

967. '(^' HOO IS L-ZVL 'WL = T'P' HI)

9Ζ. Ό

'P Ή HNI ⁰丄 εε 1) 8 / .9 Ό "Ή2) 09'ε-0 ^ ε''Η¾05'Ζ" 0ε〉)

 '(s'H8) ^ 7' (s'H9) 9 di

 (s Ή Z

6 is '( ^sj q'Hl) 0-31-0 U' Ή2) Ζ8 ~ 9

• 8 '0 "' Ηε) 091-09 L '(VHl) 937.'(P'H HOOO HNI ^Q丄

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( ^S 'H9) 883'(s'HS) 2E Z -9 CtJ '6SS:

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-ί '(ω'Η2) εε -Ό2 · Ζ.' (ZH8K)

HOOO HN ^ _N W η τ '( ^ζ Ηε ι = τ'ρ' HD9Z. '(ΖΗ6 Ό = Γ' ^b Ή HNIC 丄

( ^Z H0)

 Εε '(^' W) 9L Z-Od Z '("J'H2) 99'3- t7

 τ '(s'H9) 627' (s 'Η9) 02 τ- 9 di' 8S:

ΌΙ '(2Η6 "Ζ. = Γ'Ρ Ή 89 Ζ.' (S'hU) LS

 ') 9' (ZH6 'L = C' Ή08ΓΖ. '(^ Ηε' L =

 9 sleep 3

Γ'Ρ 'HL) 08 "9'(s'HL) S9 Q '(s'H 3L"9' ( ^z HN | o 丄

^Z ( ² H0)

H6 '9 = Γ' b * H2) 898 'C "W98 -9Z.2' (z 9W

Η8 ・ 9 = Γ VH 7 '(s'HS) Z' ( ^s Ή9)

623 '(Ή8) SZ L: S>ON' 9Lfr ^: d

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89Z, £ 0 / 00df / lDd 0869 mu / 00 OAV

89Z. £ 0 / 00dUT / XDd 0869 mu / 00 OAV

Claims

Harm 5 scope

1. A nitrogen-containing heterocyclic derivative represented by the following general formula (I) or a derivative thereof

(The symbols in the above formula have the following meanings, respectively.

 D: aryl which may have a substituent, cycloalkyl which may have a substituent, and heteroaryl which may have a substituent;

R ′: —N (R ⁵ ) R ⁶ , may have a substituent, may have a lower alkylene N (R ⁵ ) R ⁶ , OH, or may have an l * S substituent, and may have a heteroaryl,

A ¹ , A ² : the same or different, lower alkylene optionally having a substituent, a bond, lower alkylene optionally having a group, H "E lower alkylene optionally having a substituent,

 Ring E: cycloalkylene optionally having substituent (s), arylene optionally having substituent (s), heteroarylene optionally having substituent (s),

A ³ : NR ⁷ , CO, 0, S, may have a substituent, a lower alkylene, or a bond,

R ² , R ³ , RR ⁵ , R ⁶ and R ⁷ : the same or different, a hydrogen atom, a halogen, OH, NH ₂ , CN, -CHO, -C (= NH) -NH ₂ , lower alkyl optionally having substituent (s), -C (= 〇) -lower alkyl optionally having substituent (s), -c (= o) -o-lower alkyl optionally having substituent (s), -so ₂ -substituent may be substituted, lower alkyl, -c (= o) -heteroaryl optionally having substituent (s), substituent Cycloalkyl which may have a substituent, aryl which may have a substituent, heteroaryl which may have a substituent, may have a substituent, and may have a lower alkyl O-substituent. , Lower alkyl,

However, R ′ and R ³ may be combined with adjacent A ² and N to form a heteroaryl which may have a substituent, and when R ⁵ is a hydrogen atom, means the R ⁶ 1 Contact K atom other than the group)

2. A nitrogen-containing heterocyclic derivative represented by the following general formula (II),

(The symbols in the above formula have the following meanings, respectively.

X

NT A ³

 D: aryl which may have a substituent, heteroaryl which may have a substituent,

R ¹ : -N (R ⁵ ) R ⁶ ,

A \ A ² : same or different, lower alkylene which may have a substituent, a bond, or

Ring E: cycloalkylene which may have a substituent, arylene which may have a ^ substituent, A ³ : NR ⁷ or a bond,

R ² , R ³ , RR ⁵ , R ⁶ and R ⁷ : identical or different, having a hydrogen atom, halogen, OH, NH ₂ , CN, -CHO, -C (= NH) -NH ₂ , having a substituent Lower alkyl, one C (= 〇) -substituent Good have a lower alkyl, -c (= o) - 0- good even have a substituent, lower alkyl, -so ₂ - a lower alkyl which may have a location substituent, -c ( = o) -heteroaryl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, heteroaryl which may have a substituent, and a substituent May have a lower alkyl o-substituent, may have a lower alkyl,

However, when R ⁵ is a hydrogen atom means a group other than R ⁶ 1 Contact J atom)

3. The nitrogen-containing heterocyclic derivative described in claim 1 represented by the following general formula (') or a derivative thereof.

)

(The symbols in the above formula have the following meanings, respectively.

 D: aryl which may have a substituent, heteroaryl which may have a substituent,

R ¹ -N (R ⁵ ) R ⁶

A ¹ : join,

A ² : may have a substituent, lower alkylene, or

 Ring E: a cycloalkylene which may have a substituent,

R ⁴ R ⁵ , and R ⁶ : the same or different, which may have a substituent, lower alkyl,

However, when R ⁵ is a hydrogen atom, it means a group other than an oxygen atom.)

4. 2-[(2-dimethylaminoethyl) amino] "~ (3-methylanilino)" 4-pyrimidone "5" force Lupoxamide, 6- (4-bromoanilino) -2- [(2-dimethylamino Ethyl) amino] 4-Pyrimidone-5 "carboxamide, 6- (3,5" mobirino) 2-[(2 "dimethylaminoethyl) amino" "4-pyrimidone" & "carpoxamide, 6 -(3, 4-dichloroanilino)-2 ~ [(2 "dimethylaminoethyl) amino" ~ 4-pyrimidone "5" carboxamide, 6- (3-bromo "4-methylanilino) -2" [(2 -Dimethylaminoethyl) amino] ~ Pyrimidone "5" -Lipoxamide, 2 "[(2-Dimethinoleaminoethyl) amino] (3,4, &" Trilic laurinino) -4-pyrimidone " 5 ~ carboxamide, 6- (3,5 "dibromo" -methylanilino) -2 ~ [(2 "dimethylaminoethyl) amino]" 4-pyrimidone "5" carboxamide, 6- (3,5-dibromo ^ I-methoxyanilino) -2 ~ [(2-dimethizoleaminoethyl) amino] "4-pyrimidone" 5 "carboxamide, 2 ~ [(" dimethylaminocyclopentyl) amino] "6 ~ (3-Methylanilino) -pyrimidone ~ 5 ~ carboxamide, 2"

[(2-dimethylaminopropyl) amino]-& · (3-methylarilino) 4-pyrimido ~ 5 ~ casolepoxamide, 2-[(2 "dimethylaminobutyl) amino" (3-methylarilino)- Pyrimido "5-carboxamide, 2-[[(2-dimethylylamino-3-methyl) butyl] amino]" 6- (3-methylanilino) -pyrimidone "5" carpoxamide, 5-[(2 "dimethylaminoethyl) amino ] -3-

(3-Methisorea dilino) pyrazine-2-carboxamide, 6-cloth "5 ~ [(2" Dimethinoleaminoethyl) amino "-3- (3-methylanilino) pyrazine-2" carpoxamide, 6 "cyano [(2 "dimethylaminolethyl) amino" — 3 "(3-methylarilino) pyrazine-1" carboxamide, 5 "

 [(2-Dimethylaminoethyl) amino]-3- (3-methoxycarbonylanilino) pyrazi ~ 2 "carboxamide, 5-[(2-dimethylaminoethyl) amino] -3- (3-ditroarilino ) Pyrazin -2 "casoleboxamide, 5- [(2-dimethinoleaminoethyl) amino] -3- (3-methylalanilino) -6-methylvirazine-2 -carboxamide, 5- [(2-dimethylaminoethyl ) Amino] -3- (3 "methylilirino) -6" etyl virazine-2 ~ carpoxamide or their

5. A substance comprising a nitrogen-containing heterocyclic derivative or a salt thereof as claimed in claim 1 as an active ingredient.

6. The pharmaceutical composition according to claim 4, which has a protein kinase C P and harmful effect.

7. Claim 4 used in the treatment of diabetic complications Bt!