CA1315780C - Porphyrin derivatives - Google Patents
Porphyrin derivativesInfo
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- CA1315780C CA1315780C CA000527443A CA527443A CA1315780C CA 1315780 C CA1315780 C CA 1315780C CA 000527443 A CA000527443 A CA 000527443A CA 527443 A CA527443 A CA 527443A CA 1315780 C CA1315780 C CA 1315780C
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- group
- porphin
- bis
- alkyl
- tetramethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Abstract
Abstract:
Porphyrin derivatives Novel porphyrin derivatives of -the general formula:
wherein R1 each independently denotes a hydrogen, a C1-C4 alkyl group or an ethenyl group, and R2 each independently denotes COZ(CmH2m)Q, COZCH(CmH2mQ)2, -CH2-Q [wherein Z
is O, S or NH, m is an interger of 1 to 23, and Q is a di-(C1-C4 alkyl)amino group or tri-(C1-C4 alkyl)ammonium halide group] or (wherein X is a halogen); or R1 each independently denotes -C2H4-Q (wherein Q is the same as defined above), -C2H4- or
Porphyrin derivatives Novel porphyrin derivatives of -the general formula:
wherein R1 each independently denotes a hydrogen, a C1-C4 alkyl group or an ethenyl group, and R2 each independently denotes COZ(CmH2m)Q, COZCH(CmH2mQ)2, -CH2-Q [wherein Z
is O, S or NH, m is an interger of 1 to 23, and Q is a di-(C1-C4 alkyl)amino group or tri-(C1-C4 alkyl)ammonium halide group] or (wherein X is a halogen); or R1 each independently denotes -C2H4-Q (wherein Q is the same as defined above), -C2H4- or
Description
1 31 57~',0 , Porphyrin derivatives This invention relates to novel porphyrin derivatives which are utilizable for the diagnosis and treatment of cancer.
In recent years, the porphyrin derivatives exhibiting photosensitizing activity and affinity for cancer cells when employed in conjunction with irradiation of laser light, can increasingly produce excellent results in the diagnosis and treatment of cancer (T. J. Dougherty, "Por-phyrin Localization and Treatment of Tumors", pp. 75-78 (1984)]. For this purpose, frequently use is made mainly of hematoporphyrin or hematoporphyrin derivative. Ilowever, the former compound is difficult to be obtained in the pure state ~R. K. DiNello et al., "The Porphyrins", vol. 1, pp. 297-298 (1978)]., whereas the latter is produced by acetylating the fo}mer, followed by treatment with a]kali and acid and consists of a mixture of several kinds of porphyrin derivatives. Accordingly, such porphyrins are considered to present significant problems in clinical application.
At present, the hematoporphyrin derivative~ the utili-zation of which is being trled in the diagnosis and treat-ment of cancer, is obtainable only in a mixture of several kinds of different compounds as mentioned in the above.
This renders it quite difficult to obtain the compound of invariably constant quality and consequently constitutes great difficulty in conducting tests on the efficacy or toxicity and the like. In ~-rder to solve such problem, it is considered important to obtain the pure porphyrin de-rivative that can demonstrate both photosensitizing activi-ty and affinity for cancer cells.
The present inventors synthesized various kinds of porphyrin derivatives exhibiting phtosensitizing activity and affinity for cancer cells by chemical modification of the propionic acid groups at the 2- and 18-positions, --``i I 31 57~() O.L- ethellyl groups at 7- and 12 ` of porphy~ repre-sented by the gelleral formu].a;
3 l~J~Il l z9 21 ~ 5 ( II ) N ~IN- ( 2~///f~
10 r COOII COO~I
(wherein Rl is a hydrogen, a C1-C4 alkyl group or an ethenyl group).
This invention is directed to a porphyrin derivative 15 represented by the general formula:
Il~ CJ-13 C~3 lc~
~ ~t llM ~ (I) C~lJ- ~ J ~ D ~ C~13 ~2 R2 wherein R1 each independently denotes a hydrogen, a C1-C4 alkyl group or an ethenyl group, and R2 each independently (Crnll2m)Qr CZC~I(CmllzmQ)2~ -C112-Q [wherein Z
is O, S or Nll, m is an integer of 1 to 23, and Q is a dl-(Cl-C4 alkyl)amino group or tri-(C1-C4 alkyl)a~ onium halide groupl or -C112-N ~ X (wherein X is a halogen); or ~1 each independently denotes -C2119-Q (wherein Q is the same as defined above), -C21-14-N ~ X or C2114 N ~ X
~ >
(whereill X is the same as defined above), and R2 each inde-pendently denotes a carboxyl group or a Cl-C4 allcoxycarbonyl group .
~, , f :` ~J
1 31 57~0 C1-C4 alkyl group denoted by R1 in the formula (I), C.1-C4 alkyl in di-(C1-C4 alkyl)amino group or tri-(C1-C4 alkyl)ammonium halide group included in the definition of Q, or C1-C4 alkyl in C1-C4 alkoxycarbonyl group denoted by R2 in the formula (I) is an alkyl group such as methyl, ethyl, propyl or butyl. C3-C4 alky~ group may be a straight or branched chain.
The embodiments of the porphyrin derivative (I) can b~ illustratedby the formulas (III), (IV) and (VI) des-cribed below:
One group of porphyrin derivatives (I) can be repre-sented by the following formula;
~ 3 C113~
~ IN ~ (III) C11~ C~13 C.Oil3 CO113 (wherein R1' is a hydrogen, a C1-C4 alkyl group or an ethenyl group; R3 is O(CmH2m)N(R)2, OCH(CH2N(R)2)2, S(Cm-H )N(R)2' NH(CmH2m)N(R)2, O(CmH2m) 3 2 N (R)3)2 2X 7 S(CmH2m)N tR)3-x or NH(CmH2m)N (R)3-X
(wherein R is a C1-C4 alkyl group; X is a halogen; m is an integer oE 1 to 23; n is an integer of 1 to 4).
Referring to the formula, R is C1 to C4 alkyl, such as methyl or ethyl, or staight or branched propyl or butyl.
By halogenating porphyrin of the general formula (II) and conducting a condensation reaction of the resulti.ng acid halide with a compound represented by the formula HO(CmH2m)N(R)2, HOCH(CH2N(R)2)2, 11S(CmH2m)N(R)2 or ......
t3157~0 H2N(CmH2m)NtR)2 (wherein R, m and n are as defined herein-before) or its salt in a solvent in the presence or absence of an acid-capturing agent, there are obtained the porphyrin derivatives of the formula (III) wherein R2 is O(CmH2m)-2 ( 2 (R)2)2' S(CmH2m)N(R)2 or NH(C H2 )N(R) .
As the solvent employed in this condensation reaction,there may be mentioned methylene chloride, chloroform, ethyl acetate, etc., with methylene chloride normally being preferentially employed; Examples of the acid-capturing agent include triethylamine, pyridine, quinoline and the like, with triethylamine being preferably used. The reaction temperature and reaction time can be suitably selected.
Ordinarily, the reaction is completed at 0C for 0.5 to 5 hours. When methylene chloride is used as a solvent, for example, the condensation reaction can be completed at a temperature maintained at the refluxing temperature of methylene chloride for 1 to 2 hours. The porphyrin derivatives of the formula (III) where R3 is O(CmH2m)N (R)3 2 )3)2 2X ~ S(CmH2m)N (R)3-X or NH(C H
N+(R)3 X can be obtained by the following procedure;
The porphyrin derivative of the formula (III) wherein 3 m 2m ( )21 OCH(CH2N(R)2)2, S(C H2 )N(R) or NH
(CmH2m)N(R)2 is reacted with a lower alkyl halide in the presence or absence of a solvent to convert to its quater-nary ammonium salt. As the preferred solvent which is used in this reaction, there may be mentioned methylene chloride chloroform, ethylene dichloride, etc. The reaction tempera-ture and reaction time can be suitably selected. For example, the reaction is completed at 0C to 100C for 5 minutes to 5 hours, but the reaction can normally be concluded at 20C to 30C for 0.5 to 1 hour.
- 5 _ 1 31 57~0 ~nother group of the present porphyrin derivatives (I) can be represented by the formula;
r~ I C1-1~
~ 5 (~ C ~
Cl~ C113 n ,~ ,7 [wherein R1' is the same as defined above and R4 is N (R)3 X (wherein R is a C1-C4 alkyl group and X is a halogen) or pyridinium halide group]. The porphyrin deriva-tive (IV) can be obtained by halogenating a porphyrin deriv-ative of the formula, 11l' Cl~3 C7-l3 ~ nl~
~ ' (V) HO - OH
to convert respective OH groups in the above Eormula to halogens and reacting the halogenated compound with a terti-ary amine.
The halogenation may be carried out by reacting a porphyrin derivative of the formula (V) with a halogenating agent in the presence of a solvent. As the halogenating agent which is utilizable in the reaction, there may be mentioned thionyl halides, hydrogen halides, etc., while the solvent includes, for example, methylene chloride, chloroform, pyridine and the like. The reaction may normally be completed at 0 to 80C for 1 to 5 hours. When 1 31 57~,0 thionyl bromide is used as a halogenating agent, however, the reaction is ordinarily completed at 20 to 30C for 3 to 5 hours.
The halogenated derivative thus obtained is reacted 5 with a corresponding tertiary amine in the pres-ence or absence of a solvent. As the solvent employable in the reaction, there may be mentioned methylene chloride, chloroform, ethylene dichloride, etc. The reaction may normally be completed at 0 to 100C for 5 minutes to 5 10 hours. When pyridine is used as an amine, for example, the reaction is normally completed by refluxing the mixture of the halogenated derivative with pyridine for 1 to 3 hours.
A further group o-E the present porphyrin derivative 15 can be represented by the Eormula;
Cl-l3~ J-1~5 ~ ~ (VI) 25 Cll~- ~ ,J ~ Lcll~3 CO~fi Co~6 [wherein R5 is N (R)3 X ~wherein R is a C1-C4 alkyl group and X is a halogen), pyridinium halide group or quinolinium halide group; and R6 is a hydrogen or a C1-C4 alkyl group].
The derivative (VI) can be obtained by reacting a porphyrin derivative of the formula;
\
_ 7 _ 1 31 57 ~n L ll3 _~
Cl-l3) ~
~ (VII) c~.~3 l~J~J~Lc.~3 l~ 1 ~2~ C~2l~6 (wherein X6 and X are the same as deEined above) with a corresponding tertiary amine.
The C1-C4 alkyl groups each denoted by R6 or by R
in N+(R)3 ~ which is included in the definition of R5 is independently an alkyl yroup such as methyl or ethyl, or propyl or butyl which may branches.
As pyridinium halide group denoted by R5, there may be exemplified pyridinium chloride or pyridinium bromide group, and as quinolinium halide group, yunolinium chloride or qunolinium bromide group.
The reaction of the derivative (VII) with the tertiary amine may be carried out in the presence or absence of ; a solvent such as methylene chloride, chloroform, ethylene dichloride, etc. The reaction may generally be conducted at 0 to 100C for 5 minutes -to 5 hours. When pyridine is used as the tertiary amine, the reaction may ordinally be com~pleted by refluxing the derivative (VII', with pyridine ; for 1 to 5 hours.
The novel porphyrin derivatives thus obtained may be purified from the reaction mixture by a usual method, for example, extraction with a suitable solvent, recrystal-lization, column chromatography, etc.
- 8 -~ 1 31 57~0 The compounds of present invention have the following characteristic features effective in diagnosing and traating cancer;
1. Generating fluorescence under the irradiation of light, 5 2. Generating singlet oxygen ('2) under irradiation of light in the presence of oxygen (The generated '2 has cell-cidal effect), and 3. Exhibiting marked accumulation at cancer tissue as com-pared with normal tissue.
Namely, when the present compoundselectively accumulates at cancer tissue after administration to cancer-bearing living body, the cancer tissue markedly generates fluores-cence by light irradiation. Therefore, the position and size of the cancer can be ascertained by determining the fluorescence. Thus, if the position and size is ascertained, then, by irradiating the light of an appropriate wave length on the position, '2 generates at the cancer tissue which can be necrotized by the '2 The present compound rarely accumulates in a normal tissue surrounding the cancer, 20 therefore, there is no '2 generation nor damage at the normal tissue. In such manner, cancer tissue can be selec-tively necrotized, which is effective in cancer treatment.
Various ways may be employed for a~ministrating the present compound. For example, it can be administered intravenously, suboutaneously, intraperitoneally, orally or intrarectal-ly .
As for dosage, it may be administered at a dose of 1-350 mg/kg.
When administered intraveneously,the present compound 30 accumulates into a normal tissue such as muscle, intestine, stomach, liver, kidney, heart, brain, etc. and reaches to the maximum within several hours and thereafter it is excluded by process of time. However, in the case of cancer tissue, the accumulation reaches to the maximum within 35 several hours and the compound still remains 24 to 72 hours after the administration. Thus selective accumulation of the compound at cancer tissue as compared with normal tissue is observed in the hours above-mentioned. Therefore, the diagnosis and treatment of cancer under irradiation of light is effective, when it is carried out in the above-men-5 tioned hours.
In the case of the diagnosis, a light having a short wave length, about 400 nm, may be employed. In the case of the treatment, a light having a long wave length ,usually about 620 nm, being well penetrable into tissue may be 10 employed in order to allow the light to reach deeply into the cancer tissue.
The source of the light is not particularly limited, however, it is preferable to use a laser light for irradi-ating a localized position so as to irradiate high energy 15 to the cancer and not to irradiate the peripheric portion of the cancer.
The present invention ls further explained by Reference examples and Examples in the following:
20 Reference example 1 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride:
Gram of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-25 porphin-2,18-dipropionic acid is suspended in 35 ml of methylene chloride and 2.5 ml of oxalyl chloride is added dropwise thereto under refluxing. After further refluxing for 15 minutes, solvent is distilled off from lthe mixture under reduced pressure to give 1.1 g of 7,12-diethenyl--30 3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride as the residue.
10 - 1 31 57 ~0 Example 1 Synthesis of 7,12-diethenyl-3,8,13,17--tetramethyl-2,18-bis [2-(dimethylaminoethyloxy)carbonylethyl]-21H,23H-porphin:
1.1 Gram of 7,12-diethenyl-3,8,13,17-tetramethyl-21H, 23H-porphin-2,18-dipropionic acid chloride is added to 60 ml of methylene chloride and the mixture is refluxed under addition of 5 ml of 2-dimethylaminoethanol for 45 minutes, followed by further refluxing under addition of 5 ml of 2-dimethylaminoethanol for 45 minu-tes. Solvent is removed from -the reaction mixture under reduced pressure to give residue. The residue is dissolved in 100 ml of chloroform, washed with 100 ml of water and -the chloroform layer is concentrated under reduced pressure -to dryness.
The resultant is purified with column chromatography packed 15 with 100 g of alumina (activity V) using chloroform as a solvent. This procedure gives 850 mg of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-dimethylaminoethyloxy)-carbonylethyl~-21H,23H-porphin as brownish black crystals melting at 187-191C.
20 Electronic spectrum (~max, chloroform):
407, 506, 541, 577, 630 (nm) IR spectrum (KBr):
3305, 2960, 2940, 2900, 2850, 2810, 2760, 1735 (cm 1) NMR spectrum (CDCl3):
~; 9.70, 9.56, 9.49 (s, 2H, 1H, 1H) 8.10- 7.72, (m, 2H), 6.24-5.92 (m, 4H), 4.26 (t, 4H), 4.15 (t, 4H), 3.44, 3.38, 3.36, 3.34 (s, 3Hx4) 3.19 (t, 4H), 2.36 (t, 4EI), 2.06 (s, 1211), -4.48 (s, 2H) Example 2 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis [2-(1,3-bis(dimethylamino)-2-propyloxy)-carbonylethyl]-21H, 23H-porphin:
According to the process of Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17--tetrame-thyl-21H,23H-porphin-2,18-di-11 1 31 57~n propionic acid chloride is condensed with 5 ml of 1,3-bis-(dimethylamino)-2-propanol to give 480 mg of 7,12-diethenyl-3, 8 ,13 ,1 7-tetramethyl-2,18-bis[2-~1,3-bisldimethylamino)-2-propyloxy)carbonylethyl]-21H,23H-porphin as brownish black 5 substance melting at 181-190C.
Electronic spectrum (~max, chloroform):
407.5, 505.5, 541, 576, 630.5 (nm) IR spectrum (KBr)o 3305, 2960, 2930, 2900, 2850, 2810, 2760, 1730 (cm~1) 10 NMR spectrum (CDCl3):
~; 9.79, 9.76, 9.62, 9.56 (s, lHx4) 8.14-7.76 (m, 2H) 6.24-5.92 (m, 4H) 5.13 (t, 2H), 4.32 (t, 4H), 3.48, 3.44, 3.39 (s, 3H, 3H, 6H), 3.21 (t, 4H), 2.21 (d, 8H), 2.04 (s, 24H~, -4.32 (s, 2H) Example 3 Synthesis of 7~12-diiet~eny~ 3,8,13,17-tetramethyl-2,18-bis-[2-(6-dimethylamino-1-hexyloxy)carbonylethyl]-21H~23H
porphin:
According to the process in Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-di-25 propionic acid chloride is condensed with 5 ml of 6-di-methylamino-1-hexanol to give 450 mg of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(6-dimethylamino-1-hexyl-oxy)carbonylethyl]-21H,23H-porphin as brownish black crys-tals melting at 160 to 165C.
30 Electronic spectrum (~max, CHCl3):
407.5, 505.5, 541, 576, 630.5 (nm) IR spectrum (KBr):
3300, 2920, 2850, 2800, 2750, 1735 (cm NMR spectrum (CDCl3):
35 ~; ~.7, g.6, 9.52 (s, 2H, 1H) 8.2-7.7 ~broad, 2H) 6.28-5.9 (m, 4H) ... ..
- 12 - 1 3 1 57~0 4.27 (t, 4H) 4.02 (-t, 4H) 3.42, 3.38 (s, 6H, 6H) 3.16 (t, 4H) 2.02 (s, 12H) 2-1.8 (m, 4H) 1.5-1.2 (m, 4H) 1.2-0.9 (~, 16H) -4.6 (broad, 2H) Example 4 Synthesis of 7,12-die-thenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(2-dimethylaminoethyl)carbamoyl)ethyl]-21H,23H-porphin:
According to the process of Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-di-propionic acid chloride is condensed with 5 ml of 2-di-methylaminoethylamine to give 740 mg of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(2-dime-thylaminoethyl)-carbamoyl)ethyl]-21H,23H-porphin as brownish black crystals melting at 300C or higher.
Electronic spectrum (~max, chloroform):
406.5, 506, 541, 576, 630 (nm) IR spectrum (KBr):
3290, 2925, 2850, 2805, 2750, 1640 (cm NMR spectrum (CDCl3):
~; 9.44, 9.39, 9.34, 9.19 (s, 1Hx4) 8.06-7.62 (m, 2H) 6.8-6.6 (m, 2H) 6.21-5.88 (m, 4H) 4.02 (broad, 4H) 3.28, 3.26, 3.24, 3.15, (s, 3Hx4) 3.04-2.76 (m, 4Hx2) 1.76, 1.73 (t, 2Hx2) 1.57, 1.53 (s, 6Hx2) -5.05 (s, 2H) 1 3 1 5 7 ~ 3 Example 5 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(3-dime-thylaminopropyl)carbamoyl)ethyl]-21H,23H-porphin:
According to the process of Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17-te-tramethyl-21H,23H-porphin-2,18-di-propionic acid chloride is condensed wi-th 5 ml of 3-di-methylaminopropylamine to give 650 mg oE 7,12-diethenyl-10 3~8~13~17-tetramethyl-2~18-bis[2-N-(3-dimethylaminopropyl)-carbamoyl)ethyl]-21H,23H-porphin as brownish black crystals melting at 300C or hihger.
Electronic spectrum (~max, chloroform):
407, 505.5, 541, 576, 630 (nm) 15 IR spec-trum (KBr):
3300, 3075, 2920, 2850, 2800, 2750, 1640 (cm NMR spectrum (CDCl3):
~; 9.53, 9.39, 9.28 (s, 2il, 1H~ 1H) 8.09-7.65 (m, 2H), 7.55-7.35 (m, 2H), 6.23-5.88 (m, 4H), 4.05 (t, 4H) 3.33, 3.28, 3.27, 3.12 (s, 3Hx4) 2.92 (t, 4H), 2.85 (t, 4H), 1.66-1.5 (t, 4H) 1.63, 1.59 (s, 6Hx2) 1.11 (q, 4H), -4.88 (s, 2H) Reference example 2 Synthesis of 3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride:
1 Gram of 3,8,13,17-tetramethyl-2111,23H-porphin-2,18-dipropionic acid is suspended in 35 ml of methylene chlo-ride, and 2.5 ml of oxalyl chloride is dropwise added there-to under refluxing, followed by refluxing for further 15 minutes whereby the reaction is completed. Solvent in the 35 reaction mixture is removed under reduced pressure to give, as the residue, 1.1 g of 3,8,13,17-tetramethyl-21H,23 porphin-2,18-dipropionic acid chloride.
13157~0 Example 6 Synthesis of 3,8,13,17-tetramethyl-2,18-bis[2-~2-dlmethyl-aminoethyloxy)carbonylethyl]-21H,23H-porphin:
1.1 Gram of 3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride is added to 60 ml of methylene chloride, and the mixture is refluxed under addi-tion of 5 ml of 2-dimethylaminoethanol for 45 minutes, followed by refluxing under addition of further 5 ml of 2-dimethylaminoethanol for another 45 minutes. Solvent is removed from the reaction mixture under reduced pres-sure, and the residue is dissolved in 100 ml of chloroform, washed with 100 ml of water, and the chloroform layer is concentrated to dryness under reduced pressure. The residue thus obtained is purified with column chromatography packed with 100 g of alumina (activity V) with the use of chloro-form as solvent to give 330 mg of 3,8,13,17-tetrame-thyl-2,18-bis[2-t2-dimethylaminoethyloxy)carbonylethyl]-21H,23H-porphin as brownish balc~ crystal melting at 159-160C.
~o Electronic spectrum (~max, chloroform):
399, 496.5, 529.5, 566, 591.5, 619 (nm) IR spectrum (KBr):
3300, 2925, 2845, 2805, 2755, 1735 (cm 1) NMR spectrum (CDCl3):
~; 9.77, 9.68, 9.67 (s,1H, 1H, 2H) 8.76, 8.75 (s, 1Hx2) 4.25 (t, 4H), 4.12 (t, 4H), 3.56, 3.48, 3.44, 3.39 (s, 3Hx4) 3.10 (t, 4H), 2.32 (t, 4H), 2.04 (s, 6H), -4.31 (s, 2H) Reference example 3 Synthesis of 7,12-diethyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride:
1 Gram of 7,12-diethyl-3,8,13,17-tetramethyl-21H,23H-Po~phan~2~18-dipropionic acid is suspended in 35 ml of meth-ylene chloride, and 2.5 ml of oxalyl chloride is dropwise - 15 - 1 3 1 57 ~
added thereto under refluxing, followed by refluxing for a further 15 minutes, whereby the reaction is completed. The reaction mixture is subjected to distillation under reduced pressure to remove the solvent, whereby there is obtained, 5 as the residue, 1.1 g of 7,12-diethyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride.
Example 7 Synthesis of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-dimethylaminoethyloxy)carbonylethyl]-21H,23H-porphin:
60 Milliliters of methylene chloride is added to 1.1 g of 7,12-diethyl-3,8,13,17--tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride, and 5 ml of 2-dimethylamino-15 ethanol is added thereto under refluxing, followed by keep-ing the reflux for 45 minutes, and further refluxed after addition of another 5 ml of 2-dimethylamino-ethanol for 45 minutes. Solvent is removed from the mixture under reduced pressure, and the resulting residue is dis-20 solved in 100 ml of chloroform and washed with water. Thechloroform layer is concentrated to dryness under reduced pressure and the resultant residue is purified with column chromatography packed with alumina (activity V) with the use of chloroform as solvent. This procedure gives 930 25 mg of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis[2(2-di-methylaminoethyloxy)carbonylethyl]-21H,23H-porphin as brown-ish black crystal melting at 168-172C.
Electronic spectrum (~max, chloroform):
399.5, 498, 532, 567, 593.5, 620.5 (nm) 30 IR spectrum (KBr):
3305, 2955, 2930, 2855, 2810, 2710, 1735 (cm 1) NMR spectrum (CDCl3):
~; 9.92, 9.87, 9.83, 9.81 (s, 1Hx4) 4.35,, 4.32 (t, 2Hx2) 4.13 ~t, 4H) 3.94, 3.91 (q, 2Hx2) 3.56, 3.50, 3.44 (s, 3H, 6H, 3H) 3.25 (t, 4H), 2.33 (t, 4H), 2.02 (s, 6H), . ~
.
1.78, 1.77 (t~ 2Hx2) -3.92 (s, 2H) Example 8 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-trimethylammonioethyloxy)carbonylethyl]-21H,23H-porphin diiodide:
100 Milligrams o~ 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-dimethyla~inoethyloxy)carbonylethyl]-21H,23H-porphin obtained in Example 1 is dissolved in 10 ml of methylene chloride, and 1 ml of methyl iodide is added thereto and the precipitated crys-tals are recovered by filtration to give 126 mg of 7,12-diethenyl-3,8,13,17-tetra-methyl-2,18-bis[2-(2-trimethylammonioethyloxy)carbonyl-ethyl]-21H,23H-porphin diiodide as brownish black crystals.
Electronic spectrum (~max, water):
376, 512, 548, 576.S, 630.5 (nm) ~R spectrum (Ksr):
3300, 2900, 1725 (cm~1) NMR spectrum (DMSO-d6) ~; 9.74, 9.66 (s, 2Hx2) 8.4-7.8 (m, 2H), 6.4-6.0 (m, 4H), 4.5-4.0 (broad, 4Hx2) 3.48 (s, 3Hx4), 3.26 (broad, 4Hx2~, 2.79 (s, 18H), -5.08 (broad, 2H~
Example 9 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(1,3-bis(trimethylammonio)-2-propyloxy)carbonylethyl]-21H,23H-porphin tetraiodide:
100 Milligrams of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(1,3-bis(dimethylamino)-2-propyloxy)carbonyl-ethyl]-21H,23H-porphin obtained in Example 2 is dissolved in 10 ml of methylene chloride, and 1 ml of methyl iodide is added thereto and the precipi-tated crystals are recov-ered by fil-tration to give 100 mg of 7,12-diethenyl-f "., ~ ' - 17 - 1 31 57~0 3,8,13,17-tetramethyl-2,18-bis[2-(1,3-bis(trime-thylammonio-2-propyloxy)carbonylethyl)-21H,231-l-porphin tetraiodide as brownish black crystals.
Electronic spectrum (Amax, water):
398, 509, 543.5, 573.5, 628.5 (nm) IR spectrum (KBr):
3300, 2995, 2930, 2850, 1740 (cm 1) NMR spectrum (DMSO-d6):
~; 10.20-9.96 (s, 1Hx4), 8.52-8.02 (m, 2H), 6.44-6.06 (m, 4H), 5.88-5.58 (broad, 2H), 4.68-4.28 (broad, 4Hj, 3.96-3.4 (m, 4H, 4H, 4H), 3.64-3.56 (s, 3Hx4), 3.08 (s, 36H), -4.26 (broad, 2H) Example 10 Synthesis of 7,12-diethenyl-3,8,13,17--tetramethyl-2,18-bis[2-(N-(2-trimethylammonioethyl)carbamoyl)ethyl]-21H,23H-porphin diiodide:
100 Milligrams of 7,12-diethenyl-3,8,13,17-tetramethyl-2l18-bis[2-~N-(2-dimethylaminoethyl)carbamoyl)ethyl]-21H,23H-porphin obtained in Example 4 is dissolved in 20 ml of methylene chloride under heating. After cooling the mixture to room tempera-ture, 1 ml of me-thyl iodide is added thereto, and the precipitated crys-tals are recovered by fil-tration to give 127 mg of 7,12-diethenyl-3,8,13,17-te-tramethyl-2,18-bis[2-(N-(2--trimethylammonioe-thyl)carbamoyl)ethyl]-21H,23H-porphin diiodide as brownish black crystals.
Electronic spectrum (Amax, water):
377.5, 510, 548, 575.5, 630 (nm) IR specrum (KBr):
3300, 3230, 2995, 2900, 2845, 1655 (cm 1) NMR spectrum (in DMSO-d6):
~; 10.2-10.05 (s, 1Hx4), 8.6-8.0 (m, 2H), 6.6-6.0 (m, 4H) 4.37 (t, 4H), 3.8-3.6 (m, 8H), 3.28 (broad, 3Mx4), 3.14 (-t, 4H), 2.54 (s, 18H) ,8 - 1 3 1 5780 Example 11 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(3-trimethylammoniopropyl)carbamoyl)ethyl]-21H,23H-porphin diiodide:
100 Milligrams of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(3-diethylaminopropyl)carbamoyl)ethyl]-21H,23H-porphin is dissolved in 10 ml of methylene chloride, and 1 ml of methyl iodide is added thereto. The precipitated crystals are recovered by filtration to give 126 mg of 7,12-10 diethenyl-3l8l13l17-tetramethyl-2~18-bis[2-(N-(3-trimeth ammoniopropyl)carbamoyl)ethyl]-21H,23H-porphin diiodide as brownish black crystals.
Electronic spectrum (~max, wa-ter):
380.5, 510, 546, 577, 631 (nm~
IR spectrum (KBr~:
3300, 3250, 2900, 2850, 1640 (cm~1) NMR spectrum (DMSO-d6):
~; 9.94, 9.86, 9.78 (s, 1H, 1H, 2H) 8.5-8.06 (m, 2H), 8.02-7.86 ~m, 2H), 6.4-6.09 (m, 4H), 4.3 (broad, 4H), 3.54 (broad, 12H), 3.1-2.8 (broad, 8H), 2.62 (broad, 4H), 1.3 (broad, 4H), -4.9 (broad, 2H) Reference example 4 Affinity to _ancer cells 1 x 107 MKSA cells originated from mouse nephradenoma were -transplanted on the back of 3-week-aged Balb/c mouse, and after 2-3 weeks, the present porphin derivative is intravenously administered to the tail of the mouse at a dose of 20 mg/kg body weight. After 24 hours from the administration, organs and cancer cells were excised from the mouse, and fluorescence generated from them, which was originated from the porphin derivative, was measured on each of them by using laser diagnosis apparatus (K.
Aizawa et al., LASER IGAKU KAISHI, Vol. 5, pp. 63-68, (1984)). The results are summarized to strength of the fluorescence at cancer tissue and strength ratio of the - ~\
,9 1 31 57~0 fluorescence at normal tissues to the fluorescence at cancer tissue in Table 1.
In the Table, respective [8~ and [10] denote the com-pounds obtained in Examples 8 and 10, Hp denotes hemato-porphyrin and HpD denotes theporphyrin derivative obtainedby the procedure described in Porphyrin Locali~ation and Treatment of Tumors, pp. 75-78, (1984).
Table 1 Compound Strength of Strength ratio of fluorescence fluorescence (normal organs / cancer) at cancer Skin Lung Liver Kidney [8] 15.080.47 0.01 0.09 0~00 [10] 14.890.74 0.07 0.04 -HpD 5.700.84 0.01 0.09 0.00 Hp 3.45 - 0.45 0.45 0.45 25 Reference example 5 Therapeutic effect 1x10 MKSA cells originated from mouse nephradenoma were transplanted on the back of 3-week-aged Balb/c mouse, and at the stage when the tumor had grown up to have dia-30 meter of about 1 cm after 2 to 3 weeks, the compound obtain-ed in Example 8 was intraveneously administered to the tail of the mouse at a dose of 20 mg/kg body weigh-t.
At 24 hours after the administration, the hair on the tumor was taken off to lay the skin bare, and excimer 35 laser (wave length 625 nm) was irradiated, whereby the tumor disappeared after 3 days.
- 20 ~ 13157~
Reference example 6 Synthesis of 7,12-diethyl~3,8,13,17-tetramethyl-2,18-bis-(3-bromopropyl)-21H,23H-porphin:
To 1 liter of methylene chloride, 50 ml of dimethyl-formamide is added and the mixture is agitated, followed by addition of 25 ml of thionyl bromide, 60 g of potassium carbonate and 2.5 g of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis(3-hydroxypropyl)-21H,23H-porphin. The mixture is stirred at room temperature for 5 hours. The reaction solution is poured on 1 kg of ice to decompose excess thionyl bromide and the mixture is subjected to iayer sepa-ration. The methylene chloride layer is washed with each 100 ml of water three times, dried on anhydrous magnesium sulfate and subjected to distillation under reduced pressure to give 4.5 g of crude product. The crude product is washed with 30 ml oE methanol, dried and purified with column chromatography packed with alumina (activity V) in an amount of 200 g with the use of methylene chloride as solvent, whereby 2.7 g (yield 87.4 ~) of the desired compound is obtained as dark reddish brown substance.
Melting point: 300~C or higher Electronic spectrum (~max, DMF): 620.5, 566.3, 529.5, 496.7, 396.0 (nm) IR spectrum (KBr)~ 3320, 2950, 2920, 2850, 835, 740 (cm NMR spectrum (CDCl3):
~; -3.78 (2H, s), 1.82 (6H, t), 2,70 (4H, t), 3.48-3.68 - (16H, m), 4.02 (8H, m), 9.80 (1H, s), 9.83 (3H, s) Example 13 Synthesis of 7,12-diethyl-3,8,13,17--tetramethyl-2,18-bis(3-pyridiniopropyl)-21H,23H-porphin dibromide: -To 100 mg of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis(3-bromopropyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. The precipitated crystals are reco~ered by filtration, washed with 3 ml of .. , 1 31 ~7~30 pyridine and dried, whereby 100 mg (yield 81.1 %~ of dark reddish brown desired compound is obtained.
Melting point: 300C or higher Electronic spectrum (~max, DMF): 620.5, 566.5, 529.5, 497.0, 397.5 (nm) IR spectrum (KBr): 3300, 3000, 2960, 2930, 2850, 1630, 1480, 835, 740, 675 (cm NMR specrum (DMSO-d6):
~; -3.96 (2H, s), 1.74 (6H, t), 2.85 (4H, broad), 3.20 (12H, s), 3.96 (4H, broad), 4.30 ~4H, broad), 5.30 (4H, broad), 8.02 (4H, t), 8.42 (2H, t), 9.36 (4H, d), 9.86 (1H, s), 9.90 (3H, s) Example 14 Synthesis oE 3,8,13,17-tetrame-thyl-2,18-bis(3-pyridinio-propyl)-21H,23H-porphin dibromide:
To 120 mg of 3,8,13,17-te-tramethyl-2,18-bis(3-bromo-propyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. T~e precipitated crystals are recovered by filtra-tion, washed with 3 ml of pyridine and dried, whereby 140 mg (yield-92.8 %) of brownish black desired compound is obtained.
Melting point: 300C or higher Electronic spectrum (~max, DMF): 623.3, 568.9, 533.3, 500.1, 401.0 (nm) IR spectrum (KBr): 3300, 3000, 2950, 2900, 2850, 1630, 1480, 835, 720, 675 (cm NMR spectrurn (DMSO-d6):
~i 2.74 (4H, broad), 3.30 (12H, s), 4.20 (4H, broad), 5.24 (4H, broad), 8.04 (6H,- broad), 8.44 (2H, broad), 8.80-9.40 (8H, m) Example 15 Syn-thesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis(3-pyridiniopropyl)-21H,23H-porphin dibromide:
- 22 ~ 1 31 57 ~ 0 To 100 mg of 7,12-dlethenyl-3,8,13,17--tetramethyl-2,18-bis(3-bromopropyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. The precipi-tated crystals are recovered by filtration, washed with 3 ml of pyridine and dried, whereby 116 mg (yield 94.5 %) of brownish black desired compound is obtained.
Melting point: 300C or higher Electronic spectrum (~max, DME): 632.0, 576.8, 542.0, 506.5, 409.0 (nm) IR spectrum (KBr): 3300, 3000, 2900, 2850, 1625, 1480, 835, 725, 680 (cm 1) Reference example 7 Affinity to cancer cells 1x107 MKSA cells originated from mouse nephradenoma are transplanted on the back of 3-week-aged Balb/c mouse, and after 2-3 weeks, the porphin derivative obtained by the present invention is intraveneously administered to the tail of the mouse at a dose of 20 mg/kg body weight.
After 24 hours, organs and cancer tissue are taken out and fluorescence genera-ted from -them, which is originated from the prophin derivative, is measured on each of them by using laser diagnosis apparatus (K. Aizawa et al., LASER
IGAKU KAISHI, Vol. 5, pp. 63-68, (1984)). The results are summarized to the fluorescence strength a-t cancer tissue and the ratio of the fluorescence strength at normal tissue to that at cancer tissue in Table 2. In the Table, [13]
denotes the product compound in Example 13, Hp deno-tes hematoporphyrin and HpD denotes the porphyrin derivative obtained by the procedure described in Porphyrin Localiza-tion and Treatment of Tumors, pp. 75-78, (1984).
1 31 ~7~0 Table 2 Compound Strength of Strength ratio oE fluorescence fluorescence (normal organs / cancer) at cancer Skin l,ung Liver Kidney [13~ 16.36 - 0.01 0.06 0.01 HpD 5.70 0.84 0.01 0.09 0.00 Hp 3.45 - 0.45 0.45 0.45 Example 16 Synthesis of 7,12-bis(2-pyridinioe-thyl)-3,8,13,17-te-tra-15 methyl-2,18-bis(2-methoxycarbonylethyl)-21H,23H-porphin dibromide:
To 500 mg of 7,12-bis(2-bromoethyl)-3,8,13,17-tetra-methyl-21H,23H-porphin-2,18-dipropionic acid methyl ester, 20 10 ml of pyridine :is added, followed by refluxing for 5 hours. The precipitated crystals are recovered by filtra-tion, washed with 5 ml of pyridine and dried, whereby 550 mg (yield 99.5 %) of dark reddish desired compound is ob-tained.
25 Electronic spectrum (Amax, PBS): 621.5, 569, 543, 508, 370.5 (nm) IR spectrum (KBr): 3425, 3325, 3050, 2950, 2850, 1730, 1630, 1485, 1460, 1440, 1270, 1220, 1200, 1165, 1100, 840, 740, 680 (cm 1) Example 17 Synthesis of 7,12-bis(2-quino:Linioethyl)-3,8,13,17-te-tra-methyl-2,18-bis(2-methoxycarbonyle-thyl)-21H,23~-l-porphin dibromide:
To 100 mg of 7,12-bis(2-bromoethyl)-3,8,13,17--tetra-methyl-21H,23H-porphin-2,18-dipropionic acid methyl ester, 2 ml of quinoline is added, followed by refluxing for 5 ~ 31 57~0 hours To the resultant, 20 ml of hexane is added, and the precipitated crystals are recovered by filtration, washed with 5 ml of hexane and dried, whereby 135 mg (yield 99.6 ~t of dark reddish desired compound is obtained.
IR spectrum (KBr): 3400, 3300, 2920, 2850, 1725, 1590, 1520, 1430, 1395, 1365, 1255, 1225, 1195, 1160, 1110, 830, 760, 740 (cm 1) C NMR spectrum (CD30D): 173~8, 148.6, 146.9, 143.8, 142.5, 139.3, 139.1, 138.3, 136.9, 136.6, 136.0, 132.0, 130.8, 130.4, 129.0, 128.3,-126.7, 125.1, 120.8, 118.0, 96.8, 95.4, 36.7, 21.2, 11.2, 10.2, 10.9, 10.6 (ppm) Example 18 Synthesis of 7,12~bis(2-quinolinioethyl)-3,8,13,17-tetra-methyl-2,18-bis-(2-carboxyethyl)-21H,23H-porphin dibromide:
To 100 mg of 7,12-bis(2-bromoethyl)-3,8,13,17-tetra-methyl-21H,23~-porphin-2,18-dipropionic aci,d, 2 ml of quin-oline is added, followed by refluxing for 5 hours. To the resultant, 20 ml of hexane is added, and the precipitated ~rystals are recovered by filtration, washed with 5 ml of hexane and dried, whereby 110 mg (yield 95.5 %) of desired compound is obtained in dark reddish brown colour.
IR spectrum (KBr): 3400, 3100, 2920, 2850, 1720, 1630, 1590, 1525, 1455, 1380, 1225, 1160, 1105, 815, 770, 740 (cm Reference example 8 Affinity to cancer cells 1x107 MKSA cells originated from mouse nephradenoma are transplanted on the back of 3-week-aged Balb/c mouse, and after 2 to 3 weeks, the porphin derivative obtained by the present invention is intraveneously administered to the tail of the mouse at a dose oE 20 mg/kg body weight.
After 24 hours, organs and cancer tissue are taken out and fluorescence generated from them, which is originated from the porphin derivative, are measured on each of them ,~,1 - 25 - 13157~0 by using laser diagnosis apparatus (K. Aizawa et al., LASER
IGAKU KAISHI, Vol. 5, pp. 63-68, (1984)). The results are shown in Table 3 as strength of the fluorescence at cancer tissue and the ratio of fluorescence strength at normal tissue to -that at cancer tissue. In -the Table, [16] denotes the product compound in Example 16, Hp denotes hematopor-phirin and HpD denotes the porphyrin derivative obtained by the procedure described in Porphyrin Localization and Treatment of Tumors, pp.-75-78, (1984).
Table 3 Compound Strength of Strength ratio of fluorescence fluorescence (normal organs / cancer) at cancer Skin Lung Liver Kidney [16] 3.00 0.00 0.00 0.00 0.00 HpD 5.70 0.84 0.01 0.09 0.00 Hp 3.45 - 0.45 0.45 0.45
In recent years, the porphyrin derivatives exhibiting photosensitizing activity and affinity for cancer cells when employed in conjunction with irradiation of laser light, can increasingly produce excellent results in the diagnosis and treatment of cancer (T. J. Dougherty, "Por-phyrin Localization and Treatment of Tumors", pp. 75-78 (1984)]. For this purpose, frequently use is made mainly of hematoporphyrin or hematoporphyrin derivative. Ilowever, the former compound is difficult to be obtained in the pure state ~R. K. DiNello et al., "The Porphyrins", vol. 1, pp. 297-298 (1978)]., whereas the latter is produced by acetylating the fo}mer, followed by treatment with a]kali and acid and consists of a mixture of several kinds of porphyrin derivatives. Accordingly, such porphyrins are considered to present significant problems in clinical application.
At present, the hematoporphyrin derivative~ the utili-zation of which is being trled in the diagnosis and treat-ment of cancer, is obtainable only in a mixture of several kinds of different compounds as mentioned in the above.
This renders it quite difficult to obtain the compound of invariably constant quality and consequently constitutes great difficulty in conducting tests on the efficacy or toxicity and the like. In ~-rder to solve such problem, it is considered important to obtain the pure porphyrin de-rivative that can demonstrate both photosensitizing activi-ty and affinity for cancer cells.
The present inventors synthesized various kinds of porphyrin derivatives exhibiting phtosensitizing activity and affinity for cancer cells by chemical modification of the propionic acid groups at the 2- and 18-positions, --``i I 31 57~() O.L- ethellyl groups at 7- and 12 ` of porphy~ repre-sented by the gelleral formu].a;
3 l~J~Il l z9 21 ~ 5 ( II ) N ~IN- ( 2~///f~
10 r COOII COO~I
(wherein Rl is a hydrogen, a C1-C4 alkyl group or an ethenyl group).
This invention is directed to a porphyrin derivative 15 represented by the general formula:
Il~ CJ-13 C~3 lc~
~ ~t llM ~ (I) C~lJ- ~ J ~ D ~ C~13 ~2 R2 wherein R1 each independently denotes a hydrogen, a C1-C4 alkyl group or an ethenyl group, and R2 each independently (Crnll2m)Qr CZC~I(CmllzmQ)2~ -C112-Q [wherein Z
is O, S or Nll, m is an integer of 1 to 23, and Q is a dl-(Cl-C4 alkyl)amino group or tri-(C1-C4 alkyl)a~ onium halide groupl or -C112-N ~ X (wherein X is a halogen); or ~1 each independently denotes -C2119-Q (wherein Q is the same as defined above), -C21-14-N ~ X or C2114 N ~ X
~ >
(whereill X is the same as defined above), and R2 each inde-pendently denotes a carboxyl group or a Cl-C4 allcoxycarbonyl group .
~, , f :` ~J
1 31 57~0 C1-C4 alkyl group denoted by R1 in the formula (I), C.1-C4 alkyl in di-(C1-C4 alkyl)amino group or tri-(C1-C4 alkyl)ammonium halide group included in the definition of Q, or C1-C4 alkyl in C1-C4 alkoxycarbonyl group denoted by R2 in the formula (I) is an alkyl group such as methyl, ethyl, propyl or butyl. C3-C4 alky~ group may be a straight or branched chain.
The embodiments of the porphyrin derivative (I) can b~ illustratedby the formulas (III), (IV) and (VI) des-cribed below:
One group of porphyrin derivatives (I) can be repre-sented by the following formula;
~ 3 C113~
~ IN ~ (III) C11~ C~13 C.Oil3 CO113 (wherein R1' is a hydrogen, a C1-C4 alkyl group or an ethenyl group; R3 is O(CmH2m)N(R)2, OCH(CH2N(R)2)2, S(Cm-H )N(R)2' NH(CmH2m)N(R)2, O(CmH2m) 3 2 N (R)3)2 2X 7 S(CmH2m)N tR)3-x or NH(CmH2m)N (R)3-X
(wherein R is a C1-C4 alkyl group; X is a halogen; m is an integer oE 1 to 23; n is an integer of 1 to 4).
Referring to the formula, R is C1 to C4 alkyl, such as methyl or ethyl, or staight or branched propyl or butyl.
By halogenating porphyrin of the general formula (II) and conducting a condensation reaction of the resulti.ng acid halide with a compound represented by the formula HO(CmH2m)N(R)2, HOCH(CH2N(R)2)2, 11S(CmH2m)N(R)2 or ......
t3157~0 H2N(CmH2m)NtR)2 (wherein R, m and n are as defined herein-before) or its salt in a solvent in the presence or absence of an acid-capturing agent, there are obtained the porphyrin derivatives of the formula (III) wherein R2 is O(CmH2m)-2 ( 2 (R)2)2' S(CmH2m)N(R)2 or NH(C H2 )N(R) .
As the solvent employed in this condensation reaction,there may be mentioned methylene chloride, chloroform, ethyl acetate, etc., with methylene chloride normally being preferentially employed; Examples of the acid-capturing agent include triethylamine, pyridine, quinoline and the like, with triethylamine being preferably used. The reaction temperature and reaction time can be suitably selected.
Ordinarily, the reaction is completed at 0C for 0.5 to 5 hours. When methylene chloride is used as a solvent, for example, the condensation reaction can be completed at a temperature maintained at the refluxing temperature of methylene chloride for 1 to 2 hours. The porphyrin derivatives of the formula (III) where R3 is O(CmH2m)N (R)3 2 )3)2 2X ~ S(CmH2m)N (R)3-X or NH(C H
N+(R)3 X can be obtained by the following procedure;
The porphyrin derivative of the formula (III) wherein 3 m 2m ( )21 OCH(CH2N(R)2)2, S(C H2 )N(R) or NH
(CmH2m)N(R)2 is reacted with a lower alkyl halide in the presence or absence of a solvent to convert to its quater-nary ammonium salt. As the preferred solvent which is used in this reaction, there may be mentioned methylene chloride chloroform, ethylene dichloride, etc. The reaction tempera-ture and reaction time can be suitably selected. For example, the reaction is completed at 0C to 100C for 5 minutes to 5 hours, but the reaction can normally be concluded at 20C to 30C for 0.5 to 1 hour.
- 5 _ 1 31 57~0 ~nother group of the present porphyrin derivatives (I) can be represented by the formula;
r~ I C1-1~
~ 5 (~ C ~
Cl~ C113 n ,~ ,7 [wherein R1' is the same as defined above and R4 is N (R)3 X (wherein R is a C1-C4 alkyl group and X is a halogen) or pyridinium halide group]. The porphyrin deriva-tive (IV) can be obtained by halogenating a porphyrin deriv-ative of the formula, 11l' Cl~3 C7-l3 ~ nl~
~ ' (V) HO - OH
to convert respective OH groups in the above Eormula to halogens and reacting the halogenated compound with a terti-ary amine.
The halogenation may be carried out by reacting a porphyrin derivative of the formula (V) with a halogenating agent in the presence of a solvent. As the halogenating agent which is utilizable in the reaction, there may be mentioned thionyl halides, hydrogen halides, etc., while the solvent includes, for example, methylene chloride, chloroform, pyridine and the like. The reaction may normally be completed at 0 to 80C for 1 to 5 hours. When 1 31 57~,0 thionyl bromide is used as a halogenating agent, however, the reaction is ordinarily completed at 20 to 30C for 3 to 5 hours.
The halogenated derivative thus obtained is reacted 5 with a corresponding tertiary amine in the pres-ence or absence of a solvent. As the solvent employable in the reaction, there may be mentioned methylene chloride, chloroform, ethylene dichloride, etc. The reaction may normally be completed at 0 to 100C for 5 minutes to 5 10 hours. When pyridine is used as an amine, for example, the reaction is normally completed by refluxing the mixture of the halogenated derivative with pyridine for 1 to 3 hours.
A further group o-E the present porphyrin derivative 15 can be represented by the Eormula;
Cl-l3~ J-1~5 ~ ~ (VI) 25 Cll~- ~ ,J ~ Lcll~3 CO~fi Co~6 [wherein R5 is N (R)3 X ~wherein R is a C1-C4 alkyl group and X is a halogen), pyridinium halide group or quinolinium halide group; and R6 is a hydrogen or a C1-C4 alkyl group].
The derivative (VI) can be obtained by reacting a porphyrin derivative of the formula;
\
_ 7 _ 1 31 57 ~n L ll3 _~
Cl-l3) ~
~ (VII) c~.~3 l~J~J~Lc.~3 l~ 1 ~2~ C~2l~6 (wherein X6 and X are the same as deEined above) with a corresponding tertiary amine.
The C1-C4 alkyl groups each denoted by R6 or by R
in N+(R)3 ~ which is included in the definition of R5 is independently an alkyl yroup such as methyl or ethyl, or propyl or butyl which may branches.
As pyridinium halide group denoted by R5, there may be exemplified pyridinium chloride or pyridinium bromide group, and as quinolinium halide group, yunolinium chloride or qunolinium bromide group.
The reaction of the derivative (VII) with the tertiary amine may be carried out in the presence or absence of ; a solvent such as methylene chloride, chloroform, ethylene dichloride, etc. The reaction may generally be conducted at 0 to 100C for 5 minutes -to 5 hours. When pyridine is used as the tertiary amine, the reaction may ordinally be com~pleted by refluxing the derivative (VII', with pyridine ; for 1 to 5 hours.
The novel porphyrin derivatives thus obtained may be purified from the reaction mixture by a usual method, for example, extraction with a suitable solvent, recrystal-lization, column chromatography, etc.
- 8 -~ 1 31 57~0 The compounds of present invention have the following characteristic features effective in diagnosing and traating cancer;
1. Generating fluorescence under the irradiation of light, 5 2. Generating singlet oxygen ('2) under irradiation of light in the presence of oxygen (The generated '2 has cell-cidal effect), and 3. Exhibiting marked accumulation at cancer tissue as com-pared with normal tissue.
Namely, when the present compoundselectively accumulates at cancer tissue after administration to cancer-bearing living body, the cancer tissue markedly generates fluores-cence by light irradiation. Therefore, the position and size of the cancer can be ascertained by determining the fluorescence. Thus, if the position and size is ascertained, then, by irradiating the light of an appropriate wave length on the position, '2 generates at the cancer tissue which can be necrotized by the '2 The present compound rarely accumulates in a normal tissue surrounding the cancer, 20 therefore, there is no '2 generation nor damage at the normal tissue. In such manner, cancer tissue can be selec-tively necrotized, which is effective in cancer treatment.
Various ways may be employed for a~ministrating the present compound. For example, it can be administered intravenously, suboutaneously, intraperitoneally, orally or intrarectal-ly .
As for dosage, it may be administered at a dose of 1-350 mg/kg.
When administered intraveneously,the present compound 30 accumulates into a normal tissue such as muscle, intestine, stomach, liver, kidney, heart, brain, etc. and reaches to the maximum within several hours and thereafter it is excluded by process of time. However, in the case of cancer tissue, the accumulation reaches to the maximum within 35 several hours and the compound still remains 24 to 72 hours after the administration. Thus selective accumulation of the compound at cancer tissue as compared with normal tissue is observed in the hours above-mentioned. Therefore, the diagnosis and treatment of cancer under irradiation of light is effective, when it is carried out in the above-men-5 tioned hours.
In the case of the diagnosis, a light having a short wave length, about 400 nm, may be employed. In the case of the treatment, a light having a long wave length ,usually about 620 nm, being well penetrable into tissue may be 10 employed in order to allow the light to reach deeply into the cancer tissue.
The source of the light is not particularly limited, however, it is preferable to use a laser light for irradi-ating a localized position so as to irradiate high energy 15 to the cancer and not to irradiate the peripheric portion of the cancer.
The present invention ls further explained by Reference examples and Examples in the following:
20 Reference example 1 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride:
Gram of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-25 porphin-2,18-dipropionic acid is suspended in 35 ml of methylene chloride and 2.5 ml of oxalyl chloride is added dropwise thereto under refluxing. After further refluxing for 15 minutes, solvent is distilled off from lthe mixture under reduced pressure to give 1.1 g of 7,12-diethenyl--30 3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride as the residue.
10 - 1 31 57 ~0 Example 1 Synthesis of 7,12-diethenyl-3,8,13,17--tetramethyl-2,18-bis [2-(dimethylaminoethyloxy)carbonylethyl]-21H,23H-porphin:
1.1 Gram of 7,12-diethenyl-3,8,13,17-tetramethyl-21H, 23H-porphin-2,18-dipropionic acid chloride is added to 60 ml of methylene chloride and the mixture is refluxed under addition of 5 ml of 2-dimethylaminoethanol for 45 minutes, followed by further refluxing under addition of 5 ml of 2-dimethylaminoethanol for 45 minu-tes. Solvent is removed from -the reaction mixture under reduced pressure to give residue. The residue is dissolved in 100 ml of chloroform, washed with 100 ml of water and -the chloroform layer is concentrated under reduced pressure -to dryness.
The resultant is purified with column chromatography packed 15 with 100 g of alumina (activity V) using chloroform as a solvent. This procedure gives 850 mg of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-dimethylaminoethyloxy)-carbonylethyl~-21H,23H-porphin as brownish black crystals melting at 187-191C.
20 Electronic spectrum (~max, chloroform):
407, 506, 541, 577, 630 (nm) IR spectrum (KBr):
3305, 2960, 2940, 2900, 2850, 2810, 2760, 1735 (cm 1) NMR spectrum (CDCl3):
~; 9.70, 9.56, 9.49 (s, 2H, 1H, 1H) 8.10- 7.72, (m, 2H), 6.24-5.92 (m, 4H), 4.26 (t, 4H), 4.15 (t, 4H), 3.44, 3.38, 3.36, 3.34 (s, 3Hx4) 3.19 (t, 4H), 2.36 (t, 4EI), 2.06 (s, 1211), -4.48 (s, 2H) Example 2 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis [2-(1,3-bis(dimethylamino)-2-propyloxy)-carbonylethyl]-21H, 23H-porphin:
According to the process of Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17--tetrame-thyl-21H,23H-porphin-2,18-di-11 1 31 57~n propionic acid chloride is condensed with 5 ml of 1,3-bis-(dimethylamino)-2-propanol to give 480 mg of 7,12-diethenyl-3, 8 ,13 ,1 7-tetramethyl-2,18-bis[2-~1,3-bisldimethylamino)-2-propyloxy)carbonylethyl]-21H,23H-porphin as brownish black 5 substance melting at 181-190C.
Electronic spectrum (~max, chloroform):
407.5, 505.5, 541, 576, 630.5 (nm) IR spectrum (KBr)o 3305, 2960, 2930, 2900, 2850, 2810, 2760, 1730 (cm~1) 10 NMR spectrum (CDCl3):
~; 9.79, 9.76, 9.62, 9.56 (s, lHx4) 8.14-7.76 (m, 2H) 6.24-5.92 (m, 4H) 5.13 (t, 2H), 4.32 (t, 4H), 3.48, 3.44, 3.39 (s, 3H, 3H, 6H), 3.21 (t, 4H), 2.21 (d, 8H), 2.04 (s, 24H~, -4.32 (s, 2H) Example 3 Synthesis of 7~12-diiet~eny~ 3,8,13,17-tetramethyl-2,18-bis-[2-(6-dimethylamino-1-hexyloxy)carbonylethyl]-21H~23H
porphin:
According to the process in Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-di-25 propionic acid chloride is condensed with 5 ml of 6-di-methylamino-1-hexanol to give 450 mg of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(6-dimethylamino-1-hexyl-oxy)carbonylethyl]-21H,23H-porphin as brownish black crys-tals melting at 160 to 165C.
30 Electronic spectrum (~max, CHCl3):
407.5, 505.5, 541, 576, 630.5 (nm) IR spectrum (KBr):
3300, 2920, 2850, 2800, 2750, 1735 (cm NMR spectrum (CDCl3):
35 ~; ~.7, g.6, 9.52 (s, 2H, 1H) 8.2-7.7 ~broad, 2H) 6.28-5.9 (m, 4H) ... ..
- 12 - 1 3 1 57~0 4.27 (t, 4H) 4.02 (-t, 4H) 3.42, 3.38 (s, 6H, 6H) 3.16 (t, 4H) 2.02 (s, 12H) 2-1.8 (m, 4H) 1.5-1.2 (m, 4H) 1.2-0.9 (~, 16H) -4.6 (broad, 2H) Example 4 Synthesis of 7,12-die-thenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(2-dimethylaminoethyl)carbamoyl)ethyl]-21H,23H-porphin:
According to the process of Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-di-propionic acid chloride is condensed with 5 ml of 2-di-methylaminoethylamine to give 740 mg of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(2-dime-thylaminoethyl)-carbamoyl)ethyl]-21H,23H-porphin as brownish black crystals melting at 300C or higher.
Electronic spectrum (~max, chloroform):
406.5, 506, 541, 576, 630 (nm) IR spectrum (KBr):
3290, 2925, 2850, 2805, 2750, 1640 (cm NMR spectrum (CDCl3):
~; 9.44, 9.39, 9.34, 9.19 (s, 1Hx4) 8.06-7.62 (m, 2H) 6.8-6.6 (m, 2H) 6.21-5.88 (m, 4H) 4.02 (broad, 4H) 3.28, 3.26, 3.24, 3.15, (s, 3Hx4) 3.04-2.76 (m, 4Hx2) 1.76, 1.73 (t, 2Hx2) 1.57, 1.53 (s, 6Hx2) -5.05 (s, 2H) 1 3 1 5 7 ~ 3 Example 5 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(3-dime-thylaminopropyl)carbamoyl)ethyl]-21H,23H-porphin:
According to the process of Example 1, 1.1 g of 7,12-diethenyl-3,8,13,17-te-tramethyl-21H,23H-porphin-2,18-di-propionic acid chloride is condensed wi-th 5 ml of 3-di-methylaminopropylamine to give 650 mg oE 7,12-diethenyl-10 3~8~13~17-tetramethyl-2~18-bis[2-N-(3-dimethylaminopropyl)-carbamoyl)ethyl]-21H,23H-porphin as brownish black crystals melting at 300C or hihger.
Electronic spectrum (~max, chloroform):
407, 505.5, 541, 576, 630 (nm) 15 IR spec-trum (KBr):
3300, 3075, 2920, 2850, 2800, 2750, 1640 (cm NMR spectrum (CDCl3):
~; 9.53, 9.39, 9.28 (s, 2il, 1H~ 1H) 8.09-7.65 (m, 2H), 7.55-7.35 (m, 2H), 6.23-5.88 (m, 4H), 4.05 (t, 4H) 3.33, 3.28, 3.27, 3.12 (s, 3Hx4) 2.92 (t, 4H), 2.85 (t, 4H), 1.66-1.5 (t, 4H) 1.63, 1.59 (s, 6Hx2) 1.11 (q, 4H), -4.88 (s, 2H) Reference example 2 Synthesis of 3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride:
1 Gram of 3,8,13,17-tetramethyl-2111,23H-porphin-2,18-dipropionic acid is suspended in 35 ml of methylene chlo-ride, and 2.5 ml of oxalyl chloride is dropwise added there-to under refluxing, followed by refluxing for further 15 minutes whereby the reaction is completed. Solvent in the 35 reaction mixture is removed under reduced pressure to give, as the residue, 1.1 g of 3,8,13,17-tetramethyl-21H,23 porphin-2,18-dipropionic acid chloride.
13157~0 Example 6 Synthesis of 3,8,13,17-tetramethyl-2,18-bis[2-~2-dlmethyl-aminoethyloxy)carbonylethyl]-21H,23H-porphin:
1.1 Gram of 3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride is added to 60 ml of methylene chloride, and the mixture is refluxed under addi-tion of 5 ml of 2-dimethylaminoethanol for 45 minutes, followed by refluxing under addition of further 5 ml of 2-dimethylaminoethanol for another 45 minutes. Solvent is removed from the reaction mixture under reduced pres-sure, and the residue is dissolved in 100 ml of chloroform, washed with 100 ml of water, and the chloroform layer is concentrated to dryness under reduced pressure. The residue thus obtained is purified with column chromatography packed with 100 g of alumina (activity V) with the use of chloro-form as solvent to give 330 mg of 3,8,13,17-tetrame-thyl-2,18-bis[2-t2-dimethylaminoethyloxy)carbonylethyl]-21H,23H-porphin as brownish balc~ crystal melting at 159-160C.
~o Electronic spectrum (~max, chloroform):
399, 496.5, 529.5, 566, 591.5, 619 (nm) IR spectrum (KBr):
3300, 2925, 2845, 2805, 2755, 1735 (cm 1) NMR spectrum (CDCl3):
~; 9.77, 9.68, 9.67 (s,1H, 1H, 2H) 8.76, 8.75 (s, 1Hx2) 4.25 (t, 4H), 4.12 (t, 4H), 3.56, 3.48, 3.44, 3.39 (s, 3Hx4) 3.10 (t, 4H), 2.32 (t, 4H), 2.04 (s, 6H), -4.31 (s, 2H) Reference example 3 Synthesis of 7,12-diethyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride:
1 Gram of 7,12-diethyl-3,8,13,17-tetramethyl-21H,23H-Po~phan~2~18-dipropionic acid is suspended in 35 ml of meth-ylene chloride, and 2.5 ml of oxalyl chloride is dropwise - 15 - 1 3 1 57 ~
added thereto under refluxing, followed by refluxing for a further 15 minutes, whereby the reaction is completed. The reaction mixture is subjected to distillation under reduced pressure to remove the solvent, whereby there is obtained, 5 as the residue, 1.1 g of 7,12-diethyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride.
Example 7 Synthesis of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-dimethylaminoethyloxy)carbonylethyl]-21H,23H-porphin:
60 Milliliters of methylene chloride is added to 1.1 g of 7,12-diethyl-3,8,13,17--tetramethyl-21H,23H-porphin-2,18-dipropionic acid chloride, and 5 ml of 2-dimethylamino-15 ethanol is added thereto under refluxing, followed by keep-ing the reflux for 45 minutes, and further refluxed after addition of another 5 ml of 2-dimethylamino-ethanol for 45 minutes. Solvent is removed from the mixture under reduced pressure, and the resulting residue is dis-20 solved in 100 ml of chloroform and washed with water. Thechloroform layer is concentrated to dryness under reduced pressure and the resultant residue is purified with column chromatography packed with alumina (activity V) with the use of chloroform as solvent. This procedure gives 930 25 mg of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis[2(2-di-methylaminoethyloxy)carbonylethyl]-21H,23H-porphin as brown-ish black crystal melting at 168-172C.
Electronic spectrum (~max, chloroform):
399.5, 498, 532, 567, 593.5, 620.5 (nm) 30 IR spectrum (KBr):
3305, 2955, 2930, 2855, 2810, 2710, 1735 (cm 1) NMR spectrum (CDCl3):
~; 9.92, 9.87, 9.83, 9.81 (s, 1Hx4) 4.35,, 4.32 (t, 2Hx2) 4.13 ~t, 4H) 3.94, 3.91 (q, 2Hx2) 3.56, 3.50, 3.44 (s, 3H, 6H, 3H) 3.25 (t, 4H), 2.33 (t, 4H), 2.02 (s, 6H), . ~
.
1.78, 1.77 (t~ 2Hx2) -3.92 (s, 2H) Example 8 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-trimethylammonioethyloxy)carbonylethyl]-21H,23H-porphin diiodide:
100 Milligrams o~ 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(2-dimethyla~inoethyloxy)carbonylethyl]-21H,23H-porphin obtained in Example 1 is dissolved in 10 ml of methylene chloride, and 1 ml of methyl iodide is added thereto and the precipitated crys-tals are recovered by filtration to give 126 mg of 7,12-diethenyl-3,8,13,17-tetra-methyl-2,18-bis[2-(2-trimethylammonioethyloxy)carbonyl-ethyl]-21H,23H-porphin diiodide as brownish black crystals.
Electronic spectrum (~max, water):
376, 512, 548, 576.S, 630.5 (nm) ~R spectrum (Ksr):
3300, 2900, 1725 (cm~1) NMR spectrum (DMSO-d6) ~; 9.74, 9.66 (s, 2Hx2) 8.4-7.8 (m, 2H), 6.4-6.0 (m, 4H), 4.5-4.0 (broad, 4Hx2) 3.48 (s, 3Hx4), 3.26 (broad, 4Hx2~, 2.79 (s, 18H), -5.08 (broad, 2H~
Example 9 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(1,3-bis(trimethylammonio)-2-propyloxy)carbonylethyl]-21H,23H-porphin tetraiodide:
100 Milligrams of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(1,3-bis(dimethylamino)-2-propyloxy)carbonyl-ethyl]-21H,23H-porphin obtained in Example 2 is dissolved in 10 ml of methylene chloride, and 1 ml of methyl iodide is added thereto and the precipi-tated crystals are recov-ered by fil-tration to give 100 mg of 7,12-diethenyl-f "., ~ ' - 17 - 1 31 57~0 3,8,13,17-tetramethyl-2,18-bis[2-(1,3-bis(trime-thylammonio-2-propyloxy)carbonylethyl)-21H,231-l-porphin tetraiodide as brownish black crystals.
Electronic spectrum (Amax, water):
398, 509, 543.5, 573.5, 628.5 (nm) IR spectrum (KBr):
3300, 2995, 2930, 2850, 1740 (cm 1) NMR spectrum (DMSO-d6):
~; 10.20-9.96 (s, 1Hx4), 8.52-8.02 (m, 2H), 6.44-6.06 (m, 4H), 5.88-5.58 (broad, 2H), 4.68-4.28 (broad, 4Hj, 3.96-3.4 (m, 4H, 4H, 4H), 3.64-3.56 (s, 3Hx4), 3.08 (s, 36H), -4.26 (broad, 2H) Example 10 Synthesis of 7,12-diethenyl-3,8,13,17--tetramethyl-2,18-bis[2-(N-(2-trimethylammonioethyl)carbamoyl)ethyl]-21H,23H-porphin diiodide:
100 Milligrams of 7,12-diethenyl-3,8,13,17-tetramethyl-2l18-bis[2-~N-(2-dimethylaminoethyl)carbamoyl)ethyl]-21H,23H-porphin obtained in Example 4 is dissolved in 20 ml of methylene chloride under heating. After cooling the mixture to room tempera-ture, 1 ml of me-thyl iodide is added thereto, and the precipitated crys-tals are recovered by fil-tration to give 127 mg of 7,12-diethenyl-3,8,13,17-te-tramethyl-2,18-bis[2-(N-(2--trimethylammonioe-thyl)carbamoyl)ethyl]-21H,23H-porphin diiodide as brownish black crystals.
Electronic spectrum (Amax, water):
377.5, 510, 548, 575.5, 630 (nm) IR specrum (KBr):
3300, 3230, 2995, 2900, 2845, 1655 (cm 1) NMR spectrum (in DMSO-d6):
~; 10.2-10.05 (s, 1Hx4), 8.6-8.0 (m, 2H), 6.6-6.0 (m, 4H) 4.37 (t, 4H), 3.8-3.6 (m, 8H), 3.28 (broad, 3Mx4), 3.14 (-t, 4H), 2.54 (s, 18H) ,8 - 1 3 1 5780 Example 11 Synthesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(3-trimethylammoniopropyl)carbamoyl)ethyl]-21H,23H-porphin diiodide:
100 Milligrams of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(3-diethylaminopropyl)carbamoyl)ethyl]-21H,23H-porphin is dissolved in 10 ml of methylene chloride, and 1 ml of methyl iodide is added thereto. The precipitated crystals are recovered by filtration to give 126 mg of 7,12-10 diethenyl-3l8l13l17-tetramethyl-2~18-bis[2-(N-(3-trimeth ammoniopropyl)carbamoyl)ethyl]-21H,23H-porphin diiodide as brownish black crystals.
Electronic spectrum (~max, wa-ter):
380.5, 510, 546, 577, 631 (nm~
IR spectrum (KBr~:
3300, 3250, 2900, 2850, 1640 (cm~1) NMR spectrum (DMSO-d6):
~; 9.94, 9.86, 9.78 (s, 1H, 1H, 2H) 8.5-8.06 (m, 2H), 8.02-7.86 ~m, 2H), 6.4-6.09 (m, 4H), 4.3 (broad, 4H), 3.54 (broad, 12H), 3.1-2.8 (broad, 8H), 2.62 (broad, 4H), 1.3 (broad, 4H), -4.9 (broad, 2H) Reference example 4 Affinity to _ancer cells 1 x 107 MKSA cells originated from mouse nephradenoma were -transplanted on the back of 3-week-aged Balb/c mouse, and after 2-3 weeks, the present porphin derivative is intravenously administered to the tail of the mouse at a dose of 20 mg/kg body weight. After 24 hours from the administration, organs and cancer cells were excised from the mouse, and fluorescence generated from them, which was originated from the porphin derivative, was measured on each of them by using laser diagnosis apparatus (K.
Aizawa et al., LASER IGAKU KAISHI, Vol. 5, pp. 63-68, (1984)). The results are summarized to strength of the fluorescence at cancer tissue and strength ratio of the - ~\
,9 1 31 57~0 fluorescence at normal tissues to the fluorescence at cancer tissue in Table 1.
In the Table, respective [8~ and [10] denote the com-pounds obtained in Examples 8 and 10, Hp denotes hemato-porphyrin and HpD denotes theporphyrin derivative obtainedby the procedure described in Porphyrin Locali~ation and Treatment of Tumors, pp. 75-78, (1984).
Table 1 Compound Strength of Strength ratio of fluorescence fluorescence (normal organs / cancer) at cancer Skin Lung Liver Kidney [8] 15.080.47 0.01 0.09 0~00 [10] 14.890.74 0.07 0.04 -HpD 5.700.84 0.01 0.09 0.00 Hp 3.45 - 0.45 0.45 0.45 25 Reference example 5 Therapeutic effect 1x10 MKSA cells originated from mouse nephradenoma were transplanted on the back of 3-week-aged Balb/c mouse, and at the stage when the tumor had grown up to have dia-30 meter of about 1 cm after 2 to 3 weeks, the compound obtain-ed in Example 8 was intraveneously administered to the tail of the mouse at a dose of 20 mg/kg body weigh-t.
At 24 hours after the administration, the hair on the tumor was taken off to lay the skin bare, and excimer 35 laser (wave length 625 nm) was irradiated, whereby the tumor disappeared after 3 days.
- 20 ~ 13157~
Reference example 6 Synthesis of 7,12-diethyl~3,8,13,17-tetramethyl-2,18-bis-(3-bromopropyl)-21H,23H-porphin:
To 1 liter of methylene chloride, 50 ml of dimethyl-formamide is added and the mixture is agitated, followed by addition of 25 ml of thionyl bromide, 60 g of potassium carbonate and 2.5 g of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis(3-hydroxypropyl)-21H,23H-porphin. The mixture is stirred at room temperature for 5 hours. The reaction solution is poured on 1 kg of ice to decompose excess thionyl bromide and the mixture is subjected to iayer sepa-ration. The methylene chloride layer is washed with each 100 ml of water three times, dried on anhydrous magnesium sulfate and subjected to distillation under reduced pressure to give 4.5 g of crude product. The crude product is washed with 30 ml oE methanol, dried and purified with column chromatography packed with alumina (activity V) in an amount of 200 g with the use of methylene chloride as solvent, whereby 2.7 g (yield 87.4 ~) of the desired compound is obtained as dark reddish brown substance.
Melting point: 300~C or higher Electronic spectrum (~max, DMF): 620.5, 566.3, 529.5, 496.7, 396.0 (nm) IR spectrum (KBr)~ 3320, 2950, 2920, 2850, 835, 740 (cm NMR spectrum (CDCl3):
~; -3.78 (2H, s), 1.82 (6H, t), 2,70 (4H, t), 3.48-3.68 - (16H, m), 4.02 (8H, m), 9.80 (1H, s), 9.83 (3H, s) Example 13 Synthesis of 7,12-diethyl-3,8,13,17--tetramethyl-2,18-bis(3-pyridiniopropyl)-21H,23H-porphin dibromide: -To 100 mg of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis(3-bromopropyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. The precipitated crystals are reco~ered by filtration, washed with 3 ml of .. , 1 31 ~7~30 pyridine and dried, whereby 100 mg (yield 81.1 %~ of dark reddish brown desired compound is obtained.
Melting point: 300C or higher Electronic spectrum (~max, DMF): 620.5, 566.5, 529.5, 497.0, 397.5 (nm) IR spectrum (KBr): 3300, 3000, 2960, 2930, 2850, 1630, 1480, 835, 740, 675 (cm NMR specrum (DMSO-d6):
~; -3.96 (2H, s), 1.74 (6H, t), 2.85 (4H, broad), 3.20 (12H, s), 3.96 (4H, broad), 4.30 ~4H, broad), 5.30 (4H, broad), 8.02 (4H, t), 8.42 (2H, t), 9.36 (4H, d), 9.86 (1H, s), 9.90 (3H, s) Example 14 Synthesis oE 3,8,13,17-tetrame-thyl-2,18-bis(3-pyridinio-propyl)-21H,23H-porphin dibromide:
To 120 mg of 3,8,13,17-te-tramethyl-2,18-bis(3-bromo-propyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. T~e precipitated crystals are recovered by filtra-tion, washed with 3 ml of pyridine and dried, whereby 140 mg (yield-92.8 %) of brownish black desired compound is obtained.
Melting point: 300C or higher Electronic spectrum (~max, DMF): 623.3, 568.9, 533.3, 500.1, 401.0 (nm) IR spectrum (KBr): 3300, 3000, 2950, 2900, 2850, 1630, 1480, 835, 720, 675 (cm NMR spectrurn (DMSO-d6):
~i 2.74 (4H, broad), 3.30 (12H, s), 4.20 (4H, broad), 5.24 (4H, broad), 8.04 (6H,- broad), 8.44 (2H, broad), 8.80-9.40 (8H, m) Example 15 Syn-thesis of 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis(3-pyridiniopropyl)-21H,23H-porphin dibromide:
- 22 ~ 1 31 57 ~ 0 To 100 mg of 7,12-dlethenyl-3,8,13,17--tetramethyl-2,18-bis(3-bromopropyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. The precipi-tated crystals are recovered by filtration, washed with 3 ml of pyridine and dried, whereby 116 mg (yield 94.5 %) of brownish black desired compound is obtained.
Melting point: 300C or higher Electronic spectrum (~max, DME): 632.0, 576.8, 542.0, 506.5, 409.0 (nm) IR spectrum (KBr): 3300, 3000, 2900, 2850, 1625, 1480, 835, 725, 680 (cm 1) Reference example 7 Affinity to cancer cells 1x107 MKSA cells originated from mouse nephradenoma are transplanted on the back of 3-week-aged Balb/c mouse, and after 2-3 weeks, the porphin derivative obtained by the present invention is intraveneously administered to the tail of the mouse at a dose of 20 mg/kg body weight.
After 24 hours, organs and cancer tissue are taken out and fluorescence genera-ted from -them, which is originated from the prophin derivative, is measured on each of them by using laser diagnosis apparatus (K. Aizawa et al., LASER
IGAKU KAISHI, Vol. 5, pp. 63-68, (1984)). The results are summarized to the fluorescence strength a-t cancer tissue and the ratio of the fluorescence strength at normal tissue to that at cancer tissue in Table 2. In the Table, [13]
denotes the product compound in Example 13, Hp deno-tes hematoporphyrin and HpD denotes the porphyrin derivative obtained by the procedure described in Porphyrin Localiza-tion and Treatment of Tumors, pp. 75-78, (1984).
1 31 ~7~0 Table 2 Compound Strength of Strength ratio oE fluorescence fluorescence (normal organs / cancer) at cancer Skin l,ung Liver Kidney [13~ 16.36 - 0.01 0.06 0.01 HpD 5.70 0.84 0.01 0.09 0.00 Hp 3.45 - 0.45 0.45 0.45 Example 16 Synthesis of 7,12-bis(2-pyridinioe-thyl)-3,8,13,17-te-tra-15 methyl-2,18-bis(2-methoxycarbonylethyl)-21H,23H-porphin dibromide:
To 500 mg of 7,12-bis(2-bromoethyl)-3,8,13,17-tetra-methyl-21H,23H-porphin-2,18-dipropionic acid methyl ester, 20 10 ml of pyridine :is added, followed by refluxing for 5 hours. The precipitated crystals are recovered by filtra-tion, washed with 5 ml of pyridine and dried, whereby 550 mg (yield 99.5 %) of dark reddish desired compound is ob-tained.
25 Electronic spectrum (Amax, PBS): 621.5, 569, 543, 508, 370.5 (nm) IR spectrum (KBr): 3425, 3325, 3050, 2950, 2850, 1730, 1630, 1485, 1460, 1440, 1270, 1220, 1200, 1165, 1100, 840, 740, 680 (cm 1) Example 17 Synthesis of 7,12-bis(2-quino:Linioethyl)-3,8,13,17-te-tra-methyl-2,18-bis(2-methoxycarbonyle-thyl)-21H,23~-l-porphin dibromide:
To 100 mg of 7,12-bis(2-bromoethyl)-3,8,13,17--tetra-methyl-21H,23H-porphin-2,18-dipropionic acid methyl ester, 2 ml of quinoline is added, followed by refluxing for 5 ~ 31 57~0 hours To the resultant, 20 ml of hexane is added, and the precipitated crystals are recovered by filtration, washed with 5 ml of hexane and dried, whereby 135 mg (yield 99.6 ~t of dark reddish desired compound is obtained.
IR spectrum (KBr): 3400, 3300, 2920, 2850, 1725, 1590, 1520, 1430, 1395, 1365, 1255, 1225, 1195, 1160, 1110, 830, 760, 740 (cm 1) C NMR spectrum (CD30D): 173~8, 148.6, 146.9, 143.8, 142.5, 139.3, 139.1, 138.3, 136.9, 136.6, 136.0, 132.0, 130.8, 130.4, 129.0, 128.3,-126.7, 125.1, 120.8, 118.0, 96.8, 95.4, 36.7, 21.2, 11.2, 10.2, 10.9, 10.6 (ppm) Example 18 Synthesis of 7,12~bis(2-quinolinioethyl)-3,8,13,17-tetra-methyl-2,18-bis-(2-carboxyethyl)-21H,23H-porphin dibromide:
To 100 mg of 7,12-bis(2-bromoethyl)-3,8,13,17-tetra-methyl-21H,23~-porphin-2,18-dipropionic aci,d, 2 ml of quin-oline is added, followed by refluxing for 5 hours. To the resultant, 20 ml of hexane is added, and the precipitated ~rystals are recovered by filtration, washed with 5 ml of hexane and dried, whereby 110 mg (yield 95.5 %) of desired compound is obtained in dark reddish brown colour.
IR spectrum (KBr): 3400, 3100, 2920, 2850, 1720, 1630, 1590, 1525, 1455, 1380, 1225, 1160, 1105, 815, 770, 740 (cm Reference example 8 Affinity to cancer cells 1x107 MKSA cells originated from mouse nephradenoma are transplanted on the back of 3-week-aged Balb/c mouse, and after 2 to 3 weeks, the porphin derivative obtained by the present invention is intraveneously administered to the tail of the mouse at a dose oE 20 mg/kg body weight.
After 24 hours, organs and cancer tissue are taken out and fluorescence generated from them, which is originated from the porphin derivative, are measured on each of them ,~,1 - 25 - 13157~0 by using laser diagnosis apparatus (K. Aizawa et al., LASER
IGAKU KAISHI, Vol. 5, pp. 63-68, (1984)). The results are shown in Table 3 as strength of the fluorescence at cancer tissue and the ratio of fluorescence strength at normal tissue to -that at cancer tissue. In -the Table, [16] denotes the product compound in Example 16, Hp denotes hematopor-phirin and HpD denotes the porphyrin derivative obtained by the procedure described in Porphyrin Localization and Treatment of Tumors, pp.-75-78, (1984).
Table 3 Compound Strength of Strength ratio of fluorescence fluorescence (normal organs / cancer) at cancer Skin Lung Liver Kidney [16] 3.00 0.00 0.00 0.00 0.00 HpD 5.70 0.84 0.01 0.09 0.00 Hp 3.45 - 0.45 0.45 0.45
Claims (7)
1. A porphyrin derivative of the general formula:
wherein R1 each independently denotes a hydrogen, a C1-C4 alkyl group or an ethenyl group, and R2 each independently denotes COZ(CmH2m)Q,COZCH(CmH2mQ)2,-CH2-Q [wherein Z is O, S or NH, m is an integer of 1 to 23, and Q is a di-(C1-C4 alkyl)amino group or tri-(C1-C4 alkyl)ammonium halide group] or (wherein X is a halogen); or R1 each independently denotes -C2H4-Q(wherein Q is the same as defined above), (wherein X is the same as defined above), and R2 each independently denotes a carboxyl group or a C1-C4 alkoxycarbonyl group.
wherein R1 each independently denotes a hydrogen, a C1-C4 alkyl group or an ethenyl group, and R2 each independently denotes COZ(CmH2m)Q,COZCH(CmH2mQ)2,-CH2-Q [wherein Z is O, S or NH, m is an integer of 1 to 23, and Q is a di-(C1-C4 alkyl)amino group or tri-(C1-C4 alkyl)ammonium halide group] or (wherein X is a halogen); or R1 each independently denotes -C2H4-Q(wherein Q is the same as defined above), (wherein X is the same as defined above), and R2 each independently denotes a carboxyl group or a C1-C4 alkoxycarbonyl group.
2. A porphyrin derivative as claimed in claim 1, which is represented by the formula:
wherein each R1' is a hydrogen, a C1-C4 alkyl group or an ethenyl group, and each R3 is O(CmH2m)Q, OCH(CH2Q)2, S(CmH2m)Q or NH(CmH2m)Q wherein m and Q are the same as defined in claim 1.
wherein each R1' is a hydrogen, a C1-C4 alkyl group or an ethenyl group, and each R3 is O(CmH2m)Q, OCH(CH2Q)2, S(CmH2m)Q or NH(CmH2m)Q wherein m and Q are the same as defined in claim 1.
3. A prophyrin derivative as claimed in claim 1, which is represented by the formula:
wherein each R1' is a hydrogen, a C1-C4 alkyl group or an ethenyl group, and each R4 is a tri(C1-C4 alkyl)ammonium halide group or pyridinium halide group.
wherein each R1' is a hydrogen, a C1-C4 alkyl group or an ethenyl group, and each R4 is a tri(C1-C4 alkyl)ammonium halide group or pyridinium halide group.
4. A porphyrin derivative as claimed in claim 1, which is represented by the formula:
(wherein each R5 is a tri-(C1-C4 alkyl)ammonium halide group, pyridinium halide group or quinolinium halide group, and each R6 is a hydrogen or a C1-C4 alkyl group).
(wherein each R5 is a tri-(C1-C4 alkyl)ammonium halide group, pyridinium halide group or quinolinium halide group, and each R6 is a hydrogen or a C1-C4 alkyl group).
5. The porphyrin derivative of claim 1 which is 7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-trimethylammonioethyloxy)carbonylethyl]-21H,23H-porphin dibromide.
6. The porphyrin derivative of claim 1 which is
7,12-diethenyl-3,8,13,17-tetramethyl-2,18-bis[2-(N-(2-trimethylammonioethyl)carbamoyl)ethyl]-21H,23H-porphin dibromide.
7. The porphyrin derivative of claim 1 which is 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis[3-pyridinio-propyl)-21H,23H-porphin dibromide.
7. The porphyrin derivative of claim 1 which is 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis[3-pyridinio-propyl)-21H,23H-porphin dibromide.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8789/86 | 1986-01-17 | ||
| JP61008789A JPH0720963B2 (en) | 1986-01-17 | 1986-01-17 | Porphyrin derivative |
| JP46000/86 | 1986-03-03 | ||
| JP61046000A JPH0714942B2 (en) | 1986-03-03 | 1986-03-03 | Porphyrin derivative |
| JP29190486A JPS63145283A (en) | 1986-12-08 | 1986-12-08 | Porphyrin derivative |
| JP291904/86 | 1986-12-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1315780C true CA1315780C (en) | 1993-04-06 |
Family
ID=27278179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000527443A Expired - Fee Related CA1315780C (en) | 1986-01-17 | 1987-01-15 | Porphyrin derivatives |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US4772681A (en) |
| EP (1) | EP0233701B1 (en) |
| CA (1) | CA1315780C (en) |
| DE (1) | DE3772064D1 (en) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0786109B2 (en) * | 1987-12-21 | 1995-09-20 | 浜理薬品工業株式会社 | Pheophorbide derivative |
| US4979935A (en) * | 1989-02-21 | 1990-12-25 | Quantex Corporation | Method of photodynamic therapy employing electron trapping material |
| US5457183A (en) * | 1989-03-06 | 1995-10-10 | Board Of Regents, The University Of Texas System | Hydroxylated texaphyrins |
| US5272142A (en) * | 1989-03-06 | 1993-12-21 | Board Of Regents, The University Of Texas System | Expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles and methods for treating tumors |
| US5599923A (en) * | 1989-03-06 | 1997-02-04 | Board Of Regents, University Of Tx | Texaphyrin metal complexes having improved functionalization |
| US5041078A (en) * | 1989-03-06 | 1991-08-20 | Baylor Research Foundation, A Nonprofit Corporation Of The State Of Texas | Photodynamic viral deactivation with sapphyrins |
| US5559207A (en) * | 1989-03-06 | 1996-09-24 | Board Of Regents, University Of Texas | Texaphyrin metal complex mediated ester hydrolysis |
| US5162509A (en) * | 1989-03-06 | 1992-11-10 | Board Of Regents, The University Of Texas System | Process for preparing expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles |
| US5256399A (en) * | 1989-03-06 | 1993-10-26 | Board Of Regents, The University Of Texas System | Aromatic pentadentate expanded porphyrins in magnetic resonance imaging |
| US5252720A (en) * | 1989-03-06 | 1993-10-12 | Board Of Regents, The University Of Texas System | Metal complexes of water soluble texaphyrins |
| US4935498A (en) * | 1989-03-06 | 1990-06-19 | Board Of Regents, The University Of Texas System | Expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles |
| US5567687A (en) * | 1989-03-06 | 1996-10-22 | University Of Texas | Texaphyrins and uses thereof |
| US20020058008A1 (en) * | 1989-07-28 | 2002-05-16 | Kennedy James C. | Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins |
| US6710066B2 (en) * | 1989-07-28 | 2004-03-23 | Queen's University At Kingston | Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins |
| US5079262A (en) * | 1989-07-28 | 1992-01-07 | Queen's University At Kingston | Method of detection and treatment of malignant and non-malignant lesions utilizing 5-aminolevulinic acid |
| US5955490A (en) * | 1989-07-28 | 1999-09-21 | Queen's University At Kingston | Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins |
| US5234940A (en) * | 1989-07-28 | 1993-08-10 | Queen's University | Photochemotherapeutic method using 5-aminolevulinic acid and precursors thereof |
| US5120411A (en) * | 1989-12-21 | 1992-06-09 | Board Of Regents, The University Of Texas System | Photodynamic activity of sapphyrins |
| US5594136A (en) * | 1989-12-21 | 1997-01-14 | Pharmacyclics, Inc. | Texaphyrin solid supports and devices |
| US5457195A (en) * | 1989-12-21 | 1995-10-10 | Board Of Regents, The University Of Texas System | Sapphyrin derivatives and conjugates |
| US5543514A (en) * | 1989-12-21 | 1996-08-06 | Board Of Regents, The University Of Texas System | Water-soluble sapphyrins |
| US5159065A (en) * | 1989-12-21 | 1992-10-27 | Board Of Regents, The University Of Texas System | Sapphyrins, derivatives and syntheses |
| US5358931A (en) * | 1990-01-17 | 1994-10-25 | The Regents Of The University Of California | Interaction of thermal hysteresis proteins with cells and cell membranes and associated applications |
| DE4016299A1 (en) * | 1990-05-21 | 1991-11-28 | Basf Ag | CHLORINE DERIVATIVES |
| US5149801A (en) * | 1990-11-21 | 1992-09-22 | The Regents Of The University Of California | Boronated porphyrin compounds |
| DE4121876A1 (en) * | 1991-07-02 | 1993-01-14 | Scheer Hugo | New modified bacterial chlorophyll derivs. - for diagnosis and treatment of tumours |
| US20040110819A1 (en) * | 1991-10-28 | 2004-06-10 | Queen's University At Kingston | Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins |
| US5763172A (en) * | 1992-01-21 | 1998-06-09 | Board Of Regents, The University Of Texas System | Method of phosphate ester hydrolysis |
| US5565552A (en) * | 1992-01-21 | 1996-10-15 | Pharmacyclics, Inc. | Method of expanded porphyrin-oligonucleotide conjugate synthesis |
| US5888997A (en) * | 1994-04-14 | 1999-03-30 | Pharmacyclics, Inc. | Radiation sensitization using texaphyrins |
| US5595726A (en) * | 1992-01-21 | 1997-01-21 | Pharmacyclics, Inc. | Chromophore probe for detection of nucleic acid |
| US5607924A (en) * | 1992-01-21 | 1997-03-04 | Pharmacyclics, Inc. | DNA photocleavage using texaphyrins |
| US5410045A (en) * | 1992-08-04 | 1995-04-25 | Board Of Regents, The University Of Texas System | Rubyrin and related expanded porphyrins |
| US5252698A (en) * | 1992-10-09 | 1993-10-12 | Sri International | Metal ion porphyrin-containing poly(azine) |
| US5969111A (en) * | 1994-04-14 | 1999-10-19 | Board Of Regents, The University Of Texas System | Texaphyrins substituted with imidazole are provided |
| US5837866A (en) * | 1994-09-21 | 1998-11-17 | Board Of Regents, The University Of Texas | Phosphoramidite derivatives of macrocycles |
| US5633354A (en) * | 1994-09-21 | 1997-05-27 | Pharmacyclics, Inc. | Phosphoramidite derivatives of texaphyrins |
| US5756726A (en) * | 1995-06-02 | 1998-05-26 | Pharmacyclics, Inc. | Methods of producing singlet oxygen using compounds having improved functionalization |
| US5714328A (en) * | 1995-06-07 | 1998-02-03 | Board Of Regents, The University Of Texas System | RNA photocleavage using texaphyrins |
| US7041819B2 (en) | 1996-04-05 | 2006-05-09 | Board Of Regents, The University Of Texas System | Halogenated calixpyrroles and uses thereof |
| US6262257B1 (en) | 1996-04-05 | 2001-07-17 | Board Of Regents, University Of Texas System | Calixpyrroles, calixpyridinopyrroles and calixpyridines |
| ES2269138T3 (en) * | 1999-04-30 | 2007-04-01 | Cellgate, Inc. | POLYAMINS AND ITS USE IN THERAPY. |
| US6750037B2 (en) | 1999-12-27 | 2004-06-15 | Edwin L. Adair | Method of cancer screening primarily utilizing non-invasive cell collection, fluorescence detection techniques, and radio tracing detection techniques |
| US8802074B2 (en) | 2008-11-26 | 2014-08-12 | Board Of Regents, The University Of Texas System | Polymers functionalized with ion-specific recognition elements |
| CA2877585C (en) | 2013-03-15 | 2016-04-12 | Suncor Energy Inc. | Herbicidal compositions |
| CN103601727A (en) * | 2013-10-23 | 2014-02-26 | 中国医学科学院生物医学工程研究所 | Use of novel amine compound modified protoporphyrin |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4649151A (en) * | 1982-09-27 | 1987-03-10 | Health Research, Inc. | Drugs comprising porphyrins |
| JPS6092287A (en) * | 1983-10-24 | 1985-05-23 | Toyo Hatsuka Kogyo Kk | 9-desoxo-9-hydroxy-pheophorbide derivative and its alkali metal salt |
| DE3481125D1 (en) * | 1983-10-24 | 1990-03-01 | Toyo Hakka Kogyo Kk | PHEOPHORBIDE DERIVATIVES AND PHARMACEUTICAL PRODUCTS CONTAINING THEM. |
| JPS60152487A (en) * | 1984-01-18 | 1985-08-10 | Sato Yakugaku Kenkyusho:Kk | Deuteroporphyrin derivative and salt thereof |
| US4675338A (en) * | 1984-07-18 | 1987-06-23 | Nippon Petrochemicals Co., Ltd. | Tetrapyrrole therapeutic agents |
| US4656186A (en) * | 1985-04-30 | 1987-04-07 | Nippon Petrochemicals Co., Ltd. | Tetrapyrrole therapeutic agents |
| AU603999B2 (en) * | 1985-10-23 | 1990-12-06 | Photochemical Co., Ltd. | Porphyrin derivatives, and their production and use |
-
1987
- 1987-01-15 US US07/004,333 patent/US4772681A/en not_active Expired - Fee Related
- 1987-01-15 CA CA000527443A patent/CA1315780C/en not_active Expired - Fee Related
- 1987-01-16 DE DE8787300374T patent/DE3772064D1/en not_active Expired - Lifetime
- 1987-01-16 EP EP87300374A patent/EP0233701B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US4772681A (en) | 1988-09-20 |
| EP0233701B1 (en) | 1991-08-14 |
| EP0233701A3 (en) | 1988-09-21 |
| DE3772064D1 (en) | 1991-09-19 |
| EP0233701A2 (en) | 1987-08-26 |
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