JPH05117148A - Anticancer composition - Google Patents

Abstract

(57) [Summary] [Object] To provide an anticancer composition having high selectivity for cancer cells and high solubility in a diluent suitable for administration to humans. [Structure] An anticancer composition containing a rhodocyanine compound represented by the following formula as an active ingredient in an amount of 0.1 to about 1% by weight in the composition. [Chemical 1] (Wherein X ₂ , X ₃ and Y ₁ are O, S, or Se; Z ₁ represents an atomic group necessary for forming a saturated or unsaturated 5-membered or 6-membered ring; Z ₂ Represents an atomic group necessary for forming a naphthalene ring, an anthracene ring or a phenanthrene ring which may have a substituent; R ₁ and R ₃
Represents an unsubstituted or substituted alkyl group; R ₂ represents an unsubstituted or substituted alkyl group, aryl group or heterocycle; L ₁ , L ₂ and L ₃ represent a methine group or a substituted methine group, respectively. the expressed; Q ^- represents an anion pharmaceutically acceptable; n is 0 or 1; l represents 1 or 2. )

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to compositions useful in the treatment of many different types of cancer, especially carcinomas or melanomas. More particularly, the present invention relates to pharmaceutical compositions containing a selected class of rhodocyanine dyes useful in the treatment of cancer.

[0002]

BACKGROUND OF THE INVENTION Cancer is a major health problem in the world. Therefore, much research has been conducted to develop a therapeutic method suitable for curing human cancer and reducing symptoms. In the field of chemotherapy, research has been conducted to develop effective antitumor agents for various types of cancer. Often antitumor agents have been developed and found to be effective on cancer cells, but unfortunately they are toxic to normal cells. When administered to patients in need of cancer treatment, this toxicity can result in hair loss, nausea, weight loss, vomiting, hallucinations,
Causes fatigue, itching, loss of appetite, etc. Furthermore, conventionally used chemotherapeutic agents do not have the desired degree of effect or have a wide range of effects on the different types of cancer desired. Therefore, a chemotherapeutic agent with higher selectivity that has greater efficacy against cancer and kills cancer cells with no or minimal effect on normal healthy cells. Is desired. Especially colon, bladder, prostate, stomach, pancreas, breast, lung,
There is a need for an antitumor agent having high efficacy and selectivity against cancers of organs such as liver, brain, testis, ovary, neck, skin, vulva, small intestine. Antitumor agents for cancers such as colon cancer and melanoma are particularly desirable because there is currently no particularly effective treatment.

So far, certain types of cyanine dyes have been disclosed as having antitumor activity (for example, JP-A-54-151133, 55-31024).
No. 55-69513, 55-100318,
Japanese Patent Publication No. 1-54325, EP No. 286252A
2). However, these cyanine dyes
It is highly toxic not only to cancer cells but also to healthy cells and cannot be used in human therapy. Furthermore, these cyanine dyes often have poor solubility in diluents that can be used for human administration.

[0004]

Therefore, an object of the present invention is to provide an antitumor agent effective against cancer cells. A further object of the present invention is to provide an antitumor agent which is useful for treating cancer and has a higher selectivity for cancer cells than the antitumor agents found in the prior art. A still further object of the present invention is to provide an anti-tumor agent that is effective in the treatment of carcinomas and melanomas and has not been found to be particularly effective in the prior art.
A further object of the present invention is to provide a pharmaceutical composition effective for treating cancer and alleviating symptoms in mammals such as humans. Another object of the present invention is to have a high solubility in aqueous diluents suitable for human administration, for example by forming a pharmaceutically acceptable salt using acetate or chloride as counterion. Another object of the present invention is to provide a rhodocyanine dye having

[0005]

As a result of extensive research, the above-mentioned objects of the present invention have been achieved by several classes of rhodacyanine type dyes, which have hitherto been known to be mainly used for producing photosensitive materials. I knew it would be done.
These rhodocyanine dyes are effective in treating cancers or tumors, especially in carcinomas and melanomas. In one aspect, the present invention provides a compound of the general formula (1), (2),
The present invention provides a composition containing a therapeutically effective amount of a rhodacyanine compound selected from the group consisting of the compounds (3), (4), (5) and (6).

[0006]

[Chemical 3]

[0007]

[Chemical 4]

(Wherein X ₁ is O, S, Se, or -N
R ₁₄ - a and; X ₂ is _{O, S, Se, -NR 15} -, - C
R ₁₆ R ₁₇ -, or -CH = CH- and is; X ₃ is O,
S or Se; X ₄ is —NR ₁₉ — or —C.
R ₂₀ R ₂₁ —; Y ₁ is O, S, Se, or —NR
_18- ; Z ₁ represents an atomic group necessary for forming a saturated or unsaturated 5- or 6-membered ring which may have a substituent or may form a condensed ring with another ring. Z ₂ represents an atomic group necessary for forming a naphthalene ring, an anthracene ring or a phenanthrene ring which may have a substituent;

R ₁ , R ₃ , R ₁₄ , R ₁₅ and R ₁₉ each represent an unsubstituted or substituted alkyl group, which may be the same or different; R ₂ and R ₁₈ are each unsubstituted. Or a substituted alkyl group, an unsubstituted or substituted aryl group or an unsubstituted or substituted heterocycle, which may be the same or different; L
₁ , L ₂ and L ₃ each represent a methine group or a substituted methine group, which may be the same or different,
When it is a substituted methine group, L ₁ and R ₁ and / or L
₃ and R ₃ may combine to form a saturated or unsaturated 5- or 6-membered ring; R ₄ and R ₅ are each a hydrogen atom, an unsubstituted or substituted alkyl group or an unsubstituted or substituted Represents an aryl group and may be the same or different; R ₆ , R ₇ , R ₈ and R ₉ are each a hydrogen atom, an unsubstituted or substituted alkyl group or an unsubstituted or substituted aryl group. And may be the same or different, or two or more of R _{6 to} R ₉ are bonded to form a saturated or unsaturated 5-membered or 6-membered group.
May form a member ring;

R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted alkoxy group, an unsubstituted or substituted Aryloxy group, unsubstituted or substituted acyl group, unsubstituted or substituted alkoxycarbonyl group, trifluoromethyl group, unsubstituted or substituted benzoyl group,
Unsubstituted or substituted ureido group, unsubstituted or substituted amino group, unsubstituted or substituted amide group, unsubstituted or substituted sulfamide group, unsubstituted or substituted carbamyl group, unsubstituted or substituted And a sulfamoyl group, a halogen atom, a nitro group, a cyano group, a hydroxyl group or a carboxyl group, which may be the same or different, or two adjacent groups of R _{10 to} R ₁₃ are bonded to each other to form a saturated or unsaturated group. 5 or 6 members of saturation
A member ring, which may have a substituent or may form a condensed ring with another ring; R ₁₆ , R ₁₇ , R ₂₀ and R ₂₁ are each an unsubstituted or substituted alkyl group. Represents a group and may be the same or different;

Q ^- represents a pharmaceutically acceptable anion; n represents 0 or 1; l represents 1 or 2. )
In a specific embodiment of the present invention, the pharmaceutical composition of the present invention comprises a cyanine compound selected from the group consisting of compounds represented by the general formulas (1) to (6) together with a pharmaceutically acceptable carrier or diluent. Included as an anti-cancer agent.

More specifically, in the general formulas (1) to (6),
X₁, X₂And X₃Is an oxygen atom,
Represents a sulfur atom or a selenium atom. Furthermore, X₁Is an expression
-NR₁₄Represents a group of-, X₂Is the formula −NR₁₅-, -CR ₁₆
R₁₇-Or- represents a group of CH = CH-, X_FourIs the formula -N
R₁₉-Or-CR₂₀R_{twenty one}Represents a group of-. here,
R₁₄, R₁₅, R₁₆, R₁₇, R₁₉, R₂₀And R_{twenty one}Is that
Unsubstituted, such as straight chain, branched or cyclic alkyl groups.
Or represents a substituted alkyl group. Y₁Is an oxygen atom, sulfur
Yellow atom, selenium atom or formula-NR₁₈-Group of
And here, R₁₈Is a linear, branched or cyclic alkyl
Unsubstituted or substituted alkyl group such as alkyl group, monocycle
Unsubstituted or substituted, such as system or bicyclic aryl groups
Aryl group, or saturated or unsaturated
May be 1 or 2 or more nitrogen atoms, oxygen atoms and sulfur
Such as a 5- to 6-membered heterocyclic group which may contain a yellow atom.
Represents an unsubstituted or substituted heterocyclic group.

R ₁ , R ₂ and R ₃ each independently represent an unsubstituted or substituted alkyl group such as a linear, branched or cyclic alkyl group, and R ₂ is a monocyclic or bicyclic ring group. Unsubstituted or substituted aryl groups such as system or tricyclic aryl groups, or may be saturated or unsaturated and may contain one or more nitrogen atoms, oxygen atoms and sulfur atoms as hetero atoms. It may be an unsubstituted or substituted heterocyclic group such as a 5- or 6-membered heterocyclic group. Z ₁ is a saturated or unsaturated 5 which may contain one or more nitrogen atoms, oxygen atoms, sulfur atoms or selenium atoms as hetero atoms.
Represents an atomic group necessary to form a six-membered ring or a six-membered ring, and Z
₁ may be substituted or may form a fused ring with other rings such as saturated or unsaturated. Z ₂ represents an atomic group necessary for forming a naphthalene ring, an anthracene ring or a phenanthrene ring which may have a substituent. L ₁ , L
₂ and L ₃ each independently represent a methine group or a substituted methine group, and when any one of L ₁ , L ₂ and L ₃ is a substituted methine group, L ₁ and R ₁ and / or L ₃ R ₃ may combine to form a saturated or unsaturated 5- or 6-membered ring.

[0014] R ₄ and R ₅ each represent a hydrogen atom or a linear, branched or cyclic alkyl group unsubstituted or substituted alkyl group such as, further R ₄ and R ₅ are monocyclic, bicyclic Represents an unsubstituted or substituted aryl group such as a system or tricyclic aryl group. R ₆ , R ₇ , R ₈ and R ₉ each represent a hydrogen atom or an unsubstituted or substituted alkyl group such as a linear, branched or cyclic alkyl group, and further R ₆ , R ₇ , R ₈ and R ₉ represents an unsubstituted or substituted aryl group such as a monocyclic, bicyclic or tricyclic aryl group. Further, two groups out of R _{6 to} R ₉ may combine to form an unsubstituted or substituted 5-membered or 6-membered carbon ring. R ₁₀ , R ₁₁ , R ₁₂ and R
₁₃ represents a hydrogen atom or an unsubstituted or substituted alkyl group such as a linear, branched or cyclic alkyl group, and R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each a monocyclic system or a bicyclic system. Represents an unsubstituted or substituted aryl group such as a system aryl group.

Further, each of R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is, for example, an unsubstituted or substituted alkoxy group whose alkyl moiety is a straight chain or branched alkyl; An unsubstituted or substituted aryloxy group whose part is a monocyclic or bicyclic aryl; for example, an alkylacyl group whose alkyl part is a linear or branched alkyl, or whose aryl part is a monocyclic ring Unsubstituted or substituted acyl groups such as arylacyl groups which are system or bicyclic aryls; eg unsubstituted or substituted alkoxycarbonyl groups whose alkyl moieties are linear or branched alkyl A trifluoromethyl group; an unsubstituted or substituted benzoyl group; for example, the alkyl moiety of which is linear or branched. An unsubstituted or substituted ureido group, such as an alkylureido group which is a alkyl or an arylureido group whose aryl part is a monocyclic or bicyclic aryl; for example, a linear or branched alkyl part of the alkyl part thereof An unsubstituted or substituted amino group such as a mono- or dialkylamino group or a mono- or diarylamino group whose aryl part is a monocyclic or bicyclic aryl;

Unsubstituted or substituted, such as, for example, a mono- or di-alkyl amide group whose alkyl part is a straight-chain or branched alkyl or a mono- or di-aryl amide group whose aryl part is a monocyclic or bicyclic aryl. A substituted amide group; such as, for example, an alkylsulfamide group whose alkyl moiety is a linear or branched alkyl or an arylsulfamide group whose aryl moiety is a monocyclic or bicyclic aryl An unsubstituted or substituted sulfamide group; for example, an alkylcarbamyl group whose alkyl moiety is a linear or branched alkyl or an arylcarbamyl group whose aryl moiety is a monocyclic or bicyclic aryl An unsubstituted or substituted carbamyl group; eg, where the alkyl moiety is An unsubstituted or substituted sulfamoyl group such as an alkylsulfamoyl group which is a chain or branched alkyl or an arylsulfamoyl group whose aryl moiety is a monocyclic or bicyclic aryl; bromine atom, chlorine A halogen atom such as an atom, an iodine atom or a fluorine atom; a nitro group; a cyano group; a hydroxyl group; or a carboxyl group, or two adjacent groups of R _{10 to} R ₁₃ are bonded to each other to form a condensed ring. It may form a saturated or unsaturated 5-membered or 6-membered ring. R ₁₆ , R ₁₇ , R ₂₀ and R ₂₁ each represent an unsubstituted or substituted alkyl group which may be a linear, branched or cyclic alkyl group. Q ⁻ represents a pharmaceutically acceptable anion necessary for charge balance, l represents 1 or 2, and n represents 0 or 1.

More specifically, as described above, R ₁ and R
₃ represents an unsubstituted or optionally substituted alkyl group. Suitable examples of the alkyl group have 1 to 1 carbon atoms
5, more preferably C1-C10, even more preferably C1-C8 straight chain, branched and cyclic alkyl groups. Specific examples of the alkyl group of R ₁ and R ₃ include methyl, ethyl, n-propyl, iso-propyl and n.
-Butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclopentyl, cyclohexyl, 2-
Propenyl, 2-butenyl, 3-hexenyl group and the like can be mentioned. When R ₁ and R ₃ represent a substituted alkyl group, specific examples of suitable substituents that may be present on the alkyl group include halogen atoms such as chlorine, bromine, fluorine and iodine, alkyl groups, aryl groups, Examples thereof include an alkoxy group and a hydroxyl group. The number of carbon atoms of the unsubstituted or substituted alkyl group for R ₁ and R ₃ is preferably 1 to 15, more preferably 1 to 10.

As defined above, R₂And R₁₈Is it
Each may be a linear, branched or cyclic alkyl group
Represents an alkyl group and may be substituted. Alkyl group
And suitable examples of its substituents are R₁And R₃About
As I did. R₂And R ₁₈Represented by Archi
The number of carbon atoms in the group is preferably 1 to 15, more preferably
It is 1 to 10. R above₂And R₁₈Represented by
Aryl groups are phenyl, biphenyl, naphthyl
Group or monocyclic ring system such as anthracenyl group, bicyclic ring system or
It may be a tricyclic aryl group, and such aryl group is
It may be unsubstituted or substituted. R₂And R₁₈
Suitable substitutions that may be present on the aryl group represented by
Examples of groups such as chlorine, bromine, fluorine or iodine
Halogen atoms, alkyl groups, alkoxy groups, hydroxyl groups,
Toro group, cyano group, amino group, alkyl group or aryl
Group substituted with an amino group, an acylamino group, a sulfonyl group
Luamino group, carbamoyl group, sulfamoyl group, cal
1 or 2 or more such as a voxyl group and an alkoxycarbonyl group
Above is mentioned. R₂And R₁₈Preferred charcoal of aryl groups
The number of elementary atoms is 6 to 20, preferably 6 to 15.
It

The heterocycles represented by R ₂ and R ₁₈ are 5- and 6-membered heterocycles containing one or more oxygen atoms, sulfur atoms or nitrogen atoms as heteroatoms. Preferable examples of the hetero ring represented by R ₂ and R ₁₈ include an imidazole ring, a thiazole ring, a pyrrole ring,
Examples thereof include a pyrazole ring, a furan ring, a thiophene ring, a piperidine ring, a morpholine ring, a piperazine ring, a pyrazine ring, a pyridine ring and a pyrimidine ring. These heterocycles may be substituted, for example, with the substituents described above for aryl of R ₂ and R ₁₈ , and may form a condensed ring with another ring such as a saturated or unsaturated ring. R ₁₆ ,
Examples of alkyl groups represented by R ₁₇ , R ₂₀ and R ₂₁ include unsubstituted or substituted alkyl groups having 1 to 15 carbon atoms, more preferably 1 to 10 carbon atoms.
Preferable examples of the alkyl group include those described above for R ₁ and R ₃ , and examples of the substituent which may be present on the alkyl group represented by R ₁₆ , R ₁₇ , R ₂₀ and R ₂₁ are alkyl. Group, alkoxy group, hydroxyl group, cyano group, halogen atom and the like.

R above₁₄, R₁₅, R₁₈And R₁₉Represented by
Examples of the alkyl group₁₆, R ₁₇, R₂₀And R_{twenty one}To
The alkyl groups mentioned above can be mentioned. R₁₄, R₁₅,
R₁₈And R₁₉The preferred number of carbon atoms of the alkyl group is 1 to 1
5 and more preferably 1-10. Furthermore R₁₄,
R₁₅, R₁₈And R₁₉Is monocyclic, bicyclic and tricyclic aryl
Represents an unsubstituted or substituted aryl group including a phenyl group.
R₁₄, R₁₅, R₁₈And R₁₉Preferred carbon sources for aryl groups of
The number of offspring is 6 to 20, and more preferably 6 to 15.
It R₁₄, R₁₅, R₁₈And R₁₉Preferred aryl groups of
Specific examples of the substituent include R₂The above
Is mentioned.

R above_Four, R_Five, R₆, R₇, R₈, R
₉, R_Ten, R₁₁, R₁₂And R₁₃The alkyl group represented by
It may be a linear, branched or cyclic alkyl group,
1 to 15 carbon atoms, more preferably 1 to 10, still more
It may preferably have 1-8. R_Four, R_Five, R
₆, R₇, R₈, R₉, R_Ten, R₁₁, R₁₂And R₁₃Table
The alkyl group represented by is also a substituted alkyl group.
You may. R_Four, R _Five, R₆, R₇, R₈, R₉, R
_Ten, R₁₁, R₁₂And R₁₃Specific examples of the alkyl group of
Methyl, ethyl, n-propyl, iso-propyl, 2-
Propenyl, n-butyl, iso-butyl, sec-butyl
, Tert-butyl, n-pentyl, hexyl, hepti
Le, octyl, cyclopropyl, cyclopentyl, shiku
Examples thereof include a lohexyl group. R_Four, R_Five, R₆,
R₇, R₈, R₉, R_Ten, R₁₁, R₁₂And R₁₃Is replaced
May be present on an alkyl group when it represents an alkyl group
Examples of suitable substituents are chlorine, bromine, fluorine and iodo.
Halogen atoms such as hydrogen, alkyl groups, aryl groups,
Examples thereof include a coxy group and a hydroxyl group. R_Four, R_Five, R₆,
R₇, R₈, R₉, R_Ten, R₁₁, R₁₂And R₁₃No substitution of
And the preferred number of carbon atoms in the substituted alkyl group is 1.
-15, more preferably 1-10.

R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R
_The aryl group represented by ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ may be a monocyclic, bicyclic or tricyclic aryl group such as a phenyl group, a biphenyl group, a naphthyl group or an anthracenyl group. The aryl group may be unsubstituted or substituted. Suitable examples of suitable substituents which may be present on the aryl group represented by R _{4 to} R ₁₃ include halogen atoms such as chlorine, bromine, fluorine and iodine, alkyl groups, alkoxy groups, hydroxyl groups, nitro groups, cyano. Group, an amino group, an amino group substituted with an alkyl group or an aryl group, an acylamino group, a sulfonylamino group, a carbamoyl group, a sulfamoyl group, a carboxyl group, an alkoxycarbonyl group and the like. R ₄ ~
The number of carbon atoms of the aryl group of R ₁₃ is 6 to 20, preferably 6 to 15. Furthermore, R ₆ , R ₇ , R
Two groups of ₈ and R ₉ may combine to form a 5- or 6-membered carbocycle. The suitable number of carbon atoms in the carbocycle is 3 to 15, preferably 3 to 10, including the substituents on R ₆ , R ₇ , R ₈ and R ₉ to the carbocycle. Typical examples of the 5- or 6-membered carbon ring include a cyclopentane ring, a cyclopentene ring, a cyclohexane ring, a cyclohexene ring and the like.

Z₁Forms a saturated or unsaturated carbocycle
Represents the atomic group necessary for. Furthermore, Z ₁Formed by
Ring may be substituted with one or more substituents,
, For example, cyclohexene ring, benzene ring or naphth
Fused to another saturated or unsaturated ring such as a tarene ring
May be. Z₁A position that may exist on the ring formed by
Preferable examples of the substituent include one or more alkyl groups,
Alkoxy group, aryloxy group, halogen atom (salt
Element, bromine, fluorine and iodine), aryl group, hydroxyl group,
An amino group, an alkyl group, or an aryl group substituted
Mino group, acylamino group, sulfonylamino group, carba
Moyl group, sulfamoyl group, carboxyl group, alcohol
Xycarbonyl group, acyloxy group, heterocycle (pillow
Ring, furan ring, piperidine ring, morpholine ring, pyridinium ring
Ring, etc.), cyano group, nitro group, trifluoromethyl group
Etc., and a saturated or unsaturated ring fused therewith
Preferred examples of are cyclopentene ring, cyclohexene
Ring, benzene ring, naphthalene ring, anthracene ring,
Nantrane ring, thiophene ring, pyridine ring, etc.
It

A specific example of the heterocycle formed by Z ₁ is a thiazole ring (eg, thiazole, 4-
Methylthiazole, 4-phenylthiazole, 4,5-
Diphenylthiazole, 4,5-dimethylthiazole, etc.), benzothiazole ring (eg, benzothiazole, 5-chlorobenzothiazole, 5-methylbenzothiazole, 5-phenylbenzothiazole, 5-methoxybenzothiazole, 4-fluoro) Benzothiazole, 5,6-dioxymethylenebenzothiazole, 5-
Nitrobenzothiazole, 5-trifluoromethylbenzothiazole, 5-methoxycarbonylbenzothiazole, 5-hydroxybenzothiazole, 5-cyanobenzothiazole, 5-iodobenzothiazole, etc., naphthothiazole ring (eg, α-naphtho) Thiazole,
β-naphthothiazole, γ-naphthothiazole, 5-methoxy-β-naphthothiazole, 8-methoxy-α-naphthothiazole, 6-methoxy-8-acetyloxy-
β-naphthothiazole, 8,9-dihydro-β-naphthothiazole, etc.), an oxazole-based ring (for example, 4-methyloxazole, 4,5-diphenyloxazole,
4-phenoxyoxazole, etc.), a benzoxazole-based ring (for example, benzoxazole, 5-chlorobenzoxazole, 5,6-dimethylbenzoxazole, 6-hydroxybenzoxazole, 5-phenylbenzoxazole, etc.),

A ring of naphthoxazole system (for example, α-
Naphthoxazole, β-naphthoxazole, etc.), selenazole ring (eg, 4-methylselenazole,
4-phenylselenazole, etc.), benzoselenazole-based rings (eg, benzoselenazole, 5-chlorobenzoselenazole, 5-methoxybenzoselenazole, 5-
Hydroxybenzoselenazole, etc.), thiazoline ring (eg, thiazoline, 4,4-dimethylthiazoline etc.), 2-pyridine ring (eg, 2-pyridine, 5
-Methyl-2-pyridine, 5-methoxy-2-pyridine, 4-chloro-2-pyridine, 5-carbamoyl-2
-Pyridine, 5-methoxycarbonyl-2-pyridine,
4-acetylamino-2-pyridine, etc.), 4-pyridine ring (for example, 4-pyridine, 3-methoxy-4-pyridine, 3,5-dimethyl-4-pyridine, 3-chloro-4-pyridine, 3-methyl-4-pyridine etc.), 2-
Quinoline-based rings (eg, 2-quinoline, 6-methyl-
2-quinoline, 6-chloro-2-quinoline, 6-ethoxy-2-quinoline, 6-hydroxy-2-quinoline, 6
-Nitro-2-quinoline, 6-acetylamino-2-quinoline, 6-dimethylaminocarbonyl-2-quinoline, 8-fluoro-2-quinoline, etc.),

4-quinoline type rings (for example, 4-quinoline, 6-methoxy-4-quinoline, 6-acetylamino-4-quinoline, 8-chloro-4-quinoline, 6-trifluoromethyl-4-quinoline) Etc.) 1-isoquinoline-based ring (eg, 1-isoquinoline, 6-methoxy-1
-Isoquinoline, 6-chloro-1-isoquinoline, etc.),
3,3-dialkylindolenine-based rings (for example, 3,
3-dimethylindolenine, 3,3,7-trimethylindolenine, 5-chloro-3,3-dimethylindolenine, 5-ethoxycarbonyl-3,3-dimethylindolenine, 5-nitro-3,3-dimethyl Indolenine,
3,3-dimethyl-4,5-phenylene indolenine,
3,3-dimethyl-6,7-phenylene indolenine,
5-acetylamino-3,3-dimethylindolenine,
5-diethylamino-3,3-dimethylindolenine,
5-methanesulfonylamino-3,3-dimethylindolenine, 5-benzoylamino-3,3-dimethylindolenine, etc., an imidazole ring (eg, imidazole, 1-alkyl-4-phenylimidazole, 1-
Alkyl-4,5-dimethylimidazole, etc.),

Benzimidazole-based rings (eg, benzimidazole, 1-alkylbenzimidazoles, 1
-Alkyl-5-trifluorobenzimidazoles, 1
-Alkyl-5-chlorobenzimidazoles, 1-alkyl-5-sulfamoylbenzimidazoles, 1-aryl-5-methoxy-carbonylbenzimidazoles, 1-alkyl-5-acetylaminobenzimidazoles, 1-alkyl-5- Nitrobenzimidazole,
1-alkyl-5-diethylaminobenzimidazole, 1-alkyl-5-pentyloxybenzimidazole, etc., naphthimidazole-based rings (eg 1-alkyl-α-naphthoimidazole, 1-alkyl-5-
5-membered and 6-membered heterocycles such as rings containing a nucleus-containing ring such as methoxy-β-naphthimidazole). The above Z ₂ represents an atomic group necessary for forming a naphthalene ring, an anthracene ring or a phenanthrene ring, that is, one of these rings condensed with the ring containing X ₃ . The ring formed by Z ₂ may be substituted, and preferable examples of the substituent include one or more alkyl groups, alkoxy groups, aryloxy groups, halogen atoms (chlorine, bromine,
Fluorine, iodine, etc.), hydroxyl group, acyloxy group and the like.

Typical examples of the substituted ring formed by Z ₂ include hydroxynaphthalene, methoxynaphthalene, trimethoxynaphthalene, acetoxynaphthalene, methylnaphthalene, bromonaphthalene, hydroxyphenanthrene, methoxyphenanthrene and the like. Preferable examples of the substituent which may be present on the substituted methine groups L ₁ , L ₂ and L ₃ include an alkyl group (eg, methyl, ethyl, butyl group, etc.), an aryl group (eg, phenyl, tolyl group, etc.) ), A halogen atom (eg, chlorine,
Bromine, fluorine and iodine), or an alkoxy group (eg, methoxy, ethoxy group, etc.), L ₁ and R ₁
And / or a suitable ring formed by the bond of L ₃ and R ₃ includes a 5-membered heterocycle (eg, pyrroline ring) and a 6-membered heterocycle (eg, tetrahydropyridine ring, oxazine ring, etc.).

The term "pharmaceutically acceptable anion" for Q, which is required for charge balance in the above compounds, is nontoxic when the compounds are administered to a host and dissolves the compounds in an aqueous system. Intended to mean ion. Suitable examples of the pharmaceutically acceptable anion represented by Q include halogen ions such as chloride ion, bromide ion and iodide ion; for example, methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion. , Sulfonate ions such as aliphatic and aromatic sulfonate ions such as naphthalenesulfonate ion and 2-hydroxyethanesulfonate ion; Sulfamate ion such as cyclohexanesulfamate ion; Sulfate ion such as methylsulfate ion and ethylsulfate ion Hydrogen sulfate; borate ion; alkyl and dialkyl phosphate ions such as diethyl phosphate ion and methyl hydrogen phosphate ion; pyrophosphate ion such as trimethyl pyrophosphate ion and diethyl hydrogen pyrophosphate ion; carbo Acid ion (carboxylate ions carboxy group and hydroxyl group is substituted with conveniently used) include and carbonate ions. A preferred example of a pharmaceutically acceptable anion is chloride ion,
Examples thereof include acetate ion, propionate ion, valerate ion, citrate ion, maleate ion, fumarate ion, lactate ion, succinate ion, tartrate ion and benzoate ion.

In particular, the compounds of the general formula (1) in which Y ₁ is a sulfur atom:
The cyanine compound (6) is preferred. A particularly preferred cyanine compound is _{one in} which Y ₁ is a sulfur atom, and = L ₁ -L ₂ =
Is ═CH—CH═, and L ₃ is ═CH—, which are compounds of the general formulas (1) to (6). General formula (1) to
Compounds of (6) are compounds of British Patent Nos. 487,051 and 489,335 and US Pat. Nos. 2,536,986, 2,454,629, 2,961,318,
It can be easily prepared from known starting materials according to the methods disclosed in 2,388,963 and 2,504,468, the disclosure of which is included in the present specification. The following compounds are mentioned as a typical example of the compound of General formula (1)-(6) which can be used by this invention. However, the invention should not be construed as limited to these compounds.

[0031]

[Chemical 5]

[0032]

[Chemical 6]

[0033]

[Chemical 7]

[0034]

[Chemical 8]

[0035]

[Chemical 9]

[0036]

[Chemical 10]

[0037]

[Chemical 11]

[0038]

[Chemical 12]

[0039]

[Chemical 13]

[0040]

[Chemical 14]

[0041]

[Chemical 15]

[0042]

[Chemical 16]

[0043]

[Chemical 17]

[0044]

[Chemical 18]

[0045]

[Chemical 19]

[0046]

[Chemical 20]

[0047]

[Chemical 21]

[0048]

[Chemical formula 22]

[0049]

[Chemical formula 23]

[0050]

[Chemical formula 24]

[0051]

[Chemical 25]

[0052]

[Chemical formula 26]

[0053]

[Chemical 27]

[0054]

[Chemical 28]

[0055]

[Chemical 29]

[0056]

[Chemical 30]

[0057]

[Chemical 31]

[0058]

[Chemical 32]

[0059]

[Chemical 33]

[0060]

[Chemical 34]

[0061]

[Chemical 35]

[0062]

[Chemical 36]

[0063]

[Chemical 37]

[0064]

[Chemical 38]

[0065]

[Chemical Formula 39]

[0066]

[Chemical 40]

[0067]

[Chemical 41]

[0068]

[Chemical 42]

[0069]

[Chemical 43]

[0070]

[Chemical 44]

[0071]

[Chemical 45]

[0072]

[Chemical 46]

[0073]

[Chemical 47]

[0074]

[Chemical 48]

[0075]

[Chemical 49]

[0076]

[Chemical 50]

[0077]

[Chemical 51]

[0078]

[Chemical 52]

[0079]

[Chemical 53]

[0080]

[Chemical 54]

[0081]

[Chemical 55]

[0082]

[Chemical 56]

[0083]

[Chemical 57]

[0084]

[Chemical 58]

[0085]

[Chemical 59]

[0086]

[Chemical 60]

[0087]

[Chemical formula 61]

[0088]

[Chemical formula 62]

[0089]

[Chemical 63]

[0090]

[Chemical 64]

[0091]

[Chemical 65]

[0092]

[Chemical 66]

[0093]

[Chemical 67]

[0094]

[Chemical 68]

[0095]

[Chemical 69]

[0096]

[Chemical 70]

[0097]

[Chemical 71]

[0098]

[Chemical 72]

[0099]

[Chemical formula 73]

[0100]

[Chemical 74]

[0101]

[Chemical 75]

[0102]

[Chemical 76]

[0103]

[Chemical 77]

[0104]

[Chemical 78]

[0105]

[Chemical 79]

[0106]

[Chemical 80]

[0107]

[Chemical 81]

[0108]

[Chemical formula 82]

[0109]

[Chemical 83]

[0110]

[Chemical 84]

[0111]

[Chemical 85]

[0112]

[Chemical formula 86]

[0113]

[Chemical 87]

[0114]

[Chemical 88]

[0115]

[Chemical 89]

[0116]

[Chemical 90]

[0117]

[Chemical Formula 91]

[0118]

[Chemical Formula 92]

[0119]

[Chemical formula 93]

[0120]

[Chemical 94]

[0121]

[Chemical 95]

[0122]

[Chemical 96]

[0123]

[Chemical 97]

[0124]

[Chemical 98]

[0125]

[Chemical 99]

[0126]

[Chemical 100]

[0127]

[Chemical 101]

[0128]

[Chemical 102]

[0129]

[Chemical 103]

[0130]

[Chemical 104]

[0131]

[Chemical 105]

[0132]

[Chemical formula 106]

[0133]

[Chemical formula 107]

[0134]

[Chemical 108]

[0135]

[Chemical 109]

[0136]

[Chemical 110]

[0137]

[Chemical 111]

[0138]

[Chemical 112]

[0139]

[Chemical 113]

[0140]

[Chemical 114]

[0141]

[Chemical 115]

[0142]

[Chemical formula 116]

[0143]

[Chemical 117]

[0144]

[Chemical 118]

[0145]

[Chemical 119]

[0146]

[Chemical 120]

[0147]

[Chemical 121]

[0148]

[Chemical formula 122]

[0149]

[Chemical 123]

[0150]

[Chemical formula 124]

[0151]

[Chemical 125]

[0152]

[Chemical formula 126]

[0153]

[Chemical 127]

[0154]

[Chemical 128]

[0155]

[Chemical formula 129]

[0156]

[Chemical 130]

[0157]

[Chemical 131]

[0158]

[Chemical 132]

[0159]

[Chemical 133]

The following synthetic examples are based on the above general formulas (1) to (1).
A typical synthetic method for the specific compound contained in (6) will be described in more detail. Unless otherwise specified, all parts, percentages, ratios, etc. are by weight.

Synthesis Example 1-1 (Compound 247) 28 g of 5-[(1-ethyl-2 (1H) -1,2-dihydroquinolinylidene) ethylidene] -2-methylmercapto-4-thiazolone eth- p-Toluenesulfonate and 20 g of 1-ethyl-4-methylquinolinium p-toluenesulfonate were mixed in 700 cc of acetonitrile. 20 cc of triethylamine was added to the mixture at ice water temperature, and after 10 minutes, 1 liter of ethyl acetate was added. Then the mixture was stirred for 30 minutes. The precipitate was filtered off and washed with ethyl acetate. Then, the obtained product was dissolved in 1 liter of methanol, a solution of 20 g of sodium iodide in 50 cc of methanol was added, and then the mixture was stirred at room temperature (20 to 30 ° C.) for 3 hours. The crude compound 247 that precipitated was filtered off, washed with methanol and dried. Crystallized from methanol / chloroform (1: 1 volume ratio), mp 305-31
0 ° C. (decomposition), λ ^MeOH _max 672 nm (ε ^MeOH _max = 8.
00 × 10 ⁴ ) pure product was obtained with a yield of 28%.

Synthesis Example 1-2 (Compound 262) (a) Method using silver acetate: Compound 2 obtained above
3.5 g of 47 was suspended in 600 cc of chloroform,
With stirring, 2 g of silver acetate was added at room temperature. One hour later,
The reaction mixture was added to Celite (Celite 545, Manville Sal
diatomaceous earth available from es) and the filtrate was dried under reduced pressure. To this residue was added 50 ml of chloroform followed by 1 liter of ethyl acetate. The formed precipitate was separated by suction filtration and washed with ethyl acetate. After drying, 2.55 g melting point 189-190 ° C. (decomposition), λ ^MeOH _max 672 nm (ε ^MeOH _max = 8.00 × 1)
0 ⁴ ) of pure compound 262 was obtained with a yield of 82%. (B) Method using an ion exchange resin: 100 g of an ion exchange resin (DIATON WA-21, manufactured by Mitsubishi Kasei Co., Ltd.) was packed in a column, treated with 1 liter of 1N sodium hydroxide / methanol solution, and then treated with 0. Treated with 5 liters of 1N acetic acid / methanol solution. 7 g of compound 247 dissolved in 1 liter of 1N acetic acid / methanol solution was passed through the above column. Compound 262 was eluted with a 1N acetic acid / methanol solution, the eluent was concentrated under reduced pressure to about 200 ml, and 0.7 liter of ethyl acetate was added to the residue. The formed precipitate was separated by suction filtration and washed with ethyl acetate. After drying, 0.5 g of pure compound 262, 84% yield
Got with. Melting points and λ ^MeOH _max (ε ^MeOH _max ) were as described above.

Synthesis Example 2-1 (Compound 55) 17.1 g of 5-[(3-methyl-2 (1H) -naphtho [1,2-d] thiazolinylidene) ethylidene] -2-
Methylmercapto-4-thiazolone eth-p-toluenesulfonate and 12.0 g of 3-ethyl-2-methylnaphtho [2,1-d] thiazolium p-toluenesulfonate were added to 1000 ml of methanol. The mixture was added to 8 ml of triethylamine at room temperature and stirred for 3 hours. The precipitate formed was separated by suction filtration, washed with methanol and then recrystallized from chloroform-methanol (1: 1 by volume). Melting point 300-304 ° C (decomposition)
Was obtained in a yield of 60%. λ ^MeOH _max 621nm
(Ε ^MeOH _max = 1.06 × 10 ⁵ ).

Synthesis Example 2-2 (Compound 57) (a) Method using concentrated hydrochloric acid: Compound 5 obtained above
4.0 g of 5 was dissolved in 300 ml of a methanol-chloroform (1: 1 volume ratio) mixture. To the solution was added 4 ml concentrated hydrochloric acid (35%), then the volume was about 15 ° C at 35 ° C.
Concentrate under reduced pressure to 0 ml. The formed precipitate was separated by suction filtration and washed with ethanol. methanol-
After recrystallizing from chloroform (1: 1 volume ratio),
3.2 g of pure compound 57 with a melting point of 223-227 ° C. (decomposition) were obtained with a yield of 98%. λ ^MeOH _max 621nm
(Ε ^MeOH _max = 9.72 × 10 ⁴ ). (B) Method using ion exchange resin: 100 g of ion exchange resin (AMBERLYST A-26, manufactured by Rhom & Haas) was packed in a column, and 6.5 g of compound 55 was added to 500 ml of methanol-chloroform (volume ratio 1 The solution dissolved in 1) was passed through this column. Compound 55 was eluted with 2 liters of methanol and the eluent was concentrated to about 200 ml.
After adding 500 ml of ethanol to this residue,
Concentrated to about 500 ml. The formed precipitate was separated by suction filtration and washed with ethanol. After drying, 4.6 g of pure compound 57 was obtained with a yield of 86%. Melting point and λ
^MeOH _max (ε ^MeOH _max ) was as described above.

Synthesis Example 2-3 (Compound 32) Sodium iodide (2.5 molar equivalent) instead of concentrated hydrochloric acid
The above operation was repeated except that was used. 24.5 g
From the compound 55 of 22.7 g, mp 223-226 ° C.
Compound 32 of (decomposition) was obtained with a yield of 98%. λ ^MeOH
_max 621 nm (ε ^MeOH _max = 9.71 × 10 ⁴ ).

Synthesis Example 2-4 (Compound 56) 16.2 g of Compound 32 was added to 1.6 liters of a methanol-chloroform (1: 1 volume ratio) mixture, and the mixture was stirred at room temperature. To this suspension was added 11 g of silver acetate and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in 500 cc of methanol and filtered. The filtrate was concentrated under reduced pressure to about 200 cc, and 300 cc of diethyl ether and 100 cc of ethyl acetate were added to this solution to precipitate compound 56. The product was isolated by suction filtration and 13.5 g of pure compound 56, mp 190-194 ° C (dec) was obtained in 92% yield. λ
^MeOH _max 621 nm (ε ^MeOH _max = 9.43 x 10 ⁴ ).
Other compounds of the general formulas (1) to (6) useful in the present invention could be easily synthesized by using the same procedure as above. The compounds are shown in Tables 1-12 below along with their maximum absorption wavelength and maximum extinction coefficient.

[0167]

[Table 1]

[0168]

[Table 2]

[0169]

[Table 3]

[0170]

[Table 4]

[0171]

[Table 5]

[0172]

[Table 6]

[0173]

[Table 7]

[0174]

[Table 8]

[0175]

[Table 9]

[0176]

[Table 10]

[0177]

[Table 11]

[0178]

[Table 12]

The compounds of the above general formulas (1) to (6) are
Alternatively, the pharmaceutical composition of the present invention containing two or more is melanoma,
Treatment of various types of cancer including liver cancer, glioma, neuroblastoma, sarcoma and cancer of lung, colon, breast, bladder, ovary, testis, prostate, cervix, pancreas, stomach, small intestine and other organs Can be used effectively. The pharmaceutical composition of the present invention may contain one or more compounds of the above general formulas (1) to (6), and, if desired, known compounds conventionally used in the art. It may be used in combination with other therapeutic agents including anti-tumor agents. Suitable examples of such conventionally used antitumor agents include adriamycin, cisplatin, colchicine and CCNU (Lomas
tine), BCNU (Carmustine), actinomycin D,
5-Fluorouracil, thiotepa, cytosine arabinoside, cyclophosphamide, mitomycin C and the like can be mentioned.

Suitable examples of pharmaceutical carriers or diluents which may be used in the pharmaceutical composition of the present invention in combination with the compounds of the general formulas (1) to (6) are glucose; saccharose; lactose; ethyl alcohol; glycerin. ;
Mannitol; sorbitol; pentaerythritol;
Diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, other polyethylene glycols; mono and di saturated fatty acids such as glyceryl trilaurate, glyceryl monostearate, glyceryl tristearate and glyceryl distearate. And triglycerides; pectin; starch; alginic acid; xylose; talc; Ishimatsuko; olive oil,
Fats and oils such as peanut oil, castor oil, corn oil, wheat malt oil, sesame oil, cottonseed oil, sunflower oil and cod liver oil; gelatin; lecithin; silica; cellulose; cellulose derivatives such as methylhydroxypropylcellulose, methylcellulose, hydroxyethylcellulose; calcium stearate. , Calcium laurate, magnesium oleate, calcium palmitate, calcium behenate, magnesium stearate and the like, magnesium or calcium salts of fatty acids having 12 to 22 carbon atoms; cyclodextrins; eg α-cyclodextrin, β- Cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cydextrin B dextrin, carboxymethyl ethyl -β- cyclodextrin and dimethyl -β
-Cyclodextrins; emulsifiers; for example saturated and unsaturated fatty acids having 2 to 22, especially 10 to 18 carbon atoms and monohydric aliphatic alcohols (for example those having 1 to 20 carbon atoms such as alkanols). Alternatively, mention may be made of esters with polyhydric alcohols such as glycol, glycerin, diethylene glycol, pentaerythritol, ethyl alcohol, butyl alcohol and octadecyl alcohol; and silicones such as dimethylpolysiloxane. Further, other carriers conventionally used for pharmaceutical compositions can be said to be suitable for the present invention.

The pharmaceutically effective amount of the compound of the general formulas (1) to (6) and the administration method or administration means which can be used are as follows: nature of cancer, treatment policy, severity of illness, degree of malignancy, degree of metastasis, Tumor volume, general health, weight, age, sex,
And will depend on the (genetic) racial background of the patient.
However, generally suitable administration methods include, for example, the compounds of the general formulas (1) to (6) dissolved in, for example, 5% aqueous glucose solution or other suitable carrier or diluent as described above. In an associated form, intravenously,
Methods include intraperitoneal, intramuscular or intravesical injection. A suitable therapeutically effective amount of a compound of general formulas (1)-(6) in a pharmaceutical composition is from about 0.01 to about 10% by weight, more usually 0. 1 to
It is about 1% by weight.

As noted above, a pharmaceutically effective amount will generally be determined by the practitioner based on factors such as clinically observed symptoms, the extent of disease progression, etc. A suitable therapeutically effective amount of a compound of 1) to (6) is generally 1 per day per 70 kg body weight.
It may be administered in a range of 0 to 500 mg, more generally 100 to 200 mg, and may be taken in a single dose or in a plurality of divided doses depending on the treatment required. It is determined. In order to clarify the effectiveness of the compounds of the general formulas (1) to (6) and the pharmaceutical composition thereof of the present invention, the following examples are shown and the above-mentioned general formula (1) used in the composition of the present invention is shown. )-(6), the efficacy and selectivity values of many compounds were revealed together with the values obtained for the comparative compounds. The results obtained are shown in the table.

[0183]

EXAMPLES Example 1 The data shown in Tables 13 to 15 were obtained by the following method. Human colon cancer cell line CX-1 and normal monkey kidney epithelial cell line CV-1 were selected as representatives of cancer cells and normal cells, respectively. This test reveals the selectivity of cancer cell killing by the compounds of the general formulas (1) to (6).
CX-1 cells and CV-1 cells were placed in 24-well plastic culture plates (CX-1 cells: 2.00
0 cells / well, CV-1 cells: 1,000 cells / well). The compounds of the general formulas (1) to (6) are dissolved in dimethyl sulfoxide so as to have a concentration of 1 mg / ml, and this solution is diluted stepwise with cell medium to 20 to 0.0025 μg / ml. Of wells. Only the medium was added to the control. The cells were treated with the compounds of general formulas (1) to (6) at 37 ° C. for 24 hours. After washing three times with fresh medium, the cells were further incubated at 37 ° C for 7-10 days. Fix the cell colony and fix it to 70
It was dyed with 2% crystal violet prepared with 10% ethanol for 10 minutes and lightly washed with water. The number of colonies in each well was counted, and the concentration (IC ₅₀ ) of the compound that acted on the wells in which the number of colonies had decreased to 50% of the control was confirmed. Selectivity was defined as the ratio of the IC ₅₀ for CV-1 to the IC ₅₀ for CX-1.

[0184]

[Table 13]

[0185]

[Table 14]

[0186]

[Table 15]

Compounds A, B and C used for comparison
Is as follows.

[0188]

[Chemical 134]

From the results shown in Tables 13 to 15, the compounds of the general formulas (1) to (6) used in the present invention are compound A,
It is quite clear that it has a distinctly higher selectivity compared to B and C. According to the findings from the literature, compounds B and C would have a selectivity of 20 and <2 respectively and would be highly toxic to animals and thus to humans. In fact, compounds B and C have been found to be highly toxic to normal nude mice. Although compound A has low toxicity to normal nude mice,
Since it has a low selectivity as compared with the other compounds of the general formulas (1) to (6), it cannot be expected to be very effective in treating not only human cancer but also animal cancer.

Example 2 To further demonstrate the uniqueness of the present invention, the procedure described in Example 1 was used except that human bladder cancer EJ cell line was used in place of human colon cancer cell line CX-1. The compounds of general formulas (1) to (6) were tested. The selectivity values, EJ values and CV-1 values for the compounds of the invention are shown in Table 16.

[0191]

[Table 16]

Example 3 To further demonstrate the uniqueness of the present invention, the procedure described in Example 1 was used except that the human melanoma LOX cell line was used in place of the human colon cancer cell line CX-1. The compounds of general formulas (1) to (6) were tested. The selectivity values, LOX values and CV-1 values for the compounds of the invention are shown in Table 17.

[0193]

[Table 17]

Example 4 To further demonstrate the uniqueness of the present invention, the procedure described in Example 1 was followed except that human breast cancer MCF-7 cell line was used in place of human colon cancer cell line CX-1. Were used to test compounds of general formulas (1)-(6). Selectivity values, MCF-7 values and CV for compounds of the invention
The values of -1 are shown in Table 18.

[0195]

[Table 18]

Example 5 To further demonstrate the uniqueness of the present invention, the procedure described in Example 1 was used except that the human pancreatic cancer CRL1420 cell line was used in place of the human colon cancer cell line CX-1. The compounds of general formulas (1) to (6) were tested. The selectivity values, CRL1420 values and CV-1 values for the compounds of the invention are shown in Table 19.

[0197]

[Table 19]

Example 6 Human Melanoma Carrying Nude Mouse as a Model System LOX, which is a human melanoma cell line grown subcutaneously in a nude mouse, was excised and trypsinized, and single cell suspension was performed using a metal mesh of 4 mm mesh. A suspension was prepared. Erythrocytes were hemolyzed by incubating with 0.17M ammonium chloride for 20 minutes at 4 ° C. Five million viable trypan blue negative cells made in 0.1 ml Dulbecco's Modified Eagle Medium (DME) were injected intraperitoneally into male athymic Swiss nu / nu mice. The number of mice in the control group and each treatment group was 5 to 10. Treatment was started the following day by intraperitoneal injection. Control mice were injected with 0.25 ml of 2% dextrose on the day of injection of the compounds of the invention into the treated mice.
The compounds of the general formulas (1) to (6) of the present invention used in the test are listed in Table 20, and the obtained results are shown in Table 20 and FIGS. 1 to 6 of the accompanying drawings. T / C represents the average survival time of the treatment group as a percentage of the average survival time of the untreated control group.

[0199]

[Table 20]

Example 7 Ovarian Carcinoma Test Using the Nude Mouse Method The human ovarian carcinoma cell line OVCAR-3 was used. 10 million cells of this cell line were injected intraperitoneally into 10 athymic Swiss nu / nu mice. Of the mice injected with these cancer cells, 10 mice were selected as a control group, and 5% dextrose in the same volume as the mice in the treatment group was injected. The tested compounds of the general formulas (1) to (6) of the present invention and the obtained results are shown in Table 21 and FIGS. 7 to 9 of the accompanying drawings.

[0201]

[Table 21]

Example 8 Anti-Human Colon Carcinoma CX-1 Activity Using Nude Mice Human colon carcinoma cell line CX-1 has been adopted by the National Cancer Institute as a mode of screening anti-cancer agents (NCI method 3C2H2). .. It was established in culture from a surgical explant of primary colon adenocarcinoma in a 44 year old woman who had not yet received chemotherapy. This culture CX-1
Cells can easily grow as moderately to well differentiated human colon carcinomas in nude mice when injected subcutaneously. CEA is the notation for a differentiated colon carcinoma cell. The same keratin as the original epithelium exists. Increased absorption of delocalized lipophilic cations and prolonged retention were observed.

Swiss nu / nu mice obtained from Taconic Farm were housed in a pathogen-free environment. Tumors subcutaneously inoculated into nude mice were excised under sterile conditions to prepare single cell suspensions using 0.4 mm mesh metal mesh. Erythrocytes were hemolyzed by incubating with 0.17M ammonium chloride for 20 minutes at 4 ° C. Cells were tested for viability using trypan blue. Viable CX-1 cells (2.5 million) prepared in 0.1 ml of cell culture were subcutaneously injected into each nude mouse. Control group of these mice (5)
And the treatment groups (5 animals in each group) were randomly distributed. The drug treatment started the next day. Dosages and schedules are empirically determined and are primarily LDs obtained from preliminary toxicity studies.
Based on findings of 50 and LD10. The control group was injected with the same volume of hydroxypropyl-β-cyclodextrin-5% glucose solution as the mice in the treatment group were injected.

A sample of the pharmaceutical composition in a 5% glucose solution was sonicated at a concentration of 1 mg / ml. Compounds that were not completely soluble by this procedure were dissolved in hydroxypropyl-β-cyclodextrin using the following method. That is, hydroxypropyl-β-cyclodextrin (45 g) was added to 100 ml of water that had been sterilized and distilled twice.
Were mixed and stirred for 4 hours. Each compound to be tested (20m
g) was mixed with 10 ml of the hydroxypropyl-β-cyclodextrin solution and sonicated for 60 minutes in the dark. This solution is then diluted to a 5% glucose concentration to bring the final compound concentration to 0.5 mg / ml and 6 more in the dark.
Sonicate for 0 min to completely dissolve the compound. The experiment was terminated when the tumor growth reached the exponential growth phase and the tumor size became palpable in the control group (usually 20-30 days after tumor injection). The tumor of each mouse was excised and weighed using an analytical balance.
The total weight of tumors from 5 mice for each group was calculated and then the percent tumor suppression between the treatment and control groups was calculated for each group. The obtained results are shown in Table 22 and illustrated in FIGS.

[0205]

[Table 22]

While the present invention has been described in detail and specific examples thereof have been described above, it is understood that various changes and modifications can be made without departing from the spirit and scope of the present invention. It will be obvious to those skilled in the field.

[Brief description of drawings]

FIG. 1 is a graph showing the survival days and survival rate when human melanoma-bearing nude mice were injected with Compound 32.
The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 2 is a graph showing the survival days and survival rate when human melanoma-bearing nude mice were injected with compound 53.
The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 3 is a graph showing the survival days and the survival rate when compound 96 was injected into human melanoma-bearing nude mice.
The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 4 is a graph showing the survival days and survival rates when compound 204 was injected into human melanoma-bearing nude mice. The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 5 is a graph showing the survival days and survival rates when human melanoma-bearing nude mice were injected with compound 247. The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 6 is a graph showing survival time and survival rate when compound 116 was injected into human melanoma-bearing nude mice. The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 7: Compound 116 in nude mice carrying human ovarian carcinoma
It is the figure which shows the survival days and the survival rate in case of injecting. The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 8: Compound 247 in nude mice carrying human ovarian carcinoma
It is the figure which shows the survival days and the survival rate in case of injecting. The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 9: Compound 290 in nude mice carrying human ovarian carcinoma
It is the figure which shows the survival days and the survival rate in case of injecting. The horizontal axis represents the number of days of survival and the vertical axis represents the survival rate.

FIG. 10: Compound 56 in nude mice bearing human colon carcinoma
5 is a graph showing the tumor growth inhibitory effect when infused with. The vertical axis represents the total weight of tumors grown in the body of 5 mice.

FIG. 11: Compound 24 in nude mice carrying human colon carcinoma
7 is a graph showing the tumor growth inhibitory effect when 7 is injected. The vertical axis represents the total weight of tumors grown in the body of 5 mice.

FIG. 12: Compound 4 in nude mice carrying human colon carcinoma
4 is a graph showing the effect of suppressing tumor growth when 4, 45, 47 and 48 are respectively injected. The vertical axis represents the total weight of tumors grown in the body of 5 mice.

FIG. 13: Compound 14 in nude mice carrying human colon carcinoma
6 illustrates the tumor growth inhibitory effect when 6 and 304 are respectively injected. The vertical axis represents the total weight of tumors grown in the body of 5 mice.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] July 27, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0028

[Correction method] Change

[Correction content]

Typical examples of the substituted ring formed by Z ₂ are hydroxynaphthalene, methoxynaphthalene, trimethoxynaphthalene, acetoxynaphthalene , methylnaphthalene, promonaphthalene , dihydrona.
Examples thereof include phthalene, hydroxyphenanthrene, methoxyphenanthrene and the like. Substituted methine groups L ₁ and L
Suitable examples of the substituent which may be present on ₂ and L ₃ include an alkyl group (eg, methyl, ethyl, butyl group, etc.), an aryl group (eg, phenyl, tolyl group, etc.), a halogen atom (eg, chlorine, Bromine, fluorine and iodine), or an alkoxy group (eg, methoxy, ethoxy group, etc.), and a suitable ring formed by the bond of L ₁ and R ₁ and / or L ₃ and R ₃ is a 5-membered hetero. Examples thereof include a ring (eg, pyrroline ring) and a 6-membered hetero ring (eg, tetrahydropyridine ring, oxazine ring, etc.).

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

The term "pharmaceutically acceptable anion" for Q, which is required for charge balance in the above compounds, is nontoxic when the compounds are administered to a host and dissolves the compounds in an aqueous system. Intended to mean ion. Suitable examples of pharmaceutically acceptable anions represented by Q include halogen ions such as chloride ion, bromide ion and iodide ion; for example, methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion. , Sulfonate ions such as aliphatic and aromatic sulfonate ions such as naphthalene sulfonate ion and 2-hydroxyethane sulfonate ion; sulfamate ion such as cyclohexanesulfamate ion; sulfate ion such as methylsulfate ion and ethylsulfate ion Hydrogen sulfate; borate ion; alkyl and dialkyl phosphate ions such as diethyl phosphate ion and methyl hydrogen phosphate ion; pyrophosphate ion such as trimethyl pyrophosphate ion and diethyl hydrogen pyrophosphate ion; carbo Acid ion (carboxylate ions Karupokishi group and hydroxyl group is substituted with conveniently used) include and carbonate ions. Chlorine is a preferred example of an anion that is acceptable in terms of chestnut,
Examples thereof include bromine ion, iodine ion, acetate ion, propionate ion, valerate ion, counate ion, maleate ion, fumarate ion, lactate ion, succinate ion, tartrate ion and benzoate ion.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0051

[Correction method] Change

[Correction content]

[0051]

[Chemical 25]

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0079

[Correction method] Change

[Correction content]

[0079]

[Chemical 53]

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0140

[Correction method] Change

[Correction content]

[0140]

[Chemical 114]

[Procedure correction 6]

[Document name to be amended] Statement

[Correction target item name] 0152

[Correction method] Change

[Correction content]

[0152]

[Chemical formula 126]

[Procedure Amendment 7]

[Document name to be amended] Statement

[Name of item to be corrected] 0162

[Correction method] Change

[Correction content]

Synthesis Example 1-2 (Compound 262) (a) Method using silver acetate: Compound 2 obtained above
3.5 g of 47 was suspended in 600 cc of chloroform, and 2 g of silver acetate was added at room temperature while stirring. After 1 hour, the reaction mixture was added to Celite (Celite 545, Manv.
diatomaceous earth (available from ill Sales), and the filtrate was dried under reduced pressure. 50 on this residue
ml of chloroform was added, followed by 1 liter of ethyl acetate. The formed precipitate was separated by suction filtration and washed with ethyl acetate. After drying, 2.55 g melting point 18
9 to 190 ° C. (decomposition), λ ^MeOH _max 672 nm
(Ε ^MeOH _max = 8.00 × 10 ⁴ ) of pure compound 262 was obtained with a yield of 82%. (B) How to use the ion exchange resin: 100g of ion exchange resin (DIA I ON WA-21, manufactured by Mitsubishi Chemical Industries, Ltd.) was packed into a column, treated with 1 liter of 1N sodium hydroxide / methanol solution, Treated with 0.5 liter of 1N acetic acid / methanol solution. 1 liter of 1
7 g of compound 247 dissolved in N acetic acid / methanol solution
Was passed through the above column. Compound 262 was eluted with a 1N acetic acid / methanol solution and the eluent was evaporated under reduced pressure to ca.
It was concentrated to ml and 0.7 liter of ethyl acetate was added to this residue. The formed precipitate was separated by suction filtration and washed with ethyl acetate. After drying, 0.5 g of pure compound 2
62 was obtained with a yield of 84%. Melting point and λ
^MeOH _max (ε ^MeOH _max ) was as described above.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07D 277/60 7019-4C 277/64 7019-4C 277/84 7019-4C 413/14 8829-4C 417/06 9051-4C 417/14 9051-4C 421/06 9051-4C 513/04 325 8415-4C (72) Inventor Lambeau Chien USA Massachusetts State 02173 Lexington East Emerson Road 184

Claims (16)

[Claims] 1. A pharmaceutical composition for treating cancer or tumor, which comprises at least one compound selected from the group consisting of compounds represented by formulas (1) to (6). [Chemical 1] [Chemical 2] (In the formula, X ₁ is O, S, Se, or —NR ₁₄ —; X ₂ is O, S, Se, —NR ₁₅ —, or —CR ₁₆ R.
₁₇ - or a -CH = CH-; X ₃ is an O, S or Se,; X ₄ is -NR ₁₉ -, or -CR ₂₀ R
₂₁ −; Y ₁ is O, S, Se, or —NR ₁₈ —; Z ₁ is a saturated or unsaturated group which may have a substituent or may form a condensed ring with another ring. Represents an atomic group necessary for forming a 5-membered or 6-membered ring; and Z ₂ is an atomic group necessary for forming an optionally substituted naphthalene ring, anthracene ring or phenanthrene ring;
R ₁ , R ₃ , R ₁₄ , R ₁₅ and R ₁₉ may be the same or different and each represents an unsubstituted or substituted alkyl group; R ₂ and R ₁₈ are the same or different. Each represents an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group or an unsubstituted or substituted heterocycle; L ₁ , L ₂ and L ₃ may be the same or different. And each represents a methine group or a substituted methine group, and in the case of a substituted methine group, L ₁ and R ₁ and / or L ₃ and R ₃ are combined to form a saturated or unsaturated 5 member or _May form a 6-membered ring; R ₄ and R ₅ may be the same or different and each represents a hydrogen atom, an unsubstituted or substituted alkyl group or an unsubstituted or substituted aryl group. _{; R 6, R 7, R} 8 Fine R ₉ may be the same or different and each a hydrogen atom, an unsubstituted or substituted alkyl or unsubstituted or substituted aryl group, or two groups of R ₆ to R ₉ May combine with each other to form a saturated or unsaturated 5- or 6-membered ring; R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ may be the same or different; Substituted or substituted alkyl group, unsubstituted or substituted aryl group, unsubstituted or substituted alkoxy group, unsubstituted or substituted aryloxy group, unsubstituted or substituted acyl group, unsubstituted or substituted Alkoxycarbonyl group, trifluoromethyl group, unsubstituted or substituted benzoyl group, unsubstituted or substituted ureido group, unsubstituted or substituted Amino group,
An unsubstituted or substituted amide group, an unsubstituted or substituted sulfamide group, an unsubstituted or substituted carbamyl group, an unsubstituted or substituted sulfamoyl group, a halogen atom, a nitro group, a cyano group, a hydroxyl group or a carboxyl group Or two adjacent R _{10 to} R ₁₃
One group may combine to form a saturated or unsaturated 5- or 6-membered ring, which may have a substituent or may form a condensed ring with another ring; R ₁₆ , R ₁₇ , R ₂₀ and R ₂₁
Or different and the same each represent a substituted or unsubstituted alkyl group; Q ^- represents an anion pharmaceutically acceptable; n is 0 or 1; l is 1 or 2 Represents. ) 2. The composition according to claim 1, wherein at least one compound of the general formulas (1) to (6) is a compound selected from the group consisting of compounds represented by the general formula (1). .. 3. The composition according to claim 1, wherein at least one compound of the general formulas (1) to (6) is a compound selected from the group consisting of compounds represented by the general formula (2). .. 4. The composition according to claim 1, wherein at least one compound of the general formulas (1) to (6) is a compound selected from the group consisting of compounds represented by the general formula (3). .. 5. The composition according to claim 1, wherein at least one compound of the general formulas (1) to (6) is a compound selected from the group consisting of compounds represented by the general formula (4). .. 6. The composition according to claim 1, wherein at least one compound of the general formulas (1) to (6) is a compound selected from the group consisting of compounds represented by the general formula (5). .. 7. The composition according to claim 1, wherein at least one compound of the general formulas (1) to (6) is a compound selected from the group consisting of compounds represented by the general formula (6). .. 8. A composition according to claim 1, which comprises an aqueous solution of glucose or saline as a pharmaceutically acceptable carrier or diluent. 9. At least one compound of the general formulas (1) to (6) is present in the composition in an amount of 0.01 to 10% by weight, based on the total weight of the composition. The composition of claim 1. 10. The R₁, R₂And R₃Alkyl group of
Is a linear, branched or cyclic alkyl group;
₂The aryl group of is a monocyclic, bicyclic or tricyclic aryl
A group; R₂The heterocyclic group of is as a hetero atom
Or contains two or more nitrogen atoms, oxygen atoms and sulfur atoms
A 5- to 6-membered heterocyclic group₁By
A 5-membered or 6-membered ring formed by
Or contains two or more nitrogen, oxygen and sulfur atoms
A saturated or unsaturated ring which may be Z₁Is replaced
Other, which may be saturated or unsaturated
May form a condensed ring with the ring of L;₁, L₂And L
₃The substituted methine group of is an alkyl-substituted methine group, aryl group
Substituted methine group, halogen-substituted methine group or alkoxy group
A methine group;_FourAnd R_FiveThe alkyl group of
A chain, branched or cyclic alkyl group;₆,
R₇, R₈And R₉The alkyl group of is linear, branched or
Is a cyclic alkyl group;_Four, R_Five, R₆,
R₇, R₈And R₉The aryl group of is monocyclic, bicyclic or
Is a tricyclic aryl group;₆~ R₉Two out of
The ring formed by combining the groups of is unsubstituted or substituted
A 5- or 6-membered carbocycle;_Ten, R₁₁, R₁₂Over
And R₁₃The alkyl group of is a linear, branched or cyclic alkyl group.
A R group;_Ten, R₁₁, R₁₂And R₁₃Aryl
The group is a monocyclic, bicyclic or tricyclic aryl group;
Note R_Ten, R₁₁, R₁₂And R ₁₃The alkoxy group of
Or an alkoxy group containing a branched alkyl moiety.
R; R above_Ten, R₁₁, R₁₂And R₁₃Aryloxy group of
Is an aryl containing a monocyclic or bicyclic aryl moiety
An oxy group; R_Ten, R₁₁, R₁₂And R ₁₃Reed
Is an alkylacyl group or an arylacyl group
R; R above_Ten, R ₁₁, R₁₂And R₁₃Alkoxy carbo
An alkenyl group that contains a straight or branched alkyl moiety.
Rucoxycarbonyl group; R_Ten, R₁₁, R₁₂Over
And R₁₃The ureido group of is an alkylureido group or aryl.
A Rureido group; R_Ten, R ₁₁, R₁₂And R₁₃of
Amino group is mono or dialkylamino group or mono
Or a diarylamino group;_Ten, R₁₁,
R₁₂And R₁₃The amide group of is a mono- or dialkylamido
And a mono- or diarylamido group;
Note R_Ten, R₁₁, R₁₂And R₁₃The sulfamide group of
A sulphamide group or an arylsulfamide group
R; R above_Ten, R₁₁, R₁₂And R₁₃The carbamyl group of
A rukylcarbamyl group or an arylcarbamyl group
And R _Ten, R₁₁, R₁₂And R₁₃The sulfa
Moyl group is alkylsulfamoyl group or aryls
A rufamoyl group; and a pharmaceutically acceptable group of Q
Possible anions are halogen ion, sulfonate ion,
Sulfamate ion, sulfate ion, hydrogen sulfate ion,
Borate ion, alkyl phosphate ion, dialkyl phosphorus
From acid ions, pyrophosphate ions and carboxylate ions
The composition of claim 1 selected from the group consisting of: 11. The cancer is melanoma, liver cancer, glioma, neuroblastoma, sarcoma or lung, colon, pancreas, breast, bladder,
The composition according to claim 1, which is a carcinoma of the ovary, testis, prostate, cervix, stomach or small intestine. 12. The composition of claim 11, wherein the cancer is carcinoma. 13. The composition of claim 12, wherein the cancer is melanoma. 14. The composition of claim 11, wherein the cancer is colon cancer. 15. The composition of claim 1, wherein the cancer or tumor is a mammalian cancer or tumor. 16. The mammal of claim 1, wherein the mammal is a human.
The composition according to 5.