JPH11292876A - Polyaryl antitumor agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful for treating a tumor such as adult leukemia, lung cancer or colon cancer. SOLUTION: This antitumor agent is a compound expressed by the formula: Ar1-B-Ar2 (Ar1 is phenyl or the like; B is R-substituted phenylene; R is H, an alkyl or the like; Ar2 is a thienyl substituted by an alkyl, or the like, or the like), e.g. 1,4-bis[2-(5-formyl)thienyl] benzene. The compound of the formula is obtained by, e.g. coupling a dihalo-substituted phenylene (e.g. 1,4- dibromobenzene) with a substituted thiophene or the like of 2 equivalents [e.g. 2-(diethoxymethyl)-5-(tributylstanyl)thiophene].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a polyaryl antitumor agent, particularly, for example, leukemia, lung cancer, colon cancer, C
The present invention relates to a polyaryl compound effective for treating tumors such as NS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer, and a pharmaceutical composition containing the same as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION In the United States, cancer is second only to heart disease.
It is the second cause of death for humans. According to estimates by the American Cancer Society, approximately 400
Ten million people die from cancer. Cancer treatment usually includes chemotherapy, surgery, radiation, hormones,
And immunotherapy is being performed. Chemotherapy is an effective method of treatment, especially for cancers where surgery is not possible or metastases have advanced.

[0003] Many aryl group-containing compounds have been reported to have cytotoxic activity, for example, 2-aryl-1,8-naphthyridin-4 (1H) -ones (Chen).
etal., J. of Med. Chem. 1997, 40 (19), 3049-56.
), 3-aryl-substituted oxatriazole-5-imine derivatives (Vilpo et al., Anti-Cancer Drug Design, 1
997, 12 (2), 75-89), and 1,2-dihydropyrido [3,4-b] pyrazines (Temple et al., J. of Me
d. Chem. 1987, 30 (10), 1746-51).

[0004]

SUMMARY OF THE INVENTION The present inventors have studied the cytotoxic activity of an aryl group-containing compound, and have found a novel aryl group-containing compound that exhibits cytotoxic activity against tumors.

It is an object of the present invention to provide leukemia, lung cancer, colon cancer,
It is an object of the present invention to provide a polyaryl compound effective for treating tumors such as CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer, and a pharmaceutical composition containing the same as an active ingredient.

The above and other objects and novel features of the present invention will become apparent from the description of the present specification.

[0007]

SUMMARY OF THE INVENTION Among the inventions disclosed in the present application, the outline of a representative one will be briefly described.
It is as follows.

An embodiment of the present invention is directed to a compound of the formula: Ar1-BA
r2 (In the formula, Ar1 is phenyl, thienyl, furanyl, or pyrrolyl, B is R-substituted phenylene, -CH = CH-, or -C≡C-, wherein R is H, alkyl, Hydroxyl or its ester, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or its ester, -C
H (OR1) 2 or NR2 R3, where R1
Is each independently H, alkyl, or acyl; and R2 and R3 are each independently H, alkyl, hydroxyalkyl, or aminoalkyl; and Ar2 is substituted phenyl, substituted thienyl,
Substituted furanyl, or substituted pyrrolyl, and the substituents of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl are each independently an amide,
Nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide,
Aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl,
Or hydroxyalkylaminoalkylaminoalkyl. ) Or a salt thereof (ie, a compound having at least two aryl groups).

The salt of the polyaryl compound is formed between the polyaryl compound of the above formula and a counter ion of an ionizable group. For example, a sodium salt of a polyaryl compound is formed between a sodium ion and a carboxyl group of the compound. The basic acid salt of a polyaryl compound is formed between a pharmaceutically usable acid and an amino derivative of the compound.

[0010] One preferred embodiment of the compounds covered by the above formula is where B is R-substituted phenylene. Preferably, each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. As used herein, the term "substituted" is defined as having one or more substituents on the referred structure.

Another preferred embodiment of the compounds covered by the above formula is where B is -CH = CH-. Preferably, each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl.

Still another preferred embodiment of the compounds covered by the above formula is where B is -C≡C-. Preferably, each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl.

A further aspect of the invention is a polyaryl compound covered by the same formula as above,
r1 is substituted phenyl, substituted thienyl, substituted furanyl,
Or substituted pyrrolyl, and each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano, acetal, ketal Oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, and B is , R-substituted phenylene, -CH
ＣＨCH—, or —C≡C—, where R is H,
Alkyl, hydroxyl or ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or ester thereof, -CH (OR1
) 2, or NR 2 R 3, wherein R 1 is H,
Alkyl or acyl, and R2 and R3
Is each independently H, alkyl, hydroxyalkyl, or aminoalkyl; and Ar2 is

[0014]

Embedded image

Or phenyl having 1 to 3 substituents, wherein A is nitrogen, oxygen or sulfur;
X is H, carboxyl or its ester, amide,
Nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl,
Haloalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, wherein Y is H, aldehyde, acyl, carboxyl or its ester, amide, Nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkyl Aminoalkylaminoalkyl, wherein Z is H, acyl, carboxyl or an ester, amide, Lil, nitro, cyano, acetal, ketal, oxo, aminoalkyl, hydroxyalkyl, haloalkyl, alkyl imino alkyl, carboxyalkyl, acid halides, aminoalkyl aminoalkyl, hydroxyalkyl aminoalkyl,
Or hydroxyalkylaminoalkylaminoalkyl, and each substituent of the substituted phenyl is independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano,
Acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl , A polyaryl compound or a salt thereof.

One preferred embodiment of the above compound is where B is R-substituted phenylene. Preferably, Ar
Each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl represented by 1 is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl . More preferably, Ar2 is

[0017]

Embedded image

Or phenyl having 1 to 3 substituents, wherein X and Z are each independently H, hydroxyalkyl, and Y is H, aldehyde or hydroxyalkyl; Is independently an aldehyde or hydroxyalkyl.

Another preferred embodiment of the above compound is
B is -CH = CH-. Preferably, A
each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl represented by r 1 is
Each is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. More preferably, Ar2 is

[0020]

Embedded image

Or phenyl having 1 to 3 substituents, wherein X and Z are each independently H, hydroxyalkyl, and Y is H, aldehyde or hydroxyalkyl; Is each independently a hydroxyl, aldehyde, or hydroxyalkyl.

Still another preferred embodiment of the above compound is that wherein B is -C≡C-. Preferably, A
each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl represented by r 1 is
Each is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. More preferably, Ar2 is

[0023]

Embedded image

Or phenyl having 1 to 3 substituents, wherein X and Z are each independently H, hydroxyalkyl; Y is H, aldehyde or hydroxyalkyl; Is independently hydroxyl, alkoxyl, aldehyde, or hydroxyalkyl.

Yet another embodiment of the present invention is an asymmetric compound as described above, wherein Ar 1 and Ar 2 are
Each independently a phenyl having 1 to 3 substituents,
Pyrrolyl having 1 to 2 substituents, furanyl having 1 to 2 substituents, or thienyl having 1 to 2 substituents, wherein the substituted phenyl, substituted pyrrolyl, substituted furanyl, and substituted thienyl Each substituent is
Each independently is an acetal, ketal, oxoalkyl, hydroxyalkyl, aminoalkyl, alkyliminoalkyl, acyl, carboxyl or ester thereof, amide, acid halide, nitrile, or hydroxyalkylaminoalkylaminoalkyl; and B is R Substituted phenylene, -CH = CH-, or -C
≡C-, where R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2 R3
Wherein R 1 is H, alkyl, or acyl, and R 2 and R 3 are each independently H,
It relates to an asymmetric compound or a salt thereof, which is alkyl, hydroxyalkyl or aminoalkyl.

One preferred embodiment of the above compound is Ar
A compound in which each substituent of 1 and Ar2 is independently an aldehyde, an alkoxy, a hydroxyalkyl, an acyl, a carboxyl or an ester thereof, or a salt thereof.

Another preferred embodiment of the above compound is
A compound or a salt thereof, in which each substituent of Ar1 and Ar2 is independently aldehyde or hydroxyalkyl.

Yet another embodiment of the present invention is a pharmaceutically acceptable carrier and an effective amount of a polyaryl compound of the above formula wherein Ar 1 and Ar 2 are each independently pyrrolyl, 1-2 Pyrrolyl having a substituent, furanyl, furanyl having 1 to 2 substituents, thienyl, thienyl having 1 to 2 substituents, phenyl, or phenyl having 1 to 3 substituents, Each substituent of the substituted pyrrolyl, substituted furanyl, substituted thienyl, and substituted phenyl is independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, Hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide Iid, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkylamino, or hydroxyalkylaminoalkylaminoalkyl, B is R-substituted phenylene, -CH = CH-, or -C−C-,
Wherein R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2R3, wherein R1 is H, alkyl Or acyl, and R2 and R3 are each independently H, alkyl,
The present invention relates to a pharmaceutical composition containing at least one polyaryl compound that is hydroxyalkyl or aminoalkyl.

Preferred compounds that can be used in the above pharmaceutical composition include those in which each substituent of Ar 1 and Ar 2 is independently aldehyde or hydroxyalkyl.

As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain having 1 to 8 carbon atoms, or a cyclic hydrocarbon group having 3 to 8 carbon atoms. . Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl, hexyl, isohexyl, heptyl, octyl, cyclopropyl, cyclopentyl, cyclohexyl, Cycloheptyl, adamantyl, norbornyl, isobornyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl, and 1-, 2-, or 3-cyclohexylpropyl. As used herein, “halo” or “halide” refers to fluoro, chloro, bromo, and iodo. Any of the amide, ester, and cyano groups may be bound to the polyaryl compound. For example, an amide group may be at the nitrogen terminus (-NH-CO-R ') or at the carbon terminus (-CO-
NH-R '), wherein R' is an alkyl group, and can be attached to the remainder of the compound. Here, the substitution pattern of B as phenylene is para,
Meta or ortho. As used herein, the term "substitution" is defined as mono-substitution. As used herein, an "asymmetric" polyaryl compound means that the substituent of Ar1 in the compound cannot be the same as the substituent of Ar2.

[0031] Other features and advantages of the present invention will become apparent from the following description of the preferred embodiments.

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION The above-mentioned polyaryl antitumor compound can be produced by a method according to a known technique.
For example, a dihalo-substituted polyarylethylene compound is reacted with an excess of a suitable nucleophile having a formyl group such as, for example, dimethylformamide, by a nucleophilic substitution reaction. To produce a product. As another example, a diformyl polyarylacetylene derivative can be obtained by first replacing a properly activated acetylene nucleus, such as copper trimethylsilyl acetylide, with a formyl group such as palladium catalyzed formylthiophene by reductive elimination. It can be synthesized by reacting with furan chloride, pyrrole or thiophene. This substituted monoarylacetylene reacts with other catalyzed substituted thiophenes to give the desired diformyl-substituted products. Sonogashiraet al., Tet
See rahedron Lett. 1975, 4467. As yet another example,
Diformyl polyarylphenylene derivatives are synthesized by coupling a dihalo-substituted phenylene with two equivalents of an appropriately substituted furan, thiophene, or pyrrole, such as formyltributylstannylthiophene, to produce the desired product. Can be manufactured. These diformyl-substituted compounds can be further reduced with sodium borohydride to produce the corresponding hydroxyalkyl derivatives. On the other hand, these diformyl-substituted polyaryl derivatives can be reductively aminated with an appropriately substituted amine and sodium borohydride to produce the corresponding hydroxyalkylaminoalkyl or hydroxyalkylaminoalkylaminoalkyl-substituted polyaryl derivative. .

Tumors (eg, leukemia, lung cancer, colon cancer, C
In addition to the above various polyaryl compounds used for the treatment of NS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer), a method of treating a tumor by administering the composition to a patient is also described. , Is considered as an aspect of the present invention. Also included within the scope of the present invention are the uses of the polyaryl compounds used in the manufacture of medicaments for treating tumors.

As used herein, an effective amount of a formulation refers to the administration to a patient in need thereof, to inhibit tumor cell growth, kill malignant cells, or shrink tumors, or otherwise to a treated patient. It is defined as the amount of the polyaryl compound that confers a therapeutic effect. The effective amount to be administered to a patient will generally be determined based on body surface area, weight, and condition. The interrelationship between animal and human (milligrams per square meter of body surface area) doses is described in Freireich et al., Cancer
Chemother. Rep. 1966, 50, 219. Body surface area is roughly determined from the height and weight of the patient.
Scientific Tables, Geigy Pharmaceuticls, Ardley, N
See ew York, 1970, 537. Effective amounts of the polyaryl compound used to practice the present invention can range from about 5 mg / kg to about 50 mg / kg. The effective dose is
As will be appreciated by those skilled in the art, it will vary based on the method of administration, the amount of excipients, and the possibility of using other treatment methods, including the use of other anti-tumor agents and radiation therapy.

The pharmaceutical composition can be used subcutaneously, intraperitoneally, intramuscularly,
And parenteral routes, including intravenous. Examples of parenteral dosage forms include 5% glucose or other known pharmaceutically acceptable excipients and an aqueous solution of the active agent in an isotonic salt solution. Solubilizing agents such as cyclodextrin, or other solubilizing agents well known to those skilled in the art, can also be used as pharmaceutical excipients for administering the therapeutic compound.

The above-mentioned polyaryl compound can also be incorporated into the preparation by other administration methods utilizing known methods. Pharmaceutical compositions can be formulated in formulations for oral administration such as, for example, capsules, gel mountants or tablets. Capsules are made of known pharmaceutically usable materials such as gelatin or cellulose derivatives. Tablets
A mixture of the active polyaryl compound and the solid carrier, and a lubricant is formulated by compression in known manner. Examples of solid carriers include starch and sugar bentonite. The polyaryl compounds can be administered, for example, in the form of hard shell tablets or capsules containing lactose or mannitol as a binder and known fillers and tableting reagents.

The antitumor activity of the polyaryl compound is as follows:
It can be preliminarily evaluated by in vitro assay, and then in vivo testing.
). For example, polyaryl compounds can be tested for in vitro cytotoxicity in 3- (4,5
-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) Boyd, in Princ
iple of Practice of Oncology, Devita, Hellman, Ro
It can be evaluated by microculture analysis using senberg (eds.) Vol. 3, PPO Update, No. 10, 1989. The MTT assay is based on the production of dark blue formazan product by dehydrogenase in mitochondria of live tumor cells after 6 days of drug exposure.
et al., Cancer Res. 1988, 48, 589. In this way, only live cells are stained and can be measured at 570 nm. Anti-tumor cytotoxicity has been reported as an IC50, which indicates that cell growth is a factor of 5 in symmetric cultures of tumor cells.
It means that the drug dose has an effect of delaying to 0%.

Without further elaboration, those skilled in the art will, based on the description herein, be able to utilize the present invention to a sufficient extent. Accordingly, the following specific examples are intended to be merely illustrative, and not limiting, of the remainder of the specification in any manner.

[0039]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in more detail with reference to embodiments.

Example 1 Synthesis of 1,2-bis [2- (5-formyl) -thienyl] acetylene In a 100 ml flask, 20 ml of benzene and 1.1 were added.
2 g (5 mmol) of 2-formyl-5-iodothiophene were charged. While stirring this mixture, 0.98 g (1
0 mmol) of (trimethylsilyl) acetylene, 600 mg
Of tetrakis (triphenylphosphine) palladium,
160 mg of cuprous iodide, 120 mg of triethylbenzylammonium chloride (TEBAC) and 20 ml of 2.5N deoxygenated KOH were added. Mix the mixture at 40 ° C for 48
Stirred for hours. After lowering the temperature to room temperature (rt), a saturated ammonium chloride solution was added and the mixture was stirred for 0.5 hour and the precipitate formed was removed by filtration. The filtrate was extracted with ether. The organic extract is washed with saturated sodium bicarbonate and brine, then anhydrous MgSO
4 and dried. After filtration and concentration, the residue was chromatographed on a silica gel column (eluted with EtOAc / n-hexane) to obtain 0.34 g (yield: 58%) of a product (mp: 154 ° C).

[0041]

[Table 1]

Example 2 Synthesis of 1,2-bis [2- (5-hydroxymethyl) -thienyl] acetylene- 1,2-bis [2- (5-formyl) -thienyl] acetylene (3 mmol) Was dissolved in 30 ml of ethanol, and 1 mm
ol of sodium borohydride. After stirring at room temperature for 4 hours, water was added to stop the reaction. The mixture was extracted with ether. The organic extract is washed with saturated sodium bicarbonate and brine, then dried over anhydrous Mg
Dried with SO4. Filtration and concentration gave 1,2-bis [2- (5-hydroxymethyl) -thienyl] acetylene in almost quantitative yield.

1,2-bis [2- (5-hydroxymethyl) -thienyl] acetylene (mp: 146-147)
° C):

[0044]

[Table 2]

Example 3 Synthesis of (E) -1,2-bis [2- (5-formyl) -thienyl] ethene In a 25 ml flask, 5 ml of DMF and 0.16 ml
(1.74 mmol) of phosphorus oxychloride. The mixture was stirred in an ice bath for 0.5 hours. The mixture is then added to 303
The mixture was treated with mg (1.58 mmol) of (E) -1,2-bis (2-thienyl) ethylene and stirred at 50 ° C. for 48 hours.
After lowering the temperature to room temperature, 10 ml of 10% sodium bicarbonate were added and the mixture was extracted with CH2 Cl2. The organic extract was washed with brine and then dried over anhydrous MgSO4. After filtration and concentration, the residue was chromatographed on a silica gel column (eluted with EtOAc / n-hexane) to obtain 0.04 g of a bis-formyl derivative. The bis-formyl derivative was recrystallized from EtOAc to give
03 g (yield: 6%) of pure product were obtained.

(E) -1,2-bis [2- (5-formyl) -thienyl] ethene (mp: 209 ° C.):

[0047]

[Table 3]

Example 4 Synthesis of (E) -1,2-bis [2- (5-hydroxymethyl) -thienyl] ethene- (E) -1,2-bis [2- (5-formyl) ) -Thienyl] ethene (3 mmol) in 30 ml of ethanol,
Treated with 1 mmol of sodium borohydride.

After stirring at room temperature for 4 hours, water was added to stop the reaction. The mixture was extracted with ether.
The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After filtration and concentration, the corresponding hydroxymethyl derivative was obtained in almost quantitative yield.

(E) -1,2-bis [2- (5-hydroxymethyl) -thienyl] ethene (mp: 133-13)
4 ° C):

[0051]

[Table 4]

Example 5-(E) -1- (2-thienyl) -2- {2- [5-
Synthesis of (aminomethyl)]-thienyl ethene-(i) In a 25 ml flask, 2.22 g (10 mmol) of (E) -1- (2-thienyl) -2- [2- (5-hydroxymethyl) Thienyl] ethene, 1.62 g (11 mm
ol) of phthalimide, 2.89 g (11 mmol) of trifenylphosphine, and 20 ml of tetrahydrofuran. To this mixture, slowly add 1.92 g (1
(1 mmol) of diethyl azodicarboxylate.
Stir for 4 hours. Water was added to stop the reaction.
The mixture was extracted with ether. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After filtration and concentration, the residue was chromatographed on a silica gel column (eluted with EtOAc / n-hexane) to obtain 2.22 g (yield: 64%) of a pure product (mp: 160 ° C).

[0053]

[Table 5]

(Ii) (E) -1- (2-thienyl) -2
-{2- [5- (N-phthalimidomethyl)]-thienyl} ethene (0.35 g, 1 mmol) is dissolved in 5 ml of ethanol, and heated with 0.055 g (1.1 mmol) of 80% hydrazine. At 60 ° C. This mixture is
The mixture was heated at reflux for 4 hours, and then concentrated under reduced pressure. The residue was treated with 7 ml of 0.5N HCl and the precipitate formed was removed by filtration. 1N until pH> 12 in the filtrate
NaOH was added, followed by extraction with chloroform. The organic extract is washed with brine, then anhydrous MgSO
Dried at 4. After filtration and concentration, 0.18 g (yield:
83%) of the product (mp: 89-90 ° C.).

[0055]

[Table 6]

Example 6-(E) -1- (2-thienyl) -2- [2- {5-
Synthesis of [N- (2-hydroxyethyl) aminomethyl] {thienyl] ethene-In a 100 ml flask, 30 ml of methanol, 10 mmol
Of ethanolamine and a few drops of acetic acid.
(E) -1- (2-Thienyl) -2- [2- (5-formyl) thienyl] ethene (1.10 g, 5 mmol) was added slowly at room temperature. The reaction was monitored by TLC until the formyl group containing compound was consumed. Excess sodium borohydride was added and the reaction was again monitored by TLC until the imine intermediate disappeared. The mixture was concentrated under reduced pressure and the residue was treated with 50 ml of EtOAc and 50 ml of 0.1
Treated with N HCl. The precipitate obtained is filtered and the filtrate is filtered.
Washed with EtOAc. After combining with the precipitate, the filtrate was washed with 2N
Treat with NaOH until pH> 12, then Et
Extracted with OAc. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After the reaction solution was filtered and concentrated, 1.30 g of (E) -1- (2-thienyl) -2- [2- {5- [N
-(2-Hydroxyethyl) aminomethyl] {thienyl] ethene was obtained. Recrystallization from n-hexane gave 1.22 g of the desired product. (E) -1-
(2-thienyl) -2- [2- {5- [N- (2-hydroxyethyl) aminomethyl]} thienyl] ethene (m
p: 91 ° C):

[0057]

[Table 7]

Example 7-(E) -1- (2-thienyl) -2- [2- {5-
Synthesis of [N- (2-aminoethyl) aminomethyl] {thienyl] ethene-In a 100 ml flask, 30 ml of methanol, 10 mmol
Of ethylenediamine and a few drops of acetic acid.
(E) -1- (2-Thienyl) -2- [2- (5-formyl) thienyl] ethene (1.10 g, 5 mmol) at 0 ° C.
And added slowly. The reaction was monitored by TLC until the formyl group containing compound was consumed. Excess sodium borohydride was added and the reaction was again monitored by TLC until the imine intermediate disappeared. The mixture was concentrated under reduced pressure and the residue was treated with 50 ml of EtOAc and 50 ml of 0.1
Treated with N HCl. The precipitate obtained is filtered and the filtrate is filtered.
Washed with EtOAc. After combining with the precipitate, the filtrate was washed with 2N
Treat with NaOH until pH> 12, then Et
Extracted with OAc. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After the reaction solution was filtered and concentrated, 0.74 g of (E) -1- (2-thienyl) -2- [2- {5- [N
-(2-Aminoethyl) aminomethyl] {thienyl] ethene was obtained. By recrystallizing with n-hexane,
0.72 g of desired product is obtained. (E) -1- (2-
Thienyl) -2- [2- {5- [N- (2-aminoethyl) aminomethyl]} thienyl] ethene (mp: 104
To 105 ° C):

[0059]

[Table 8]

Example 8-(E) -1- (2-thienyl) -2- (2- [5-
{N- [N- (2-hydroxyethyl) aminoethyl]
Synthesis of aminomethyl {] thienyl) ethene—30 ml of methanol, 10 mmol in a 100 ml flask
Of 2- (2-aminoethylamino) ethanol and a few drops of acetic acid. (E) -1- (2-thienyl)-
2- [2- (5-formyl) thienyl] ethene (1.1
(0 g, 5 mmol) was added slowly at room temperature. The reaction,
The TLC was monitored until the formyl group-containing compound was consumed. Excess sodium borohydride was added and the reaction was again monitored by TLC until the imine intermediate disappeared. The mixture was concentrated under reduced pressure and the residue was treated with 50 ml of EtOAc
And 50 ml of 0.1 N HCl. The resulting precipitate was filtered and the filtrate was washed with EtOAc. After combining with the precipitate, the filtrate was treated with 2N NaOH until pH> 12 and then extracted with EtOAc. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After filtration and concentration of the reaction solution, 1.36 g of (E) -1- (2-thienyl)
-2- (2- [5- {N- [N- (2-hydroxyethyl) aminoethyl] aminomethyl}] thienyl) ethene was obtained. By recrystallization from n-hexane, 1.2
9 g of desired product were obtained. (E) -1- (2-thienyl) -2- (2- [5- {N- [N- (2-hydroxyethyl) aminoethyl] aminomethyl}] thienyl) ethene (mp: 51-52 ° C) :

[0061]

[Table 9]

Example 9 -1- (2- (5-formylfuryl))-4- (2-
Synthesis of (5-formylthienyl)) benzene-(i) 1,4-dibromobenzene (1
(3.5 g, 57 mmol) along with the catalyst Pd (PPh3) 4 and 30 ml of benzene and 6 ml of a 2M aqueous Na2 CO3 solution were added. A methanol solution of dihydroxy- (2- (5-formylfuryl)) borane (2 g, 14 mmol) was added to the mixture, and the mixture was refluxed for 12 hours. TLC showed two fluorescent spots. The less polar spot is
Identified as the desired dimer product. The mixture was extracted with ether. Extract the combined ether extracts with anhydrous Mg
Dried over SO4 and concentrated. By chromatography, 30% of 1-bromo-4- (2-formylfuryl)
Benzene was obtained.

[0063]

[Table 10]

(Ii) In a two-necked flask, add 1-bromo-4-
(2- (5-formylfuryl)) benzene (0.25
g, 1 mmol), 2- (diethoxymethyl) -5- (tributylstannyl) thiophene (0.95 g, 2 mmol),
And 5 mol% of the catalyst Pd (PPh3) 2Cl2. 50m
After addition of 1 THF, the mixture was heated to reflux for 12 hours. The reaction was quenched by adding aqueous ammonium hydroxide solution and extracted with ether. The combined ether extracts were dried over anhydrous MgSO4 and concentrated to give the desired product in 50% yield.

[0065]

[Table 11]

Example 10 Synthesis of 1,4-bis [2- (5-formyl) thienyl] benzene In a two-necked flask, 0.236 of 1,4-dibromobenzene was added.
g (1 mmol), 0.95 g (2 mmol) of 2- (diethoxymethyl) -5- (tributylstannyl) thiophene, and 5 mol% of catalyst Pd (PPh3) 2Cl2. 50 ml
Of THF was added and the mixture was heated at reflux for 12 hours.
The reaction was quenched by adding aqueous ammonium hydroxide solution and extracted with ether. The combined ether extracts were dried over anhydrous MgSO4 and concentrated to give 0.24 g
(Yield: 80%) with desired product (mp> 268)
° C, decomposition).

[0067]

[Table 12]

Example 11 Synthesis of 1,4-bis [2- (5-hydroxymethyl) thienyl] benzene- 1,4-bis [2- (5-formyl) thienyl] benzene (100 ml) in ethanol (50 ml) An excess of NaBH4 was added to the solution at room temperature under a nitrogen atmosphere. The reaction is 4
Stirred for hours, stopped by adding aqueous ammonium hydroxide solution and then extracted with ether.
The combined ether extracts were dried over anhydrous MgSO4 and concentrated to give the desired product (mp> 300 DEG C.) in 90% (yield: 91 mg).

[0069]

[Table 13]

Example 12 Screening of Compounds for Antitumor Activity The cytotoxic activity of the polyaryl compounds was measured using cytotoxicity against a panel of 61 different NCI human tumor cell lines.

The following are 61 types of tumor cell lines used for the antitumor activity test of the above polyaryl compounds.

Leukemia CCRF-CEM, HL-60 (TB), K-562,
MOLT-4, RPMI-8226, and SR.

Lung cancer A549 / ATCC, EKVX, HOP-62, HOP
-92, NCI-H226, NCI-H23, NCI-
H322M, NCI-H460, and NCI-H52
2.

Colon cancer COLO 205, HCC-2998, HCT-11
6, HCT-15, HT-29, KM-12, and S
W-620.

CNS cancer SF-268, SF-295, SF-539, SNB-
19, SNB-75, and U-251.

Melanoma LOX-IMVI, MALME-3M, M-14, SK
-MEL-2, SK-MEL-28, SK-MEL-
5, UACC-257, and UACC-62.

Ovarian cancer IGR-OVI, OVCAR-3, OVCAR-4, O
VCAR-5, OVCAR-8, and SK-OV-
3.

Kidney cancer 786-0, A-498, SCHN, CAKI-1, R
XF-393, RXF-631, SN12C, TK-1
0, and U0-31.

Prostate cancer PC-3 and DU-145.

Breast cancer MCF 7, MCF7 / ADR-RES, MDA-MB
231 / ATCC, HS578T, MDA-MB-4
35, MDA-N, BT-549, and T-47D.

This NCI antitumor activity screening assay gives data on the general cytotoxicity of individual compounds. In particular, this type of analysis is useful for identifying compounds that exhibit effective cytotoxic activity against slow growing tumor cells as compared to fast growing tumor cells, such as leukemia tumor cell lines. Identification of such compounds is important. This is because previously identified antitumor agents show low cytotoxic activity against slow growing tumors.

The antitumor cytotoxicity of the polyaryl compounds tested in the in vitro assay was determined by microscopic analysis using either 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT). Measured by culture analysis. The analysis is advantageous when compared to an in vivo analysis that takes months, as the results are obtained within a week. This analysis was performed in a 96-well microtiter plate. MTT analysis is based on the production of dark blue formazan product by dehydrogenase in mitochondria of live tumor cells after 6 days of drug exposure. MC Alley, DA Scudiero, A. Monks,
ML Hursey, MJ Czerwinski, DL Fine, BJ Abbo
ut, JG Mayo, RH Shoemaker and MR Boyd, Cance
r Res., 48, 589, 1988. In this way, only live cells are stained and can be measured at 570 nm. Antitumor cytotoxicity has been reported as IC50, which
It is meant to be a drug dose effective to slow cell growth to 50% of the symmetric culture of tumor cells.

As described above, the invention made by the present inventor has been specifically described based on the embodiment. However, the present invention is not limited to the embodiment, and can be variously modified without departing from the gist thereof. Needless to say.

[0084]

Advantageous effects obtained by typical ones of the inventions disclosed in the present application will be briefly described.
It is as follows.

That is, leukemia, lung cancer, colon cancer, CNS
Tumors such as cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer can be effectively treated.

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

[Procedure amendment]

[Submission date] July 29, 1999

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction contents]

[Title of the Invention] Polyaryl antitumor agent

[Claims]

Embedded image Where A is oxygen or sulfur and X is oxo
Alkyl or hydroxyalkyl, Y and Z
Is a compound or a compound characterized by being H
Salt.

Embedded image Where X is hydroxyalkyl, Y and Z
Is a compound or a salt thereof , each being H.

Embedded image Where A is oxygen or sulfur and X is oxoa
Alkyl, aminoalkyl, hydroxyalkyl, amino
Alkylaminoalkyl, hydroxyalkylaminoa
Alkyl or hydroxyalkylaminoalkylamido
And Y and Z are H.
Or a salt thereof for an antitumor agent.

Embedded image In, where X is a hydroxycarboxylic alkyl, Y and Z
Is a compound or a salt thereof for an antitumor agent , each being H.

Embedded image Or phenyl having one substituent, wherein A
Is sulfur and X is oxoalkyl or hydroxya.
And Y and Z are each H,
Each substituent of the substituted phenyl is independently
Aldehyde or oxoalkyl
Or a salt thereof for an antitumor agent.

Embedded image Or phenyl having one substituent, wherein X is
Is hydroxyalkyl, Y and Z are H,
The substituent of the substituted phenyl is an aldehyde.
A compound for use as an antitumor agent or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a polyaryl antitumor agent, particularly, for example, leukemia, lung cancer, colon cancer, C
The present invention relates to a polyaryl compound effective for treating tumors such as NS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer, and a pharmaceutical composition containing the same as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION In the United States, cancer is second only to heart disease.
It is the second cause of death for humans. According to estimates by the American Cancer Society, approximately 400
Ten million people die from cancer. Cancer treatment usually includes chemotherapy, surgery, radiation, hormones,
And immunotherapy is being performed. Chemotherapy is an effective method of treatment, especially for cancers where surgery is not possible or metastases have advanced.

[0003] Many aryl group-containing compounds have been reported to have cytotoxic activity, for example, 2-aryl-1,8-naphthyridin-4 (1H) -ones (Chen).
etal., J. of Med. Chem. 1997, 40 (19), 3049-56.
), 3-aryl-substituted oxatriazole-5-imine derivatives (Vilpo et al., Anti-Cancer Drug Design, 1
997, 12 (2), 75-89), and 1,2-dihydropyrido [3,4-b] pyrazines (Temple et al., J. of Me
d. Chem. 1987, 30 (10), 1746-51).

[0004]

SUMMARY OF THE INVENTION The present inventors have studied the cytotoxic activity of an aryl group-containing compound, and have found a novel aryl group-containing compound that exhibits cytotoxic activity against tumors.

It is an object of the present invention to provide leukemia, lung cancer, colon cancer,
It is an object of the present invention to provide a polyaryl compound effective for treating tumors such as CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer, and a pharmaceutical composition containing the same as an active ingredient.

The above and other objects and novel features of the present invention will become apparent from the description of the present specification.

[0007]

SUMMARY OF THE INVENTION Among the inventions disclosed in the present application, the outline of a representative one will be briefly described.
It is as follows.

An embodiment of the present invention is directed to a compound of the formula: Ar1-BA
r2 (In the formula, Ar1 is phenyl, thienyl, furanyl, or pyrrolyl, B is R-substituted phenylene, -CH = CH-, or -C≡C-, wherein R is H, alkyl, Hydroxyl or its ester, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or its ester, -C
H (OR1) 2 or NR2 R3, where R1
Is each independently H, alkyl, or acyl; and R2 and R3 are each independently H, alkyl, hydroxyalkyl, or aminoalkyl; and Ar2 is substituted phenyl, substituted thienyl,
Substituted furanyl, or substituted pyrrolyl, and the substituents of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl are each independently an amide,
Nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide,
Aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl,
Or hydroxyalkylaminoalkylaminoalkyl. ) Or a salt thereof (ie, a compound having at least two aryl groups). The salt of the polyaryl compound is formed between the ionizable group and the counter ion of the polyaryl compound represented by the above chemical formula. For example,
The sodium salt of the polyaryl compound is formed between a sodium ion and a carboxyl group of the compound. The basic acid salt of a polyaryl compound is formed between a pharmaceutically usable acid and an amino derivative of the compound.

One preferred embodiment of the compounds covered by the above formula is where B is R-substituted phenylene. Preferably, each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. As used herein, the term "substituted" is defined as having one or more substituents on the referred structure.

Another preferred embodiment of the compounds covered by the above formula is where B is -CH = CH-. Preferably, each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl.

Still another preferred embodiment of the compounds covered by the above formula is where B is -C≡C-. Preferably, each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl.

A further aspect of the present invention is a polyaryl compound covered by the same formula as above,
r1 is substituted phenyl, substituted thienyl, substituted furanyl,
Or substituted pyrrolyl, and each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano, acetal, ketal Oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, and B is , R-substituted phenylene, -CH
ＣＨCH—, or —C≡C—, where R is H,
Alkyl, hydroxyl or ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or ester thereof, -CH (OR1
) 2, or NR 2 R 3, wherein R 1 is H,
Alkyl or acyl, and R2 and R3
Is each independently H, alkyl, hydroxyalkyl, or aminoalkyl; and Ar2 is

[0013]

Embedded image

Or phenyl having 1 to 3 substituents, wherein A is nitrogen, oxygen or sulfur;
X is H, carboxyl or its ester, amide,
Nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl,
Haloalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, wherein Y is H, aldehyde, acyl, carboxyl or its ester, amide, Nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkyl Aminoalkylaminoalkyl, wherein Z is H, acyl, carboxyl or an ester, amide, Lil, nitro, cyano, acetal, ketal, oxo, aminoalkyl, hydroxyalkyl, haloalkyl, alkyl imino alkyl, carboxyalkyl, acid halides, aminoalkyl aminoalkyl, hydroxyalkyl aminoalkyl,
Or hydroxyalkylaminoalkylaminoalkyl, and each substituent of the substituted phenyl is independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano,
Acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl , A polyaryl compound or a salt thereof.

One preferred embodiment of the above compound is where B is R-substituted phenylene. Preferably, Ar
Each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl represented by 1 is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl . More preferably, Ar2 is

[0016]

Embedded image

Or phenyl having 1 to 3 substituents, wherein X and Z are each independently H, hydroxyalkyl, and Y is H, aldehyde or hydroxyalkyl; Is independently an aldehyde or hydroxyalkyl.

Another preferred embodiment of the above compound is
B is -CH = CH-. Preferably, A
each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl represented by r 1 is
Each is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. More preferably, Ar2 is

[0019]

Embedded image

Or phenyl having 1 to 3 substituents, wherein X and Z are each independently H, hydroxyalkyl, and Y is H, aldehyde or hydroxyalkyl; Is each independently a hydroxyl, aldehyde, or hydroxyalkyl.

In another preferred embodiment of the above compound, B is -C≡C-. Preferably, A
each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl represented by r 1 is
Each is independently oxoalkyl, aminoalkyl, haloalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. More preferably, Ar2 is

[0022]

Embedded image

Or phenyl having 1 to 3 substituents, wherein X and Z are each independently H, hydroxyalkyl, and Y is H, aldehyde or hydroxyalkyl; Is independently hydroxyl, alkoxyl, aldehyde, or hydroxyalkyl.

Still another embodiment of the present invention is an asymmetric compound as described above, wherein Ar 1 and Ar 2 are
Each independently a phenyl having 1 to 3 substituents,
Pyrrolyl having 1 to 2 substituents, furanyl having 1 to 2 substituents, or thienyl having 1 to 2 substituents, wherein the substituted phenyl, substituted pyrrolyl, substituted furanyl, and substituted thienyl Each substituent is
Each independently is an acetal, ketal, oxoalkyl, hydroxyalkyl, aminoalkyl, alkyliminoalkyl, acyl, carboxyl or ester thereof, amide, acid halide, nitrile, or hydroxyalkylaminoalkylaminoalkyl; and B is R Substituted phenylene, -CH = CH-, or -C
≡C-, where R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2 R3
Wherein R 1 is H, alkyl, or acyl, and R 2 and R 3 are each independently H,
It relates to an asymmetric compound or a salt thereof, which is alkyl, hydroxyalkyl or aminoalkyl.

One preferred embodiment of the above compound is Ar
A compound in which each substituent of 1 and Ar2 is independently an aldehyde, an alkoxy, a hydroxyalkyl, an acyl, a carboxyl or an ester thereof, or a salt thereof.

Another preferred embodiment of the above compound is
A compound or a salt thereof, in which each substituent of Ar1 and Ar2 is independently aldehyde or hydroxyalkyl.

Yet another embodiment of the present invention is a pharmaceutically acceptable carrier and an effective amount of a polyaryl compound of the above formula wherein Ar1 and Ar2 are each independently pyrrolyl, 1-2 Pyrrolyl having a substituent, furanyl, furanyl having 1 to 2 substituents, thienyl, thienyl having 1 to 2 substituents, phenyl, or phenyl having 1 to 3 substituents, Each substituent of the substituted pyrrolyl, substituted furanyl, substituted thienyl, and substituted phenyl is independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, Hydroxyalkyl, haloalkyl, alkyliminoalkyl, carboxyalkyl, acid halide Iid, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkylamino, or hydroxyalkylaminoalkylaminoalkyl, B is R-substituted phenylene, -CH = CH-, or -C−C-,
Wherein R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2R3, wherein R1 is H, alkyl Or acyl, and R2 and R3 are each independently H, alkyl,
The present invention relates to a pharmaceutical composition containing at least one polyaryl compound that is hydroxyalkyl or aminoalkyl.

Preferred compounds that can be used in the above-mentioned pharmaceutical composition include those in which each substituent of Ar 1 and Ar 2 is independently aldehyde or hydroxyalkyl.

As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain having from 1 to 8 carbon atoms, or a cyclic hydrocarbon group having from 3 to 8 carbon atoms. . Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl, hexyl, isohexyl, heptyl, octyl, cyclopropyl, cyclopentyl, cyclohexyl, Cycloheptyl, adamantyl, norbornyl, isobornyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl, and 1-, 2-, or 3-cyclohexylpropyl. As used herein, “halo” or “halide” refers to fluoro, chloro, bromo, and iodo. Any of the amide, ester, and cyano groups may be bound to the polyaryl compound. For example, an amide group may be at the nitrogen terminus (-NH-CO-R ') or at the carbon terminus (-CO-
NH-R '), wherein R' is an alkyl group, and can be attached to the remainder of the compound. Here, the substitution pattern of B as phenylene is para,
Meta or ortho. As used herein, the term "substitution" is defined as mono-substitution. As used herein, an "asymmetric" polyaryl compound means that the substituent of Ar1 in the compound cannot be the same as the substituent of Ar2.

[0030] In the invention having the above structure, the invention described in each of the claims has the following structure.

The invention according to claim 1 has the chemical formula: Ar 1-
A compound having B-Ar2 or a salt thereof, wherein Ar
1 is phenyl, thienyl, or furanyl;
Is R-substituted phenylene, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl, and Ar2 is substituted thienyl or substituted furanyl, wherein each substituent of said substituted thienyl and substituted furanyl is , Each independently, alkyl, oxoalkyl, aminoalkyl, aminoalkylaminoalkyl,
It is a hydroxyalkylaminoalkyl or a hydroxyalkylaminoalkylaminoalkyl.

The invention according to claim 2 has the chemical formula: Ar 1-
A compound having B-Ar2 or a salt thereof, wherein Ar
1 is substituted thienyl or substituted furanyl, and each substituent of the substituted thienyl and substituted furanyl is
Each independently is an aldehyde, acyl, oxoalkyl, or hydroxyalkyl, B is R-substituted phenylene, where R is H, alkyl, hydroxyalkyl, aminoalkyl, and Ar2 is

[0033]

Embedded image

Wherein A is oxygen or sulfur;
X is oxoalkyl or hydroxyalkyl, and Y and Z are each H.

According to a third aspect of the present invention, there is provided the compound according to the second aspect or a salt thereof, wherein each substituent of Ar 1 is independently aldehyde, acyl or hydroxyalkyl. Features.

According to a fourth aspect of the present invention, there is provided a compound according to the third aspect or a salt thereof, wherein Ar 2 is

[0037]

Embedded image

Wherein X is hydroxyalkyl, and Y and Z are each H.

According to a fifth aspect of the present invention, there is provided the compound according to the fourth aspect or a salt thereof, wherein each substituent of Ar 1 is independently aldehyde or hydroxyalkyl. .

The invention according to claim 6 has the chemical formula: Ar1
An asymmetric compound having the formula -B-Ar2 or a salt thereof, wherein Ar1 and Ar2 are each independently substituted furanyl or substituted thienyl, and each substituent of the substituted furanyl and substituted thienyl is each independently an acyl group. Oxoalkyl, hydroxyalkyl, aminoalkyl, hydroxyalkylaminoalkylaminoalkyl, and B is R-substituted phenylene, where R is H, alkyl, hydroxyalkyl,
It is an aminoalkyl.

According to a seventh aspect of the present invention, there is provided the asymmetric compound or a salt thereof according to the sixth aspect, wherein each substituent of Ar 1 and Ar 2 is independently aldehyde, acyl, or hydroxyalkyl. It is characterized by the following.

An eighth aspect of the present invention is the asymmetric compound or a salt thereof according to the seventh aspect, wherein each substituent of Ar 1 and Ar 2 is independently aldehyde or hydroxyalkyl. Features.

A ninth aspect of the present invention provides a pharmaceutical composition comprising an effective amount of a compound having the chemical formula: Ar 1 -B-Ar 2 and a pharmaceutically usable carrier, wherein Ar 1
And Ar2 are each independently furanyl, furanyl having 1 to 2 substituents, thienyl, thienyl having 1 to 2 substituents, or phenyl, and each substituent of the substituted furanyl and substituted thienyl is , Each independently, is an aldehyde, oxoalkyl, aminoalkyl, or hydroxyalkyl, and B is R-substituted phenylene, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl.

A tenth aspect of the present invention is the pharmaceutical composition according to the ninth aspect, wherein each substituent of Ar1 and Ar2 is independently aldehyde or hydroxyalkyl. .

An eleventh aspect of the present invention provides a compound of the formula: Ar1
-B-Ar2 or a salt thereof, wherein A
r1 is thienyl or furanyl, and B is -CH
= CH-, and Ar2 is substituted thienyl or substituted furanyl, and the substituents of the substituted thienyl and substituted furanyl are each independently oxoalkyl, aminoalkyl, aminoalkylaminoalkyl, hydroxyalkylaminoalkyl, or hydroxyalkyl. A compound for an antitumor agent, which is an alkylaminoalkylaminoalkyl, or a salt thereof.

The invention according to claim 12 is the compound or a salt thereof for an antitumor agent according to claim 11, wherein the substituents of the substituted thienyl and the substituted furanyl are each independently oxoalkyl, amino or amino. Alkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl.

The invention according to claim 13 has the chemical formula: Ar
A compound having 1-B-Ar2 or a salt thereof,
Ar1 is a substituted thienyl or a substituted furanyl, and the substituents of the substituted thienyl and the substituted furanyl are each independently an aldehyde, an acyl, an oxoalkyl, or a hydroxyalkyl; and B is -CH = CH-; Ar2 is

[0048]

Embedded image

Where A is oxygen or sulfur and X
Is an oxoalkyl, aminoalkyl, hydroxyalkyl, aminoalkylaminoalkyl, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, and Y and Z are H, a compound for an antitumor agent, Or a salt thereof.

According to a fourteenth aspect of the present invention, there is provided the compound for an antitumor agent or a salt thereof according to the thirteenth aspect, wherein the substituents of Ar 1 are each independently aldehyde, acyl or hydroxyalkyl. It is characterized by the following.

The invention according to claim 15 is the compound for an antitumor agent according to claim 14 or a salt thereof, wherein the Ar 2 is

[0052]

Embedded image

Wherein X is hydroxyalkyl, and Y and Z are each H.

The invention according to claim 16 is the compound or a salt thereof for an antitumor agent according to claim 15, wherein the substituents of Ar1 are each independently aldehyde or hydroxyalkyl. Features.

The invention according to claim 17 has the chemical formula: Ar
An asymmetric compound having 1-B-Ar2 or a salt thereof, wherein Ar1 and Ar2 are substituted thienyl or substituted furanyl, and each substituent of the substituted thienyl and substituted furanyl is independently oxoalkyl, hydroxy Alkyl, aminoalkyl, or hydroxyalkylaminoalkylaminoalkyl;
And B is an asymmetric compound for an antitumor agent or a salt thereof, wherein -CH = CH-.

The invention according to claim 18 is an asymmetric compound for an antitumor agent according to claim 17 or a salt thereof,
The substituents of Ar1 and Ar2 are each independently aldehyde or hydroxyalkyl.

The invention according to claim 19 is a pharmaceutical composition comprising an effective amount of a compound having the chemical formula: Ar 1 -B-Ar 2 and a pharmaceutically usable carrier,
1 and Ar2 are each independently furanyl, or 1-2 substituted furanyl, thienyl, or thienyl having 1-2 substituents, wherein each substituent of the substituted thienyl is independently Aldehyde, oxoalkyl, aminoalkyl, hydroxyalkyl, aminoalkylaminoalkyl, hydroxyalkylaminoalkyl or hydroxyalkylaminoalkylaminoalkyl, wherein B is -CH = CH- Is a pharmaceutical composition.

The invention according to claim 20 is the pharmaceutical composition for an antitumor agent according to claim 19, wherein each substituent of Ar1 and Ar2 is independently aldehyde or hydroxyalkyl. There is a feature.

The invention according to claim 21 has the chemical formula: Ar
A compound having 1-B-Ar2 or a salt thereof,
Ar1 is phenyl or thienyl, and B is -C≡
C-, Ar2 is substituted phenyl or substituted thienyl, and the substituents of the substituted phenyl and substituted thienyl are each independently oxoalkyl, aminoalkyl, aminoalkylaminoalkyl, hydroxyalkylaminoalkyl, or It is a hydroxyalkylaminoalkylaminoalkyl.

The invention according to claim 22 has the chemical formula: Ar
A compound having 1-B-Ar2 or a salt thereof,
Ar1 is substituted thienyl or substituted phenyl, and each substituent of the substituted thienyl and substituted phenyl is independently aldehyde, oxoalkyl, aminoalkyl, hydroxyalkyl, aminoalkylaminoalkyl, hydroxyalkylaminoalkyl, or Hydroxyalkylaminoalkylaminoalkyl, B is -C≡C-, and Ar2 is

[0061]

Embedded image

Or phenyl having one substituent, wherein A is sulfur, X is oxoalkyl or hydroxyalkyl, and Y and Z are each H
Wherein each substituent of the substituted phenyl is independently aldehyde or oxoalkyl.

The invention according to claim 23 is the compound or a salt thereof for an antitumor agent according to claim 22, wherein each substituent of Ar 1 is independently aldehyde or hydroxyalkyl. It is characterized by the following.

The invention according to claim 24 is the compound for an antitumor agent according to claim 23 or a salt thereof, wherein Ar2 is

[0065]

Embedded image

Or phenyl having one substituent, wherein X is hydroxyalkyl, Y and Z
Is H, and the substituent of the substituted phenyl is an aldehyde.

The invention according to claim 25 has the chemical formula: Ar
An asymmetric compound having 1-B-Ar2 or a salt thereof, wherein Ar1 and Ar2 are each independently a substituted phenyl or substituted thienyl, and each substituent of the substituted phenyl and substituted thienyl is each independently Oxoalkyl, hydroxyalkyl, aminoalkyl, hydroxyalkylaminoalkylaminoalkyl, and B is an asymmetric compound or a salt thereof for an antitumor agent, wherein -C≡C-.

The invention according to claim 26 is the asymmetric compound for an antitumor agent according to claim 25 or a salt thereof, wherein each substituent of Ar1 and Ar2 is independently aldehyde or hydroxy. It is characterized by being alkyl.

The invention according to claim 27 is a pharmaceutical composition comprising an effective amount of a compound having the chemical formula: Ar 1 -B-Ar 2 and a pharmaceutically usable carrier,
1 and Ar2 are each independently thienyl, 1-2
Thienyl having 3 substituents, phenyl, or 1-3
Phenyl having two substituents, wherein each substituent of the substituted thienyl and substituted phenyl is independently aldehyde, oxoalkyl, aminoalkyl,
Hydroxyalkyl, aminoalkylaminoalkyl,
Hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, wherein B is
A pharmaceutical composition for an antitumor agent, wherein -C≡C-.

The invention according to claim 28 is the pharmaceutical composition for an antitumor agent according to claim 27, wherein each substituent of Ar1 and Ar2 is independently aldehyde or hydroxyalkyl. There is a feature.

Other features and advantages of the present invention will become apparent from the following description of the preferred embodiments.

[0072]

BEST MODE FOR CARRYING OUT THE INVENTION The above-mentioned polyaryl antitumor compound can be produced by a method according to a known technique.
For example, a dihalo-substituted polyarylethylene compound is reacted with an excess of a suitable nucleophile having a formyl group such as, for example, dimethylformamide, by a nucleophilic substitution reaction. To produce a product. As another example, a diformyl polyarylacetylene derivative can be obtained by first replacing a properly activated acetylene nucleus, such as copper trimethylsilyl acetylide, with a formyl group such as palladium catalyzed formylthiophene by reductive elimination. It can be synthesized by reacting with furan chloride, pyrrole or thiophene. This substituted monoarylacetylene reacts with other catalyzed substituted thiophenes to give the desired diformyl-substituted products. Sonogashiraet al., Tet
See rahedron Lett. 1975, 4467. As yet another example,
Diformyl polyarylphenylene derivatives are synthesized by coupling a dihalo-substituted phenylene with two equivalents of an appropriately substituted furan, thiophene, or pyrrole, such as formyltributylstannylthiophene, to produce the desired product. Can be manufactured. These diformyl-substituted compounds can be further reduced with sodium borohydride to produce the corresponding hydroxyalkyl derivatives. On the other hand, these diformyl-substituted polyaryl derivatives can be reductively aminated with an appropriately substituted amine and sodium borohydride to produce the corresponding hydroxyalkylaminoalkyl or hydroxyalkylaminoalkylaminoalkyl-substituted polyaryl derivative. .

Tumors (eg, leukemia, lung cancer, colon cancer, C
In addition to the above various polyaryl compounds used for the treatment of NS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer), a method of treating a tumor by administering the composition to a patient is also described. , Is considered as an aspect of the present invention. Also included within the scope of the present invention are the uses of the polyaryl compounds used in the manufacture of medicaments for treating tumors.

As used herein, an effective amount of a formulation refers to the administration to a patient in need thereof, which suppresses tumor cell growth, kills malignant cells, or shrinks the tumor, or otherwise treats the treated patient. It is defined as the amount of the polyaryl compound that confers a therapeutic effect. The effective amount to be administered to a patient will generally be determined based on body surface area, weight, and condition. The interrelationship between animal and human (milligrams per square meter of body surface area) doses is described in Freireich et al., Cancer
Chemother. Rep. 1966, 50, 219. Body surface area is roughly determined from the height and weight of the patient.
Scientific Tables, Geigy Pharmaceuticls, Ardley, N
See ew York, 1970, 537. Effective amounts of the polyaryl compound used to practice the present invention can range from about 5 mg / kg to about 50 mg / kg. The effective dose is
As will be appreciated by those skilled in the art, it will vary based on the method of administration, the amount of excipients, and the possibility of using other treatment methods, including the use of other anti-tumor agents and radiation therapy.

The pharmaceutical composition may be used subcutaneously, intraperitoneally, intramuscularly,
And parenteral routes, including intravenous. Examples of parenteral dosage forms include 5% glucose or other known pharmaceutically acceptable excipients and an aqueous solution of the active agent in an isotonic salt solution. Solubilizing agents such as cyclodextrin, or other solubilizing agents well known to those skilled in the art, can also be used as pharmaceutical excipients for administering the therapeutic compound.

The above-mentioned polyaryl compound can also be incorporated into the preparation by other administration methods utilizing known methods. Pharmaceutical compositions can be formulated in formulations for oral administration such as, for example, capsules, gel mountants or tablets. Capsules are made of known pharmaceutically usable materials such as gelatin or cellulose derivatives. Tablets
A mixture of the active polyaryl compound and the solid carrier, and a lubricant is formulated by compression in known manner. Examples of solid carriers include starch and sugar bentonite. The polyaryl compounds can be administered, for example, in the form of hard shell tablets or capsules containing lactose or mannitol as a binder and known fillers and tableting reagents.

The antitumor activity of the polyaryl compound is as follows:
It can be preliminarily evaluated by in vitro assay, and then in vivo testing.
). For example, polyaryl compounds can be tested for in vitro cytotoxicity in 3- (4,5
-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) Boyd, in Princ
iple of Practice of Oncology, Devita, Hellman, Ro
It can be evaluated by microculture analysis using senberg (eds.) Vol. 3, PPO Update, No. 10, 1989. The MTT assay is based on the production of dark blue formazan product by dehydrogenase in mitochondria of live tumor cells after 6 days of drug exposure.
et al., Cancer Res. 1988, 48, 589. In this way, only live cells are stained and can be measured at 570 nm. Anti-tumor cytotoxicity has been reported as an IC50, which indicates that cell growth is a factor of 5 in symmetric cultures of tumor cells.
It means that the drug dose has an effect of delaying to 0%.

Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. Accordingly, the following specific examples are intended to be merely illustrative, and not limiting, of the remainder of the specification in any manner.

[0079]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in more detail with reference to embodiments.

Example 1 Synthesis of 1,2-bis [2- (5-formyl) -thienyl] acetylene In a 100-ml flask, 20 ml of benzene and 1.1 were added.
2 g (5 mmol) of 2-formyl-5-iodothiophene were charged. While stirring this mixture, 0.98 g (1
0 mmol) of (trimethylsilyl) acetylene, 600 mg
Of tetrakis (triphenylphosphine) palladium,
160 mg of cuprous iodide, 120 mg of triethylbenzylammonium chloride (TEBAC) and 20 ml of 2.5N deoxygenated KOH were added. Mix the mixture at 40 ° C for 48
Stirred for hours. After lowering the temperature to room temperature (rt), a saturated ammonium chloride solution was added and the mixture was stirred for 0.5 hour and the precipitate formed was removed by filtration. The filtrate was extracted with ether. The organic extract is washed with saturated sodium bicarbonate and brine, then anhydrous MgSO
4 and dried. After filtration and concentration, the residue was chromatographed on a silica gel column (eluted with EtOAc / n-hexane) to obtain 0.34 g (yield: 58%) of a product (mp: 154 ° C).

[0081]

[Table 1]

Example 2 Synthesis of 1,2-bis [2- (5-hydroxymethyl) -thienyl] acetylene- 1,2-bis [2- (5-formyl) -thienyl] acetylene (3 mmol) Was dissolved in 30 ml of ethanol, and 1 mm
ol of sodium borohydride. After stirring at room temperature for 4 hours, water was added to stop the reaction. The mixture was extracted with ether. The organic extract is washed with saturated sodium bicarbonate and brine, then dried over anhydrous Mg
Dried with SO4. Filtration and concentration gave 1,2-bis [2- (5-hydroxymethyl) -thienyl] acetylene in almost quantitative yield.

1,2-bis [2- (5-hydroxymethyl) -thienyl] acetylene (mp: 146-147)
° C):

[0084]

[Table 2]

Example 3 Synthesis of (E) -1,2-bis [2- (5-formyl) -thienyl] ethene In a 25 ml flask, 5 ml of DMF and 0.16 ml
(1.74 mmol) of phosphorus oxychloride. The mixture was stirred in an ice bath for 0.5 hours. The mixture is then added to 303
The mixture was treated with mg (1.58 mmol) of (E) -1,2-bis (2-thienyl) ethylene and stirred at 50 ° C. for 48 hours.
After lowering the temperature to room temperature, 10 ml of 10% sodium bicarbonate were added and the mixture was extracted with CH2 Cl2. The organic extract was washed with brine and then dried over anhydrous MgSO4. After filtration and concentration, the residue was chromatographed on a silica gel column (eluted with EtOAc / n-hexane) to obtain 0.04 g of a bis-formyl derivative. The bis-formyl derivative was recrystallized from EtOAc to give
03 g (yield: 6%) of pure product were obtained.

(E) -1,2-bis [2- (5-formyl) -thienyl] ethene (mp: 209 ° C.):

[0087]

[Table 3]

Example 4 Synthesis of (E) -1,2-bis [2- (5-hydroxymethyl) -thienyl] ethene (E) -1,2-bis [2- (5-formyl) ) -Thienyl] ethene (3 mmol) in 30 ml of ethanol,
Treated with 1 mmol of sodium borohydride. 4 at room temperature
After stirring for an hour, water was added to stop the reaction.
The mixture was extracted with ether. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After filtration and concentration, the corresponding hydroxymethyl derivative was obtained in almost quantitative yield.

(E) -1,2-bis [2- (5-hydroxymethyl) -thienyl] ethene (mp: 133-13)
4 ° C):

[0090]

[Table 4]

Example 5-(E) -1- (2-thienyl) -2- {2- [5-
Synthesis of (aminomethyl)]-thienyl ethene-(i) In a 25 ml flask, 2.22 g (10 mmol) of (E) -1- (2-thienyl) -2- [2- (5-hydroxymethyl) Thienyl] ethene, 1.62 g (11 mm
ol) of phthalimide, 2.89 g (11 mmol) of trifenylphosphine, and 20 ml of tetrahydrofuran. To this mixture, slowly add 1.92 g (1
(1 mmol) of diethyl azodicarboxylate.
Stir for 4 hours. Water was added to stop the reaction.
The mixture was extracted with ether. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After filtration and concentration, the residue was chromatographed on a silica gel column (eluted with EtOAc / n-hexane) to obtain 2.22 g (yield: 64%) of a pure product (mp: 160 ° C).

[0092]

[Table 5]

(Ii) (E) -1- (2-thienyl) -2
-{2- [5- (N-phthalimidomethyl)]-thienyl} ethene (0.35 g, 1 mmol) is dissolved in 5 ml of ethanol, and heated with 0.055 g (1.1 mmol) of 80% hydrazine. At 60 ° C. This mixture is
The mixture was heated at reflux for 4 hours, and then concentrated under reduced pressure. The residue was treated with 7 ml of 0.5N HCl and the precipitate formed was removed by filtration. 1N until pH> 12 in the filtrate
NaOH was added, followed by extraction with chloroform. The organic extract is washed with brine, then anhydrous MgSO
Dried at 4. After filtration and concentration, 0.18 g (yield:
83%) of the product (mp: 89-90 ° C.).

[0094]

[Table 6]

Example 6-(E) -1- (2-thienyl) -2- [2- {5-
Synthesis of [N- (2-hydroxyethyl) aminomethyl] {thienyl] ethene-In a 100 ml flask, 30 ml of methanol, 10 mmol
Of ethanolamine and a few drops of acetic acid.
(E) -1- (2-Thienyl) -2- [2- (5-formyl) thienyl] ethene (1.10 g, 5 mmol) was added slowly at room temperature. The reaction was monitored by TLC until the formyl group containing compound was consumed. Excess sodium borohydride was added and the reaction was again monitored by TLC until the imine intermediate disappeared. The mixture was concentrated under reduced pressure and the residue was treated with 50 ml of EtOAc and 50 ml of 0.1
Treated with N HCl. The precipitate obtained is filtered and the filtrate is filtered.
Washed with EtOAc. After combining with the precipitate, the filtrate was washed with 2N
Treat with NaOH until pH> 12, then Et
Extracted with OAc. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After the reaction solution was filtered and concentrated, 1.30 g of (E) -1- (2-thienyl) -2- [2- {5- [N
-(2-Hydroxyethyl) aminomethyl] {thienyl] ethene was obtained. Recrystallization from n-hexane gave 1.22 g of the desired product. (E) -1-
(2-thienyl) -2- [2- {5- [N- (2-hydroxyethyl) aminomethyl]} thienyl] ethene (m
p: 91 ° C):

[0096]

[Table 7]

Example 7-(E) -1- (2-thienyl) -2- [2- {5-
Synthesis of [N- (2-aminoethyl) aminomethyl] {thienyl] ethene-In a 100 ml flask, 30 ml of methanol, 10 mmol
Of ethylenediamine and a few drops of acetic acid.
(E) -1- (2-Thienyl) -2- [2- (5-formyl) thienyl] ethene (1.10 g, 5 mmol) at 0 ° C.
And added slowly. The reaction was monitored by TLC until the formyl group containing compound was consumed. Excess sodium borohydride was added and the reaction was again monitored by TLC until the imine intermediate disappeared. The mixture was concentrated under reduced pressure and the residue was treated with 50 ml of EtOAc and 50 ml of 0.1
Treated with N HCl. The precipitate obtained is filtered and the filtrate is filtered.
Washed with EtOAc. After combining with the precipitate, the filtrate was washed with 2N
Treat with NaOH until pH> 12, then Et
Extracted with OAc. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After the reaction solution was filtered and concentrated, 0.74 g of (E) -1- (2-thienyl) -2- [2- {5- [N
-(2-Aminoethyl) aminomethyl] {thienyl] ethene was obtained. By recrystallizing with n-hexane,
0.72 g of desired product is obtained. (E) -1- (2-
Thienyl) -2- [2- {5- [N- (2-aminoethyl) aminomethyl]} thienyl] ethene (mp: 104
To 105 ° C):

[0098]

[Table 8]

Example 8-(E) -1- (2-thienyl) -2- (2- [5-
{N- [N- (2-hydroxyethyl) aminoethyl]
Synthesis of aminomethyl {] thienyl) ethene—30 ml of methanol, 10 mmol in a 100 ml flask
Of 2- (2-aminoethylamino) ethanol and a few drops of acetic acid. (E) -1- (2-thienyl)-
2- [2- (5-formyl) thienyl] ethene (1.1
(0 g, 5 mmol) was added slowly at room temperature. The reaction,
The TLC was monitored until the formyl group-containing compound was consumed. Excess sodium borohydride was added and the reaction was again monitored by TLC until the imine intermediate disappeared. The mixture was concentrated under reduced pressure and the residue was treated with 50 ml of EtOAc
And 50 ml of 0.1 N HCl. The resulting precipitate was filtered and the filtrate was washed with EtOAc. After combining with the precipitate, the filtrate was treated with 2N NaOH until pH> 12 and then extracted with EtOAc. The organic extract was washed with saturated sodium bicarbonate and brine, then dried over anhydrous MgSO4. After filtration and concentration of the reaction solution, 1.36 g of (E) -1- (2-thienyl)
-2- (2- [5- {N- [N- (2-hydroxyethyl) aminoethyl] aminomethyl}] thienyl) ethene was obtained. By recrystallization from n-hexane, 1.2
9 g of desired product were obtained. (E) -1- (2-thienyl) -2- (2- [5- {N- [N- (2-hydroxyethyl) aminoethyl] aminomethyl}] thienyl) ethene (mp: 51-52 ° C) :

[0100]

[Table 9]

Example 9 -1- (2- (5-formylfuryl))-4- (2-
Synthesis of (5-formylthienyl)) benzene-(i) 1,4-dibromobenzene (1
(3.5 g, 57 mmol) along with the catalyst Pd (PPh3) 4 and 30 ml of benzene and 6 ml of a 2M aqueous Na2 CO3 solution were added. A methanol solution of dihydroxy- (2- (5-formylfuryl)) borane (2 g, 14 mmol) was added to the mixture, and the mixture was refluxed for 12 hours. TLC showed two fluorescent spots. The less polar spot is
Identified as the desired dimer product. The mixture was extracted with ether. Extract the combined ether extracts with anhydrous Mg
Dried over SO4 and concentrated. By chromatography, 30% of 1-bromo-4- (2-formylfuryl)
Benzene was obtained.

[0102]

[Table 10]

(Ii) In a two-necked flask, add 1-bromo-4-
(2- (5-formylfuryl)) benzene (0.25
g, 1 mmol), 2- (diethoxymethyl) -5- (tributylstannyl) thiophene (0.95 g, 2 mmol),
And 5 mol% of the catalyst Pd (PPh3) 2Cl2. 50m
After addition of 1 THF, the mixture was heated to reflux for 12 hours. The reaction was quenched by adding aqueous ammonium hydroxide solution and extracted with ether. The combined ether extracts were dried over anhydrous MgSO4 and concentrated to give the desired product in 50% yield.

[0104]

[Table 11]

Example 10-Synthesis of 1,4-bis [2- (5-formyl) thienyl] benzene- In a two-neck flask, 0.236 of 1,4-dibromobenzene was added.
g (1 mmol), 0.95 g (2 mmol) of 2- (diethoxymethyl) -5- (tributylstannyl) thiophene, and 5 mol% of catalyst Pd (PPh3) 2Cl2. 50 ml
Of THF was added and the mixture was heated at reflux for 12 hours.
The reaction was quenched by adding aqueous ammonium hydroxide solution and extracted with ether. The combined ether extracts were dried over anhydrous MgSO4 and concentrated to give 0.24 g
(Yield: 80%) with desired product (mp> 268)
° C, decomposition).

[0106]

[Table 12]

Example 11 Synthesis of 1,4-bis [2- (5-hydroxymethyl) thienyl] benzene-Ethanol of 1,4-bis [2- (5-formyl) thienyl] benzene (100 ml) (50 ml) An excess of NaBH4 was added to the solution at room temperature under a nitrogen atmosphere. The reaction is 4
Stirred for hours, stopped by adding aqueous ammonium hydroxide solution and then extracted with ether.
The combined ether extracts were dried over anhydrous MgSO4 and concentrated to give the desired product (mp> 300 DEG C.) in 90% (yield: 91 mg).

[0108]

[Table 13]

Example 12 Screening of Compounds for Antitumor Activity The cytotoxic activity of the polyaryl compounds was measured using cytotoxicity against a panel of 61 different NCI human tumor cell lines.

[0110] The 61 types of tumor cell lines used in the antitumor activity test of the above polyaryl compounds are described below.

Leukemia CCRF-CEM, HL-60 (TB), K-562,
MOLT-4, RPMI-8226, and SR.

Lung cancer A549 / ATCC, EKVX, HOP-62, HOP
-92, NCI-H226, NCI-H23, NCI-
H322M, NCI-H460, and NCI-H52
2.

Colon cancer COLO 205, HCC-2998, HCT-11
6, HCT-15, HT-29, KM-12, and S
W-620.

CNS cancer SF-268, SF-295, SF-539, SNB-
19, SNB-75, and U-251.

Melanoma LOX-IMVI, MALME-3M, M-14, SK
-MEL-2, SK-MEL-28, SK-MEL-
5, UACC-257, and UACC-62.

Ovarian cancer IGR-OVI, OVCAR-3, OVCAR-4, OVCAR-4
VCAR-5, OVCAR-8, and SK-OV-
3.

Kidney cancer 786-0, A-498, SCHN, CAKI-1, R
XF-393, RXF-631, SN12C, TK-1
0, and U0-31.

Prostate cancer PC-3 and DU-145.

Breast cancer MCF 7, MCF7 / ADR-RES, MDA-MB
231 / ATCC, HS578T, MDA-MB-4
35, MDA-N, BT-549, and T-47D.

This NCI antitumor activity screening assay gives data on the general cytotoxicity of individual compounds. In particular, this type of analysis is useful for identifying compounds that exhibit effective cytotoxic activity against slow growing tumor cells as compared to fast growing tumor cells, such as leukemia tumor cell lines. Identification of such compounds is important. This is because previously identified antitumor agents show low cytotoxic activity against slow growing tumors.

The antitumor cytotoxicity of the polyaryl compounds tested in the in vitro assay was determined by microscopic analysis using either 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT). Measured by culture analysis. The analysis is advantageous when compared to an in vivo analysis that takes months, as the results are obtained within a week. This analysis was performed in a 96-well microtiter plate. MTT analysis is based on the production of dark blue formazan product by dehydrogenase in mitochondria of live tumor cells after 6 days of drug exposure. MC Alley, DA Scudiero, A. Monks,
ML Hursey, MJ Czerwinski, DL Fine, BJ Abbo
ut, JG Mayo, RH Shoemaker and MR Boyd, Cance
r Res., 48, 589, 1988. In this way, only live cells are stained and can be measured at 570 nm. Antitumor cytotoxicity has been reported as IC50, which
It is meant to be a drug dose effective to slow cell growth to 50% of the symmetric culture of tumor cells.

Although the invention made by the inventor has been specifically described based on the embodiments, the present invention is not limited to the above-described embodiments, and can be variously modified without departing from the gist of the invention. Needless to say.

[0123]

Advantageous effects obtained by typical ones of the inventions disclosed in the present application will be briefly described.
It is as follows.

Namely, leukemia, lung cancer, colon cancer, CNS
Tumors such as cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer can be effectively treated.

Claims (25)

[Claims] 1. A compound having the formula: Ar1-B-Ar2 or a salt thereof, wherein Ar1 is phenyl, thienyl, furanyl, or pyrrolyl; and B is R-substituted phenylene, -CH = CH-, or -C
≡C-, where R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2 R3
Wherein R 1 is each independently H, alkyl, or acyl; and R 2 and R 3 are each independently H, alkyl, hydroxyalkyl, or aminoalkyl; and Ar 2 is a substituted phenyl , Substituted thienyl, substituted furanyl, or substituted pyrrolyl, wherein each substituent of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently amide, nitrile, nitro, cyano, acetal, ketal, oxo, Alkyl, aminoalkyl,
Haloalkyl, iminoalkyl, carboxyalkyl,
A compound or salt thereof, which is an acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. 2. The compound or a salt thereof according to claim 1, wherein B is R-substituted phenylene. 3. The compound or a salt thereof according to claim 2, wherein each of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl. , Hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, or a salt thereof. 4. The compound or a salt thereof according to claim 1, wherein B is —CH ＝ CH—. 5. The compound or a salt thereof according to claim 4, wherein each of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is independently oxoalkyl, aminoalkyl, haloalkyl. , Hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, or a salt thereof. 6. The compound or a salt thereof according to claim 1, wherein B is -C≡C-. 7. The compound or a salt thereof according to claim 6, wherein each of the substituents of the substituted phenyl, substituted thienyl, substituted furanyl, and substituted pyrrolyl is each independently oxoalkyl, aminoalkyl, haloalkyl. , Hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, or a salt thereof. 8. A compound having the formula: Ar 1 -B-Ar 2 or a salt thereof, wherein Ar 1 is substituted phenyl, substituted thienyl, substituted furanyl, or substituted pyrrolyl, wherein said substituted phenyl, substituted thienyl, substituted furanyl, And each substituent of substituted pyrrolyl is independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, iminoalkyl, carboxy Alkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, wherein B is R-substituted phenylene, -CH CH-, or -C
≡C-, where R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2 R3
Wherein R 1 is H, alkyl, or acyl, and R 2 and R 3 are each independently H,
Alkyl, hydroxyalkyl, or aminoalkyl, and Ar2 is Or phenyl having 1 to 3 substituents, wherein A is nitrogen, oxygen, or sulfur, and X is H, carboxyl or its ester, amide, nitrile, nitro, cyano, acetal, ketal, Oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl;
Is H, aldehyde, acyl, carboxyl or ester thereof, amide, nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, iminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, Aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, wherein Z is H,
Acyl, carboxyl or ester thereof, amide, nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, iminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, hydroxyalkylaminoalkyl, or Hydroxyalkylaminoalkylaminoalkyl, wherein each substituent of the substituted phenyl is independently an aldehyde,
Acyl, ester, carboxyl or its ester,
Amide, nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, iminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl,
A compound or salt thereof, which is aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl. 9. The compound or a salt thereof according to claim 8, wherein B is R-substituted phenylene. 10. The compound according to claim 9, or a salt thereof, wherein each substituent of Ar 1 is independently aldehyde, alkoxy, hydroxyalkyl, acyl, or ester. Compound or salt thereof. 11. The compound according to claim 10, or a salt thereof, wherein said Ar 2 is Or phenyl having 1 to 3 substituents, wherein X and Z are each, independently, H, hydroxyalkyl; Y is H, aldehyde or hydroxyalkyl; A compound or a salt thereof, wherein the substituents are each independently aldehyde or hydroxyalkyl. 12. The compound according to claim 11, or a salt thereof, wherein each substituent of Ar1 is independently aldehyde or hydroxyalkyl, or a salt thereof. 13. The compound or a salt thereof according to claim 8, wherein B is -CH = CH-. 14. The compound according to claim 13, or a salt thereof, wherein each substituent of said Ar 1 is independently an aldehyde, alkoxy, hydroxyalkyl, acyl, or ester. Compound or salt thereof. 15. The compound according to claim 14, or a salt thereof, wherein said Ar 2 is Or phenyl having 1 to 3 substituents, wherein X and Z are each, independently, H, hydroxyalkyl; Y is H, aldehyde or hydroxyalkyl; A compound or a salt thereof, wherein the substituents are each independently aldehyde or hydroxyalkyl. 16. The compound according to claim 15, or a salt thereof, wherein each substituent of Ar 1 is independently aldehyde or hydroxyalkyl, or a salt thereof. 17. The compound or a salt thereof according to claim 8, wherein B is -C≡C-. 18. The compound according to claim 17, or a salt thereof, wherein each substituent of Ar 1 is independently an aldehyde, alkoxy, hydroxyalkyl, acyl, or ester. Compound or salt thereof. 19. The compound according to claim 18, or a salt thereof, wherein said Ar2 is Or phenyl having 1 to 3 substituents, wherein X and Z are each, independently, H, hydroxyalkyl; Y is H, aldehyde or hydroxyalkyl; A compound or a salt thereof, wherein the substituents are each independently aldehyde or hydroxyalkyl. 20. The compound according to claim 19 or a salt thereof, wherein each substituent of Ar1 is independently aldehyde or hydroxyalkyl, or a salt thereof. 21. An asymmetric compound having the formula: Ar1-B-Ar2 or a salt thereof, wherein Ar1 and Ar2 are each independently a substituted phenyl, substituted pyrrolyl, substituted furanyl, or substituted thienyl; , Substituted pyrrolyl, substituted furanyl, and substituted thienyl are each independently an acetal, ketal, oxoalkyl, hydroxyalkyl, aminoalkyl, iminoalkyl,
Acyl, carboxyl or its ester, amide, acid halide, nitrile, or hydroxyalkylaminoalkylaminoalkyl, and B is R-substituted phenylene, -CH = CH-, or -C≡C-;
Wherein R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2R3, wherein R1 is H, alkyl Or acyl, and R2 and R3 are each independently H, alkyl,
An asymmetric compound or a salt thereof, which is hydroxyalkyl or aminoalkyl. 22. The asymmetric compound according to claim 21, or a salt thereof, wherein each substituent of Ar1 and Ar2 is independently aldehyde, alkoxy, hydroxyalkyl, acyl, carboxyl or an ester thereof. Or an asymmetric compound or a salt thereof. 23. The asymmetric compound according to claim 22, or a salt thereof, wherein each substituent of Ar1 and Ar2 is independently an aldehyde or hydroxyalkyl, or a salt thereof. salt. 24. An effective amount of the chemical formula: Ar 1 -B-Ar
And a pharmaceutically usable carrier, wherein Ar1 and Ar2 are each independently pyrrolyl, pyrrolyl having 1 to 2 substituents, furanyl, 1 to 2 Furanyl having two substituents,
Thienyl, thienyl having 1 to 2 substituents, phenyl, or phenyl having 1 to 3 substituents,
The substituents of the substituted pyrrolyl, substituted furanyl, substituted thienyl, and substituted phenyl are each independently aldehyde, acyl, carboxyl or its ester, amide, nitrile, nitro, cyano, acetal, ketal, oxoalkyl, aminoalkyl , Hydroxyalkyl, haloalkyl, iminoalkyl, carboxyalkyl, acid halide, aminoalkylaminoalkyl, aminoalkylaminoalkylamino, hydroxyalkylaminoalkyl, or hydroxyalkylaminoalkylaminoalkyl, B is R-substituted phenylene, -CH = CH- or -C
≡C-, where R is H, alkyl, hydroxyl or an ester thereof, alkoxy, aldehyde, hydroxyalkyl, aminoalkyl, carboxyl or an ester thereof, -CH (OR1) 2, or NR2 R3
Wherein R 1 is H, alkyl, or acyl, and R 2 and R 3 are each independently H,
A pharmaceutical composition, which is an alkyl, hydroxyalkyl, or aminoalkyl. 25. The pharmaceutical composition according to claim 24, wherein each substituent of Ar1 and Ar2 is independently aldehyde or hydroxyalkyl.