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WO1989012080A1 - Nouveaux colorants de merocyanine - Google Patents

Nouveaux colorants de merocyanine Download PDF

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Publication number
WO1989012080A1
WO1989012080A1 PCT/US1989/002303 US8902303W WO8912080A1 WO 1989012080 A1 WO1989012080 A1 WO 1989012080A1 US 8902303 W US8902303 W US 8902303W WO 8912080 A1 WO8912080 A1 WO 8912080A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
viruses
carbon atoms
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1989/002303
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English (en)
Inventor
Wolfgang Hans Heinrich Gunther
Frederick Joseph Sauter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eastman Kodak Co
Original Assignee
Eastman Kodak Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/203,956 external-priority patent/US4937344A/en
Priority claimed from US07/203,957 external-priority patent/US4906750A/en
Priority claimed from US07/203,843 external-priority patent/US4885366A/en
Application filed by Eastman Kodak Co filed Critical Eastman Kodak Co
Publication of WO1989012080A1 publication Critical patent/WO1989012080A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/10—The polymethine chain containing an even number of >CH- groups
    • C09B23/107—The polymethine chain containing an even number of >CH- groups four >CH- groups
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/10—The polymethine chain containing an even number of >CH- groups

Definitions

  • Viruses can cause human or animal diseases.
  • a merocyanine dye MC540 is a useful agent which preferentially binds to the lipids in enveloped viruses or virus-infected cells and does not or binds only minimally to the other components of the cells to inactivate the viruses and virus-infected ce.lls.
  • the MC540 dye and its use in eliminating tumor cells from bone marrow grafts is described in "Elimination of Residual Tumor Cells from Autologous Bone Marrow Grafts by Dye-Mediated Photolysis: Preclinical Data", by Dr. Fritz Sieber in Photo- chemistry and Photobiologv. Vol. 46, No. 1, pages 71-76, (1987).
  • the problem to be solved by the present invention is to provide new compounds which are useful as antiviral agents.
  • novel merocyanine dyes that can be brought into contact with an effective amount of a photosensitizing agent and exposed to visible light until the viruses and virus-infected cells have been inactivated. It has been found that these novel dyes are also useful for selectively killing leukemic cells in bone marrow by photosensitization.
  • R-, and g are H; and any of R ⁇ and R «> i, Ry. and R 2 and Rg can together comprise the atoms necessary to form a fused 6-membered carbocyclic ring on the benzene radical to which they are attached;
  • Re and R are selected independently from a group consisting essentially of alkyl and benzyl of from 1—18 carbon atoms, provided that the sum of the carbon atoms in R 5 and Rg together is at least 8;
  • Ro is an alkylene group of 2-9 nuclear carbon and hetero atoms and CONH-groups ; and
  • Z + is a cation.
  • novel compounds useful as anti-viral agents and in the inactivation of leukemia cells have the formula:
  • X is selected for the group consisting of 0, Se and S
  • R-, and R g are H and any pair of R, and R,, R, and R 2 or
  • R 2 and R g can comprise the atoms necessary to form together with the atoms on the benzene radical to which they are attached, a fused 6-membered carbocyclic aromatic ring, such as a benzo ring, including a substituted benzo ring, such as a methyl-substi- tuted benzo ring and the like.
  • R 5 and R 6 are independently selected from groups consisting essentially of alkyl or benzyl groups containing from about 1 to about 18 carbon atoms provided that the sum of the carbon atoms in R e and R, is at least 8 such as methyl, ethyl, propyl, butyl, heptyl, and including branched and substituted alkyl, such as chloropropyl, methoxymethyl, iso- propyl, benzyl, JL—butyl, sec-butyl, neopentyl, and the like.
  • g is a straight or branched alkylene group of 2 to 9 nuclear carbon atoms and CONH-groups forming the alkylene chain including alkylene chains comprising hetero atoms, or hetero atom-containing groups in the linear alkylene chain or nucleus in the case of branched chains, for example, ethylene, ethylidene, tri— methylene, propylene, propylidene, benzylidene, 3-oxo-4-imino-5,5-dimethyl—1,6-hexylene, and the like, preferably R Q is a trimethylene group.
  • Z + is any cation such as Na+, l/2Ba2+,
  • Preferred merocyanine dyes of the invention include: Compound 1
  • the compounds of the invention can be synthesized by condensation of a 2-methyl-3-sulfo- alkyloxazolium hydroxide or a 2-methyl—3—sulfo— alkylselenazolium hydroxide or a 2—ethyl—S— alkylthiazolium hydroxide or a 3,3-disubstituted- 2-methyl—1-sulfoalkyl—3H-indolium hydroxide, inner- salt with a 1,3—di— substituted
  • a tertiary amine such as triethylamine
  • a solvent such as aceto— nitrile or ethanol
  • a 5-unsubstituted barbituric acid can be condensed with the hydroxide, inner salt under similar conditions.
  • the starting oxazolium hydroxide, inner salt is most conveniently prepared by an addition reaction of a sultone such as propane sultone, butane sultone, etc., to a parent oxazole such as 2—methyl[1,2—d]- naphthoxazole.
  • such inner salts can be prepared by an addition reaction between a parent oxazole such as I above and an unsaturated sulfonic acid such as 2-acrylamido-2-methylpropanesulfonic acid as follows:
  • the starting thiazolium hydroxide, inner salt is most conveniently prepared by an addition reaction of a sultone such as propane sultone, butane sultone, etc., to a parent thiazole such as a 2-methylbenzothiazole.
  • a sultone such as propane sultone, butane sultone, etc.
  • a parent thiazole such as a 2-methylbenzothiazole.
  • such inner salts can be prepared by an addition reaction between a parent thiazole such as I above and an unsaturated sulfonic acid such as 2— acrylamido— 2— methylpropanesulfonic acid as follows :
  • the starting selenazolium hydroxide, inner salt is most conveniently prepared by an addition reaction of a sultone such as propane sultone, butane sultone, etc., to a parent benzoselenazole such as a 2-methylbenzo[d]selenazole.
  • a sultone such as propane sultone, butane sultone, etc.
  • a parent benzoselenazole such as a 2-methylbenzo[d]selenazole.
  • such inner salts can be prepared by an addition reaction between a parent selenazole such as I above and an unsaturated sulfonic acid such as 2—acrylamido—2—methylpropane— sulfonic acid as follows:
  • the 1,3-disubstituted-5-(3-alkoxy-2-pro- pen-l-ylidene)-2-thiobarbituric acid derivatives are prepared by the condensation of 1,3,3-trimethoxy-l- propene with the parent 1,3-disubstituted thiobarbi- turic acid.
  • the product is formed spontaneously as the reactants are mixed in acetone.
  • the disubsti- tuted thiobarbituric acid is obtained by condensation of an N,N'—disubstituted thiourea with diethyl malonate.
  • the N,N'-disubstituted thioureas can be purchased commercially or prepared by conventional alkylation of the nitrogen atoms on the thiourea.
  • the hydroxide, inner salt used in the alternative procedure is prepared by reaction of the parent hydroxide, inner salt with 1—anilino—3—phenylimino—1—propene hydrochloride available from Aldrich Chemical Co. These compounds have been found to be useful as agents to destroy or inactivate viruses with the aid of photosensitization. The toxicity of these compounds is relatively low.
  • the compounds are normally used with light of suitable wavelength in an amount of about 5 to about 25 micrograms per milliliter of product.
  • the effective wavelengths of visible light that can be used vary greatly depending upon the absorption spectrum of the individual dyes; however, it is generally desired that the light be of a wavelength in the green to orange range. It appears, as expected, that light that is not absorbed, i.e., blue light and long wavelength red light, is not particularly effective with these compounds. Tests have shown that:
  • Friend erythroleukemia virus complex the human T cell leukemia virus, HTLV-I and Herpes simplex 1.
  • Friend virus was obtained from cell—free supernatants of cultured erythroleukemia cells or as a cell—free extract from infected animals. Simul— taneous exposure to the compounds (15 ug/ml) and
  • Virus- infected spleen cells, bone marrow cells, and cultured Friend erythroleukemia cells were inacti- vated at about the same rate as cell-free virus ' preparations.
  • HTLV—I was also susceptible to the com ⁇ pound-mediated photosensitization.
  • the amount-of virus that could be sedimented by centrifugation was reduced after treatment with the compounds and light. The remainder of the virus were probably lysed.
  • the small fraction that was sedimented was visibly stained by the compound. It is conceivable that the sedimented virus fraction, although not lysed, had sustained enough photodynamic damages to make it noninfectious. For example, when the virus is Herpes simplex 1, the order of magnitude reduction is from 45 to 100 times.
  • the compound-mediated photolysis of viruses appears to be primarily mediated by singlet oxygen. An additional two-fold reduction in illumination time can therefore be achieved by performing the photo ⁇ sensitization step in the presence of deuterium oxide (D 2 0). Unlike heat or high doses of ionizing irradiation, this compound-mediated photolysis is more selective in its toxicity.
  • Dye-mediated photosensitization may be the preferred anti-viral treatment in situations where critical components are temperature- or radiation-sensitive.
  • the acute systemic toxicity of these dyes is very low.
  • the amount of dye that is injected with a typical mouse bone marrow graft is more than 100,000 times less than the L IQ n the same species.
  • viruses which can be inactivated by the compounds of the present invention are those previously described as well as the viruses which cause human and animal diseases, such as bovine viral diarrhea, the human immunodeficiency viruses (HIV, HTLV-III, LAV) and viruses which infect bacterial products, such as the Epstein Barr virus.
  • human and animal diseases such as bovine viral diarrhea, the human immunodeficiency viruses (HIV, HTLV-III, LAV) and viruses which infect bacterial products, such as the Epstein Barr virus.
  • the former compound was added in 25 ml of ethyl alcohol.
  • TAA triethyl- amine
  • the UV visible spectrum is consistent with the assigned structure and the compound was shown to be pure by both electrophoresis and thin layer chroma- tography.
  • the UV visible spectrum is consistent with the assigned structure and the compound was shown to be pure by both electrophoresis and thin layer chromatography.
  • the resulting mixture was refluxed for five minutes, filtered hot and 0.5 g Nal was added and the product filtered after stirring for 15 minutes.
  • the product was obtained after recrystallization in 100 ml methanol.
  • the UV visible spectrum is consistent with the assigned structure and the compound was shown to be pure by both electrophoresis and thin layer chroma— tography.
  • the inner r salt prepared in Part A (6.0 g) was combined with 5.2 g of l-anilino-3-phenylimino- 1-propene hydrochloride in 50 ml of acetic anhydride and heated at reflux for 2 hours. At this time, a sample diluted with acetonitrile and treated with triethylamine showed no evidence of dye formation indicating that all of the starting inner salt had been converted.
  • the filtered product recrystallized from methanol had a calculated molecular weight of 632.64, a ⁇ -max of 596 nm in methanol, an extinction
  • the dye having a calculated molecular weight of 715.00, had a ⁇ -max in ethanol at 613 nm,
  • Example 9 When cultured F4-6 erythroleukemia cells, spleen, or marrow cells from diseased animals, cell—free extracts of cultured cells, spleen cells, or marrow cells, or cell—free supernatants of F—6 cultures were injected into healthy B6D2F1 mice, the spleen weights increased from about 60-70 mg to about 1500 mg within days. The animals became polycythemic and, eventually, died. When cell suspensions, cell-free extracts, or culture supernatants were photosensitized and exposed to light prior to injection, spleen weights remained normal, hematocrits remained normal, and the animals survived.
  • Examples 1-4 with photolysis inactivates free Friend virus, intracellular Friend virus, and Friend virus-infected cells.
  • Example 2 Daylight 1332 Example 2 70 Watts/m 2 for 30 minutes 53.8
  • Example 3 Daylight 1488 Example 3 70 Watts/m 2 for 30 minutes 64.6
  • Example 4 Daylight 363.8
  • Example 4 70 Watts/m 2 for 30 minutes 67.4
  • Example 6 Daylight 1372 Example 6 70 Watts/m 2 for 30 minutes 68.2 Example 7 Daylight 1470 Example 7 70 Watts/m 2 for 30 minutes 61.2

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Est décrit un colorant de mérocyanine de formule (I) où X=O, Se, S; R1 et R2 sont indépendamment H, alkyle, alkoxy ou bien arylcarbocyclique, à condition que si X=S, R1 et R2 soient indépendamment choisis dans un groupe composé essentiellement d'alkyle, alkoxy et aryle, et si X=O, seul R1 ou R2 est H; R7 et R8 sont H et n'importe quel élément parmi R1 et R2, R1 et R7, et R2 et R8 peut renfermer conjointement les atomes nécessaires pour former une combinaison hexagonale aromatique carbocyclique condensée sur le radical benzène auquel ils sont combinés; R5 et R6 sont choisis indépendamment dans un groupe composé essentiellement de benzyle et d'alkyle comportant de 1 à 18 atomes de carbone, à condition que la somme des atomes de carbone contenus dans R5 et R6 conjointement soit au moins égale à 8; R9 représente un groupe alkylène de 2 à 9 atomes dépouillés de carbone et des groupes CONH; et Z+ est un cation. Ce colorant est utile dans un procédé pour inactiver des virus, consistant à mettre en contact ces virus avec le composé et à exposer le mélange obtenu à de la lumière visible pour exciter et inactiver les virus. Ces composés sont également utiles dans l'inactivation induite par irradiation de cellules leucémiques.
PCT/US1989/002303 1988-06-08 1989-05-30 Nouveaux colorants de merocyanine Ceased WO1989012080A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US20384288A 1988-06-08 1988-06-08
US203,843 1988-06-08
US203,842 1988-06-08
US203,956 1988-06-08
US07/203,956 US4937344A (en) 1988-06-08 1988-06-08 Novel sulfur-containing merocyanine dyes
US203,957 1988-06-08
US07/203,957 US4906750A (en) 1988-06-08 1988-06-08 Sulfoalkyl benzoxazoleinylidene butenylidene thiobarbituric acid derivatives
US07/203,843 US4885366A (en) 1988-06-08 1988-06-08 Novel selenium-containing merocyanine dyes

Publications (1)

Publication Number Publication Date
WO1989012080A1 true WO1989012080A1 (fr) 1989-12-14

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Application Number Title Priority Date Filing Date
PCT/US1989/002303 Ceased WO1989012080A1 (fr) 1988-06-08 1989-05-30 Nouveaux colorants de merocyanine

Country Status (2)

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EP (1) EP0418291A1 (fr)
WO (1) WO1989012080A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0467370A1 (fr) * 1990-07-19 1992-01-22 Eastman Kodak Company Colorants sensibilisateurs pour matériaux photographiques
WO1992007036A1 (fr) * 1990-10-19 1992-04-30 Sterling Winthrop Inc. Photosensibilisateurs a la selenomerocyanine
WO1992017549A3 (fr) * 1991-04-06 1992-11-26 Basf Ag Colorants a la polycetomethine
WO2013024447A1 (fr) 2011-08-18 2013-02-21 Nuhope, Llc Composés pour utilisation dans la thérapie du cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1457158A (fr) * 1964-12-08 1966-10-28 Eastman Kodak Co Nouvelles émulsions sursensibilisées et produits photographiques préparés à partir de ces émulsions
FR1470163A (fr) * 1965-03-01 1967-02-17 Eastman Kodak Co Nouvelles bétaïnes, nouveaux colorants dérivés de ces bétaïnes et émulsions photographiques chromatisées par ces colorants sensibilisateurs
DE1522409A1 (de) * 1966-11-15 1969-08-14 Agfa Gevaert Ag Spektral sensibilisiertes photographisches Material
EP0004061A2 (fr) * 1978-03-09 1979-09-19 MERCK PATENT GmbH Procédé pour la détermination de cellules leucémiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1457158A (fr) * 1964-12-08 1966-10-28 Eastman Kodak Co Nouvelles émulsions sursensibilisées et produits photographiques préparés à partir de ces émulsions
FR1470163A (fr) * 1965-03-01 1967-02-17 Eastman Kodak Co Nouvelles bétaïnes, nouveaux colorants dérivés de ces bétaïnes et émulsions photographiques chromatisées par ces colorants sensibilisateurs
DE1522409A1 (de) * 1966-11-15 1969-08-14 Agfa Gevaert Ag Spektral sensibilisiertes photographisches Material
EP0004061A2 (fr) * 1978-03-09 1979-09-19 MERCK PATENT GmbH Procédé pour la détermination de cellules leucémiques

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0467370A1 (fr) * 1990-07-19 1992-01-22 Eastman Kodak Company Colorants sensibilisateurs pour matériaux photographiques
WO1992007036A1 (fr) * 1990-10-19 1992-04-30 Sterling Winthrop Inc. Photosensibilisateurs a la selenomerocyanine
WO1992017549A3 (fr) * 1991-04-06 1992-11-26 Basf Ag Colorants a la polycetomethine
WO2013024447A1 (fr) 2011-08-18 2013-02-21 Nuhope, Llc Composés pour utilisation dans la thérapie du cancer

Also Published As

Publication number Publication date
EP0418291A1 (fr) 1991-03-27

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