JP3425676B2 - Condensed pyrimidine derivatives, their production and use - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fused pyrimidine derivative useful as an antitumor agent, a process for producing the same, and uses thereof.

[0002]

BACKGROUND ART Folic acid and its related compounds are carriers of C1 units derived from formic acid, formaldehyde and the like in the living body, and are complementary to various enzymatic reactions such as nucleic acid biosynthesis system, amino acid / peptide metabolism system and methanogenesis system. It plays the role of an enzyme. Especially in the nucleic acid biosynthesis system, 2
It is essential for the metabolism / transfer reaction of the C1 unit in one of the two pathways, the purine synthesis system and the thymidine synthesis system. Normal,
In order for folic acid to exert its biological activity, it must be reduced in two steps and converted to the active coenzyme form. The enzyme that controls the second step (dihydrofolate reductase: DH
Amethopterin (methotrexate: MTX) and its peripheral compounds are known as drugs that strongly bind to FR) and suppress the reduction of dihydrofolic acid to tetrahydrofolic acid. Since these drugs impair DNA synthesis and result in cell death, they occupy a clinically important position as therapeutic agents mainly for leukemia. Furthermore, with the remarkable progress in the field of biochemistry, particularly in the field of folic acid in cancer research, a novel DHFR inhibitor, 10-deazaaminopterin antitumor agent (10-ethyl-10-deazaaminopterin: 10- (EDAM) [NCI eye
Monograph (NCI Monograph) 5 , 127 (1987)] or aminopteroyl ornithine derivative (N (α)-(4-amino-4-deoxypteroyl) -N (δ) -hemiphthaloyl-L
-Ornithine: PT523) [Publication Patent Publication: Hei 2-5
02095], and a competitive inhibitor targeting an enzyme different from DHFR, that is, a 5-deazatetrahydrofolate antitumor agent whose main mechanism of action is glycinamide ribonucleotide transformylase inhibition (5, 10-Dideaza-5,6,7,8-tetrahydrofolic acid: DDATHF)
[Journal of Medicinal Chemistry (Jou
rnal of Medicinal Chemistry) 28 , 914 (1985)] or a quinazoline antitumor agent (2-desamino-2-methyl-10-propargyl-5,8-dideaza) whose main mechanism of action is thymidylate synthase inhibition. Forate: DMPDDF)
(British Journal of Cancer (Briti
sh Journal of Cancer) 58 , 241 (1988)]. However, all of these compounds do not fall under the category of a heterocyclic compound group having a condensed ring of 6-membered ring and 6-membered ring (6-6 condensed ring) as a basic skeleton. On the other hand, a condensed ring formed of a 6-membered ring and a 5-membered ring (6-5 condensed ring), for example, a pyrrolo [2,3-d] pyrimidine ring is not a condensed ring of a 6-membered ring and a 6-membered ring. It has been reported that an antitumor activity that is also superior to a folate antagonist, which is the basic skeleton, exists, but this pyrrolo [2,3-d] pyrimidine derivative is described as having a glutamic acid moiety in the terminal side chain as an essential condition. (USP 4,997,838, EP-A-400,562, EP-A-402,903, EP
-A-418,924, EP-A-431,953, EP-A-434,426, EP-A-438,2
61, USP 4,996,206 etc.].

[0003]

DISCLOSURE OF THE INVENTION At present, what is particularly desired in the field of cancer treatment is to develop a drug based on a new mechanism of action, which shows high selective toxicity to cancer cells and has an excellent therapeutic effect. Is. MTX, whose main mechanism of action is the inhibition of dihydrofolate reductase, is currently widely used clinically, but it has relatively satisfactory toxicity and is not very effective against solid cancer. Not listed. Furthermore, the acquisition resistance to MTX is becoming a big problem. As a resistance mechanism of MTX, DHF
These include increased R levels, decreased cell membrane drug transport capacity, and decreased levels of folate polyglutamate synthase (FPGS). By overcoming at least one of these resistance factors, it is expected to develop a compound having a novel chemical structure that exhibits an excellent therapeutic effect even on MTX resistant cancer.

[0004]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in view of the above circumstances, as a result of the basic skeleton, a heterocyclic ring having a 6-5 condensed ring and a glutamic acid-derived 2 ring at the terminal side chain is used. In addition to synthesizing novel fused pyrimidine derivatives that do not have two coexisting carboxy groups, this novel compound unexpectedly inhibits one or more of the enzymatic reactions involving folic acid and its related compounds, resulting in various tumor cells (especially Meth A The present invention was completed based on the finding that it has a high selective toxicity to cells and the like and exhibits an excellent therapeutic effect to overcome MTX resistance.

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

[Chemical 8] [In the formula, ring A is a 5-membered ring which may be hydrogenated and may have a substituent, and B is a divalent 5- or 6-membered ring which may have a substituent. An allotropic or heterocyclic group,
X is an amino group, a hydroxy group or a mercapto group, and Y is
Is a hydrogen atom, a halogen atom, or a group via a carbon, nitrogen, oxygen, or sulfur atom, Z may have a substituent, and one hetero atom may be interposed in the chain portion in series A divalent aliphatic group having not more than 5 chain-constituting atoms is represented by the formula-NHCONH-, Wherein R represents a hydrogen atom or a C _1-4 hydrocarbon group which may have a substituent, and R ¹ represents a cyclic group which may have a substituent or a substituent. COOR ² represents an optionally chain-like hydrocarbon group, COOR ² represents an optionally esterified carboxy group, and p represents an integer of 1 to 4. ]
Or a salt thereof, (2) p = 3, W =-
When NHSO ₂ —, R ¹ is a phenyl group which may have a substituent, (3)

[Chemical 9] [In the formula, m ¹ is an integer of 1 to 5, and other symbols have the same meanings as described above. ] The compound of the above (1) represented by
(4) The compound according to the above (3), wherein R ¹ is a phenyl group which may have a substituent,

(5)

[Chemical 10] (6)

[Chemical 11] [The symbols in the formulas have the same meanings as described above. ] The compound according to (1) above, which is represented by: (7) The compound according to (6) above, wherein R ¹ is an optionally substituted phenyl or C _1-4 alkyl group, (8)

[Chemical 12] Expression (9)

[Chemical 13] [The symbols in the formulas have the same meanings as described above. ] Or a salt thereof or a reactive derivative at a carboxy group,

[Chemical 14] [The symbols in the formulas have the same meanings as described above. ] The method of manufacturing the compound of the said (1) characterized by reacting with the compound represented by this, or its salt, (10) The antitumor composition characterized by containing the compound of the said (1). It is about things.

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

[Chemical 15] For convenience of description, amino-type, hydroxy-type, and mercapto-type are described throughout this specification, and the corresponding nomenclatures are adopted, but in any case, the tautomeric imino-type, oxo-type, and It also includes thioxo type. Further, the compounds (I) and (I
^a ), (I ^b ), (II) and (III) can have a plurality of asymmetric centers, the partial structural formulas in (I) and (III)

[Chemical 16] Other than the absolute configuration of S (L), the other absolute configuration of the chiral center may be S, R or a mixture of RS. In this case, a plurality of diastereoisomers exist, but if necessary, they can be easily separated by a usual separation and purification means. All the above diastereoisomers which can be separated in this way are within the scope of the invention.

In the above formula, the 5-membered ring of the optionally hydrogenated 5-membered ring represented by ring A is a carbon atom or a carbon atom and one hetero atom (eg, may be oxidized). For example, a 5-membered ring composed of a nitrogen atom, an oxygen atom, or a sulfur atom which may be oxidized) is used. The optionally hydrogenated 5-membered ring includes, for example, cyclopentadiene, cyclopentene, furan, dihydrofuran, thiophene, dihydrothiophene, thiophene-1-oxide, dihydrothiophene-
1-oxide, thiophene-1,1-dioxide, dihydrothiophene-1,1-dioxide, pyrrole, pyrroline and the like are used. Among them, pyrrole, franc,
Thiophene is often used. These 5-membered rings may have 1 to 2 substituents at possible positions, and examples of such substituents include, for example, alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl). , Iso-propyl group), alkenyl groups having 2 to 4 carbon atoms (eg vinyl,
1-methylvinyl, 1-propenyl, allyl, allenyl group), alkynyl group having 2 to 4 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group), C _3-6 cycloalkyl group (eg, cyclopropyl group) A halogen atom (eg, fluorine, chlorine, bromine, iodine), an alkanoyl group having 1 to 4 carbon atoms (eg, formyl, acetyl, propionyl, butyryl, isobutyryl group), benzoyl group,
Substituted benzoyl group (eg, halogenobenzoyl such as p-chlorobenzoyl, p-methoxybenzoyl, 3,4,5-trimethoxybenzoyl group or mono-, di- or tri-C _1-4 alkoxybenzoyl), cyano group, carboxy Group, carbamoyl group, nitro group, hydroxy group, hydroxy-C _1-4 alkyl group (eg, hydroxymethyl group, hydroxyethyl group), C _1-4 alkoxy-C
_1-4 alkyl group (eg, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group), alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy group), mercapto group, 1 carbon atom Through 4
Alkylthio group (eg, methylthio, ethylthio, propylthio group), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino group), 1 to 4 carbon atoms Alkanoylamino group (eg, formamide, acetamide group) and the like are used. When the ring A is a pyrrole or a pyrroline ring, examples of the substituent which may be substituted on N include the above-mentioned alkyl group having 1 to 4 carbon atoms, alkenyl group having 2 to 4 carbon atoms, and 2 to 4 carbon atoms. Alkynyl group, C _3-6 cycloalkyl group, alkanoyl group having 1 to 4 carbon atoms, benzoyl group, substituted benzoyl group, hydroxy-C _1-4 alkyl group, C _1-4 alkoxy-C _1-4 alkyl group (especially Other phenyl groups such as methoxyethyl group, ethoxyethyl group, etc., and substituted phenyl groups (eg, p-chlorophenyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl group, etc., halogenophenyl or mono-, di-). or tri -C _1-4 alkoxyphenyl), a benzyl group or substituted benzyl group (eg, azidohalogenobenzyl such p- chlorobenzyl, p- methoxybenzylidene C _1-4 alkoxybenzyl such as diphenylmethyl group)
Are used.

The ring A may be bonded to Z at any possible position, and when the ring A is a pyrrole or pyrroline ring, it may be bonded to Z at the N portion. B represents a divalent 5- or 6-membered homocyclic or heterocyclic group which may have a substituent. The homocyclic group represented by B is, for example, a divalent 5- or 6-membered cyclic hydrocarbon group, and such a hydrocarbon group is, for example, a 5- or 6-membered cyclic aliphatic hydrocarbon group ( Examples, cyclopentylene, cyclohexylene, 1,3- or 3,5-cyclopentadiene-1,3-ylene, cyclopentene-
(1,3-, 1,4- or 3,5-) ylene, cyclopentane-1,3-ylene, cyclohexane- (1,
3- or 1,4-) ylene, cyclohexene- (1,
3-, 1,4-, 1,5-, 3,5-or 3,6
-) Ylene, 1,3-cyclohexadiene- (1,3
-, 1,4-, 1,5-, 2,4-, 2,5- or 2,6-) ylene, 1,4-cyclohexadiene-
(1,3-, 1,4- or 1,5-) ylene, phenylene (1,2-phenylene, 1,3-phenylene, 1,4-phenylene) and the like, particularly 1,4-phenylene and the like, Commonly used. The heterocyclic group represented by B includes, for example, 1 to 3 heteroatoms (eg,
(Eg, N, O, S, etc.) and a divalent 5-membered or 6-membered heterocyclic group, etc. are used, and it is preferable that the two bonds are out of non-adjacent positions in the ring. Examples of the divalent 5-membered heterocyclic group represented by B include thiophene- (2,4
-, 2,5- or 3,4-) ylene, furan-
(2,4-, 2,5- or 3,4-) ylene, pyrrole- (1,3-, 2,4-, 2,5- or 3,4
-) Irene, thiazole- (2,4- or 2,5-)
Irene, imidazole- (1,4-, 2,4- or 2,5-) ylene, thiadiazole-2,5-ylene or their partially reduced form (one part of the multiple bond is reduced) or complete reduction Type compounds (all of the multiple bonds are reduced) etc. are used and are represented by B 2
Examples of the valent 6-membered heterocyclic group include pyridine- (2,
4-, 2,5-, 2,6- or 3,5-) ylene,
Pyran- (2,4-, 2,5-, 2,6-, 3,5-,
3,6- or 4,6-) ylene, pilatin- (2,
5- or 2,6-) ylene, pyrimidine- (2,4-
Alternatively, 2,5-) ylene, pyridazine-3,5-ylene or a partially reduced or completely reduced compound thereof is used.

Particularly preferred examples of B include phenyl-1,4-ylene, thiophene-2,5-ylene,
Thiazole-2,5-ylene and pyridine-2,5-
For example, iren. The divalent 5- or 6-membered homo or heterocyclic group represented by B may have 1 to 2 substituents at substitutable positions. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), an alkenyl group having 2 to 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1 -Propenyl, allyl, allenyl group), alkynyl group having 2 to 4 carbon atoms (ethynyl, 1-propynyl, propargyl group), C _3-6 cycloalkyl group (eg, cyclopropyl group), halogen atom (eg, chlorine, Bromine, fluorine, iodine), hydroxy group, C _1-4 alkoxy group (eg, methoxy group), di-C _1-4 alkylamino group (eg, dimethylamino group), halogeno-C _1-4 alkyl group (eg, , Trifluoromethyl group), oxo group, C _1-4 acyl group (eg, formyl group), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2-ethoxyethyl group), etc. It is done. Among them, for example, a halogen atom (for example, chlorine,
Bromine, fluorine, iodine, etc.) are often used. X is
It represents an amino group, a hydroxy group or a mercapto group. Particularly, an amino group and a hydroxy group are frequently used. Y represents a hydrogen atom, a halogen atom or a group via a carbon, nitrogen, oxygen or sulfur atom. As the halogen atom represented by Y, fluorine, chlorine, bromine or iodine is used.

The group represented by Y via a carbon, nitrogen, oxygen or sulfur atom includes a cyano group, a carboxy group,
Carbamoyl group, amino group, nitro group, hydroxy group,
A mercapto group, for example, an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group),
An alkenyl group having 2 to 4 carbon atoms (eg vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group), an alkynyl group having 2 to 4 carbon atoms (eg ethynyl, 1-propynyl, propargyl group) or C _3-6 lower alkyl group such as cycloalkyl group (eg, cyclopropyl group), C
_6-10 aryl group (eg, phenyl group, naphthyl group), for example, 5- or 6-membered heterocyclic group containing 1 to 4 hetero atoms such as N, S, O (eg, pyrrolyl, imidazolyl, pyrazolyl) , Thienyl, furyl, thiazolyl,
Thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl or their partially reduced or completely reduced groups, dioxolanyl, piperidino, morpholino, dioxanyl) and the like are used. The lower hydrocarbon group, C _6-10 aryl group or 5- or 6-membered heterocyclic group represented by Y may have 1 to 2 substituents, and examples of such substituents include carbon. An alkyl group having 1 to 4 (eg, methyl, ethyl, propyl, iso-propyl group), an alkenyl group having 2 to 4 carbon atoms (eg, vinyl,
1-methylvinyl, 1-propenyl, allyl, allenyl group), alkynyl group having 2 to 4 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group) or C _3-6 cycloalkyl group (eg, cyclopropyl group) In addition to, halogen atom (eg, fluorine), hydroxy group, oxo group,
C _1-4 alkoxy group (eg, methoxy group), di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino group), halogeno-C _1-4 alkyl group (eg, trifluoromethyl group), C _1-4 acyl group (eg, formyl group), hydroxy-C _1-4 alkyl group (eg, hydroxymethyl,
2-hydroxyethyl group), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2-ethoxyethyl group) and the like are used. The group represented by Y via a carbon, nitrogen, oxygen or sulfur atom may be an alkoxy group, an alkylthio group, an alkylcarbonylamino group or an alkylcarbonyloxy group, and the alkyl moiety of these groups may be any of the above. The groups described in detail in the lower hydrocarbon group are used as they are, and may be an aryloxy group, an arylthio group, an aroylamino group and an aroyloxy group, and the aryl portion of these groups may be a phenyl group, a naphthyl group, or the like. It may be a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic carbonylamino group or a heterocyclic carbonyloxy group,
As the heterocyclic moiety of these groups, the groups represented by the above-mentioned 5- or 6-membered heterocyclic group can be used as they are, or a substituted amino group such as a mono- or di-substituted amino group can be used. As the substituent portion of the group, the above-mentioned lower hydrocarbon group, aryl group, or 5- or 6-membered heterocyclic group can be used as it is. As Y, for example, an amino group is often used.

Z may have a substituent, and 5 in series may have one hetero atom (for example, nitrogen atom, oxygen atom, sulfur atom, etc.) interposed in the chain portion. A divalent aliphatic group having chain constituent atoms not exceeding is shown. As the divalent aliphatic group having not more than 5 chain-constituting atoms in series, for example, a C _1-5 alkylene group such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene group, for example, vinylene, propenylene, 1- Or a C _2-5 alkenylene group such as 2-butenylene, butadienylene, 1- or 2-pentenylene, 1,3- or 1,4-pentadienylene group, for example ethynylene, 1- or 2-propynylene, 1- or 2-butynylene. , 1-,
C _2-5 alkynylene groups such as 2- or 3-pentynylene groups are used. Further, it may have a substituent,
Examples of the divalent aliphatic group having not more than 5 chain-constituting atoms in series with one heteroatom interposed in the chain portion include, for example, formula —Z ¹ —Z ² —Z ³ — ¹ and Z ³ are the same or different and each is a divalent lower hydrocarbon group having 1 to 4 carbon atoms which may have a bond or a substituent (provided that Z is
The total number of carbon atoms of ¹ and Z ³ is 1 to 4), -Z
^2- is -O-, formula -S (In the formula, R ⁴ represents a hydrogen atom or a lower hydrocarbon group which may have a substituent). ] The group etc. which are represented by these are used. The divalent lower hydrocarbon group having 1 to 4 carbon atoms in the divalent lower hydrocarbon group having 1 to 4 carbon atoms which may have a substituent represented by Z ¹ and Z ³ is For example, C _1-4 alkylene group such as methylene, ethylene, trimethylene, tetramethylene, etc., C _2-4 alkenylene group such as vinylene, propenylene, 1- or 2-butenylene, butadienylene, for example, ethynylene, 1- or 2-propynylene. A C _2-4 alkynylene group such as 1, 1- or 2-butynylene is used, and the lower hydrocarbon group in the lower hydrocarbon group which may have a substituent represented by R ⁴ has 1 to 1 carbon atoms. 4 alkyl groups (eg methyl, ethyl, propyl, iso-propyl groups), alkenyl groups having 2 to 4 carbon atoms (eg vinyl,
1-methylvinyl, 1-propenyl, allyl, allenyl group), alkynyl group having 2 to 4 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group), C _3-6 cycloalkyl group (eg, cyclopropyl group) Are used.

A divalent aliphatic group represented by Z and having a chain-constituting atom not exceeding 5 in series, a divalent lower hydrocarbon group having 1 to 4 carbon atoms represented by Z ¹ and Z ³ , and R ^The lower hydrocarbon group represented by ⁴ may have 1 or 2 substituents, and examples of such a substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), alkenyl group having 2 to 4 carbon atoms (eg vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group), alkynyl group having 2 to 4 carbon atoms (eg ethynyl, 1-propynyl) , Propargyl group) or C _3-6 cycloalkyl group (eg, cyclopropyl group), halogen atom (eg, fluorine), hydroxy group, oxo group, C _1-4 alkoxy group (eg, methoxy group), di -C _1-4 alkylamino (Eg, dimethylamino, diethylamino group), halogeno -C _1-4 A alkyl group (e.g., trifluoromethyl group), C _1-4 acyl group (e.g.,
Formyl, acetyl group), hydroxy-C _1-4 alkyl group (eg, hydroxymethyl, 2-hydroxyethyl group), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2-ethoxyethyl) Group), a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl) and the like. Z is, for example, a C _1-5 alkylene group (eg, methylene, ethylene, trimethyl group). (Z ¹ ′ is a C _1-4 alkylene group, R ⁴ ′ is a hydrogen atom, C
_1-4 C which may be substituted with alkoxy-carbonyl
_1-4 alkyl group, formyl group, or C _1-4 alkoxy-
A group represented by (indicating a carbonyl group) and the like are preferable. Z
^The C _1-4 alkylene group represented by ¹ ′ is methylene,
Ethylene, trimethylene, tetraethylene and the like are used, and particularly ethylene and trimethylene are frequently used. R
Represented by ⁴ '- The "C _1-4 alkyl group" of the "C _1-4 alkoxy which may C _1-4 alkyl group optionally substituted by carbonyl", such as methyl, ethyl, n- propyl,
n-Butyl or the like is used. As the "C _1-4 alkoxy-carbonyl", for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl and the like can be used. As R ⁴ ′, tert-butoxycarbonylmethyl, tert-butoxycarbonyl and the like are often used.

[0014] , R is a hydrogen atom or C _1-4 which may have a substituent.
Indicates a hydrocarbon group. The C _1-4 hydrocarbon group in the C _1-4 hydrocarbon group which may have a substituent represented by R is a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl,
(tert-butyl group), C _2-4 alkenyl group (eg vinyl, allyl, 1-methylvinyl, 2-methylvinyl group), C _3-4 cycloalkyl group (eg cyclopropyl, cyclobutyl group) are used. . Examples of the substituent of the C _1-4 hydrocarbon group include, for example, an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group),
C2-C4 alkenyl group (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group), C2-C4 alkynyl group (eg, ethynyl, 1-propynyl, propargyl group) or C _{In addition to 3-6} cycloalkyl groups (eg, cyclopropyl group), halogen atoms (eg, fluorine, chlorine, bromine, iodine), hydroxy groups,
Oxo group, C _1-4 alkoxy group (eg, methoxy group), di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino group), halogeno-C _1-4 alkyl group (eg, trifluoro) Methyl group), C _1-4 acyl group (eg, formyl, acetyl group), hydroxy-C _1-4 alkyl group (eg, hydroxymethyl, 2-hydroxyethyl group), C
_1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2-ethoxyethyl group) and the like are used.

As R, for example, a hydrogen atom is often used. The cyclic group in the cyclic group which may have a substituent represented by R ¹ is, for example, a 5- or 6-membered cyclic hydrocarbon group or a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom, in addition to a carbon atom. A heterocyclic group which may contain 1 to 4 atoms in the ring, or a condensed ring group thereof is used. The 5-membered cyclic group represented by R ¹ includes, for example, cyclopentanedienyl, cyclopentenyl, cyclopentyl, thienyl, furyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl or their partially reduced or fully reduced compounds. Examples of the 6-membered cyclic group include phenyl, cyclohexyl, cyclohexenyl, cyclohexanedienyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, and their partially reduced or fully reduced compounds. Or as a condensed ring group of a 6-membered cyclic hydrocarbon or heterocyclic group, for example, naphthyl, indenyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl, or a partially reduced form thereof or Such as whole-reduction compound. Particularly, phenyl, cyclohexyl, naphthyl, thienyl, cyclopentyl, tetrazolyl and the like are preferable.

The chain hydrocarbon group in the chain hydrocarbon group which may have a substituent represented by R ¹ is preferably a lower chain hydrocarbon group having 1 to 4 carbon atoms,
For example, C _1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group, vinyl, allyl, 1-methylvinyl, 2
- C _2-4 alkenyl group such as a methyl vinyl group, cyclopropyl and C _3-6 cycloalkyl group such as cyclobutyl group are used. The cyclic group or chain hydrocarbon group represented by R ¹ may have ¹ or 2 substituents at substitutable positions. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, tert
-Butyl group), an alkenyl group having 2 or 4 carbon atoms (eg,
Vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl group), alkynyl group having 2 or 4 carbon atoms (ethynyl, 1-propynyl, propargyl group), cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl) , Cyclobutyl, cyclopentyl, cyclohexyl group), C5-C6 cycloalkenyl group (eg, cyclopentenyl, cyclohexenyl group), C7-C8 aralkyl group (eg, benzyl, α-methylbenzyl, phenethyl group) ), Phenyl group, substituent (for example, halogen such as Cl and Br, C _1-4 alkyl group such as methyl and ethyl)
A 5- to 6-membered heterocyclic group which may have 1 or 2 of (eg, tetrazolyl, triazolyl, imidazolyl, oxazolyl, furanyl, thiazolyl, pyridyl,
Pyrazyl, triazyl), alkoxy groups having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, te
rt-butoxy group), phenoxy group, alkanoyl group having 1 to 4 carbon atoms (eg formyl, acetyl, propionyl, n-butyryl, iso-butyryl group), benzoyl group, alkanoyloxy group having 1 to 4 carbon atoms (eg , Formyloxy, acetyloxy, ethylyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy group), benzoyloxy group, carboxy group, C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl) , Iso-propoxycarbonyl group, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl), carboxy-C _1-4 alkyl (eg, carboxymethyl, carboxyethyl), C _1-4 alkoxy-carbonyl C _1-4 Alkyl (eg, methoxycarbonylmethyl, Butoxycarbonyl methyl) carbamoyl group, N- substituted carbamoyl group (e.g., N- methylcarbamoyl, N- ethylcarbamoyl,
N-C _1-4 alkylcarbamoyl group such as N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl), N, N-disubstituted carbamoyl group (eg, N, N
-Dimethylcarbamoyl, N, N-diethylcarbamoyl,
In addition to N, N-di-C _1-4 alkylcarbamoyl such as N, N-dipropylcarbamoyl and N, N-dibutylcarbamoyl, 1-acetylidinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinini Rucarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl group), halogen atom (eg, fluorine, chlorine,
Bromine, iodine), mono-, di- or tri-halogeno-C
_1-4 alkyl group (eg, trifluoromethyl group), amidino group, imino group, amino group, mono-substituted amino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc. mono-C _{1 -4} alkylamino group), disubstituted amino group (eg, dimethylamino,
Di-C _1-4 alkylamino groups such as diethylamino, dipropylamino, diisopropylamino and dibutylamino), 3- to 6-membered cyclic amino groups (eg, atyridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, virazolyl, imidazolidinyl) , Piperidino, morpholino, dihydropyridyl, pyridyl,
N-methylpiperazinyl, N-ethylpiperazinyl group), alkanoylamide group (eg, formamide, acetamide,
C _1-4 alkanoylamide groups such as trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide), benzamide group, carbamoylamino group, N-substituted carbamoylamino group (eg, N-methylcarbamoylamino, N- N-C _1-4 alkylcarbamoylamino groups such as ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, N, N-disubstituted carbamoylamino groups (eg, N, N- Dimethylcarbamoylamino,
In addition to N, N-di-C _1-4 alkylcarbamoylamino groups such as N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino and N, N-dibutylcarbamoylamino, 1-acetylidinylcarbonylamino, 1-azetidinylcarbonylamino, 1-pyrrolidinylcarbonylamino, 1-piperidinylcarbonylamino, N-methylpiperazinylcarbonylamino, morpholinocarbonylamino group), C _1-3 alkylenedioxy (eg, methylene Dioxy, ethylenedioxy), hydroxy group, epoxy group (-O-), nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, dihydroxyboryl group, sulfamoyl group, N-substituted sulfamoyl group ( Example, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isop Pils sulfamoyl, C _1-4 alkylsulfamoyl group such as N- butylsulfamoyl), N, N- disubstituted scan Rufamoiru group (e.g., N, N- dimethylsulfamoyl, N, N- Jiechirusuru In addition to di-C _1-4 alkylsulfamoyl groups such as famoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, 1-pyrrolidinylsulfonyl, 1-piperidinylsulfonyl, N -Methyl-1-piperazinylsulfonyl, morpholinosulfonyl group), an alkylthio group having 1 to 4 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio group), A phenylthio group, an alkylsulfinyl group having 1 to 4 carbon atoms (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl group), A phenylsulfinyl group, an alkylsulfonyl group having 1 to 4 carbon atoms (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl group), a phenylsulfonyl group and the like are used, and particularly preferable substituents are a hydroxy group and a carboxy group. , Tetrazolyl group, sulfo group, phosphono group, dihydroxyboryl group and the like are used.

Among these substituents, those which can be further substituted are 1 to 2 alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group), C _1-4 alkoxy group (eg, methoxy group, ethoxy group), halogen atom (eg, fluorine, chlorine, bromine, iodine), water-soluble group (eg, hydroxyl group, carboxy group, sulfo group, Phosphono, amidino, amino, methylamino, ethylamino, dimethylamino, diethylamino, morpholino, piperidyl, N-methylpiperazyl, pyridyl, trimethylammonium, triethylammonium, pyridinium, tetrazolyl Group, carboxymethyl group) or the like. The carboxy group may be esterified with an alkyl group having 1 to 4 carbon atoms (methyl, ethyl, etc.). Examples of R ¹ include hydroxy, carboxy, and
B (OH) ₂ , tetrazolyl, methylenedioxy, C _1-4 alkyl (eg, methyl), C _1-4 alkoxy (eg, methoxy), carboxy C _1-4 alkyl (eg, carboxymethyl), C _{1- 4} Alkoxy-carbonyl C _1-4 alkyl (eg, methoxycarbonylmethyl, ethoxycarbonylmethyl), C _1-4 alkanoylamide (eg, formamide, acetamide) or 1 or 2 substituted with 1-pyrrolidinylcarbonyl group _Optionally C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl,
Naphthyl or tetrazolyl groups are commonly used.

COOR ² represents an optionally esterified carboxy group. The COOR ² may be, for example, a compound used as a synthetic intermediate, a pharmacologically acceptable compound, or a compound that is first transformed into a pharmacologically acceptable compound in vivo. Specifically, for example, a lower alkyl group having 1 to 5 carbon atoms, a benzyl group which may have a substituent, or a carboxy group which may be esterified with a phenyl group which may have a substituent. Are used. Examples of the lower alkyl group having 1 to 5 carbon atoms include methyl, ethyl,
Propyl, iso-propyl, n-butyl, iso-butyl, sec-
Butyl, tert-butyl, n-pentyl, iso-pentyl, sec
- pentyl, neo-pentyl, tert- pentyl, the benzyl which may have a substituent, such as benzyl, nitrobenzyl, to 1 nitro or C _1-4 alkoxy such as methoxy benzyl are three substituents The benzyl group which may be present, and the phenyl which may have a substituent are, for example, phenyl, nitrophenyl,
A phenyl group which may be substituted 1 to 3 with nitro such as methoxyphenyl or C _1-4 alkoxy is used. As COOR ² , for example, a lower alkyl group having 1 to 5 carbon atoms, particularly a carboxy group which may be esterified with methyl or the like is frequently used. P represents an integer of 1 to 4.

Next, a method for producing the compound (I) of the present invention or a salt thereof will be described. Compound (I) or a salt thereof can be obtained by reacting compound (III) or a salt thereof with compound (II) or a salt thereof or a reactive derivative at the carboxyl group. In this reaction, for example, a method of acylating compound (III) or a salt thereof with compound (II) or a salt thereof or a reactive derivative at the carboxyl group is used. This reaction can also be carried out in the presence of carbodiimides, diphenylphosphoric acid azide, diethyl cyanophosphoric acid and the like. The amount of compound (III) or its salt to be used is generally about 1 to 20 mol, preferably about 1 to 5 mol, per 1 mol of compound (II) or its salt or the reactive derivative at the carboxyl group. The carbodiimides, diphenylphosphoric acid azide, diethyl cyanophosphate, etc. are generally used in an amount of about 1 to 25 mol, preferably about 1 to 5 mol, per 1 mol of the compound (II) or its salt or the reactive derivative at the carboxyl group. do it.

As the carbodiimides, dicyclohexylcarbodiimide is practically preferable, and other carbodiimides such as diphenylcarbodiimide and di-o.
-Tolyl carbodiimide, di-p-tolyl carbodiimide,
Di-tert-butylcarbodiimide, 1-cyclohexyl-3-
(2-morpholinoethyl) carbodiimide, 1-cyclohexyl-3- (4-diethylaminocyclohexyl) carbodiimide, 1-ethyl-3- (2-diethylaminopropyl) carbodiimide and 1-ethyl-3- (3-diethylaminopropyl)
You may use carbodiimide etc. This reaction can also be carried out in the presence of an appropriate solvent, and as the solvent,
For example, water, alcohols (eg, methanol, ethanol)
), Ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (eg, acetonitrile),
Esters (eg, ethyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride),
Aromatic hydrocarbons (eg, benzene, toluene, xylene), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane or a suitable mixed solvent thereof are used. This reaction usually has a pH of about 2 to 1.
4, preferably at a pH in the range of about 6-9. It is usually carried out at a reaction temperature in the range of about -10 ° C to about the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C. Usually, the reaction can be carried out for about 1 to 100 hours. The pH of the reaction solution is appropriately determined by using, for example, an acid (eg, hydrochloric acid, sulfuric acid,
Phosphoric acid, nitric acid, acetic acid), bases (eg, sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogen carbonate) , Trimethylamine, triethylamine, triethanolamine, pyridine) or a buffer solution (eg, phosphate buffer solution, borate buffer solution, acetic acid buffer solution) or the like as necessary. In addition, the reaction can be proceeded more advantageously by using a catalyst capable of promoting acylation.

As such a catalyst, for example, a base catalyst or an acid catalyst is used. Examples of such a base catalyst include tertiary amines (eg, aliphatic tertiary amines such as triethylamine; pyridine, α-, β- or γ-picoline, 2,
6-lutidine, 4-dimethylaminopyridine, 4- (1
-Pyrrolidinyl) pyridine, aromatic tertiary amines such as dimethylaniline, diethylaniline) and the like,
As the acid catalyst, for example, Lewis acid [eg, anhydrous zinc chloride,
Anhydrous aluminum chloride (AlCl _3), anhydrous ferric chloride, titanium tetrachloride (TiCl _4), tin tetrachloride (SnCl _4), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.], etc. Is used. Among the above catalysts,
4-dimethylaminopyridine or 4- (1-pyrrolidinyl)
Pyridine and the like are often preferred. The amount of catalyst used is
The amount of the catalyst capable of promoting the acylation is usually about 0.01 to 10 mol, preferably about 0.1 to 1 mol, per 1 mol of the compound (II) or its salt or the reactive derivative at the carboxy group. is there. Examples of the reactive derivative at the carboxyl group of compound (II) include, for example, acid halides (eg, fluoride, chloride, bromide, iodide) of compound (II), acid anhydrides.
(Eg, iodoacetic anhydride, isobutyric anhydride), lower monoalkyl carbonate (eg, monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono
Mixed acid anhydride with iso-propyl carbonate, monobutyl carbonate, mono iso-butyl carbonate, mono sec-butyl carbonate, mono tert-butyl carbonate, active ester (eg, cyanomethyl ester, ethoxycarbonylmethyl ester) , Methoxymethyl ester, phenyl ester, o-nitrophenyl ester, p-nitrophenyl ester, p-carbometoxyphenyl ester, p-cyanophenyl ester, phenylthioester, 1-hydroxybenzotriazolyl ester, N-hydroxy-5-ester Norbornene-2,
3-dicarboximide ester, succinimide ester, hydroxysuccinimide ester, 8-oxyquinolyl ester), acid azide, phosphoric diester (eg, dimethyl phosphate, diethyl phosphate,
Mixed acid anhydrides with dibenzyl phosphate, diphenyl phosphate) and mixed acid anhydrides with phosphite diesters (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite, diphenyl phosphite) are also used, and especially acid halides. Etc. are often used. In this reaction using such a reactive derivative, a solvent, a catalyst,
The reaction temperature and the reaction time are the same as those in the presence of the carbodiimides and the like.

Of the compounds (I) or salts thereof,
When producing a compound or a salt thereof containing a hydroxy group, an amino group, a mercapto group, a carboxyl group or the like as a substituent, the hydroxy group of the raw material compound,
Amino group, mercapto group or carboxyl group is known per se (eg, JFW McOmine, Protective Groups in Organic Chemistry, Plenum)
The compound (I) or a target compound thereof which is subjected to a deprotection reaction according to a method known per se, after reacting with a suitable protecting group according to the method described in Press, London and New York (1973, etc.) It is also possible to produce salts. Next, a method for producing the starting compound (II) or a salt thereof or a reactive derivative at the carboxy group will be described. For example, it can be produced by the following reaction steps.

[0023]

[Chemical 17] In the above formula, ring A, B, X, Y and Z have the same meanings as described above, and R ³ in the optionally esterified carboxyl group represented by COOR ³ is a hydrogen atom or COOR ² 1 to 5 carbon atoms detailed
A lower alkyl group, a benzyl group which may have a substituent, or a phenyl group which may have a substituent. D and E are groups which can combine with each other to form Z. In the above reaction step, a covalent bond is formed between D and E, which may have a substituent represented by Z, and one hetero atom may be present in the chain portion. It is possible to produce divalent aliphatic groups having not more than 5 chain-constituting atoms in series. As a synthetic method for forming a covalent bond between a compound (V) or a salt thereof and a compound (VI) or a salt thereof, Z may have a chain-constituting atom which does not exceed 5 and which may have a substituent in series. Regarding the divalent aliphatic group having,

[0024]

[Chemical 18] When D = E 'and E = D' in combination, a so-called carbon-carbon bond forming reaction is carried out between the compound (V) or a salt thereof and (VI) or a salt thereof, and then the obtained product is obtained. If necessary, the compound (IV) or a salt thereof can be produced by subjecting it to a reduction reaction.

In the above formula, a, b, m, n (= a + b) and m + n represent an integer within the range of 0 to 3, G represents phenyl, butyl or cyclohexyl, and M represents ethyl or phenyl. R ⁵ , R ⁶ and R ⁷ are the same or different and each is a bond, a hydrogen atom or a divalent lower hydrocarbon group having 1 to 4 carbon atoms and a lower hydrogen atom which are described in detail for Z ¹ , Z ³ and R ^4. R represents a substituent of a hydrocarbon group, R
⁵ , R ⁶ may be different in a, b, m and n repeats. For the in group composed, - Z is Z = -Z ¹ -Z ² -Z ³

[Chemical 19] If, or vice versa, D = E ¹ and E = D ¹ , a so-called alkylation type reaction is used,

[0026]

[Chemical 20] , Or vice versa, D = E ³ and E = D ³
In this case, a method of forming a Schiff base or an enamine and reducing it if necessary, or directly subjecting it to a reductive alkylation reaction is used.

In the above formula, m, n, m + n, R ⁴ , R ⁵ and R
⁶ , R ⁷ and Z ² have the same meanings as described above, L is a leaving group, and R ⁸ and R ⁹ are the same or different and each is a hydrogen atom or a hydrocarbon group. Examples of the leaving group represented by L include a leaving group which can be easily derived from a halogen atom (eg, chlorine atom, bromine atom, iodine atom) or a hydroxy group (eg, methanesulfonyloxy group, benzenesulfonyloxy group). Group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyl group) and the like are used. R ⁸ and R ⁹ are the same or different and each represents a hydrocarbon group which may have a substituent, and R ⁸ and R ⁹ together have a substituent with an adjacent nitrogen atom. May also form a cyclic amino group. The hydrocarbon group represented by R ⁸ and R ⁹ has, for example, 1 to 18 carbon atoms.
Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, Octadecyl, 1,2-dimethylpropyl, 1-ethylpropyl,
1,2,2-trimethylpropyl, 1-propylbutyl, 2
-Ethylhexyl group), an alkenyl group having 2 to 12 carbon atoms (eg, vinyl, allyl, 1-methylvinyl, 2-methylvinyl, 1-octenyl, 1-decenyl group), 3 carbon atoms
To 12 cycloalkyl groups (eg, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, andamantyl group), cycloalkenyl group having 3 to 8 carbon atoms (eg, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclohepta) Dienyl, cyclooctadienyl group), aralkyl group having 7 to 13 carbon atoms (eg, benzyl, α-methylbenzyl, phenethyl, diphenylmethyl group), or aryl group having 6 to 10 carbon atoms (eg,
Phenyl, α-naphthyl, β-naphthyl group) and the like are used. The cyclic amino group formed by R ⁸ and R ⁹ together with the adjacent nitrogen atom is 4 to 10
Member rings are preferred, for example azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolinyl, piperidino, morpholino, dihydropyridyl, tethydropyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, azacycloheptyl,
Azacyclooctyl, isoindolyl, indolyl,
Indolinyl, 2-isoindolinyl, azacyclononyl, azacyclodecyl groups and the like are used.

The hydrocarbon group cyclic amino group or R ⁸ and R ⁹ are formed together with the adjacent nitrogen atom together, represented by these R ⁸ and R ^9, 1 to have a two substituents You may have. Examples of such a substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl group), an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy,
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy group), alkanoyl group having 1 to 4 carbon atoms (eg formyl, acetyl, propionyl, n-butyryl, iso-butyryl group). , Carbon number 1 to 4
Alkanoyloxy group (eg, formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy group), carboxy group, carbon number 2
To about 4 alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl group, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl), halogen atoms (eg, fluorine, chlorine) , Bromine, iodine), hydroxy group, nitro group, cyano group, trifluoromethyl group, amino group, mono C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino group), di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino,
Dipropylamino, diisopropylamino, dibutylamino group), alkanoylamide group (eg, formamide,
Acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide group), carbamoyl group, N—C _1-4 alkylcarbamoyl group (eg, N
-Methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,
N-butylcarbamoyl group), N, N-disubstituted carbamoyl group (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl,
In addition to N, N-diC _1-4 alkylcarbamoyl groups such as N, N-dibutylcarbamoyl, 1-acetylidinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl group, etc.),
Carbamoylamino group, N-C _1-4 alkylcarbamoylamino group (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino group), N , N-disubstituted carbamoylamino group (eg, N, N-dimethylcarbamoylamino, N, N-
In addition to N, N-diC _1-4 alkylcarbamoylamino groups such as diethylcarbamoylamino, N, N-dipropylcarbamoylamino and N, N-dibutylcarbamoylamino, 1-acetylidinylcarbonylamino, 1-azetidinini Carbonylamino, 1-pyrrolidinylcarbonylamino, 1-piperidinylcarbonylamino, N-methylpiperazinylcarbonylamino, morpholinocarbonylamino groups, etc.), mercapto groups, sulfo groups, sulfino groups,
Phosphono group, sulfamoyl group, N-C _1-4 alkylsulfamoyl group (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N- Butylsulfamoyl group), N, N-disubstituted sulfamoyl group (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl,
In addition to N, N-diC _1-4 alkylsulfamoyl groups such as N, N-dipropylsulfamoyl and N, N-dibutylsulfamoyl, 1-pyrrolidinylsulfonyl, 1-piperidinylsulfonyl, N-methyl-1-piperazinylsulfonyl, morpholinosulfonyl group, etc.), 1 to 4 carbon atoms
Degree of alkylthio group (eg, methylthio, ethylthio,
Propylthio, isopropylthio, n-butylthio, sec
-Butylthio, tert-butylthio group), an alkylsulfinyl group having 1 to 4 carbon atoms (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl group), an alkylsulfonyl group having 1 to 4 carbons (eg, methyl) Sulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl group) and the like are used.

The first step will be described in detail below.
Condensation reaction by carbon-carbon bond formation is a known reaction (eg,
Aldol reaction, Reformatsky reaction, Wittig reaction, etc.), and the reduction reaction is usually a catalytic reduction reaction or a hydride reduction reaction. When the aldol reaction is used as the condensation reaction, examples of the base catalyst include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, sodium methoxide, sodium ethoxide, potassium tert. -Metal alkoxides such as butoxide, sodium amide, metal amides such as lithium diisopropylamide, metal hydrides such as sodium hydride and potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-, β -Or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, amines such as dimethylaniline and diethylaniline are used, and examples of the acid catalyst include:
Mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, organic acids such as oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid are used. To be Also,
Known method [Ei-Ichi Negishi, Organometallics in Org
anic Synthesis vol.1, John Wiley & Sons, New York,
According to Chichester, Brisbane, Tronto (1980)], a ketone body is converted into a silyl enol ether body, and a Lewis acid [eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ )]
, Anhydrous ferric chloride, titanium tetrachloride (TiCl ₄ ), tin tetrachloride
(SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate], fluorine anion (eg, tetrabutylammonium fluoride) or trityl perchloride in the presence of aldehyde or its It is subjected to a condensation reaction with an equivalent, or a ketone is subjected to amines (eg, triethylamine, pyridine, α-, β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- ( 1-pyrrolidinyl) pyridine, dimethylaniline, diethylaniline) in the presence of a metal triflate (eg, dialkylboron triflate, tin (II) triflate, etc.) to convert into an enolate, and then a condensation reaction with an aldehyde or its equivalent. Can also be carried out.

The condensation reaction is carried out by reacting in a suitable solvent at -100 ° C to the boiling point of the solvent, preferably in the range of -78 to 100 ° C, for 1 minute to 3 days. Examples of the reaction solvent include water, liquid ammonia, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-
Butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxy ethanol, ethoxy ethanol), ethers (eg dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons (eg dichloromethane, chloroform, Carbon tetrachloride), aliphatic hydrocarbons (eg pentane, hexane, heptane), aromatic hydrocarbons (eg benzene, toluene, xylene), acetonitrile, nitromethane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane Alternatively, an appropriate mixed solvent thereof is used. When the Wittig reaction is used as the condensation reaction, examples of the reagent include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, sodium methoxide, sodium ethoxide and potassium t.
Metal alkoxides such as ert-butoxide, sodium amide, metal amides such as lithium diisopropylamide, sodium hydride, metal hydrides such as potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-, Amines such as β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, dimethylaniline and diethylaniline are used. The reaction is carried out at -20 ° C to the boiling point of the solvent, preferably 0 to 150 ° C, for 1 minute to 10 days. Examples of the reaction solvent include liquid ammonia, alcohols (eg, methanol,
Ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxy ethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), Aliphatic hydrocarbons (eg,
Pentane, hexane, heptane), aromatic hydrocarbon (eg, benzene, toluene, xylene), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof is used. Furthermore, the condensation can also be carried out using the Reformatsky reaction. As the reaction conditions of the Reformatsky reaction, for example, zinc, magnesium, aluminum, tin or the like is used as the reagent. The reaction itself is carried out by reacting at -20 ° C to the boiling point of the solvent, preferably 0 to 150 ° C, for 30 minutes to 3 days. Examples of the reaction solvent include ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aliphatic hydrocarbons (eg, pentane, hexane, heptane),
Aromatic hydrocarbons (eg, benzene, toluene, xylene)
Alternatively, an appropriate mixed solvent thereof or the like is used.

In the alkylation type reaction or amine exchange type reaction, the compound (V) or a salt thereof and the compound (VI) or a salt thereof are treated at a temperature of about -10 ° C to the boiling point of the reaction solvent, preferably about 10 to 80 ° C. The reaction is carried out at a temperature within the range for about 10 minutes to 48 hours. The compound (VI) or a salt thereof is used in an amount of about 1 to 50 mol, preferably about 1 to 10 mol, based on 1 mol of the compound (V) or a salt thereof. Examples of the reaction solvent include water, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers ( Example, diethyl ether,
Tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), nitriles (eg, acetonitrile), aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane), cyclic Aliphatic hydrocarbons (eg, cyclopentane, cyclohexane), aromatic hydrocarbons (eg, benzene, toluene, xylene), nitromethane, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixture thereof. A solvent or the like is used. Further, if necessary, the reaction can be promoted in the presence of a base. As the base used, for example, the base used in the Wittig reaction and the like are used. Further, 0.01 to 0.2 equivalent, preferably 0.02 to 0.0, relative to 1 mol of the compound (V) or a salt thereof or the compound (VI) or a salt thereof.
The reaction can be advantageously proceeded by using about 05 equivalents of a phase transfer catalyst (eg, cetyltrimethylammonium chloride, etc.). In the case of an amine exchange type reaction,
When the compound (V) is made into a salt with a quaternary salt such as methyl bromide, methyl iodide, methyl methanesulfonate, methyl benzenesulfonate, and methyl p-toluenesulfonate, the reaction can proceed under milder conditions. There are cases.

In the reaction for forming the Schiff base, the compound (V) or a salt thereof and the compound (VI) or a salt thereof are mixed at a molar ratio (V) / (VI) = 10 to 0.1 of about −10.
℃ to the boiling point of the reaction solvent, preferably 0 to 50 ℃
The reaction is carried out at a temperature in the range of about 10 minutes to 48 hours. In this reaction, compounds in which the aldehyde or ketone moiety of compound (V) or a salt thereof and (VI) or a salt thereof are protected in the form of acetal or ketal may be used. The reaction solvent is preferably a non-aqueous solvent, for example, alcohols (eg, methanol, ethanol, propanol, iso-
Propanol, butyl alcohol, sec-butyl alcohol, tert-
Butyl alcohol, ethylene glycol, methoxy ethanol, ethoxy ethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), esters (eg, methyl acetate, ethyl acetate), halogenated hydrocarbons (Eg dichloromethane, chloroform, carbon tetrachloride),
Nitriles (eg, acetonitrile), aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (eg, cyclopentane, cyclohexane), aromatic hydrocarbons (eg, benzene, toluene, xylene) ), Acetone, nitromethane, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof and the like are used. As the 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 appropriately with an acid (eg, hydrochloric acid, hydrobromic acid, hydrogen iodide). Acid, sulfuric acid, nitric acid, phosphoric acid), base (eg,
Sodium hydroxide, potassium hydroxide, lithium hydroxide,
Metal hydroxides such as barium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, barium carbonate,
Calcium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, triethanolamine, pyridine) or buffer (eg, phosphate buffer, borate buffer,
The reaction rate and yield can be improved by adjusting with an acetate buffer). The reduction reaction of the Schiff base and the reductive alkylation reaction are carried out by hydride reduction or catalytic reduction using a suitable solvent at a reaction temperature of about -40 ° C to the boiling point of the solvent, more preferably about 0 to 50 ° C. Be seen. As the solvent to be used, in addition to the reaction solvent used in the above-mentioned alkylation type reaction or amine exchange type reaction, acetic acid esters (eg, methyl acetate,
Ethyl acetate) and the like are also used.

The catalytic reduction reaction is carried out by using an appropriate solvent in about −
It is carried out at a temperature in the range of 40 ° C to the boiling point of the reaction solvent, more preferably in the range of about 0 to 50 ° C. As the solvent, water, alcohols (eg, methanol, ethanol,
Propanol, iso-propanol, butyl alcohol,
sec-Butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), acetic acid esters (eg, methyl acetate, ethyl acetate), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme) ), Aromatic hydrocarbons (eg, benzene, toluene, xylene), pyridine, dimethylformamide,
In addition, an appropriate mixed solvent thereof or the like is used. As the catalyst for catalytic reduction, for example, palladium, platinum, rhodium, Raney nickel, etc. are used. At this time, a slight amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like may be added to favorably proceed the reaction. Examples of the hydride reduction reagent include lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, and the like. The amount of the reducing reagent used is about equimolar to 100 times the molar amount of the substance to be reduced, usually 2 to 20.
Double moles are used. Further, ring A has furan, thiophene, thiophene-1-oxide, thiophene-1,1-
In dioxide or N- substituted pyrrole ring -Z ² - is -
In the case of NH-, the -HN- group is condensed with ring A to form a tricyclic compound (eg, pyrrolo [3 ', 2': 4,5] pyrrolo [2,3-d] pyrimidine compound). I have something to do. In this case, the desired bicyclic compound can be easily converted by treating with an acid or a base.

Step 2 The compound (IV) or salt thereof obtained in Step 1 is subjected to a deesterification reaction of the ester residue [R ³ ] thereof according to a method known per se to give compound (II) or a salt thereof. Can be converted to. The starting compound (II) or a salt thereof can also be produced, for example, by the reaction steps shown below.

[0035]

[Chemical 21] In the above step, A ring, B, R ³ , X, Y and Z have the same meanings as described above, J ¹ and J ² are the same or different and are oxygen or sulfur, and R ¹⁰ and R ¹¹ are the same or different. And a hydrocarbon group, L'is a halogen atom (eg, chlorine, bromine,
Iodine), T is a cyano group or the formula —COOR ¹² , —
A group represented by CSSOR ¹² or — CSSR ¹² (in the formula, R
¹² represents a hydrocarbon group. And R'and R "are the same or different and each is a hydrogen atom or a substituent on the A ring, which is described in detail as an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or a carbon number 2 the to the hydrocarbon group represented by .R ^10, R ¹¹ and R ¹² which indicates an alkynyl group or a cyclopropyl group of 4, a lower alkyl group (e.g. with 1-5 carbon atoms, methyl, ethyl, propyl, iso- propyl , N-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, tert-pentyl group), benzyl group or phenyl group. Carbon number 1
The lower alkyl group, the benzyl group or the phenyl group of 5 to 5 may have 1 to 3 substituents. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine), a nitro group, a cyano group, a carbon number of 1 to 4
Degree of alkoxy group (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, se
c-butoxy, tert-butoxy group), an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group), having about 1 to 4 carbon atoms Alkanoyl groups (eg,
Formyl, acetyl, propionyl, n-butyryl, iso-
Butyryl group), trifluoromethyl group and the like are used. Hereinafter, the reaction step will be described in detail.

Third step

[Chemical formula 22] The amount used is generally about 0.5 to 4 moles, preferably about 0.8 to 1.5 mole equivalents. This reaction is carried out in the presence of a suitable solvent at a reaction temperature of about -10 ° C to about the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C, for about 30 minutes to 48 hours. It can be carried out. Examples of the solvent used in the reaction include alcohols (eg, methanol, ethanol), ethers (eg, dimethyl ether, diethyl ether,
Tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (eg, acetonitrile), esters (eg, ethyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (eg, benzene) , Toluene, xylene) or an appropriate mixed solvent thereof. During the reaction, it is possible to proceed more advantageously by adding light or an organic peroxide. Examples of the organic peroxide include t-
Butyl hydroperoxide, peracetic acid, perbenzoic acid, m-
Examples thereof include chloroperbenzoic acid. The compound (VIII) or a salt thereof thus obtained is relatively highly reactive and may be isolated at this stage, but it is also possible to proceed directly to the next step without isolation.

Step 4 The compound (VIII) or salt thereof obtained in Step 3 is R
^In the presence of an alcohol or thiol represented by ^11- J ² -H and an appropriate solvent, the reaction solvent has a boiling point of about -10 ° C to about the boiling point (up to about 100 ° C), preferably about 0 to 50 ° C. Compound (IX) or a salt thereof can be obtained by reacting at a reaction temperature within the range for about 10 minutes to 24 hours. Examples of the solvent used in the reaction include ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme),
Nitriles (eg, acetonitrile), Esters (eg,
Ethyl acetate), halogenated hydrocarbon (eg, dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbon (eg, benzene, toluene, xylene) or an appropriate mixed solvent thereof or the like is used. Also, R ¹¹ -J ^2-
The alcohol or thiol represented by H may be used in excess as a solvent.

Fifth step

[Chemical formula 23] [In the formula, Y has the same meaning as described above. ] When reacted with a compound represented by the formula or a salt thereof, it reacts with a cyano group, an ester group or a thioester group represented by T, and then undergoes cyclization to form a pyrimidine ring to form a compound (X) or a salt thereof. Examples of the salt of compound (XI) include:
Salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, oxalic acid, tartaric acid, lactic acid,
A salt with an organic acid such as citric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid is used, and Y = hydroxy group or mercapto group. In the case of, for example, a salt with a base such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonia, trimethylamine, triethylamine, triethanolamine, pyridine, or substituted pyridine is used.

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

Sixth step

[Chemical formula 24] The compound can be converted to compound (IV) or a salt thereof by spontaneously inducing an intramolecular ring closure reaction and a dehydration reaction with the amino group on the pyrimidine ring. The reversion reaction to a carbonyl group is carried out, for example, by using the compound (X) or a salt thereof in a suitable solvent, from about -10 ° C to the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C. The reaction temperature may range from about 10 minutes to 100 hours. The intramolecular ring-closing reaction and dehydration reaction in the step of producing compound (IV) or a salt thereof are usually carried out in the process of recovering to a carbonyl group (> C = O) or after the recovering carbonyl group and the amino group on the pyrimidine ring. It happens spontaneously with the group. At this time, if an acid catalyst is present, the reaction can proceed rapidly and in high yield. As such an acid catalyst, a mineral acid, an organic acid, a Lewis acid or the like which has been described in detail in the aldol reaction is used. Further, by reducing a carbonyl group (> C = O) to form a hydroxymethyl group (> CHOH), then converting the hydroxy moiety into a leaving group L, and then subjecting the amino group in the molecule to an alkylation reaction. It is also possible to produce a compound (IV) in which the A ring is partially reduced or a salt thereof. The reduction reaction of the carbonyl group, the conversion reaction of the hydroxy group into a leaving group, and the intramolecular alkylation reaction are carried out by a method known per se or a method analogous thereto. In addition, compound (II)
Or a salt thereof or (IV) or a salt thereof, which is subjected to a catalytic reduction reaction according to a method known per se to partially reduce, and a compound (II) or a salt thereof (I) in which the A ring is partially reduced.
V) or its salt can also be converted. Compound (I
When ring A is a pyrrole or viroline ring in I) or a salt thereof, the compound (X) or a salt thereof, or (IV) or a salt thereof is subjected to an alkylation reaction or an acylation reaction known per se, It can also be converted into a compound having an N-substituted pyrrole or an N-substituted pyrroline ring. Further, using the compound (IV) or compound (II) or its salt in which the A ring is an unsubstituted pyrrole or pyrroline ring described in JP-A-02-167281 as a raw material, the above-mentioned alkylation reaction or acylation reaction is carried out. It is also possible to produce a compound in which the ring A is an N-substituted pyrrole or an N-substituted pyrroline ring.

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

[Chemical 25] In the above steps, A ring, B, R ³ , R ¹² , R ′, R ″ and Z have the same meanings as described above, and R ′, R ″ and —Z—B—
COOR ³ is assumed to be bonded at three consecutive positions on the cyclopentane ring.

Step 7 When compound (XII) or a salt thereof is heated with dicyandiamide, a cyclization reaction occurs to form a condensed pyrimidine ring to obtain compound (IV _C1 ) or a salt thereof. In this case, the reaction temperature is 100 to 300 ° C., more preferably 150 to 250 ° C., and the reaction time is 1 to 24.
Time is appropriate. Further, if necessary, an unsaturated bond can be introduced into the A ring by dehydrogenating using a known reagent by a method known per se or a method analogous thereto. Step 8 R ′, R ″ or —Z—B—COO in the α-positions on both sides of the carbonyl group in the compound (XII) or a salt thereof.
The hydrogen at the α-position which is not substituted with R ³ is abstracted by a conventional method to form a carbanion, and COOR ¹² (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, C such as tert-butyl
_A compound (XIII) or a salt thereof can be obtained by introducing a carboxy group esterified with C _7-8 aralkyl such as _1-6 alkyl or benzyl.

Step 9 When compound (XIII) or a salt thereof is reacted with compound (XI) or a salt thereof, it reacts with a carbonyl group and COOR ¹² to cause condensation / cyclization to form a new condensed pyrimidine ring. A compound (IV _C2 ) or a salt thereof is obtained. The reaction conditions are the same as those used in the fifth step. Further, if necessary, an unsaturated bond can be introduced into the A ring by dehydrogenating using a known reagent by a method known per se. The ester forms (IV _C1 ) and (IV _C2 ) or salts thereof obtained in the seventh step and the ninth step can be subjected to a deesterification reaction to convert them into the corresponding carboxylic acids. When B is a cycloalkenylene group or a phenylene group having a substituent,
These groups may be converted into the corresponding cycloalkylene groups by subjecting these groups to a catalytic reduction reaction according to a method known per se in an appropriate step from Step 9 to Step 9. Y is hydroxy group, alkoxy group, aryloxy group, 5- or 6-membered heterocyclic oxy group, mercapto group, alkylthio group, arylthio group, 5- or 6-membered heterocyclic thio group, substituted amino group, alkanoylamino group, aroylamino In the case of a group or a 5- or 6-membered heterocyclic carbonylamino group, it is subjected to a conversion reaction according to a method known per se in an appropriate step among the second step, the sixth step, the seventh step or the ninth step, and is defined as Y. 5- or 6-membered heterocyclic group, halogen atom, cyano group, carboxy group, carbamoyl group, nitro group, hydroxy group, alkoxy group, aryloxy group, 5- or 6-membered heterocyclic oxy group, mercapto group, alkylthio group Group, arylthio group, 5- or 6-membered heterocyclic thio group, substituted amino group, alkanoylamino group, aroylamido Group, 5- or 6-membered heterocyclic carbonyl amino group,
It may be converted into an alkanoyloxy group, an aroyloxy group or a 5- or 6-membered heterocyclic carbonyloxy group.

When the ring A and the ring B contain a sulfur atom, or when -Z ² -is -S- (sulfur atom), the compound (I) of the present invention or a salt thereof is directly subjected to an oxidation reaction or any possible method. subjected to the oxidation reaction at any step of the process, a ring, B and -Z ² - of the sulfur atom S (O) n
It can be converted into a compound in which [n = 1 to 2]. Oxidation reaction is usually 0.3 to
In the presence of 3.0 equivalents, preferably 0.5 to 2.5 equivalents of an oxidizing agent, in a suitable solvent, at -10 to + 100 ° C, preferably 0 to + 50 ° C, for 10 minutes to 48 hours, preferably 3
It can be produced by reacting for 0 minutes to 24 hours. As the oxidizing agent used in the reaction, peracids (eg, sodium metaperiodate, hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid) are preferable.
As the reaction solvent, water, acetic acid, ketones (eg, acetone, ethyl methyl ketone), ethers (eg, dimethyl ether, diethyl ether, dioxane, monoglyme, diglyme), halogenated hydrocarbons (eg, dichloromethane, chloroform, Carbon chloride), aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (eg, cyclopentane, cyclohexane), aromatic hydrocarbons (eg, benzene, toluene, xylene), acetonitrile or An appropriate mixed solvent thereof is used. Further, in the compounds (I), (II) (IV) or salts thereof, the amino group, hydroxy group or mercapto group represented by X may be converted into each other, if necessary, according to a substituent conversion reaction on the pyrimidine ring known in the literature. You can also do [separate volume protein nucleic acid enzyme, chemical synthesis of nucleic acid,
Kyoritsu Publishing (1968)]. Next, a method for producing the raw material compound (III) or a salt thereof will be described. The starting compound (III) or a salt thereof can be produced, for example, by the reaction steps shown below.

[0045]

[Chemical formula 26] In the above formula, W, R ¹ , R ² , and p have the same meanings as described above. Q and V are groups which can combine with each other to form W. R ¹³ represents an amino-protecting group, and R ¹⁴ represents a carboxy-protecting group.

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

In the bond forming reaction of the 11th step W, a known reaction is used.
When W = NHCONH, compound (XV) or a salt thereof,
(XVI) or a salt thereof, when Q is NH ₂ , V is an isocyanate group or a phenoxycarbonylamino group, or when Q is an isocyanate group or a phenoxycarbonylamino group, V is NH ₂ It is a siloxy group and V is an amino group. W is -NH
SO ₂ - For, Q is NH _2, V is a sulfonyl halide.

12th step The compound (XVII) or its salt obtained in the 11th step is
The amino protecting group [TW Green, Protective
Groups in Organic Synthesis (Protec
tive Groups in Organic Synthesis), John Wiley & S
ons, New York (1981)] and subjected to a deprotection reaction to convert it to compound (III) or a salt thereof. When both an amino group and a carboxy group are simultaneously protected with a copper salt, for example, decopperization with hydrogen sulfate, 6N hydrochloric acid, EDTA (ethylenediaminetetraacetic acid), etc. under acidic conditions is followed by esterification of the carboxy group. (III) or a salt thereof can be converted. In addition, the formation reaction of W can also be performed on the compound (XX) or a salt thereof.

[0049]

[Chemical 27] In the above formula, X, Y, A ring, Z, B, R ¹ , p, W, R ² and V are as defined above. R ¹⁵ is a protecting group for an amino group, and includes, for example, carbamates (eg, methoxycarbonyl, etoxycarbonyl, proproxycarbonyl, isopropyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc. ), Amides (eg, chloroacetyl, etc.), silyl groups (trimethylsilyl, triethylsilyl, dimethyl-tert-butylsilyl, diphenyl-
(tert-butylsilyl, etc.) is used.

Step 13 Compound (I) or a salt thereof can be produced by subjecting compound (III) or a salt thereof to compound (II) or a salt thereof and an amide formation reaction known per se. Step 14 Compound (XIX) or a salt thereof can be produced by subjecting compound (II) or a salt thereof to a condensation reaction of compound (XVIII) or a salt thereof in the same manner as in Step 13. Fifteenth step The compound (XIX) or a salt thereof obtained in the fourteenth step can be subjected to a deprotection reaction of an amino group in the same manner as in the twelfth step to produce a compound (XX) or a salt thereof. Sixteenth Step Compound (XX) or a salt thereof obtained in the fifteenth step is subjected to the same W formation reaction as in the eleventh step with compound (XVI) to form a bond W from an amino group and V to form compound (I ) Or a salt thereof can be prepared. Further, regarding the reaction, the reagent, the reaction conditions and the application of a protecting group to each functional group used as necessary, which are carried out or used in the first to fifteenth steps, or the manufacturing step of the starting material compound, Detailed explanations known in the cited documents can be followed. (JFM McOmine, Protective Groups in Organic Chemistry, Plenum
PressLondon and New York (1973)], [Pine Hendrickson Hammond, Organic Chemistry (4th Edition) [I]-[I
I], Hirokawa Shoten (1982)] and [M. Fieser and L. Fi
eser, Regents for Organic Synthesis Volume 1-13 (Reagents for Organic Synthesis vo
1.-13), Wiley-Interscience, New York, London, Sy
dney and Toronto (1969-1988))

Each of the intermediates of the compound of the present invention produced by the above method and the compound (I) of the present invention or a salt thereof are:
The reaction mixture can be isolated by a conventional separation means such as concentration, solvent extraction, chromatography, recrystallization and the like. Further, the reaction mixture may be used as it is as a raw material for the next step. Compounds (I), (II), (III), (IV), (IVc ₁ ), (IVc ₂ ), obtained by the above production method
(V), (VI), (VII), (VIII), (IX), (X), (XI
I), (XIII), (XIV), (XV), (XVI), (XVII), (X
Examples of the salts of VIII), (XIX) and (XX) include alkali metals, alkaline earth metals, non-toxic metals, ammonium or substituted ammonium, and specifically,
For example, a salt with a base such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium, pyridinium, or substituted pyridinium, or, for example, hydrochloric acid,
Salts with mineral acids such as sulfuric acid, nitric acid, phosphoric acid, boric acid, organic acids such as oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. A salt with an acid or the like is used. In addition, raw material compounds compound (V), (VI),
(VII), (X), (XI), (XII), (XIV), (XVI) and (XVIII) or salts thereof can be easily produced by a known method or a method analogous thereto.

Action The compound (I) of the present invention or a salt thereof has an inhibitory action on one or more enzymes that utilize folic acid and its related compounds as substrates. Therefore, these compounds treat various tumors resistant to MTX, as well as choriocarcinoma, leukemia, breast adenocarcinoma, head and neck epidermoid carcinoma, squamous cell carcinoma, small cell lung cancer and lymphosarcoma which have been treated with MTX to date. It has low toxicity and can be safely used alone or in combination with other antitumor agents for the purpose. For example, the compound (I) of the present invention or a salt thereof is used in the mouse tumor cell line system (P388, L12
10, L5178Y, B16 melanoma, MethA, Lewis Lung Carcin
oma, S180 sarcoma, Erhlich Carcinoma, Colon26 and 38), and human tumor cell line lines (A549, HL60,
It has an excellent anti-tumor effect on
Tumors carried by warm-blooded animals (eg, leukemia, melanoma, sarcoma, mastocytom)
a), carcinoma, neoplasia, etc.], and prolongs the survival period of warm-blooded animals bearing tumors. Hereinafter, experimental results showing the pharmacological effects of the compound (I) or a salt thereof in the present invention will be described.

Me of the compound obtained in Example 5 described later
Cell proliferation inhibitory effect (IC ₅₀ ) on th A cells and dihydrofolate reductase (DHFR) inhibitory activity (IC)
₅₀ ) was measured by the following method. Cytostatic effect on Meth A cells (IC ₅₀ ): M
10% fetal calf serum (FC
S; Flow Laboratories Inc.) added Eagle's minimum esse
3 using ntial medium medium (MEM; Nissui Pharmaceutical)
It was carried out at 7 ° C. in a 5% CO ₂ incubator. Tumor cells 2.
0 × 10 ⁴ / ml 12-well plate [Corning, No.
The cells were cultured for 72 hours at 25815, culture area 3.8 cm ² (inner diameter 22.1 mm), liquid volume 2 ml), and the number of cells was counted by a Coulter counter (Coulter Electronics). The drug was dissolved in physiological saline or MEM at a high concentration, diluted at the same time the cell culture was started, and added to the culture medium, and brought into contact with the cells for 72 hours. The concentration of the drug required to reduce the number of cells in the untreated control group to 50% was taken as the IC ₅₀ value of the compound. The obtained results are shown in [Table 1].

Inhibitory activity against dihydrofolate reductase (IC ₅₀ value): (Preparation of reaction solution) 3 ml of a 1.2 mM dihydrofolate solution was prepared with a reaction buffer containing 90 mM 2-mercaptoethanol. To this, 3 ml of a 1.5 mM NADPH solution was added to prepare a dihydrofolic acid / NADPH mixed solution. These were placed in a 1.5 ml Eppendorf tube and stored at 30 ° C. in the dark until the measurement. Vertical 1 row of 96-well plate (A)
Add 6 dihydrofolic acid / NADPH mixture to each hole.
5 μl each was added. 50 μl of the enzyme solution was added to each of the vertical wells of one row of another 96-well plate (B) at 30 ° C.
200 µl of the 2-fold serial dilution of the test drug stored in 1 was added to each well of each concentration. In addition, a reaction buffer solution containing no test drug was added to one of the eight vertical holes. Dihydrofolic acid / NADPH from 96-well plate (A)
50 μl of the mixed solution was dispensed and mixed using an 8-strip multipipette (Flow) to start the enzyme reaction.

(Calculation method of IC ₅₀ value) The reaction rate without addition of the test drug was defined as 100%, and the ratio (y%) of the reaction rate at each test drug concentration to this was calculated. This value
The regression line was obtained by logit transformation using the following formula, and the IC ₅₀ value was obtained from the X-axis intercept of this regression line.

[Equation 1] That is, when [I] = IC ₅₀ , y = 50 (%), so the left side of the above equation = 0. Therefore, IC ₅₀ = 10 ^{b / a} is calculated. The obtained results are shown in [Table 1].

[0056]

[Table 1] ───────────────────────────── Meth A DHFR Test compound IC ₅₀ (μM) IC ₅₀ (μM) Implementation Compound of Example 5 0.00087 0.0062 ───────────────────────────── As is clear from the above experimental results, the compound (I) or a salt thereof. Shows an excellent cytostatic effect on mouse MethA cells and a strong DHFR inhibitory activity. Further, the compound (I) of the present invention or a salt thereof has low toxicity and has a remarkable antitumor action. Therefore, the preparation containing the compound (I) or a salt thereof can be used as an antitumor agent for treating tumors of warm-blooded animals, particularly mammals (eg, mice, rats, cats, dogs, rabbits, etc.). it can.

When used as an antitumor agent, the compound (I)
Alternatively, the salt thereof may be used by itself or a pharmaceutically acceptable carrier, excipient, diluent or the like by a commonly used method, for example, powder, granules, tablets, capsules, suppositories, injections. It may be administered orally or parenterally. The dose depends on the target animal, disease, condition,
Depending on the type of compound, administration route, etc., for example,
In the case of oral administration, the above-mentioned warm-blooded animal is used as the compound of the present invention.
About 2.0-200, preferably 4.0-80m per day
g / kg body weight, and about 1.0-100, preferably 5-100 mg / kg per day for parenteral administration. As a method of administration as an injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intravenous injection and the like are used. The above formulation is carried out according to a method known per se. In the production of the above oral preparations, for example, tablets, a binder (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.), a disintegrant (eg, starch, carboxymethylcellulose calcium, etc.),
Lubricants (eg magnesium stearate, talc, etc.)
And the like can be appropriately mixed. Also, parenteral formulations,
For example, when producing an injection, a tonicity agent (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), an antiseptic (eg, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, paraoxy). Propyl benzoate, etc.), a buffer solution (eg, phosphate buffer solution, sodium acetate buffer solution, etc.) and the like can be appropriately mixed.

A specific example of the production of tablets is, for example, about 1.0-50 m of the compound of the present invention as the amount used per tablet.
g, lactose 100-500 mg, corn starch about 50-
100 mg, hydroxypropyl cellulose about 5-20
mg by a conventional method, granulate, mix with cornstarch and magnesium stearate, and compress to 1
The tablet is about 100-500 mg and the diameter is about 3-10 mm. In addition, this tablet is used per tablet as hydroxypropylmethylmethylcellulose phthalate (about 10-20 mg) and castor oil (about 0.5-2.0 m).
An enteric coated tablet can also be obtained by coating with an acetone-ethanol mixed solution prepared by dissolving g) and g) in a concentration of about 5-10%. As a specific example of the preparation of the injection, for example, the amount of sodium salt of the compound (I) of the present invention is about 2.0-
50 mg of (1) dissolved in about 2 ml of physiological saline was injected into an ampoule, then sealed and heat sterilized at about 110 ° C. for about 30 minutes, or (2) about 10-40 m.
g of mannitol or sorbitol was dissolved in about 2 ml of sterilized distilled water, dissolved and poured into an ampoule,
It can also be adjusted by freeze-drying and sealing. For use of the lyophilized injection, the ampoule is opened at the time of use and, for example, physiological saline is injected and dissolved at a compound concentration of about 1.0-50 mg / ml to give a solution, which is subcutaneously, intravenously or intramuscularly administered. can do.

[0058]

EXAMPLES The present invention will be described in detail below with reference to reference examples and examples, but these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. You may change in the range. Room temperature is usually 10 ° C
To 35 ° C. Reference Example 1 Preparation of ethyl 3-[[(3S) -3- (t-butoxycarbonylamino) -3- (methoxycarbonyl) propyl] carbamoyl] aminobenzoate N- (t-butoxycarbonyl) -L-glutamic acid α
-Methyl ester (532 mg) and triethylamine (0.56 ml) were dissolved in toluene (20 ml) and diphenylphosphoryl azide (607 mg) was stirred at 80 ° C for 1 hour. Ethyl aminobenzoate (330 ml) was added and the temperature was 80 ° C.
Stir for 0 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was passed through a silica gel column (30 g) ethyl acetate: n-.
Elution with hexane (2: 3) gave the title compound (349 mg, 41.3%) in the form of a colorless candy. IR (KBr) ν: 3360,3150,3100,2980,2950,2930,2880,17
40,1715,1640,1605,1590,1550,1515,1485,1435,1390,13
^{. 65,1300,1285,1235,1165,1125,1100cm -1 1 H-NMR (} CDCl 3) δ: 1.38 (3H, t, J = 7.2
Hz), 1.44 (9H, s), 2.13 (1H,
m), 3.02 (1H, m), 3.4-3.8 (2H,
m), 3.73 (3H, s), 4.36 (2H, q, J
= 7.2 Hz), 4.36 (1 H, m), 5.38 (1
H, d, J = 8.6 Hz), 5.81 (1 H, m),
7.05 (1H, s), 7.35 (1H, t, J = 8.
0 Hz), 7.72 (2H, m), 7.90 (1H,
t, J = 2.0 Hz).

Reference Example 2 3-[[(3S) -3- (t-butoxycarbonylamino) -3- (methoxycarbonyl) propyl] carbamoyl] aminophenylboric acid N- (t-butoxy) was prepared in the same manner as in Reference Example 1. Carbonyl) -L
-Glutamic acid α-methyl ester (532 mg), 3
The title compound (321 mg, 40.6%) in the form of a colorless candy was obtained using -aminophenylboric acid (372 mg). IR (neat) ν: 3330,2980,2930,2880,2850,2820,1750,1
710,1555,1480,1440,1395,1370,1305,1285,1230,1160,1
^{. 090,1070,1020,995,850,780,750,720,710,660,650cm -1 1 H-NMR (} CDCl 3) δ: 1.41 (9H, s), 1.8-2.35 (2H, m), 2.95-
3.40 (2H, m), 3.78 (3H, s), 4.40 (1H, m), 5.52 (1H, t, J = 4.8H
z), 5.95-6.25 (3H, m), 7.25 (1H, t, J = 7.6Hz), 7.35-7.55 (2
H, m), 7.60 (1H, s). Reference Example 3 Reference for the production of ethyl 3-[[(2S) -2- (t-butoxycarbonylamino) -2- (methoxycarbonyl) ethyl] carbamoyl] aminobenzoate N- (t-butoxycarbonyl) -L as in Example 1
-Aspartic acid α-methyl ester (1.29 g),
The title compound (200 mg, 16.6%) was obtained as a colorless solid using ethyl 3-aminobenzoate (826 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.2Hz), 1.41 (9H, s),
3.64 (2H, m), 3.76 (3H, s), 4.31 (3H, q, J = 7.2Hz), 5.67 (1H, b
rs), 5.74 (1H, t, J = 7.4Hz), 7.33 (1H, t, J = 8.0Hz), 7.43 (1H,
brs), 7.69 (1H, d, J = 8.0Hz), 7.73 (1H, d, J = 8.0Hz), 7.86 (1
H, s).

Reference Example 4 (2S) -2- (t-butoxycarbonylamino) -5
Preparation of methyl hydroxypentanoate Ethyl chlorocarbonate (1.3 g) was dissolved in tetrahydrofuran (1.5 ml) and N- (t-butoxycarbonyl) -glutamic acid α-methyl ester (1.5) was dissolved at -5 ° C.
66 g) was added, and triethylamine (1.68 m) was added.
A mixed solution of l) and tetrahydrofuran (9 ml) was added, and the mixture was stirred for 30 minutes at the same temperature. The precipitated triethylamine hydrochloride was filtered off, and the mother liquor was treated with sodium borohydride (1.0
It was added to a water (6 ml) solution containing g) and stirred at room temperature for 30 minutes. The reaction solution was once acidified with acetic acid, adjusted to pH 7.0 with saturated aqueous sodium hydrogen carbonate solution, and saturated saline solution (2
0 ml) and dichloromethane (20 ml) were added, and the mixture was vigorously stirred for a while and the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (45 g) ethyl acetate: n-hexane (2: 2).
The title compound (840 mg, 5)
6.7%). IR (neat) ν: 3370,2980,2950,2875,1740,1710,1695,1
520,1455,1440,1390,1365,1280,1250,1210,1165,1050,1
^{. 020cm -1 1 H-NMR (} DMSO-d 6) δ: 1.38 (9H, s), 1.39-1.85 (4H, m), 3.
37 (2H, q, J = 5.0Hz), 3.62 (3H, s), 3.94 (1H, m), 4.41 (1H, t, J
= 5.0Hz), 7.22 (1H, d, J = 7.8Hz).

Reference Example 5 (2S) -2- (t-butoxycarbonylamino) -5
-Preparation of methyl iodopentanoate (2S) -2- (t-butoxycarbonylamino) -5
Methyl hydroxypentanoate (840 mg) was dissolved in dichloromethane (16 ml) and triethylamine (0.7 ml) was added.
1 ml), and methanesulfonic acid chloride (506
mg) was added and the mixture was stirred for 30 minutes at the same temperature. Aqueous saturated sodium hydrogencarbonate solution (5 ml) and water (20 ml) were added to the reaction solution, ethyl ether (20 ml) was further added, and the mixture was vigorously stirred for a while. The organic layer was separated, dried over sodium sulfate and dried under reduced pressure. Concentrated to dryness to give colorless candy-like (2S) -2- (t-butoxycarbonylamino) -5.
-Methyl methanesulfonyloxypentanoate (1.11
8 g, 100%) was obtained. IR (neat) ν: 3380,2980,2930,1745,1710,1515,1450,1
395,1355,1245,1215,1170,1050,1020,975,960,930,830,
^{. 780,530cm -1 1 H-NMR (} CDCl 3) δ: 1.45 (9H, s), 1.62-2.10 (4H, m), 3.02
(3H, s), 3.77 (3H, s), 4.26 (2H, t, J = 5.8Hz), 4.35 (1H, m), 5.
08 (1H, brr). (2S) -2- (t-butoxycarbonylamino) -5
-Methyl methanesulfonyloxypentanoate (1.11
8 g (3.43 mM) was dissolved in acetone (4 ml), sodium iodide (2.0 g, 13.34 mM) was added, and the mixture was stirred at room temperature for 16 hours. Water (20 ml) and ethyl ether (20 ml) were added to the reaction solution and the mixture was vigorously stirred for a while, then the organic layer was separated and dried over sodium sulfate,
After concentrating to dryness under reduced pressure, the title compound (1.10 in the form of colorless candy) was obtained.
3g, 90.0%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (9H, s), 1.5-1.9 (4H, m), 3.22
(2H, dd, J = 6.7Hz, 5.9Hz), 3.63 (3H, s), 3.97 (1H, m), 7.29 (1
H, d, J = 7.8Hz).

Reference Example 6 Production of N-[(4S) -4- (t-butoxycarbonylamino) -4- (methoxycarbonyl) butyl] -diethyl L-glutamate (2S) -2 obtained in Reference Example 5. Methyl-(t-butoxycarbonylamino) -5-iodopentanoate (357
60 mg of L-glutamate (620 mg)
Stir at 16 ° C. for 16 hours. Dichloromethane (2
5 ml), washed with 2% acetic acid (25 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and water (25 ml), the organic layer was dried over sodium sulfate, and then passed through an ammonia-treated silica gel column (20 g) to pass acetic acid. Ethyl, n
Elution with -hexane (3: 2) gave the colorless candy-like title compound (270 mg, 62.5%). IR (neat) ν: 3370,3320,2980,2930,2870,1740,1710,1
520,1450,1420,1390,1370,1275,1250,1200,1170,1100,1
^{. 045,1030cm -1 1 H-NMR (} CDCl 3) δ: 1.30 (6H, t, J = 7.0Hz), 1.44 (9H, s),
1.50-2.20 (4H, m), 2.2-2.6 (4H, m), 3.00 (1H, m), 3.62 (1H,
m), 3.74 (3H, s), 4.19 (2H, m), 4.23 (4H, q, J = 7.0Hz), 5.10 (1
H, brs), 5.85 (1H, brs).

Reference Example 7 Preparation of ethyl 3-[(4S) -4- (t-butoxycarbonylamino) -4- (methoxycarbonyl) butyl] aminobenzoate To ethyl 3-aminobenzoate (1.0 g) ( 2S) -2
Methyl-(t-butoxycarbonylamino) -5-iodopentanoate (535 mg) was dissolved and stirred at 70 ° C for 10 hours. The reaction solution was adsorbed on a silica gel column (30 g) treated with ammonia and eluted with ethyl acetate and n-hexane (15:85) to give the colorless candy-shaped title compound (4
11 mg, 75.5%) was obtained. IR (neat) ν: 3380,2975,2930,2860,1740,1715,1605,1
585,1515,1490,1475,1450,1435,1390,1365,1335,1280,1
^{. 240,1165,1100,1020,750cm -1 1 H-NMR (} CDCl 3) δ: 1.30 (3H, t, J = 7.0Hz), 1.38 (9H, s),
1.45-1.85 (4H, m), 3.00 (2H, m), 3.62 (3H, s), 3.98 (3H, s),
3.98 (1H, m), 4.27 (2H, q, J = 7.0Hz), 5.89 (1H, t, J = 5.8Hz),
6.77 (1H, dt, J = 1.2Hz, 5.4Hz), 7.05-7.35 (4H, m).

Reference Example 8 Methyl N ^α- [4- [2- (2,4-diamino-7H
Preparation of -pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N [ ^delta ]-(t-butyroxycarbonyl) -L-ornithinate 4- [2- (2,4-diamino-7H- Pyrrolo [2,3-
d] pyrimidin-5-yl) ethyl] benzoic acid (1.5
2g) and N [ ^delta] -(t-butyroxycarbonyl) -L-
A solution of ornithine methyl ester (1.3 g) in dimethylformamide (DMF) was added to diethyl cyanophosphate (1.
4 g) and triethylamine (3.0 g) were added, and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (carrier: 30 g; chloroform: ethanol containing 1% ammonia = 20: 1 → 15: 1) to give the title compound (2.30 g; yield). Rate of 85%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (9H, s), 1.40-1.60 (2H, m), 1.
70-1.85 (2H, m), 2.90-3.15 (6H, m), 3.64 (3H, s), 4.40 (1H,
m), 6.61 (1H, s), 6.81 (1H, t, J = 7.0Hz), 6.97 (2H, brs), 7.33
(2H, d, J = 8.2Hz), 7.63 (2H, brs), 7.80 (2H, d, J = 8.2Hz), 8.6
3 (1H, d, J = 7.4Hz), 11.35 (1H, brs).

Example 1 N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^γ- (3-carboxy Preparation of phenylcarbamoyl) -L-2,4-diaminobutyric acid Ethyl 3-[[(3S) -3- (t-butoxycarbonylamino) -3- (methoxycarbonyl) propyl] carbamoyl] aminobenzoate (340 mg) 2N-HC
It was dissolved in 1 / ethyl acetate (10 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was thoroughly dried and then dissolved in N, N-dimethylformamide (4 ml). 4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid / 2-trifluoroacetic acid salt (368 mg) and diethylphosphorylcyanide (143 mg) were added. In addition, triethylamine (0.56 ml) was added under ice cooling and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was washed with water, passed through an ammonia-treated silica gel column (25 g) and purified with methanol: chloroform (3:47) to obtain a colorless solid N ^α- [4-. [2- (2,4-diamino-7H
- pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^gamma - (3-ethoxycarbonyl phenyl carbamoyl) -L-2,4-diaminobutyric acid methyl (415 mg, 98.5%) Obtained. IR (KBr) ν: 3425,2930,2855,1710,1635,1610,1575,15
50,1490,1435,1350,1300,1285,1235,1200,1100,1080,10
^{. 20,660cm -1 1 H-NMR (} DMSO-d 6) δ: 1.31 (3H, t, J = 7.0Hz), 1.99 (2H,
m), 2.97 (4H, m), 3.02 (1H, m), 3.28 (1H, m), 3.65 (3H, s), 4.3
0 (2H, q, J = 7.0Hz), 4.53 (1H, m), 5.44 (2H, s), 6.06 (2H, s),
6.30 (1H, t, J = 6.0Hz), 6.38 (1H, s), 7.34 (2H, d, J = 8.0Hz),
7.35 (1H, t, J = 7.6Hz), 7.49 (1H, d, J = 7.6Hz), 7.61 (1H, d, J =
7.6Hz), 7.82 (2H, d, J = 8.0Hz), 8.08 (1H, s), 8.71 (1H, d, J =
7.6Hz), 8.85 (1H, s), 10.40 (1H, s) .N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^gamma - (3- ethoxycarbonyl-phenylcarbamoyl) -L-2,4-diaminobutyric acid methyl (41
5 mg) was dissolved in a mixture of 1N sodium hydroxide (4.0 ml), tetrahydrofuran (4.0 ml) and methanol (2.0 ml) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in water (5 ml), and 2N-hydrochloric acid (2.0 ml) was added to precipitate the title compound (3).
63 mg, 93.9%). IR (KBr) ν: 3350,3200,2930,2850,1660,1645,1610,15
00,1440,1385,1300,1280,1240,1165,1090,800,760,680,
^{. 650cm -1 1 H-NMR (} DMSO-d 6) δ: 2.00 (1H, m), 3.30 (4H, m), 3.0-3.4
(2H, m), 4.45 (1H, m), 5.91 (2H, s), 6.31 (1H, t, J = 1.2Hz), 6.
44 (1H, s), 6.56 (2H, s), 7.32 (1H, t, J = 7.6Hz), 7.34 (2H, d, J
= 8.0Hz), 7.47 (1H, d, J = 7.6Hz), 7.59 (1H, d, J = 7.6Hz), 7.83
(2H, d, J = 8.0Hz), 8.05 (1H, s), 8.56 (1H, d, J = 6.4Hz), 8.82
(1H, s), 10.68 (1H, s).

Example 2 N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^γ- (3-boro Phenylcarbamoyl)-
Production of L-2,4-diaminobutyric acid As in Example 1, 3-[[(3S) -3- (t-butoxycarbonylamino) -3- (methoxycarbonyl) propyl] carbamoyl] aminophenyl boric acid (310
mg), 4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid ・ 2 trifluoroacetic acid salt (315 mg), to give a colorless solid. objects of N ^alpha - [4- [2- (2,4-diamino -7H
- pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^gamma - (3- boro phenylcarbamoyl) -L-2,4-diamino-methyl acetate (234m
g, 68%). IR (KBr) ν: 3400,2980,2950,2930,2855,1735,1635,16
10,1550,1500,1430,1340,1275,1230,1160,1110,1080,10
^{. 50,950,795,760,710cm -1 1 H-NMR (} DMSO-d 6) δ: 1.98 (2H, m), 2.97 (4H, m), 3.10-3.
50 (2H, m), 3.64 (3H, s), 4.53 (1H, m), 5.61 (2H, brs), 6.23 (1
H, m), 6.30 (2H, brs), 6.39 (1H, s), 7.16 (1H, t, J = 7.8Hz), 7.
33 (3H, d, J = 8.0Hz), 7.58 (1H, m), 7.82 (2H, d, J = 8.0Hz), 8.0
1 (1H, s), 8.46 (1H, s), 8.72 (1H, d, J = 7.6Hz), 10.52 (1H, s) .N ^α- [4- [2- (2,4-diamino-7H - pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^gamma - (3- boro phenylcarbamoyl) -
Methyl L-2,4-diaminobutyrate (230 mg) was ester-hydrolyzed in the same manner as in Example 1 to obtain the title compound (204 mg, 92.4%) as a colorless powder. IR (KBr) ν: 3330,3200,2930,2850,1640,1545,1500,14
^{. 20,1335,1275,1230,1185,760,700cm -1 1 H-NMR (} DMSO-d 6) δ: 1.8-2.15 (2H, m), 2.96 (4H, m), 3.1
5-3.40 (2H, m), 4.43 (1H, m), 5.99 (2H, s), 6.26 (1H, m), 6.45
(1H, s), 6.62 (3H, brs), 7.16 (1H, t, J = 7.6Hz), 7.33 (3H, d, J
= 8.2Hz), 7.56 (2H, s), 7.82 (2H, d, J = 8.2Hz), 7.95 (1H, br
s), 8.46 (1H, s), 8.57 (1H, d, J = 8.0Hz), 10.73 (1H, s).

Example 3 N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^β- (3-carboxy Preparation of phenylcarbamoyl) -L-2,3-diaminopropionic acid 3-[[(2S) -2- (t-butoxycarbonylamino) -2- (methoxycarbonyl) ethyl] carbamoyl] amino was prepared in the same manner as in Example 1. Ethyl benzoate (200m
g), 4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid-2 trifluoroacetic acid salt (188 mg) was used to give a colorless solid. objects of N ^alpha - [4- [2- (2,4-diamino -7H
- (3-ethoxycarbonyl phenyl carbamoyl) -L-2,3-diaminopropionic acid methyl (228 mg, 100%) - pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^beta It was IR (KBr) ν: 3380,2930,2850,1660,1630,1610,1550,14
90,1430,1365,1300,1285,1235,1200,1130,1115,830,80
^{. 0,755,720cm -1 1 H-NMR (} DMSO-d 6) δ: 1.31 (3H, t, J = 7.0Hz), 2.97 (4H,
m), 3.35-3.85 (2H, m), 3.66 (3H, s), 4.30 (2H, q, J = 7.0Hz),
4.50 (1H, m), 5.80 (2H, s), 6.42 (4H, brs), 7.34 (2H, d, J = 8.0
Hz), 7.36 (1H, t, J = 7.6Hz), 7.50 (1H, dt, J = 1.2Hz, 7.6Hz),
7.61 (1H, dt, J = 1.2Hz, 7.6Hz), 7.80 (2H, d, J = 8.0Hz), 8.07
(1H, t, J = 1.2Hz), 8.78 (1H, d, J = 7.2Hz), 9.00 (1H, s), 10.61
(1H, s). N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^β- (3-ethoxy Methyl carbonylphenylcarbamoyl) -L-2,3-diaminopropionate (212 mg) was subjected to ester hydrolysis in the same manner as in Example 1 to obtain the title compound (166 mg, 84.5%) as a colorless powder. IR (KBr) ν: 3380,3200,2920,2850,1640,1545,1500,14
^{. 35,1380,1300,1280,1235,755cm -1 1 H-NMR (} DMSO-d 6) δ: 3.48 (1H, m), 3.69 (1H, m), 4.47 (1
H, m), 6.09 (1H, s), 6.44 (1H, brs), 6.47 (1H, s), 6.73 (2H, br
s), 7.33 (1H, t, J = 6.2Hz), 7.35 (2H, d, J = 8.0Hz), 7.49 (1H,
d, J = 6.2Hz), 7.59 (1H, d, J = 6.2Hz), 7.82 (2H, d, J = 8.0Hz),
7.07 (1H, s), 8.68 (1H, d, J = 7.0Hz), 9.00 (1H, s), 10.80 (1H,
s).

Example 4 N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (4-fluoro Preparation of phenylcarbamoyl) -L-ornithine Methyl N ^α- [4- [2- (2,4-diamino-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N [ ^delta ]-(t-butyroxycarbonyl) -L-ornithinate (200 mg) in tetrahydrofuran (3 ml) solution in 4N hydrochloric acid ethyl acetate (1.
5 ml) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to dryness and the resulting residue was added to dimethylformamide (4 ml).
Dissolved in 4-fluorophenylisocyanate (5
3 mg) and triethylamine (1 ml) were added, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, washed with water, and washed with a silica gel column at a chloroform: methanol = 20: 1 ratio to give N as colorless powder.
^alpha - [4- [2- (2,4-diamine Bruno -7H- pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^[delta] - (4-fluoro-phenylcarbamoyl) -L- Ornithine methyl ester (152mg, 71
%) Was obtained. IR (KBr) ν: 3330,2950,1740,1610,1570,1550,1510,14
^{. 30,1405,1385,1310,1215,1155,830,760cm -1 1 H-NMR (} DMSO-d 6) δ: 1.40-1.60 (2H,
m), 1.70-1.90 (2H, m), 2.96 (4
H, m), 3.11 (2H, m), 3.64 (3H,
s), 4.44 (1H, m), 5.34 (2H, br
s), 5.69 (2H, s), 6.17 (1H, t, J
= 6.0 Hz), 6.35 (1 H, s), 7.03 (2
H, t, J = 9.0 Hz), 7.30-7.45 (4
H, m), 7.80 (2H, d, J = 7.8Hz),
8.46 (1H, brs), 8.67 (1H, d, J =
7.0 Hz), 10.34 (1H, brs). N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (4-fluorophenylcarbamoyl) -L- Ornithine methyl ester (143mg) 1
N-sodium hydroxide (1.0 ml), methanol (6.0 ml)
ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in water (5 ml) and 1N-
Hydrochloric acid (1.0 ml) was added to give the title compound (108 mg, 77%) as a colorless powder that precipitated. IR (KBr) ν: 3330,3200,2930,1660,1640,1610,1560,15
^{. 45,1510,1455,1400,1305,1210,830cm -1 1 H-NMR (} DMSO-d 6) δ: 1.40-1.60 (2H, m), 1.70-1.90 (2H,
m), 2.96 (4H, brs), 3.10 (2H, m), 4.36 (1H, m), 5.69 (2H, br
s), 6.16 (1H, t, J = 7.0Hz), 6.32 (2H, brs), 6.40 (1H, s), 7.03
(2H, t, J = 8.8Hz), 7.32 (2H, d, J = 8.2Hz), 7.37 (2H, dd, J = 8.
8,5.0Hz), 7.80 (2H, d, J = 8.2Hz), 8.43 (1H, s), 8.52 (1H, d, J
= 8.0Hz), 10.55 (1H, brs).

Example 5 N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (3-carboxy Preparation of phenyl) -L-ornithine Ethyl 3-[(4S) -4- (t-butoxycarbonylamino) -4- (methoxycarbonyl) butyl] aminobenzoate (411 mg) was added to 2N-HCl / ethyl acetate (12 ml). And was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was diluted with dichloromethane (20 m
l), ice water (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added and the mixture was vigorously stirred for a while, and then the dichloromethane layer was separated. The dichloromethane layer was dried over sodium sulfate and then concentrated to dryness under reduced pressure.
-[2- (2,4-diamino-7H-pyrrolo [2,3-
d] pyrimidin-5-yl) ethyl] benzoic acid-2 trifluoroacetate salt (428 mg), diethylphosphoryl cyanide (172 mg), N, N-dimethylformamide (8 m
l) was added, and triethylamine (0.67 ml, 4.
8 mM) was added and the mixture was stirred for 2 hours under ice cooling. The reaction mixture was concentrated to dryness under reduced pressure, the residue was washed with water, passed through an ammonia-treated silica gel column (30 g), and purified with methanol: dichloromethane (2:23) to give N as a colorless solid.
^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (3-ethoxycarbonylphenyl)
-L-ornithine methyl ester (430 mg, 92.6
%) Was obtained. IR (KBr) ν: 3370,2920,2850,1730,1710,1605,1570,15
^{. 40,1490,1425,1365,1280,1235,1180,1100,750cm -1 1 H-NMR (} DMSO-d 6) δ: 1.29 (3H, t, J = 7.0Hz), 1.5-2.05 (4
H, m), 2.96 (4H, m), 3.06 (2H, t, J = 5.8Hz), 3.64 (3H, s), 4.26
(1H, q, J = 7.0Hz), 4.48 (1H, m), 5.34 (2H, s), 5.92 (1H, t, J =
5.2Hz), 5.96 (2H, s), 6.35 (1H, d, J = 1.8Hz), 6.78 (1H, dt, J =
1.6Hz, 8.4Hz), 7.05-7.25 (3H, m), 7.32 (2H, d, J = 8.2Hz), 7.
79 (2H, d, J = 8.2Hz), 8.65 (1H, d, J = 7.6Hz), 10.33 (1H, d, J =
1.8Hz).

N ^α- [4- [2- (2,4-diamino-
7H- pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^[delta] - (3- ethoxycarbonyl-phenyl) -L- ornithine methyl ester (425
mg) was dissolved in a mixture of 1N-sodium hydroxide (4.0 ml), tetrahydrofuran (4.0 ml) and methanol (2.0 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in water (5 ml), 1N-hydrochloric acid (4.0 ml) was added, and the title compound (3) was precipitated as a colorless powder.
86 mg, 98.2) was obtained. IR (KBr) ν: 3390,3200,2920,2850,1640,1610,1540,14
^{. 95,1450,1435,1380,1335,1270,1190,760cm -1 1 H-NMR (} DMSO-d 6) δ: 1.55-2.10 (4H, m), 2.96 (4H, m), 3.
10 (2H, m), 4.40 (1H, m), 5.45 (2H, brs), 5.85 (1H, brs), 6.09
(2H, s), 6.37 (1H, s), 6.76 (1H, dt, J = 7.6Hz, 2.0Hz), 7.05-
7.25 (3H, m), 7.32 (2H, d, J = 8.2Hz), 7.80 (2H, d, J = 8.2Hz),
8.49 (1H, d, J = 7.8Hz), 10.40 (1H, s).

Example 6 N ^α- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -N ^δ- (3-carboxy Phenyl) -L-
Production of ornithine: Ethyl 3-[(4S) -4- (t-butoxycarbonylamino) -4- (methoxycarbonyl) butyl] aminobenzoate (295 mg) and 4- [3-
(2,4-Diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoic acid (230 mg) was used to give a colorless solid N ^α- [4- [3- (2,4 -Diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -N [ ^delta ]-(3-ethoxycarbonylphenyl) -L-ornithine methyl ester (316 mg, 72.7%) was obtained. It was IR (KBr) ν: 3380,3180,2930,2850,1740,1710,1610,15
75,1550,1535,1490,1425,1370,1325,1280,1240,1180,11
^{. 05,1020,990,800,755cm -1 1 H-NMR (} DMSO-d 6) δ: 1.29 (3H, t, J = 7.0Hz), 1.67 (1H,
m), 1.86 (4H, m), 3.04 (2H, m), 3.64 (3H, s), 4.27 (2H, q, J = 7.
0Hz), 4.46 (1H, m), 5.31 (2H, s), 5.92 (1H, t, J = 8.0Hz), 6.42
(1H, s), 6.76 (1H, dd, J = 1.4,3.8Hz), 7.13 (3H, m), 7.30 (2H,
d, J = 8.2Hz), 7.80 (2H, d, J = 8.2Hz), 8.65 (1H, d, J = 7.2Hz), 1
0.36 (1H, s).

N ^α- [4- [3- (2,4-diamino-
-5-7H-pyrrolo [2,3-d] pyrimidin-yl) propyl] benzoyl] -N ^[delta] - (3- ethoxy-carboxyphenyl) -L- ornithine methyl ester (31
0 mg) was subjected to ester hydrolysis in the same manner as in Example 1 to obtain the title compound (297 mg, 100%) as a colorless powder. IR (KBr) ν: 3400,3200,2930,2850,1645,1610,1540,15
^{. 00,1385,1335,1265,1230,1185,755cm -1 1 H-NMR (} DMSO-d 6) δ: 1.69 (2H, m), 1.85 (4H, m), 2.70 (4
H, m), 3.46 (2H, m), 4.413 (1H, m), 5.72 (2H, brs), 5.86 (1H, b
rs), 6.29 (2H, s), 6.49 (1H, s), 6.76 (1H, dt, J = 7.4,2.2Hz),
7.05-7.23 (3H, m), 7.30 (2H, d, J = 8.4Hz), 7.82 (2H, d, J = 8.4
Hz), 8.51 (1H, d, J = 7.8Hz), 10.61 (1H, s).

Example 7 N-[(4S) -4- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
Ethyl] benzoylamino] -4-carboxybutyl]
Production of -L-glutamic acid N-[(4S) -4- (t-butoxycarbonylamino) -4- (methoxycarbonyl) butyl] -L-glutamic acid diethyl (270 mg), 4-
[2- (2,4-diamino-7H-pyrrolo [2,3-d]
Pyrimidin-5-yl) ethyl] benzoic acid ditrifluoroacetate (192 mg) was used to give a colorless candy-like product N-
[(4S) -4- [4- [3- (2,4-diamino-7
H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoylamino] -4-methoxycarbonylbutyl] -diethyl L-glutamate (291 mg, 100
%) Was obtained. IR (KBr) ν: 3330,3200,2990,2950,1740,1690,1680,16
15,1575,1545,1500,1455,1430,1200,1130,830,800,720c
^{. m -1 1 H-NMR (} DMSO-d 6) δ: 1.81 (6H, t, J = 7.2Hz), 1.52 (2H,
m), 1.72 (2H, m), 1.93 (1H, m), 2.27 (3H, m), 2.96 (5H, m), 3.5
1 (1H, m), 3.64 (3H, s), 4.10 (1H, m), 4.12 (4H, q, J = 7.2Hz),
4.30 (1H, m), 4.42 (1H, m), 5.98 (2H, brs), 6.46 (1H, s), 6.61
(2H, brs), 7.34 (2H, d, J = 8.0Hz), 7.79 (2H, d, J = 8.0Hz), 8.6
2 (1H, d, J = 8.0Hz), 10.74 (1H, s). N-[(4S) -4- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d ] Pyrimidin-5-yl)
Ethyl] benzoylamino] -4-methoxycarbonylbutyl] -diethyl L-glutamate (286 mg) was hydrolyzed in the same manner as in Example 5 to give the title compound as a colorless powder (1
67 mg, 75.1%). IR (KBr) ν: 3400,3330,3180,2920,2860,1720,1640,15
40,1500,1460,1420,1385,1335,1280,1230,1200,1145,11
^{. 05,1090,730,650cm -1 1 H-NMR (} DMSO-d 6) δ: 1.56 (2H, m), 1.74 (2H, m), 1.95 (1
H, m), 2.25 (3H, m), 2.95 (4H, m), 3.53 (2H, m), 4.16 (1H, m),
4.37 (1H, m), 6.38 (2H, brs), 6.53 (1H, s), 7.03 (2H, s), 7.31
(2H, d, J = 8.2Hz), 7.79 (2H, d, J = 8.2Hz), 8.48 (1H, d, J = 7.4H
z), 10.99 (1H, s).

Example 8 N^α -[4- [2- (2,4-diamino-7H-pyrrolo
[2,3-d] pyrimidin-5-yl) ethyl] benzo
Il] -N^δ -(2-carboxybenzenesulfoni
Le) -L-ornithine production N^α -[4- [2- (2,4-diamino-7H-pyrrolo
[2,3-d] pyrimidin-5-yl) ethyl] benzo
Il] -N^δ -(T-Butoxycarbonyl) -L-o
Lunitine methyl ester (200mg) tetrahydrof
4N hydrochloric acid ethyl acetate solution (2 ml) in orchid (3 ml) solution
Was added and the mixture was stirred at room temperature for 10 minutes. Concentrate the reaction mixture to dryness
The residue obtained was dissolved in dimethylformamide (4 ml).
2-methoxycarbonylbenzenesulfonyl chloride
Add sodium (89 mg) and triethylamine (1 ml) for 30 minutes.
It was stirred. The reaction mixture is concentrated under reduced pressure, washed with water, and washed with silica gel.
Purified with chloroform: methanol = 15: 1
Colorless powder N^α -[4- [2- (2,4-diamino-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) e
Cyl] benzoyl] -N^δ -(2-Methoxycarbonyl
Lubenzenesulfonyl) -L-ornithine methyl ester
(130 mg, 55%). IR (KBr) ν: 3400,1730,1610,1580,1550,1500,1435,13
30,1300,1160,760cm^-1. ¹ H-NMR (DMSO-d₆) Δ: 1.35-1.55 (2H, m), 1.65-1.90 (2H,
m), 2.86 (2H, m), 2.96 (4H, brs), 3.62 (3H, s), 3.83 (3H, s),
4.34 (1H, m), 5.35 (2H, brs), 5.97 (2H, brs), 6.35 (1H, s), 7.
33 (2H, d, J = 8.0Hz), 7.47 (1H, t, J = 8.2Hz), 7.60-7.90 (6H,
m), 8.59 (1H, d, J = 7.2Hz), 10.34 (1H, brs). N^α -[4- [2- (2,4-diamino-7H-pyrrolo
[2,3-d] pyrimidin-5-yl) ethyl] benzo
Il] -N^δ -(2-methoxycarbonylbenzenes
Rufonyl) -L-ornithine methyl ester (120m
g) was hydrolyzed as in Example 5 to give a colorless powder,
A compound (90 mg, 79%) was obtained. IR (KBr) ν: 3340,3200,2930,1660,1640,1540,1500,14
50,1380,1320,1220,1190,1160,1120,1080,1015,760,610
cm^-1.¹ H-NMR (DMSO-d₆) Δ: 1.40-1.55 (2H, m), 1.60-1.85 (2H,
m), 2.80 (2H, m), 2.95 (4H, m), 4.30 (1H, m), 6.40 (2H, br), 6.
51 (1H, m), 6.84 (1H, brs), 7.03 (1H, br), 7.28 (2H, d, J = 8.0H
z), 7.40-7.90 (6H, m), 8.42 (1H, d, J = 8.0Hz), 11.03 (1H, br
s).

Example 9 N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (3,5 Preparation of -dicarboxybenzenesulfonyl) -L-ornithine N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) as in Example 8. Ethyl] benzoyl] -N ^δ- (t-butoxycarbonyl) -L-ornithine methyl ester (120 m
g) and 3,5-dimethoxycarbonylbenzenesulfonyl chloride (67 mg) as a colorless powder of N ^α- [4-
[2- (2,4-diamino-7H-pyrrolo [2,3-d]
Pyrimidin-5-yl) ethyl] benzoyl] -N [ ^delta ]
-(3,5-Dimethoxycarbonylbenzenesulfonyl) -L-ornithine methyl ester (45 mg, 29
%) Was obtained. IR (KBr) ν: 3380,3200,2950,1730,1610,1580,1550,15
^{. 00,1430,1325,1250,1160,750cm -1 1 H-NMR (} DMSO-d 6) δ: 1.30-1.55 (2H, m), 1.60-1.85 (2H,
m), 2.77 (2H, m), 2.95 (4H, brs), 3.60 (3H, s), 3.93 (6H, s),
4.30 (1H, m), 5.35 (2H, s), 5.96 (2H, s), 6.35 (1H, s), 7.31 (2
H, d, J = 7.8Hz), 7.72 (2H, d, J = 7.8Hz), 8.00 (1H, t, J = 6.0H
z), 8.52 (2H, s), 8.56 (1H, d, J = 7.6Hz), 8.60 (1H, s), 10.34
(1H, brs) .N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (3,5 -Dimethoxycarbonylbenzenesulfonyl) -L-ornithine methyl ester (41
was hydrolyzed in the same manner as in Example 5 to obtain the title compound (32 mg, 83%) as a colorless powder. IR (KBr) ν: 3390,3200,2930,1700,1650,1640,1540,14
^{. 60,1380,1330,1310,1180,1150,1100,760,670,590cm -1 1 H-NMR (} DMSO-d 6) δ: 1.35-1.95 (4H, m), 2.85 (2H, m), 3.
00 (4H, m), 4.28 (1H, m), 6.56 (3H, brs), 6.71 (2H, brs), 7.28
(2H, d, J = 7.6Hz), 7.74 (2H, d, J = 7.6Hz), 7.91 (1H, m), 8.42
(1H, d, J = 7.6Hz), 8.42 (1H, d, J = 7.6Hz), 8.42 (2H, s), 8.65
(1H, s), 8.65 (1H, s), 10.84 (1H, brs).

Example 10 N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (4-toluene) Preparation of sulfonyl) -L-ornithine N ^α- [4- [2- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] as in Example 8. -N [ ^delta] -(t-butoxycarbonyl) -L-ornithine methyl ester (100 m
g) and 4-toluenesulfonyl chloride (36 mg) as colorless powder of N ^α- [4- [2- (2,4-diammino-
7H- pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^[delta] - (4-toluenesulfonyl) -L- ornithine methyl ester (64 mg, 58
%) Was obtained. IR (KBr) ν: 3380,3200,2930,1740,1610,1580,1545,14
^{. 95,1430,1320,1215,1155,1090,750,660,550cm -1 1 H-NMR (} CD 3 OD) δ: 1.45-1.65 (2H, m), 1.70-2.05 (2H,
m), 2.38 (3H, s), 2.88 (2H, t, J = 6.6Hz), 3.04 (4H, brs), 3.71
(3H, s), 4.51 (1H, dd, J = 9.0,4.8Hz), 6.38 (1H, s), 7.27 (2H,
d, J = 8.0Hz), 7.32 (2H, d, J = 8.0Hz), 7.70 (2H, d, J = 8.0Hz),
7.73 (2H, d, J = 8.0Hz) .N ^α- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -N ^δ- (4-Toluenesulfonyl) -L-ornithine methyl ester (50 mg) was hydrolyzed in the same manner as in Example 5 to give the title compound as a colorless powder (43 mg, 88%).
Got IR (KBr) ν: 3400,3200,2930,1640,1565,1540,1500,14
^{. 50,1395,1320,1300,1155,1090,810,660,550cm -1 1 H-NMR (} DMSO-d 6) δ: 1.35-1.55 (2H,
m), 1.60-1.90 (2H, m), 2.35 (3
H, s), 2.73 (2H, m), 2.96 (4H, b
rs), 4.29 (1H, m), 5.82 (2H, br)
s), 6.34 (3H, brs), 7.32 (2H,
d, J = 8.2 Hz), 7.35 (2H, d, J = 8.
2Hz), 7.50 (1H, t, J = 5.6Hz),
7.65 (2H, d, J = 8.2Hz), 7.77 (2
H, d, J = 8.2 Hz), 8.43 (1H, d, J =
7.6 Hz), 10.63 (1H, brs).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI C07D 491/048 C07D 491/048 495/04 105 495/04 105Z (56) Reference JP-A-6-49069 (JP, A) JP-A-4-117381 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 487/04 140 A61K 31/517-31/554 C07D 239/70 C07D 401/06 C07D 491 / 048 C07D 495/04 105 CA (STN) REGISTRY (STN)

Claims (10)

(57) [Claims] 1. A formula [Chemical 1] [In the formula, ring A is a 5-membered ring which may be hydrogenated.
The substituentAs (a1) alkyl having 1 to 4 carbons
Group, (a2) alkenyl group having 2 to 4 carbon atoms, (a
3) an alkynyl group having 2 to 4 carbon atoms, (a4) C
_3-8 Cycloalkyl group, (a5) halogen atom, (a
6) Alkanoyl group having 1 to 4 carbon atoms, (a7) Ben
Zoyl group, (a8) halogenobenzoyl, (a9) mono
-, Di- or tri-C _1-4 Alkoxy benzoyl,
(A10) cyano group, (a11) carboxy group, (a1
2) carbamoyl group, (a13) nitro group, (a14)
Hydroxy group, (a15) hydroxy-C _1-4 Archi
Ru radical, (a16) C _1-4 Alkoxy-C _1-4 Archi
Group, (a17) an alkoxy group having 1 to 4 carbon atoms,
(A18) mercapto group, (a19) carbon number 1 to 4
Alkylthio group, (a20) amino group, (a21)
No or di-C _1-4 Alkylamino group and (a2
2) selected from alkanoylamino groups having 1 to 4 carbon atoms
1- or 2-membered ring, wherein the 5-membered ring is
Or a pyrroline ring, N is a substituent,
An alkyl group having 1 to 4 carbon atoms, an alkyl group having 2 to 4 carbon atoms
Lucenyl group, alkynyl group having 2 to 4 carbon atoms, C
_3-6 Cycloalkyl group, alkano having 1 to 4 carbon atoms
Yl group, benzoyl group, halogenobenzoyl, mono-,
Di- or tri-C _1-4 Alkoxybenzoyl, hydr
Roxy-C _1-4 Alkyl group, C _1-4 Alkoxy-C
_1-4 Alkyl group, phenyl group, halogenophenyl,
No-, di- or tri-C _1-4 Alkoxyphenyl,
Benzyl group, halogenobenzyl, C _1-4 Alkoxy
Or diphenylmethylMay have B
Is a substituentAs an alkyl group having 1 to 4 carbon atoms, carbon number
2 to 4 alkenyl groups, 2 to 4 carbon atoms
Nyl group, C _3-6 Cycloalkyl group, halogen atom,
Droxy group, C _1-4 Alkoxy group, di-C _1-4 Al
Killamino group, halogen No-C _1-4 Alkyl group, oxo
Base, C _1-4 Acyl group or C _1-4 Alkoxy-C
_1-4 1 or 2 selected from alkyl groupsHave
An optionally divalent 5- or 6-membered homo or heterocyclic group,
X is an amino group, a hydroxy group or a mercapto group, and Y is
Is(Y1)Hydrogen atom,(Y2)Halogen atom,(Y3)
Cyano group, (Y4) carboxy group, (Y5) carbamoy
Group, (Y6) amino group, (Y7) nitro group, (Y8)
Hydroxy group, (Y9) mercapto group, (Y10) carbon
An alkyl group having 1 to 4 carbon atoms (Y11) having 2 to 4 carbon atoms
4 alkenyl groups, (Y12) C2-C4 alkenyl groups
Quinyl group, (Y13) C _3-6 Cycloalkyl group, (Y
14) C _6-10 Aryl group, (Y15) N, S, O
5 or 6 member containing 1 to 4 heteroatoms selected from
Heterocyclic group, (Y16) alkoxy group, (Y17) ar
Kirthio group, (Y18) alkylcarbonylamino group,
(Y19) alkylcarbonyloxy group, (Y20) a
Reeloxy group, (Y21) arylthio group, (Y2
2) aroylamino group, (Y23) aroyloxy group,
(Y24) heterocyclic oxy group, (Y25) heterocyclic thio group,
(Y26) heterocyclic carbonylamino group, (Y27) hetero
Ring carbonyloxy group, (Y28) mono-substitution or di-position
Represents a substituted amino group, and represents (Y16), (Y17), (Y1
8) and the alkyl moiety of (Y19) has no carbon atoms.
A C4 alkyl group, a C2-C4 alkenyl group,
C2-C4 alkynyl group or C _3-8 Cyclo
An alkyl group, (Y20), (Y21), (Y2
2) and the aryl moiety of (Y23) is a phenyl group or
Is a naphthyl group, and is (Y24), (Y25), (Y2
6) and the heterocyclic moiety of (Y27) is composed of N, S, O
5- or 6-membered containing 1 to 4 selected heteroatoms
And the substituted portion of (Y28) has 1 to 4 carbon atoms.
Alkyl group, C2-C4 alkenyl group, carbon
An alkynyl group of the number 2 to 4, C _3-8 Cycloalkyl
Base, C _6-10 Aryl group or het such as N, S, O
(B) 5- or 6-membered heterocyclic group containing 1 to 4 atoms
, (Y10), (Y11), (Y12), (Y1
3), (Y14) and (Y15) are carbon atoms as substituents.
Alkyl group having 1 to 4 primes, Al group having 2 to 4 carbons
Kenyl group, alkynyl group having 2 to 4 carbon atoms, C _3-8
Cycloalkyl group, halogen atom, hydroxy group, oxy
So group, C _1-4 Alkoxy group, di-C _1-4 Alkyla
Mino group, halogeno-C _1-4 Alkyl group, C _1-4 Reed
Group, hydroxy-C _1-4 Alkyl group and C _1-4
Alkoxy-C _1-4 Selected from the group consisting of alkyl groups
May have one or two,Z is(Z1) C
_1-5 Alkylene group, (Z2) C _2-5 Alkenylene
Group, (Z3) C _2-5 Alkynylene group or (Z4) formula
-Z ¹ -Z ^Two -Z ^Three -[Wherein Z ¹ And Z ^Three Are the same
Or differently (Za1) bond, (Za2) C _1-4 A
Ruylene group, (Za3) C _2-4 Alkenylene group or
(Za4) C _2-4 Alkynylene group (however, Z ¹ And Z ^Three
The total number of carbon atoms of 1 to 4), -Z ^Two − Is
-O-, formula -S (O) n ¹ − (Where n ¹ Is an integer from 0 to 2
Indicates a number. ) Or the formula -N (R ^Four )-(Wherein R ^Four Is
(R ^Four 1) hydrogen atom, (R ^Four 2) Carbon number 1 to 4
Rukiru group, (R ^Four 3) Alkenyl having 2 to 4 carbon atoms
Group, (R ^Four 4) an alkynyl group having 2 to 4 carbon atoms or
(R ^Four 5) C _3-8 Represents a cycloalkyl group)
You ] The group represented by these is shown, (Z1), (Z2), (Z
3), (Za2), (Za3), (Za4), (R
^Four 2), (R ^Four 3), (R ^Four 4) and (R ^Four 5) is
Alkyl group having 1 to 4 carbon atoms as a substituent, 2 carbon atoms
Alkenyl group having 4 to 4 alkynyl having 2 to 4 carbon atoms
Lu group, C _3-8 Cycloalkyl group, halogen atom, hydr
Roxy group, oxo group, C _1-4 Alkoxy group, di-C
_1-4 Alkylamino group, halogeno-C _1-4 Alkyl
Base, C _1-4 Acyl group, hydroxy-C _1-4 Alkyl
Base, C _1-4 Alkoxy-C _1-4 Alkyl group and C
_1-4 Selected from the group consisting of alkoxy-carbonyl groups
May have one or two,W is -NHCON
H-, -N (R)-or -NHSO_TwoGroup represented by-
(R is a hydrogen atom or a substituentWith 1 to 4 carbon atoms
Alkyl group, alkenyl group having 2 to 4 carbon atoms, carbon number
2 to 4 alkynyl groups, C _3-8 Cycloalkyl
Group, halogen atom, hydroxy group, oxo group, C _1-4
Alkoxy group, di-C _1-4 Alkylamino group, halogen
No-C _1-4 Alkyl group, C _1-4 Acyl group, hydroxy
Sea C _1-4 Alkyl group, C _1-4 Alkoxy-C
_1-4 C which may have an alkyl group _1-4hydrocarbon
R represents a group)¹IsLower chain carbon with 1 to 4 carbons
Hydrogenated group, 5- or 6-membered cyclic hydrocarbon group or carbon source
In addition to children, hetero atoms such as nitrogen atom, oxygen atom, sulfur atom, etc.
A heterocyclic group which may contain 1 to 4 atoms in the ring.
Rui shows its fused ring group, these Is carbon as a substituent
An alkyl group having 1 to 4 carbon atoms, an alke having 2 or 4 carbon atoms
Nyl group, C2-4 alkynyl group, C3
Ishi6 cycloalkyl group, C5-6 cyclo
Alkenyl groups, aralkyl groups having 7 to 8 carbon atoms,
Nyl group, 5- to 6-membered heterocyclic group, having 1 to 4 carbon atoms
Alkoxy group, phenoxy group, C1-C4 alkenyl group
Canoyl group, benzoyl group, C1-C4 alkayl
Noyloxy group, benzoyloxy group, carboxy group,
C _1-4 Alkoxycarbonyl group, carboxy-C
_1-4 Alkyl, C _1-4 Alkoxycarbonyl-C
_1-4 Alkyl, carbamoyl group, N-C _1-4 Archi
Rucarbamoyl group, N, N-di-C _1-4 Alkylcal
Vamoyl, 1-Achiridinylcarbonyl, 1-Azetidi
Nylcarbonyl, 1-pyrrolidinylcarbonyl, 1-pi
Peridinyl carbonyl, N-methyl piperazinyl carb
Nyl, morpholinocarbonyl group, halogen atom, mono
-, Di- or tri-halogeno-C _1-4 An alkyl group,
Amidino group, imino group, amino group, mono-C _1-4 Al
Kiramino group, di-C _1-4 Alkylamino group, atili
Dinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pi
Loril, imidazolyl, pyrazolyl, imidazolidini
Le, piperidino, morpholino, dihydropyridyl, pyri
Zil, N-methyl piperazinyl, N-ethyl piperazini
Lu group, C _1-4 Alkanoylamide group, benzamide
Group, carbamoylamino group, N-C _1-4 Alkylcal
Vamoylamino group, N, N-di-C _1-4 Alkylcal
Vamoylamino group, 1-Achiridinylcarbonylami
No, 1-azetidinylcarbonylamino, 1-pyrrolidi
Nylcarbonylamino, 1-piperidinylcarbonyla
Mino, N-methylpiperazinylcarbonylamino, mol
Holinocarbonylamino group, C _1-3 Alkylene Dioki
Si, hydroxy group, epoxy group (-O-), nitro group,
Ano group, mercapto group, sulfo group, sulfino group, phos
Hono group, dihydroxyboryl group, sulfamoyl group,
N-C _1-4 Alkylsulfamoyl group, di-C _1-4
Alkylsulfamoyl group, 1-pyrrolidinylsulfoni
1-piperidinylsulfonyl, N-methyl-1-pi
Perazinylsulfonyl, morpholinosulfonyl group, carbon
Number 1 to 4 alkylthio group, phenylthio group, carbon
Number 1 to 4 alkylsulfinyl group, phenylsulfin
Finyl group, alkylsulfonyl group having 1 to 4 carbon atoms
And phenylsulfonyl group 1 selected from the group
Or may have two, COOR^TwoIs an ester
An optionally carboxyl group, p is 1 to 4
Indicates an integer. ] The compound or its salt represented by these. Wherein _{p = 3, W = -NHSO 2} - when, ^{R 1} is C 1 -C as a substituent 4 alkyl, carbon atoms 2
Or an alkenyl group having 4 or 4 alkynyl having 2 to 4 carbon atoms
Group, cycloalkyl group having 3 to 6 carbon atoms, 5 carbon atoms
A cycloalkenyl group having 6 to 6 carbon atoms,
Ralalkyl group, phenyl group, 5- or 6-membered heterocyclic group, charcoal
Alkoxy group, phenoxy group, carbon number of 1 to 4
1 to 4 alkanoyl group, benzoyl group, carbon number 1
To 4 alkanoyloxy groups, benzoyloxy
Group, carboxy group, C _1-4 alkoxycarbonyl group,
Carboxy-C _1-4 alkyl, C _1-4 alkoxyl
Rubonyl-C _1-4 alkyl, carbamoyl group, N-C
_1-4 alkylcarbamoyl group, N, N-di-C _1-4
Alkylcarbamoyl, 1-acetylidinylcarbonyl,
1-azetidinylcarbonyl, 1-pyrrolidinylcarbo
Nyl, 1-piperidinyl carbonyl, N-methyl pipera
Dinylcarbonyl, morpholinocarbonyl group, halogen
Atom, mono-, di- or tri-halogeno-C _1-4 a
Alkyl group, amidino group, imino group, amino group, mono-C
_1-4 alkylamino group, di-C _1-4 alkylamino
Group, atyridinyl, azetidinyl, pyrrolidinyl, pyro
Linyl, pyrrolyl, imidazolyl, pyrazolyl, imidazole
Zolidinyl, piperidino, morpholino, dihydropyridi
L, pyridyl, N-methylpiperazinyl, N-ethylpi
Perazinyl group, C _1-4 alkanoylamide group, benz
Amido group, carbamoylamino group, N-C _1-4 alk
Lucarbamoylamino group, N, N-di-C _1-4 alk
Rucarbamoylamino group, 1-acetylidinylcarbonyl
Amino, 1-azetidinylcarbonylamino, 1-pyro
Lysinyl carbonylamino, 1-piperidinyl carbonyl
Luamino, N-methylpiperazinylcarbonylamino,
Morpholinocarbonylamino group, C _1-3 alkylenedi
Oxy, hydroxy group, epoxy group (-O-), nitro
Group, cyano group, mercapto group, sulfo group, sulfino
Group, phosphono group, dihydroxyboryl group, sulfamo
Group, N—C _1-4 alkylsulfamoyl group, di-
C _1-4 alkylsulfamoyl group, 1-pyrrolidinyl
Sulfonyl, 1-piperidinylsulfonyl , N-methyl
-1-Piperazinylsulfonyl, morpholinosulfonyl
Group, alkylthio group having 1 to 4 carbon atoms, phenylthio group
Group, an alkylsulfinyl group having 1 to 4 carbon atoms, and
Nylsulfinyl group, alkylsulfur having 1 to 4 carbon atoms
Selected from the group consisting of phenyl and phenylsulfonyl groups.
The compound according to claim 1, which is a phenyl group which may have 1 or 2 groups attached. 3. A chemical formula: [In the formula, m ¹ is an integer of 1 to 5, and other symbols have the same meanings as in claim 1. ] The compound of Claim 1 represented by these. 4. R ¹ is a substituent having 1 to 4 carbon atoms.
Rualkyl group, alkenyl group having 2 or 4 carbon atoms, 2 carbon atoms
To 4 alkynyl groups, 3 to 6 carbon cycloalkyl
Rukyl group, cycloalkenyl group having 5 to 6 carbon atoms, charcoal
Aralkyl group having a prime number of 7 to 8, phenyl group, 5 to
6-membered heterocyclic group, alkoxy group having 1 to 4 carbon atoms,
Enoxy group, alkanoyl group having 1 to 4 carbon atoms, benzene
A zoyl group, an alkanoyloxy group having 1 to 4 carbon atoms,
Benzoyloxy group, a carboxy _{group, C 1-4} alkoxy
Sicarbonyl group, carboxy-C _1-4 alkyl, C
_1-4 alkoxycarbonyl-C _1-4 alkyl, cal
A vamoyl group, an N—C _1-4 alkylcarbamoyl group,
N, N-di-C _1-4 alkylcarbamoyl, 1-acetyl
Lysinyl carbonyl, 1-azetidinyl carbonyl, 1
-Pyrrolidinyl carbonyl, 1-piperidinyl carbonyl
L, N-methylpiperazinyl carbonyl, morpholinoca
Rubonyl group, halogen atom, mono-, di- or tri-
Halogeno-C _1-4 alkyl group, amidino group, imino
Group, amino group, mono-C _1-4 alkylamino group, di-
C _1-4 alkylamino group, achiridinyl, azetidinii
L, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazoli
Le, pyrazolyl, imidazolidinyl, piperidino, mol
Holino, dihydropyridyl, pyridyl, N-methylpipet
Piperazinyl, N- ethylpiperazinyl _{group, C 1-4} alk
Noylamide group, benzamide group, carbamoylamino
Group, N—C _1-4 alkylcarbamoylamino group, N,
N-di-C _1-4 alkylcarbamoylamino group, 1-
Achiridinylcarbonylamino, 1-azetidinylcar
Bonylamino, 1-pyrrolidinylcarbonylamino, 1
-Piperidinyl carbonylamino, N-methyl piperazi
Nylcarbonylamino, morpholinocarbonylamino
Group, C _1-3 alkylenedioxy, hydroxy group, epo
Xy group (-O-), nitro group, cyano group, mercapto group,
Sulfo group, sulfino group, phosphono group, dihydroxy group
Reel group, sulfamoyl group, N-C _1-4 alkyls
Rufamoyl group, di-C _1-4 alkylsulfamoyl
Group, 1-pyrrolidinylsulfonyl, 1-piperidinyls
Rufonyl, N-methyl-1-piperazinylsulfonyl,
Morpholinosulfonyl group, alkyl having 1 to 4 carbons
Thio group, phenylthio group, alkyl having 1 to 4 carbon atoms
Sulfinyl group, phenylsulfinyl group, carbon number 1
Alkylsulfonyl group and phenylsulfoni
4. The compound according to claim 3, which is a phenyl group which may have 1 or 2 selected from the group consisting of phenyl groups. 5. R ¹ is The compound according to claim 3, which is (m ² represents 0, 1 or 2). 6. The formula : [In the formula, m ¹ is an integer of 1 to 5, and other symbols have the same meanings as in claim 1. ] The compound of Claim 1 represented by these. 7. R ¹ is a substituent having 1 to 4 carbon atoms.
Rualkyl group, alkenyl group having 2 or 4 carbon atoms, 2 carbon atoms
To 4 alkynyl groups, 3 to 6 carbon cycloalkyl
Rukyl group, cycloalkenyl group having 5 to 6 carbon atoms, charcoal
Aralkyl group having a prime number of 7 to 8 , phenyl group, 5 to
6-membered heterocyclic group, alkoxy group having 1 to 4 carbon atoms,
Enoxy group, alkanoyl group having 1 to 4 carbon atoms, benzene
A zoyl group, an alkanoyloxy group having 1 to 4 carbon atoms,
Benzoyloxy group, a carboxy _{group, C 1-4} alkoxy
Sicarbonyl group, carboxy-C _1-4 alkyl, C
_1-4 alkoxycarbonyl-C _1-4 alkyl, cal
A vamoyl group, an N—C _1-4 alkylcarbamoyl group,
N, N-di-C _1-4 alkylcarbamoyl, 1-acetyl
Lysinyl carbonyl, 1-azetidinyl carbonyl, 1
-Pyrrolidinyl carbonyl, 1-piperidinyl carbonyl
L, N-methylpiperazinyl carbonyl, morpholinoca
Rubonyl group, halogen atom, mono-, di- or tri-
Halogeno-C _1-4 alkyl group, amidino group, imino
Group, amino group, mono-C _1-4 alkylamino group, di-
C _1-4 alkylamino group, achiridinyl, azetidinii
L, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazoli
Le, pyrazolyl, imidazolidinyl, piperidino, mol
Holino, dihydropyridyl, pyridyl, N-methylpipet
Piperazinyl, N- ethylpiperazinyl _{group, C 1-4} alk
Noylamide group, benzamide group, carbamoylamino
Group, N—C _1-4 alkylcarbamoylamino group, N,
N-di-C _1-4 alkylcarbamoylamino group, 1-
Achiridinylcarbonylamino, 1-azetidinylcar
Bonylamino, 1-pyrrolidinylcarbonylamino, 1
-Piperidinyl carbonylamino, N-methyl piperazi
Nylcarbonylamino, morpholinocarbonylamino
Group, C _1-3 alkylenedioxy, hydroxy group, epo
Xy group (-O-), nitro group, cyano group, mercapto group,
Sulfo group, sulfino group, phosphono group, dihydroxy group
Reel group, sulfamoyl group, N-C _1-4 alkyls
Rufamoyl group, di-C _1-4 alkylsulfamoyl
Group, 1-pyrrolidinylsulfonyl, 1-piperidinyls
Rufonyl, N-methyl-1-piperazinylsulfonyl,
Morpholinosulfonyl group, alkyl having 1 to 4 carbons
Thio group, phenylthio group, alkyl having 1 to 4 carbon atoms
Sulfinyl group, phenylsulfinyl group, carbon number 1
Alkylsulfonyl group and phenylsulfoni
7. The compound according to claim 6, which is a phenyl group or C _1-4 alkyl group which may have 1 or 2 selected from the group consisting of alkyl groups. 8. R ¹ is (M ² is 0, 1 or 2 and m ³ is 1 or 2)
The compound according to claim 6, which is 9. The formula: [In the formula, each symbol has the same meaning as in claim 1 . ] Or a salt thereof or a reactive derivative at a carboxy group, and a compound of the formula: [In the formula, each symbol has the same meaning as in claim 1 . ] The compound of Claim 1 or its salt is made to react, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 10. The formula : [In the formula, the ring A'is a 5-membered ring which may be hydrogenated, and has (a1) an alkyl group having 1 to 4 carbon atoms as a substituent.
Group, (a2) alkenyl group having 2 to 4 carbon atoms, (a
3) an alkynyl group having 2 to 4 carbon atoms, (a4) C
_3-8 cycloalkyl group, (a5) halogen atom, (a
6) Alkanoyl group having 1 to 4 carbon atoms, (a7) Ben
Zoyl group, (a8) halogenobenzoyl, (a9) mono
-, Di- or tri-C _1-4 alkoxybenzoyl,
(A10) cyano group, (a11) carboxy group, (a1
2) carbamoyl group, (a13) nitro group, (a14)
Hydroxy group, (a15) hydroxy-C _1-4 alk
Group, (a16) C _1-4 alkoxy-C _1-4 alk
Group, (a17) an alkoxy group having 1 to 4 carbon atoms,
(A18) mercapto group, (a19) carbon number 1 to 4
Alkylthio group, (a20) amino group, (a21)
No- or di-C _1-4 alkylamino group and (a2
2) selected from alkanoylamino groups having 1 to 4 carbon atoms
1 or 2 of them may be included, and N is a substituent.
An alkyl group having 1 to 4 carbon atoms, 2 to 4 carbon atoms
Alkenyl group, alkynyl group having 2 to 4 carbon atoms, C
_3-6 cycloalkyl group, alkano having 1 to 4 carbon atoms
Yl group, benzoyl group, halogenobenzoyl, mono-,
Di- or tri-C _1-4 alkoxybenzoyl, hydr
Roxy-C _1-4 alkyl group, C _1-4 alkoxy-C
_1-4 alkyl group, phenyl group, halogenophenyl,
No-, di- or tri-C _1-4 alkoxyphenyl,
Benzyl group, halogenobenzyl, C _1-4 alkoxy ester
May have diphenyl or diphenylmethyl, etc.
Symbol has the same meaning as in claim 1 . ] The antitumor composition containing the compound or its salt represented by these.