JP2003128548A - Medicinal composition containing condensed imidazolium derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for cancers such as solid carcinomas and lymphomas. SOLUTION: This medicinal composition contains an imidazolium derivative condensed with an aryl ring or a heteroaryl ring and characterized by being substituted at its 1-position and/or 3-position with a substituted alkyl and is an antitumor agent having good antitumor activity, low toxicity and a wide margin of safety. And, thereby, the composition is useful for treatment of all solid carcinomas and lymphomas and especially useful for tumors such as cutaneous cancer, urinary bladder cancer, mastocarcinoma, uterine cancer, ovarian cancer, prostatic cancer, lung cancer, colon cancer, pancreatic cancer, renal carcinoma and stomach cancer.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition particularly useful as an anticancer agent.

[0002]

[Prior Art] Khim.-Farm. Zh., 32 (6), 10-11 (199
8), the following compound I (abbreviated as KP-1 in the present specification), compound II and compound III having the same condensed imidazolium skeleton as the compound represented by the general formula (I) of the present invention described below.
It describes the synthesis of (abbreviated as KP-3 in the present specification) and the cancer growth inhibitory activity in animal models transplanted with cancer cells. The compound of the general formula (I) of the present invention has a different structure from the compounds described in this document in that at least one of R ¹ and R ² is a lower alkyl group having a specific substituent. To do. In addition, the result of the toxicity test of Example 3 below,
The compounds KP-1 and KP-3 described in this document are highly toxic, and
As a result of the pharmacological test of Example 2, KP-3 did not show significant cancer growth inhibitory activity.

[Chemical 2] (In the formula, Et represents ethyl, Me represents methyl, and Ph represents phenyl. The same applies hereinafter.) J. Med. Chem., 7 (3), 362-364 (1964) describes the general formula of the present invention described below. In (I), R ¹ and R ² are both lower alkyl, or one is -lower alkylene- (aryl optionally having one or more substituents) and the other is -C.
_{H 3, - (CH 2)} 3 CH 3, or - a compound which is a phenyl group, or, one - a lower alkylene -CO- (1 or more substituents which may be the have aryl), the other ,
There is a description of a compound having an antibacterial action which is —CH ₂ CH (CH ₃ ) ₂ or — (CH ₂ ) ₃ CH ₃ . The compound of the following general formula (I) of the present invention is characterized in that at least one of R ¹ and R ² is a lower alkyl group having a specific substituent,
It differs in structure from the compounds described in this document. Kohei
Japanese Patent Publication No. 3-258765 discloses a novel method for synthesizing a specific naphthoimidazolium salt used as a raw material of a dye or a medicine. However, there is no description about the use of the anticancer agent. Although there is a specific description in the specification of the compound of the general formula (I) of the present application, wherein R ¹ and R ² are both — (CH ₂ ) ₂ OC ₂ H ₅ , the present invention includes the compound. do not do.

Further, J. Org. Chem. USSR, 1, 1479-85
(1965), JP-A-3-258765 and JP-A-6-
In the general formula (I) of the present invention described later, R ¹ and R ² are both lower alkyl groups, 4,9-
Dioxonaphtho [2,3-d] imidazolium derivatives are disclosed. However, there is no disclosure about the pharmaceutical use of these compounds.

[0004]

There is still a long-felt demand for the creation of anticancer agents having a good anticancer activity and low toxicity.

[0005]

Means for Solving the Problems As a result of intensive investigations by the present inventors on an anticancer agent having few side effects, the aryl group is characterized in that the 1-position and / or the 3-position are substituted with an alkyl group having a substituent. The present invention has been completed by finding that an imidazolium derivative fused with a ring or a heteroaryl ring has good antitumor activity and low toxicity, and can be an anticancer agent having a wide safety margin.

That is, the present invention relates to a pharmaceutical composition containing a condensed imidazolium derivative represented by the following general formula (I) as an active ingredient, particularly an anticancer agent.

[Chemical 3] (The symbols in the formulas have the following meanings. R¹And R²: Same or different,-(selected from group B
Lower alkyl optionally having one or more substituents),
-(Even if it has one or more substituents selected from Group B
Good lower alkenyl),-(one or more selected from group B)
A lower alkynyl which may have a substituent) or -R
inD, but R¹And R²At least one of -OR
^a, -NR^aR^b, -NR^a-COR^b, -O-lower alk
Ren-OR^a, -O-lower alkylene-O-lower alk
Ren-OR^aAnd-(hetero which may have a substituent)
One or more substituents selected from the group consisting of aryl)
Has lower alkyl. Group B: -OR^a, -SR^a, -Prodrugated O
H, -O-lower alkylene-OR^a, -O-lower alk
Len-O-lower alkylene-OR^a, -O-lower alk
Ren-NR^aR^b, -O-lower alkylene-O-lower ar
Killen-NR^aR^b, -O-lower alkylene-NR^c-Low
Alkylene-NR^aR^b, -OCO-NR^aR ^b, -SO
R^a, -SO₂R^a, -SO₂NR^aR^b, -NR^a-SO₂R
^b, -NR^aR^b, -NR^c-Lower alkylene-NR^aR^b,
-N (-lower alkylene-NR^aR^b)₂, -RinD,
-NO₂, -CN, -halogen, -CO₂R^a, -CO
O^-, -CONR^aR^b, -CONR^a-OR^b, -NR^a
-COR^b, -NR^a-CO-NR^bR ^c, -OCOR^aOver
And -CO-R^a. R^a, R^bAnd R^c: Same or different, -H, -lower
Alkyl, -lower alkylene-RinD, or -Rin
D. RinD :-( 5 that may have one or more substituents
To 7-membered saturated heterocycle),-(having one or more substituents)
Optionally cycloalkyl),-(having one or more substituents
Optional cycloalkenyl),-(one or more substituents
Optionally substituted aryl) or-(one or more substituents
A heteroaryl which may have). R³: -H or-
(Lower alkyl optionally having one or more substituents),
Or R²And R³Together, O, S or NR
^Four(R^Four: -H or -lower alkyl)
Good, lower alkylene having 3 to 6 carbon atoms may be formed.
Yes. A ring: an aryl ring which may have one or more substituents, or
Is heteroaryl optionally having one or more substituents
ring. X^-: Counter anion, provided that the group B substituent is -CO
O^-And the imidazolium cation form an inner salt
Ki X^-Does not exist. However, R¹And R²Together-
(CH₂)₂OC₂H_FiveExcluding compounds that are The same applies below. )

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The pharmaceutical composition of the present invention will be further described. In the present specification, the term "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. The "lower alkyl" is preferably an alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group. The "lower alkenyl" is preferably a vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl group. The "lower alkynyl" is preferably an ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl group. Further, as the “lower alkylene”, preferably,
Methylene, ethylene, trimethylene and 2,2-dimethyltrimethylene groups.

"Aryl" means an aromatic hydrocarbon ring group, preferably an aryl group having 6 to 14 carbon atoms, and preferably a phenyl, naphthyl or fluorenyl group. The “aryl ring” in ring A is a ring forming the aryl group, and is preferably a benzene or naphthalene ring. The “heteroaryl” is a 5- to 6-membered monocyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, S and O, and a benzene ring or a 5- to 6-membered monocyclic heteroaryl. It is a fused bicyclic heteroaryl group, which may be partially saturated. When it contains an N atom, N-
It may form an oxide. The 5- to 6-membered monocyclic heteroaryl includes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl groups. Preferred as the bicyclic heteroaryl are benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl,
Preferred are isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl and imidazopyridyl groups. Examples of the partially saturated heteroaryl include a 1,2,3,4-tetrahydroquinolyl group and the like. Further preferred are furyl, thienyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzimidazolyl, benzodioxonyl and quinolyl groups, and particularly preferred are pyridyl, pyrazinyl and pyrimidinyl groups. The heteroaryl ring in ring A is a ring forming the above heteroaryl group, preferably a 5- to 6-membered monocyclic heteroaryl ring, and more preferably thiophene, furan, pyrrole, imidazole, oxazole, thiazole, Pyridine, pyrazine and pyrimidine rings. The "cycloalkyl" is preferably a cycloalkyl group having 3 to 10 carbon atoms, and particularly preferably a cyclopropyl, cyclopentyl, cyclohexyl and adamantyl group. The "cycloalkenyl" is preferably a cycloalkenyl group having 3 to 8 carbon atoms, and particularly preferably a cyclopentenyl or cyclohexenyl group. The "counter anion" is an anion that is pharmaceutically acceptable as a counter anion of the imidazolium cation, and preferably,
Halogen ion, organic sulfonate ion (for example, methane sulfonate ion, ethane sulfonate ion, benzene sulfonate ion, toluene sulfonate ion, etc.),
Examples thereof include monovalent or divalent anions such as acetate ion, trifluoroacetate ion, carbonate ion and sulfate ion, with halogen ion being particularly preferred. “Halogen” includes F, Cl, Br and I atoms,
"Halogen ion" is these anions. The “halogeno lower alkyl” is the above lower alkyl substituted with one or more of the above halogens, preferably —CF ₃ . "5- to 7-membered saturated heterocycle" means N,
It is a 5- to 7-membered monocyclic saturated heterocycle containing 1 to 4 heteroatoms selected from S and O, or a bridged ring thereof.
Preferred are the tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, quinuclidinyl, piperidyl and morpholinyl groups.

The "-prodrug OH" is a group which forms a reversible prodrug derivative which is restored to the parent compound (original hydroxy compound) in vivo, and is, for example, Prog. Med., 5, 2157-2161 (1985). Preferably, lower alkylene-COOR optionally having -OCO- substituent (R represents H or lower alkyl, the same applies hereinafter), lower alkenylene-COOR optionally having -OCO- substituent, -OCO-aryl optionally having a substituent, -OCO lower alkylene-O-lower alkylene-COOR, -OCO-CO-
R, lower alkyl optionally having -OCO- substituent, lower alkylene optionally having -OSO ₂ -COOR, -O-phthalidyl, 5-methyl-1,
3-dioxolen-2-one-4-yl-methyloxy and the like can be mentioned. -(5- to 7-membered monocyclic saturated heterocycle which may have one or more substituents),-(cycloalkyl which may have one or more substituents),-(one or more substituents The cycloalkenyl which may have),-(aryl which may have one or more substituents) or-(heteroaryl which may have one or more substituents) may be a substituent. , Preferably 1 selected from the following group C
~ 4 substituents. Group C: - lower alkyl, - halogen, - halogeno-lower alkyl, -OR ^a, -O- lower alkylene ^{-OR a, -SR a, -NR a} R b, -NO 2,
^{_{-CN, -CO 2 R a, -CO}} -NR a R b, -COR a,
_{^{-NR a -COR b, -SO 2 NR}} a R b, - lower alkylene -NR ^a R ^b, - aryl, - heteroaryl, - lower alkylene - in the aryl and --OCO-R ^a (wherein, R ^a and R ^b has the same meaning as above). More preferable groups in the group C are -lower alkyl, -halogen, -halogeno lower alkyl, -OH, -O-lower alkyl and -O-.
Lower alkylene--OH, -O- lower alkylene -O- lower alkyl, - lower alkylene -NH _2, -NH _2, -N
H-lower alkyl, -N (lower alkyl) ₂ , -CO
₂ H, -CO ₂ - lower alkyl, -CO-NH _2, -SO ₂
-NH _2, -NO _2, -CN and - aryl. The substituent in the “aryl ring which may have one or more substituents” or the “heteroaryl ring which may have one or more substituents” in ring A is preferably a group of the above C group. A group is mentioned, and more preferable groups are also the same as above. Particularly preferably -NO _2. There are no particular restrictions on the substituent of "lower alkyl which may have one or more substituents" of R ³ , but it is preferably a substituent of group B above, more preferably -halogen,- OR ^a ,
-SR ^a, -NR ^a R ^b, is -NO _2, and -CN. In the above group B and group C, the group shown by the R ^a, R ^b and R ^c, R ^a, R ^b and R ^c are -H or - group is more preferably a lower alkyl. "R ² and R ³ are united and may be interrupted by O, S or NR ⁴ (R ⁴ : -H or -lower alkyl), having 3 to 6 carbon atoms.
The term "forms a lower alkylene" means that a lower alkylene chain which is optionally interrupted by O, S or NR ⁴ formed by R ² and R ³ (preferably-(CH ₂ ) ₄ -,-(CH ₂ ) ₂ OCH ₂ - and - (CH
₂ ) ₂ N (Me) CH _2- ) and N and C atoms of the imidazole ring are united to form a 5- to 8-membered heterocycle.

In the compound (I) which is an active ingredient of the pharmaceutical composition of the present invention, at least one of R ¹ and R ² is -O.
^{R a, -NR a R b,} -NR a -COR b, -O- lower alkylene -OR ^a, -O- lower alkylene -O- lower alkylene -OR ^a and - (one or more selected from group C The compound which is a lower alkyl having one or more substituents selected from the group consisting of optionally substituted heteroaryl) has a cancer cell-specific antiproliferative activity and also a cancer regression activity. It has the potential to be a new type of anticancer drug with low side effects. In particular, at least one of R ¹ and R ² , preferably both are the same or different,
A compound which is a lower alkyl having one or more substituents selected from the group consisting of Ra ^and- (heteroaryl optionally having one or more substituents selected from group C) has high anticancer activity. And is useful as a compound having safety. Therefore, in the compound (I) which is an active ingredient of the pharmaceutical composition of the present invention, preferable compound groups are as follows. (1) At least one of R ¹ and R ² may have one or more substituents selected from the group C (furyl, thienyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl. , Benzimidazolyl, benzodioxonyl and quinolyl groups), wherein the lower alkyl is substituted with a heteroaryl group. (2) One of R ¹ and R ² is lower alkyl substituted with —O-lower alkyl, and the other is —O-lower alkylene-O-lower alkyl, —O-lower alkylene-O-lower alkylene- O-lower alkyl,-(aryl optionally having one or more substituents selected from Group C),-
(A heteroaryl which may have one or more substituents selected from Group C) and a compound which is a lower alkyl having one substituent selected from the group consisting of -O-lower alkyl. (3) Pyridyl in which ^one of R ¹ and R ² is lower alkyl substituted with —O-lower alkyl, and the other has optionally one or more substituents selected from — (C group) A lower alkyl substituted with a heteroaryl) selected from pyrazinyl and pyrimidinyl groups. (4) In the compounds of (1) to (3), R ³ is a methyl group, A ring is a benzene ring which may be substituted with —NO ₂ , and X ⁻ is a halogen ion. Compound. Among the compounds (I) which are the active ingredients of the pharmaceutical composition of the present invention, a particularly preferred compound is (Production Example 3) 1-[(6-chloro-3-pyridyl) methyl] -3- (2-methoxyethyl)- 2-methyl-4,9-dioxo-4,9-dihydro-1
H-naphtho [2,3-d] imidazol-3-ium, (Production Example 22) 1,3-bis (2-methoxyethyl) -2-methyl-4,
9-dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 28) 3- (2-methoxyethyl) -2-methyl-4,9-dioxo- 1- (2-pyrazinylmethyl) -4,9-dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, (Production Example 35) 1- [3- (1H-4-imidazolyl) propyl] -3- (2
-Methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 42) 3- (2-methoxyethyl) -2-Methyl-1-[(5-methyl-2-pyrazinyl) methyl] -4,9-dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 43) 2-Methyl-4,9-dioxo-1,3-bis (2-pyrazinylmethyl) -4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 48) ) 1- [2- (2-Methoxyethoxy) ethyl] -3- (2-
Methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro
-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 49) 1- {2- [2- (2-methoxyethoxy) ethoxy]
Ethyl} -3- (2-methoxyethyl) -2-methyl-4,9-dioxo
-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 51) 1- (2-methoxyethyl) -2-methyl-4,9-dioxo-3- ( 3-Pyridylmethyl) -4,9-dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, (Production Example 52) 3- (2-methoxyethyl) -2-methyl-4,9-dioxo-1- (2-pyridylmethyl) -4,9- Dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, (Production Example 53) 3- (2-methoxyethyl) -2-methyl-4,9-dioxo-1- (4-pyridylmethyl) -4,9- Dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, (Production Example 55) 1-[(2-chloro-3-pyridyl) methyl] -3- (2-
Methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro
-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 56) 1-[(2-hydroxy-4-pyridyl) methyl] -3-
(2-Methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 57) 3- (2-methoxy Ethyl) -1-[(6-methoxy-3-
Pyridyl) methyl] -2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 63) 1-[(2-chloro- 4-Pyridyl) methyl] -3- (2-
Methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro
-1H-naphtho [2,3-d] imidazol-3-ium, (Production Example 68) 1- (4-chlorobenzyl) -3- (2-methoxyethyl) -2-methyl-4,9-dioxo- 4,9-dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, (Production Example 78) 1- (4-fluorobenzyl) -3- (2-methoxyethyl) -2-methyl-4,9-dioxo-4,9- Dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, (Production Example 87) 1,3-bis (2-methoxyethyl) -2-methyl-5-
Nitro-4,9-dioxo-4,9-dihydro-1H-naphtho [2,3-d]
Imidazole-3-ium, (Production Example 102) 3- (2-methoxyethyl) -2-methyl-4,9-dioxo-1- (5-thiazolylmethyl) -4,9-dihydro-1H-naphtho [2, 3-d] imidazol-3-ium (Production Example 103) 3- (2-methoxyethyl) -2-methyl-4,9-dioxo-1- (4-pyrimidinylmethyl) -4,9-dihydro-1H- It is a salt of naphtho [2,3-d] imidazol-3-ium or a tautomer thereof with a halogen ion. Among them, the salts of the compounds of Production Examples 28, 51, 53, 56, 57 and 103 with halogen ions are most preferable.

The compound (I), which is an active ingredient of the pharmaceutical composition of the present invention, has a tautomer represented by the following formula due to delocalization of cations. Included are those separated or a mixture. Therefore, in the present specification, the compound represented as a 1H-imidazol-3-ium derivative is a tautomeric 3H-imidazol-1-
Includes indium derivatives, as well as mixtures of both isomers. When compound (I) has a substituent —COO ⁻ and forms an inner salt with an imidazolium cation, X ⁻ does not exist.

[Chemical 4] The compound (I) may form a salt depending on the kind of the substituent other than the salt with the counter anion, and the compound (I) also includes these salts. Here, the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, but specific examples of the acid addition salt include hydrochloric acid, hydrobromic acid,
Inorganic acids such as hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid,
Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,
Examples thereof include acid addition salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid. As a salt with a base, sodium is used. Inorganic bases containing metals such as potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts. Compound (I), which is the active ingredient of the pharmaceutical composition of the present invention, may have geometrical isomers or tautomers depending on the kind of substituents.
Compound (I) includes a separated form of these isomers or a mixture. Further, the compound (I) may have an asymmetric carbon atom, and isomers based on the asymmetric carbon atom may exist. The compound (I) includes a mixture of these optical isomers and an isolated one. In addition, compound (I)
May form an N-oxide depending on the kind of the substituent, and these N-oxides are also included in the compound (I). Further, the compound (I) includes various hydrates, solvates and polymorphic substances.

(Production Method) Compound (I), which is an active ingredient of the pharmaceutical composition of the present invention, can be prepared by the method described in the literature, for example, J. Org.
Chem. USSR, 1, 1479-85 (1965), J. Med. Chem., 7
(3), 362-364 (1964) and the method described in JP-A-3-258765 and the like, or the method known to those skilled in the art can be easily applied. . Depending on the type of functional group, it may be effective in terms of manufacturing technology to replace the functional group with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group that can be easily converted into the functional group. is there. After that, the protecting group can be removed if necessary to obtain the desired compound. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and protective groups thereof include, for example, Green and Wuts.
s), “Protective Groups in Organic Synthesi
s ", second edition, and the protective groups described in the second edition can be used as appropriate according to the reaction conditions. A typical manufacturing method will be described below.

[0013]

[Chemical 5] (In the formula, R'is hydrogen, methoxy, or a halogen group, H-
X is an acid forming an anion (preferably hydrogen fluoride,
Hydrogen chloride, hydrogen bromide, hydrogen iodide, methanesulfonic acid,
Ethanesulfonic acid). The same applies below. )

The compound (II) of the first production method is prepared by converting the compound (IV) into amines by a conventional method.
It can be produced by reacting (V). The reaction is, for example, Chem. Pharm. Bull., 44 (6), 1181-1187.
(1996), Tetrahedron. Lett., 39 (42), 7677-7678 (19
98) and the like, and can be produced by using an appropriate inert solvent (such as benzene) in an amount corresponding to the reaction in an amount corresponding to the compounds (IV) and (V) or an excess amount thereof. It is advantageous to use a suitable inorganic base (potassium carbonate or the like) or organic base (triethylamine or the like) as an acid scavenger, if necessary, at room temperature or under heating. The second production method compound (I) can be produced by cyclizing and quaternizing the compound (II) by a conventional method. The reaction is carried out, for example, by J. Org. Chem. USSR, 1, 1479-85 (1965).
It can be carried out by applying the method described, and it is advantageous to carry out the reaction in a suitable inert solvent (for example, an alcoholic solvent, etc.) at a room temperature or under heating using an acid corresponding to or excessive amount of the reaction. .

Third method

[Chemical 6] (In the formula, R ^d and R ^e represent any groups defined in R ¹ and R ^2. )

Two kinds of compounds (IIa) and (IIb) can be obtained by hydrolyzing the compound (I) by a conventional method. The obtained compound can be further subjected to a well-known group modification reaction to give a desired intermediate for the production of compound (I). The hydrolysis reaction can be performed, for example, according to J. Med. Chem., 7
(3), 362-364 (1964) and the like can be applied, and in water and a suitable inert solvent (for example, ethanol), using a reaction-corresponding amount or an excess amount of a base, at room temperature or under heating. This is advantageous. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.

Compound (III) of the fourth process is J. Med. Chem., 39 (7), 1447-1451 (199).
It can be produced by subjecting compound (VI) to a cyclization reaction in the presence of a base such as sodium hydroxide according to the method described in 6) and the like.

The fifth production method compound (I) is obtained by converting the compound (III) into a halide (VII).
It can be manufactured by reacting with a quaternary salt. For example, the reaction is described in J. Med. Chem., 7 (3), 362-364 (1
964) can be carried out by applying the method described above, preferably in a suitable inert solvent (such as acetonitrile),
It is advantageous to use an excess amount of the compound (III) and / or (VII) in an amount corresponding to the reaction, at an ordinary temperature to under heating, preferably at the reflux temperature of the solvent.

Other Production Methods The compound (I), which is an active ingredient of the pharmaceutical composition of the present invention, can be produced by various known modification reactions of substituents in addition to the above production methods. For example, a compound having a substituent containing a sulfonyl bond can be produced from a compound having a sulfide bond or a sulfinyl bond by a conventional oxidation reaction. Further, the N-oxide derivative of a compound having a heteroaryl having an N atom such as a pyridyl group as a substituent can be produced by a conventional oxidation reaction. The compound having a substituent containing a carboxylic acid can be produced from a compound having an ester or amide bond by a conventional hydrolysis reaction. The compound having a substituent containing an aminoalkyl group can be produced from the compound having a halogen-substituted alkyl group by a conventional amination reaction.

Synthesis of Starting Compounds Some of the starting compounds for compound (I) are novel compounds,
These compounds can be easily synthesized in the same manner as known starting compounds or by using methods known to those skilled in the art. A typical synthesis method is shown below. Synthesis method 1

[Chemical 7] Compound (IV) can be obtained, for example, by J. Org. Chem. USSR, 1, 147.
9-85 (1965) etc., the compound (VII
It can be produced by a conventional acylation reaction in which I) is reacted with a reactive carboxylic acid derivative such as an acid halide or an acid anhydride. Synthesis method 2

[Chemical 8] (In the formula, B ¹ represents a pyridine ring which may have a substituent. The same applies hereinafter.) Aminomethylpyridine derivative (X)
Can be produced by reduction of compound (IX) according to the method described in German Patent No. 3726993 (1989) and the like. Synthesis method 3

[Chemical 9] Compound (VI) is described in J. Med. Chem., 39 (7), 1447-1451 (19
It can be produced by amination of compound (XI) according to the method described in 96) and the like. Synthesis method 4

[Chemical 10] Compound (VIII) was prepared according to J. Het. Chem., 33 (1), 113-117 (19
96), Tetrahedron. Lett., 39 (42), 7677-7678 (1998).
Can be produced by amination of compound (XII) according to the method described in et al. Synthesis method 5

[Chemical 11] Compound (IV) can be produced by amidation of compound (XII). The reaction is carried out in a suitable inert solvent (eg
N, N-dimethylformamide (DMF) etc.), after activating the reaction-corresponding amount of compound (XIII) using a suitable inorganic base (NaH etc.) or organic base (NaOMe etc.), It is advantageous to react with an excess amount of compound (XII) at room temperature or under heating. The compound (I) thus produced can be isolated and purified by extraction, concentration, distillation,
The usual chemical operations such as crystallization, filtration, recrystallization and various chromatographies are applied. Various isomers can be isolated by a conventional method by utilizing the difference in physicochemical properties between the isomers. For example, a racemic compound can be converted into a stereomerically pure isomer by a general optical resolution method [for example, a method of converting the compound to a diastereomeric salt with a general optically active acid (tartaric acid, etc. and performing optical resolution, etc.)]. You can In addition, the mixture of diastereomers can be separated by, for example, fractional crystallization or chromatography. The optically active compound can also be produced by using an appropriate optically active raw material.

The pharmaceutical composition of the present invention comprises one or more compounds represented by the general formula (I) and a pharmaceutically acceptable carrier (a carrier for pharmaceuticals) commonly used in the art. , Excipient, etc.) and can be prepared by a commonly used method. The administration is oral administration by tablets, pills, capsules, granules, powders, solutions, inhalants, etc., or injections such as intravenous injection and intramuscular injection, suppositories, eye drops, eye ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal solution, and a transmucosal patch may be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, one or more active substances are combined with at least one inert excipient such as lactose,
It is mixed with mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate and the like. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with sugar coating or gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., commonly used inert solvents such as purified water, Contains ethanol. In addition to an inert solvent, this composition contains auxiliary agents such as solubilizers, wetting agents, suspending agents,
It may contain a sweetening agent, a flavoring agent, an aromatic agent, and a preservative. Injections for parenteral administration include sterile aqueous or non-aqueous liquids, suspensions and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like. Such a composition may further contain a tonicity agent, a preservative, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, and a solubilizing agent. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

The dose of compound (I), which is the active ingredient of the pharmaceutical composition of the present invention, is usually about 0.001 to 50 mg / kg, preferably 0, for oral administration. 0.01 to 30 mg / kg is suitable. When administered intravenously, the daily dose is about 0.
0001 to 50 mg / kg, preferably about 0.00
1 to 10 mg / kg is suitable, and it is preferable to administer this once to several times a day or to administer it continuously by infusion. Administration frequency, dose, drip administration time, etc.
It will be decided as appropriate for each individual case, taking into consideration symptoms, age, sex, etc.

[0025]

Example 1 Cancer cell growth inhibition test (test method) Cell culture: Cervical cancer HeLa S3 cells or melanoma A375 cells were added with 10% Fetal Calf Serum (FCS) Dulbecco's modified eagle medium (DMEM) (GIBCO) Culture). Other cancer cells (Non-small cell lung cancer (EKV
X, HOP-92, NCI-H358, A-549, NCI-H460), Breast cancer (MDA-
MB-231, MCF7), prostate cancer (PC-3), pancreatic cancer (MIA PaCa-
2), colorectal cancer (WiDr), renal cancer (A-498), skin cancer (SK-MEL)
-2), bladder cancer (UC-14) and fibrosarcoma (HT-1080)) 5%
The cells were cultured in RPMI-1640 (GIBCO) supplemented with FCS. Compound evaluation: Cervical cancer HeLa S3 cells or melanoma A375
Cells were seeded in DMEM and other cancer cells in RPMI-1640 on 96-well plates for cultured cells (manufactured by IWAKI) and cultured overnight. The next day, the final concentration of dimethyl sulfoxide (DMSO) was made the same at 0.1%, DMSO solutions of the evaluation compounds were added at various concentrations, and 48 hours after the addition, Alamar Blue (Biosou) for cervical cancer HeLa S3 cells or melanoma A375 cells was added.
Cell growth was evaluated by a color reaction by Rce), and by using a color reaction by Sulforhodamine B (manufactured by Sigma) for other cancer cells. (Results) The concentrations (nM) of the test compounds that inhibit the cell growth of cervical cancer HeLa S3 cells and melanoma A375 cell carcinoma cells by 50% are shown in the table below. The production example compounds shown in the table below, which are the active ingredients of the pharmaceutical composition of the present invention, successfully inhibited the growth of cervical cancer HeLa S3 cells and melanoma A375 cell carcinoma cells.

[0026]

[Table 1]

The compounds of Production Examples 51 and 53 were non-small cell lung cancer (EKVX, HOP-92, NCI-H358, A-549, NCI-H46).
0), breast cancer (MDA-MB-231, MCF7), prostate cancer (PC-3),
Pancreatic cancer (MIAPaCa-2), colon cancer (WiDr), renal cancer (A-498),
Skin cancer (SK-MEL-2), bladder cancer (UC-14) and fibrosarcoma (H
It had a good cell growth inhibitory activity against T-1080). The concentration (nM) that inhibits cell growth by 50% is shown in the table below.

[0028]

[Table 2]

Example 2 In Vivo Cancer Growth Inhibition Test (Test Method) 2 × 10 ⁶ melanoma A375 cell lines were subcutaneously transplanted into the dorsal region of male Balb / c nude mice. The evaluation compound was intravenously administered once a day for 2 weeks after the tumor volume reached 50 to 100 mm ³ . In addition, physiological saline was intravenously administered to the control group. A caliper is used to measure the tumor diameter,
The measurement was carried out over time until the day after the final administration. The tumor volume was calculated by the following formula. Tumor volume (mm ³ ) = 1/2 x [minor axis (mm)] ² x major axis (mm)

(Results) The compounds of Production Examples 4, 7, 22, 28, 51 and 53 of the present application showed 50% or more growth inhibitory activity as compared to the control group at the dose of 0.3 or 1 mg / kg. For example,
The compound of Production Example 51 showed 89% antiproliferative activity when administered at 0.3 mg / kg, and 103% antiproliferative activity when administered at 1 mg / kg. Some of the compounds of Production Examples of the present application are used in other cancer cells (prostate cancer (PC-3) or non-small cell lung cancer (NCI-H358, A-54
9)) also shows a good cancer growth inhibitory effect in the animal model transplanted, for example, in the animal model transplanted A-549, the compound of Production Example 53 at a dose of 1 mg / kg compared to the control group It showed a growth inhibitory activity of 73% (P <0.01). Further, in an animal model transplanted with PC-3, a comparative test with the compound KP-3 disclosed in the prior document Khim.-Farm. Zh., 32 (6), 10-11 (1998) was similarly performed. . KP-3 is 1 mg /
Since all of the animals died when administered kg, 0.3 mg / kg, which is expected to be the maximum tolerated dose, was administered. Its growth inhibitory activity was 16%, which showed no significant drug effect. On the other hand, the compound of Production Example 53 of the present application showed a significant drug efficacy of 75% (P <0.001) at the dose of 2 mg / kg. Furthermore, in a test in which the compound of Production Example of the present application was continuously administered using an animal model transplanted with PC-3 or the like, some of the compounds tested showed a cancer regression effect.

Example 3 Single-dose toxicity test on mice (Test method) A compound, which is an active ingredient of the pharmaceutical composition of the present invention, was administered once to Balb / C mice by intravenous administration for a 2-week observation period. We examined whether there were any deaths. (Results) Production Examples 3, 7, 14, 22, 28, 32, 51, 53, 55, 5
None of the compounds 6, 57, 63 and 68 died after a single dose of 3 mg / kg. On the other hand, the prior document Khim.-Farm.
Kh-1 and Kh-3 disclosed in Zh., 32 (6), 10-11 (1998).
In a single dose of 3 mg / kg, all of 2 cases died. Therefore, it was shown that the compound of the above-mentioned Production Example, which is an active ingredient of the pharmaceutical composition of the present invention, has lower toxicity than the compounds of the prior art. From the above examples, the compound, which is the active ingredient of the pharmaceutical composition of the present invention, has good antitumor activity against a plurality of cancer types and has low toxicity. Therefore, the pharmaceutical composition of the present invention is good. It has been shown to be useful as a therapeutic agent for cancer having various profiles.

[0032]

[Production Examples] Production examples of compound (I), which is an active ingredient of the pharmaceutical composition of the present invention, are shown below. A production example of the raw material compound is shown in Reference Example.

Reference Example 1: Saturated aqueous ammonia (17 ml) and Raney nickel (3.0 g) were added to a solution of 3-cyano-2- (dimethylamino) pyridine (2.45 g) in ethanol (50 ml), and hydrogen atmosphere at 1 atm was added. The mixture was stirred at room temperature for 8 hours. Hydrogen 760m
After absorption, the catalyst was filtered off. Concentrate the mother liquor to a yellow oil.
-(Aminomethyl) -2- (dimethylamino) pyridine (2.61g)
Got Reference Example 2: 2-chloro-3-[(2-methoxyethyl) amino]-
A few drops of concentrated sulfuric acid were added to a solution of 1,4-naphthoquinone (33 g) in acetic anhydride (100 ml), and the mixture was stirred at 45 ° C. for 1 hour. Ethanol (100 ml) was added to the reaction solution to esterify excess acetic anhydride. After cooling, ethyl acetate was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was crystallized from diethyl ether, and yellow powder of N- (3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl) -N- (2-methoxyethyl) ) Acetamide (29 g) was obtained.

Reference Example 3: 2,3-dichloro-1,4-dihydro-
To a solution of 1,4-dioxonaphthalene (3.0 g) in benzene (90 ml)
2- (Aminomethyl) pyrazine (3.2 g) and diisopropylethylamine (5.8 ml) were added, and the mixture was stirred at room temperature for 8 hours.
Water was added to the reaction solution, the precipitated solid was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography (eluted with chloroform) to give brown powder of 2-chloro-1,4.
-Dihydro-1,4-dioxo-3-[(2-pyrazinylmethyl) amino] naphthalene (0.23 g) was obtained.

Reference Example 4 A solution of 2-chloro-1,4-dihydro-3-methylamino-1,4-dioxonaphthalene (2.2 g) in 1,4-dioxane (30 ml) was treated with 2-chloroacetyl chloride ( 3.3 ml) was added, and the mixture was stirred under reflux for 14 hours. After allowing the reaction solution to cool, the solvent was distilled off. Ethanol was added to the residue, and the precipitated solid was collected by filtration. The obtained solid is recrystallized from ethanol,
Yellow powder of 2-chloro-N- (3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl) -N-methylacetamide (2.6 g) was obtained. Reference Example 5: 2-oxopiperidine (1.0 g) in DMF (20 ml)
60% NaH (440 mg) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. This solution was added all at once to a DMF (150 ml) solution of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (6.9 g), and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into saturated aqueous ammonia, the precipitated solid was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluted with ethyl acetate-hexane 1:10 solution) to give brown powder of 2-chloro-1,4-dihydro-1,4-dioxo-. 3- (2-oxopiperidino) naphthalene (0.49 g) was obtained.

Reference Example 6: 2-methoxyethylamine was added to a solution of methyl 4,7-dihydro-4,7-dioxobenzo [b] thiophene-2-carboxylate (2.4 g) in tetrahydrofuran (100 ml).
(1.6 ml) was added, and the mixture was stirred at room temperature for 27 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluted with chloroform) to give 4,7-dihydro-5- (2-methoxyethyl) amino-4,7-dioxobenzo as a yellow powder.
Methyl [b] thiophene-2-carboxylate (1.5 g) was obtained. Reference Example 7: 4,7-Dihydro-5- (2-methoxyethyl) amino-4,7-dioxobenzo [b] thiophene-2-carboxylate (1.2 g) in acetic anhydride (20 ml) was added to concentrated sulfuric acid 5 Add drops,
The mixture was stirred at room temperature for 1 hour. After gradually adding methanol (20 ml) to the reaction solution, the solvent was distilled off. Add water to the residue,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with ethyl acetate-hexane 1: 1 solution) to give 5- [N-acetyl-N- (2-methoxyethyl) amino as a reddish brown oil. ] -4,7-Dihydro-4,7-dioxobenzo [b] thiophene-2
-Methyl carboxylate (0.39 g) was obtained. Reference Examples 8 to 12: In the same manner as in Reference Example 1, the compounds of Reference Examples 8 to 10 shown in Table 3 were treated in the same manner as in Reference Example 2, and the compounds of Reference Example 11 shown in Table 4 were designated as Reference Example 4. Similarly, the compounds of Reference Example 12 shown in Table 4 were obtained.

Reference Example 13 To a solution of N- (2-oxopropyl) phthalimide (3.0 g) in dichloromethane (100 ml) was added butyltrimethylammonium tribromide (6.1 g), and the mixture was stirred under reflux for 1.5 hours. After allowing to cool, water (50 ml) and saturated aqueous sodium hydrogen sulfite solution (100 ml) were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was dissolved in ethanol (100 ml), and pyridine-3-carbothioamide (2.1
g) was added, and the mixture was stirred under reflux for 3 hours. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform-methanol 50: 1).
The product was purified by elution with a solution) to obtain N-{[2- (3-pyridyl) -4-thiazolyl] methyl} phthalimide (3.0 g) as a light brown powder (FAB-MS (M + H) ⁺ : 322). Similarly, N-{[2- (4-pyridyl) -4-thiazolyl] methyl} phthalimide was obtained (FA
B-MS (M + H) ⁺ : 322).

Reference Example 14: N-{[2- (3-pyridyl) -4-thiazolyl] methyl} phthalimide (3.0 g) in ethanol (150
hydrazine monohydrate (0.48 ml) was added to the solution), and the mixture was stirred under reflux for 17 hours. The precipitated crystals were collected by filtration and washed with ethanol. The obtained crude crystals were purified by silica gel column chromatography (eluted with chloroform-methanol-saturated aqueous ammonia solution 30: 1: 0.1) to give 4- (aminomethyl) -2- (3-pyridyl) brown powder. Thiazole (360
mg) was obtained (FAB-MS (M + H) ⁺ : 192). Similarly, 4- (aminomethyl) -2- (4-pyridyl) thiazole was obtained (EI-MS
(M) ⁺ : 191). Reference Example 15: Pyridazine-4-carbaldehyde oxime
To a solution of (0.82 g) in methanol (30 ml) was added 10% palladium-carbon (1.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere at 1 atm for 4 hours.
Stir for 0 minutes. After absorbing 370 ml of hydrogen, the catalyst was filtered off. The mother liquor was concentrated to give 4- (aminomethyl) pyridazine as a reddish purple oil.
(0.68 g) was obtained (FAB-MS (M + H) ⁺ : 110).

Reference Example 16: N- (3-chloro-1,4-dihydro
-1,4-dioxo-2-naphthalenyl) -N- (2-methoxyethyl)
Benzylamine (0.5 ml) was added to a benzene (15 ml) solution of acetamide (0.5 g), and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate-hexane to give a red powder of N-.
(3-Benzylamino-1,4-dihydro-1,4-dioxo-2-naphthalenyl) -N- (2-methoxyethyl) acetamide (0.51 g) was obtained.

Reference Example 17: N- (2-methoxyethyl) -N-
To a solution of [3- (3-pyridylmethyl) amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl] acetamide (0.95 g) in dichloromethane (20 ml) was added 80% 3-chloroperbenzoic acid (0.6 g) was added, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane.
The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform-methanol-
Elution with saturated ammonia water 10: 1: 0.1 solution),
Brown amorphous solid 3-[({3- [N-acetyl-N- (2-methoxyethyl)] amino-1,4-dihydro-1,4-dioxo-2-
Naphthalenyl} amino) methyl] pyridine 1-oxide (0.
84g) was obtained.

Reference Example 18: 1- (2-methoxyethyl) chloride
2-Methyl-3- (4-pyridylmethyl) -4,9-dihydro-4,9-dioxo-1H-naphtho [2,3-d] imidazol-3-ium monohydrochloride (1.1 g) in ethanol To the (30 ml) solution, 1M aqueous sodium hydroxide solution (5.0 ml) was added and stirred at room temperature for 30 minutes.
Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (fraction A: ethyl acetate-
Elution with a 1: 1 hexane solution, fraction B: elution with ethyl acetate). Fraction A was crystallized from diethyl ether to give a red powder of N- [3- (2-methoxyethyl) amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl] -N- (4-pyridyl Methyl) acetamide (0.2 g) was obtained. Fraction B was crystallized from ethyl acetate to obtain a yellow powder (0.31 g), which was obtained in Reference Example 42 described later.
N- (2-methoxyethyl) -N- [3- (4-pyridylmethyl) described
It was the same compound as amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl] acetamide. Reference Example 19: 2-chloro-N- [1,4-dihydro-3- (2-methoxyethyl) amino-1,4-dioxo-2-naphthalenyl] -N-methylacetamide (0.5 g) in tetrahydrofuran (30 ml) 2M dimethylamine / tetrahydrofuran solution (3.0m
l) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was crystallized from ethanol and brown powder of N- [1,4-dihydro-3- (2-methoxyethyl) amino-1,4-
Dioxo-2-naphthalenyl] -N-methyl-2- (dimethylamino) acetamide (0.19 g) was obtained.

Reference Example 20: 5- [N-acetyl-N- (2-methoxyethyl) amino] -4,7-dihydro-4,7-dioxobenzo
To a solution of methyl [b] thiophene-2-carboxylate (0.39g) in tetrahydrofuran (30ml) was added 2-methoxyethylamine (0.15m
l) was added, and the mixture was stirred at room temperature for 6.5 hours. After distilling off the solvent,
The residue was purified by silica gel column chromatography (eluted with hexane-ethyl acetate 50: 1 solution) to give 5- [N-acetyl-N- (2-methoxyethyl) amino] -4, a reddish purple oil.
There was obtained methyl 7-dihydro-6- (2-methoxyethyl) amino-4,7-dioxobenzo [b] thiophene-2-carboxylate (0.39 g). Reference Examples 21 to 121: Similar to Reference Example 16 above, Reference Examples 21 to 56 and 58 described in Tables 6 to 13 below.
~ 121 in the same manner as in Reference Example 18 Table 8 below.
To obtain the compound of Reference Example 57.

Production Example 1: N- [3- (2-hydroxyethyl)
Amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl] -N
-Methylacetamide (0.4g) was suspended in ethanol (3ml), 4M hydrogen chloride / ethyl acetate solution (3ml) was added, and
The mixture was stirred at 0 ° C for 1 hour. After allowing to cool, the generated precipitate was collected by filtration and washed with ethyl acetate. The obtained solid was recrystallized from ethanol-ethyl acetate, and colorless powder of 1- (2-hydroxyethyl) -2,3-dimethyl-4,9-dihydro-4,9-dioxo-1 chloride was obtained.
H-naphtho [2,3-d] imidazol-3-ium (0.28 g) was obtained.

Production Example 2: In the same manner as in Production Example 1,
N- (2-methoxyethyl) -N- {3-[(2-methoxy-3-pyridyl)
Methyl] amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl} acetamide (0.49g), brown powder 1- (2-hydroxy-3-pyridyl) methyl-3- (2-methoxy chloride) Ethyl) -2-
Methyl-4,9-dihydro-4,9-dioxo-1H-naphtho [2,3-d]
Imidazole-3-ium (0.39 g) was obtained.

Production Example 3: N- {3-[(6-chloro-3-pyridyl) methyl] amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl} -N- (2-methoxyethyl) ) Acetamide (0.8 g) in ethanol (10 ml) solution in 4M hydrogen chloride / ethyl acetate solution (1
0 ml) was added, and the mixture was stirred at room temperature for 1 day. After distilling off the solvent,
The residue is collected by filtration, washed with ethyl acetate, and the pale yellow powder is chlorinated.
1-[(6-chloro-3-pyridyl) methyl] -3- (2-methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho
[2,3-d] imidazol-3-ium (0.82 g) was obtained.

Production Examples 4 to 104: In the same manner as in Production Examples 1 to 3 above, Production Example compounds described in Tables 14 to 22 below were obtained. Structural formulas and physicochemical properties of the reference example compounds are shown in Tables 3 to 13 and the production example compounds are shown in Tables 14 to 22, respectively. Abbreviations in the table are Ref: Reference example; Ex: Production example; S
al: salt; Sy: production method (the numbers indicate the numbers of the above-mentioned production examples, and indicate that the compound was produced by the same method as the above-mentioned production examples);-: not present; Dat: physicochemical Properties (F: FAB-MS (M) ⁺ ; F ': FAB-MS (M) ^- ; F +: F
AB-MS (M + H) ⁺ ; F-: FAB-MS (MH) ^- ; E: EI-MS
^{(M) +; N1: 1} H-NMR (DMSO-d 6, TMS internal standard) characteristic peaks δppm of); i-Pr: Isopropyl; Ad: 1-adamantyl; Ac: acetyl; Bn: benzyl; Py2; 2-
Py3; 3-pyridyl; Py4; 4-pyridyl; Th; 2-thienyl; Fu; 2-furyl; Pyr;
2-pyrazinyl; 5-MePyr; 5-methyl-2-pyrazinyl; Pym; 4-pyrimidinyl; Qu; 3-quinolyl;
Dio; 4-benzodioxolyl; Im; 4-imidazolyl; Bim; 2-benzimidazolyl; and In; 2
-Indrills are shown respectively. The number before the substituent indicates the position of substitution, for example, 3,4-Cl : Indicates that -Cl is substituted at the 3-position and 4-position, respectively.

[0047]

[Table 3]

[0048]

[Table 4]

[0049]

[Table 5]

[0050]

[Table 6]

[0051]

[Table 7]

[0052]

[Table 8]

[0053]

[Table 9]

[0054]

[Table 10]

[0055]

[Table 11]

[0056]

[Table 12]

[0057]

[Table 13]

[0058]

[Table 14]

[0059]

[Table 15]

[0060]

[Table 16]

[0061]

[Table 17]

[0062]

[Table 18]

[0063]

[Table 19]

[0064]

[Table 20]

[0065]

[Table 21]

[0066]

[Table 22]

[0067]

INDUSTRIAL APPLICABILITY The pharmaceutical composition of the present invention has good cancer cell growth inhibitory action and further cancer regression, and is useful as an anticancer agent having a low toxicity and a wide safety range. Therefore, the pharmaceutical composition of the present invention comprises cancer, preferably all solid cancers and lymphomas, especially skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer,
It has an inhibitory effect on the growth of tumors such as prostate cancer, lung cancer, colon cancer, pancreatic cancer, renal cancer and gastric cancer, and is useful for the treatment of these. In particular, we used a cancer cell growth inhibition test and a mouse tumor-bearing model
In an in vivo cancer growth inhibition test, it has a good antitumor activity against multiple cancer types over existing anticancer agents, and is expected as a therapeutic agent for cancer types resistant to existing anticancer agents.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4439 A61K 31/4439 31/4709 31/4709 31/497 31/497 31/501 31/501 31 / 506 31/506 A61P 35/00 A61P 35/00 43/00 123 43/00 123 C07D 235/08 C07D 235/08 401/06 401/06 401/12 401/12 403/06 403/06 405/06 405/06 409/06 409/06 413/06 413/06 417/06 417/06 417/14 417/14 471/04 105 105 471/04 105P 108 108A 495/04 495/04 (72) Inventor Kei Toyoshima 3-17-1, Hasune, Itabashi-ku, Tokyo Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Takato Nakahara Miyukigaoka, Tsukuba City, Ibaraki 21 Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Masahiro Takeuchi Miyuki Tsukuba, Ibaraki Prefecture Hill 21 Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Minoru Okada Miyukigaoka 21 Tsukuba, Ibaraki Prefecture Nonouchi Pharmaceutical Co., Ltd. In-house F-term (reference) 4C063 AA01 AA03 BB01 BB03 BB08 CC26 CC28 CC29 CC34 CC51 CC58 CC62 CC75 CC81 CC92 DD06 DD12 DD14 DD26 EE01 4C065 AA03 AA04 AA19 BB06 CC01 DD02 DD03 EE02 HH01 KK01 JJ01 KK01 JJ01 JJ01 KK01 AA08 BB01 BB05 CC02 CC21 EE13 FF04 GG03 HH28 LL01 4C086 AA01 AA02 BC39 BC41 BC42 BC48 BC67 BC71 BC82 CB05 CB27 GA02 GA04 GA07 GA08 GA09 GA10 MA01 MA04 NA14 NA15 ZB26

Claims (3)

[Claims] 1. A condensed imida represented by the following general formula (I):
A pharmaceutical composition containing a zolium derivative as an active ingredient. [Chemical 1] (The symbols in the formulas have the following meanings. R¹And R²: Same or different,-(selected from group B
Lower alkyl optionally having one or more substituents),
-(Even if it has one or more substituents selected from Group B
Good lower alkenyl),-(one or more selected from group B)
A lower alkynyl which may have a substituent) or -R
inD, but R¹And R²At least one of -OR
^a, -NR^aR^b, -NR^a-COR^b, -O-lower alk
Ren-OR^a, -O-lower alkylene-O-lower alk
Ren-OR^aAnd-(hetero which may have a substituent)
One or more substituents selected from the group consisting of aryl)
Has lower alkyl. Group B: -OR^a, -SR^a, -Prodrugated O
H, -O-lower alkylene-OR^a, -O-lower alk
Len-O-lower alkylene-OR^a, -O-lower alk
Ren-NR^aR^b, -O-lower alkylene-O-lower ar
Killen-NR^aR^b, -O-lower alkylene-NR^c-Low
Alkylene-NR^aR^b, -OCO-NR^aR ^b, -SO
R^a, -SO₂R^a, -SO₂NR^aR^b, -NR^a-SO₂R
^b, -NR^aR^b, -NR^c-Lower alkylene-NR^aR^b,
-N (-lower alkylene-NR^aR^b)₂, -RinD,
-NO₂, -CN, -halogen, -CO₂R^a, -CO
O^-, -CONR^aR^b, -CONR^a-OR^b, -NR^a
-COR^b, -NR^a-CO-NR^bR ^c, -OCOR^aOver
And -CO-R^a. R^a, R^bAnd R^c: Same or different, -H, -lower
Alkyl, -lower alkylene-RinD, or -Rin
D. RinD :-( 5 that may have one or more substituents
To 7-membered saturated heterocycle),-(having one or more substituents)
Optionally cycloalkyl),-(having one or more substituents
Optional cycloalkenyl),-(one or more substituents
Optionally substituted aryl) or-(one or more substituents
A heteroaryl which may have). R³: -H or-
(Lower alkyl optionally having one or more substituents),
Or R²And R³Together, O, S or NR
^Four(R^Four: -H or -lower alkyl)
Good, lower alkylene having 3 to 6 carbon atoms may be formed.
Yes. A ring: an aryl ring which may have one or more substituents, or
Is heteroaryl optionally having one or more substituents
ring. X^-: Counter anion, provided that the group B substituent is -CO
O^-And the imidazolium cation form an inner salt
Ki X^-Does not exist. However, R¹And R²Together-
(CH₂)₂OC₂H_FiveExcluding compounds that are ) 2. The pharmaceutical composition according to claim 1, which is an anticancer agent. 3. The condensed imidazolium derivative is 1-[(6-chloro-3-pyridyl) methyl] -3- (2-methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro. -1H-naphtho [2,3-d] imidazol-3-ium, 1,3-bis (2-methoxyethyl) -2-
Methyl-4,9-dioxo-4,9-dihydro-1H-naphtho [2,3-d]
Imidazole-3-ium, 3- (2-methoxyethyl) -2-methyl-4,9-dioxo-1- (2-pyrazinylmethyl) -4,9-dihydro-1H-naphtho [2,3-d] imidazole -3-ium, 1- [3- (1H
-4-Imidazolyl) propyl] -3- (2-methoxyethyl) -2-
Methyl-4,9-dioxo-4,9-dihydro-1H-naphtho [2,3-d]
Imidazole-3-ium, 3- (2-methoxyethyl) -2-methyl-1-[(5-methyl-2-pyrazinyl) methyl] -4,9-dioxo-
4,9-Dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 2-methyl-4,9-dioxo-1,3-bis (2-pyrazinylmethyl) -4,9-dihydro-1H -Naphtho [2,3-d] imidazol-3-
Ium, 1- [2- (2-methoxyethoxy) ethyl] -3- (2-methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro-1H-
Naphtho [2,3-d] imidazol-3-ium, 1- {2- [2- (2-methoxyethoxy) ethoxy] ethyl} -3- (2-methoxyethyl) -2-methyl-4,9- Dioxo-4,9-dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, 1- (2-methoxyethyl)
-2-Methyl-4,9-dioxo-3- (3-pyridylmethyl) -4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 3- (2
-Methoxyethyl) -2-methyl-4,9-dioxo-1- (2-pyridylmethyl) -4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 3- (2 -Methoxyethyl) -2-methyl-4,9-dioxo-1- (4-pyridylmethyl) -4,9-dihydro-1H-naphtho
[2,3-d] imidazol-3-ium, 1-[(2-chloro-3-pyridyl) methyl] -3- (2-methoxyethyl) -2-methyl-4,9-dioxo-4,9 -Dihydro-1H-naphtho [2,3-d] imidazole-3
-Ium, 1-[(2-hydroxy-4-pyridyl) methyl] -3- (2-
Methoxyethyl) -2-methyl-4,9-dioxo-4,9-dihydro
-1H-naphtho [2,3-d] imidazol-3-ium, 3- (2-methoxyethyl) -1-[(6-methoxy-3-pyridyl) methyl] -2-methyl-4,9-dioxo -4,9-Dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 1-[(2-chloro-4-pyridyl) methyl] -3- (2-methoxyethyl) -2-methyl -4,9-dioxo-4,9
-Dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 1
-(4-chlorobenzyl) -3- (2-methoxyethyl) -2-methyl-
4,9-Dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 1- (4-fluorobenzyl) -3- (2-methoxyethyl) -2-methyl- 4,9-Dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 1,3-bis (2-methoxyethyl) -2-methyl-5-nitro-4, 9-dioxo-4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 3- (2
-Methoxyethyl) -2-methyl-4,9-dioxo-1- (5-thiazolylmethyl) -4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium, 3- (2- Methoxyethyl) -2-methyl-4,9-
Dioxo-1- (4-pyrimidinylmethyl) -4,9-dihydro-1H-
The pharmaceutical composition according to claim 1 or 2, which is a salt of naphtho [2,3-d] imidazol-3-ium or a tautomer thereof and a halogen ion.