TW397836B - Tumour localising photosensitising compounds - Google Patents

Abstract

Improved tumour localisation of polyether-substituted photosensitising compounds is given leading to their more efficient uptake into turmour cells. Lower overall doses of drug give an improved side-effect profile of the treatment especially with regard to skin photosensitisation. Compounds being polyethylene glycol derivatised, pharmaceutically acceptable tumour locating dihydro or tetrahydro porphyrins of the formulae (3) and (4) wherein R1 may be partly hydroxyl but at least one chain of formula -O-X-[CH2CH2O]m-Y wherein m = 25 to 150; the group Y may be a C1-C4 alkyl group but preferably a methyl group and the group X is of formula (5).

Description

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _ _B7_ V. Description of the invention (1) The invention of the invention is based on the use of polyether-substituted chiguang compounds and their use in the treatment of tumors. Photodynamic therapy involves administering a light-sensitive compound and then irradiating the tissue containing the compound with visible light of a specific wavelength. The resulting activated compound and oxygen act as osmium to form active free radicals, which can cause necrosis in the periphery. The success of this form depends on the comparison between the administered compound and the normal tissue, and its choice {to stay in the tumor tissue, and therefore when the tumor is irradiated with visible light, the amount of damage caused by strangulation and tumor formation will Proportionally higher than in regular organizations. However, some injuries caused by IE Changjie may also occur and can be seen in a special side effect of many prodrugs: skin exposed to the E light standard (especially daylight) will be red and swollen (erythema). This requires the patient to stay in the sun and light for several weeks after treatment, which can limit their quality of life. The Qiguang compound is more effectively delivered to the tumor tissue, and thus providing a higher ratio of drug concentration to the normal skin is able to dramatically reduce the possibility of this treatment φ for skin anemia. This accumulated tumor location can also be used as a diagnostic tool to determine the location and size of the tumor and its treatment options. Some photosensitizers can be used as diagnostic tools if used as detectable / thin fluorescent light. In addition, certain radiation-labeled entities can also be used to determine tumor compounds for Wλ diagnostic purposes. Previously, a group of photosensitizers He Jun has been the subject of ΕΡ (Π 3 7 β 0 1 A 1. This search. 1h compound is the formula Π.) Of the dihydro tree > (Crowling, C h 〖〇 r 丨 ns) and four equivalents of the equivalent formula m (Porphyrin): -4.- This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (please (Read the notes on the back before filling out this page)

V. Description of the invention (Eve)

kl B7

Among them, it is positive, the deduction K is accepted by δ An Naohan! ^ I »The red end of the known, Rongzhi alcohol r pjt printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Each R is a hydroxyl group. Or alignment. The radical is in its free, substituted alkyl '). Piperidine in Pseudo-water-based Solvent to determine the absorption of light at the end-A-ί · ^ PJSJ __N: *: Tan p 丨 one further description of any of these hydrates or their species) In the formula, the two numbers (.N 〇) in the formula S are relative to the position of the cage ring connected to the core. The benzene * group may be at the same or different positions, and may be partially or partially substituted (for example, by containing 1 To 4 physiological tolerances, a little solubility in pharmacology (as required, so that the drug quickly distributes to tumors), visible absorption, and absorption in cancer fibers can be maintained. Then this step will replace it. The compound can exist in the salt or other solvates of its acidic or basic center. Especially the compounds with low alkanes (such as: ct-c 4) are listed in the following table: Table 1 0H room 0 P; -----: --.--- (\ ------ order ------ f V (Please read the precautions on the back before filling this page) This paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (9) The present invention relates to the use of polyethylene glycol with a triazine group to link compounds of formula (1) and (2). Phenolic hydroxyl Group derivatized or partially derivatized with its terminal hydroxyl Qi C t - C 4 alkyl group is methyl i optimum) etherified or esterified type (3) and (4) compounds in Gao knot as follows:

(4) (Please read the precautions on the f 'side before filling out this page) Among them, the K part of R 1 may be R but at least one of them is chain-〇- XP-[CH2CH20] «-Υ, where m = 5 to 250. This group is a -1: 4 alkane «, preferably a methyl group. The linking group X is of formula (5).

, 1T Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

O-iCHiCHjOJnjY (δ) To interfere with the two S1 generations of polyethylene glycol_ to φ — the average must be connected to

(3) This paper size applies Chinese National Standards (CNS > A4 size (210X297 mm). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. A7 B7. 5. Description of the invention (< /) Type U) and (2) Compounds. ; And preferably, each key must be counted and can provide the total molecular weight of types (3) and (4) not less than 50 0 0 ears and not more than 2 (). 0 0 0 道 百 呑. In any of the above compounds, it is possible to form salts and hydrates of inorganic acids (ie, europium chlorochlorate, sulfate, etc.) and derivatized with low-alkane (i: j-C 4) alcohols ( All such forms are included in the scope of this patent. Forms (3) and (4) (wherein 'R is defined as previously described) are obtained by using the form (: β) compound (' Among them, the definitions at m and Y 眈 are the same as those of the former '1 and the formula (1) and f 2) (wherein, R 呔 琮 is the same as above). In the presence of carbonate, a catalytic amount of a catalytic conversion catalyst such as cetyltrimethyl clamp bromide and a suitable solvent (such as propylene) are reacted at a temperature of 0 to 60 ° C, and then reacted by adding water. π. In the presence of a saturated aqueous solution of osmium carbonate, it catalyzes the most phase-inverted fb catalyst (such as cetyltrimethylammonium bromide) and a suitable non-permanently compatible solvent (such as dioxane ) Reaction in the two systems at strontium degrees from 0 to '600 in. iii. In the presence of a mixture of carbonic acid and water, a suitable water-soluble non-hydroxyl solvent {'such as 1,4-dioxane) is reacted at <) to 40 T: The combination of the two oxygen oxoxox C2 and oxh 3) and (4) has the following temporary effects:! 2-Ask Bima when the meat is exhausted. ----- ：------- ^ clothing ------ order ----- 、 line (please read the precautions on the back before filling this page) This paper size applies Chinese national standard (CNS) A4 size (210X297 mm) A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (i) • 3. Increase in the number of eggs in the blood. When the λ. 轺 a.fb compound is compared, the cumulative rate of tumor growth + rate increases. 5. Reduced photosensitivity of skin pain. When compared with Yanniu's morpholine (as disclosed in Wim / 1 8 R 3 0 (D K. Z ') 丨 ntera Π a), polyethylene_derivative tetra- (3-hydroxycagel) g Rollinz 3) It has been shown to promote tumor-concentrating properties to an astonishing degree when compared to its parent drug in various animal tumor tumors. For compounds (3) and (4), the color in the visible light range in the spectrum is not changed for the corresponding compounds 0) and (2). The average molecular weight of compounds > (3) and (4) has the following formula: Shown: For example, compound (3a): (U) 's MW- (la)' s at 650 nm 荜 evenly divided 鼍 (3 a) = __ ί 3 3) A 1 jealous of β 5 0 n in If luxury has been confirmed by the flea analysis of the polyethylene derivatives of dihydrocaprofen and pilohydrophenol and the most confirmed by the recovered underivatized ®.宁 例 1 楫 Same f | H® Luhydrona u 7)) to 7, 8 -dihydro-tetra-5,1 0,1 5,2 ()-ί 3 ·-锊 荣 基) leaf 1 « (Parts 1 and 3), trimethyl + hexaalkylammonium bromide (part +0 · 1), and compound Ua. R1 has B = 35-55, Y = CH3. 16) in C (part 300) In the solution of 1, at 20-25T: the mixture of simmered linseed for 15-24 hours. Remove propane in vacuum, add yong (part 400), and then search for the mixture for 1-2 hours. Freeze-dried After the thirsty compound, K 2 methane (400 parts) is removed, K is filtered to remove the insoluble sodium, and 2 is removed in a vacuum. I ----'------------ --Order ----- K Bismuth (Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 397836 a? B7 V. Description of the invention (to Methyl chloride, the residue was re-dissolved in water (100 parts), and the water in the 0DS3 reverse-phase silica P column (400 parts) was used as the eluent. Chromatographic analysis = and the brown part. 0.2 / ί I «filtered through a filter to remove particles, and freeze-dried to produce a brown amorphous powder (3 a, R 1 With m = 3 5-5 5, Y = C Η 3, 8-10 0 part '!, Π. Η. 5 0 -55 ^ »MW (K fcb I? II V) = 7 5 0 0-8 0 0 0-II V = λ ：: 4 16 nm (Al0 ^ = 1 5 0.7) * 5 20 nm (A 1 = 2 0. 4) * 5 48 n in (A]% = ί 5. 2), 5 Q 8 n ro (A 1 94 = 8 '· 1), 6 5 2 nm (A 1%' = 4 0-4.), And the A value will change slightly in each subsequent operation. 3 a Μ Η P 丨 (] PC display contains Group-3 compounds, gallery (please read the precautions on the back before filling out this page) People • W 4 4R: [Key 7 0-8 0% 3 s / 3 3R: 1 5-2 0% 3a / 2 2 R 1 _ 5-1 0% Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and re-operating the above-mentioned substance generators 3 a / 4, m. P. 5 0-5 5 Π, MW (W comparison 丨 丨 V) = 8000-8500. The 7,8-dihydro-tetra-5,1 (K 15,2 0-(3, -hydroxyfluorenyl W oxoline (1 a)) M The equivalent amount of 7,, 1,7, U -tetrahydro-tetra-5,1,0,1 Γ), 2-(3, -hydroxyfluorenyl) ρoline (2 a) was substituted to obtain (4 a, R 1 with m = 3 5-5 5. Y = (: Η 3. 8-10 part), ra. d. 5 0-5 Vn, tU! (Μ ratio Ιί V) = 7 5 ⑼-8 0 0 0. Π V: 3 5 6 nmUl 嗥 = 196.8). 373 nm (Al% = 19U5), 522 =. 742 =〗 16. 1). In each case, Aqian will revise the case slightly. The compound distribution of preparation (48) is similar to that of bromine in (3a) above. Analysis of Yuan Xiao: N talked about 2.5-2.9¾, and actually measured 2.6%. For the Tears of N :! ; Park 丨 luxury in polyethylene glycol 2 0 0 0 (that is, m = 4 5) and the connection 2.3 The size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Central Standard of the Ministry of Economic Affairs Bureau of the Consumer Cooperatives printed 397838 g77 V. Description of invention (y) or the average molecular weight of 4 sit species. Example 2 'Add a saturated aqueous solution of sodium bicarbonate (part 17) to 7,8-dihydro-tetra-5, 1 0. 1 5,2 0-(3, -hydroxyphenyl) v ibuline (1 a , Part 1) in trimethylhexadecyl ammonium bromide (part 0.1) and compounds ((5 a, R 1 with m = 3 5-5 5, Y = C Η 3.1 β part) in Dichloromethane · (suspension in part 200) solution * Suspend the two-phase mixture at 20-25 t for 15-24 hours. Remove the dichloromethane in vacuum and add water (3 0 Part 0), and then stir the mixture for 1_-2 hours. Freeze-drying the mixture, then K2: 氡 methane (4 0 0 '! Search and stir, K over to remove insoluble sodium salt. Under vacuum Dichloromethane was removed from the solution, and the residue was redissolved in water (200 parts) *. Chromatographic analysis was carried out in a C1DS3 reverse-phase silica gel tube pestle (800 parts) with M water as the eluent. The brown part was hydroxyl 0.2. Am filter to remove particles * a freeze-dried and produce brown amorphous powder (3 a, R 1 with hi = 3 5-5 5, Y = C Η 3.6-10 part), m. d. 5 0-5 5 Ό, | · ί ΙΠ Μ comparison 丨 ί V) = 5 0 0 0-8 0 0 0. It is found that the distribution and structure of the compound prepared by this method are very different. In a very small-scale (100 mg) product, it contains a higher ratio of 3 a / 4 than that of Example 1; however, it exceeds 4S product 'MW ~ 5000 At the same time, it contains a large proportion of 3a / 3 and 3a / 2 and even 3a / 1 compounds with only one polyoxyethylene. Example 2 Beat 7, S-Dihydro-tetra-5, 1 0, 1 5, 2 0-(3 '-hydroxycryl) line (1 a, 1 part) solution, and fb compound (Γ) a, R 1 with m = 3 5-5 5. Y = C Η 3, Part 1 β) Yu Erpin (part 2 0 0) and water-soluble sodium bicarbonate (part 5 in part 200 water), stir the sample at 20-25'm " F for 15-24 hours. Freeze and dry the mixture, and then (please read the precautions on the back before filling this page),-° line -10- This paper size applies to China National Standard (CNS) 8-4 (210 X 297 mm) Central Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Standards Bureau 391836 a7 B7 V. Description of the invention (J) Part K 0 of the dibenzoxane is stirred, and K is removed to remove the insoluble sodium salt. Dichloromethane was removed in vacuo, and the residue was redissolved in water (part 200). 1 ethyl acetate (part 2 x 20 0) was extracted in 0DS3 reverse phase silica gel column (part S 0 0). Chromatographic analysis of the eluate. The brown part was filtered through 0.22ΪΏ to remove particles through a filter, and freeze-dried to produce a brown amorphous powder (3a s R 1 with m = 3 5-5 5, Y = C Η 3, 4 -6 parts) * m. P · 5 0 -5 f. ≪ 1 MW W f M bb compared to ijV), three 5000-6500 () 3 a sample K Η PLC / PC display contains group 4 compounds, ie 3 a / 4 4R 1 bond-40-60% 3 a / 3 3R1 bond 2 0-3 0% 3 a / 2 2R 1 chain 20 -30¾ 3a / 1 1R1 chain 0-10¾ fc terror. Phase M is performed in U mode, but (6a) K equivalent (6b, R1 with m = 100-120. Y = ch3) is substituted (3b, R1 with ir = 100-120, Y = CH3) * S -10 part), m · p · 5 2-5 7 10, MW (Μ comparison 1) \ Π = ί Ο Ο Ο Ο-1 2 Ο Ο 0. ij V: the extremum value is the same as 3 a but Low strength. -11------.-- r --- ^ ^ -------- Order ----- h (please read the precautions on the back before filling this page) Applicable to China National Standard (CNS) A4 specification (210X297 mm)

Claims (1)

A8 B8 C8 D8 A compound derived from polyethylene glycol, a pharmacologically acceptable dihydro or tetrafluorene Q morpholine for tumor localization, and having the formulae (3) and «4) (3) (4) wherein R 1 may be a hydroxyl group, but at least one bond is -0-X-[CH2CH2 0 UY * where m = 25 to 150; the group Y may be "-f :. alkyl, But methyl is preferred; the linking group X is represented by formula (5). N NH N (5) (Please read the precautions on the back before filling out this page.) The compound printed by the Central Bureau of Standards of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, according to item 1 of the scope of patent application, is a derivative, and it is a salt made of an inorganic acid. Acid salts, sulfates, etc .; or they can be made into hydrates or solvates with low-carbon C, -C4) alcohols. 12 This paper size is applicable to China National Standards of Standards (CNS) 8.4 (210 × 297 mm) 39 Office 6?! D8 ____ One patent scope a chemical compound manufactured using the formulas (3) and. (4) is used to treat the easily necrotic Teng, i-* A method for tumor drugs, which involves administering this compound to localize the tumor, and then irradiating the tumor with visible light absorbed by the compound, the method is by combining pharmaceutical dilution Agent or carrier and the compound to use 0 '', according to the compounds in the scope of patent application No. 1 or 2, wherein the molecular weight of the compound 4 * (3) and (4) is 5,000 ears to 20,000. 〇〇 Road ear swallow. The method according to item 3 of the scope of patent application, wherein the molecular weights of the compounds (3) and 5 · (4) are 5,000 to 20,000. ί ^-(Please read the back of the feed first. Note the ί item before filling out this page) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs® Industrial and Commercial Cooperatives «. This paper size applies to China National Standards (CNS) Α4 specifications (210X2S »7 mm)