CA2187445A1 - Water-soluble methine compound and pharmaceutical composition for treatment of cancer comprising the same - Google Patents

Abstract

There are provided methine compounds having the structure (1-13) or (1-3) and their analogs. These methine compounds have a high solubility and are useful as an active ingredient for pharmaceutical composition for treatment of cancer.

Description

WO 96/03393 1 i~ 2 ~ 8 7 4 4 5 ~ J . i SPECIFICATION

Title of the Invention Water-soluble methine compound 2nd pharmaceutical composition for L.~ of cancer comprising the same ~;dckyLOulld of the Invention The present invention relates to a methine compound useful as a photograhic material, medicine or the like, and to ~ rtl~rra~elltica composition for treatment of cancer comprising the methine compound.
In the f ield of the photographic science, various methine ~ 'c are described in, for example, U. S. Patent Nos. 2,388,963, 2,454,629, 2,947,630, 3,979,213 and 3,796,733, ~rench Patent Nos.
2,117,337 and 1,486,987, and West German Patent No. 2,140,323. These c are used as spectral sensitizing dyes. Among these, methine '- which fall in rhodacyanine dyes usually have a low solubility, which causes a problem when they are in~ uL~o-~-Led into a pl~c,LoyLd~llic emulsion. For improving the solubility of these _ ~c, there is proposed a method wherein a hydroxyl group 2nd '- ~LIIyl group are introduced into the molecular structure of each compound. Although such a method is ~ rlr ca~ in, for eYample, Japanese Patent ~ln~YAminacl PUblished Arrl;r7t;rn (hereinafter referred to as "J. P. }~OKAI"~ Nos.
shO 63-228,145, 63-123,054 and 63-280,243, and ~ei 3-168,634, 4-145,431 and 1-196,032, and European Patent No. 318,936, no C~t;~ac~ry results have been obtained yet. FUrther, although the introduction of a sulfoalkyl group is also an ordinarily employed tarhn;qlla, this group seriously changes the charge of the compound, so that it is often that the essential properties of the compound cannot be r-int;~;na,l.

I

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ .

WO96/~3393 "~ S 21~7445 r~l,J. cC~l The ~ ~irin~l effect of the methine ~ . A': is expected in the medical and rh~rr-^r~ fields, but the solubility is an important problem also in these fields and particularly in a medium having a high salt ~ullCe:llLL~-Lion such as blood in a living body, the precipitation or coagulation of such a compound is undesirable. For example, US Patent No. 5,360,803 and J. P. KO~AI Eei 6-80892 disclose _ '~ having a high solubility, but further i _ u~ ~ on the solubility is desired.
Thus, the solubility of the methine ~ ~. AC is an important problem in both fields.

Summary of the Invention Theref ore, an ob ject of the present invention is to provide a methine compound which falls in rhodacyanine dyes and which has a high solubility .
Another object of the present invention is to provide a good rhArr~ ;C~l composition for treatment of cancer.
These and other objects of the present invention will be apparent from the f~llo~rin~ description and Examples.
The object of the present invention has been attained with a methine compound of the following formula ~

Z; ~ ~N N - (I) wherein Z, represents a non-metallic atomic group necessitated for forming a fi~ d nitLog~ ;nin5 heterocyclic ring together with _N~R, )-C-, Z, Le~L~_.ILS a non-metallic atomic group necessitated _ _ _ _ _ . .. ....... .. ...... _ _ _ _ _ _ .

W0 96103393 ~ ~ 2 1 8 7 4 4 5 . ~ . . 5 ~1408 .
for ~orming a five-membered nitrogen-containing heterocyclic ring together with -N ~ ~R~ )=C-, R,, R, and R, each Le~Lès~l~L an alkyl group and at least one of R,, R, and R, Le~Lasel.Ls a~ alkyl group substituted with a polyethylene o~ide group wherein one end of the polyalkylene oxide having a degree of polymerization of 2 to 6 is tPrmi nAtP~ with a hydrophobic group or substituted with a h~LeLo~ y~.lic ring r~nn~Aining two or more Qxygen atoms, Q represents an anion, k represents a numeral necessitated to control the charge in the molecule at zero, p represents 0 or 1, and Y LepLase~s a methine group or nitrogen atom.
There is also provided a pharmaceu*ical composition for treatment of cancer which comprises a therAreu*irAlly effective amount of the methine compound and a pharmaceutically acceptable diluent and/or carrier.

Description of the Preferred F'-hr,~; ' As the methine compounds L~:~Lase..Led by the above formula (I), those Le~La~e..Led by the following formula ~II) are preferred:

~=CH--CH~ `FY~
N P ,~N~ N~ W2 (II) R1 ' R2 R3 Q
wherein Z, together with -N(R, )-C- represents a non-n~etallic atomic group nprpqc;*Atp~l for forming a ~h;A7nl;ll;nP ring, benzothiA701;nP ring, b~-n7rYA7rl;nP ring, naphthr~th;A7nl;np ring or llaphthoxazoline ring, W, and W, each represent a hydrogen atom or they together form a non-metallic atomic group necessitated for forming a naphthalene crn~'Pnced ring or benzene rrn~ncP-l ring, Q represents a halogen ion or organic W0 96/03393 ! ~ t ~ 2 1 8 7 4 4 5 ~ ~"~
acid anion, p represents O or 1, Y represents a methine group or nitrogen atom, R" R, and R, each Le~Lese..L an alkyl group and at least one of s,, R, and R, has a substituent of the following formula III-a or III-b:

O "
tCH2CH20~R4 or _< (CH2) n ( III-a ) ( III-b ~
wherein R, Le~LeSe..Ls an alkyl group having 2 or less carbon atoms, m Le~LèSe-LS 3 or 4 and n LepLesèl~Ls 2 or 3.
In particular, the heterocyclic rings formed by Z, and -N(R, )-C-together are preferably thiazolidine ring, benzothiazoline ring, naphtho~hi~7~lin~ ring and nah1hoY~7olin~ ring. More preferred are benzothiazoline ring and naphthothiazoline ring. Among them, benzothiazoline ring is the most preferred. The heterocyclic ring formed by Z, and -N(R, )-C- together may have a substituent. The substituent is preferably a halogen atom, alkyl group, alkoxy group, hydroxyl group or the like. The most preferred is methoxy group. The condensed ring formed by W, and W, may have a substituent, which is preferably a halogen atom, alkyl group, alkoxy group, hydroxyl group or the like. The alkyl groups Le~.ese--Led by R,, R, and R, are preferably those having 1 to 5 carbon atoms, more preferably those having 1 to 3 carbon atoms. Among the polyalkylene oxides having a degree of polymerization of 2 to 6 and terminated with a hydrophobic group, preferred are polymers of ethylene oxide, propylene oxide or butylene oxide. Particularly preferred are ethylene oxide polymers. The degree of polymerization is preferably 3 to 5, particularly preferably 3 to 4.
The hydrophobic groups which terminate the polyalkylene oxide are WO96l03393 ,~ C 2187445 ~I/J, ~
preferably lower alkyl groups such as those having l to 3 carbon atoms.
The mode of the termination is, for example, an ether bond or ester bond. Particularly preferred is the ether bond with an alkyl group having l to 3 carbon atoms, and most preferred is with methyl group.
Examples of the heLe.u~ lic rings c~nt~;n;n~ two or more oxygen atoms include dioxolane and dioxane. Particularly preferred are 1,3-dioxolanyl group and 1, 3-dioxanyl group. The alkyl group substituted with a polyalkylene oxide group having a degree of polymerization of 2 to 6 and terminated with a hydrophobic group or substituted with a heLe.u~y.;lic ring rt-tn1-:~;n;nq two or more oxygen atoms is preferably R,.
The halogen ion or organic acid anion Le~-ese.-Led by Q is preferably an iodide ion, chloride ion or sulfonic acid ion. Among them, the chloride ion is more preferred. Y is preferably a methine group, and p is pref erably O .
The methine compound of the present in~ention is usable as a spectral sensitizing dye or :-n1-; c~n~--.r agent. The methine compound of the present invention can be usually synth~ci~ed by a synthesis method described in ~. s. Patent No. 2,388,963.
Examples of the ~ ~ of the general formula (II) of the present invention will be given below, which by no means limit the in ~ention .

21 ~ 74 45 r~llJ. ~tl408 1 1 ~S~--N N ~O CN,~SO, C2HS ~,0--O~OCH3 CH~
C2HS ~ --O~OCH3 1-3 ~ ~_~CH~ Cl C2Hs ~O o~ocH3 4 ~X )=S_`FCH-(`N;q~ Cl C2Hs ~O o~O OCH3 J. S 1~.
WO 96103393 ` I ` - - ' 2 1 8 7 4 4 5 1-5 ~ `rCH~N~ Cl C2Hs ~,O o~OCH3 ~O~ --OCH3 1-6 ~S~CH--GN3 C2H5 C2Hs C~
~=5_~ CH--(`N.lCI ~}' 7 I~J O I~o ~OCHJ
CH
1-8 &~ F CH~ ~ Cl~
C2HS l o o ~ 3 wo 9C/03393 ~, 2 1 ~ 7 ~ 4 5 PCT1JP9S/01408 ~5~ ~H ~q~ Cl 0^0 CHJ
~o)~ `FCH-<~ ~ Cl' 1-10 C2H ~,o o~oCH3 1-11 O~5~CH~ ~?C~-C2H5 ~ ~OCH
,CH3 t-l~ ~Es~ ~eCH~ r~
zHs ~ O o~OCH3 3 j r ~ 2 1 8 7 4 4 5 PC~/JP95/01408 ' CH30~ CH~ --!0 cl C2H~ ~,O--O~OCH3 ~S~
C2Hs l O o~OCH3 C2H5 ~,O o~OCH3 1 16 g )=CIt-CH=~ `FCH--<~N ~Cl' C2Hs ~0 ~OCH

Wo 96l03393 ~ ?~ 2 1 8 7 4 4 5 PCTIJP95101408 The methine ~ e of the present invention are widely usable as spectral sensitizing dyes or - ~; ri n~5 such as anticancer agents .
When one of the methine, ~- of the present invention is used as a medicine, it is usually administered, for e~cample, by the following preferred method: the methine compound, dissolved in, for eYample, 5 ~
glucose solution or together with a suitable carrier or diluent, is injected into a vein, AhA~ nAl cavity, muscle or bladder. In animal tests conducted for the purpose of confirming the effect of the treatment, the practical solubility suitable for the injection preparations is O.l to l ~ by weight. sy using the methine compound of the present invention, an injection preparation having a high solubility is thus provided.
Sr-~;firA11y, the rhArr~ irAl compositions of this invention containing one or more ~ ~c of the general formulas (I) to ~II) described above can be effectively used to treat various types of cancer including --lAn~ c, hepatomas, gliomas, neuroblastomas, sarcomas and carcinomas of the lung, colon, breast, bladder, ovary, testis, prostate, cervix, pancreas, stomach, small intestine and other organs .
The phArr-rentir~Al compositions of this invention can contain one or more cr~ oun~lc of the general formul~s (I) to (II) and a rhArr^A~ ;rAlly Ar~A~rtAhle diluent and/or carrier, and if desired, can further contain other therapeutic agents including conventional anti-tumor agents known in the art. Suitable examples of such conventional anti-tumor agents which can be used include a~riamycin, cisplatin, colchicine, CCN~ ~ Lomastine ), sCNU ( Carmustine ), Actinomycin D, 5-f luorouracil, thiotepa, cytosinearabinoside, cyclophosphamide, mitomycin C, and the like.

. .

WO 96/03393 j f~ ?~ ~ f ~ ~ 2 1 8 7 4 4 ~ PCT/JP9~/01408 .
Suitable examples of the rhArr~ tlcal carriers or diluents include glucose, sucrose, lactose, ethyl alcohol, glycerin, mannitol, sorbito~, pentaerythritol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, other polyethylene glycols, mono-, di- and triglycerides of saturated fatty acids such as glyceryl trilaurate, glyceryl monostearate, glyceryl tristearate and glyceryl distearate, pectin, starch, alginic acid, xylose, talc, lycopodium, oils and fats such as olive oil! peanut oil, castor oil, corn oil, wheat germ oil, sesame oil, 1 oil, s1lnflo~ ~- seed oil and cod-liver oil, gelatin, lecithin, silica, cellulose, cellulose derivatives such as methyl hydLu,~yu~u~uyl cellulose, methyl cellulose, hydroxyethyl cellulose, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms such as calcium stearate, calcium laureate, r-~npci oleate, calcium palmitate, calcium behenate and r~n~-cj stearate, emulsifyers, esters of saturated and u..,,_LuLc.Led fatty acids, e.g., having 2 to 22 carbon atoms, ~.CreriAlly 10 to 18 carbon atoms, with m ~.lLiC Al;~hA~;~` alcohols (e.g., having 1 to 20 carbon atoms such as alkanols ) or polyhydric alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, ethyl alcohol, butyl alcohol, octadecyl alcohol and silico31es such as dimethyl polysiloxane. Additional carriers conventiona;ly used in rh~rr-~ellt;~~Al compositions may also be appropriate for this invention.
The pharr~~eu~;cAlly effective amount of the compound of the general formulas (I) to (II) and the mode or manner of administration will be dependent upon the nature of the cancer, the therapy sought, the severity of the disease, the degree of malignancy, the extent of metastatic spread, the tumor load, general health status, body weight, age, sex, and the genetic or racial background of the patient. E~owever, _ _ _ _, _ _ _ . _ _ _ . . _ _ _ _ . . . _ . .

~1 ~7~45 . ..
in general, suLtable modes of administration include intravenous, hypodermic, intraperitoneal, intL 1Ar or intravesicular injection or oral use in the form of, for example, a compound of the general formulas (I) to (II) in, e.g., a 5% glucose aqueous solution or with other appropriate carriers or diluents as described above. A suitable I hf~ e..,l ;r:~l ly effective amount of a compound of the general formulas (I) to (II) in the composition is about 0.01% b~ weight to about 10% by weight, more generally 0.1% by weight to about 1%, based on the weight of the composition.
Again, as noted above, rh~rr~^e~t~ir~1 ly effective amounts will be generally determined by the practitioner based on the clinical symptoms observed and degree of L;LuyL~aaiOn of disease and like factors but a suitable th~.~p~l i,r:llly effective amount of the compound of the general formulas (I) to (II) generally can range from lO mg to 500 mg, more generally lO0 mg to 200 mg, ~ n; q~Pred per day per 70 kg of body weight, in single or multiple doses, as determined appropriate for the therapy involved.
The wide use of the methine _ c of the present invention as photosensitive materials f or photography or as - - ~; r; n.oq such as anticancer agent is expected, since they have a solubility in water or the like far higher than that of an ~n~1o~o~q rhodacyanine dye.
The following Examples will further illustrate the present invention .
Example l (l) synthesis of compound l-l:
l) synthesis of 3-ethyl-5-(3-methylnaphtho[l,2-dlth;~7O1;n-2-ylidene) ~h;:-701;~1;n~-4-on-2-thion:
20 g of 2-methylthio[1,2-d]naphthr~thi~7olium=p-toluene sulfonate, W096l03393 ~' 2i 8744~ T l,J~ ~ ~
7.7 g of 3-ethyl~hi~7nlin~-s-on-2-thion and 240 ml o~ acetonitrile were fed into a 1 0 th.ce n6~ kdd flask provided with a reflux ~ c "
and the resultant mixture was cooled to C - 10 m e of triethylamine was added dropwise to the mixture, and the resultant mixture was stirred for 3 hours. Yellow prer;rit~t~s thus formed were suction-filtered and washed with S0 ml of acetonitrile to obtain 18 9 of crude crystals.
The crude crystals thus obtained and 500 ml of methanol were fed into a 1 ~ th.ee ne~ d flask provided with a reflux cnn~l~nc~r~ and the resultant mixture was heated under reflux and stirring ~or l hour, and then cooled to 25-C . The mixture thus obtained was suction-filtered, washed with 100 ml of methanol and dried.
Yield: 97.9 96.
2) Synthesis of 3-ethyl-5-(3-methylnaphtho[1,2-dl~h;~l;n-2-ylidene)-2-methylthio-4-oYo-2-l h;~7o~ in; p-toluenesulfonate:
17 9 of 3-ethyl-5-(3-methylnaphtho[1,2-d]~h;A7ol;n-2-ylidene) fh;~7nl;~;n~-4-on-2-thion and 80 ml of methyl p-toluenesulfonate were fed into a 1 ~ three r_ckLd flask provided with a reflux cnn~rn~Pr.
The resultant mixture was heated to 120-C under stirring for 4 hours.
700 ml of acetone was added to the resultant mixture. After cooling to 25-C, the pr~rip;~tos thus formed were suction-filtered, washed with 100 ml of acetone and dried. M. p.: 300 C or above.
Yield: 89 ~.
3) Synthesis of 3 - ' ~d~ c,AyeLI,o..y~:LIIyl-2-methyl-ban~o~h;~7r toluenesulfonate:
50 g of methoxyethoxyethyl p-toluenesulfonate, 15 ml of 2-methylben20thia201e and 240 ml of xylene were fed into a 500 mQ
three-necked f lask provided with a ref lux rr~nrl~nc~r The resultant mixture was heated to 110 C under stirring for lO hours, and then .. . . . ...... _ . _ . . . ..... .. . .. .. _ _ _ _ _ _ WO 96l03393 ~ 2 1 ~ 7 4 4 5 . ~
cooled to 25 C . 400 ml of ethyl acetate was added to the resultant mixture. The crystals thus formed were suction-filtered, washed with ethyl acetate and dried.
Yield: 44 %.
M. p.: 70 to 75C.

4) Synthesis of 3-methoxyethoxyethoxyethyl-2- 1 [3-ethyl-5-(3-methylnaphtho[l,2-d]thiazolin-2-ylidene) ]-4-oxothiazolidin-2-yl;~r Lhyl~ ben~o~h;~7~ m=p-tolll~n~clllfnn~te (compound 1-1):
0.5 g of 3-methoxyethc.-y~Lhu,-y~Lhyl-2-methyl-benzothiazolium=p-toluenesulfonate, 0.5 g of 3-ethyl-5-(3-methylnaphtho[1,2-d]~hiA7nlin-2-ylidene)-2-methylthio-4-oxo-2-th;;.70l;~;n; ~-toluenesulfonate and 20 ml of acetonitrile were fed into a 100 m O three-necked flask provided with a reflux ~ .. The resultant mixture was heated to 60 C . O . 26 ml of triethylamine was added dropwise to the mixture .
After stirring the mixture at that temperature for 15 minutes, the reaction liquid was cooled to room l _ c.Lu.a. 80 ml of ethyl acetate was added to the resultant mixture . The crystals thus f ormed were suction-filtered, washed with 50 ml of ethyl acetate and dried.
Yield: 0.54 g.
?5. p.: 208 to 214 C -(2) synthesis of compound 1-2:
1) synthesis of 3-methoxyethoxyethoxyethyl-2-methyl-benzo~h;~nl; iodide:
8 . 5 g of 2-methoxyethoxyethoxyl-1-iodoethane and 3 . 5 ml of 2-methylh~n~nth;~nlP were fed into a 300 mO Ll~ ne- ktd flask provided with a reflux cnn~nC~r. The resultant mixture was heated to loO-C
under stirring for 6 hours and then cooled to 25 C- 150 ml of ethyl acetate was added thereto. The crystals thus formed were suction-WO sCl03393 ' i~ A,;~r~ ~;~ 2 1 8 7 4 4 5 r_~". C"ll 1:

iiltered, washed with ethyl acetate and dried.
Yield: 16 ~.
N. p.: 110 to 144 C -2) Synthesis of 3-methoxyethoxyethoxyethyl-2- { [3-ethyl-5-~3-methylnaphtho[1,2-d]thiazolin-2-ylidene) ]-4-oxothiazolidin-2-yli~Pn -Lhyl~ benzo~h;~7^1i-1m=iodide (compound 1-2):
1. 25 g of 3-methoxyethoxyethoxylethyl-2-methyl-benzothiazolium=iodide, 1.25 g of 3-ethyl-5-~3-methylnaphtho[1,2-d]thiazolin-2-ylidene)-2-methylthio-4-oxo-2-thiazolidinium=p-toluenesulfonate and 125 ml of acetonitrile were fed into a 300 m 0 three-necked flask provided with a reflux cnnlPncPr. The resultant mixture was heated to 6b ~C. 2 ml of triethylamine was added dropwise to the mixture. After stirring the mixture at that tL..~aL~ILuLd for l5 minutes, 100 ml of ethyl acetate was added thereto, and the reaction liquid was cooled to room ~ LUL~. The crystals thus formed were suction-filtered, washed with 50 ml of ethyl ac~tate and dried at room temperature under reduced pressure to obtain the intended compound.
Yield: 1.2 g.
M. p.: 194 to 204 C -( 3 ) Synthesis of Compound 1-3:
l g of the compound 1-2, 2 ml of a strongly basic ion exchange resin (PA 318; a product of M;tcllbichi Chemical Industries I.td,) and 20 ml of methanol were fed into a 200 ml beaker. The resultant mixture was stirred at room temperature for 3 hours, passed through a column filled with the strongly basic ion exchange resin (PA 318; a product of Nitsubishi Chemical Industries I,td. ) and eluted with methanol. The eluate was collected and naturally filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in _ _ _ _ _ _ _ _ .. , . , . .. , _ _ _, .. _ . .. . _ _ _ _ _ _ _ _ _ _ _ _ _ .
W096/03393 ~ 2187445 ~ [.,~
meth~nol, and then ethyl acetate was added to the solution to precipitate the crystals, which were then suction-filtered, washed with ethyl acetate and dried at room temperature under reduced pressure.
Yield: 1 g.
M. p.: 190 to 195 C
4 ) Synthesis of Compound 1-4:
The intended compound was obtained f rom 3 -ethyl-5- ( 3 -methylnaphtho[l,2-d]thiazolin-2-ylidene)-2-methylthio-4-oxo-2-th;A7nl;~in; ~-tn~ n~c~llfonate and 3 ` yeLI,."~y-:Lhv~y~:Lhoxyethyl-2-methy1han7n~hi~7nli p-~nluanaclllfnn~ta in the same manner as that of the steps of the synthesis of compound 1-3. M p.: 170 to 180 C-( 5 ) Synthesis of Compound 1-5:
The intended compound was obtained from 3-ethyl-5-(3-methylnaphtho [ 1, 2-d ] thiazolin-2-ylidene ) -2-methylthio-4-oxo-2-thiazolidinium=p-toluenesulfonate and 3 ~ Ll~ yeLhG~-yeLl~ yeLhyl-2-methylnaphtho [ 2, l-d ] ~ h; ~ 7 o l i ~-toluenesul f onate in the same manner as that of the steps of the synthesis of compound 1-3. M. p.: 160 to ( 6 ) Synthesis of Compound 1-6:
1) Synthesis of naphtho[2~l-d]~hi~7olin~-2-on:
10.0 g of 2-methylnaphtho[2,1-d]thiazole, 15.0 g of potassium hydroxide, 0.9 g of sodium borohydride, 25 ml of ethylene glycol and 6 ml of water were fed into a 100 ml thL~ ne- l~ed flask provided with a reflux cnn~anca~. The resultant mixture was heated at 180 C for 12 hours, cooled to room ~Lu.e and added to 200 ml of ice/water. 1~
ml of ~u...e..LL~Led hydrochloric acid was added to the resultant mixture and the p~ of the mixture was ad justed to 8 with sodium hydrogencarbonate. After extraction with 200 ml of chloroform three _ _ _ .. . ... ... ... _ _ W096/03393 ;~ 4 ~ 2 1 ~ 7~ 45 I~,IIJ. _. .1:
times followed by drying over sodium sulfate, chloroform was ~l; ct~ fl off under reduced pressure to obtain 2-amino-l-LhinnArh~hnl. 2-Amino-l-thionaphthol thus obtained was fed into a 50 ml short-neck flask provided with a reflux nnn~l~nc~r and heated at 180 C for 4 hours. The resultant mixture was added to 200 ml of water. After extraction with 200 ml of ethyl acetate three times followed by drying over sodium sulfate, ethyl acetate was distilled off under reduced pressure to obtain the intended compound.
Yield: 71. 9 % .
.p.: 210 to 224 C-2) Synthesis of 3-methoxyethv~yeLl~v~yeLllylnaphtho[2~l-d]~h;A7nlin-2-on:
2.0 g of naphtho[2,1-d]thiazolille-2-on, 3.0 g of 2-methoxyethoxyethoxy-l-iodoethane (synthesized from yeUlu~ye~llu~LyeU~yl p-to~ npclllfnnA~ and sodium iodide), 0.6 g of potassium hydroxide and 20 ml of ethanol were fed into a 50 ml short-neck flask provided with a reflux nnn~nC~r~ and heated under reflux and under stirring for 4 hours. After cooling to room ' clLULe followed by extraction with 300 ml of ethyl acetate ar.d 150 ml of water, the thus-obtained ethyl acetate layer was dried over sodium sulfate, and ethyl acetate was distilled of f under reduced pressure . The obtained compound was purified by column ~ L-I ' , , ' y (hexane: ethyl acetate =
1:1 ) to obtain the intended compound.
Yield: 51.9 % (oily ,. uba~llce).
3) synthesis of 3 - Lllv~yeLl.u.~ .v.syeLhylnaphtho[2~l-d]~hiA7nl;n~-2 thion:
1.7 g of 3-methoxyetho~yeLl~o~yeLhylnaphtho[2~l-d]~h;A7nl;n~-2-on~
2 . 4 g of I,awesson ' 8 reagent and 10 ml of toluelle were fed into a 50 ml short-neck flask provided with a reflux condenser. The resultant 2 1 ~7445 Wo 96l033s3 , ~ /J. 5 C. ~

mixture was heated under rer1uY and stirring for 2 hours. After cooling to room temperature followed by purification by column chL, LOY-G~I.Y ~heYane: ethyl acetate = 3:1), the intended compound was obtained.
Yield: lO0 % (oily auLaLanc~).
4 ) Synthesis of 3-ethyl-5- ( 3-methoxyethoxyethoxyethylnaphtho [ 2 ,1-d]~hiA~ol;n-2-ylidene)~hiA-oli~l;n~-4-on-2-thion:
1.9 g of 3 - Lh~y~:Lhu,.yeLhoAy~Lhylnaphtho[2~l-d]thiazoline-2 thion and l . 8 g of methyl p-toluenesulfonate were fed into a 50 ml 6hort-neck flask provided with a reflux condenser. The resultant mixture was heated at 120C for 4 hours. After cooling the reaction mixture to room temperature followed by addition of 0 . 8 g o~ 3-ethyl~h;A~rl;~;n~-4-on-2-thion and 24 ml of acetonitrile, the resultant mixture was cooled to sC, and 1.0 g of triethylamine was added thereto After stirring at lO C for 24 hours, yellow prer;ritAt~C thus obtained were suction-filtered, washed with lO ml of acetonitrile three times, and dried to obtain the intended compound.
Yield: 30.0 ~.

5) S y n t h e s i s o f 3 - e t h y l - 2 - ( [ 3 - e t h y l - 5 - ( 3 -methoxyethoxyethoxyethylnaphtho[2,1-dlthiazolin-2-ylidene) ]-4-n-rnth;A7nl;~;n--2--yl;~'~~ Ll~yl~ b~n~n~h;~-n1; I.loride (compound 1--6):

0 . 7 9 of 3 -ethyl -5- ( 3 -methoxyethoxyethoxyethylnaphtho [ 2 ,1-d]~h;A~nl;n-2-ylidene)~h;A~ol;~;n~-4-on-2-thion), 0.8 g of methyl p-toluenesulfonate and l ml of dimethylfnrr-mi~p were fed into a 100 ml short-neck f lask provided with a ref lux condenser . The resultant mixture was heated at 120 C ~or 3 hours. After cooling the reaction mixture to room, GLu.e followed by addition of 0 . 5 9 of 3-ethyl-2-WO 96/03393 2 1 ~ 7 4 4 5 . l,JA
.
methylbenzothiazolium=p-toluenesulfonate (synthesized from 2-methylbenzothiazole and ethyl p-toluenesulfonate) and 7 ml of acetonitrile, the resultant mixture was heated to 50~C. 0.6 g of triethylamine was added thereto. The resultant mixture was stirred at that ~ - o.LUL~ for 1.5 hours and then cooled to room temperature.
50 ml of ethyl acetate and 50 ml of hexane were added to the reaction mixture, and the resultant miYture was stirred at room temperature for 30 minutes. The sl~rPrn~t~nt liguid thus ~ormed was removed. The residue was dissolved in 10 ml of methanol, and the solution was passed through a column filled with a strongly basic ion exchange resin (Diaion PA-318; a product of Mitsubishi Chemical Industries 1td. ) and eluted with methanol. The eluate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 8:1) to obtain the intended compound .
Yield: 0.6 g.
M. p.: 254 to 257 C
( 7 ) Synthesis of compound 1-7:
1) Synthesis of ~-methoxyeth~",y~ ~,c".y,U.ylrh~h~l;mi~P
1. 3 g of potassium phthalimide, 2-methoxyethoxyethoxy-1-; n~e~h~n-~ and 5 ml of dimethyl ~ ~P were fed into a 100 ml short-neck f lask provided with a ref lux n nnAPnePr . The resultant mixture was heated at 90C for 3 hours. 100 ml of ethyl acetate was added thereto and the resultant mixture was cooled to room temperature. White precipitates thus obtained were suction-filtered, and the filtrate was washed with 100 ml of water. The obtained ethyl acetate layer was dried over r~n~si sulfate, and ethyl acetate was distilled off under reduced pressure to obtain the intended compound.

WO 96/03393 , ~ f, 1!~ ; 2 1 8 ~ 4 ~ 5 1 ~.,J. 1408 Yield: 100 % (oily substance).
2) synthesis of 3-methoxyethoxyethoxyethyl~h;:~7nl;~;np-4-on-2-thion:
2.1 g of N-methoxyethoxyethoxyethylphthalimide, 0.4 9 of hydrazine monohydrate and 3 ml of methanol were fed into a 50 ml short-neck f lask provided with a ref lux n nndpncpr . The resultant mixture was heated under reflux and stirring for 2 hours. The white precipitates thus formed were suction-filtered through Celite. lO ml of triethylamine was added to the filtrate, and the resultant mixture was cooled to 5C. 0.6 g of carbon ~l;clllf;~e was added to the mixture.
After stirring at room temperature for 1 hour, O.9 g of ethyl chloroacetate was added to the mixture. After stirring at 40 C for l hour, the reaction mixture was added to lO0 ml of water. The precipitates thus formed were suction-filtered. Thc obtained filtrate was subjected to the extraction with lO0 ml of ethyl acetate three times and the extract was dried over r-~nPci sulfate. Ethyl acetate was distilled off under reduced pressure to obtain the intended compound.
Yield: 86.9 % ~oily sllhc1-AnnP).
3 ) Synthesis of 3 -methoxyethoxyethoxyethyl - 5- ( 3 -methylnaphtho [ 2 ,1-d]th;~7olin-2-ylidene)fh;~7nl;~1inP-4-on-2-thio~:
2.5 g of 3-methyl-2-methylthionaphtho[2,1-dlthiazolium p-tol~l~nPslllfnn~te (syn~hpc;7~p~ from 2-methyl~h;nn~rh~hn[2~l-d]thiazole and methyl p-toluenesul f onate ), l . 7 g of 3 -methoxyethoxyethoxyethylthiazolidine-4-on-2-thion and 30 ml of acetonitrile were fed into a lO0 ml thrcc n~_h~ad flask, and cooled to 5 'C. 1.2 g of triethylamine was added to the resultant mixture. ~fter stirring at 10 C for 4 hours, yellow precipitates thus formed were suction-filtered, washed with 10 ml of acetonitrile twice and dried to obtain the intended compound.

_ _ _ _ _ _ , . .. . .. .... . ..

Wo 96/03393 ~ ~ 2 1 8 7 4 ~ 5 r_l,J. ~"
Yield: 71.2 ~
M. p.: 188 to 192 C
4 ) Synthesi s of 3 -methoxyethoxyethoxyethyl- 5 - ( 3 -methylnaphtho [ 2 ,1-d]thiazolin-2-ylidene)-2-methylthio-4-oxo-2-thiazolium=p-toluenesulf onate:
l . 0 g of 3 -methoxyethoYyethoxyethyl-5 - ( 3 -methylnaphtho [ 2 ,1-d]thiazolin-2-ylidene)thiazolidine-4-on-2-thion, 1.2 9 of- methyl p-toluenesulfonate and 2 ml of dimethylformamide were fed into a 100 ml short-neck flask provided with a reflux cnn~PnC~r. The resultant mixture was heated at 120 C for 3 hours. 50 ml of ethyl acetate was added to the resultant mixture. After cooling to room temperature, yellow crystals thus formed were suction-filtered, washed with lO ml of ethyl acetate twice and dried to obtain the intended compound.
Yield: 100 ~.
M. p.: 126 to 134 C .
5) Synthesis of 3-ethyl-2- ~ [3-methoxyethoxyethoxyethyl-5-(3-methylnaphtho [ 2, l-d ] thiazolin-2-ylidene ) ~ -4-oxothiazolidin-2-yl;ll~r Lhyl ~ be-n7o~h;A7nli~l--chloride (compound 1-7):
l . 4 g of 3 -methoxyethoxyethoxyethyl -5- ( 3 -methylnaphtho [ 2 ,1-d]thiazolin-2-ylidene)-2-methylthio-4-oxo-2-thiazolium=p-toluenesulfonate, 0.7 g of 3-ethyl-2-methylbenzothiazolinium=p-toluenesulfonate and lO ml of acetonitrile were fed into a 100 ml U..cc n~k~d flask provided with a reflux ~ , and then heated to 50 C . 0 . 8 g of triethylamine was added to the resultant mixture .
After stirring at that temperature for 1.5 hours followed by the addition of 80 ml of ethyl acetate, the obtained mixture was cooled to room t. _ .ILULe. Red precipitates thus formed were suction-filtered ~nd washed with 20 ml of ethyl acetate twice. The crystals thus W096/03393 ' "' ;' ~ 21~7445 ~ ;
obt4ined were dissolved in 25 ml o~ methanol/chloroform ~4/1~, and the solution was passed through a column filled with a strongly basic ion eYchange resin (Diaion PA 318; a product of Mitsubishi Chemical Industries 1td. ) and eluted with methanol. The eluate was ~u..c~..LL4Led under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 5:1) to obtain the intended compound .
Yield: 0.7 g.
M. p.: 228 to 235 C
( 8 ) Synthesis of Compound 1-8:
The intended compound was obtained from 3-metho,.yeLh~,.y~u~ ye u-yl-2-methyl-benzothiazolium=iodide and 3-ethyl-5-(3-methylnaphtho[2,1-d]fhi~701in-2-ylidene)-2-methylthio-4-oxo-2-~h; ~7nl; p-tol~ npclllfnn:lt~ in the same manner as that of the steps of the synthesis of compound 1-3.
Yield: 0.72 g M. p.: 228 to 235 C -( 9 ) Synthesis of Compound 1-9:
1) Synthesis of 3-(1,3-dioxane-2-ethyl)-benzoth;~7nl; _'LI 'rlf':
3 . 8 ml of 2- ( 2-bromoethyl ) -1, 3-dioxane and 5 ml of 2-methylbenzothiazole were fed into a 100 ml thL.e n~_k~d flask provided with a reflux cnn~nC~r~ and heated at 110 C under stirring for 3 hours. 50 ml of acetone and 30 ml of ethyl acetate were added to the resultant mixture. After stirring at room temperature, the formed crystals were suction-f iltered, washed with ethyl acetate and dried .
Yield: 8 g.
M. p.: 110 to 119 C -2 ) synthesis of 3- ( 1, 3-dioxane-2-ethyl ) -2- ¦ [ 3-ethyl-5- ( 3-W096/03393 ; ~ 2 1 ~ 74 4 5 methylnaph~ho[l,2-d]thiazolin-2-ylidene) ]-4-oxothiazolidin-2-yli~r- L~.yll hen7othi~7oli '` loride (compound l-9):
0.95 g of 3-(1,3-dioYane-2-ethyl)-benzofhi~7rlli bromide, 1.5 g of 3-ethyl-5-(3-methylnaphtho~1,2-d]~h;~7r~l;n-2-ylidene)-2-methylthio-4-oYo-2-thiazolium=p-tol~nr~culfnn~te and 30 ml of acetonitrile were fed into a 100 mQ Ll~.~L ne~kt:d flask proYided with a reflux ~ n~c~nc~r, The resultant mixture was heated to 60 C- 1 ml of triethylamine was added dropwise to the mixture. After stirring the mixture at that temperature for 5 minutes followed by addition of 100 ml of ethyl acetate, the reaction liquid was cooled to room temperature. The crystals thus formed were suction-filtered and washed with 50 ml of ethyl acetate. The crude crystals thus formed were dissolved in 50 ml of chloroform/methanol (1:1). 400 ml of ethyl acetate was added to the solution, and the crystals thus formed were suction-filtered.
The crystals thus obtained were dissolved in lO0 ml of methanol/chloroform (4:1). The solution was passed through a column filled with a strongly basic ion exchange resin (PA 318; a product of Nitsubishi Chemical Industries ~td. ) and eluted with methanol. The eluate was collected and then naturally filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, and ethyl acetate was added to the solution to precipitate the crystals. The crystals were suction-filtered, washed with ethyl acetate and dried at room -~u.~ under redu~ed pressure to obtain the intended compound.
Yield: 0 . 8 g.
N. p.: 170 to 175 C
( 10 ) Synthesis of Compound l-10:
The intended compound was obtained f rom 3 -WO 96103393 ~ 2 1 8 ~ ~ 4 5 p~ ,,J~ ~ ~ ~
methoxyethoxyethoxyethyl-2-methyl-benzothiazolium=iodide and 3-ethyl-5-(3-methylnaphtho[2,1-d]thi~701;n-2-ylidene)-2-methylthio-4-oxo-2-~h;~7nli p-tnlllPn~ lfnn~tp in the same manner as that of the steps of the synthesis of compound 1-3.
M. p.: 216 to 223 C .
( 11 ) Synthesis of Compound 1-11:
1 ) Synthesis o~ 3-methoxyethoxyethoxyethyl-2-methyl - [ 2 ,1-d ] nArhthnth i ~ 7n 1 i ~ . p~. 1 f tln~t~:
3.8 g of (1-methoxyethoxy)ethyl h~ lfnn~te, 3 g of 2-methylnaphtnothiazole and 3 ml of xylene were fed into a 200 ml three-necked flasX provided with a reflux condenser, and heated at 110 C
under stirring for 5 hours. 150 ml of ethyl acetate was added to the resultant mixture. After stirring at room temperature, the formed crystals were suction-filtered, washed with ethyl acetate and dried.
Yield: 8 g.
M. p.: 80 to 88 C .
2) Synthesis of 3-ethyl-5-(3-methylbenzothiazolin-2-ylidene)-2-methylthio- 4 -oxo-2 -~h i / 7n 1 i ~-tol uenesulf onate:
17 g of 3-ethyl-5-(3-methylbenzothiazolin-2-ylidene) thiazolidine-4-on-2-thion and 80 ml of methyl p-toluenesulfonate were fed into a 1 G tllL~_~ n~.k~:d flask provided with a reflux , ~ , and then heated at 120C under stirring for 4 hour$. 700 ml of acetone was added to the obtained mixture. After cooling to 25 C, the precipitates formed were suction-filtered, washed with 100 ml of acetone and dried.
M.p.: 200 to 208 'C .
3~ Synthesis of 3-methoxyethoxyethoxyethyl-2- ~ [3-ethyl-5-(3-methylbenzo~hi~7^1in-2-ylidene)]-4-oxothiazolidin-2-yli~Pn ~hyl naphtho [ 2, l-d ] ~h i ~7~ loride ( compound 1-11 ):

W096/03393 ~ h~ 74~5 l .1 g of 3-methoYyethoYyethoYyethyl-2-methyl - [ 2 ,1-d ] naphthothiazolium=benzenesulf onate, l g of 3-ethyl-5- ( 3 -methylbenzothiazolin-2-ylidene ) -2-methylthio-4-oxo-2-thiazolium=p-toluenesulfonate and 20 ml of acetonitrile were fed into a 200 mQ
three-necked flask provided with a reflux c-ln~nC~r. The resultant miYture was heated to 60 'C- 2 ml of triethylamine was added dropwise to the miYture. After stirring the mixture at that temperature for 5 minutes followed by addition of 150 ml of ethyl acetate, the reaction liquid was cooled to room temperature. The resultant crystals were suction-filtered and then washed with 50 ml of ethyl acetate.
The crude crystals thus formed, 2 ml of a strongly basic ion exchange resin (PA 318; a product of Nitsubishi Chemical Industries Ltd. ) and 150 ml of methanol/chloroform (4:1) were fed into a 300 ml beaker. After stirring at room temperature for 3 hours, the miYture was passed through a column filled with the strongly basic ion eYchange resin (PA 318; a product of Mitsubishi Chemical Industries Ltd. ) and eluted with methanol. The eluate was collected and then naturally filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, and ethyl acetate was added to the solution to precipitate the crystals. The crystals were suction-filtered, washed with ethyl acetate and dried at room temperature under reduced pressure to obtain the intended compound.
Yield: 0 . 5 g .
M. p.: 208 to 220 C
( 12 ) Synthesis of compound 1-12:
The intended compound was obtained f rom 3-methoxyethoxyethoxyethyl-2-methyl-benzo~hiA7~l; iodide and 3-ethyl-5-(3-methylbenzo~hiA7r~l in-2-ylidene)-2-methylthio-4-oxo-2-thiazolium=

_ _ _ _ . _ _ _ . _ _ .. . , ... . .. . _ _ . , _ _ ... _ . . ... , _ WO 96103393 ' ~ $ . . ~ ~ Q 7 ~ ~ 5 p-toluenesulfonate ln the same manner as that of the steps of the synthesis of compound 1-3.
M. p.: 236 to 238 C .
( 13 ) Synthesis of compound 1-13:
The intended compound was obtained f rom 3-methoxyethoxyethoxyethyl-2-methyl-benzo~h;l7n~ ^-iodide and 3-ethyl-5-(5-methoYy-3-methylbenzo~hi~7ol in-2-ylidene~-2-methylthio-4-oxo-2-~hi;~7nl; ,-tolll"n~clllfnnA~,~ in the same manner as that of the steps of the synthesis of compound 1-3.
M. p.: 221 to 227 C .
(14) Synthesis of compound 1-14:
The intended compound was obtained f rom 3-ethyl-5- ( 3-methylthiazolin-2-ylidene ) -2-methylthio-4-oxo-2-thiazolidinium=p-toluenesulfonate and 3-methuAy~ o~Lyt:Lhoxyethyl-2-methylnaphtho[2,1-d]thi;~7~1; p Lolll.on~ fnnAte in the same manner as that of the steps of the synthesis of compound 1-3.
M. p.: 193 to 203 C .
( 15 ) Synthesis of compound 1-15:
1) Synthesis of 2-amino-3-methoxyethoxyethoxyethylthiazolium=p-tol~Pn-~e-- 1 fnnltP
2-Aminothiazole and l . 4 equivalents of methoxyethoxyethoxyethyl=
p-toluenesulfonate were heated on an oil bath of a temperature of 120 C under stiring for 4 hours. ~thyl acetate was added to the resultant mixture. After the d~nln~t;nn~ the ~-esidue was used for the æ~ reaction.
2) Synthesis of compound 1-15:
The intended compound was obtained from 3-ethyl-5-(3-methylnaphtho ~ 2, l-d ] thiazoline-2-ylidene ) -2-methylthio-4-oxo-2-53 `` .
W096/03393 - 2 1 87445 ~ J~
.
~hi~701i,tini p-tol~n-~c--lfnnAt.~ and the reaction product obtained in the above step 1 ) in the same manner as that: of the steps of the synthesis of compound 1-3.
N. p.: 85 to 92~C.
(16) synthesis of compound 1-16:
The intended compound was obtained f rom 3-ethyl-5- ( 3-methylnaphtho[l,2-d]~h;~701;n~-2-ethylidene)-2-methylthio-4-oYo-2-fh;sl7~ ;n;um=p-toluenesulfonate and 3-methoxyethoxyethoxyethyl-2-methylnaphtho[2,1-d]~h;A7nl; p toll~n~c~lfnn~te in the same manner as that of the steps of the synthesis o~ compound 1-3.
M. p.: 167 to 177 C ~
The melting points and MNR data of the methine, _ ~c 1-l to 1-16 of the present invention synth~c;7~1 in Example l are given in the following Table l.

2~ 87445 W096103393 , ¦~ `) tJ~ F~
.
Table l Compound No. M-P. (-C) NMR chemical shift(DMSO-d6) TMS standard -- 1 208~214 o 8.50(1H, d, 8.0Ez), 8.08(1H, d, 8.0~z~, 8.00(1E, d, 8.0Hz), 7.95(2E, dd, 8;0, 6.7Hz), 7.82(1H, d, 8.0Ez), 7.68(2E,m), 7.50(1E, dd, 20.0, 6.7Hz), 7.50(1H, d, 8.0Ez), 7.10(2E,d, 8.0Hz), 6.72(1E,s), 4.85(2E,m), 4.55(2E, m), 4.32(2E, q, 6.7Ez), 3.90(2H, m), 3.52(2E, m), 3.40(2E, m~, 3.32(4E, m~, 3.15(3H, s~, 2.27 (3H, s~, 1.30(3H, t, 6.7Ez) -- 2 194~204 a 8.58(1H, d, 8.0Hz), 8.15(1H, d, 8.0Hz), 8.06(1E, d, 8.0Hz), 8.00(2H, dd,l3.0, 8.0Hz), 7.90(1H, d, 8.0Hz), 7.70(2H, dd, 8.0, 6.7Hz), 7.60(1H, d, 6.7Ez), 7.50(1H, t, 6.7Hz), 6.78 (lE, s), 4.92(2E,m~, 4.55(3H, s~, 4.28(2H, q, 6.7Ez~, 3.90(2E, m~, 3.50(2H, m~, 3.40(2E,m~, 3.28(4E, m), 3.15(3H, s), 1.30(3H, t, 6.7Ez) -- 3 190~195 G 8.5~(1H, d, 8.0Hz), 8.15(1H, d, 8.0Hz), 8.06(1E, d, 8.0Hz), 8.00(2H, dd,l3.0, 8.0Hz~, 7.90(1H, d, 8.0Hz), 7:70(2E, dd, 8.0, 6.7Hz), 7.60(1E, d, 6.7Ez), 7.50(1E, t, 6.7Ez), 6.78 (lH, s), 4.92(2E,m), 4.55(3E, s), 4.28(2E, q, 6.7Hz), 3.90(2H, m), 3.50(2H, m), 3.40(2H,m), 3.28(4H, m), 3.15(3E, s), 1.30(3E, t, 6.7Ez) W0~6103393 ~ 2187445 .
Compound No. M.P. (C) NMR chemical shift~SSO-d6) - TMS standard -- 4 170~180 ~ 8.56(1H, d, 8.0Hz), 8.13(1H, d, 8.0Ez), 8.03(2H, t, 6.7Hz), 7.90(2H, t, 8.0Hz), 7.73 (2H, t, 6.7Ez), 7.60-7.45(2H, m), 6.73(1E,s), 4.96-4.86~2E,m), 4.56(3E,s), 4.37-4.21(2E,m), 3.98-3.87(2E, m), 3.57-3.47(2E, m), 3.47-3.34 (8E, m), 3.16(3E, s), 1.33(3H, t, 6.7Ez) -- 5 160~170 ~ 8.53-8.37(1E, m), 8.25-7.88(4E, m), 7.83 (lH, d, 8.0Ez), 7.74-7.37(3E, m), 7.34(1E, t, 8.0Hz), 6.96(1H, t, 8.0Hz), 6.66(1H, s), 5.02 -4.86(2E,m), 4.57(3E,s), 4.34-4.14(2E,m),4.12 --3.96(2E, m), 3.52-3.47(2E, m), 3.46-3.35(2E, m), 3.35-3.24(2E, m), 3.24-3.12(2H, m), 3.06 (3E, s), 1.32(3H, t, 6.7Hz) -- 6 254~257 ~ 8.22(m,1E), 7.63~7.80(m, 3E), 7.53(d, lH, 8.0Hz),7.21 ~7.45(m, 5E), 6.89(s,1E), 4.95~5.05(m, 2E), 4.75~4.86(m, 2E), 4.64 ~ 4.75(m, 2E), 4.10~ 4.20(m, 2H), 3 .50~
3.60(m, 2H), 3.35~3.45(m, 2E), 3.20~3.28 (m, 2E), 3.16~3.24(m, 2E), 3.14(s, 3E),1.35 ~1.47(m, 6H) -- 7 228~235 ~j 8.19(d, lE, 8.0Hz), 7.82~8.06(m, 5E), 7.68(dd, lE, 8.0,8.0Ez), 7.51(dd,1E, 8.0,8.0 Hz), 7.41(dd, lH, 8.0,8.0Hz), 7.33(dd, lE, 8.0,8.0Ez), 6.56(s, lH), 4.50(q, 2H, 6.7Hz), 2 1 ~7445 WO 96l033g3 ~ /J. 5 ~; ~
.
4.40(t, 2~, 6.7~z), 4.21(s, 3H), 3.8(t, 2}~, 6.7Hz), 3.57~3.61(m, 2H), 3.46~3.51(m,2H), 3.37~3.43(m, 2H),3.29~3.34(m, 2H), 3.08(s, 3H), 1.33(t, 3H, 6.7Hz) -- 8 228~235 o 8.20(1H, d, 8.0Hz), 7.94(6H, m), 7.68 (lH, t, 8.0Ez), 7.48(2H, m), 6.62(1H, s), 4.80(2H, m), 4.28(3H,s), 3.88(2H, m), 3.54 2H, m), 3.40(2H, m), 3.30(4H, m), 3.15(3H,s), 1.30(3H, t, 6.7Hz) -- 9 170~175 a 8.58(1H, d, 8.0Hz), 8.16(1H, d, 8.0Hz), 8.04(2}I, d, 8.0Hz), 7.90(2H, m), 7.70(2H, m), 7.55(2H, m), 6.64(1H,s), 4.74(1H, s), 4.70 2H, m), 4.55(3H, s), 4.24(2H, m), 4.00(2H,dd, 10.0, 3.3Hz), 3.68(2H, dd, 10.0, 8.0Hz), 2.10 (2H, m), 1.32(5H, m) * Compound No.s 1-6 arld 1-7: NMR chemcial shift (C3Cl, ) W0 96/03393 ~ F f 2 1 8 7 4 4 5 ~ s 5 . 1 . ~
.
Compound No. M.P. ( C) NM}~ chemical shift(DMSO-d6) TMS standard -- l 0 216~223 O 8.54~1H, d, 8.0Hz), 8.26(1H, d, 8.0Hz), 8.14(1H, d, 8.0Hz), 8.00(2H, dd, 16.7,6.7Hz), 7.92(1H, d, 8.0Hz), 7.60(4H, m), 6.-80(1H, s), 4.88(2H, m), 4.55(3EI, s), 4.22(2H, m), 3.90 (2H, m), 3.52(2H, m), 3.40(2H,m), 3.30(4H,m), 3.15(3H, s), 1.20(3H, t, 6.7Hz) -- 1 1 208~220 o 8.30(1H, d, 8.0Hz), 8.17(1H, d, 8.0Hz), 8.05(1H, d, 8.0Hz), 8.05(2H, d, 6.7Ez), 7.85 (lH, d, 6.7Hz), 7.75(2H, t, 6.7Ez), 7.64(1H, d, 8.0Hz), 7.55(1H, t, 6.7Hz), 7.28(1H,t,6.7 Hz), 7.20(1H, t, 6.7Hz), 6.75(1H,s), 5.00(2H, m), 4.22(2H, 5), 4.22(3E, 8), 3.94(2H,m), 3.50(2H, m), 3.45(2H, m), 3.25(2H, m), 3.15 (2H, m), 3.05(3H, s), 1.28(3H, t, 6.7Hz) -- l 2 236~238 o 8.20(1H,d,8.0Hz),7.88(1H,d,8.0Hz),7.75(1H, d, 8.0Hz), 7.65(1H, d, 8.0Hz), 7.48(1H,t, 8.0 Hz), 7.20(1H, d, 3.3/Iz), 6.80(1H,dd,8.0, 3.3 Hz), 6.67(1H, s), 4.80(2H, m), 4.25(2H,m), 4.
18(3H, s), 3.85(2H, mj, 3.68(3H, s), 3.50(2H, m), 3.40(2H, m), 3.28(4H,m), 1.27(3H,t,6.7Hz) -- 1 3 221~227 o 8.20(1H, d, 8.0Hz), 7.92(2H, d, 8.0Hz), 7.75(1H, d, 8.0Hz), 7.70(1H, dd, 13.0,8.0Hz), 7.52(1H, d, 8.0Hz), 7.~2(1E, t, 8.0Hz), 7.25 (lH, t, 8.0Hz), 6.75(1H,s), 4.90(2H,m), 4.28 . . . , .. _ . . . . ... . .

WO 96103393 ! .~ 2 1 8 7 4 4 5 ~ . . s (2H, m),4.20~3H, s~, 3.90(2H,m), 3.S0~2H,m), 3.40~2H, m), 3.28(4H, m), 3.15(3H,s), 1.27 (3H, t, 6.7Hz) -- 1 4 193~203 ,~i 8.40-8.06(4}~, m~, 7.82(1H, t, 8.0H2), 7.72(1H, t, 8.0Hz), 6.83(1H, s), 5.07-4.96 2H, m), 4.17(2H, q, 6.7Hz), 4.05(2H,t,8.0Hz), 3.97-3.86(2H, m), 3.53(3H, s), 3.S4-3.45(2H, m), 3.26-3.17(2H, m), 3.04(3H, s), 1.23(3H,t, 6.7Hz) -- 1 5 85~92 ~ 8.56(1H, d, 8.0Hz), 8.14(1H, d, 8.0}~z), 8.07(1H, d, 8.0Hz), 8.05(1H, m), 7.96(1H, d, 8.0Hz), 7.83(1H, d, 8.0Hz), 7.77-7.62(2H, m), 4.56(2H, t, 6.7Hz), 4.47(3H, s), 4.10(2H, q, 6.7Hz), 3.86(2H, t, 6.7Hz), 3.65-3.86(8~, m), 3.24(3H, s), 1.32~3H, t, 6.7Hz) -- 1 6 167~177 ~i 8.17-7.25~11H, m), 6.94-6.82~2H, m), 6.54 (lH, s), 5.96(1H, d, 12Hz), 4.95-4.74(2E, m), 4.20(3H, s), 4.14-3.97(2H,m), 3.97-3.84(2E,m), 3.53-3.50(2H, m), 3.47-3.38(2H, m), 3.35-3.27 2H, m), 3.26-3.17(2H,m), 3.10(3H,s), 1.26(3H, t, 6.7Hz) The absorption spectrum of each of the methine ~ ' ~ of the present invention synthesized in EYample 1, in the f orm of a solution thereof in methanol, was ~t~min-~d. The maximum absorption wave length and molar extinction ~o~ffir;~nt: of each compound are given in Table 2.

7 4 4 5 . ~ ~14:
WO 96/03393 P- ""
.
T~ble 2 Compound No. 1 u- o~ ~
(nm~ ( x 1 0 ' 1 - 1 5 1 7 6.8 9 1 - 4 5 1 7 6.8 0 1 -7 5 l 4 7-7 4 1 - 1 4 9 1 6.0 7 1 - 1 1 5 1 2 7 . 6 3 1 -12 5 0 2 7.4 1 1-14 4 8 3 5.3 8 1 - 1 5 4 6 2 4 . 5 1 1 - 1 6 6 2 3 9.7 4 xample 2 The solubility test of each of the compounds of the present invention synth~ci 7-.~1 in EYample 1 was Conditions of eYperiment of solubility:
The solubility tests were conducted by the following methods of tests 1 and 2:
est 1: S mg of a methine compound is fed into a test tube, to which S

W0 96/03393 ~ 2 1 8 7 ~ 4 5 I-1/JA 1~
ml of ion-~oYrh~n~d water is added, the result~nt mixture ia shaken at room temperature for 5 minutes, and the solubility thereof is macrnccori~ ly cnnf; ' ~1 mg/ml solution).
Test 2: 5 mg of a methine compound is fed into a test tube, to which 0.5 ml of ion-~Y~h~n~ water is added, the resultant mixture is shaken at room temperature for 5 minutes, and the solubility thereof is macroscopically confirmed ~10 mg/ml solution) .
The results of the solubility test 1 are given in Table 3, and those of the test 2 are given in Table 4.
Comparative ~c The following compounds S-l to S-3 were used as comparative ' c /~ CH
S- 1 C2Hs ~N N
C2Hs ~,OCH
S-3 ~`rCH~ ~ cr C2Hs l o--OH

W096/03393 . .~ -L. 2 1 8 ~ 4 4 5 ~ J.. 1408 .
Table 3 Compound No. solubility 1 mg/mL 10 mg/mL
1-3 soluble soluble 1-4 soluble soluble 1-5 soluble Sllcr~nc; nr 1-6 soluble soluble 1-7 soluble soluble 1-8 soluble Sl~crc.nci nr 1-9 . soluble sllcr~ncinn 1-10 soluble soluble 1-11 soluble solùble 1-12 soluble soluble 1-13 soluble soluble 1-14 soluble soluble 1-15 soluble soluble 1-16 soluble S-lcr~.nci nr~
S-l S~lcF~nc;nn Sllcr~nc;nr~
S--2 sllcr~nc; nn Sllcp~nc; nr~
S--3 Sllcr~nc; nn SllCr.~nc; nr~

In the above-described solubility tests, all of the 's l-3 to 1-16 of the present invention were dissolved to form a solution having a concentration of at least l mg/ml, while the comparative compounds S-l, 5-2 and S-3 were not dissolved.
EYample 3 The solubility of each of the ~ of the present invention ... . ... . . . . . _ _ . .. .. . _ ..... .. .. _ .. . . ... . , _ .. . ..

WO 96l03393 ~ X ~' ~ 2 1 8 7 4 4 5 PCT/~ /01408 synthesized in Example 1 in 5 ~ glucose solution f or in jection was examined .
Experimental conditions:
5 mg of a methine compound was f ed into a test tube, to which 0.5 ml of 5 ~ glucose solution for injection was added, the resultant mixture was shaken at room; ' 1: for 5 minutes, and the solubility thereof was macroscopically cnnf; e~l (lO mg/ml solution). The results are given in Table 4.

Table 4 Compound ~o. Solubility 10 mg/mL
1-3 soluble 1-4 soluble 1-7 soluble 1-8 soluble 1-10 soluble 1-11 soluble 1-12 soluble 1-13 soluble 1-14 soluble 1-15 soluble 1-16 soluble S--1 Sllernnc; nn S-2 Sllcpnnc; nn S -3 s-- cp~n c inn It is apparent from the results that the methine . _ ~c Of ~ 6 W096l03393 ;~ ~h ~ f~ 2 t ~ 7~ 4 5 r~ .. 1408 .
th~ present invention have a far higher solubility than the ordinary rhodacyanine dyes in the preparation of the injection preparations.
Example 4 Activity of the present pharmaceutical compositions against human colonic epithelial carcinoma LS174T was ~t~rm;nP~l by use of nude mouse as follows:
As the human colonic epithelial carcinoma cell lines LS174T, there was used the established line by tryr~ini7in~ piece o~ LS174T
obtained from the operating theatre of the original adenocarcinoma of colon in such that the piece becomes suitable for cultivation. When this cultured cells 1S174T are hy~d~rm;~ ly injected to a nude mouse, the cells can be easily grown in the body of the nude mouse as a moderately to sufficiently differentiated hu~nan colonic epithelial carcinoma. The cells L5174T produce CEA in high level and can pro1if~rat~ in hamster cheek pouches or; -'~rived mice, so that it has been proven that the cells L5174T have neoplastic properties.
sALs/C nu/nu mice ~male, five weeks age) available from Charles River Japan Inc. were placed in an atmosphere having no pathogen.
Tumors formed by the hypodermic injection of human colonic epithelial carcinoma cell lines L5174T into the mice were cut off under the aseptic rrm~;t;nn, and the surrounding skin and connective tissue of the tumor tissues as well as the necrotic tissue located in the center of the tumor tissues were removed. The tumor tissues were cut in the form of 3-5 mm square, and the resulting one tissue was charged into a needle for ~rAn~rl~ntat;r~n to hyrQ~;~rm;~-~l ly transplant it into the mouse. The resulting mice were randomly divided into control group (six mice) and treating group ~ six mice ) . The intravenous administration of the pharr~^eu~; c~ 1 composition into the treating group started next day.

Wo96103393 !'~ C 21 ~7445 r l,J. s ;.~
The amount and schedule of the administration were determined based on the experience, mainly the knowledge ~rom the pretoxic-test data of LD
50 and LD 10. 5 % glucose solution or physiologic saline for injection was injected to the control group in the s2me amount as that to be illLL~V~ uusly injected to the treating group.
The rhArr-r~lt;cal composition was dissolved in 5 % glucose solution or physiologic saline for injection in such that the amount of the r~Arr-~etlt;cAl composition contained in the glucose solution or physiologic saline is 5 ml per one kg of weight of the mouse to be injected so as to prepare an injection liguid. When the proli~eration of tumor in the control group reached exponential growth phase and the size of the tumor became ~oterfAhl~ by touch with hand, i.e., generally three weeks a~ter the trAnerlAntA~;nr~, the experiment was stopped. Then the tumor of each mouse was cut off and the weight of the resulting tumor was measured by use of chemical balance. Regarding each group, tumor ;nh;h;~;nn pt~ L~y~ between the treating group and control group was ~Alc~lAt~d. The results obtained are shown in Table 5.

W0 96/03393 ' L` l` '~ ` 2 ~ g 7 4 ~ 5 r~l,J. .
Table S
Compound No . Dose schedule ( intravenous Tumor ~nhibition (mg/kg) administration: day) Ratio (%) 1-3 10 3, 7 51.1 13 9, 13, 15, 17 51, 3 1-47.5 6 71.5 10 8, 10 12 . 5 13, 15, 17 51, 17 1-77.5 3 83.0 10 6, 8, 10, 13 1-9 3 1, 4, 7 65.6 9, 11, 13, 18 1-11 8 1 6 7 . 9 10 3, 6, 8, 10, 15, 17 1-13 20 1, 3, 7, 11, 16, 18 45.2 1-15 10 1, ', 6, 8, 10, 13, 15 60.0 EYample 6: Nude Mice seariPg ~uman Melanoma as a Model System LOX, a human melanoma cell line, grown s~lh~-ut~n~m~ely in nude - mice was eYcised, trypsinized to yield a single cell si~er~neinn using a metal grid with a 4 mm mesh. Red blood cells were lysed by ;n-~llh~tinn with 0.17 molar ammonium chloride at 4 'C for 20 minutes. Five million , . . . ..... . .

W096/03393 h;' "~ 'C 21 8 7 4 4 5 P~ l408 .
viable trypan blue negative cells made up in 0.1 ml of Dul~ecco modified Eagles' medium ~DME) were injected into the peritoneal cavity of a male athymic Swiss nu/nu mouse. The control group and each LLI ' ' group consisted of 5 to 10 mice. ILI-' ' was, ~ ' the following day by intraperitoneal injection.
Ten control mice received 0 . 25 ml of 2~ dextrose on those days the treated groups were injected with the , '- of this-invention.
The compounds of the General FormUlas ~ I ) to ( II ) used in this invention which were tested are listed in Table 6 ~elow and the results obtained are shown in Table 6 of the accompanying drawings. T/C is the ratio, e~Lessed as a ~eL-:ellL~-ye of the mean survival age of the treated group to the mean survival age of the untreated control group.

W0 96/03393 ~ 2 1 8 7 4 4 5 l . l~J. . . I
Ta~le 6 C ~ ~c Dose schedule T/C %
(mg/kg) (day) 1-3 7.5 1, 2, 5, 7, 9, 13, 15, 20 153 %
1-7 5 1, 9, 15 129 %
10 2, 5, 7, 13 1, 13, 15 1-9 10 2, 5, 7 153 ~6 1, 15 1-11 10 2, 5, 7, 13 129 %

1-12 5 1 124 %
10 2, 5, 7, 9, 13, 15 1-13 7 . 5 2, 5 124 %
7, 9, 13, 15

Claims (18)

claims

1. A methine compound represented by the following formula (I):

(I) wherein Z1 represents a non-metallic atomic group necessitated for forming a five-membered nitrogen-containing heterocyclic ring together with -N(R1)-C-, Z? represents a non-metallic atomic group necessitated for forming a five-membered nitrogen-containing heterocyclic ring together with -N + (R? )=C-, R1, R2 and R3 each represent an alkyl group and at least one of R1, R2 and R3 represents an alkyl group substituted with a polyethylene oxide group wherein one end of the polyalkylene oxide having a degree of polymerization of 2 to 6 is terminated with a hydrophobic group or substituted with a heterocyclic ring containing two or more oxygen atoms, Q represents an anion, k represents a numeral necessitated to control the charge in the molecule at zero, p represents 0 or 1, and Y represents a methine group or nitrogen atom.

2. The methine compound of claim 1 which is represented by the following formula (II):

(II) wherein Z1 represents a non-metallic atomic group necessitated for forming a thiazolidine ring, benzothiazoline ring, benzoxazoline ring, naphthothiazoline ring or naphthoxazoline ring together with -N(R1)-C-, W1, and W2, each represent a hydrogen atom or they together form a non-metallic atomic group necessitated for forming a naphthalene condensed ring or benzene condensed ring, Q represents a halogen ion or organic acid anion, p represents 0 or 1, Y represents a methine group or nitrogen atom, R1, R2 and R3 each represent an alkyl group and at least one of R1, R2 and R3 has a substituent of the following formula III-a or III-b:

or (III-a) (III-b) wherein R4 represents an alkyl group having 2 or less carbon atoms, m represents 3 or 4 and n represents 2 or 3.

3. The methine compound of claim 2 wherein Z1 together with -N(R1)-C-forms an unsubstituted thiazolidine ring, benzothiazolidine ring, benzoxazoline ring, naphthothiazolidine ring or naphthoxazoline ring, the number of carbon atoms of the alkyl groups R1, R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocyclic ring is 5 or below, and Q represents iodine ion, chloride ion or sulfonic acid ion.

4. The methine compound of claim 2 wherein Z1 together with -N(R1)-C-forms a thiazolidine ring, benzothiazolidine ring, benzoxazoline ring, naphthothiazolidine ring or naphthoxazoline ring which has a substituent selected from the group consisting of halogen atoms, alkyl groups, alkoxy groups and hydroxyl group, the number of carbon atoms of the alkyl groups R1, R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocyclic ring is 5 or below, and Q represents iodine ion, chloride ion or sulfonic acid ion.

5. The methine compound of claim 2 wherein Z1 together with -N(R1)-C-forms an unsubstituted benzothiazolidine ring or naphthothiazolidine, the number of carbon atoms of the alkyl groups R1, R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocyclic ring is 5 or below, and Q represents iodine ion, chloride ion or sulfonic acid ion.

6. The methine compound of claim 2 wherein Z1 together with -N(R1)-C-forms a benzothiazolidine ring or naphthothiazolidine which has a substituent selected from the group consisting of halogen atoms, alkyl groups, alkoxy groups and hydroxyl group, the number of carbon atoms of the alkyl groups R1, R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocyclic ring is 5 or below, and Q represents iodine ion, chloride ion or sulfonic acid ion.

7. The methine compound of claim 2 wherein Z1 together with -N(R1)-C-forms an unsubstituted benzothiazolidine ring or napthothiazolidine, W1 and W2 together form a benzene condensed ring or naphthalene condensed ring, the number of carbon atoms of each of the alkyl groups R1 and R2 is 1 to 3, R, is represented by the formula (III-a) wherein m is 2 to 4 and R4 is an alkyl group having 1 to 3 carbon atoms, Y is a methine group and Q represents iodine ion, chloride ion or sulfonic acid ion.

8. The methine compound of claim 2 wherein Z1 together with -N(R1)-C-forms a benzothiazolidine ring which has an alkoxy group of 1 to 3 carbon atoms, the number of carbon atoms of each of the alkyl groups R1 and R2 is 1 to 3, R3 is represented by the formula (III-a) wherein m is 2 to 4 and R4 is an alkyl group having 1 to 3 carbonn atoms, Y is a methine group and Q represents iodine ion, chloride ion or sulfonic acid ion.

9. The methine compound of claim 2 wherein Z1 together with -N(R1)-C-forms a benzothiazolidine ring which has a methoxy group; W1 and W2 together form a benzene condensed ring, the number of carbon atoms of each of the alkyl groups R1 and R2 is 1 to 3, R3 is represented by the formula (III-a) wherein m is 3 to 4 and R4 is an alkyl group having 1 to 3 carbonn atoms, Y is a methine group and Q represents iodine ion, chloride ion or sulfonic acid ion.

10. A pharmaceutical composition for treatment of cancer which comprises:
(a) a therapeutically effective amount of a methine compound represented by the following formula (I):

(I) wherein Z1 represents a non-metallic atomic group necessitated for forming a five-membered nitrogen-containing heterocyclic ring together with -N(R1)-C-, Z2 represents a non-metallic atomic group necessitated for forming a five-membered nitrogen-containing heterocyclic ring together with -N + (R3)=C-, R1, R2 and R3 each represent an alkyl group and at least one of R1, R2, and R3, represents an alkyl group substituted with a polyethylene oxide group wherein one end of the polyalkylene oxide having a degree of polymerization of 2 to 6 is terminated with a hydrophobic group or substituted with a heterocyclic ring containing two or more oxygen atoms, Q represents an anion, k represents a numeral necessitated to control the charge in the molecule at zero, p represents 0 or 1, and Y represents a methine group or nitrogen atom, and (b) a pharmaceutical acceptable diluent and/or carrier.

11. The pharmaceutical composition of claim 10 wherein the methine compound is represented by the following formula (II):

(II) wherein Z1 represents a non-metallic atomic group necessitated for forming a thiazolidine ring, benzothiazoline ring, benzoxazoline ring, naphthothiazoline ring or naphthoxazoline ring together with -N(R1)-C-, W1 and W2 each represent a hydrogen atom or they together form a non-metallic atomic group necessitated for forming a naphthalene condensed ring or benzene condesed ring, Q represents a halogen ion or organic acid anion, p represents 0 or 1, Y represents a methine group or nitrogen atom, R1, R2 and R3 each represent an alkyl group and at least one of R1, R2 and R3 has a substituent of the following formula III-a or III-b:

or (III-a) (III-b) wherein R4 represents an alkyl group having 2 or less carbon atoms, m represents 3 or 4 and n represents 2 or 3.

12. The pharmaceutical composition of claim 11 wherein Z, together with -N(R1-C- forms an unsubstituted thiazolidine ring, benzothiazolidine ring, benzoxazoline ring, naphthothiazolidine ring or naphthoxazoline ring , the number of carbon atoms of the alkyl groups R1, R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocylic ring is 5 or below, and Q represents iodine ion, chloride ion or sulfonic acid ion.

13. The pharmaceutical composition of claim 11 wherein Z, together with -N(R1)-C- forms a thiazolidine ring, benzothiazolidine ring, benzoxazoline ring, naphthothiazolidine ring or naphthoxazoline ring which has a substituent selected from the group consisting of halogen atoms, alkyl groups, alkoxy groups and hydroxyl group, the number of carbon atoms of the alkyl groups R1 , R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocyclic ring is 5 or below, and Q represents iodine ion, chloride ion or sulfonic acid ion.

14. The pharmaceutical composition of claim 11 wherein Z1 together with -N(R1)-C- forms an unsubstituted benzothiazolidine ring or naphthothiazolidine, the number of carbon atoms of the alkyl groups R1 , R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocyclic ring is 5 or below, and Q
represents iodine ion, chloride ion or sulfonic acid ion.

15. The pharmaceutical composition of claim 11 wherein Z1 together with -N(R1)-C- forms a benzothiazolidine ring or naphthothiazolidine which has a substituent selected from the group consisting of halogen atoms, alkyl groups, alkoxy groups and hydroxyl group, the number of carbon atoms of the alkyl groups R1, R2 and R3 excluding the alkyl group substituted with the polyethylene oxide group or the heterocyclic ring is 5 or below, and Q represents iodine ion, chloride ion or sulfonic acid ion.

16. The pharmaceutical composition of claim 11 wherein Z1 together with -N(R1)-C- forms an unsubstituted benzothiazolidine ring or naphthothiazolidine, W1 and W2 together form a benzene condensed ring or naphthalene condensed ring, the number of carbon atoms of each of the alkyl groups R1 and R2 is 1 to 3, R3 is represented by the formula (III-a) wherein m is 2 to 4 and R1 is an alkyl group having 1 to 3 carbonn atoms, Y is a methine group and Q represents iodine ion, chloride ion or sulfonic acid ion.

17. The pharmaceutical composition of claim 11 wherein Z1 together with -N(R1)-C- forms a benzothiazolidine ring which has an alkoxy group of 1 to 3 carbon atoms, the number of carbon atoms of each of the alkyl groups R1 and R2 is 1 to 3, R3 is represented by the formula (III-a) wherein m is 2 to 4 and R4 is an alkyl group having 1 to 3 carbonn atoms, Y is a methine group and Q represents iodine ion, chloride ion or sulfonic acid ion.

18. The pharmaceutical composition of claim 11 wherein Z1 together with -N(R1)-C- forms a benzothiazolidine ring which has a methoxy group, W1 and W2 together form a benzene condensed ring, the number of carbon atoms of each of the alkyl groups R1 and R2 is 1 to 3, R3 is represented by the formula (III-a) wherein m is 3 to 4 and R4 is an alkyl group having 1 to 3 carbonn atoms, Y is a methine group and Q represents iodine ion, chloride ion or sulfonic acid ion.