JPH05306226A - Therapeutic agent for chronic immunological disease - Google Patents

Abstract

PURPOSE:To obtain a low toxic therapeutic agent for chronic immunological diseases, comprising a condensed pyrimidine derivative and excellent in effects. CONSTITUTION:The objective therapeutic agent is obtained by including a compound of formula I [ring A is 5-membered ring which may have a substituent group; B is bivalent or chainlike group which may have a substituent group; X is NH2, OH or SH; Y is H, halogen or a group through C, O or S; Z is bivalent group constructed from series <=5 chainlike atoms which may have one hetero-atom present therebetween; COOR<1> is carboxyl which may be esterified; (m) is 1-6; (n) is 1-4; W is COOR<2>, NR<3>-CO-R<4> or CO-NR<3>-R<4> (COOR<2> is carboxyl which may be esterified; R<3> is H or 1-4C hydrocarbon group which may have a substituent group; R<4> is cyclic or chainlke group which ma have a substituent group)], e.g. N-[4-[3-(2,4-diamino-5,6-dihydropyrrolo[2,3- d]pyrimidin-5-yl)propyl[ benzoyl]-L-glutamic acid. This compound is obtained by carrying out the acylating reaction of compounds expressed by formulas II and III.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for chronic immune disease containing a fused pyrimidine derivative which is effective for preventing or treating various chronic immune diseases in mammals.

[0002]

2. Description of the Related Art Chronic immune diseases such as rheumatism result from the fact that the living body itself recognizes itself as non-self based on the cognitive deficiency of self and non-self, and attacks the self-organization. This disease usually manifests as vasculitis, heart disease, anemia, subcutaneous nodule, visual acuity, etc., but sometimes causes severe pain and tissue destruction, and even causes physical disability. Currently, as therapeutic agents for this disease, three systems of drugs are being developed and studied in addition to anti-inflammatory steroid drugs. The first drug is a non-steroidal anti-inflammatory drug represented by aspirin, indomethacin and the like, and it is possible to control inflammation and relieve pain and swelling. However, it is difficult to prevent the progression of this disease with this type of drug. The second drug is an immunosuppressant typified by cyclosporin A, FK506 and the like, and is considered to exert an immunosuppressive action by controlling the production of IL-2 and the expression of IL-2 receptor. There is. Although the mechanism of action itself is not yet clear, the third drug is a compound having a sedative / ameliorating action on the disease itself, such as gold salt, hydroxychloroquine, ribamizole, cyclophosphamide, azathioprine, and methotrexate (MTX). Etc. are included in this category. Especially with regard to MTX, in recent years, low content tablets (Rheumatrex
(Brand name)) was launched as a therapeutic drug for rheumatism, and its clinical efficacy has been confirmed.

Further, with the recent remarkable progress in the field of biochemistry, as a carrier of C1 unit in which folic acid is derived from formic acid, formaldehyde, etc. in vivo, nucleic acid biosynthesis system, amino acid / peptide metabolism system, methanogenesis system, etc. It was clarified that it plays a role of coenzyme in various enzyme reactions of. Particularly, in the nucleic acid biosynthesis system, it is essential for the metabolism and transfer reaction of the C1 unit in two pathways, namely, the purine synthesis system and the thymidine synthesis system. Normally, in order for folic acid to exert its biological activity, it must undergo reduction in two steps and be converted into an active coenzyme form. MTX and its peripheral compounds are known as drugs that strongly bind to the enzyme that controls the second step (dihydrofolate reductase) and suppress the reduction of dihydrofolate to tetrahydrofolate. These drugs are developed as antitumor agents because they impair DNA synthesis and result in cell death, and are still clinically used as therapeutic agents mainly for leukemia. Furthermore, unlike these MTX agents, 5,10-dideaza-5,6,7,8-tetrahydroaminopterin (DDATHF) [JDATF] that targets a folate-related enzyme other than dihydrofolate reductase as an inhibitory target Journal of Medicinal Che
mistry) 28 , 914 (1985)] or 2-desamino-2-methyl-10-propargyl-5,8-dideazaforate (DMPDDF) [British Journal
Of Cancer (British Journal of Cancer) 58 , 241 (198
8)] etc. have also been reported. On the other hand, it is structurally completely different from a conventional antifolate having a condensed skeleton of a 6-membered ring and a 6-membered ring as a basic skeleton, and a condensed heterocyclic ring of a 5-membered ring and a 6-membered ring as a basic skeleton. It has recently been found that the compound has a strong competitive inhibitory action on the folate-related enzyme and exerts an antitumor effect superior to that of MTX.

For example, European Published Patent 334,636.
In the formula

[Chemical 5] Roxyl group, Y is hydrogen atom, amino group or hydroxyl group, R is hydrogen atom, fluorine atom, alkyl group, alkenyl group or alkynyl group, and -COOR ¹ and -COOR ² are the same or different and are esterified. And n is an integer of 2 to 4, and R may be different in n repeating units. ] The compound or salt thereof represented by the formula

[Chemical 6] A divalent cyclic group or a lower alkylene group is replaced with -COOR ⁶
And —COOR ⁷ are the same or different and each represents an optionally esterified carboxy group, and i and j each represent an integer of 0 to 3 in the range of i + j of 1 to 3. ] The compound or its salt represented by

European Published Patent 418,924
formula

[Chemical 7] A divalent heterocyclic group or a lower alkylene group is shown, and Z is a divalent group consisting of 2 to 4 carbon atoms in series and may have a substituent. ] The compound represented by the formula or a salt thereof is described in European Patent Publication 431,953 by the formula

[Chemical 8] [In the formula, ring A is an optionally hydrogenated pyrrole ring,
X is an amino group, a hydroxyl group or a mercapto group,
Y is a hydrogen atom or a hydroxyl group, -COOR ¹ and -COOR ² are the same or different and may be esterified carboxyl groups, and B ring is a cycloalkylene group which may have a substituent, a substituent Represents a cycloalkenylene group which may have or a phenylene group having a substituent, and Z is a divalent group consisting of 2 to 4 carbon atoms in series and may have a substituent. ]
A compound represented by or a salt thereof,

[0006] US Pat.

[Chemical 9] [Wherein R ¹ is —OH or —NH ₂ and R ³ is 1,4-phenylene, 1,3-phenylene, thienidyl or optionally substituted with chlorine, fluorine, methyl, methoxy or trifluoromethyl. Furanidyl, cyclohexazinyl or alkanediyl, R ⁴ is hydrogen, methyl or hydroxymethyl, R ⁵ is hydrogen or alkyl having 1 to 6 carbons, and the coordination of the carbon atom with * is S
Indicates. ] Or a pharmaceutically acceptable salt thereof is disclosed in US Pat. No. 5,028,608.

[Chemical 10] [In the formula, R ¹ is —OH or —NH ₂ , R ³ is thienidyl or furanidyl optionally substituted with chlorine, fluorine, methyl, methoxy or trifluoromethyl, cyclohexazinyl or alkanediyl, R ⁴ Is hydrogen,
Coordination of methyl or hydroxymethyl and the carbon atom with * indicates S. ] The compound or its medically acceptable salt represented by these,

European Published Patents 434,426 include:
formula

[Chemical 11] [In the formula, ring A is an optionally hydrogenated pyrrole ring,
-B- is a divalent cyclic or chain group which may have a substituent, and in Q ¹ and Q ² , one is N and the other is N or CH.
W is a hydrogen atom, a halogen atom, or carbon, nitrogen,
A group having an oxygen or sulfur atom (not including an amino group), X is an amino group, a hydroxyl group or a mercapto group, Y is a hydrogen atom, a hydroxyl group or an amino group, and Z is a substituent. A carbon atom which may be substituted or a carbon atom which may have a substituent and one hetero atom which may have a substituent, and is a straight chain having 2 to 5 atoms. A divalent group,
COOR ¹ and -COOR ² are the same or different and each represents an optionally esterified carboxyl group. ] The compound represented by the formula or a salt thereof is described in European Patent Publication 438,261.

[Chemical formula 12] [Wherein the ring A is a 5-membered ring, and in the case of a pyrrole or pyrroline ring, (i) has no active proton on the nitrogen atom or (ii) is bonded to Z at the α-position, B is a substituent A divalent cyclic or chain group which may have, ^one of Q ¹ and Q ² is N and the other is N or CH, and Y is a hydrogen atom, a halogen atom, or carbon, nitrogen, oxygen or sulfur. A group via an atom, X is an amino group, a hydroxyl group or a mercapto group, Z is a carbon atom which may have a substituent, or a carbon atom which may have a substituent and a substituent. The linear divalent group having 2 to 5 atoms, which is composed of one hetero atom which may be present, may be esterified by the same or different -COOR ¹ and -COOR ² Each represents a good carboxyl group. ] The compound represented by the formula or a compound such as a salt thereof is described as an excellent antitumor agent, but the immunosuppressive effect is not described at all.

[0008]

Although various studies have been conducted on the treatment of chronic immune diseases, drugs such as MTX currently clinically used are relatively toxic and have satisfactory therapeutic results. Not listed. Therefore, development of a drug with low toxicity and excellent effect based on a new mechanism of action is strongly desired.

[0009]

[Means for Solving the Problems] In view of the above situation, the present inventors have conducted intensive studies and as a result, have reported that a fused heterocyclic ring of a 5-membered ring and a 6-membered ring, which has been reported as an antitumor agent, is a basic skeleton. It was found that the above compound unexpectedly exhibited excellent arthritis inhibitory action and was extremely useful as a therapeutic drug for chronic immune diseases, and based on this, the present invention was completed.

That is, the present invention is based on the equation (1)

[Chemical 13] [In the formula, ring A is a 5-membered ring which may have a substituent,
B- represents a divalent cyclic group or chain group which may have a substituent, X represents an amino group, a hydroxyl group or a mercapto group, and Y represents a hydrogen atom, a halogen atom or a carbon, nitrogen or sulfur atom. Z is a divalent group composed of not more than 5 chain atoms connected in series which may have a substituent and may have one hetero atom in the chain portion. , —COOR ¹ is an optionally esterified carboxyl group, m is an integer of 1 to 6, n is an integer of 1 to 4, and R ¹ is different in m repeating units. (-COOR ² represents a carboxyl group which may be esterified, R ³ represents a hydrogen atom or a C _1-4 hydrocarbon group which may have a substituent, or is adjacent to R ⁴ together. R ⁴ represents a cyclic or chain group which may have a substituent). ] A therapeutic agent for chronic immune diseases containing a compound represented by the formula or a salt thereof, (2) Formula

[Chemical 14] [The symbols in the formulas have the same meanings as described above. ] A therapeutic agent for chronic immune disease containing a compound represented by the formula or a salt thereof,

Equation (3)

[Chemical 15] And other symbols have the same meanings as described above. ] A therapeutic agent for chronic immune diseases containing a compound represented by the formula or a salt thereof, (4) Formula

[Chemical 16] [In the formula, ring A'is an optionally hydrogenated pyrrole ring, R is a hydrogen atom or a lower alkyl group, q is an integer of 1 to 5, m'is an integer of 1 to 4, and R is Is q
R ¹ may be different from each other in m ′ repeats, and other symbols have the same meanings as described above. ] The therapeutic agent according to item (2), which comprises a compound represented by the formula or a salt thereof, (5) The therapeutic agent according to item (1), which is used as a therapeutic agent for rheumatism, (6) Used as a therapeutic agent for chronic arthritis The therapeutic agent according to item (1) above.

In the above formula, compounds (I), (II) and (II
I) and (II ') can exist as equilibrium mixtures with their tautomers. The partial structural formulas capable of tautomerism are listed below, and the equilibrium relationship between them is shown.

[Chemical 17] For convenience of display, amino-type, hydroxy-type, and mercapto-type are described throughout this specification, and nomenclatures corresponding to them are adopted. And thioxo type are also included. In addition, the compound (I) of the present invention,
Although it is possible to have a plurality of asymmetric centers in (II), (III) and (II '), the compounds (I), (II), (III)
And partial structure in (II ′)

[Chemical 18] Other than the absolute configuration of the asymmetric center of S (L), the other absolute configuration of the asymmetric center may be S, R, or a mixture of RS. In this case, a plurality of diastereoisomers exist, but if necessary, they can be easily separated by an ordinary separation and purification means. All of the above diastereoisomers which can be separated in this way are within the scope of the invention.

In the above formula, the 5-membered 5-membered ring which may have a substituent represented by ring A is, for example, a carbon atom or a carbon atom and one hetero atom (which may be oxidized). A 5-membered ring composed of a good nitrogen atom, an oxygen atom, or a sulfur atom which may be oxidized) is used. Examples of such a 5-membered ring include cyclopentadiene, cyclopentene, furan, dihydrofuran, thiophene, dihydrothiophene, thiophene-
1-oxide, dihydrothiophene-1-oxide, thiophene-1,1-dioxide, dihydrothiophene-
1,1-dioxide, pyrrole, pyrroline ring and the like are used, preferably, for example, furan, thiophene, pyrrole or pyrroline ring and the like, and more preferably pyrrole, pyrroline ring and the like are used. These 5-membered rings may have 1 to 2 substituents at possible positions, and examples of such substituents include, for example, alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl). , Iso-propyl group, etc.), an alkenyl group having 2 to 4 carbon atoms (for example, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group, etc.), an alkynyl group having 2 to 4 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group, etc.),
C _3-8 cycloalkyl group (eg, cyclopropyl group), halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), alkanoyl group having 1 to 4 carbon atoms (eg formyl, acetyl, propionyl, butyryl, Isobutyryl group etc.), a phenyl group, a phenyl group which is the same or different and is substituted with 1 to 3 halogen (s) or an alkoxy group having 1 to 4 carbon atoms (eg p-
Chlorophenyl, p-methoxyphenyl, 3,4,5-
A halogenophenyl group such as a trimethoxyphenyl group, a mono-, di- or tri-C _1-4 alkoxyphenyl group), a benzyl group, the same or different halogen or an alkoxy group having 1 to 4 carbon atoms To 3 substituted benzyl groups (eg, halogenobenzyl groups such as p-chlorobenzyl, p-methoxybenzyl, 3,4,5-trimethoxybenzyl group, or mono-,
Di- or tri-C _1-4 alkoxybenzyl group etc.), benzoyl group, benzoyl group which is the same or different and is substituted by 1 to 3 by halogen or an alkoxy group having 1 to 4 carbon atoms (eg p-chloro). Benzoyl, p-methoxybenzoyl, halogenobenzoyl group such as 3,4,5-trimethoxybenzoyl group or mono-, di- or tri-C _1-4 alkoxybenzoyl group), cyano group, carboxy group, carbamoyl group, Nitro group, hydroxy group, hydroxy-C _1-4 alkyl group (for example, hydroxymethyl group, hydroxyethyl group, etc.), C _1-4 alkoxy-C _1-4 alkyl group (for example, methoxymethyl group, ethoxymethyl group, Methoxyethyl group, ethoxyethyl group, etc.), alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy group, etc.) , Propoxy, etc.), a mercapto group, having 1 to 4 carbon atoms alkylthio group (e.g., methylthio, ethylthio, propylthio group, etc.), amino group, mono - or di -C _1-4 alkylamino group (e.g., methylamino, (Ethylamino, dimethylamino, diethylamino groups, etc.), alkanoylamino groups having 1 to 4 carbon atoms (eg, formamide, acetamide groups, etc.) and the like are used. Preferred among these substituents are an alkyl group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, an amino group and the like. When the ring A is a pyrrole or a pyrroline ring, examples of the substituent which may be substituted on N include the above-mentioned alkyl group having 1 to 4 carbon atoms, alkenyl group having 2 to 4 carbon atoms, and 2 to 4 carbon atoms. An alkynyl group, a C _3-6 cycloalkyl group, an alkanoyl group having 1 to 4 carbon atoms, a benzoyl group, a benzoyl group which is the same or different and is substituted with 1 to 3 halogen (s) or an alkoxy group having 1 to 4 carbon atoms, Hydroxy-C _1-4 alkyl group, C _1-4 alkoxy-
C _1-4 alkyl group (especially methoxyethyl group, ethoxyethyl group, etc.) and the like, phenyl group, phenyl group which is the same or different and is substituted by 1 to 3 by halogen or an alkoxy group having 1 to 4 carbon atoms, A benzyl group or a benzyl group which is the same or different and has 1 to 3 substituents such as halogen or an alkoxy group having 1 to 4 carbon atoms is used, and preferably, for example, an alkyl group having 1 to 4 carbon atoms or hydroxy-C. _1-4 alkyl groups and the like are used. The ring A and Z may be bonded at any possible position, and when the ring A is a pyrrole or pyrroline ring, it may be bonded to Z at the N portion.

-B- represents a divalent chain group or a cyclic group which may have a substituent. As the divalent chain group which may have a substituent represented by -B-, a lower chain hydrocarbon group having 2 to 4 carbon atoms and the like are preferable, and for example, alkylene having 2 to 4 carbon atoms and alkenylene. , An alkynylene group (for example, ethylene, ethenylene, ethynylene, trimethylene, propenylene, propynylene, propadieneylene, tetramethylene, butenylene, butynylene, butanedienylene, etc.) is preferably used, and preferably, for example, ethylene, trimethylene or tetramethylene has 2 or more carbon atoms. The alkylene group of 4 is more preferably trimethylene or tetramethylene. -B
The divalent chain group represented by-may have the same or different 1 to 4, preferably 1 or 2 substituents, and such a substituent has, for example, a carbon number of 1
To 4 alkyl groups (eg, methyl, ethyl, propyl, iso-propyl groups, etc.), alkenyl groups having 2 to 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl groups, etc.), 2 to 4 carbon atoms
An alkynyl group (eg, ethynyl, 1-propynyl,
Propargyl group, etc.), halogen atom (eg, fluorine,
Chlorine, bromine, iodine, etc.), alkanoyl groups having 1 to 4 carbon atoms (eg formyl, acetyl, propionyl,
Butyryl, isobutyryl group, etc.), cyano group, carboxy group, carbamoyl group, nitro group, hydroxy group, hydroxy-C _1-4 alkyl group (eg, hydroxymethyl group, hydroxyethyl group, etc.), C _1-4 alkoxy-C
_1-4 alkyl group (for example, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, etc.),
An alkoxy group having 1 to 4 carbon atoms (eg, methoxy,
Ethoxy, propoxy group, etc.), mercapto group, carbon number 1
To 4 alkylthio groups (eg, methylthio, ethylthio, propylthio groups, etc.), amino groups, mono- or di-C _1-4 alkylamino groups (eg, methylamino,
Ethylamino, dimethylamino, diethylamino group, etc., alkanoylamino group having 1 to 4 carbon atoms (eg, formamide, acetamide group, etc.) and the like are used, and preferably, for example, C _1-4 alkyl group, C _2-4 alkenyl Group, C _2-4 alkynyl group, C _1-4 alkoxy-C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylthio group and the like are used. The divalent cyclic group represented by -B- may be a 5- or 6-membered homocyclic group, for example, 5 or 6
5-membered or 6-membered cyclic aliphatic hydrocarbon group (for example, 1,3- or 3,5-cyclopentadiene-1,
3-ylene, cyclopentene- (1,3-, 1,4- or 3,5-) ylene, cyclopentane-1,3-ylene, cyclohexane- (1,3- or 1,4-) ylene, cyclohexene- (1,3-, 1,4-, 1,5
-, 3,5- or 3,6-) ylene, 1,3-cyclohexadiene- (1,3-, 1,4-, 1,5-,
2,4-, 2,5- or 2,6-) ylene, 1,4
-Cyclohexadiene- (1,3-, 1,4- or 1,5-) ylene etc.) or phenylene (eg 1,
2-phenylene, 1,3-phenylene, 1,4-phenylene and the like) are used, and particularly 1,4-phenylene and the like are frequently used. The divalent cyclic group represented by -B- also represents a 5- or 6-membered heterocyclic group, which is a 5-membered ring containing 1 to 3 heteroatoms (eg, N, O, S) or A 6-membered heterocyclic group is used, and it is preferable that the two bonds are out of non-adjacent positions in the ring. Examples of the 5-membered heterocyclic group represented by -B- include, for example, thiophene- (2,4
-, 2,5- or 3,4-) ylene, furan-
(2,4-, 2,5- or 3,4-) ylene, pyrrole- (1,3-, 2,4-, 2,5- or 3,4
-) Irene, thiazole- (2,4- or 2,5-)
Irene, imidazole- (1,4-, 2,4- or 2,5-) ylene, thiadiazole-2,5-ylene or a partially reduced form thereof (one in which multiple bonds are reduced, for example, pyrroline- (1,3-, 2,4-,
2,5- or 3,4-) ylene or the like or a completely reduced compound (a compound in which all of the multiple bonds are reduced, for example, pyrrole- (1,3-, 2,4-, 2,5- or 3, 4-) ylene and the like) are used, and examples of the 6-membered heterocyclic group include pyridine- (2,4-, 2,5
-, 2,6- or 3,5-) ylene, pyran-
(2,4-, 2,5-, 2,6-, 3,5-, 3,6-
Alternatively, 4,6-) ylene, pyratin- (2,5- or 2,6-) ylene, pyrimidine- (2,4- or 2,5-) ylene, pyridatin-3,5-ylene, etc.
Alternatively, partially reduced or fully reduced compounds thereof (eg piperidine- (2,4-, 2,5-, 2,6
-Or 3,5-) ylene etc.) is used. -B-
Particularly preferred examples of are, for example, phenyl-1,4-ylene, thiophene-2,5-ylene, thiadiazole-
2,5-ylene, thiazole-2,5-ylene and pyridine-2,5-ylene. 2 shown by -B-
The 5- or 6-membered homo or heterocyclic group having a valence may be the same or different and may have 1 to 3, preferably 1 or 2 substituents. Examples of the substituent include, for example,
An alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group, etc.), 2 or 4 carbon atoms
Alkenyl groups (eg vinyl, 1-methylvinyl, 1-
Propenyl, allyl, allenyl group, etc.), alkynyl group having 2 or 4 carbon atoms (eg ethynyl, 1-propynyl, propargyl group etc.), C _3-8 cycloalkyl group (eg,
Cyclopropyl group, etc.), halogen atom (eg chlorine,
Bromine, fluorine, iodine, etc.), hydroxyl group, C _1-4 alkoxy group (eg, methoxy, ethoxy group, etc.), di-
C _1-4 alkylamino group (eg, dimethylamino, diethylamino group, etc.), halogeno-C _1-4 alkyl group (eg, trifluoromethyl group, etc.), oxo group, C _1-4 acyl group (eg, formyl group) , Acetyl group, etc.), C _1-4
An alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2-ethoxyethyl group, etc.) and the like are used, and preferably C _1-4 alkyl, halogen atom, C _1-4 alkoxy and the like are used.

The group represented by Y via a carbon, nitrogen, oxygen or sulfur atom includes a cyano group, a carboxy group,
Carbamoyl group, amino group, nitro group, hydroxy group,
Mercapto group or lower hydrocarbon group (for example, having 1 carbon atom)
To alkyl groups (eg, methyl, ethyl, propyl, iso-propyl groups, etc.), alkenyl groups having 2 or 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl groups, etc.), It may be an alkynyl group having 2 or 4 carbon atoms (eg ethynyl, 1-propynyl, propargyl group etc.) and a C _3-8 cycloalkyl group (eg cyclopropyl group) etc., and a C _6-10 aryl group (eg , Phenyl group, naphthyl group), N,
A 5- or 6-membered heterocyclic group containing 1 to 4, preferably 1 to 2 heteroatoms such as S and O, which may be the same or different (eg, pyrrolyl, imidazolyl, pyrazolyl, tenyl, furyl, thiazolyl, thiadiazolyl). , Oxazolyl, oxadiazolyl, pyridyl, pyranyl,
It may be pyrazinyl, pyrimidinyl, pyridatinyl or their partially reduced or fully reduced groups (eg, dioxolanyl, piperidino, morpholino, N-methylpiperazinyl, N-ethylpiperazinyl, dioxanyl, etc.). When Y is a lower hydrocarbon group, a C _3-8 cycloalkyl group, a C _6-10 aryl group or a 5- or 6-membered heterocyclic group, they are the same or different and are 1 to 4
And preferably 1 or 2 substituents, and examples of such substituents include, for example, 1 to 4 carbon atoms.
Alkyl groups (eg, methyl, ethyl, propyl, is
o-propyl group), alkenyl group having 2 or 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group, etc.), alkynyl group having 2 or 4 carbon atoms (eg ethynyl, 1- In addition to propynyl, propargyl group, etc.) or C _3-8 cycloalkyl group (eg, cyclopropyl group), etc., halogen atom (eg, fluorine etc.), hydroxy group, oxo group, C _1-4 alkoxy group (eg, Methoxy group, etc.), di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino group, etc.),
Halogeno-C _1-4 alkyl group (eg trifluoromethyl group etc.), C _1-4 acyl group (eg formyl group etc.), hydroxy-C _1-4 alkyl group (eg hydroxymethyl, 2- Hydroxyethyl group), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl,
2-ethoxyethyl group) and the like are used. The group represented by Y through a carbon, nitrogen, oxygen or sulfur atom may be an alkoxy group, an alkylthio group, an alkylcarbonylamino group or an alkylcarbonyloxy group, and the alkyl moiety of these groups may be Y The alkyl group having 1 to 4 carbon atoms, which has been described in detail as one example of the lower hydrocarbon group represented by, is used as it is. The group represented by Y via a carbon, nitrogen, oxygen or sulfur atom may also be an aryloxy group, an arylthio group, an aroylamino group or an aroyloxy group, and the aryl moiety of these groups may be a phenyl group or a naphthyl group. Etc. are used. Further, the group represented by Y via a carbon, nitrogen, oxygen or sulfur atom may be a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic carbonylamino group or a heterocyclic carbonyloxy group, and a heterocyclic portion of these groups As the above, the groups represented by the above-mentioned 5- or 6-membered heterocyclic group represented by Y and the like are used as they are. In addition, the group represented by Y through a carbon, nitrogen, oxygen or sulfur atom may be a mono- or di-C _1-4 alkylamino group, and the substituent may have the above-mentioned carbon number of 1 to 4 represented by Y. Is used (eg, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, etc.). As the halogen atom represented by Y, for example, fluorine, chlorine, bromine, iodine or the like is used. Preferred examples of Y include hydrogen atom, halogen atom, amino group, mono- and di-C _1-4 alkylamino group, halogeno-C _1-4 alkyl group and C _1-4 alkyl group, and more preferred Is
A hydrogen atom, an amino group, a C _1-4 alkyl group and the like are used.

Z does not exceed 5 in series which may have a substituent and in which one hetero atom (nitrogen atom, oxygen atom, sulfur atom, etc.) may be interposed in the chain portion. A divalent group composed of chain atoms is shown. When there is no intervening heteroatom, Z is optionally in series 5
Represents a divalent aliphatic group composed of not more than a chain carbon atom, and examples of the divalent aliphatic group include C _1- such as methylene, ethylene, trimethylene, tetramethylene and pentamethylene groups. ₅ alkylene groups such as vinylene,
C _2-5 alkenylene groups such as propenylene, 1- or 2-butenylene, butadienylene, 1- or 2-pentenylene, 1,3- or 1,4-pentadienylene groups, such as ethynylene, 1- or 2-propynylene,
A C _2-5 alkynylene group such as 1- or 2-butynylene, 1-, 2- or 3-pentynylene group is used, and preferably a C _1-4 alkylene group is used.
Z represents a divalent group having a chain-constituting atom which does not exceed 5 in series with one heteroatom interposed in the chain portion which may have a substituent, and is represented by, for example, formula -Z ¹ -Z ² -Z ³
-[In the formula, Z ¹ and Z ³ are the same or different and each is a divalent lower hydrocarbon group having 1 to 4 carbon atoms which may have a bond or a substituent (provided that the carbon atoms of Z ¹ and Z ³ are Total number is 0
The to a 4), -Z ² - is -O-, the formula -S (O)
p

[Chemical 19] R ⁵ represents a hydrogen atom or a lower hydrocarbon group which may have a substituent). ] And the like are used. Examples of the divalent lower hydrocarbon group represented by Z ¹ and Z ³ which may have a substituent include divalent lower hydrocarbon groups such as methylene, ethylene and trimethylene.
C _1-4 alkylene group such as tetramethylene, for example, vinylene, propenylene, 1- or 2-butenylene, C _2-4 alkenylene group such as butadienylene, for example, ethynylene, 1- or 2-propynylene, 1- or 2-
A C _2-4 alkynylene group such as butynylene is used.
The lower hydrocarbon group represented by R ⁵ and optionally having a substituent has a lower hydrocarbon group of 1 to 4 carbon atoms.
Alkyl groups (eg, methyl, ethyl, propyl, is
o-propyl group, etc., an alkenyl group having 2 or 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group, etc.), an alkynyl group having 2 or 4 carbon atoms (eg, ethynyl, 1 -Propynyl, propargyl group, etc.), C _3-8 cycloalkyl group (eg, cyclopropyl group, etc.) and the like are used, and preferably C _1-4 alkyl group, C _2-4 alkynyl group and the like are used. The divalent aliphatic group represented by Z having a chain carbon atom not exceeding 5 in series, the divalent lower hydrocarbon group represented by Z ¹ and Z ³ and the lower hydrocarbon group represented by R ⁵ are They may be the same or different and have 1 to 4, preferably 1 or 2 substituents, and examples of such a substituent include, for example, an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, Propyl, iso-propyl group, etc.), alkenyl group having 2 or 4 carbon atoms (eg vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group, etc.), alkynyl group having 2 or 4 carbon atoms (eg ethynyl) , 1-propynyl, propargyl, etc.) or C _3-8 cycloalkyl groups (eg,
In addition to cyclopropyl group etc., halogen atom (eg fluorine etc.), hydroxy group, oxo group, C _1-4 alkoxy group (eg methoxy group etc.), di-C _1-4 alkylamino group (eg , Dimethylamino, diethylamino group, etc., halogeno-C _1-4 alkyl group (eg trifluoromethyl group etc.), C _1-4 acyl group (eg formyl group etc.), hydroxy-C _1-4 alkyl group (For example,
Hydroxymethyl, 2-hydroxyethyl group, etc.), C
_1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2-ethoxyethyl group, etc.) is used, and preferably C _1-4 alkyl group, hydroxy group, oxo group, C _1-4 alkoxy group, etc. Group, hydroxy-C _1-4 alkyl group and the like are used.

[0017]

[Chemical 20] The C _1-4 hydrocarbon group in the C _1-4 hydrocarbon group which may have a substituent represented by R ³ is a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl groups, etc.), C _2-4 alkenyl groups (eg vinyl, allyl, 1
-Methylvinyl, 2-methylvinyl group, etc.) and C _3-4 cycloalkyl groups (eg, cyclopropyl, cyclobutyl group, etc.) are used. The number of such substituents is 1 to 3,
For example, an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group, etc.), 2 carbon atoms
Or an alkenyl group having 4 carbon atoms (for example, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group, etc.), an alkynyl group having 2 or 4 carbon atoms (for example, ethynyl, 1-propynyl, propargyl group, etc.) or C _{3 -8} cycloalkyl group (eg, cyclopropyl group), halogen atom (eg, fluorine), hydroxy group, oxo group, C _1-4 alkoxy group (eg, methoxy group), di-C _{1 -4} alkylamino group (for example, dimethylamino,
Diethylamino group etc.), halogeno-C _1-4 alkyl group (eg trifluoromethyl group etc.), C _1-4 acyl group (eg formyl group etc.), hydroxy-C _1-4 alkyl group (eg hydroxymethyl group) , 2-hydroxyethyl group, etc.), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2-ethoxyethyl group, etc.) and the like, and preferably C _1-4 alkyl group, hydroxy Group, oxo group, C _1-4 alkoxy group, di C _1-4 alkylamino group, C _1-4 alkoxy-C _1-4 alkyl group and the like are used.

[0018]

[Chemical 21] Examples of the preferable 5- to 13-membered cyclic group include pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, piperidino, morpholino, dihydropyridyl,
N-C _1-4 alkylpiperazinyl (eg, N-methylpiperazinyl, N-methylpiperazinyl group), azacycloheptyl, azacyclooctyl, isoindolyl, indolyl or their partially reduced or fully reduced form Groups (for example, tetrahydropyridyl and the like), 2-pyrrolidinone-1-yl, 2-piperazinone-1-yl, hexahydro-2-azepinone-1-yl, octahydro-
2-azocinone-1-yl, 2-oxoindoline-1
-Yl, 1-oxoisoindoline-2-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-1-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl , 1-oxo-5H-benzo-1,
2,3,4-tetrahydro-2-azepin-2-yl,
1-oxobenzo-1,2,3,4,5,6-hexahydro-2-azocin-2-yl, 2-oxo-5H-benzo-1,2,3,4-tetrahydro-1-azepine-
1-yl, 2-oxobenzo-1,2,3,4,5,6
-Hexahydro-1-azocin-1-yl, succinimide, glutarimide, 1,4-butanedicarboximide, 1,5-pentanedicarboximide, 1,2-cyclohexanedicarboximide, phthalimide, preferably morpholino, piperidino, 2-pyrrolidinone-1
-Yl, 2-piperazinone-1-yl and the like are used.
These groups further include a C _6-10 aromatic hydrocarbon (eg, benzene ring, naphthalene ring, etc.) or a partially reduced or fully reduced ring thereof (eg, cyclohexene ring, etc.) at a position capable of being condensed. ) Or a 5- or 6-membered heterocyclic ring (for example, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, furazan, pyran, pyridine, pyratin, pyrimidine, pyridatin) Or their partially reduced or fully reduced compounds (eg, pyrroline, etc.),
Dioxolane, dioxane, piperidine, morpholine,
N-methylpiperazine and N-ethylpiperazine) may be condensed.

[0019]

[Chemical formula 22] The 5- to 13-membered cyclic group may have the same or different 1 to 4, preferably 1 to 2 substituents at substitutable positions. Examples of such a substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl,
Ethyl, propyl, iso-propyl group, etc.), alkenyl group having 2 or 4 carbon atoms (for example, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group, etc.), 2 carbon atoms
Or an alkynyl group (eg, ethynyl, 1-propynyl, propargyl group, etc.) or a C _3-8 cycloalkyl group (eg, cyclopropyl group, etc.), a halogen atom (eg, fluorine, etc.), a hydroxy group, An oxo group,
C _1-4 alkoxy group (eg, methoxy group), di-C
_1-4 alkylamino group (eg, dimethylamino, diethylamino group etc.), halogeno-C _1-4 alkyl group (eg, trifluoromethyl group etc.), C _1-4 acyl group (eg, formyl group etc.), Hydroxy-C _1-4 alkyl group (for example, hydroxymethyl, 2-hydroxyethyl group, etc.), C _1-4 alkoxy-C _1-4 alkyl group (for example,
Methoxymethyl, 2-ethoxyethyl group, etc.), preferably C _1-4 alkyl group, halogen atom, hydroxy group, oxo group, C _1-4 alkoxy group, di-C _1-4 alkylamino group, etc. Used.

The cyclic group in the cyclic group which may have a substituent represented by R ⁴ includes a hetero atom (eg, N,
A 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may contain 1 to 3 of O, S) in the ring, or a condensed ring group thereof is used. Examples of the 5-membered cyclic group represented by R ⁴ include, for example, cyclopentanedienyl, thienyl, furyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl and the like, or partially reduced or fully reduced compounds thereof (for example, cyclopentenyl, Cyclopentyl etc.) and the like, and examples of the 6-membered cyclic group include
For example, phenyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridatinyl, etc., or their partially reduced or fully reduced compounds (eg, cyclohexyl, cyclohexenyl, cyclohexanedienyl, piperidine, etc.), etc. are used, and 5 or 6-membered As an example of the condensed ring group of the cyclic group, for example, naphthyl, indenyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl, or a partially reduced or fully reduced compound thereof (for example, tetrahydronaphthalene) is used. Be done. Particularly, for example, phenyl, cyclohexyl, naphthyl, thienyl, thiazolyl, cyclopentyl and the like are preferable. The chain group in the chain group which may have a substituent represented by R ⁴ is preferably a lower chain hydrocarbon group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, C _1-4 alkyl group such as butyl, isobutyl, sec-butyl, tert-butyl group, C _2-4 alkenyl group such as vinyl, allyl, 1-methylvinyl, 2-methylvinyl group, cyclopropyl, cyclobutyl group, etc. C _3-4 cycloalkyl group and the like are used.

The cyclic or chain group represented by R ⁴ may have the same or different 1 to 4, preferably 1 to 2 substituents at substitutable positions. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group, etc.), an alkenyl group having 2 or 4 carbon atoms. (For example, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl groups, etc.),
An alkynyl group having 2 or 4 carbon atoms (eg, ethynyl,
1-propynyl, propargyl group, etc.), carbon number 3 to 6
A cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group, etc.), a cycloalkenyl group having 5 to 6 carbon atoms (eg, cyclopentenyl, cyclohexenyl group, etc.), 7 to 8 carbon atoms
Aralkyl group (eg, benzyl, α-methylbenzyl, phenethyl group, etc.), phenyl group, carbon number of 1 to 4
An alkoxy group of (for example, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, se
c-butoxy, tert-butoxy group, etc.), phenoxy group, alkanoyl group having 1 to 4 carbon atoms (eg formyl,
Acetyl, propionyl, n-butyryl, iso-butyryl group, etc.), benzoyl group, alkanoyloxy group having 1 to 4 carbon atoms (eg formyloxy, acetyloxy,
Propionyloxy, n-butyryloxy, iso-butyryloxy group, etc.), benzoyloxy group, carboxy group, C
_1-4 Alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl group, etc.), carbamoyl group, N-substituted Carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl,
N-C _1-4 alkylcarbamoyl groups such as N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, etc.), N, N-disubstituted carbamoyl groups (eg, N, N-dimethylcarbamoyl, N, N -N-N-di-C _1-4 alkylcarbamoyl such as diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, 1-acetylidinylcarbonyl, 1-azetidinyl
Carbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl group, etc.), halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), mono-, di- Or try
Halogeno-C _1-4 alkyl group (eg, trifluoromethyl group), oxo group, amidino group, imino group, amino group, mono-substituted amino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butyl) Mono-C _1-4 alkylamino groups such as amino), di-substituted amino groups (eg, dimethylamino, diethylamino,
Di-C _1-4 alkylamino groups such as dipropylamino, diisopropylamino, dibutylamino, etc.), 3 to 6
Member cyclic amino groups (for example, atyridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, vilazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl groups, etc.), Triazolyl group, tetrazolyl group, alkanoylamide group (for example,
Formamide, acetamide, trifluoroacetamide,
C _1-4 alkanoylamide groups such as propionylamide, butyrylamide and isobutyrylamide), benzamide group, carbamoylamino group, N-substituted carbamoylamino group (eg N-methylcarbamoylamino, N-ethylcarbamoylamino) , N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc., N-C _1-4 alkylcarbamoylamino groups, etc.), N, N-disubstituted carbamoylamino groups (eg, N, N- N, N-di-, such as dimethylcarbamoylamino, N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino and N, N-dibutylcarbamoylamino
C _1-4 alkylcarbamoylamino group, 1-acetylidinylcarbonylamino, 1-azetidinylcarbonylamino, 1-pyrrolidinylcarbonylamino, 1-piperidinylcarbonylamino, N-methylpiperazinyl Carbonylamino, morpholinocarbonylamino group, etc.), hydroxy group, epoxy group (-O-), nitro group, cyano group,
Mercapto group, sulfo group, sulfino group, phosphono group,
Dihydroxyboryl group, sulfamoyl group, N-substituted sulfamoyl group (for example, N-methylsulfamoyl, N-
Ethylsulfamoyl, N-Propylsulfamoyl, N-
Isopropylsulfamoyl, C _1-4 alkylsulfamoyl group such as N-butylsulfamoyl), N, N-disubstituted sulfamoyl group (eg, N, N-dimethylsulfamoyl, N, N- Di-C such as diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl
_1-4 alkylsulfamoyl group), 1-pyrrolidinylsulfonyl, 1-piperidinylsulfonyl, N-methyl-
1-piperazinylsulfonyl, morpholinosulphonyl group, alkylthio group having 1 to 4 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio group), phenylthio group, carbon An alkylsulfinyl group having 1 to 4 (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), a phenylsulfinyl group, an alkylsulfonyl group having 1 to 4 carbon atoms (eg, methylsulfonyl, ethylsulfonyl, Propylsulfonyl, butylsulfonyl group etc.), phenylsulfonyl group etc. are used,
Preferred substituents are, for example, C _1-4 alkyl group, C
_1-4 alkoxy group, carboxy group, tetrazolyl group, carbamoyl group, N-substituted carbamoyl group, N, N-disubstituted carbamoyl group, halogen atom, amino group, monosubstituted amino group, disubstituted amino group, hydroxy group, sulfo group Base,
A phosphono group, a dihydroxyboryl group, and the like are used, and particularly preferable substituents are a carboxy group, a tetrazolyl group, a halogen atom, a sulfo group, a phosphono group, a dihydroxyboryl group, and the like.

Of these substituents, those which can be further substituted are the same or different and have 1 to 4 groups,
Preferably 1 to 2 alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl groups, etc.), C _1-4 alkoxy groups (eg, Methoxy group, ethoxy group, etc.), halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), water-soluble group (eg, hydroxyl group, carboxy group, sulfo group, phosphono group, amidino group, amino group, methylamino group) , Ethylamino group, dimethylamino group, diethylamino group, morpholino group, piperidyl group, N-methylpiperazyl group, pyridyl group, trimethylammonium group, triethylammonium group, pyridinium group, etc.) and the like.

As the optionally esterified carboxyl group represented by -COOR ¹ and -COOR ² ,
A lower alkyl group having 1 to 6 carbon atoms (eg methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo) -Pentyl, tert-pentyl, etc.), a benzyl group which may have a substituent (for example,
1 to 3 substituted with benzyl group or nitro such as nitrobenzyl, methoxybenzyl or C _1-4 alkoxy.
Benzyl group) or a phenyl group which may have a substituent (for example, a phenyl group, or a phenyl group substituted with 1 to 3 nitro groups such as nitrophenyl and methoxyphenyl, or C _1-4 alkoxy). Etc.) and the like, and a carboxy group esterified by, for example, a C _1-4 lower alkyl group, a benzyl group which may have a substituent and the like are preferably used. Examples of the optionally hydrogenated pyrrole ring represented by the A ′ ring include a pyrrole ring and a pyrroline ring. The lower alkyl group represented by R is an alkyl group having 1 to 3 carbon atoms (for example,
Methyl, ethyl, propyl, iso-propyl group, etc.) and the like are used. q is an integer of 1 to 5, preferably 1 to 3,
m'represents an integer of 1 to 4, preferably 1 to 3, R may be different in q repetitions and R ¹ may be different in m'repetitions. n represents an integer of 1 to 4.

Preferred examples of the compound (I) or a salt thereof of the present invention include compounds (II), (III) and (I
I ′) or a salt thereof and the like, and specific examples include the following compounds and salts thereof. 1) N- [4- [3- (2,4-diamino-5,6-
Dihydropyrrolo [2,3-d] pyrimidin-5-yl)
Propyl] benzoyl] -L-glutamic acid 2) N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl]
Benzoyl] -L-glutamic acid 3) N- [4- [3- (2,4-diamino-6-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5-
Yl) propyl] benzoyl] -L-glutamic acid 4) N- [4- [3- (2-diamino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl]- L-glutamic acid 5) N- [4- [3- (2,4-diamino-6,7-
Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5
-Yl) -1-methylpropyl] benzoyl] -L-glutamic acid 6) N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2 -Methylpropyl] benzoyl] -L-glutamic acid 7) N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -1-ethylpropyl] benzoyl ] -L-Glutamic acid 8) N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-ethylpropyl] benzoyl] -L-glutamic acid 9) N- [4- [3- (2,4-diamino-6,7-
Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5
-Yl) -1-ethylpropyl] benzoyl] -L-glutamic acid 10) 4- [N- [2- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethyl] -N-methylamino] benzoyl-
L-glutamic acid 11) 4- [N- [2- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) ethyl]
-N-methylamino] benzoyl-L-glutamic acid

12) 4- [N- [2- (2,4-diamino-6,7-dihydro-5H-pyrrolo [2,3-d]]
Pyrimidin-5-yl)] ethylamino] benzoyl-
L-glutamic acid 13) 4- [N- [2- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl)] ethylamino] benzoyl-L-glutamic acid 14) N- [4- [2- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethyloxy] benzoyl] -L-glutamic acid 15) N- [4- [2- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) ethyloxy] benzoyl] -L-glutamic acid 16) N- [4- [2- (2,4-diamino-6,7)
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethylthio] benzoyl] -L-glutamic acid 17) N- [4- [2- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) ethylthio] benzoyl] -L-glutamic acid 18) N- [5- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (tert-butoxycarbonyl) amino] -2-thenoyl] -L-glutamic acid 19) N- [5- [2- (2 , 4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) ethylamino] -2-thenoyl] -L-glutamic acid 20) N- [4- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-ethylamino] benzoyl] -L-glutamic acid 21) N- [4- [N- [2- ( 2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (2-hydroxyethyl) amino] benzoyl] -L-glutamic acid

22) N- [4- [N- [2- (2,4
-Diamino-6,7-dihydro-5H-pyrrolo [2,3
-D] pyrimidin-5-yl) ethyl] -N-allylamino] benzoyl] -L-glutamic acid 23) N- [4- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-propargylamino]
Benzoyl] -L-glutamic acid 24) N- [4- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-ethylamino] benzoyl] -L-glutamic acid 25) N- [4- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (2-hydroxyethyl) amino] benzoyl] -L-glutamic acid 26) N- [4- [N- [2- (2 , 4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-allylamino] benzoyl] -L-glutamic acid 27) N- [4- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-propargylamino] benzoyl] -L-
Glutamic acid 28) N- [4- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] -3-
Fluorobenzoyl] -L-glutamic acid 29) N- [4- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] -3-fluorobenzoyl] -L-glutamic acid 30) N- [4- [N- [2- (2,2 4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] cyclohexanecarbonyl] -L-glutamic acid 31) N- [4- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] cyclohexanecarbonyl] -L-glutamic acid

32) N- [4- [N- [2- (2,4
-Diamino-6,7-dihydro-5H-pyrrolo [2,3
-D] pyrimidin-5-yl) ethyl] -N-ethylamino] butyryl] -L-glutamic acid 33) N- [4- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-ethylamino] butyryl] -L-glutamic acid 34) N- [5- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] thiazol-2-carbonyl] -L-glutamic acid 35) N- [5- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-propargylamino]
Thiazole-2-carbonyl] -L-glutamic acid 36) N- [5- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] thiazol-2-carbonyl] -L-glutamic acid 37) N- [5- [N- [2- (2,2 4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-propargylamino] thiazole-2-carbonyl] -L-glutamic acid 38) N- [5- [N- [2- (2,2 4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] -2-
Thenoyl] -L-glutamic acid 39) N- [5- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-propargylamino]
-2-thenoyl] -L-glutamic acid 40) N- [5- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methylamino] -2-thenoyl] -L-glutamic acid

41) N- [5- [N- [2- (2,4
-Diamino-7H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethyl] -N-propargylamino] -2-
Thenoyl] -L-glutamic acid 42) N- [4- [N- [2- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5.
-Yl) ethyl] -N- (2-hydroxyethyl) amino] benzoyl] -L-glutamic acid 43) N- [4- [N- [2- (2-amino-4-hydroxy-7H-pyrrolo [2,2 3-d] pyrimidine-5
-Yl) ethyl] -N-propargylamino] benzoyl] -L-glutamic acid 44) N- [5- [N- [2- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine -5
-Yl) ethyl] -N-methylamino] thiazole-2
-Carbonyl] -L-glutamic acid 45) N- [5- [N- [2- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5)
-Yl) ethyl] -N-methylamino] -2-thenoyl] -L-glutamic acid 46) N- [5- [N- [2- (2-amino-4-hydroxy-7H-pyrrolo [2,3- d] pyrimidine-5
-Yl) ethyl] -N-propargylami] no-2-thenoyl] -L-glutamic acid 47) N- [5- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (tert-butoxycarbonyl) amino] -2-thenoyl] -L-glutamic acid 48) N- [5. -[2- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethylamino] -2-thenoyl] -L-glutamic acid 49) N- [5- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (iso-propyloxycarbonyl) amino] -2-thenoyl] -L-glutamic acid

50) N- [5- [N- [2- (2,4
-Diamino-7H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethyl] -N- (iso-propyloxycarbonyl) amino] -2-thenoyl] -L-glutamic acid 51) N- [4- [N- [2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (ethoxycarbonyl) amino] benzoyl] -L-glutamic acid 52) N- [4- [N- [ 2- (2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (methoxycarbonyl) amino] benzoyl] -L-glutamic acid 53) N- [4- [N- [ 2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (ethoxycarbonyl) amino] benzoyl] -L-glutamic acid 54) N- [4- [N- [2- (2,4 -Diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (methoxycarbonyl) amino] benzoyl] -L-glutamic acid 55) N- [4- [N- [2- (2,4 -Diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-methanesulfonylamino] benzoyl]-
L-glutamic acid 56) N- [4- [N- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N- (p-toluenesulfonyl) amino] benzoyl] -L-glutamic acid 57) N- [4- [N- [2- (2 , 4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-formylamino] benzoyl] -L-glutamic acid 58) N- [4- [N- [2- ( 2,4-diamino-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-acetylamino] benzoyl] -L-glutamic acid 59) N- [4- [N- [2- ( 2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -N-formylamino] benzoyl] -L-glutamic acid

60) N- [4- [N- [2- (2,4
-Diamino-7H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethyl] -N-acetylamino] benzoyl] -L-glutamic acid 61) N- [5- [3- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) propyl] -2-thenoyl] -L-glutamic acid 62) N- [5- [3- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) propyl] -2-thenoyl] -L-glutamic acid 63) N- [5- [2- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) ethyl] -2-thenoyl] -L-glutamic acid 64) N- [5- [2- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) ethyl]
-2-thenoyl] -L-glutamic acid 65) N- [5- [4- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) butyl] -2-thenoyl] -L-glutamic acid 66) N- [5- [4- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) butyl]
-2-Thenoyl] -L-glutamic acid 67) N- [5- [3- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) -1-methylpropyl] -2-thenoyl]-
L-glutamic acid 68) N- [5- [3- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] -2-thenoyl] -L-glutamic acid 69) N- [5- [3- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) -1,1-dimethylpropyl] -2-thenoyl] -L-glutamic acid

70) N- [5- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -1,1-dimethylpropyl] -2-thenoyl]-
L-glutamic acid 71) N- [5- [3- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) -1-ethylpropyl] -2-thenoyl]-
L-glutamic acid 72) N- [5- [3- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) -1-ethylpropyl] -2-thenoyl] -L-glutamic acid 73) N- [5- [3- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) propyl] -2-pyridinecarbonyl] -L
-Glutamic acid 74) N- [5- [3- (2,4-diamino-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) propyl] -2-pyridinecarbonyl] -L-glutamic acid 75) N- [4- [3- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) propyl] cyclohexylcarbonyl] -L
-Glutamic acid 76) N- [5- (2,4-diamino-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) pentanoyl] -L-glutamic acid 77) N- [5 -(2,4-Diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) pentanoyl]
-L-glutamic acid 78) N- [6- (2,4-diamino-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) hexanoyl] -L-glutamic acid 79) N- [6- (2,4-Diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) hexanoyl]
-L-glutamic acid 80) N- [5- [3- (2,4-diamino-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-
5-yl) propyl] thiazole-2-carbonyl]-
L-glutamic acid

81) N- [5- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] thiazol-2-carbonyl] -L-glutamic acid 82) N- [5- [3- (2-Amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] -2-thenoyl] -L-glutamic acid 83) N- [5 -[2- (2-Amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -2-thenoyl] -L-glutamic acid 84) N- [5- [3- (2-Amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] -2-thenoyl] -L-glutamic acid 85) N- [5- [3- (2-amino-4-hydroxy-7H-pi Boro [2,3-d] pyrimidin-5-yl) propyl] -2-pyridinecarbonyl] -L-glutamic acid 86) N- [5- [3- (2-amino-4-hydroxy-7H-pyrrolo [2 , 3-d] Pyrimidin-5-yl) propyl] thiazol-2-carbonyl] -L-glutamic acid 87) N- [5- (3- (4-amino-7H-pyrrolo [2,3-d] pyrimidine- 5-yl) propyl) -2
-Thenoyl] -L-glutamic acid 88) N- [4- (3- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl) benzoyl] -L-glutamic acid 89) N- [3-Chloro-4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid 90) N- [4- [3 -(2,4-Diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] cyclohexylcarbonyl] -L-glutamic acid

91) N- [4- [2- (2-amino-
4-hydroxy-7-methyl-7H-pyrrolo [2,3-
d] pyrimidin-5-yl) ethyl] benzoyl] -L
-Glutamic acid 92) N- [4- [3- (2-amino-4-hydroxy-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid 93 ) N- [4- [3- (4-Hydroxy-2-methyl-7-methylpyrrolo [2,3-d] pyrimidine-5-
Yl) propyl] benzoyl] -L-glutamic acid 94) N- [4- [2- (4-hydroxy-2-methyl-7-methylpyrrolo [2,3-d] pyrimidine-5-
Yl) ethyl] benzoyl] -L-glutamic acid 95) N- [4- [2- (2,4-diamino-thieno [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid 96 ) N- [4- [3- (2,4-Diamino-thieno [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid 97) N- [4- [2- (2 -Amino-4-hydroxythieno [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid 98) N- [4- [3- (2-amino-4-hydroxythieno [2,2. 3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid, and γ-diglutamate and γ-triglutamate corresponding to the L-glutamic acid moiety of these compounds. The boxy group may be pharmacologically acceptable salts and esters. Next, a method for producing the compound (I) of the present invention or a salt thereof will be described.

The compound (I) of the present invention or a salt thereof has the formula

[Chemical formula 23] [Wherein X, Y, A, Z and B have the same meanings as described above] and a reactive derivative at the carboxylic acid or carboxyl group

[Chemical formula 24] [Wherein R ¹ , W and n have the same meanings as described above, and m-1 represents an integer of 0 to 5] and the resulting amino acid derivative is subjected to an acylation reaction. As a method of the above acylation, for example, a method of acylating the compound (I-2) with the compound (I-1) or its reactive derivative is used. This reaction is advantageously carried out in the presence of carbodiimides, diphenylphosphoric acid azide, diethyl cyanophosphoric acid and the like. The amount of compound (I-2) to be used is generally about 1-20 molar equivalent, preferably about 1-5 molar equivalent, relative to compound (I-1) or its reactive derivative. Carbodiimides, diphenylphosphoric acid azide,
Diethyl cyanophosphate and the like can be used generally in about 1-25 molar equivalents, preferably in about 1-5 molar equivalents, relative to compound (I-1). As the carbodiimides,
Dicyclohexylcarbodiimide is practically preferable, and other carbodiimides such as diphenylcarbodiimide, di-o-tolylcarbodiimide, di-p-tolylcarbodiimide, di-tert-butylcarbodiimide, 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide. , 1-cyclohexyl-3- (4-diethylaminocyclohexyl) carbodiimide, 1-ethyl-3- (2-diethylaminopropyl)
Carbodiimide and 1-ethyl-3- (3-diethylaminopropyl) carbodiimide may be used. This acylation reaction is preferably carried out in the presence of an appropriate solvent, and examples of the solvent include water, alcohols (eg, methanol, ethanol, etc.), ethers (eg,
Dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme etc.), nitriles (eg acetonitrile etc.), esters (eg ethyl acetate etc.), halogenated hydrocarbons (eg dichloromethane, chloroform, carbon tetrachloride) Etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), acetone,
Nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used. This reaction is usually carried out at a pH range of about 2 to 14, preferably about pH 6 to 9. Reaction temperature is usually about -1
The reaction is carried out at 0 ° C to the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C. The reaction time may be about 1 to 100 hours, preferably 2 to 48 hours. The pH of the reaction solution may be appropriately set, for example, with an acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, etc.) or a base (eg,
Sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, triethano- Luamine,
If necessary, adjust with pyridine) or buffer (eg, phosphate buffer, borate buffer, acetate buffer, etc.). In addition, the reaction can be proceeded more advantageously by using a catalyst capable of promoting acylation.

As such a catalyst, for example, a base catalyst or an acid catalyst is used. Examples of such base catalysts include tertiary amines (eg, aliphatic tertiary amines such as triethylamine; pyridine, α-, β- or γ-picoline,
2,6-lutidine, 4-dimethylaminopyridine, 4-
(1-pyrrolidinyl) pyridine, aromatic tertiary amines such as dimethylaniline, diethylaniline, etc. are used, and examples of the acid catalyst include Lewis acids (eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ ), anhydrous Ferric chloride, titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.) are used. Of the above catalysts, 4-dimethylaminopyridine or 4- (1-pyrrolidinyl) pyridine is often preferred. The amount of the catalyst used is such that the amount of the catalyst that can accelerate the acylation is good, and is usually about 0.01-10 molar equivalents, preferably about 0.1-1 molar equivalents, relative to compound (I-1). Carboxylic acid (I
As the reactive derivative at the carboxy group of -1),
For example, carboxylic acid (I-1) acid halides (eg, fluoride, chloride, bromide, iodide, etc.), acid anhydrides (eg, iodoacetic anhydride, isobutyric anhydride, etc.), lower monoalkyl carbonates (eg , Monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono iso-propyl carbonate, monobutyl carbonate, mono iso-butyl carbonate,
Mono-sec-butyl carbonate, mono-tert-butyl carbonate, etc.) mixed acid anhydride, active ester (eg, cyanomethyl ester, ethoxycarbonylmethyl ester, methoxymethyl ester, phenyl ester, o-
Nitrophenyl ester, p-nitrophenyl ester, p-carbomethoxyphenyl ester, p-cyanophenyl ester, phenylthioester, succinimide ester, etc.), acid atide, phosphoric acid diester (eg, dimethyl phosphate, diethyl phosphite) Phosphate, dibenzyl phosphate, diphenyl phosphate, etc.) mixed acid anhydride, phosphite diester (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite,
A mixed acid anhydride with diphenylphosphite, etc.) is also used. In the acylation means using this reactive derivative, the solvent, the catalyst, the reaction temperature, the reaction time and the like are the same as those in the acylation performed in the presence of the carbodiimides and the like.

The starting compound (I-
1) is, for example, European Published Patent 334,636, European Published Patent 400,562, European Published Patent 402,903, European Published Patent 418,924,
European Published Patent 431,953, European Published Patent 434,426, European Published Patent 438,26
1, US Patent 4,996,206, US Patent 5,02
8, 608, etc., or the literature [JA Secrist III and PS Liu, Journal of Organic Chemistry (Journal of Organic
Chemistry), vol. 43, pp. 3937-3941 (1978); B. Roth,
R. Laube, MY Tidwell, and BS Rauckman, Journal of Organic Chemistry
of Organic Chemistry), Vol. 45, p. 3651-3657 (198)
[0)] It can also be produced according to a known method. Also,
The starting compound (I-2) is prepared by a method known in the literature [JP Greenst
ein and M. Winitz, Chemistry of the Amino
Acids Volume 1-3 (Chemistry of the Amino Acids
vol. 1-3), John Wiley & Sons, Inc., New York, Lond
on (1961)]. Further, among the compounds (I) of the present invention, the compound in which m = 1 is, for example, European published patent 334,636, European published patent 400,562, European published patent 40.
2,903, European Published Patent 418,924, European Published Patent 431,953, European Published Patent 4
34,426, European Published Patent 438,261, US Patent 4,996,206, US Patent 5,028,60.
It can also be directly produced by the method described in No. 8 or the like.

Of the compounds (I) or salts thereof, B,
When producing a compound or a salt thereof containing a hydroxy group, an amino group, a mercapto group, a carboxy group or the like as a substituent of Y, Z, W and R ¹ , or a compound or a salt thereof in which —COOR ¹ is a carboxy group When producing compound (I-1) and compound (I-
The hydroxy group, amino group, mercapto group or carboxy group of 2) is protected with a protecting group known per se, and then subjected to an acylation reaction, and then subjected to a deprotection reaction known per se to obtain the desired compound (I) or It is also possible to produce the salt. Reactions carried out or used in each manufacturing step,
Reagents, reaction conditions, application of protective groups to each functional group used as necessary, and the like are known and described in detail in the following documents. [JFW
McOmine, Protective Groups in Organic Chemistry
Chemistry), Plenum Press, London and New York (1
973)], [Pine Hendrickson Hammond, Organic Chemistry (4th Edition) [I]-[II], Hirokawa Shoten (1982)] and [M. Fieser and L. Fieser, Regent Fore Organic. Synthesis Volume 1-13 (Reagents
for Organic Synthesis vol. 1-13), Wiley-Intersci
ence, New York, London, Sydney and Toronto (1969-1
988)] Furthermore, in the compound (I), the amino group, hydroxy group or mercapto group represented by X can be converted into each other, if necessary, by a substituent conversion reaction on the pyrimidine ring known in the literature. [Separate Volume Protein Nucleic Acid Enzyme, Chemical Synthesis of Nucleic Acid, Kyoritsu Shuppan (1968)] Each of the intermediates of the compound of the present invention and the compound of the present invention (I) produced by the above-mentioned method can be separated by a conventional separation means such as concentration, solvent extraction,
It can be isolated from the reaction mixture by chromatography, recrystallization and the like.

The compound (I) obtained by the production method of the present invention may form a salt. As the salt with a base, for example, an alkali metal, an alkaline earth metal, a non-toxic metal, ammonium or substituted ammonium is used, and specifically, for example, sodium, potassium, lithium, calcium, magnesium, aluminum, zinc,
Examples thereof include salts with ammonium, trimethylammonium, triethylammonium, triethanolammonium, pyridinium, and substituted pyridinium. Examples of salts with acids include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p
-Salts with organic acids such as toluenesulfonic acid and camphorsulfonic acid are used.

Further, the compound (II) or its salt used as a preferred compound of the present invention is, for example, EP-A-334,636 or EP-A-4.
00,562, European Published Patent 402,903, European Published Patent 418,924, European Published Patent 431,953, European Published Patent 434,426,
European Published Patent 438,261, US Patent 4,99
6,206, the method described in US Pat. No. 5,028,608, or the formula (II-1):

[Chemical 25] [The symbols in the formulas have the same meaning as in compound (II). ] It can be obtained by acylating an oligoglutamic acid derivative represented by the following formula with a carboxylic acid represented by the formula (I-1) or a reactive derivative at its carboxy group. Examples of the acylation means include a method of acylating compound (II-1) with compound (I-1) or a reactive derivative thereof in the presence of carbodiimides, diphenylphosphoric acid azide or diethyl cyanophosphate. Is used. Compound
The amount of (II-1) used is generally about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (I-1) or its reactive derivative. The carbodiimide, diphenylphosphoryl azide or diethyl cyanophosphonate may be used generally in an amount of about 1 to 25 mol, preferably about 1 to 5 mol, per 1 mol of the compound (I-1) or its reactive derivative. As the carbodiimides, dicyclohexylcarbodiimide is practically preferable, and other carbodiimides such as diphenylcarbodiimide, di-o-tolylcarbodiimide, di-p-tolylcarbodiimide, di-tert-butylcarbodiimide, 1-
Cyclohexyl-3- (2-morpholinoethyl) carbodiimide, 1-cyclohexyl-3- (4-diethylaminocyclohexyl) carbodiimide, 1-ethyl-3
-(2-Diethylaminopropyl) carbodiimide, 1-ethyl-3- (3-diethylaminopropyl) carbodiimide and the like may be used.

This acylation reaction is preferably carried out in the presence of a suitable solvent, and examples of the solvent include, for example,
Water, alcohols (eg, methanol, ethanol), ethers (eg, dimethyl ether, diethyl ether,
Tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (eg acetonitrile), esters (eg ethyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (eg benzene) , Toluene, xylene), acetone,
Nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used. This reaction is usually carried out at about pH 2 to 14, preferably pH.
It is preferable to carry out H in the range of about 6 to 9. Reaction temperatures in the range of about -10 ° C to the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C are used.
The reaction can be carried out for about 1 to 100 hours, preferably about 2 to 48 hours. After the reaction, the pH may be acid (eg,
Hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid), bases (eg sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate) , Sodium hydrogen carbonate, trimethylamine, triethylamine, triethanolamine, pyridine) or a buffer solution (eg, phosphate buffer solution, borate buffer solution, acetic acid buffer solution) or the like, if necessary.

This reaction can be proceeded more advantageously by using a catalyst capable of promoting acylation. Examples of such a catalyst include a base catalyst and an acid catalyst. Examples of such a base catalyst include tertiary amines (eg, aliphatic tertiary amines such as triethylamine; pyridine, α-, β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine,
4- (1-pyrrolidinyl) pyridine, aromatic tertiary amines such as dimethylaniline and diethylaniline) and the like, and examples of the acid catalyst include Lewis acids [eg,
Anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ ), anhydrous ferric chloride, titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, trifluorofluoride Silicon etherate, etc.] and the like. Of the above catalysts, 4-dimethylaminopyridine or 4- (1-pyrrolidinyl) pyridine is often preferred. The amount of the catalyst used is such that it is a catalyst capable of promoting the acylation, and is usually about 0.01-10 mol, preferably about 0.1-1 mol, relative to 1 mol of the compound (I-1) or its reactive derivative. It is 1 mol. Examples of the reactive derivative at the carboxy group of the compound (I-1) include, for example, acid halides (eg, fluoride, chloride, bromide, iodide, etc.) of carboxylic acid (I-1), acid anhydrides (eg, anhydrous iodo). Acetic acid, isobutyric anhydride, etc., lower monoalkyl carbonate (eg, monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono iso-propyl carbonate, monobutyl carbonate, mono iso-butyl carbonate, mono) sec-Butyl carbonate, mono-tert-butyl carbonate, etc.) mixed acid anhydride, active ester (eg, cyanomethyl ester, carboethoxymethyl ester, methoxymethyl ester, phenyl ester, o-nitrophenyl ester, p- Nitrophenyl ester, p-carbomethoxyphenyl Ester, p- cyanophenyl ester, thiophenyl ester, etc.), acid azide, diester phosphate (eg, dimethyl phosphate, diethyl phosphate,
(Dibenzyl phosphate, diphenyl phosphate, etc.)
And mixed acid anhydrides with phosphite diesters (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite, diphenyl phosphite, etc.). In the acylation means using this reactive derivative, the solvent, catalyst, reaction temperature and the like are the same as those in the case of the acylation performed in the presence of the above-mentioned carbodiimide, diphenylphosphoryl azide or diethyl cyanophosphonates.

Of the compound (II) or its salt,-
The compound in which both COOR ¹ and —COOR ² are carboxy groups is, for example, —COOR ^{1 in the} compound (II-1).
And a compound in which —COOR ² is an esterified carboxy group are reacted with the above compound (I-1) or a reactive derivative at the carboxy group, and then subjected to a decomposition reaction or a catalytic reduction reaction known per se. It can also be produced by deesterification. As the decomposition reaction, for example, a hydrolysis reaction (A
Method), a hydrolysis reaction under acidic conditions (method B-1),
A decomposition reaction (B-2 method) and the like under acidic non-aqueous conditions can be mentioned. Examples of the base used in Method A include sodium methoxide, sodium ethoxide,
Metal alkoxides such as sodium butoxide and potassium butoxide, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, and amines such as ammonia, triethylamine and pyridine are mentioned. Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfone. Examples of the acid used in the B-2 method include mineral acids such as hydrogen chloride, hydrogen bromide, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid and trichloroacetic acid. , Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphors Organic acids such as acid, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl _3), anhydrous ferric chloride, titanium tetrachloride (TiCl _4), tin tetrachloride (SnC
l ₄ ), antimony pentachloride, cobalt chloride, cupric chloride,
Lewis acids such as boron trifluoride etherate may be mentioned. In any case, the decomposition reaction is carried out in a suitable solvent at 0 ° C to the boiling point of the solvent, preferably 10 to 80 ° C.
It is carried out by reacting for 30 minutes to 2 days. As the reaction solvent, in the case of Method A and Method B-1, for example,
Water, methanol, ethanol, propanol, butanol, ethylene glycol, methoxyethanol, ethoxyethanol, tetrahydrofuran, dioxane, monoglyme, diglyme, pyridine, dimethylformamide,
Dimethyl sulfoxide, sulfolane or an appropriate mixture thereof is used, and in the case of Method B-2, for example,
Ethyl acetate, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene, xylene, nitromethane, pyridine or an appropriate mixed solvent thereof is used.

The catalytic reduction reaction (method C) is carried out using a suitable solvent at a temperature in the range of about -40 ° C to the boiling point of the reaction solvent, more preferably about 0 to 50 ° C. As the solvent used, water, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert.
-Butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol, etc.), acetic acid esters (eg, methyl acetate, ethyl acetate, etc.), ethers (eg,
Examples thereof include dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), pyridine, dimethylformamide, and an appropriate mixed solvent thereof. As the catalyst for catalytic reduction, for example, palladium, platinum, rhodium, Raney nickel, etc. are used. At this time, the reaction may be allowed to proceed advantageously by adding a slight amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like. -COOR ¹
It depends on the properties of -COOR ¹ and -COOR ² in the starting compound (I-1) whether or not it is derived to a compound or a salt thereof in which both and -COOR ² are carboxyl groups, but it is usually the compound (I-1). -COOR ¹ and -COOR ^{2 in} are methyl, ethyl, propyl, butyl, s
Method A or B-1 in the case of a carboxy group esterified with ec-butyl, phenyl or a substituted phenyl group
Method, when -COOR ¹ and -COOR ² are carboxy groups esterified by iso-propyl or tert-butyl group, B-2 method; and when carboxy groups esterified by benzyl group or substituted benzyl group The method B-1 or the method C is advantageously applied. In addition, -CO
When OR ¹ and -COOR ² are different, the above method A, B-
The method 1, the method B-2 and the method C may be appropriately combined.

The starting compound (II-1) used in this reaction is a method known in the literature [JP Greenstein and M. Winitz, Chemistry.
Of The Amino Acids Volume 1-3 (Chemistry
of the Amino Acids vol. I-3), John Wiley & S
ons, Inc., New York, London (1961)]. Regarding the application of a protecting group for each functional group used as necessary in each of the above production steps, a method known in the following documents can be used [JFW McOmine] , Protective Groups in Organic Chemistry (Protective
Groupsin Organic Chemistry), Plenum Press and Ne
w York (1973)], [Pine Hendrickson Hammond, Organic Chemistry (4th Edition) [I]-[II], Hirokawa Shoten (1)
982)] and [M. Fieser and
L. Fieser), Regent for Organic
Synthesis Volume 1-13 (Reagents for Organic Synt
hesis vol. 1-13), Wiley-Interscience, New Yo
rk London Sydneyand Toronto (1969-198)
8)]. Further, in the compound (II) or a salt thereof, the amino group, hydroxy group or mercapto group represented by X can be converted into each other, if necessary, by a substituent conversion reaction on the pyrimidine ring known in the literature [Separate volume Protein Nucleic acid enzyme, chemical synthesis of nucleic acid, Kyoritsu Publishing].

The compound (II) may form a salt. Salts of bases include alkali metals, alkaline earth metals, non-toxic metals, ammonium and quaternary ammonium such as sodium, potassium, lithium, calcium,
Examples thereof include salts with magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium, pyridinium and substituted pyridinium. Examples of the acid salt include mineral acid salts with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. , And salts with organic acids such as camphor sulfonic acid. Among the salts, pharmacologically acceptable salts such as salts with alkali metals such as potassium, sodium and calcium, alkaline earth metals and the like are particularly preferable. Further, the compound (III) or a salt thereof used as a preferred compound of the present invention is, for example,

[Chemical formula 26] [The symbols in the formulas have the same meaning as in compound (III). ] The compound (III-1) represented by
It is obtained by acylation with 1) or its salt or a reactive derivative at the carboxyl group. As the acylation means, for example, a method of acylating the compound (III-1) or a salt thereof with the compound (I-1) or a salt thereof or a reactive derivative at a carboxyl group is used. This reaction can also be carried out in the presence of carbodiimides, diphenylphosphoric acid azide, diethyl cyanophosphoric acid and the like. The amount of compound (III-1) or a salt thereof used is generally about 1-20 molar equivalents, preferably about 1-5, relative to compound (I-1) or a salt thereof or a reactive derivative of the carboxyl group. It is a molar equivalent. The carbodiimides, diphenylphosphoric acid azide, diethyl cyanophosphate, etc. are generally about 1-25 molar equivalents, preferably about 1-5 molar equivalents with respect to the compound (I-1) or its salt or the reactive derivative at the carboxyl group. The equivalent amount should be used.

As the carbodiimides, dicyclohexylcarbodiimide is practically preferable, and other carbodiimides such as diphenylcarbodiimide and di-o.
-Tolyl carbodiimide, di-p-tolyl carbodiimide,
Di-tert-butylcarbodiimide, 1-cyclohexyl-3-
(2-morpholinoethyl) carbodiimide, 1-cyclohexyl-3- (4-diethylaminocyclohexyl) carbodiimide, 1-ethyl-3- (2-diethylaminopropyl) carbodiimide and 1-ethyl-3- (3-diethylaminopropyl)
You may use carbodiimide etc. The present acylation reaction can also be carried out in the presence of an appropriate solvent, and examples of the solvent include water, alcohols (eg, methanol,
Ethanol, etc.), ethers (eg, dimethyl ether,
Diethyl ether, tetrahydrofuran, dioxane,
Monoglyme, diglyme, etc.), nitriles (eg, acetonitrile, etc.), esters (eg, ethyl acetate, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), aromatic hydrocarbons (eg, benzene) , Toluene, xylene, etc.), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof. This reaction is usually p
H is carried out in the range of about 2 to 14, preferably about pH 6 to 9. Usually about -10 ° C to the boiling point of the reaction solvent
It is carried out at reaction temperatures (up to about 100 ° C.), preferably in the range of about 0 to 50 ° C. Usually, the reaction can be carried out for about 1 to 100 hours. The pH of the reaction solution may be, for example, an acid (eg,
Hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, etc.), base (eg, sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, Adjust as necessary with barium carbonate, calcium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, triethanolamine, pyridine, etc. or buffer (eg, phosphate buffer, borate buffer, acetate buffer, etc.) To do. In addition, the reaction can be proceeded more advantageously by using a catalyst capable of promoting acylation.

As such a catalyst, for example, a base catalyst or an acid catalyst is used. Examples of such base catalysts include tertiary amines (eg, aliphatic tertiary amines such as triethylamine; pyridine, α-, β- or γ-picoline, 2,
6-lutidine, 4-dimethylaminopyridine, 4- (1
-Pyrrolidinyl) pyridine, aromatic tertiary amines such as dimethylaniline, diethylaniline, etc.) are used, and examples of the acid catalyst include Lewis acids (eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ ), anhydrous tertiary chloride). Diiron, titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc. are used. Of the above catalysts, 4-dimethylaminopyridine or 4- (1-pyrrolidinyl) pyridine is often preferred. The amount of the catalyst used is preferably a catalytic amount capable of promoting acylation, and is usually about 0.01-10 molar equivalents relative to compound (I-1) or a salt or a reactive derivative of the carboxy group,
It is preferably about 0.1-1 molar equivalent. Compound (I-
Examples of the reactive derivative at the carboxyl group of 1) or a salt thereof include, for example, an acid halide (eg, fluoride, chloride, bromide, iodide, etc.) of a compound (I-1) or a salt thereof, an acid anhydride (eg, anhydrous iodine). -Doacetic acid, isobutyric anhydride, etc.), lower monoalkyl carbonate
(Examples: monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono iso-propyl carbonate, monobutyl carbonate, mono iso-butyl carbonate, mono sec-butyl carbonate, mono t
ert-butyl carbonate, etc.), active ester (eg, cyanomethyl ester, ethoxycarbonylmethyl ester, methoxymethyl ester, phenyl ester, o-nitrophenyl ester, p-nitrophenyl ester, p-carbomethoxy ester) Phenyl ester, p-cyanophenyl ester, phenyl thioester, succinimide ester, etc.), acid amide, phosphoric acid diester (eg, dimethyl phosphate, diethyl phosphate, dibenzyl phosphate, diphenyl phosphate) -, Etc.), mixed acid anhydrides with phosphite diesters (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite, diphenyl phosphite, etc.) and the like are also used. In the acylation means using this reactive derivative, the solvent, the catalyst, the reaction temperature, the reaction time and the like are the same as those in the acylation performed in the presence of the carbodiimides and the like.

Of the compound (III) or a salt thereof, a compound containing a hydroxy group, an amino group, a mercapto group, a carboxyl group or the like as a substituent of the cyclic or chain group represented by R ⁴ or a salt thereof is used. In the case of production, or in the case of producing a compound in which COOR ¹ is a carboxyl group or a salt thereof, the hydroxy group, amino group, mercapto group or carboxyl group of compound (III-1) or a salt thereof is protected with a protecting group known per se. After that, the compound (I-1) or a salt thereof or a reactive derivative at the carboxy group may be reacted, and then subjected to a deprotection reaction known per se to produce the desired compound (III) or a salt thereof. .

Next, a method for producing the starting compound (I-1) or a salt thereof or a reactive derivative at the carboxy group will be described. Compound (I-1) or a salt thereof or a reactive derivative at the carboxy group can also be produced, for example, by the reaction steps shown below.

[Chemical 27] In the above formula, A ring, B, X, Y and Z have the same meaning as defined above, as the R ⁶ in esterified carboxyl group which may be represented by COOR ^6, a hydrogen atom or COOR ² more It may be a lower alkyl group having 1 to 6 carbon atoms as described above, a benzyl group which may have a substituent or a phenyl group which may have a substituent. D and E are groups which can bond to each other to form Z. In the above reaction step, a covalent bond is formed between D and E, which may have a substituent represented by Z, and one hetero atom may be interposed in the chain portion. It is possible to produce divalent aliphatic groups having not more than 5 chain-constituting atoms in series. As a synthetic method for forming a covalent bond between the compound (V) or a salt thereof and the compound (VI) or a salt thereof, Z may have a chain-constituting atom which does not exceed 5 in series and may have a substituent. Regarding the divalent aliphatic group having,

[Chemical 28] When D = E 'and E = D' together, a so-called carbon-containing compound (V) or a salt thereof and (VI) or a salt thereof is used.
Compound (IV) or a salt thereof can be produced by subjecting it to a carbon bond-forming reaction and then subjecting the resulting product to a reduction reaction if necessary.

In the above formula, a, b, f, g (= a + b) and f + g represent an integer within the range of 0 to 3, G represents phenyl, butyl or cyclohexyl and M represents ethyl or phenyl. R ⁷ , R ⁸ and R ⁹ are the same or different and each is a bond, a hydrogen atom or Z described in detail.
Substituents similar to those of the divalent lower hydrocarbon group represented by ¹ , Z ³ and the lower hydrocarbon group represented by R ⁵ are used and may be different from each other in f and g repetitions. For the in group composed, - Z is Z = -Z ¹ -Z ² -Z ³

[Chemical 29] In the case, or vice versa, D = E 'and E = D'
In the case of, a so-called alkylation type reaction is used,

[Chemical 30] , Or vice versa, D = E ³ and E = D ³
In this case, a method of forming a Schiff base or an enamine and reducing it if necessary, or directly subjecting it to a reductive alkylation reaction is used.

In the above formula, f, g, f + g, R ⁵ , R ⁷ , R
⁸ and R ⁹ are as defined above, g + 1 is an integer in the range of 1 to 4, L is a leaving group, and R ¹⁰ and R ¹¹ are the same or different and each is a hydrogen atom or a hydrocarbon group. .
The leaving group represented by L is, for example, a leaving group which can be easily derived from a halogen atom (eg, chlorine atom, bromine atom, iodine atom, etc.) or a hydroxy group (eg,
Methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyl group, etc.) are used. R ¹⁰ and R
^The hydrocarbon group represented by ¹¹ may have a substituent, and R ¹⁰ and R ¹¹ may form a cyclic amino group together with the adjacent nitrogen atom. Examples of the hydrocarbon group represented by R ¹⁰ and R ¹¹ include an alkyl group having 1 to 18 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 1,2-dimethylpropyl, 1-ethylpropyl,
1,2,2-trimethylpropyl, 1-propylbutyl, 2
-Ethylhexyl group, etc.), alkenyl group having 1 to 12 carbon atoms (eg, vinyl, allyl, 1-methylvinyl, 2-
Methyl vinyl, 1-octenyl, 1-decenyl group, etc.), C3-C12 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, andamantyl group, etc.), C3 To 8 cycloalkenyl groups (eg,
Cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl groups, etc., aralkyl groups having 7 to 13 carbon atoms (eg, benzyl, α-methylbenzyl, Phenethyl, diphenylmethyl group, etc., and an aryl group having 6 to 10 carbon atoms (eg, phenyl, α-naphthyl, β-naphthyl group, etc.) and the like. The cyclic amino group formed by R ¹⁰ and R ¹¹ together with the adjacent nitrogen atom is preferably a 4- to 10-membered ring, and examples thereof include azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolinyl, piperidino, morpholino, dihydropyridyl. , Tethydropyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, azacycloheptyl,
Azacyclooctyl, isoindolyl, indolyl, indolinyl, 2-isoindolinyl, azacyclononyl,
An azacyclodecyl group or the like is used.

[0052] ring hydrocarbon residue represented by these R ¹⁰ and R ¹¹ or is the R ¹⁰ and R ^11, to form together with the adjacent nitrogen atom may be 1 to have two substituents . Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group, etc.), an alkoxy group having 1 to 4 carbon atoms. (Eg methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-
Butoxy group, etc.), alkanoyl group having 1 to 4 carbon atoms (eg, formyl, acetyl, propionyl, n-butyryl, iso-butyryl group, etc.), alkanoyloxy group having 1 to 4 carbon atoms (eg, formyloxy) , Acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy group, etc.), carboxy group, C2-4
Alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl group, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), halogen atom (eg, fluorine, Chlorine, bromine, iodine, etc.), hydroxy group, nitro group, cyano group, trifluoromethyl group,
Amino group, mono-substituted amino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino group, etc.), di-substituted amino group (eg, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino group) Etc.), alkanoylamide group (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide group, etc.), carbamoyl group, N-substituted carbamoyl group (eg, N-methylcarbamoyl, N- Ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl group, etc.), N,
N-disubstituted carbamoyl group (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, 1-
Achiridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl groups, etc.), carbamoyl amino groups, N-substituted carbamoylamino groups ( Example, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino group, etc., N, N-disubstituted carbamoylamino group (eg, N, N-dimethylcarbamoylamino, N, N-diethylcarbamoylamino,
N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, 1-acetylidinylcarbonylamino, 1-azetidinylcarbonylamino, 1-pyrrolidinylcarbonylamino, 1-piperidinylcarbonylamino, N -Methylpiperazinylcarbonylamino, morpholinocarbonylamino group, etc.), mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, N
-Substituted sulfamoyl group (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl group, etc.), N, N-disubstitutedsulfamoyl group A group (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl,
N, N-dibutylsulfamoyl, 1-pyrrolidinylsulfonyl, 1-piperidinylsulfonyl, N-methyl-1-piperazinylsulfonyl, morpholinosulfonyl group, etc.),
An alkylthio group having 1 to 4 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio group, etc.), an alkylsulfinyl group having 1 to 4 carbon atoms (eg, Methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl group, etc.), an alkylsulfonyl group having about 1 to 4 carbon atoms (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl group, etc.) and the like are used.

The first step will be described in detail below.
Condensation reaction by carbon-carbon bond formation is a known reaction (eg,
Aldol reaction, Reformatsky reaction, Wittig reaction, etc.) are used, and the reduction reaction is usually a catalytic reduction reaction or a hydride reduction reaction.
When the aldol reaction is used as the condensation reaction, examples of the base catalyst include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide, sodium amides, metal amides such as lithium diisopropylamide, metal hydrides such as sodium hydride and potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α
-, Β- or γ-picoline, 2,6-lutidine, 4-
Amines such as dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, dimethylaniline and diethylaniline are used, and examples of the acid catalyst include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, and citric acid. Organic acids such as acids, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid are used. In addition, known methods [Ei-Ichi Negishi, Organometallics in Organic Syn
thesis vol.1, John Wiley & Sons, New York, Chiches
ter, Brisbane, Tronto (1980)] to convert a ketone compound to a silyl enol ether compound, and to obtain a Lewis acid [eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ ), anhydrous ferric chloride, titanium tetrachloride (TiCl ₄₎ ), Tin tetrachloride (SnC
l ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.], fluorine anions (eg,
Tetrabutylammonium fluoride) or trityl perchloride in the presence of an aldehyde or an equivalent thereof, or a ketone is converted into an amine (eg, triethylamine, pyridine, α-, β- or γ-). In the presence of picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, dimethylaniline, diethylaniline, etc., a metal triflate (eg, dialkylboron triflate, tin (I
It can also be carried out by treating with I) a triflate or the like) to convert it into an enolate, and then subjecting it to a condensation reaction with an aldehyde or its equivalent. The condensation reaction is carried out in an appropriate solvent,
From -100 ° C to the boiling point of the solvent, preferably -78-1
It is carried out by reacting in the range of 00 ° C for 1 minute to 3 days. Examples of the reaction solvent include water, liquid ammonia, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-
Butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol, etc.), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.) Carbon tetrachloride, etc.), aliphatic hydrocarbons (eg, pentane, hexane, heptane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), acetonitrile, nitromethane, dimethylformamide, dimethylsulfoxide, hexamethylphosphole Amide, sulfolane or an appropriate mixed solvent thereof is used.
When the Wittig reaction is used as the condensation reaction, examples of the reagent include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-. Metal alkoxides such as butoxide, sodium amide, metal amides such as lithium diisopropylamide, sodium hydride, metal hydrides such as potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-,
Amines such as β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, dimethylaniline and diethylaniline are used. The reaction is carried out in an appropriate solvent at −20 ° C. to the boiling point of the solvent, preferably in the range of 0 to 150 ° C.
It is carried out by reacting for -10 minutes per minute. Examples of the reaction solvent include liquid ammonia, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol, etc.), Ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), aliphatic hydrocarbons (eg, pentane, hexane, heptane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.)
Xylene, etc.), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof is used. Furthermore, the condensation can also be carried out using the Reformatsky reaction. As the reaction conditions of the Reformatsky reaction, for example, zinc, magnesium, aluminum, tin, etc. are used as a reagent, and the reaction itself is carried out in an appropriate solvent from −20 ° C. to the boiling point of the solvent, preferably 0 to 150. 30 ° C in the range
It is carried out by reacting for 3 minutes to 3 minutes. Examples of the reaction solvent include ethers (eg, dimethyl ether,
Diethyl ether, tetrahydrofuran, dioxane,
Monoglyme, diglyme, etc.), aliphatic hydrocarbons (eg, pentane, hexane, heptane, etc.), aromatic hydrocarbons (eg,
Benzene, toluene, xylene, etc.) or an appropriate mixed solvent thereof is used.

In the alkylation type reaction or transamine type reaction, the compound (V) or a salt thereof and the compound (VI) or a salt thereof are used by themselves or in a suitable reaction solvent at about -10.
℃ to the boiling point of the reaction solvent, preferably about 10-80 ℃
The reaction is carried out at a temperature in the range of about 10 minutes to 48 hours. The compound (VI) or its salt is used in a proportion of about 1-mole relative to 1 mol of the compound (V) or its salt.
It is 50 mol, more preferably about 1-10 mol. As the reaction solvent, for example, water, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert-
Butyl alcohol, ethylene glycol, methoxy ethanol, ethoxy ethanol, etc., ethers (eg,
Diethyl ether, tetrahydrofuran, dioxane,
Monoglyme, diglyme, etc.), halogenated hydrocarbons (eg,
Dichloromethane, chloroform, carbon tetrachloride, etc.), nitriles (eg, acetonitrile, etc.), aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane, etc.),
Cycloaliphatic hydrocarbons (eg, cyclopentane, cyclohexane, etc.), aromatic hydrocarbons (eg, benzene, toluene,
Xylene, etc.), nitromethane, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane, etc., or an appropriate mixed solvent thereof is used. Further, if necessary, it may be better to carry out the reaction in the presence of a base. As the base used, for example, the base used in the Wittig reaction and the like are used. Furthermore, about 0.01 to 0.2 equivalents, preferably about 0.02 to 0.05 equivalents, of a phase transfer catalyst (eg, cetyltrimethylammonium) relative to compound (V) or a salt thereof or compound (VI) or a salt thereof. The reaction can be advantageously proceeded by using chloride).
In the case of an amine exchange type reaction, compound (V) or a salt thereof is converted to a quaternary salt such as methyl bromide, methyl iodide, methyl methanesulfonate, methyl benzenesulfonate, and methyl p-toluenesulfonate. Then, the reaction may be allowed to proceed under more mild conditions. In the reaction for forming the Schiff base, the compound (V) or a salt thereof and the compound (VI) or a salt thereof are in a molar ratio (V) / (VI) = 10 to 10.
Around 0.1, using itself or a suitable reaction solvent
From -10 ° C to the boiling point of the reaction solvent, preferably 0-5
The reaction is carried out at a temperature in the range of 0 ° C. for about 10 minutes to 48 hours. In this reaction, compounds in which the aldehyde or ketone moiety of compound (V) or a salt thereof and (VI) or a salt thereof are protected in the form of acetal or ketal may be used. The reaction solvent is preferably a non-aqueous solvent, for example, alcohols (eg, methanol, ethanol, propanol, is
o-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol,
Methoxyethanol, ethoxyethanol, etc.), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), esters (eg, methyl acetate, ethyl acetate, etc.),
Halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), Nitriles (eg, acetonitrile, etc.), Aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane, etc.), Cyclic aliphatic hydrocarbons (eg. , Cyclopentane, cyclohexane, etc.), aromatic hydrocarbons (eg,
Benzene, toluene, xylene, etc.), acetone, nitromethane, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane, etc. or an appropriate mixed solvent thereof is used. As the dehydrating agent, for example, molecular sieves, calcium chloride, magnesium sulfate, sodium sulfate, calcium sulfate, or the like is added, or the pH of the reaction solution is appropriately adjusted by adding an acid (eg, hydrochloric acid, hydrobromic acid, hydrogen iodide Acid, sulfuric acid,
Nitric acid, phosphoric acid, etc.), base (eg, metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, carbonic acid) Potassium, barium carbonate, calcium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, triethanolamine, pyridine, etc.) or buffer solution (eg,
The reaction rate and the yield can be improved by adjusting with a phosphate buffer solution, a borate buffer solution, an acetate buffer solution, etc.). The reduction reaction of the Schiff base and the reductive alkylation reaction are carried out by hydride reduction or catalytic reduction using a suitable solvent at a reaction temperature of about -40 ° C to the boiling point of the solvent, more preferably about 0 to 50 ° C. . As the solvent used, acetic acid esters (eg, methyl acetate, ethyl acetate, etc.) and the like are used in addition to the reaction solvent used in the above-mentioned alkylation type reaction or amine exchange type reaction. The catalytic reduction reaction is carried out at about -40 ° C using an appropriate solvent.
To the boiling point of the reaction solvent, more preferably about 0-50 ° C.
Is carried out at a temperature range of As the solvent, water, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol, etc.),
Acetates (eg, methyl acetate, ethyl acetate, etc.), ethers (eg, dimethyl ether, diethyl ether,
Tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), pyridine, dimethylformamide, and an appropriate mixed solvent thereof are used. As the catalyst for catalytic reduction, for example, palladium, platinum, rhodium, Raney nickel, etc. are used. At this time, the reaction may be allowed to proceed advantageously by adding a slight amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like. As the hydride reduction reagent, for example, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, etc. are used, the amount of the reducing reagent used, relative to the substance to be reduced,
This mole is about 100-fold mole, and usually 2-20-fold mole is used.

When ring A is furan, thiophene, thiophene-1-oxide, thiophene-1,1-dioxide or N-substituted pyrrole ring and --Z ² --is --NH--, its --HN-- group is A. The ring may be condensed and closed to form a tricyclic compound (eg, pyrrolo [3 ′, 2 ′: 4,5] pyrrolo [2,3-d] pyrimidine compound). In this case, the desired bicyclic compound can be easily converted by treating with an acid or a base. Second Step The compound (IV) or a salt thereof obtained in the first step is subjected to a deprotection reaction known per se using the ester residue [—COOR ⁶ ] thereof in the production of the compound (III) or a salt thereof. Then
It can be converted to the compound (I-1) or a salt thereof. The starting compound (I-1) or a salt thereof can also be produced, for example, by the reaction steps shown below.

[Chemical 31]

In the above step, A ring, B, R ⁶ , X, Y and Z have the same meanings as described above, J ¹ and J ² are the same or different and are oxygen or sulfur, and R ¹² and R ¹³ are Identical or different hydrocarbon groups, L'is a halogen atom (eg,
Chlorine, bromine, iodine), T is a cyano group or formula-C
OOR ¹⁴ , —CSOR ¹⁴ or —CSSR ¹⁴ group [in the formula,
R ¹⁴ represents a hydrocarbon residue. ] And R'and R "are the same or different and each is a hydrogen atom or a substituent on the A ring, and are described in detail as an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, or a carbon number. 2 to 3 alkynyl groups or cyclopropyl groups are shown.
As the hydrocarbon group represented by R ¹² , R ¹³ and R ¹⁴ ,
A lower alkyl group having 1 to 5 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, tert-pentyl groups, etc.), benzyl groups or phenyl groups are used.
These lower alkyl group, benzyl group or phenyl group may have 1 to 3 substituents. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine,
Iodine, etc.), nitro group, cyano group, alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-
Butoxy, tert-butoxy group, etc.), alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group, etc.), having about 1 to 4 carbon atoms Alkanoyl groups (eg,
Formyl, acetyl, propionyl, n-butyryl, iso-
Butyryl group, etc.), trifluoromethyl group, etc. are used. Hereinafter, the reaction step will be described in detail.

Third step

[Chemical 32] The amount used is generally about 0.5-4 molar equivalents, preferably about 0.8-1.5 molar equivalents. This reaction is carried out in the presence of an appropriate solvent at a reaction temperature of about -10 ° C to about the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C for about 30 minutes to 48 hours. It can be carried out. As the solvent used in the reaction, for example,
Alcohols (eg, methanol, ethanol, etc.), Ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), Nitriles (eg, acetonitrile, etc.), Esters (Eg, ethyl acetate, etc.), halogenated hydrocarbon (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), aromatic hydrocarbon (eg, benzene, toluene, xylene, etc.) or a suitable mixed solvent thereof is used. It During the reaction, it is possible to proceed more advantageously by adding light or an organic peroxide. Examples of the organic peroxide include t-butyl hypochloride, peracetic acid, perbenzoic acid,
Examples include p-chloroperbenzoic acid and the like. The compound (VIII) or a salt thereof thus obtained is relatively highly reactive and may be isolated at this stage, but it is also possible to proceed directly to the next step without isolation.

Fourth Step The compound (VIII) or its salt obtained in the third step is R
^In the presence of an alcohol or thiol represented by ^13- J ² -H and an appropriate solvent, the reaction solvent has a boiling point of about -10 ° C to about 100 ° C, preferably in the range of about 0 to 50 ° C. Compound (IX) or a salt thereof can be obtained by reacting at the reaction temperature of about 10 minutes to 24 hours. Examples of the solvent used in the reaction include ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.), nitriles (eg, acetonitrile, etc.), esters (eg, ethyl acetate, etc.) ), Halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), or an appropriate mixed solvent thereof or the like is used. Also, R
^The alcohol or thiol represented by ^13- J ² -H may be used in excess as a solvent.

Fifth step

[Chemical 33] [In the formula, Y has the same meaning as described above. ] When treated with a compound represented by the formula [1] or a salt thereof, it reacts with a cyano group, an ester group or a thioester group, and then undergoes cyclization to form a pyrimidine ring to form a compound (X) or a salt thereof.

Examples of the acid salt of compound (XI) include, for example,
Mineral salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, oxalic acid, tartaric acid, lactic acid, citric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid,
Organic acid salts with ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. are used, and as the base salt of the compound (XI-1: Y '= hydroxy group or mercapto group), For example, salts with sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium, pyridinium, substituted pyridinium and the like are used.

When the ring-closing is carried out under basic conditions, the reaction can proceed advantageously. As the base, for example, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like are used. The reaction solvent includes, for example, methanol, ethanol, propanol, tert-butyl alcohol, dimethylsulfoxide, hexamethylphosphoramide, etc., and the reaction temperature is 0-150 ° C, preferably 20-100 ° C,
The reaction time is 1-48 hours. Examples of the reaction solvent include methanol, ethanol, propanol,
Tert-butyl alcohol, dimethylsulfoxide, hexamethylphosphoramide, or the like, or an appropriate mixed solvent thereof or the like is used.

Sixth step

[Chemical 34] The compound (IV _N ) or a salt thereof can be converted to a compound (IV _N ) by spontaneously inducing an intramolecular ring closure reaction and a dehydration reaction with the X group on the pyrimidine ring. The carbonyl group-restoring reaction is carried out, for example, by using the compound (X) or a salt thereof per se or a suitable reaction solvent, from about −10 ° C. to about the boiling point of the reaction solvent (up to about 100 ° C.), preferably about About 10 minutes to 1 at a reaction temperature in the range of 0 to 50 ° C.
It can be carried out by subjecting it to a reversion reaction known per se for 00 hours. Intramolecular ring closure reaction and dehydration reaction in the step of producing compound (IV) or a salt thereof are usually carried out spontaneously with the X group on the pyrimidine ring after the step of restoring to the carbonyl group (> C = O) or after the restoration. Reacts to form ring A.
At this time, the presence of the acid catalyst also allows the reaction to proceed rapidly and in a high yield. As such an acid catalyst, a mineral acid, an organic acid, a Lewis acid, etc. which are described in detail in the aldol reaction are used. In addition, a carbonyl group (>
C = O) is reduced to give a hydroxymethyl group (> CHOH)
Then, after converting the hydroxy moiety into a leaving group L, it is subjected to an alkylation reaction with the X group in the molecule to form A
Compound (IV) in which the ring is partially reduced or a salt thereof can also be produced. Methods known per se are used for the reduction reaction of the carbonyl group, the conversion reaction of the hydroxy group into a leaving group, and the intramolecular alkylation reaction. In addition, the compound (I-1)
Or a salt thereof or (IV) or a salt thereof is subjected to a catalytic reduction reaction known per se to be partially reduced to a compound (I-1) or a salt thereof (IV) or a salt thereof in which the A ring is partially reduced. It can also be converted. Compound (I-1)
Alternatively, in the salt thereof, when ring A is a pyrrole or viroline ring, compound (X) or a salt thereof, or (IV)
Alternatively, it can be converted into a compound having an N-substituted pyrrole or N-substituted pyrroline ring, which is the compound of the present invention, by subjecting it to an alkylation reaction or an acylation reaction known per se at the stage of its salt. Further, a known compound [JP-A-02-167281] is used as a starting material to carry out the above-mentioned alkylation reaction or acylation reaction to produce a compound of the present invention in which the ring A is an N-substituted pyrrole or an N-substituted pyrroline ring. You can also do it.

The compound in which the A ring of the starting compound (I-1) or a salt thereof is composed of only carbon atoms can be produced, for example, by the reaction steps shown below.

[Chemical 35] In the above steps, ring A, B, R ⁶ , R ¹⁴ , R ′, R ″, X, Y
And Z have the same meanings as defined above, R ′, R ″ and —Z—
B-COOR ⁶ is assumed to be bonded to three consecutive positions on the cyclopentane ring.

Step 7 When compound (XII) or a salt thereof is heat-treated with dicyandiamide, a cyclization reaction occurs to form a condensed pyrimidine ring to obtain compound (IV _C1 ) or a salt thereof. In this case, the reaction temperature is 100 to 300 ° C., more preferably 1
It is 50-250 ° C., and the reaction time is suitably 1-24 hours. Further, if necessary, an unsaturated bond can be introduced into the A ring by dehydrogenating using a known reagent by a method known per se.

Step 8 Of the α-positions on both sides of the carbonyl group in compound (XII) or a salt thereof, R ', R "or -Z-B-COO.
The α-position hydrogen not substituted by R ³ is abstracted by a conventional method to form a carbanion, and an ester residue is introduced at the activated position to obtain the compound (XIII) or a salt thereof.

Step 9 When compound (XIII) or a salt thereof is treated with compound (XI) or a salt thereof, it reacts with a carbonyl group and an ester residue to cause condensation / cyclization to form a new condensed pyrimidine ring. A compound (IV _C2 ) or a salt thereof is obtained. The reaction conditions are the same as those used in the fifth step. Further, if necessary, an unsaturated bond can be introduced into the A ring by dehydrogenating using a known reagent by a method known per se.

The ester forms (IV _C1 ) and (IV _C2 ) or salts thereof obtained in the 7th and 9th steps are subjected to a deesterification reaction in the same manner as in the 2nd step to give the corresponding carboxylic acids. Can be converted. When B is a cycloalkenylene group or a phenylene group having a substituent, these groups are subjected to a catalytic reduction reaction known per se in an appropriate step among the first to ninth steps to convert them into a corresponding cycloalkylene group. May be. Y is hydroxy group, alkoxy group, aryloxy group, 5- or 6-membered heterocyclic oxy group, mercapto group, alkylthio group, arylthio group, 5- or 6-membered heterocyclic thio group, substituted amino group, alkanoylamino group, aroylamino A group or a 5- or 6-membered heterocyclic carbonylamino group, the second
Subject to a conversion reaction known per se in an appropriate step among the step, the sixth step, the seventh step or the ninth step, and a 5- or 6-membered heterocyclic group defined by Y, a halogen atom, a cyano group or a carboxy group , Carbamoyl group, nitro group, hydroxy group, alkoxy group, aryloxy group, 5 or 6
Membered heterocyclic oxy group, mercapto group, alkylthio group,
Arylthio group, 5- or 6-membered heterocyclic thio group, substituted amino group, alkanoylamino group, aroylamino group, 5
Alternatively, it may be converted to a 6-membered heterocyclic carbonylamino group, an alkanoyloxy group, an aroyloxy group or a 5- to 6-membered heterocyclic carbonyloxy group.

When the ring A and B contain a sulfur atom, and when -Z ² -is -S- (sulfur atom), the compound (III) of the present invention or a salt thereof can be directly subjected to an oxidation reaction or any possible method. subjected to the oxidation reaction at any step of the process, a ring, B and -Z ² - of the sulfur atom S (O)
It can be converted into a compound in which p-1 [p-1 = 1 to 2]. The oxidation reaction is usually 0.
In the presence of 3 to 3.0 equivalents, preferably 0.5 to 2.5 equivalents of an oxidizing agent, in a suitable solvent, at -10 to + 100 ° C, preferably 0 to + 50 ° C, for 10 minutes to 48 hours, preferably Can be produced by reacting for 30 minutes to 24 hours. As the oxidizing agent used in the reaction, peracids (eg, sodium metaperiodate, hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc.) are preferable. As the reaction solvent, water, acetic acid, ketones (eg, acetone, ethyl methyl ketone, etc.), ethers (eg, dimethyl ether, diethyl ether, dioxane, monoglyme, diglyme, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform) , Carbon tetrachloride, etc.), aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane, etc.), cycloaliphatic hydrocarbons (eg, cyclopentane, cyclohexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.) Xylene etc.), acetonitrile or an appropriate mixed solvent thereof is used. In addition, compounds (III) and (I
-1), (IV) or salts thereof, the amino group, hydroxy group or mercapto group represented by X can be converted into each other, if necessary, by a substituent conversion reaction on the pyrimidine ring known in the literature [ Separate volume Protein Nucleic Acid Enzyme, Nucleic Acid Chemical Synthesis, Kyoritsu Shuppan (1968)]. Next, a method for producing the raw material compound (III-1) or a salt thereof will be described. The raw material compound (III-1) or a salt thereof can be produced, for example, by the reaction steps shown below.

[Chemical 36] In the above formula, W ′, R ¹ , R ⁴ and n have the same meanings as described above. Q and V are groups capable of binding to each other to form an amide bond W. R ¹⁵ represents an amino-protecting group, R ¹⁶
Represents a protecting group for a carboxy group.

Step 10 This is a step of producing compound (XV) or a salt thereof by protecting the amino group and carboxy group of compound (XIV) or a salt thereof with a protecting group known per se. Examples of the amino-protecting group include salts with acids (eg, hydrochloride, sulfate, nitrate, phosphate, acetate, trifluoroacetate, p-toluenesulfonate, methanesulfonate, etc.) , Amides (eg, formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, etc.), imides (eg, phthaloyl, dithiasuccinoyl, etc.), Carbamates (eg, methoxycarbonyl, ethoxycarbonyl, isobutyroxycarbonyl,
tert-butoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, phenoxycarbonyl, etc.), benzyl groups (eg, benzyl, o-nitrobenzyl, diphenylmethyl, trityl, etc.), silyl groups (trimethylsilyl) , Triethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl, diisopropylmethylsilyl and the like) are used, and examples of the carboxy-protecting group include esters (eg, methyl, ethyl, propyl, isopropyl, butyl). , Se
c-butyl, isobutyl, tert-butyl, benzyl, p-nitrobenzyl, phenyl, etc., amides (eg, N, N-dimethylamide, pyrrolidinylamide,
Piperazinyl amide, etc.), silyl esters (eg, trimethylsilyl, triethylsilyl, dimethyl-ter)
t-butylsilyl, diphenyl-tert-butylsilyl, diisopropylmethylsilyl, etc.), metal salts (eg, sodium, lithium, potassium, calcium,
Barium, magnesium, copper, silver, etc.) and ammonium salts are used. Alternatively, the amino group and the carboxy group may be protected all at once with a copper salt. This reaction is carried out in the presence of a suitable solvent from about 20 ° C to about the boiling point of the reaction solvent,
Preferably, at a reaction temperature in the range of 0 to 80 ° C, about 1
The reaction can be carried out for 0 minutes to 48 hours. Examples of the solvent used in the reaction include water, alcohols (eg, methanol, ethanol, t-butanol, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, etc.),
Nitriles (eg, acetonitrile), esters (eg, ethyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene) Etc.), pyridine, dimethylformamide, dimethylsulfoxide, or an appropriate mixed solvent thereof and the like are used.

Eleventh step In the amide bond forming reaction of W ', a known reaction is used. In the compound (XV) or a salt thereof, (XVI) or a salt thereof, when Q is NH ₂ , V is a carboxy group or a reactive derivative thereof, or when Q is a carboxy group or a reactive derivative thereof, V Is NH ₂ .
The reactive derivative of the carboxy group or its reactive derivative has the same meaning as the reactive derivative represented by the compound (I-1) or its salt. Particularly, when a phthaloyl group is introduced, Nefken's reagent (Nefken's reagent) [Nature, 185, 309,
It is advantageous to use (1960). 12th step The compound (XVII) or its salt obtained in the 11th step is
The amino protecting group is [TW Green, Protective
Groups in Organic Synthesis (Protec
tive Groups in Organic Synthesis), John Wiley & S
ons, New York (1981)] and subjected to a known deprotection reaction to convert the compound (III-1) or a salt thereof. When both an amino group and a carboxy group are simultaneously protected with a copper salt, for example, decoppering with hydrogen sulfate, 6N hydrochloric acid, EDTA (ethylenediaminetetraacetic acid) or the like under acidic conditions is followed by esterification of the carboxy group. (III-1) or a salt thereof.

The reaction for forming the amide bond W'can also be carried out on the compound (XX) or a salt thereof.

[Chemical 37] In the above formula, X, Y, A ring, Z, B, R ¹ , n, W ′, R ⁴ ,
Q and V are as defined above. R ¹⁷ is a protecting group for the functional group Q, and when Q is an amino group, R ¹⁷ is, for example,
Carbamates (eg, methoxycarbonyl, etoxycarbonyl, proproxycarbonyl, isopropyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), amides (eg, chloroacetyl, etc.), silyl Groups (trimethylsilyl, triethylsilyl, dimethyl-
tert-butylsilyl, diphenyl-tert-butylsilyl, etc.) and Q is a carboxy group,
As R ¹⁷ , for example, esters (tert-butyl, benzyl, p-nitribenzyl, 2-trimethylsilylethyl, etc.) and the like are used.

Step 13: Compound (XIX) or a salt thereof and compound (XVIII) or a salt thereof are subjected to the same condensation reaction as in the production method of compound (III) or a salt thereof. The salt can be produced. 14th step The compound (XIX) or its salt obtained in the 13th step can be subjected to the deprotection reaction of the functional group Q in the same manner as in the 12th step to produce the compound (XX) or its salt. Fifteenth step The compound (XX) or a salt thereof obtained in the fourteenth step is subjected to an amide formation reaction known per se to form an amide bond W ′ from Q and V to produce a compound (III) or a salt thereof. be able to.

Further, regarding the reaction, the reagent, the reaction conditions and the application of the protecting group to each functional group used as necessary, etc., which are carried out or used in the first to fifteenth steps, or the manufacturing step of the starting material compound, , Which are known and explained in detail in the following documents. [J.
FM McOmine, Protective Groups In
Organic Chemistry (Protective Groups in Or
ganic Chemistry), Plenum PressLondon and New York
(1973)], [Pine Hendrickson Hammond, Organic Chemistry (4th Edition) [I]-[II], Hirokawa Shoten (1982)] and [M. Fieserand L. Fieser, Regent Fore Organic. Synthesis Volume 1-13 (Reagents
for Organic Synthesis vol. 1-13), Wiley-Interscie
nce, NewYork, London, Sydney and Toronto (1969-198)
8)] Each of the intermediates of the compound of the present invention produced by the above method and the compound of the present invention (I) or a salt thereof can be subjected to a conventional separation means such as concentration, solvent extraction, chromatography,
It can be isolated from the reaction mixture, such as by recrystallization. Compound (III) obtained by the production method of the present invention,
(I-1), (III-1), (IV) (IVc ₁ ), (IVc ₂ ), (IV
_N ), (V), (VI), (VII), (VIII), (IX),
(X), (XII), (XIII). (XIV), (XV), (XV
I), (XVII), (XVIII), (XIX) and (XX) salts include, for example, alkali metals, alkaline earth metals, non-toxic
Specific examples of the organic metal, ammonium or substituted ammonium include sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium, pyridinium and substituted pyridinium. Salts with bases or salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfone An acid, a salt with an acid such as an organic acid such as camphorsulfonic acid, or the like is used. The raw material compounds (V), (VI), (VII), (X), (XI), (XII),
(XIV), (XVI) and (XVIII) or salts thereof can be easily produced by a known method or a method known per se.

The preparation of the present invention containing the compound (I) or a salt thereof has an excellent therapeutic effect on chronic immune diseases, particularly a therapeutic effect on rheumatism. The preparation of the present invention has low toxicity and can be safely used for the purpose of treating chronic immune diseases in warm-blooded animals, particularly mammals (eg, human, monkey, dog, cat, rabbit, rat, mouse, etc.). is there. When used as a therapeutic agent for chronic immune diseases, compound (I) or a salt thereof may be used by itself or in a pharmacologically acceptable carrier, excipient, diluent or the like by a commonly used method, for example, a powder. , Granules, tablets, capsules, suppositories, injections and the like can be administered orally or parenterally,
Oral administration is particularly preferable. The dose depends on the target animal, disease,
Depending on the symptom, the type of compound, the administration route, etc., for example, in the case of oral administration, the compound of the present invention is used in the warm-blooded animal at about 0.01 to 10 mg / kg body weight per day, preferably 0.1 to 1.0 mg. / Kg body weight, and about 0.002-2.0 mg / kg per day for parenteral administration
Body weight, preferably 0.02-0.5 mg / kg body weight. The injection method includes intra-articular injection,
Intramuscular injection, intraperitoneal injection, subcutaneous injection, intravenous injection and the like are used. The above formulation is carried out according to a method known per se. When producing the above oral preparation, for example, a tablet,
Binder (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.), disintegrating agent (eg, starch, carboxymethylcellulose calcium, etc.), lubricant (eg, magnesium stearate, talc, etc.) etc. should be blended appropriately. You can In the case of producing parenteral preparations, for example, injections, isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, Methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), a buffer solution (eg, phosphate buffer solution, sodium acetate buffer solution, etc.) and the like can be appropriately added.

As a specific example of the production of tablets, for example, the amount of the compound of the present invention used is about 0.2 to 50 m per tablet.
g, lactose 100-500 mg, corn starch about 50-
100 mg, hydroxypropyl cellulose about 5.0-
20 mg was mixed by a conventional method, granulated, mixed with corn starch and magnesium stearate, and then tabletted to give one tablet about 100 to 500 mg, diameter about 3.0 to 10 m.
m tablets. In addition, the amount of this tablet used per tablet is hydroxypropylmethylmethylcellulose phthalate (about 10 to 20 mg) and castor oil (about 0.5 to
It is also possible to obtain an enteric coated tablet by coating with an acetone-ethanol mixed solution in which 2.0 mg) is dissolved to a concentration of about 5.0 to 10%.
As a specific example of the preparation of the injection, for example, as a use amount per ampoule, about 0.2 to 50 mg of sodium salt of the compound (I) of the present invention is dissolved in (1) about 2 ml of physiological saline. After injecting into ampoule, the ampoule is sealed and heat-sterilized at about 110 ° C. for about 30 minutes, or (2) about 10-40 mg of mannitol or sorbitol is dissolved in about 2 ml of sterilized distilled water, and then ampoule is dissolved. It is also possible to adjust by injecting into, and freeze-drying this and sealing. The lyophilized injection solution is prepared by opening the ampoule before use, and injecting and dissolving physiological saline, for example, at a concentration of the compound of about 0.2 to 50 mg / ml to give a solution. Can be administered intramuscularly.

[0076]

The compound (I) of the present invention or a salt thereof exhibits excellent immunosuppressive activity and rat adjuvant arthritis suppressive effect in, for example, in vitro and in vivo model experimental systems, and thus can be expected as a therapeutic agent for rheumatism and the like. Below, the test example which shows a pharmacological effect is described.

Test Example 1 In vitro inhibition of cell growth
2-fold serial dilutions of drug 50μ to use a 96-well microtiter plates
l / well, and then various tumor cell lines, vascular endothelial cells, epithelial cell lines and recombinant human interleukin 2 (IL-2), concanavalin A (ConA), phytohemagglutinin (PHA) or lipopolysaccharide. (LP
S) -stimulated mouse spleen cell suspension (5.0 × 10 ⁴ −
2.0 × 10 ⁵ cells / ml) 50 μl / well was added.
After culturing at 37 ° C. in a 5% carbon dioxide gas incubator for 2 to 7 days, the MTT method [Tada et al .: Journal of Immunological Methods, 93 , 157-16].
5 (1986)], the number of viable cells was calculated. The result is [Table 1]
It was as shown in. Leukocyte mouse T leukemia cell line L1210, mouse myeloma cell line MOPC-104E and IL-2, ConA. For mouse spleen cells stimulated with PHA or LPS, compound A was MTX 8
-15-fold strong growth inhibitory activity, but human vascular endothelial cells HUVEC and human amnion-derived epithelial cell line WISH
On the contrary, compound A is 1/5 and 1/2 of MTX
The inhibitory activity was shown.

[Table 1] Cell proliferation inhibition test ──────────────────────────────── Animal IC ₅₀ ¹⁾ (× 10 ^-9 M) ──────────────── Cell name Compound A ²⁾ MTX ──────────────────── ───────────── Mouse T leukemia cells L 1210 0.35 3.7 Mouse myeloma cells MOPC-104E 0.99 15.0 IL-2 stimulated mouse spleen cells 0.35 5.2 ConA stimulated mouse spleen cells 0.75 6.3 PHA stimulated mouse spleen Cells 0.73 8.8 LPS-stimulated mouse spleen cells 0.55 8.0 Human umbilical vein vascular endothelial cells HUVEC 2,800 630 Human amnion-derived epithelial cells WISH 23.0 12.0 ──────────────────────── ───────── ¹⁾ Concentration required to inhibit cell proliferation by 50%. ²⁾ N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid From the present test, the compound of the present invention was It can be seen that the inhibitory effect on the proliferation of leukocyte cells and cell lines, which are considered to be one of the causes of rheumatism, is excellent.

Test Example 2 Rat Adjuvant Arthritis
Suppressive effect against Freund's complete adjuvant (Freund's complet) in the right hind footpad of Lewis rats (7 weeks old, male)
e-adjuvant: 0.5 μl of liquid paraffin suspension containing 0.5% killed tuberculosis) was injected for sensitization, and then a test drug (1.5 mg / kg body weight) dissolved in phosphate buffered saline (PBS) was used. It was subcutaneously administered to the back. The same amount of drug was subcutaneously administered every 2 days for a total of 6 times, and the change in body weight with time was also tracked. Antigen sensitization 14
The arthritis score of the opposite leg was measured day after day. After sacrifice, the thymus, spleen, and adrenal gland were weighed for the 15-day sensitized case. The results were as shown in Table 2-3 and [Fig. 1]. [FIG. 1] shows changes in body weight of rats after sensitization with M. tuberculosis, and the symbols in the figure show the cases where the following groups were administered. ●: Drug non-administration control (PBS administration) group. ◯: MTX administration group. A: Compound A administration group. As shown in [Table 2], the compound A administration group suppressed arthritis in all cases by 100%, and at the same time, almost no side effects were observed. On the other hand, the MTX-administered group also showed a strong inhibitory effect on arthritis, but weight loss and prominent side effects (pellicle, coat contamination, diarrhea, bloody stool, bleeding around the eyelid, oral mucosa, and anus) were observed, and the antigen By the 15th day of sensitization, 4 out of 6 cases died. [Fig. 1] shows changes in body weight of rats after antigen sensitization.
In the (PBS administration) group, remarkable weight loss was observed with the onset of arthritis 10 days after the sensitization. In addition, MTX administration group is MT
The toxicity of X itself was also added, and a greater weight loss was shown.
On the other hand, in the compound A-administered group, continuous weight increase was observed 2 days after the antigen sensitization. [Table 3] shows organ weights of rats sacrificed 15 days after antigen sensitization. The compound A-administered group showed an organ weight equivalent to that of the antigen-sensitized group, but thymus atrophy and spleen and adrenal hypertrophy / swelling were observed in the antigen-unsensitized drug-untreated control group. In the MTX administration group, thymus atrophy and adrenal hypertrophy were particularly prominent.

[0079]

[Table 2] Rat Adjuvant Arthritis Test ---------------------------------- g) Rate ²⁾ ────────────────────────── PBS ¹⁾ 0.6 0 −3 6/6 Compound A 0.0 100 +37 5/5 MTX 0.1 98 -24 2/6 ────────────────────────── ¹⁾ Antigen-sensitized drug non-administration control group. ²⁾ Calculated 15 days after antigen sensitization.

[0080]

[Table 3] Organ weight of rat adjuvant arthritis model ────────────────────────────── Organ organ weight (mg) Detected original example ───────────────── Drug drug Sensitization number Thymus Spleen Adrenal gland ────────────────── ──────────── PBS ¹⁾ − 4 613 ± 14 59 8 ± 17 21 ± 2 PBS ²⁾ + 6 160 ± 18 1003 ± 228 26 ± 1 Compound A + 5 500 ± 40 627 ± 67 18 ± 1 MTX + 2 75 ± 28 54 2 ± 150 34 ± 3 ─────────────────────────────── ¹⁾ Antigen nonsensitivity Drug non-administration group. ²⁾ Control group not administered with antigen-sensitized drug. From this test, it can be seen that the compound of the present invention has an excellent inhibitory effect on rat adjuvant arthritis, which is considered to be one of the models for the symptoms of rheumatism.

[0081]

【Example】

Example 1 N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid (25 mg per tablet),
Lactose (250 mg per tablet), corn starch (51 mg per tablet) and hydroxypropyl cellulose L (9 mg per tablet) were mixed by a conventional method to granulate the granules, corn starch (8 mg per tablet) and magnesium steer. After mixing with the rate (2 mg per tablet), the mixture was compressed into tablets (370 mg per tablet) according to a conventional method.
mg) was obtained. Example 2 N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid disodium salt (5 g) was physiologic. It was dissolved in 1 liter of saline solution, filtered through a microfilter, dispensed in 2.2 mL aliquots and sealed. This was sterilized at 110 ° C. for 30 minutes to give an ampoule for subcutaneous, intravenous or intramuscular injection of the compound. Example 3 N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamine hydrochloride (2.5 g) Mannitol (10 g) was dissolved in distilled water (1 liter), and after sterile filtration, 2 mL each was dispensed into ampoules. When this was placed in a freeze dryer, dried and sealed, an ampoule for dissolution at use was obtained. At the time of use, the ampoule is opened and, for example, dissolved in physiological saline (2 ml) to give an injection for administration. Example 4 With the same formulation as in Preparation Example 1, N- [4- [2- (2,4-
Diamino-7H-pyrrolo [2,3-d] pyrimidine-5
-Yl) ethyl] benzoyl] -L-glutamic acid tablets were obtained. Example 5 With the same formulation as in Preparation Example 1, [N- [4- [3- (2,4
-Diamino-7H-pyrrolo [2,3-d] pyrimidine-
5-yl) propyl] benzoyl] -γ-glutamyl]
-L-glutamic acid tablets were obtained.

[0082]

INDUSTRIAL APPLICABILITY The compound of the present invention is used in vitro and in v
Since it showed excellent immunosuppressive activity and rat adjuvant arthritis suppressive effect in an ivo model experimental system, the present invention provides a therapeutic agent for chronic immune diseases, particularly a useful therapeutic agent for rheumatism and the like.

[0083]

[Brief description of drawings]

FIG. 1 shows a change in rat body weight after antigen sensitization.

Claims (6)

[Claims] 1. The formula: [In the formula, ring A is a 5-membered ring which may have a substituent,
B- represents a divalent cyclic group or chain group which may have a substituent, X represents an amino group, a hydroxyl group or a mercapto group, and Y represents a hydrogen atom, a halogen atom or a carbon, nitrogen or sulfur atom. Z is a divalent group composed of not more than 5 chain atoms connected in series which may have a substituent and may have one hetero atom in the chain portion. , —COOR ¹ is an optionally esterified carboxyl group, m is an integer of 1 to 6, n is an integer of 1 to 4, and R ¹ is different in m repeating units. (-COOR ² represents a carboxyl group which may be esterified, R ³ represents a hydrogen atom or a C _1-4 hydrocarbon group which may have a substituent, or is adjacent to R ⁴ together. R ⁴ represents a cyclic or chain group which may have a substituent). ] The chronic immune disease therapeutic agent containing the compound or its salt represented by these. 2. The formula: [In the formula, ring A is a 5-membered ring which may have a substituent,
B- is a divalent cyclic group or chain group which may have a substituent, X is an amino group, a hydroxyl group or a mercapto group, and Y is a hydrogen atom, a halogen atom or a carbon, nitrogen or sulfur atom. Z is a divalent group composed of not more than 5 chain atoms connected in series which may have a substituent and may have one hetero atom in the chain. , -COOR ¹ and -COOR ² are the same or different and may be esterified carboxy groups, m is an integer of 1 to 6, and R ¹ may be different in m repeating units. ] The chronic immune disease therapeutic agent containing the compound or its salt represented by these. 3. The formula: [In the formula, ring A is a 5-membered ring which may have a substituent,
B- is a divalent cyclic group or chain group which may have a substituent, X is an amino group, a hydroxyl group or a mercapto group, and Y is a hydrogen atom, a halogen atom or a carbon, nitrogen or sulfur atom. Z is a divalent group composed of not more than 5 chain atoms connected in series which may have a substituent and may have one hetero atom in the chain. , —COOR ¹ is an optionally esterified carboxyl group, and W ′ is Represents a cyclic or chain group which may be present), and n represents an integer of 1 to 4. ] The chronic immune disease therapeutic agent containing the compound or its salt represented by these. 4. The formula: [In the formula, ring A'is an optionally hydrogenated pyrrole ring, R is a hydrogen atom or a lower alkyl group, q is an integer of 1 to 5, m'is an integer of 1 to 4, and R is Is q
R ¹ may be different from each other in m ′ repeats, and other symbols have the same meanings as in claim 2. ] The therapeutic agent of Claim 2 containing the compound or its salt represented by these. 5. Use as a therapeutic agent for rheumatism.
The therapeutic agent described. 6. The therapeutic agent according to claim 1, which is used as a therapeutic agent for chronic arthritis.