JPH04211063A - Condensed tricyclic heterocyclic compound, its production, use and intermediate - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antitumor agent. CONSTITUTION:A compound, e.g. tert-butyl 4-[2-(2-amino-7,8-dihydropyrido[2,3-d] pyfrolo[3,2-e] pyrimidin-6-yl)ethyl]benzoate expressed by formula I {rungs A<1> and A<2> are 5 to 7-membered rung which may have substituent group; B is (substituted) cyclic group or formula II [-B'- is (substituted) bifunctional chain group; COOR and COOR' are (esterified)carboxyl]; Q<1> is H, halogen or a group through C, N, O or S; either of Q<2> and Q<3> is N and the other is N or CH; Y is formula III to V (R<1> is H, lower hydrocarbon or direct bond);-Z- is a group forming crosslinkage between the rings A<1>, A<2> and B and (substituted) bifunctional group}. The aforementioned compound is obtained by reacting a compound expressed by formula IV (D is group which, together with E, forms covalent bond), etc., with a compound expressed by the formula E-B (E is group which, together with D, forms covalent bond) and forming the crosslinkage (Z).

Description

[Detailed description of the invention]

[00011

[Industrial Field of Application] The present invention relates to a novel fused pentacyclic heterocyclic compound useful as an antitumor agent and a method for producing the same. [0002] [Prior Art] Folic acid and its related compounds are used as carriers of C1 units derived from formic acid, formaldehyde, etc. in living organisms, and are used in various enzymes such as nucleic acid biosynthesis systems, amino acid/peptide metabolic systems, and methane production systems. It plays the role of a coenzyme in reactions. In particular, in the nucleic acid biosynthesis system, 2
It is essential for the metabolism and transfer reactions of the C1 unit in two pathways, namely the purine synthesis system and the thymidine synthesis system. usually,
In order for folic acid to exert its biological activity, it must undergo two steps of reduction and be converted to its active coenzyme form. Aminopterin (methotrexor) (MTX) and its surrounding compounds are known as drugs that strongly bind to the enzyme (dihydrofolate reductase) that controls the second step and inhibit the reduction of dihydrofolate to tetrahydrofolate. Since these drugs impair DNA synthesis and result in cell death, they have been developed as antitumor agents and occupy a clinically important position. Furthermore, we have added a folate antagonist with a different mechanism of action than dihydrofolate reductase inhibition, namely tetrahydroaminopterin, whose main mechanism of action is inhibition of glycinamide ribonucleotide transformylase, which is involved in the early stages of the purine biosynthesis system. Antitumor agent (5,10-dibuaza-5,6,7,8-tetrahydroaminopterin: DDATHF) [: Journal of Me
dicinal chemistry) 28,914
(1985)] or] a quinazoline antitumor agent (2-desamino 2-methyl-10-propargyl-5, 8-Didea the Foray)-:DMPDDF) (British Journal of Cancer
i sh Journal of Canc
er) 58, 241 (1988)]. On the other hand, in addition to these folate antagonists whose basic skeleton is a condensed ring of a 6-membered ring and a 6-membered ring, they also have a pyrrolo[2,3-d)pyrimidine skeleton, which is a condensed ring of a 6-membered ring and a 5-membered ring. It has been reported that compounds with antitumor activity exist. [Patent application 01-72235:] [0003]

[Problems to be Solved by the Invention] Currently, what is particularly desired in the field of cancer treatment is the creation of drugs based on a new mechanism of action that exhibits high selective toxicity against cancer cells and has excellent therapeutic effects. It is. MTX, whose main mechanism of action is the inhibition of dihydrofolate reductase, is currently widely used in clinical practice, but its therapeutic results are not fully satisfactory, as it is relatively toxic and not very effective against solid tumors. is not listed. [0004]

[Means for Solving the Problems] In view of the above-mentioned circumstances, the present inventors have conducted extensive research, and as a result, a novel fused bicyclic heterocyclic compound has been found to be effective in one or more biosynthetic pathways involving folic acid and its related compounds. We have completed the present invention by discovering that this compound inhibits the effects of cancer, exhibits high selective toxicity against various tumor cells, and has excellent antitumor effects. [0005] That is, the present invention provides the following: (1) General formula

[30] [In the formula, A1 ring and A2 ring are the same or different 5- to 7-membered rings which may each have a substituent, -B
is a cyclic group or formula that may have substituents

[31] [In the formula, -B'- represents a divalent chain group that may have a substituent, and -COOR and -COOR' represent a carboxyl group that may be the same or different and may be esterified. Each is shown below. ], Ql is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen, or sulfur atom; one of Q2 and Q3 is N and the other is N or CH; Y is [Chemical formula 32 】 or

[Chemical formula 33] (R1 represents a hydrogen atom, a lower hydrocarbon group, or a bond.), -Z- is a group that forms a bridge between the A1 ring or the A2 ring and -B. 2 or more atoms each consisting of a carbon atom that may have a substituent, or a carbon atom that may have a substituent and one heteroatom that may have a substituent; (2) An antitumor composition containing the compound described in (1) or a salt thereof; (3) General formula

[34] [In the formula, A1 ring and A2 ring are the same or different, and each is a 5- to 7-membered ring which may have a substituent, Ql
is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen or sulfur atom; one of Q2 and Q3 is N and the other is N or CH; Y is

[Chemical formula 35] or [Chemical formula 36] (R1 represents a hydrogen atom, a lower hydrocarbon residue, or a bond.), and D represents a group that can form a covalent bond with E.] A compound represented by or a salt thereof, and the general formula E-B (wherein -B is a cyclic group which may have a substituent) or the formula

[37] [In the formula, -B'- represents a divalent chain group that may have a substituent, and -COOR and COOR' represent a carboxyl group that may be the same or different and may be esterified, respectively. show. ], and E represents a group capable of forming a covalent bond with D. ] or a salt thereof, to form a bridge Z [-Z- is a group forming a bridge between ring A1 or ring A2 and -B, and each carbon compound may have a substituent. A linear divalent group having 2 to 5 atoms, each consisting of a carbon atom that may have a substituent and one heteroatom that may have a substituent. show. ] A method for producing the compound according to item (1), characterized in that it forms the following: (4) the general formula

[38] [In the formula, A1 ring and A2 ring are the same or different, and each of the 5- to 7-membered rings which may have a substituent is represented by B''
- represents a divalent cyclic or chain group which may have a substituent; Ql represents a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen or sulfur atom; Q2 and Q
3 is N on one side, N or CH on the other side, and Y is

[C39
] or [Formula 40, R1 represents a hydrogen atom, a lower hydrocarbon residue, or a bond. ], -2- is a group forming a bridge between ring A1 or ring A2 and -B'', and each carbon atom may have a substituent, or each has a substituent. 2 to 5 atoms consisting of a carbon atom that may have a substituent and one heteroatom that may have a substituent
represents a linear divalent group, respectively. ] or a salt thereof or a reactive derivative in the carboxy group and the general formula

[41] [In the formula, -COOR and -COOR' represent a carboxy group which may be the same or different and may be esterified. ] A method for producing the compound according to item (1), which is characterized by reacting with a compound represented by the following formula: (5) General formula

[42] [In the formula, A2 ring may have a substituent from 5 to 7
A membered ring, -B is a cyclic group or formula that may have a substituent

[43] [In the formula, -B'- represents a divalent chain group that may have a substituent, and -COOR and -COOR' represent a carboxyl group that may be the same or different and may be esterified. Each is shown below. ], Ql is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen or sulfur atom, one of Q2 and Q3 is N and the other is N or CH, Y is [Chemical formula 44 】 or

[Chemical formula 45] (R1 represents a hydrogen atom, a lower hydrocarbon group, or a bond.)], -Z- is a group forming a bridge between the A2 ring and -B, and each substituent is 2 to 5 atoms each consisting of a carbon atom that may have a substituent or a carbon atom that may have a substituent and one heteroatom that may have a substituent. A linear divalent group is
” represents a divalent chain group or bond that can form the A1 ring,
L is a leaving group or a formula

[46] [In the formula, R2 represents a hydrogen atom, a lower hydrocarbon group, or a bond. ] or the isocomb shape of its carbonyl group, Xl is 10H1-8H or

embedded image [In the formula, R3 represents a hydrogen atom, a lower hydrocarbon group, or a bond. ] are shown respectively. ] or a salt thereof is subjected to a covalent bond forming reaction to form an A1 ring.
) general formula

[48] [In the formula, A1 ring and A2 ring are the same or different, and each of the 5- to 7-membered rings which may have a substituent, -B
is a cyclic group or formula that may have substituents

[49] [In the formula, -B'- represents a divalent chain group that may have a substituent, and -COOR and -COOR' represent a carboxyl group that may be the same or different and may be esterified. Each is shown below. ], Q2' and Q3' are the same or different and =O1-OR+'=S, S
RI' [In the formula, R1' and R1'' are the same or different and represent a hydrogen atom or a lower hydrocarbon residue.] or =NR1
' [wherein R'' has the same meaning as above], Y is

[C51] or

embedded image [R1 represents a hydrogen atom, a lower hydrocarbon residue, or a bond. ], -Z- is a group forming a bridge between ring A1 or ring A2 and -B, and each carbon atom may have a substituent, or each has a substituent. A dotted line in the structural formula indicates a straight chain divalent group with 2 to 5 atoms consisting of a carbon atom that may have a substituent and one heteroatom that may have a substituent. or a double bond, respectively. ] Compounds and general formula

[53] [In the formula, Ql is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen, or sulfur atom, and Q is an oxygen atom, a sulfur atom, or the formula = NR] ' [: In the formula,
R1' has the same meaning as above. ], Q′ is −OR”
-8R1' or

embedded image [wherein R” and R1” have the same meanings as above. ]
A method for producing a compound according to item (1), which comprises reacting with a compound represented by the formula (1) and cyclizing the compound, and (7) the general formula

[55] [In the formula, A1 ring and A2 ring are the same or different, and each of the 5- to 7-membered rings which may have a substituent, B''
- represents a divalent cyclic or chain group which may have a substituent; Ql represents a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen or sulfur atom; Q2 and Q
3 is N on one side, N or CH on the other side, and Y is

[C56
] or [Formula, R1 represents a hydrogen atom, a lower hydrocarbon residue, or a bond. ], -Z- is a group forming a bridge between ring A1 or ring A2 and -B'-, and each carbon atom may have a substituent, or each has a substituent. -COOR" refers to a straight chain divalent group having 2 to 5 atoms consisting of a carbon atom which may have a substituent and one heteroatom which may have a substituent. [0006] In the above formula, Ql, Q2, Q3 and Xl
Two or more of these are groups via O, S or N, and this O, S
Alternatively, in the case of a compound in which a hydrogen atom is directly bonded to N, it can exist as an equilibrium mixture of various tautomers due to hydrogen atom shifts. In these cases, the amino type, hydroxy type, and mercapto type are described throughout this specification for convenience, and the corresponding nomenclature is adopted, but in any case, the tautomers, imino type, oxo type, etc. It shall also include the type and thioxo type. [0007] In addition, the compound (I) of the present invention includes cases in which the presence of multiple asymmetric centers is possible, but the absolute configuration of the asymmetric carbon atom in the side chain derived from glutamic acid is S (L
), the other absolute configurations of irregular centers are S, R
1 or a mixture of R8. In this case, multiple diastereoisomers exist, but if necessary, they can be easily separated by conventional separation and purification means. [0008] All of the above diastereoisomers that can be separated in this manner are within the scope of the present invention. [0009] In the above formula, the 5- to 7-membered cyclic group represented by the A1 ring and the A2 ring includes a carbon atom or a carbon atom and 1 or 2 heteroatoms (nitrogen atom, oxygen atom or sulfur atom). These cyclic groups may have a substituent. Examples of the ring of the cyclic group include cyclopentadiene, furan, thiophene, thiophene-1-oxide, thiophene-1,1-dioxide, pyrrole, N-substituted pyrrole,
Oxazole, thiazole, imidazole, N-substituted imidazole, pyrazole, N-substituted pyrazole, benzene, pyridine, pyran, pyratine, pyrimidine, pyridatine or partially reduced compounds thereof, didehydrodioxolane, didehydropiperidine, N-substituted didehydro Examples include piperidine, didehydromorpholine, N-substituted didehydromorpholine, didehydropiperazine, N-substituted didehydropiperazine, didehydrodioxane, cycloheptene, cyclohebutadiene, cyclohebutatriene, azacycloheptene, azacyclohebutadiene, and the like. . (00101 These cyclic groups have 1 to 2 cyclic groups at possible positions.
Examples of such substituents include alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, 1so-propyl), alkenyl groups having 2 to 3 carbon atoms. groups (e.g., vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl), alkynyl groups having 2 to 3 carbon atoms (e.g., ethynyl, ■-propynyl, propargyl), cyclopropyl groups, halogen atoms (e.g., fluorine , chlorine, bromine, iodine), alkanoyl groups having 1 to 4 carbon atoms (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl), benzoyl groups,
Substituted benzoyl group (e.g., p-chlorobenzoyl, p-methoxybenzoyl, 3.4.5-trimethoxybenzoyl), cyano group, carboxy group, carbamoyl group,
Nitro group, hydroxy group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, ethoxymethyl group,
Methoxyethyl group, ethoxyethyl group, alkoxy group having 1 to 3 carbon atoms (e.g., methoxy, ethoxy, propoxy), mercapto group, alkylthio group having 1 to 3 carbon atoms (e.g., methylthio, ethylthio, propylthio), amino group, Substituted amino groups having 1 to 2 carbon atoms (e.g., methylamino, ethylamino, dimethylamino, diethylamino), alkanoylamino groups having 1 to 2 carbon atoms (e.g.,
Formamide, acetamide), etc. The N-substituted moiety in N-substituted pyrrole, N-substituted imidazole, N-substituted pyrazole, N-substituted didehydropiperidine, N-substituted didehydromorpholine and N-substituted didehydropiperazine includes the above-mentioned carbon atoms 1 to 3; an alkyl group having 2 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms, an alkynyl group having 2 to 3 carbon atoms, a cyclopropyl group, an alkanoyl group having 1 to 4 carbon atoms, a benzoyl group, a substituted benzoyl group, a hydroxyethyl group, a methoxyethyl group, In addition to ethoxyethyl groups, phenyl groups, substituted phenyl groups (e.g., p-chlorophenyl, p-methoxyphenyl, 3
, 4. 5-trimethoxyphenyl group), benzyl group or substituted benzyl group (e.g. p-chlorobenzyl, p
methoxybenzyl, diphenylmethyl). [0011] The bond between the AI ring, A2 ring or Y and -Z- may be bonded at any possible bonding position, and N-substituted pyrrole, N-substituted imidazole, N-substituted pyrazole, N- In the case of substituted didehydropiperidines, N-substituted didehydromorpholines and N-substituted didehydropiperazines, the linkage may be via an N-substituted moiety. [0012] The 5- to 6-membered cyclic group optionally having a substituent represented by -B may contain 1 or 2 heteroatoms (e.g., N, 0.S) in the ring. good. Examples of the 5-membered cyclic group include cyclopentadienyl, thiophen-(2- or 3-)yl, furan-(2- or 3-)yl, pyrrole-(1-12- or 3)
yl, thiazol-(2-14- or 5-)yl,
Examples of the 6-membered cyclic group include imidazol-(1-12-14- or 5-)yl, thiadiazol-2-yl, or partially reduced or completely reduced compounds thereof, and examples of the 6-membered cyclic group include phenyl, cyclohexyl,
Cyclohexenyl, cyclohexagenyl, pyridine-
(2-13- or 4-)yl, pyran-(2,3-
or 4-)yl, pyratin-2-yl, pyrimidin-(2-14- or 5-)yl, pyridatin-(3
- or 4-)yl or partially reduced or fully reduced compounds thereof, morpholino, thiomorpholino, piperidin-1-yl or piperazin-1yl, in particular phenyl and thiophen(2- or 3-)yl. , thiazole-(2-14- or 5-)
il, etc. are preferred. [0013] The 5- to 6-membered cyclic group represented by -B may have 1 to 3 substituents at substitutable positions. Examples of the substituent include an alkyl group having 1 to 5 carbon atoms (e.g., methyl, ethyl, propyl, is. propyl, butyl, tert-butyl), an alkenyl group having 2 to 5 carbon atoms (e.g., vinyl, - methylvinyl,
1-propenyl, aryl, allenyl), alkynyl groups having 2 to 5 carbon atoms (e.g. ethynyl, 1-propynyl,
propargyl), cycloalkyl groups having 3 to 5 carbon atoms (e.g. cyclopropyl, cyclohexyl), halogens (
Examples: chlorine, bromine, fluorine, iodine), nitro, cyano,
Hydroxy, alkoxy group having 1 to 5 carbon atoms (e.g. methoxy, ethoxy, propoxy, butyroxy), phenoxy group, 5- to 6-membered heterocyclic oxy group (e.g. thiazolyloxy, pyridyloxy, pyrimidinyloxy), amino group, mono C1-6 substituted amino group (e.g., methylamino, ethylamino group, di-C1-6 substituted amino group (e.g., dimethylamino, diethylamino), trifluoromethyl group,
Oxo group, carbamoyl group, N-substituted rubamoyl group [
Examples, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl,

[Chemical formula 58] (wherein C0OR and C0OR' have the same meanings as above)], an alkanoyl group having 1 to 5 carbon atoms (e.g., formyl, acetyl, propionyl), a methoxymethyl group,
2-ethoxyethyl group, phenylthio group, 5- to 6-membered heterocyclic thio group (e.g., thiazolylthio, pyridylthio,
pyrimidinylthio), alkylthio groups having 1 to 5 carbon atoms (e.g. methylthio, ethylthio), 1 to 5 carbon atoms
alkylsulfinyl groups (e.g., methylsulfinyl,
ethylsulfinyl), alkylsulfonyl groups having 1 to 5 carbon atoms (e.g., methylsulfonyl, ethylsulfonyl), and these substituents further have one or two of the above-mentioned substituents at substitutable positions. It's okay. [0014] The cyclic group in the optionally substituted divalent cyclic group represented by -B''- has 1 or 2 heteroatoms (e.g. N, O, S) in the ring. A 5- to 6-membered cyclic group which may contain is preferable, and the bonds preferably come out from non-adjacent positions in the ring. Examples of the 5-membered cyclic group represented by [0015]-B''- As 1,3- or 3,5-cyclopentadiene 1.
3-ylene, cyclopentene-(1,3-11,4 or 3.5-)ylene, cyclopentane-1,3-ylene, thiophene-(2,4-12,5- or 3,4-ylene)
-) ylene, furan - (2,4-12,5- or 3
．． 4-)ylene, pyrrole-(1,3-12,4,2,
5- or 3,4)ylene, thiazole (2,4- or 2.5-)ylene, imidazole (1,4-12
, 4-or 2. 5-) Ilene, thiadiazole-
Examples of the 6-membered cyclic group include 2,5-ylene or partially reduced or completely reduced compounds thereof, and examples of the 6-membered cyclic group include phenyl-(1,3- or 1,4)ylene, cyclohexane-(1, 3- or 1,4) ylene, cyclohexene-(1,3-1■, 4-11.5-13,5-
Or 3. 6-)ylene, 1,3cyclohexadiene-(1,3-11,4-11,5,2,4-12,5
- or 2.6-)ylene, ■, 4-cyclohexadiene- (1,3-1■, 4- or 1.5-)ylene, pyridine-(2,4-12゜5-12,6- or 3,5-)ylene, pyran(2,4-12,5-12
, 6-13, 5-13, 6 or 4. 6-) Ylene, pyratin-(2,5- or 2.6-)ylene, pyrimidine-(2,4- or 2,5-)ylene, pyridatin-3,5-ylene or partially reduced or completely reduced forms thereof type compounds, etc., especially phenyl-
Preferred are 1,4-ylene and thiophene-2,5-ylene. [0016] The optionally substituted divalent chain group represented by -B'- is preferably a lower chain hydrocarbon residue having 2 to 4 carbon atoms, such as ethylene, ethenylene, ethynylene, Examples include trimethylene, propenylene, propynylene, propadienylene, tetramethylene, butenylene, butenylene, and butanedienylene. [0017] The divalent cyclic group or lower chain hydrocarbon residue represented by -B'- or -B'' has 1 at a substitutable position.
It may have one to two substituents. Examples of the substituent include an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, 1so-propyl group), an alkenyl group having 2 or 3 carbon atoms (e.g., vinyl, -propenyl, aryl, allenyl group), alkynyl group with 2 or 3 carbon atoms (ethynyl, 1-propynyl, propargyl group), cyclopropyl, halogen (
Examples include chlorine, bromine, fluorine, iodine), hydroxy, methoxy, dimethylamino, diethylamino, trifluoromethyl, oxo, formyl, hydroxymethyl, 2hydroxyethyl, methoxymethyl, 2-ethoxyethyl, and the like. [0018] In the above formula, Ql is a cyano group, a carboxyl group, a carbamoyl group, a nitro group, a hydroxyl group, or a lower hydrocarbon residue, such as an alkyl group having 1 to 3 carbon atoms (lower, methyl, ethyl, propyl, 1so −
propyl), alkenyl groups having 2 or 3 carbon atoms (e.g. vinyl, 1-methylvinyl, 1-propenyl, aryl,
arenyl), alkynyl groups (ethynyl, 1-propynyl, propargyl) and cyclopropyl groups having 2 or 3 carbon atoms, aryl groups such as phenyl groups and naphthyl groups, 5- to 6-membered heterocyclic groups,
For example, pyrrolyl, imidazolyl, pyrazolyl, thenyl, furyl, thiazolyl, thiadiazolyl, oxasilyl, oxadiazolyl, pyridyl, pyranyl, pyratinyl, pyrimidinyl, pyrimidinyl or partially or fully reduced groups thereof, dioxanyl, piperidino, morpholino, N-methyl Piperazinyl, N-ethylpiperazinyl, dioxanyl, etc. may also be used. When Ql is a lower hydrocarbon residue, an aryl group, or a 5- to 6-membered heterocyclic group, it may have 1 to 2 substituents, and such substituents include, for example, 3 alkyl groups (e.g. methyl, ethyl, propyl, 1s
o-propyl group), alkenyl group having 2 or 3 carbon atoms (
Examples include vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl groups), alkynyl groups with 2 or 3 carbon atoms (ethynyl, 1-propynyl, propargyl groups), or cyclopropyl groups, as well as fluorine, hydroxy, oxo , methoxy, dimethylamino, diethylamino, trifluoromethyl, formyl, hydroxymethyl, 2-
Examples include hydroxyethyl, methoxymethyl, 2-ethoxyethyl and the like. [0019] The halogen atom represented by Q' is
Examples include fluorine, chlorine, bromine or iodine. Ql
may be an alkoxy group, an alkylthio group, an alkanoylamino group, or an alkanoyloxy group, and examples of the alkyl portion of these groups include the groups exemplified when Ql is a lower hydrocarbon residue. Q
l may be an aryloxy group, an arylthio group, an aroylamino group, or an aroyloxy group, and examples of the aryl portion of these groups include a phenyl group or a naphthyl group. Furthermore, Ql has 5 or 6 heterocycles.
It is a member ring. It may be a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic carbonylamino group, or a heterocyclic carbonyloxy group, and these heterocyclic moieties are exemplified when Ql is a 5- or 6-membered heterocyclic group. The groups listed above are listed as such. Ql may be a substituted amino group such as a mono-substituted amino group or a di-substituted amino group, and the substituent moiety may be a lower hydrocarbon residue, an aryl group, or a 5- to 6-membered heterocyclic group as shown in Ql above. Can be mentioned. [0020] In the above formula, [Formula 5] in Y, L, and X'
Examples of lower hydrocarbon residues represented by R1, R2, and R3 of the group represented by the formula include alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, 1so-propyl), and 2 to 3 carbon atoms. or 3 alkenyl groups (e.g. vinyl, 1-methylvinyl, ■-propenyl, aryl, allenyl), alkynyl groups having 2 or 3 carbon atoms (ethynyl,
(1-propynyl, propargyl) and cyclopropyl groups, and these lower hydrocarbon residues may have one or two substituents. Examples of the substituent include the substituents exemplified as substituents for -B'-. [0021] In the above formula, the optionally esterified carboxy group represented by -COOR1-COOR' and -COOR'' is a lower alkyl group having 1 to 5 carbon atoms, and may have a substituent. Examples include carboxy groups esterified with benzyl groups or phenyl groups that may have substituents. Examples of the lower alkyl groups include methyl, ethyl, propyl, is.propyl, n-butyl, and 1so-. Butyl, 5ec-butyl, tert-butyl, n-pentyl, 1so-pentyl, 5ec-pentyl, neo-pentyl, tert-pentyl, etc., and the benzyl which may have the substituent include benzyl, nitrobenzyl, Examples of phenyl that may have a substituent include methoxybenzyl, phenyl, nitrophenyl, methoxyphenyl, etc. [0022] In the above formula, a substituent represented by -Z- In a straight chain divalent group with 2 to 5 atoms, which is composed of a carbon atom or a carbon atom and one heteroatom (nitrogen atom, oxygen atom, or sulfur atom), Examples of the constituent groups include alkylene groups having 2 to 5 carbon atoms such as ethylene, trimethylene, tetramethylene, pentamethylene, etc., such as vinylene, propenylene, ■- or 2-butenylene, butadienylene, 1- or 2-pentenylene, ■ , 3- or 1,4-pentamethylene, C2-C5 alkenylene groups such as ethynylene, 1- or 2-provinylene, 1- or 2-butenylene, 1-12 or 3-pentynylene, etc. The alkynylene group of 5 is mentioned, and the group composed of a carbon atom and one hetero atom (nitrogen atom, oxygen atom or sulfur atom) has the formula -ZI Z2 Z3 (wherein Zl and Z3 are the same or Divalent lower hydrocarbon residues which may have different bonds or substituents, Z2 is 10, formula-8(0) n''- [where n'' is an integer of O to 2 ] or expression

[60] [In the formula, R1 has the same meaning as above. ] Examples include groups represented by the following. Examples of the divalent lower hydrocarbon residues which may have substituents represented by Zl and Z3 include alkylene groups having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene, and tetramethylene, such as vinylene, C2-C4 alkenylene groups such as propenylene, ■- or 2-butenylene, butadienylene,
For example ethynylene, 1- or 2-provinylene, 1
Alternatively, alkynylene groups having 2 to 4 carbon atoms such as 2-butenylene may be mentioned, and these groups may have a substituent. Examples of the substituent include the substituents exemplified as substituents for R1, R2 and R3. [0023] In the above formula, the leaving group represented by
Halogen atoms (e.g. chlorine atom, bromine atom, iodine atom)
Alternatively, there may be mentioned a leaving group that can be easily derived from a hydroxy group (eg, methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyl group). [0024] In the above formula, the divalent chain group that can form the A1 ring represented by AI' is a carbon atom or a carbon atom and one or two heteroatoms (nitrogen atom, oxygen atom, or sulfur atom). ) consisting of 1 to 3 atoms
Examples include lower chain hydrocarbon residues having 1 to 3 carbon atoms (e.g., methylene, ethylene, trimethylene, vinylene, propynylene, ethynylene, 1- or 2-carbon groups).
Provinylene), -0- group, -8(0) n''- [wherein n'' has the same meaning as above. ] Base,

embedded image [wherein, R1 has the same meaning as defined above]. 〇-1-3 (0) n″- [In the formula, n″ is present. 〕or

[Chemical formula 62] ] groups, each having the same meaning as defined above [wherein R1 has the same meaning as defined above]. ] methylene, ethylene, vinylene or ethynylene groups,
Examples include azomethylene group, hydrazomethylene group, N-C1-5 substituted hydrazomethylene group, and these groups
It may have one to two substituents. Examples of the substituent include the substituents exemplified as substituents for R1, R2 and R3. [0025] In the above formula, the equivalents of the carbonyl group represented by L' include dimethyl acetal, diethyl acetal, dibenzyl acetal, dimethyl ketal, diethyl ketal, dibenzyl ketal and their dithioacetals and dithioketals, 1,3 Dioxolane, 1,3-dioxane or 1,3 dithiandi-type equivalents may be mentioned. [0026] In the above formula, Q2', Q3', Q and Q'
Examples of the lower hydrocarbon residues represented by R'' and R1'' include the lower hydrocarbon residues exemplified by R1, R2 and R3. [00271] Next, a method for producing the compound (I) of the present invention or a salt thereof will be explained. Production method according to claim (3): [00281 Compound (I) of the present invention can be produced, for example, by the following reaction steps.

[0029] In the above formula, A1 ring, A2 ring, B, Ql
, Q2, Q3, Y and Z have the same meanings as above. In the above reaction step, a covalent bond is formed between D and E, and each of the carbon atoms represented by Z is composed of a carbon atom which may have a substituent or a carbon atom and one heteroatom. A linear divalent group having 2 to 5 atoms can be produced. As a synthetic method for forming a covalent bond between compound (II) and compound (III), when -Z- has a substituent and is composed of only carbon atoms, for example, D is

[C64] So E is

[C65] or

In the case of [Chemical 66] or vice versa, D=E' and E=D
In the case of ', compounds (II) and (III) are subjected to a so-called carbon-carbon bond forming reaction, and the resulting product is then subjected to a reduction reaction if necessary to form the compound (
I) can be produced. [00301 In the above formula, a, b, m, n (=a
+b) and m+n represent integers within the range of 0 to 3, G
represents phenyl, butyl or cyclohexyl, and M represents ethyl or phenyl. R2, R3 and R4 have the same meanings as above and may be different from each other in m and n repeats.

For a group in which Z is composed of Z=-Zl-Z2-Z''- (wherein Zl, Z2 and Z3 have the same meanings as above), for example, D is

[C67] So E is

In the case of [Chemical 68] or vice versa, D=EI and E=D
1, a so-called alkylation type reaction is used, for example when D is

[C69] So E is

In the case of [Chemical 70] or the reverse combination, D=E2 and E=D
In the case of 2, a so-called transamination type reaction (gramamine decomposition type reaction) is advantageously used, for example, when D is

[C71] So E is

In the case of [Chemical 72] or vice versa, D=E3 and E=D
In the case of No. 3, a method of forming a Schiff base and reducing it if necessary, or directly subjecting it to a reductive alkylation reaction is used. [0032] In the above formula, m, n, m+n, L,
R', R2, R3, Zl, Z2 and Z3 have the same meanings as above, R4 has the same meaning as R1, and R6 and R7 are the same or different and represent a hydrogen atom or a hydrocarbon residue. The hydrocarbon residues represented by R6 and R7 may have a substituent, or R6 and R7 may form a cyclic amino group together with the adjacent nitrogen atom. R6
And the hydrocarbon residue represented by R7 has 1 carbon number.
to 18 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-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), C1-C12 alkenyl group (e.g. vinyl, allyl,
-methylvinyl, 2-methylvinyl, ■-octenyl,
1-decenyl group), cycloalkyl group having 3 to 12 carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, andamantyl group), cycloalkenyl group having 3 to 8 carbon atoms (e.g., cyclopentenyl, cyclohexenyl, cyclohebutenyl, cyclooctenyl, cyclopentagenyl, cyclohexagenyl, cyclohebutagenyl, cyclooctagenyl group), aralkyl group having 7 to 13 carbon atoms (e.g., benzyl, α-methylbenzyl , phenethyl, diphenylmethyl group), and C6-C10 aryl group (e.g. phenyl, α-naphthyl, β
-naphthyl group). The cyclic amino group formed by R6 and R7 together with the adjacent nitrogen atom is preferably a 4- to 10-membered ring, such as azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolinyl, piperidino, morpholino, dihydropyridyl, tetra Hydropyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, azacycloheptyl, azacyclooctyl, isoindolyl, indolyl, indolinyl, 2-isoindolinyl, azacyclononyl, azacyclodecyl group, and the like. These hydrocarbon residues represented by R6 and R7, or R6
The ring formed by and R7 together with the adjacent nitrogen atom is 1
It may have one to two substituents. Such substituents include alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl groups), alkoxy groups having about 1 to 4 carbon atoms (e.g., methoxy, ethoxy,
Propoxy, 1so-propoxy, n-butoxy, 1s
o-butoxy, 5ec-butoxy, tert-butoxy group), alkanoyl group having about 1 to 4 carbon atoms (e.g., formyl, acetyl, propionyl, n-butyryl, 1s
o-butyryl group), alkanoyloxy group having about 1 to 4 carbon atoms (e.g., formyloxy, acetyloxy, propionyloxy, n-butyryloxy, 1so-butyryloxy group), carboxy group, alkoxycarbonyl having about 2 to 4 carbon atoms groups (e.g., methoxycarbonyl,
Ethoxycarbonyl, n-propoxycarbonyl, 1s
o-propoxycarbonyl group, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl), halogen atom (e.g. fluorine, chlorine, bromine, iodine), hydroxyl group, nitro group, cyano group, trifluoromethyl group, amino group , monosubstituted amino groups (e.g., methylamino,
ethylamino, propylamino, isopropylamino,
butylamino group), di-substituted amino group (e.g. dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino group), alkanoylamide group (e.g. formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, iso butyrylamide group), carbamoyl group, N-substituted rubamoyl group (e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl group), N, N-
Disubstituted carbamoyl groups (e.g., N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-
Dipropylcarbamoyl, N, N-dibutylcarbamoyl, 1-acyridinylcarbonyl, 1-azetidinylcarbonyl, ■-pyrrolidinylcarbonyl, ■-piperidinylcarbonyl, N-methylpiperazinylcarbonyl,
morpholinocarbonyl group), carbamoylamino group, N
- Substitution power Rubamoylamino group (e.g., N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino group), N, N
-disubstituted carbamoylamino group (e.g., N, N-dimethylcarbamoylamino, N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino,
N, N-dibutylcarbamoylamino, 1-azetidinylcarbonylamino, ■-azetidinylcarbonylamino, ■-pyrrolidinylcarbonylamino, 1-piperidinylcarbonylamino, N-methylpiperazinylcarbonylamino, morpholino carbonylamino group), mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, N-substituted sulfamoyl group (e.g., N-methylsulfamoyl, N-ethylsulfamoyl, N-
propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl group), N,N-disubstituted sulfamoyl group (e.g., N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N, N-
dipropylsulfamoyl, N, N-dibutylsulfamoyl, 1-pyrrolidinylsulfonyl, 1-piperidinylsulfonyl, N-methyl-1-piperazinylsulfonyl, morpholinosulfonyl group), about 1 to 4 carbon atoms alkylthio groups (e.g., methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, 5e
c-butylthio, tert-butylthio group), carbon number 1
Alkylsulfinyl group having 1 to 4 carbon atoms (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl group), alkylsulfonyl group having 1 to 4 carbon atoms (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl group) Examples include. [00331 Below, the first step will be explained in detail. The condensation reaction by carbon-carbon bond formation is a known reaction (e.g.
Aldol reaction, Leformadski reaction, Wittig reaction) are used, and as the reduction reaction, catalytic reduction reaction is usually advantageously used. When using an aldol reaction as the condensation reaction, examples of the base catalyst used include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide, sodium methoxide, sodium ethoxide, and potassium hydroxide. Metal alkoxides such as tert-butoxy, metal amides such as sodium amide and lithium cyisopropylamide, metal hydrides such as sodium hydride and potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α- 1β- or τ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4
-(1-pyrrolidinyl)pyridine, dimethylaniline,
Examples of acid catalysts include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid, silicic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and benzene. Examples include organic acids such as sulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid. In addition, a known method [: E i −I c
h iNegishi, Organometallic
s in Organic 5 synthesis
vol. 1, John Wiley & 5ons, Ne
w York, Chichester, Br1sba
ne, Tronto (1980)), the ketone body was converted to a silyl enol ether body, and the Lewis acid [
Examples, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl2
), anhydrous ferric chloride, titanium tetrachloride (TiCL), tin tetrachloride (SnC14), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.], aldenide or its equivalent. Alternatively, the ketone body can be subjected to a condensation reaction with amines (e.g. triethylamine,
metal triflates (e.g., dialkyl boron triflates, It can also be carried out by treating the enolate with tin (■■) triflate, etc.) 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,
The reaction is preferably carried out at a temperature in the range of 78-100°C for 1 minute to 3 days. As the reaction solvent, for example,
Water, liquid ammonia, alcohols (e.g. methanol,
Ethanol, propatool, 1so-propatool, butyl alcohol, 5ec-butyl alcohol, tert
-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), fats group hydrocarbons (e.g., pentane, hexane, heptane), aromatic hydrocarbons (e.g., benzene, toluene,
xylene), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof. When using the Wittig reaction as the condensation reaction, the reagents used include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide, sodium methoxide, sodium ethoxide, potassium te
Metal alkoxides such as rt-butoxide, metal amides such as sodium amide and lithium diisopropylamide, metal hydrides such as sodium hydride and potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-1β - or τ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4-(1-pyrrolidinyl)pyridine, dimethylaniline, diethylanilino, and other amines. The reaction is carried out for 1 minute in a suitable solvent at a temperature ranging from -20°C to the boiling point of the solvent, preferably 0-150°C.
This is done by reacting for 0 days. As a reaction solvent,
For example, liquid ammonia, alcohols (e.g., methanol, ethanol, propatool, 1so-propatool, butyl alcohol, 5ec-butyl alcohol, te
rt-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aliphatic hydrocarbons (e.g. pentane, hexane, heptane), aromatics A hydrocarbon (eg, benzene, toluene, xylene), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used. Furthermore, condensation can also be carried out using the Leformadsky reaction. The reaction conditions for the Leformadsky reaction include, for example, zinc,
Magnesium, aluminum, tin, etc. are mentioned, and the reaction itself is carried out in a suitable solvent at a temperature ranging from -20°C to the boiling point of the solvent, preferably from 0 to 150°C, for 30 minutes to 3 days. Examples of reaction solvents include ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aliphatic hydrocarbons (e.g. pentane, hexane,
heptane), aromatic hydrocarbons (eg, benzene, toluene, xylene), or a suitable mixed solvent thereof. [0034] The catalytic photoreaction (method A) is carried out using a suitable solvent at a reaction temperature ranging from about -40°C to the boiling point of the reaction solvent, more preferably about 0-50°C. As the solvent used, water, alcohols (e.g., methanol, ethanol, propatool, 1so-propatol, butyl alcohol, and an appropriate mixed solvent thereof are used.Furthermore, using Leformadsky reaction, Condensation can also be carried out.Reaction conditions for the Leformadsky reaction include, for example, zinc, magnesium, aluminum, tin, etc. as the reagents used, and the reaction itself is carried out in an appropriate solvent from -20°C. The reaction is carried out at a boiling point, preferably in the range of 0 to 150°C, for 30 minutes to 3 days. Examples of reaction solvents include ethers (e.g., dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme). , aliphatic hydrocarbons (e.g., pentane, hexane, heptane),
Aromatic hydrocarbons (e.g. benzene, toluene, xylene)
Or an appropriate mixed solvent thereof is used. [0035] The catalytic photoreaction (method A) is carried out using a suitable solvent at a reaction temperature ranging from about -40°C to the boiling point of the reaction solvent, more preferably about 0-50°C. Solvents used include water, alcohols (e.g. methanol, ethanol, propatool, 1so-propanol, butyl alcohol, 5ec-butyl alcohol,
tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), acetic acid esters (e.g., methyl acetate, ethyl acetate), ethers (e.g., dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aromatic carbonization Examples include hydrogen (eg, benzene, toluene, xylene), pyridine, dimethylformamide, and appropriate mixed solvents thereof. As the catalyst for the catalytic reduction, for example, palladium, platinum, rhodium, Raney nickel, etc. are used. At this time, the reaction may proceed advantageously by adding a small amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. [0036] In the alkylation type reaction or the transamination type reaction, compound (II) and compound (III) are reacted by themselves or using a suitable reaction solvent from about -10°C to the boiling point of the reaction solvent, preferably about 10- Approximately 1 at temperatures in the range of 80°C
This is carried out by reacting for about 0 minutes to 48 hours. The usage ratio of compound (III) is about 1-50 mol, more preferably about 1-10 mol, per 1 mol of compound (II).
It is a mole. Examples of reaction solvents include water, alcohols (e.g., methanol, ethanol, propatool,
so-propanol, butyl alcohol, 5ec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons ( Nitriles (e.g., acetonitrile), aliphatic hydrocarbons (e.g., pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (e.g., cyclopentane, cyclohexane), aromatic Group hydrocarbons (eg, benzene, toluene, xylene), nitromethane, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or a suitable mixed solvent thereof are used. Moreover, if necessary, it may be better to carry out the reaction in the presence of a base. Examples of the base used include bases used in the Wittig reaction. Furthermore, if a phase transfer catalyst (e.g., cetyltrimethylammonium chloride) is used in an amount of about 0.01 to 0.2 equivalent, preferably about 0.02 to 0.05 equivalent, relative to compound (II) or compound (III), It is also possible to advance the reaction advantageously. In the case of a transamination reaction, compound (II) can be converted into a quaternary salt such as methyl bromide, methyl iodide, methyl methanesulfonate, methyl benzenesulfonate, methyl p-toluenesulfonate, etc. to further reduce the reaction. In some cases, the reaction may proceed under certain conditions. (0037) The reaction that forms Schiff's base involves the compound (
II) and compound (III) at a molar ratio (II)/(II
I) = about 10 to 0°1, and react by itself or with a suitable reaction solvent at a temperature in the range of -10°C to the boiling point of the reaction solvent, preferably 0 to 50°C, for about 10 minutes to 48 hours. This is done by letting In addition, in this reaction, compounds in which the aldehyde or ketone moiety of compounds (II) and (III) are protected in the form of acetal or ketul may be used. As the reaction solvent, non-aqueous solvents are preferred, such as alcohols (
Examples, methanol, ethanol, propatool, 1so-
propatool, butyl alcohol, 5ec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (e.g. dimethyl ether, diethyl ether,
Tetrahydrofuran, dioxane, monoglyme, diglyme), esters (e.g., methyl acetate, ethyl acetate), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride), nitriles (e.g., acetonitrile),
Aliphatic hydrocarbons (e.g., pentane, hexane, heptane,
octane), cycloaliphatic hydrocarbons (e.g., cyclopentane, cyclohexane), aromatic hydrocarbons (e.g., benzene,
toluene, xylene), acetone, nitromethane, pyridine, dimethylformamide, dimethyl sulfoxide,
Hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used. As a dehydrating agent, for example, molecular sieves, calcium chloride, magnesium sulfate, sodium sulfate, calcium sulfate, etc. may be added, or the pH of the reaction solution may be adjusted with an acid (e.g., hydrochloric acid, hydrobromic acid, hydrogen iodide). acids, sulfuric acid, nitric acid, phosphoric acid),
Bases (e.g. metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, potassium te
rt-butoxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium bicarbonate, trimethylamine, triethylamine, triethanolamine, pyridine) or buffers (e.g., phosphate buffer, borate buffer, acetate buffer) By adjusting this, the reaction rate and yield can be improved. [0038] Schiff base reduction reactions and reductive alkylation reactions are carried out by hydride reduction or catalytic reduction using a suitable solvent at reaction temperatures ranging from about -40°C to the boiling point of the solvent, more preferably from about 0 to 50°C. This is done by As the solvent used, in addition to the reaction solvent used in the above-mentioned alkylation type reaction or amination type reaction, acetic acid esters (eg, methyl acetate, ethyl acetate), etc. are also used. For the catalytic reduction reaction, the method A described above is applied as is. Examples of reagents for hydride reduction include lithium aluminum hydride, sodium borohydride, lithium borohydride, and lithium cyanoborohydride. About twice the molar amount, usually 2 to 20 times the molar amount, is used. [0039] In addition, when A1 ring or A2 ring is N-substituted pyrrole, furan, thiophene, thiophene-1-oxide or thiophene-1,1-dioxide and -Z2 is -NH-, the -HN- group is A1 Ring or A2
It may be condensed and closed with a ring to form a tetracyclic compound. In this case, it can be easily converted into the desired bicyclic compound by treatment with an acid or a base.

In addition, the compound (I) of the present invention obtained in this magazine
is subjected to a catalytic reduction reaction based on method A if necessary.
It is also possible to partially reduce ring 1 or ring A2 to convert it into a compound (■') included in the compounds of the present invention. Production method according to claim (4): [0041] Compound (I) of the present invention can also be produced, for example, by the following reaction steps.

[0042] In the above formula, AI , A2, -B'-1Q1
, Q2, Q3, Y, Z, R and R' have the same meanings as above. In the above reaction step (second step), the compound (I) of the present invention or a salt thereof is converted into a glutamic acid derivative represented by the formula (V), a carboxylic acid represented by the formula (IV), or a reactive derivative at the carboxy group thereof. It can be obtained by acylation with Examples of the above-mentioned acylation method include a method of acylating compound (V) with compound (■■) or a reactive derivative thereof in the presence of carbodiimides, diphenylphosphate azide or diethyl cyanophosphate. The amount of compound (V) to be used is generally about 1% per compound (IV) or its reactive derivative.
-20 molar equivalents, preferably 1-5 molar equivalents. The carbodiimide may be used in an amount of generally about 1 to 25 molar equivalents, preferably about 1 to 5 molar equivalents, based on compound (■■). As the carbodiimide, dicyclohexylcarbodiimide is practically preferred, and other carbodiimides such as diphenylcarbodiimide, di-0-tolylcarbodiimide, di1)-)lylcarbodiimide, di-tertbutylcarbodiimide,
-Cyclohexyl-3(2-morpholinoethyl)carbodiimide, ■-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 an appropriate solvent, such as water, alcohols (e.g. methanol,
ethanol), ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (e.g. acetonitrile), esters (e.g. ethyl acetate), halogenated hydrocarbons (e.g. dichloromethane, chloroform, (carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), acetone, nitromethane, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof. . This reaction is usually carried out at a pH of about 2 to 1.
4, preferably at a pH in the range of about 6 to 9, at about -10°C
The reaction can be carried out at a reaction temperature in the range from about 100 to about the boiling point of the reaction solvent (about 100°C), preferably from about 0 to 50°C, for about 1 to 100 hours. Adjust the pH of the reaction solution as appropriate, such as with an acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid).
, bases (e.g., sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium bicarbonate, trimethylamine, triethylamine, ethanolamine, pyridine) or buffers (e.g. phosphate buffer,
Adjust as necessary with borate buffer, acetate buffer), etc. Note that the reaction can proceed more advantageously by using a catalyst that can promote acylation. Examples of such catalysts include base catalysts and acid catalysts. Such base catalysts include, for example, tertiary amines (
Examples, aliphatic tertiary amines such as triethylamine; such as pyridine, α-1β- or τ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4-(1-pyrrolidinyl)pyridine, dimethylaniline, diethylaniline. Acid catalysts include, for example, Lewis acids [e.g., anhydrous zinc chloride, anhydrous aluminum chloride (A I C13), anhydrous ferric chloride, titanium tetrachloride (T 1C14), Silver chloride (SnC14)
, antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.). Among the above catalysts, 4-dimethylaminopyridine or 4-(1
-pyrrolidinyl)pyridine and the like are often preferred. The amount of catalyst to be used is such that it can promote acylation, and is usually about 0.01-100 molar equivalents, preferably about 0.1-1 molar equivalents, based on compound (IV). Examples of reactive derivatives at the carboxy group of carboxylic acid (IV) include acid halides (e.g., fluoride, chloride, bromide, iodide) and acid anhydrides (e.g., iodoacetic anhydride, isobutyric anhydride) of carboxylic acid (IV). )
, lower monoalkyl carbonate (e.g., monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono-1so-propyl carbonate, mono-butyl carbonate, mono-1so-butyl carbonate,
Mixed acid anhydrides with mono-5ec-butyl carbonate, mono-tert-butyl carbonate), active esters (e.g.
Cyanomethyl ester, ethoxycarbonyl methyl ester, methoxymethyl ester, phenyl ester, O
-nitrophenyl ester, p-nitrophenyl ester, p-carbomethoxyphenyl ester, p-cyanophenyl ester, phenylthioester), acid amide, phosphoric acid diester (e.g. dimethyl phosphate, diethyl phosphate, dibenzyl phosphate, diphenyl phosphate) mixed acid anhydrides, phosphorous diesters (e.g. dimethyl phosphite, diethyl phosphite,
Also included are mixed acid anhydrides with dibenzyl phosphite and diphenyl phosphite. In the acylation procedure using this reactive derivative, the solvent, catalyst, reaction temperature, etc. are the same as in the case of the acylation carried out in the presence of the carbodiimide. [0043] Furthermore, among compound (I) or a salt thereof,
When producing compound (I-1) or a salt thereof in which C0OR and -COOR' are carboxyl groups, compound (
Of V), a compound in which -COOR and -COOR' are esterified carboxyl groups is reacted with compound (IV) or a reactive derivative of its carboxyl group, and then subjected to a known decomposition reaction or catalytic reduction reaction. It is preferable to perform deesterification. Examples of the decomposition reaction include a hydrolysis reaction under basic conditions (method B), a hydrolysis reaction under acidic conditions (method C-1), a decomposition reaction under acidic non-aqueous conditions (method C-2), etc. can be mentioned. Examples of the base used in Method B include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium butoxide, and potassium butoxide, and metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide. Examples of acids used in the C-1 method include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, trifluoroacetic acid, and trichloroacetic acid. B2
Catalysts used in the process include, for example, mineral acids such as hydrogen chloride, hydrogen bromide, perchloric acid, sulfuric acid, nitric acid, and phosphoric acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluene. Sulfonic acid,
Organic acids such as camphorsulfonic acid, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl2), anhydrous ferric chloride,
Titanium tetrachloride (TiC14), silver tetrachloride (S n C1
4) Antimony pentachloride, cobalt chloride, cupric chloride,
Lewis acids such as boron trifluoride etherate may be mentioned. The decomposition reaction is carried out in each case in a suitable solvent in the range from 0°C to the boiling point of that solvent, preferably 10-80°C.
This is done by reacting for 30 minutes to 2 days. In the case of method B and method C-1, for example, water,
methanol, ethanol, propatool, butanol,
Ethylene glycol, methoxyethanol, ethoxyethanol, tetrahydrofuran, dioxane, monoglyme, diglyme, pyridine, dimethylformamide, dimethyl sulfoxide, sulfolane or suitable mixtures thereof are used, in the case of process C-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 includes A described in detail in the first step.
The law may be applied as is. Which reaction induces compound (I-1) is -COOR and COOR
Although it varies depending on the nature of ', usually -COOR and -COOR' are methyl, ethyl, propyl, butyl, 5
For carboxy groups esterified with ec-butyl, phenyl or substituted phenyl groups, method B or C-
1 method, -COOR and -COOR' is. When the carboxy group is esterified with a propyl or tert-butyl group, the C-2 method is advantageously applied, and when the carboxy group is esterified with a benzyl group or a substituted benzyl group, the C-1 method or A method is advantageously applied. be done. In addition, when -COOR and -COOR' are different, what is necessary is just to combine the said A method, B method, C-1 method, and C-2 method suitably. Production method according to claim (5): [0044] The compound (I) of the present invention can also be produced, for example, by the following reaction steps.

embedded image [0045] In the above formula, AI, AI 2 , A2, -B. L', Ql, Q2, Q3, X1', Y and Z have the same meanings as above. The above reaction step (third step) is
This is a method for producing the compound (I) of the present invention or a salt thereof by forming a covalent bond between and A'' or X1' and L' to form an AI ring. When L' is a leaving group, an alkylation type reaction or an exchange type reaction is used, and when L' is a leaving group, an alkylation type reaction or an exchange type reaction is used.

[75] [In the formula, R1 has the same meaning as above. ], Schiff base formation reaction, Schiff base reduction reaction, reductive alkylation reaction, etc. are advantageously used. These alkylation type reactions, transamination type reactions, Schiff base formation reactions,
Regarding the reaction reagent, reaction solvent, reaction conditions, etc. in the Schiff base reduction reaction or reductive alkylation reaction, the conditions detailed in the first step are applied as they are. Production method according to claim (6): [00461 Compound (I) of the present invention can also be produced, for example, by the following reaction steps.

[0047] In the above formula, AI, A2-B, Q, Q',
Ql, Q2, Q2', Q3, Q3', Y and Z have the same meanings as above. The above reaction step (fourth step) involves subjecting compound (nI) and compound (VIII) to a cyclization reaction,
This is a method for producing the compound (I) of the present invention or a salt thereof. When compound (nII) can form a salt, those salts may be used. Examples of the acid salt of compound (VIII) include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
Mineral acid salts with nitric acid, phosphoric acid, boric acid, etc., silicic acid, tartaric acid, lactic acid, citric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p
- Organic acid salts with toluenesulfonic acid, camphorsulfonic acid, etc., and examples of base salts of compound (VIII) include sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, etc. , triethylammonium, triethanolammorum, pyridinium,
Examples include salts with substituted pyridinium and the like. [0048] Compound used in the cyclization reaction (
The amount of VIII) is usually about 1-20 molar equivalents, more preferably about 1-5 molar equivalents, relative to compound (II). Furthermore, the cyclization reaction can be advantageously carried out under basic conditions. Examples of the base used in this case include metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide. Examples of the reaction solvent include methanol, ethanol, propatool, tert-butyl alcohol, dimethyl sulfoxide, hexamethylphosphoramide, etc., the reaction temperature is 0-150°C, preferably 20-100°C, and the reaction time is 1. -48 hours. Examples of the reaction solvent include water, methanol, ethanol, propatool, tert-butyl alcohol,
Dimethyl sulfoxide, hexamethylphosphoramide, or an appropriate mixed solvent thereof is used. [0049] When B' included in the definitions of -B and -B is a cycloalkenyl group, a cycloalkenylene group, a phenyl group, or a phenylene group, these groups are It may be converted into the corresponding cycloalkyl group or cycloalkylene group by subjecting it to a catalytic reduction reaction. As the catalytic reduction reaction,
The aforementioned method A is advantageously applied as is. [0050] Q' is a hydroxyl group, an alkoxy group,
Aryloxy group, 5- to 6-membered heterocyclic oxy group, mercapto group, alkylthio group, arylthio group, 5- to 6-membered heterocyclic thio group, substituted amino group, alkanoylamino group, aroylamino group, or 5- to 6-membered heterocyclic group In the case of a ring carbonylamino group, it is subjected to a conversion reaction known per se in an appropriate step among the first to fourth steps,
5- to 6-membered heterocyclic group defined by Ql, halogen atom, cyano group, carboxy group, carbamoyl group, nitro group, hydroxy group, alkoxy group, aryloxy group,
5- to 6-membered heterooxy group, mercapto group, alkylthio group, arylthio group, 5- to 6-membered heterocyclic thio group, substituted amino group, alkanoylamino group, aroylamino group, 5- to 6-membered heterocyclic carbonylamino group, It may be converted into an alkanoyloxy group, an aroyloxy group, or a 5- to 6-membered heterocyclic carbonyloxy group. [0051] When the AI ring, the A2 ring, -B and -B'- contain a sulfur atom, or when -72- is -S- (sulfur atom), the compound (I) of the present invention is directly subjected to an oxidation reaction. The sulfur atoms of ring A1, ring A2, -B, -B'- and -Z2- are converted into S (0) n [n= 1 to 2]. The oxidation reaction is usually carried out in an appropriate solvent at -10 to +100°C, preferably in the presence of an oxidizing agent of 0.3 to 3.0 equivalents, preferably 0.5 to 2.5 equivalents, based on the compound to be oxidized. is 0~+50℃
It can be produced by reacting for 10 minutes to 48 hours, preferably 30 minutes to 24 hours. Oxidizing agents used in the reaction include peracids (e.g. hydrogen peroxide,
Peracetic acid, perbenzoacetic acid, m-chloroperbenzoacetic acid) are preferred. Reaction solvents include water, acetic acid, ketones (e.g.
acetone, ethyl methyl ketone), ethers (e.g. dimethyl ether, diethyl ether, dioxane, monoglyme, diglyme), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), aliphatic hydrocarbons (e.g. pentane, hexane) , heptane, octane),
A cycloaliphatic hydrocarbon (eg, cyclopentane, cyclohexane), an aromatic hydrocarbon (eg, benzene, toluene, xylene), or an appropriate mixed solvent thereof is used. [0052] Also, compounds (I), (II), (IV
), (VI) and (IX), the amino group, hydroxyl group or mercapto group represented by Ql can be converted into each other by a substituent conversion reaction known in the literature, if necessary. [Separate volume Protein Nucleic Acid Enzyme, Chemical Synthesis of Nucleic Acid, Prefectural Publishing (1
968)) [0053] Furthermore, reactions carried out or used in the first to fourth steps, reagents, reaction conditions, and general synthetic methods for raw material compounds, as well as protection for various functional groups used as necessary. Applications of the groups are well known and explained in detail in the following documents. [J, F, W, McOmine, Protective Groups in Organic Chemistry (
P r o tectivGroups in O
rganic chemistry plenum
PressLond. n and New York (1973))
, [Pine Hentrickson Hammond, Organic Chemistry (
4th edition) [I]-[I■], Tokoyou Shoten (1982)) and CM. Fieser and L, Fieser1 Regient for Organic Synthesis No. 1-13
Volume (Reagents for Organic 5
ynthes is vol, 1-13), Wi
1ey-Interscience, New Yo
rk, Lond. n, 5ydney andToronto (196
91988)] [0054] Compound (I) of the present invention produced by the above method
can be isolated from the reaction mixture by conventional separation and purification means such as concentration, solvent extraction, chromatography, recrystallization, etc. [0055] Compound obtained by the production method of the present invention (
I), (II), (IV), (VI) and (IX)
may form a salt. Base salts include alkali metals, alkaline earth metals, non-toxic metals, ammonium and substituted ammoniums, such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium. ,
Examples include salts of pyridinium and substituted pyridinium. Examples of acid salts include mineral acid salts with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, etc., silicic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. and organic acid salts with camphorsulfonic acid and the like. [0056]

[Action and Effects of the Invention] The compound (I) of the present invention or a salt thereof has an inhibitory effect on one or more enzymes that utilize folic acid and its related compounds as substrates. Therefore, these compounds may be used to treat hair cancer, leukemia, breast adenocarcinoma, epidermal carcinoma of the head and neck, squamous cell carcinoma, small cell lung cancer, and lymphosarcoma, as well as various other tumors that have been treated with MTX to date. It can be used alone or in combination with other antitumor agents. [0057] When used as an antitumor agent, compound (I)
or their salts by itself or by using pharmacologically acceptable carriers, excipients, diluents, etc., by conventional methods, such as powder, granule, tablet, capsule, flattening, injection. It can be administered orally or parenterally in the form of a drug. The dosage varies depending on the target animal, disease, symptoms, type of compound, administration route, etc., but for example, in the case of oral administration, the compound of the present invention may be administered to the warm-blooded animal at a dose of about 2.0-500 mg/kg body weight per day. Yes, approximately 1.0-200mg/k per day for parenteral administration
It is g. Examples of administration methods for injections include intramuscular injection, intraperitoneal injection, subcutaneous injection, and intravenous injection. [0058] The above formulation is performed according to a method known per se. When manufacturing the above oral preparations, for example, tablets, binders (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.),
Disintegrants (eg, starch, carboxymethylcellulose calcium, etc.), lubricants (eg, magnesium stearate, talc, etc.), and the like can be appropriately blended. [0059] In addition, when manufacturing parenteral preparations, such as injections, tonicity agents (e.g., glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (e.g., benzyl alcohol, Chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffers (eg, phosphate buffer, sodium acetate buffer, etc.), etc. can be blended as appropriate. [00601 As a specific example of the production of tablets, for example, the amount of the compound of the present invention used per needle may be 1.0-100 m
g1 lactose 100-500 mg, corn starch approx. 501
00mg, hydroxypropylcellulose approx. 5-20m
g is mixed in a conventional manner, granulated, mixed with cornstarch and magnesium stearate, and then compressed into tablets each weighing approximately 100-500 mg and having a diameter of approximately 3-10 mm. In addition, this tablet contains hydroxypropyl methyl methyl cellulose phthalate (about 10-20 mg) and castor oil (about 0.5-2.0 mg) per needle.
and acetone dissolved at a concentration of 5-10%.
Enteric-coated tablets can also be made by coating with an ethanol mixture. As a specific example of preparing an injection, for example, the amount used per ampoule is about 2.0-100 mg of the sodium salt of the compound of the present invention.
is dissolved in about 2 ml of physiological saline and poured into an ampoule, which is then sealed and heat sterilized at about 110°C for about 30 minutes, or about 10-40 mg of mannitol or sorbitol is sterilized into about 2 ml. It can also be prepared by dissolving it in distilled water, pouring it into an ampoule, freeze-drying it, and sealing it. When using the lyophilized compound, open the ampoule and add the compound to physiological saline at a concentration of about 1.0-50 mg/m2.
It can be prepared as a solution and prepared as an injection to be administered subcutaneously, intravenously or intramuscularly. (00611 To specifically illustrate the compound of the present invention, for example, 2-amino-6-(((3,4,5-trimethoxyphenyl)amino)methyl)-8,9-dihydro-7H-dihydro(2, 3-d: 3', 2'
-e) Pyrimidine, N-[4-[:N-((2-amino-5Hfuro[2,3,4-deEquinazolin-6-yl)methyl)-N-2-propynylamino]benzoyl]
-L glutamic acid, N-(4-[N-[(2-aminocyclobento[d]pyrido[:3.2-e]pyrimidin-7-yl)methyl-N-2-propynylaminocobenzoyl]L- Glutamic acid, N-(4-(2-(2-amino7,8-dihydro-7H-dipyrido(2,3-d:
3',2'-e]pyrimidin-7-yl]ethyl]benzoyl)-L-glutamic acid, N-(4-(2-(2amino-7,8-dihydro-pyrido[2,3-d:] pyrrolo[3,2-e)pyrimidin-6-yl]ethyl]benzoyl)-L-glutamic acid, N-[:4-[:3-(
2-amino-5,6,6a, 7. 8. 9-hexahydro-4H-dipyrido (2,3-d: 3', 2
'-elpyrimidin-6a-yl]propyl]benzoyl)-L-glutamic acid, N-[4-[2-[2-amino-IH-nato[1,8-de)pyrimidin-6-yl]ethyl]benzoyl )-L-glutamic acid and the like. [0062]

[Reference Examples and Examples] The present invention will be specifically explained below with reference examples and examples. [0063] Reference Example 1 5(4-(tert-butoxycarbonyl)phenyl)
-Production of methyl 2-pentenoate: Toluene solution (50 ml) of tert-butyl 4-(3-oxopropyl)benzoate (6,06 g) and methyl (triphenylphosphoranylidene) acetate (9,51 g)
) was heated under reflux for 45 minutes, then cooled to room temperature, hexane (100 ml) was added to the reaction solution, and the formed crystals were filtered off. The residue obtained by concentrating the filtrate was purified by flash column chromatography (silica gel 150 g, developing solvent ethyl acetate-hexane 1:10) to obtain the title compound (7.62 g) as white crystals. IR(N
eat): 2985, 2950, 1730, 1715.
1660, 1610, 850 cm-1,'H-NMR (
CDC13) δ: 1. 59 (9H, s),
2. 54 (2H, tdd, J=8Hz, 7Hz,
2Hz), 2°83 (2H, t, J=8Hz)
, 3. 72 (3H. s), 5.83 (LH, dt, J=16Hz, 2H
z), 6.98 (LH, dt, J=16Hz, 7H
z), 7. 22 (2H, d, J=8Hz)
, 7. 92 (2H, d, J=8Hz). [0064] Reference Example 2 5[4-(tert-butoxycarbonyl)phenyl)
-3-[:methylsulfinyl(methylthio)methyl]
Production of methyl pentanoate: Methylmethylsulfinylmethylsulfide (869g
) in tetrahydrofuran solution (5 ml) at -30°C was a hexane solution of butyllithium (7.0 mmol) (
4.4ml) was added thereto, and the mixture was stirred at -20°C for 20 minutes. A tetrahydrofuran solution (5 ml) of the compound of Reference Example 1 (1.45 g) was added dropwise to the reaction mixture at -78°C, and the mixture was stirred for 2 hours. Add 1N potassium hydrogen sulfate aqueous solution (10m
1) was added and extracted with ether. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by flash column chromatography (silica gel 50 g, developing solvent ethyl acetate-hexane 3:1) to give the title compound (
1.39 g) was obtained as a colorless oil. This is a mixture of diastereomers (diastereomer ratio 1=1)
, and the physical and chemical data for each are shown. The isomer IR that elutes first in chromatography (
Neat): 2975, 2925, 1730, 1710
．． 1605,1045cm-1,'H-NMR (CDC
13) δ:1. 59 (9H, s), 1. 75
-2. 30 (3H, m), 2. 35 (3H
,s), 2. 56-2゜95 (4H, m)
, 2. 63 (3H,s), 3. 5
0 (LH, d, J=5Hz), 3. 63
(3H,s). 7.25 (2H, d, J=8Hz), 7.92 (2
H. d, J = 8 Hz), later eluted isomer IR (
Neat): 2975, 2925, 1735, 1710
．． 1605,1040cm-1,'H-NMR (CDC
13) δ: 1. 59 (9H,s), 1.9
0-2.40 (3H, m), 2.27 (3H,
s), 2. 65-2゜90 (4H, m),
2. 74 (3H,s), 3. 59 (L
H, d, J=4Hz), 3. 69 (3H,
s). 7, 25 (2H, d, J=8H2), 7.
92 (2H. d, J=8Hz). [0065] Reference Example 3 Production of methyl 5-(4-(tert-butoxycarbonyl)phenyl)-3-(dimethoxymethyl)pentanoate: A methanol solution (2
To 0ml) was added methyl orthoformate (20ml) followed by boronic trifluoride (355mg),
Stirred at room temperature for 5.5 hours. Ether (50 ml) and saturated aqueous sodium bicarbonate solution (20 ml) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred for 15 minutes and then extracted with ether. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by flash column chromatography (silica gel 25 g, developing solvent ethyl acetate-hexane 1:8) to give the title compound (352 mg).
was obtained as a colorless oil. IR(KBr): 29
75°2930.1740,1710.1608cm-
1,'HNMR (CDC1a) δ:1. 50-
1. 72 (2H, m), 1. 72-1.
93 (LH, m), 1. 59 (9H, s)
, 2. 20-2.40 (2H, m), 2
゜60-2. 75 (2H, m), 3. 33
(3H,s). 3, 36 (3H,s), 3. 68 (3H
,s), 4. 23 (LH, d, J=5Hz
), 7. 23 (2H, d, J8Hz),
7.90 (2H, d, J=8Hz). [0066] Reference Example 4 5 (4-(tert-butoxycarbonyl)phenyl)
Production of methyl -3-(dimethoxymethyl)-2-iodopentanoate: Diisopropylamine (5.87 g) under argon atmosphere
A hexane solution (3,8 mmol) of butyllithium (5,8 mmol) was added to a tetrahydrofuran solution (25 ml) at 0°C.
6ml) was added and stirred for 10 minutes. After cooling to -78°C, a solution of the compound of Reference Example 3 (2.14 g) in tetrahydrofuran (10 ml) was added dropwise over 30 minutes. After stirring for 30 minutes, a solution of iodine (1.35 g) in tetrahydrofuran (10 ml) was added, and the mixture was further stirred for 20 minutes. The temperature was raised to 0°C over 30 minutes, a 1N aqueous potassium hydrogen sulfate solution (6 ml) was added dropwise, and the mixture was extracted with ether. The organic layer was washed with a 1N aqueous potassium carbonate solution, then with saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by flash column chromatography (silica gel 50 g, developing solvent ether-hexane 1:10) to give the title compound (
1.62 g) was obtained. IR(Neat):2980
．． 2925, 1740, 1715, 1610cm-1'
HNMR (CDC13) δ: 1.45-1. 80 (2
H, m), 1. 59 (9H,s), 1
．． 90-2°50 (3H, m), 3. 36
(3H,s), 3. 40 (3H, s), 3
．． 72 (3H,s), 4. 35 (IH, d,
J=5Hz), 4.47 (2H, d, J=7Hz),
7. 20 (2H, d, J=8Hz),
7. 90 (2H, d, J=8Hz). [0067] Reference Example 5 Production of methyl 5-(4-(tert--butoxycarbonyl)phenyl)-2-(dicyanomethyl)-3-(dimethoxymethyl)pentanoate: Suspension of sodium hydride (394 mg) in dimethyl sulfoxide A solution of malononitrile (1,083 g) in dimethyl sulfoxide (3 ml) was added to a solution produced by stirring the cloudy liquid (3 ml) at 70° C. for 2 hours under water-cooling conditions, and the mixture was stirred for 15 minutes. Add the compound of Reference Example 4 (1,615 g) to this solution.
A dimethyl sulfoxide solution (4 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour.
15 ml) was added and extracted with ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel 40 g, developing solvent ethyl acetate-hexane 1:5) to give the title compound (1, 201g
)was gotten. IR(Neat):2970,2935
．． 2250, 1735, 1710.1605cm-1'
HNMR (CDC13) δ:t, 45-1. 9
5 (2H, m), 1. 58 (9H, s),
2. 05-3゜25 (4H, m), 3
．． 39 (3H,s), 3. 46 (3H,
s), 3. 85 (3H, s), 4. 1
5 (IH, d, J=5Hz), 4.38 (LH,
d, J=4Hz), 7. 20 (2H, d,
J=8Hz), 7. 92 (2H, d, J=8H
z). [0068] Reference Example 6 4-(3-(2,4-diamino-6-oxo-6,7
Dihydro 5H-pyrrolo(2,3-d)pyrimidine-5
Preparation of tert-butyl)-3-(dimethoxymethyl)propyl]benzoate: Potassium tert-butoxide (39
9 mg) and guanidine hydrochloride (314 mg).
A tert-butyl alcohol solution (3 ml) of the compound of Reference Example 5 (1,181 g) was added to an rt-butyl alcohol solution (4 ml), and the mixture was heated under reflux for 4 hours. The reaction solution was cooled, poured into ice water, and the resulting crystals were collected by filtration and washed with methanol and then ether to obtain the title compound (1,02
8 g) were obtained as white crystals. IR (KBr)
: 3435.3360,1710,1625,158
0.1433cm','H-NMR (CDC13/Me
2s. de ) δ: 1. 25-1. 84 (2H, m)
, 1. 57 (9H,s), 1. 8
8-2. 95 (3H, m). 3, 23-3. 52 (LH, m), 3.
47 (3H.s), 3. 53 (3H,s), 4. 3
5 (IH, d, J=4Hz), 5.42
(2H, brs), 5. 56 (2H,brs
), 6. 34 (LH, brs), 7. 1
7 (2H, d, J=8Hz), 7. 92
(2H, d, J8Hz). [0069] Reference Example 7 4-[:3-(2,4-diamino-6,7-sihydro-5H-pyrrolo[2,3-d)pyrimidin-5-yl)-3(dimethoxymethyl)propyl]benzoic acid ter
Production of t-butyl A tetrahydrofuran solution (28 mmol) of borane-tetrahydrofuran complex (28 mmol) was added to a tetrahydrofuran solution (35 ml) of the compound of Reference Example 6 (1.60 g) at 0°C.
After stirring for 10 minutes, the mixture was stirred at room temperature for 22 hours. After cooling, acetic acid-methanol (1:2
, 63ml) and stirred at 50°C for 3.5 hours, the solvent was distilled off under reduced pressure and the resulting residue was subjected to flash column chromatography (silica gel: 140g, developing solvent: dichloromethane:ethanol = 19:1 → dichloromethane). :Ethanol containing 9% ammonia-19:1) to give the title compound (562 mg). [00701IR(KBr):3360,3330,3
150.2980, 1715, 1660, 1605, 1
580.1440,1290crrr”H-NMR(C
DC13) δ: 1. 58 (9H, s),
1. 63-1. 90 (3H, m), 2.71
(2H, t, J=7.4Hz), 3.12 (L
H, dd, J=9.3Hz, 3H2), 3.32 (
3H,S), 3.41 (3H,S). 3, 34-3. 42 (LH, m), 3.
69 (LH, dt, J=9.6Hz, 1.8Hz),
4.31 (LH. s), 4.36 (LH, d, J=6Hz), 4.5
3(2H,s), 5. 02 (2H,s)
, 7. 19 (2H, d, J=8. 2H
z), 7. 89 (2H, d, J8.2H
z). [00711 Example 1 4-(2-(2-amino-7,8-dihydropyride)
Production of tert-butyl 2,3-d:]pyrrolo[3,2-e)pyrimidin-6yl)ethyl]benzoate: The compound of Reference Example 6 (1,010 g) was added to a solution of tetrahydrofuran (10 ml) at 0°C. A tetrahydrofuran solution (22,1 ml) of borane-tetrahydrofuran complex (22,1 m mol 1) was added, stirred for 10 minutes, and then heated at 50°C for 5 minutes.
Stir for hours. After cooling, acetic acid-methanol (1
: 1. After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure and the resulting residue was subjected to flash column chromatography (30 g of silica gel, developing solvent dichloromethane-ethanol 30:1 → 15:1 → dichloromethane-ammonia 6%). Purification with ethanol containing 20:1) gave the title compound (542 mg). IR
(KBr): 3350, 3200, 2980°2935
．． 1715,1603crrr','H-NMR(
CDC13/Me2 so de) δ: 1.57 (9
H,s), 2.85-3. 18 (4H,br
), 3. 67-4. 22 (2H, m),
4. 85 (2H, brs), 5. 45
(LH, brs), 7. 19 (2H. d, J=8Hz), 7.80 (2H, d, J=8H
z), 8.38 (LH,s). [0072] Example 2 N-(4-(2-(2-amino-7,8-dihydropyrido[:2.3-d]pyrrolo[:3.2-e:]pyrimidin-6yl)ethyl]benzoyl ] - Production of diethyl L-glutamate: Trifluoroacetic acid (3 ml) was added to the compound of Example 1 (520 mg) under an argon atmosphere, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the mixture was heated to 70°C. The residue obtained by drying under reduced pressure and diethyl glutamate hydrochloride (496 mg
) was added with a dimethylformamide solution (5 ml) of diethylphosphorocyanidate (236 mg) at 0°C and stirred for 15 minutes, followed by a dimethylformamide solution (6 ml) of triethylamine (630 mg) at the same temperature. ) was added dropwise. After stirring at 0°C for 30 minutes and at room temperature for 2 hours, the solvent was distilled off from the insoluble matter under reduced pressure, and the resulting residue was subjected to flash column chromatography (30 g of silica gel, developing solvent: dichloromethane-ethanol containing 6% ammonia 30:1). →20
:1) The title compound (591 mg) was obtained by purification by
I got it. IR (KBr): 3375, 3200, 29
75.2930,1735,1605,853crrr
','H-NMR (CDC13/Me2so-de)δ
: 1. 23 (3H, t, J=7Hz),
1. 31 (3H, d, J=7Hz), 2
．． 10-2. 55 (4H. m), 2.85-3. 18 (4H,br)
, 3. 604, 25 (2H, m), 4. 1
2 (2H, q, J=7Hz), 4.25 (
2H, q, J=7Hz), 4. 704, 8
5 (LH, m), 4. 98 (2H, brs)
. 5, 43 (LH, brs), 7.20 (2H,
d, J=8Hz), 7.81 (2H,d,
J=8Hz), 8. 53 (LH,s),
8.66 (LH, d, J=7Hz). [0073] Example 3 N-[4-(2-(2-amino-7,8-dihydropyrido[2,3-d)pyrrolo[:3.2-e)pyrimidin-6yl)ethyl]benzoyl)- Production of L-glutamic acid: A 1N aqueous sodium hydroxide solution (2.92 ml) was added to a mixed solution of the compound of Example 2 (508 mg) in tetrahydrofuran water (5:3.16 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was concentrated to 5 ml under reduced pressure, filtered through a Millipore filter, acetic acid (0.7 ml) was added, and the resulting crystals were collected by filtration and thoroughly washed with ice water. The title compound (38
5 mg) was obtained as white crystals. IR(KBr): 3
320.1690, 1680-1610, 1635, 1
540.850cm-1,'H-NMR(Me2So-
d6) δ: 1. 87-2. 65 (4H, m)
, 2. 90-3°15 (4H, m), 3
．． 55-4.40 (3H, m). 5, 50 (2H, brs), 6. 00
(LH, brs), 7. 28 (2H,d,
J=8Hz), 7. 78 (2H, d, J=8
Hz), 8. 25-8. 38 (LH, m
), 8. 55 (LH,s). [0074] Example 4 N-(2-(2-amino-5-ethoxy-4,5,6°6a,7.8-hexahydropyrido[:2.3-d]
Piroro [:3. Production of ethyl 2-e:]pyrimidin-6-yl)ethylbenzoate The compound of Reference Example 7 (A: 444 mg) was dissolved in a 20% hydrogen chloride ethanol solution (45 ml), and the
Stir for hours. After neutralization by adding 9% ammonia-containing ethanol under water cooling, the solvent was distilled off. The residue was extracted with chloroform, and the extracted product was purified by flash column chromatography (silica gel: 50 g, developing solvent: chloroform:methanol = 24:1) to give the title compound (189
mg) was obtained. IR(KBr):3380,322
0.2980, 1720, 1640, 1615, 144
0.1280,1110cm-1,'H-NMR(Me
2SOd6) δ: 1. 10 (3H,t,
J=7.2Hz), 1. 31 (3H,t,
J=7.2Hz), 1. 60-1. 89
(2H, m), 2. 68 (2H, t, J
=6, 6Hz), 2. 84-3. 10 (
2H, m), 3゜28-3.41 (2H, m)
, 3. 68 (2H, q, J=7. 2H
z), 4. 29 (2H, q, J=7.
2Hz), 4. 46-4. 52 (IH, m
), 5. 59 (2H, s), 5. 81
(LH,s), 7. 29 (IH. d, J=4.4Hz), 7. 36 (2H
, d, J=8°2Hz), 7. 88 (2
H, d, J=8. 2Hz) [0075] Example 5 N-(4-[:2-(2-amino-5-ethoxy-4
゜5, 6. 6a, 7. 8-hexahydropyrido[2,3d]pyrrolo(3,2-e]pyrimidine-6-
Production of diethyl (benzoyl)-ethyl)-L-glutamate The compound of Example 4 (179 mg) was dissolved in tetrahydrofuran methyl alcohol (1:1.18 ml), and a normal sodium hydroxide solution (1.35 ml) was added. After that, the mixture was stirred at room temperature for 15 hours. In addition to this, 1 stipulation-
After neutralization by adding hydrochloric acid (1.35ml), the solvent was distilled off and the residue was dried under reduced pressure at 70°C to give crude 4-C2-(2-
Amino 5-ethoxy-4,5,6,6a, 7. 8
-hexahydropyrido(2,3-d)pyrrolo[:3.2
-e:]]pyrimidin-6-yl]ethyl]benzoin was obtained. This whole amount was mixed with a dimethylformamide solution (13,
Then, a dimethylformamide solution (1 ml) of diethyl cyanophosphate (77 mg) was dissolved at 0°C.
After adding triethylamine (160 mg) at the same temperature
A dimethylformamide solution (1.0 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to flash column chromatography (silica gel: 28 g, dichloromethane separated from concentrated aqueous ammonia → 10% NHs).
Purification with ethanol-containing chloroform (1:24) gave the title compound (126 mg) as white crystals. IHNMR (Me2 so d6) δ: 1. 12
(3H, t. J=7.2Hz), 1.17 (3H, t.
J=7.2Hz), 1. 19 (3H,t,
J=7. 2Hz), 1. 61-2. 18
(4H, m), 2.44 (2H, t, J
=7, 4Hz), 2. 67 (2H,t,
J=6. 6Hz), 2. 84-3. 11
(2H, m), 3. 283, 41 (2
H, m), 3. 88 (2H, q, J=7
゜2Hz), 4. 05 (2H, q, J
=7. 2Hz). 4, 11 (2H, q, J=7.2Hz),
4. 364, 48 (LH, m), 4
．． 49-4. 53 (LH. m), 5. 60 (2H, s), 5. 82
(IH, s). 7, 28 (LH, d, J=4.4Hz),
7. 37 (2H, d, J=8.2Hz)
, 7. 88 (2H, d, J=8, 2Hz
), 8. 65 (LH, d, J=7.8H
z) [0076] Example 6 N-(4-[2-(2-amino-5-ethoxy-4°5
, 6. 6a, 7. 8-hexahydropyride [
Preparation of [2,3d]pyrrolo(3,2-elpyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid The compound of Example 5 (120 mg) was subjected to the same reaction as in Example 3 to yield the title compound (94 mg). )was gotten. IHNMR
(Me2 so d6) δ:1. 10 (3H,t
. J=7. 2Hz), 1. 63-2. 19
(4H, m). 2, 36 (2H, t, J=7.2Hz),
2. 66 (2H, t, J=5.6Hz),
2. 81-3. 12 (2H, m),
3. 27-3. 42 (2H, m), 3.
69 (2H, q, J=7.2Hz), 4.
34-4. 47 (LH, m), 4. 48-
4. 53 (IH, m), 5゜68 (2H
, s), 5. 91 (IH,s), 7
．． 26 (IH, d, J=4.4Hz),
7. 36 (2H, d.

Claims (7)

[Claims] Claim 1 General formula [1] [In the formula, A1 ring and A2 ring are the same or different and each is a 5- to 7-membered ring which may have a substituent, -B
is a cyclic group which may have a substituent or formula [2] [In the formula, -B'- is a divalent chain group which may have a substituent, and -COOR and -COOR' are Each represents a carboxyl group which may be esterified in the same or different ways. ], Ql is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen, or sulfur atom, Q2 and Q3 are one of N and the other of N or CH, and Y is a group represented by [Chemical formula 3 ] or [Chemical Formula 4] [RI represents a hydrogen atom, a lower hydrocarbon group, or a bond. ], -Z- is a group forming a bridge between ring A1 or ring A2 and -B, each of which is a carbon atom which may have a substituent, or each of which has a substituent. Each represents a linear divalent group having 2 to 5 atoms and composed of a carbon atom which may be optionally substituted and one heteroatom which may have a substituent. ] or its salt. 2. An antitumor composition containing the compound according to claim 1 or a salt thereof. [Claim 3] General formula [5] [In the formula, A1 ring and A2 ring are the same or different and each is a 5- to 7-membered ring which may have a substituent, Ql
is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen or sulfur atom, one of Q2 and Q3 is N and the other is N or CH, Y is [Chemical formula 6] or [Chemical formula 7] (R1 is represents a hydrogen atom, a lower hydrocarbon residue, or a bond. D represents a group that can form a covalent bond with E. ] or a salt thereof, and a compound represented by the general formula E-B (wherein -B is a cyclic group which may have a substituent) or formula [8] [wherein -B'- is a divalent chain which may have a substituent] -COOR and COOR' each represent a carboxyl group which may be the same or different and may be esterified.E represents a group capable of forming a covalent bond with D.] A compound represented by or a salt thereof is reacted to form a bridge Z [-Z- is a group forming a bridge between ring A1 or ring A2 and -B, and each carbon atom may have a substituent. or a linear divalent group having 2 to 5 atoms each consisting of a carbon atom that may have a substituent and one heteroatom that may have a substituent. . ] A method for producing the compound according to claim 1 . [Claim 4] General formula [9] [In the formula, A1 ring and A2 ring are the same or different, and each of the 5- to 7-membered rings which may have a substituent is represented by B/
/- represents a divalent cyclic or chain group that may have a substituent; Ql represents a hydrogen atom, a halogen atom, or carbon;
One of Q2 and Q3 is N and the other is N or CH, and Y is [Formula 1
0] or [Formula 11] [In the formula, R1 represents a hydrogen atom, a lower hydrocarbon residue, or a bond. ], -2- is a group forming a bridge between ring A1 or ring A2 and -B'', and each carbon atom may have a substituent, or each has a substituent. 2 to 5 atoms consisting of a carbon atom that may have a substituent and one heteroatom that may have a substituent
represents a linear divalent group, respectively. A compound represented by the formula [12] or a salt thereof or a reactive derivative with a carboxyl group, and a compound represented by the formula [12] [wherein -COOR and -COOR' are the same or different and represent a carboxyl group which may be esterified. 2. The method for producing the compound according to claim 1, which comprises reacting the compound represented by: [Claim 5] General formula [13] [In the formula, A2 ring may have a substituent from 5 to 7]
A membered ring, -B is a cyclic group which may have a substituent or the formula [14] [wherein, -B'- is a divalent chain group which may have a substituent, - COOR and -COOR' each represent a carboxyl group which may be the same or different and may be esterified. ], Ql is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen, or sulfur atom; one of Q2 and Q3 is N and the other is N or CH; Y is [Chemical formula 15 ] or [Chemical formula 16] [R1 represents a hydrogen atom, a lower hydrocarbon group, or a bond. ], -Z- is a group forming a bridge between the A2 ring and -B, and each carbon atom may have a substituent, or each may have a substituent A linear divalent group having 2 to 5 atoms consisting of a carbon atom and one heteroatom which may have a substituent,
” represents a divalent chain group or bond that can form the A1 ring,
L is a leaving group or the formula [17] [wherein R2 represents a hydrogen atom, a lower hydrocarbon group, or a bond]. ] or the isocomb shape of the carbonyl group, Xl is 10H1-3H or [Formula 18, R3 represents a hydrogen atom, a lower hydrocarbon group or a bond. ] are shown respectively. 2. The method for producing the compound according to claim 1, which comprises subjecting the compound represented by the formula or a salt thereof to a covalent bond formation reaction to form an A1 ring. [Claim 6] General formula [19] [In the formula, A1 ring and A2 ring are the same or different, and each of the 5- to 7-membered rings which may have a substituent is represented by -B
is a cyclic group which may have a substituent or formula [20] [wherein -B'- represents a divalent chain group which may have a substituent, and -COOR and -COOR' represent a divalent chain group which may have a substituent; Each represents a carboxyl group which may be esterified in the same or different ways. ], Q2' and Q3' are the same or different and are 10, -0R1'-8, S
RI' [In the formula, R'' and R1'' are the same or different and represent a hydrogen atom or a lower hydrocarbon residue. ] or =NR1'
[In the formula, R1' has the same meaning as above. ], Y is [Formula 22] or [Formula 23] [R1 represents a hydrogen atom, a lower hydrocarbon residue, or a bond. ], -Z- is a group forming a bridge between ring A1 or ring A2 and -B, each of which is a carbon atom which may have a substituent, or each of which has a substituent. A dotted line in the structural formula indicates a straight chain divalent group with 2 to 5 atoms consisting of a carbon atom that may have a substituent and one heteroatom that may have a substituent. or a double bond, respectively. ] and the general formula [24] [wherein, Ql is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen, or sulfur atom, and Q is an oxygen atom, a sulfur atom, or the formula =NR] ' [In the formula, R
1' has the same meaning as above. ], Q' is [Chemical formula 25] OR", -8R1' or [Chemical formula 26] [In the formula, R" and R1" have the same meanings as above.]
2. A method for producing a compound according to claim 1, which comprises reacting with a compound represented by the formula to cyclize the compound. [Claim 7] General formula [27] [In the formula, A1 ring and A2 ring are the same or different, and a 5- to 7-membered ring which may have a substituent, respectively, B''
- represents a divalent cyclic or chain group which may have a substituent; Ql represents a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen or sulfur atom; Q2 and Q
3 is N on one side, N or CH on the other side, and Y is [Chemical formula 28
] or [Formula, R1 represents a hydrogen atom, a lower hydrocarbon residue, or a bond. ], -Z- is a group forming a bridge between ring A1 or ring A2 and -B'-, and each carbon atom may have a substituent, or each has a substituent. -COOR'' refers to a linear divalent group having 2 to 5 atoms consisting of a carbon atom that may be substituted and one heteroatom that may have a substituent; A compound represented by the following formula or a salt thereof.