JPS62205081A - Porphyrin derivative - Google Patents
Porphyrin derivativeInfo
- Publication number
- JPS62205081A JPS62205081A JP4599986A JP4599986A JPS62205081A JP S62205081 A JPS62205081 A JP S62205081A JP 4599986 A JP4599986 A JP 4599986A JP 4599986 A JP4599986 A JP 4599986A JP S62205081 A JPS62205081 A JP S62205081A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- ethyloxy
- porphyrin derivative
- hydroxyethyloxy
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000004033 porphyrin derivatives Chemical class 0.000 title claims abstract description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 18
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 15
- 201000011510 cancer Diseases 0.000 abstract description 12
- 238000003745 diagnosis Methods 0.000 abstract description 4
- 230000002165 photosensitisation Effects 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- -1 ethyloxy Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical class CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 1
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical class OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 101000822667 Mus musculus Something about silencing protein 10 Proteins 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000003698 laser cutting Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は癌の診断、治療に用いる新規なポルフィリン誘
導体を提供するものである。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention provides novel porphyrin derivatives for use in the diagnosis and treatment of cancer.
（従来の技術）
最近、癌細胞との親和性及び光増感作用を有するポルフ
ィリン誘導体は、レーザー光の照射と組み合わせるＩＩ
Ｓにより、癌の診断、治療に成果を上げてきている（
Ｔ、Ｊ 、Ｄｏｕｇｈｅｒｔｙ、 ’Ｐｏｒｐｈｙｒｉ
ｎＬｏｃａｌｉｚａｔｉｏｎ ａｎｄ Ｔｒｅａｔ
ｍｅｎｔ ｏｆ Ｔｕｍｏｒｓ’７５〜７８頁（１
９８４））。これには主としてベマトボルフィリン（以
下ＨＰと略す）或いはへマドポルフィリン誘導体（以下
ＨＰＤと略す）が盛んに用いられているが、前者は純粋
なものを得る事かむつかしく （Ｒ，に、ＤｉＮｅｌｌ
Ｏら、’７ｈｅ Ｐｏｒｐｈｙｒｉｎｓ’ １巻、２
９７〜２９８頁（１９７８） ）、後者は前者をアセ
チル化した後にアルカリ及び酸で処理したものであり、
数十種類ものポルフィリン誘導体の混合物であり臨床に
応用する場合に大きな問題となっている。(Prior Art) Recently, porphyrin derivatives that have affinity for cancer cells and photosensitizing effects have been developed by combining them with laser light irradiation.
S has achieved results in cancer diagnosis and treatment (
T., J., Dougherty, 'Porphyri.
nLocalization and Treat
ment of Tumors' pages 75-78 (1
984)). Bematoporphyrin (hereinafter abbreviated as HP) and hematoporphyrin derivatives (hereinafter abbreviated as HPD) are mainly used for this, but the former is difficult to obtain in pure form (R, ni, DiNell
O et al., '7he Porphyrins' vol. 1, 2
97-298 (1978)), the latter is obtained by acetylating the former and then treating it with alkali and acid.
It is a mixture of dozens of porphyrin derivatives and poses a major problem when applied clinically.
（発明が解決しようとする問題点）
現在、癌の診断並びに治療に利用が試みられているＨＰ
Ｄは前述の通り数十種類の混合物としてしか得られず、
またＨＰも純粋なものを得る事がむつかしい。その構成
成分も構造の確認されていないものが多い。従って、臨
床に用いるにあたり、毒性発現の見極め及び一定の品質
確保の面で大きな支障となっている。この問題を解決す
るためには、純粋なポルフィリン誘導体であって光増感
作用と癌細胞との親和性を併せて持つ化合物を得る事が
重要である。(Problems to be solved by the invention) HP currently being used for cancer diagnosis and treatment
As mentioned above, D can only be obtained as a mixture of several dozen types,
Also, it is difficult to obtain pure HP. The structures of many of its constituent components have not been confirmed. Therefore, in clinical use, it is a major hindrance in terms of determining toxicity and ensuring a certain level of quality. In order to solve this problem, it is important to obtain a compound that is a pure porphyrin derivative and has both photosensitizing action and affinity for cancer cells.
（問題を解決するための手段）
本発明者らは側鎖にエーテル結合でエチレングリコール
をいくつかつけたポルフィリン誘導体を合成することに
より、光増感作用及び癌細胞との親和性を有する種々の
ポルフィリン誘導体を得、本発明を完成した。(Means for Solving the Problem) The present inventors have synthesized porphyrin derivatives with several ethylene glycols attached to the side chains through ether bonds, and have synthesized various porphyrin derivatives that have photosensitizing action and affinity for cancer cells. The present invention was completed by obtaining a porphyrin derivative.
本発明において得られるポルフィリン誘導体の合成経路
を略記すると次のとおりである。The synthetic route of the porphyrin derivative obtained in the present invention is abbreviated as follows.
ＨＯ２ＣＣＯｚＨ
７．１２−ビスエチニル−３，８，１３，１７−テトラ
メチル−２１Ｈ，２３Ｈ−ポルフィン−２，１８−ジプ
ロピオン酸を臭化水素の酢酸溶液で臭化水素アダクトと
し、これに
一般式 ＨＯ（ＣＨ２ＣＨ２Ｏ）１ Ｈ（式中、ｎは
２〜６の整数を示す。）で表わされる化合物を反応させ
て、一般式（ＩＩ） （式中、ｎは前記と同義）で表わ
されるポルフィリン誘導体が得られる。本反応で用いら
れる臭化水素の酢酸溶液の臭化水素濃度は特に限定しな
いが通常３０％のものが好ましく、本反応は０〜１５０
°Ｃで５分〜５時間で完了するが、通常８０℃前後で２
時間程度の反応が好ましい。HO2CCOzH 7. 12-bisethynyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropionic acid is converted into a hydrogen bromide adduct with an acetic acid solution of hydrogen bromide, and the general formula HO A compound represented by (CH2CH2O)1H (wherein n represents an integer of 2 to 6) is reacted to produce a porphyrin derivative represented by general formula (II) (wherein n is the same as defined above). can get. The concentration of hydrogen bromide in the acetic acid solution of hydrogen bromide used in this reaction is not particularly limited, but is usually preferably 30%.
It can be completed in 5 minutes to 5 hours at °C, but it usually takes 2 to 2 hours at around 80 °C.
A reaction time of about hours is preferred.
一般式（１）（式中、ｎは前記と同義）で表わされるポ
ルフィリン誘導体を、常法により酸又はアルカリを用い
て加水分解することにより一般式（ＩＩＤ（式中、ｎは
前記と同ａ）で１表わされるポルフィリン誘導体が得ら
れる。通常加水分解に使用される酸としては例えば塩醸
、硫酸などの鉱酸或いは酢酸、ｐ−トルエンスルホン酸
などの有機酸が用いられ、アルカリとしては水酸化ナト
リウム、水酸化カリウム、アンモニアなどが用いられる
が通常水酸化す） ＩＪウムが好んで用いられる。本反
応は０〜１５０°Ｃで５分〜４８時間で完了する。例え
ば水酸化す） ＩＪウムを用いる反応では１００〜１２
０℃で３０分間で完了する。A porphyrin derivative represented by the general formula (1) (where n is the same as above) is hydrolyzed using an acid or an alkali in a conventional manner to produce a porphyrin derivative represented by the general formula (IID (where n is the same as above). ) A porphyrin derivative represented by 1 is obtained.The acid used for hydrolysis is usually a mineral acid such as salt solution or sulfuric acid, or an organic acid such as acetic acid or p-toluenesulfonic acid, and the alkali is water. Sodium oxide, potassium hydroxide, ammonia, etc. are used, but hydroxide is preferably used. This reaction is completed in 5 minutes to 48 hours at 0 to 150°C. For example, in the reaction using IJium (hydroxide), 100 to 12
Complete in 30 minutes at 0°C.
これらの新規なポルフィリン誘導体の反応後の処理及び
精製は通常の方法、例えば抽出、再結晶、カラムクロマ
トグラフィーなどによって行なわれる。Post-reaction treatments and purification of these novel porphyrin derivatives are carried out by conventional methods, such as extraction, recrystallization, column chromatography, and the like.
以下に実施例を挙げて本発明を説明する。The present invention will be explained below with reference to Examples.
実施例１
７．１２−ジエテニル−３，８，１３，１７−テトラメ
チル−２１Ｈ，２３Ｈ−ポルフィン−２，１８−ジプロ
ピオン酸１ｙを酢酸５ｍ／に懸濁させ、これに３０％臭
化水素−酢酸溶液６０−を加え一夜攪拌し、減圧下で濃
縮乾固し臭化水素アダクトを得る。これにジエチレング
リコール３０ｒｎｌを加え８０°Ｃで２時間攪拌し放冷
後、塩化メチレン３００−に溶解し塩化メチレン溶液を
７００．ｎｌの水で６回洗浄し硫酸マグネシウムで乾燥
した後溶媒を濃縮する。この残渣を塩化メチレンを溶媒
とし、アルミナ（活性度Ｖ）１００ｇを充填剤としだカ
ラムクロマトグラフィーにより精製して黒褐色オイル状
の７．１２−ビス（１−（２−（２−ヒドロキシエチル
オキシ）エチルオキシ）エチル）−３，８，１３，１７
−チトラメチルー２゜１８−ビス（２−（２−（２−ヒ
ドロキシエチルオキシ）エチルオキシ）カルボニルエチ
ル）−２１Ｈ，２３Ｈ−ポルフィン（以下ＨＰＤＧ４と
略する。Example 1 7.12-Diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropionic acid 1y was suspended in 5 m/a of acetic acid, and 30% hydrogen bromide was added to this. -Acetic acid solution 60- was added, stirred overnight, and concentrated to dryness under reduced pressure to obtain a hydrogen bromide adduct. Add 30 rnl of diethylene glycol to this, stir at 80°C for 2 hours, let it cool, then dissolve in 300ml of methylene chloride, and make a 700ml methylene chloride solution. After washing six times with nl of water and drying over magnesium sulfate, the solvent is concentrated. This residue was purified by column chromatography using methylene chloride as a solvent and 100 g of alumina (activity V) as a packing material to obtain 7.12-bis(1-(2-(2-hydroxyethyloxy)) as a dark brown oil. ethyloxy)ethyl)-3,8,13,17
-Titramethyl-2°18-bis(2-(2-(2-hydroxyethyloxy)ethyloxy)carbonylethyl)-21H,23H-porphine (hereinafter abbreviated as HPDG4).
）を５５５ｍ９得た。) was obtained in an amount of 555 m9.
可視吸収スペクトル（ＤＭＦ ） ｎｍ ；３９９．５
、４９８ 、５３０．５ 、５６７．５ 、５９５
、６２２Ｉ Ｒ（ｒｌｅａｔ ）Ｃ１ｍ−” ；３４０
０ 、３３００ 、２９５０ 、２９１０ 、２８５５
、１７２５ＮＭＲ（ＣＤＣｌ３ ）δ；
１０．５２．１０．４９．１０．４６．９．９８（４Ｈ
、ｓ ）６．１０（２Ｈ，ｑ）
４．３８．４−３２（４Ｈ，ｔ）
３．６８．３．６４．３．６２（１２Ｈ，３）３．３４
（４Ｈ，ｔ）
４．１４−２．８４（３２Ｂ 、ｍ）
２．２６（６Ｈ，ｄ）
２．０２ （４Ｈ、ｂｒｏａｄ ）
−３，７２（２Ｈ，ｓ）
実施例２
実施例１と同様にして得た臭化水素アダクトとトリエチ
レングリコール３０ｍ１を用い実施例１と同様の操作を
行ない黒褐色オイル吠の７．１２−ビス（１−（２−（
２−（２−ヒドロキシエチルオキシ）エチルオキシ）エ
チルオキシ）エチル）−３，８，１３，１７−テトラメ
チル−２，１８−ビス（２−（２−（２−（２−ヒドロ
キシエチルオキシ）エチルオキシ）エチルオキシ）カル
ボニルエチル）−２１Ｈ，２３Ｈ−ポルフィン（以下Ｈ
ＰＴｒＧ、と略する。）を３７０Ｆｎ９得た。Visible absorption spectrum (DMF) nm; 399.5
, 498 , 530.5 , 567.5 , 595
, 622I R(rleat)C1m-”;340
0, 3300, 2950, 2910, 2855
, 1725NMR(CDCl3)δ; 10.52.10.49.10.46.9.98(4H
, s ) 6.10 (2H, q) 4.38.4-32 (4H, t) 3.68.3.64.3.62 (12H, 3) 3.34
(4H, t) 4.14-2.84 (32B, m) 2.26 (6H, d) 2.02 (4H, broad) -3,72 (2H, s) Example 2 Same as Example 1 The same procedure as in Example 1 was carried out using the hydrogen bromide adduct obtained in Example 1 and 30 ml of triethylene glycol to obtain 7.12-bis(1-(2-(
2-(2-hydroxyethyloxy)ethyloxy)ethyloxy)ethyl)-3,8,13,17-tetramethyl-2,18-bis(2-(2-(2-(2-hydroxyethyloxy)ethyloxy) ethyloxy)carbonylethyl)-21H,23H-porphine (hereinafter H
It is abbreviated as PTrG. ) was obtained as 370Fn9.
可視吸収スペクトル（ＤＭＦ ） ｎｍ ；３９９．５
、４９８ 、５３０．５ 、５６７．５ 、５９５
、６２２１ Ｒ（ｎｅａｔ ）ｃｌｌ−１；
３４００．３３００，２９００．２８６０．１７２５Ｎ
ＭＲ（ＣＤＣｌ３ ）δ；
１０．５４ 、１０．５０ 、１０．０５（４Ｈ，ｓ
）６．１３（２Ｈ，Ｑ）
４．３９（４Ｈ，ｔ）
３．６８．３．６７．３．６４．３．６０（１２Ｈ，ｓ
）４．１８−２．７２（５２Ｈ，ｍ）
２．６ （４Ｈ、ｂｒｏａｄ ）
２．２６（６Ｈ，ｄ）
−３，５８（２８，ｓ）
実施例３
実施例１と同様にして得た臭化水素アダクトとテトラエ
チレングリコール３０．、ｌ／を用い実施例１と同様の
操作を行ない黒褐色オイル状の７，１２−ビス（１−（
２−（２−（２−（２−ヒドロキシエチルオキシ）エチ
ルオキシ）エチルオキシ）エチルオキシ）エチル、−３
，８，１３，，１７−テトラメチル−２，１８−ビス（
２−（２−（２−（２−（２−ヒドロキシエチルオキシ
）エチルオキシ）エチルオキシ）エチルオキシ）カルボ
ニルエチル）−２ＬＨ，２３Ｈ−ポルフィン（以下Ｉ（
ＰＴｅＧ４と略する。）を６１０η得た。Visible absorption spectrum (DMF) nm; 399.5
, 498 , 530.5 , 567.5 , 595
, 6221 R (neat) cll-1; 3400.3300, 2900.2860.1725N
MR (CDCl3) δ; 10.54, 10.50, 10.05 (4H, s
)6.13(2H,Q) 4.39(4H,t) 3.68.3.67.3.64.3.60(12H,s
) 4.18-2.72 (52H, m) 2.6 (4H, broad) 2.26 (6H, d) -3,58 (28, s) Example 3 Obtained in the same manner as Example 1 Hydrogen bromide adduct and tetraethylene glycol30. , l/ was carried out in the same manner as in Example 1 to obtain 7,12-bis(1-(
2-(2-(2-(2-hydroxyethyloxy)ethyloxy)ethyloxy)ethyloxy)ethyl, -3
,8,13,,17-tetramethyl-2,18-bis(
2-(2-(2-(2-(2-hydroxyethyloxy)ethyloxy)ethyloxy)ethyloxy)carbonylethyl)-2LH,23H-porphine (hereinafter referred to as I(
It is abbreviated as PTeG4. ) was obtained for 610η.
可視吸収スペクトル（ＤＭＦ）ｎｍ；
４００ 、４９８ 、５３０．５ 、５６７．５ 、５
９５ 、６２２■Ｒ（ｎｅ” ｔ ）ＣＩ＋−’
３４１０ 、３３００ 、２９００ 、２８６０ 、１
７３ＯＮＭＲ（ＣＤＣｌ３ ）δ；
１０．５２ 、１０．５０ 、１０．４９ 、１０．０
３（４Ｈ、ｓ ）６．１４（２Ｈ，（１）
４．４１（４Ｈ，ｔ）
３．６７．３−６４．３．６２（１２Ｈ，ｓ）４．２３
−２．８６（６４Ｈ，ｍ）
２．５（４Ｈ，ｂｒｏａｄ）
２．２６（６Ｈ，ｄ）
−３，６８（２Ｈ，ｓ）
実施例４
実施例１で得たＨＰＤＧ４２００■をピリジン１００、
ｎ１９１５分間還流し、水２〇−及び４％水階化す）
ＩＪウム水溶液２０ｒｎｌを加え１５分間還流し、更に
水２０．ｎｌを加えて１５分間還流する。反応液を減圧
下濃縮乾固し、残渣に水５０−を加えて溶解し、水冷下
酢酸４−を加え析出した結晶を遠沈で集め１８７■の黒
褐色の７．１２−ビス（１−（２−（２−ヒドロキシエ
チルオキシ）エチルオキシ）エチル）−３，８，１３，
１７−テトラメチル−２１Ｈ，２３Ｈ−ポルフィン−２
，１８−シフロピオン酸（以下ＨＰＤＧと略する。）を
得たＯ
ｍ、ｐ、 １５０℃
可視吸収スペクトル（ＤＭＦ）ｎｍ；
４００．４９８．５３１．５６７．５．５９５．６２２
Ｉ Ｒ（ＫＢｒ ） ｃｒｌ−１；
３３８０ 、３３００ 、２９６０ 、２９１０ 、２
８５０ 、１７１ＯＮＭＲ（ＣＦ３ＣＯ２０）δ；
６．３８ （２Ｈ、ｂｒｏａｄ ）
４．６４ （４Ｈ、ｂｒｏａｄ ）
４．３−３．９（１６Ｈ、ｍ）
３．８０（１２Ｈ，ｓ）
３．３６ 、３．３５（４Ｈ、ｂｒｏａｄ ）２．２１
．２．２０（６Ｈ，ｄ）
実施例５
実施例２で得たＨＰＴｒＧｎ ２００■を用い、実施
例４と同様の操作を行なって黒褐色の７．１２−ビス（
１−（２−（２−（２−ヒドロキシエチルオキシ）エチ
ルオキシ）エチルオキシ）エチル）−３，８，１３，１
７−テトラメチル−２ＬＨ９２３Ｈ−ポルフィン−２，
１８−ジプロピオン醜（以下ＨＰＴｒＧと略する。）を
１９０■得た。Visible absorption spectrum (DMF) nm; 400, 498, 530.5, 567.5, 5
95, 622■R(ne"t)CI+-' 3410, 3300, 2900, 2860, 1
73ONMR(CDCl3)δ; 10.52, 10.50, 10.49, 10.0
3 (4H, s ) 6.14 (2H, (1) 4.41 (4H, t) 3.67.3-64.3.62 (12H, s) 4.23
-2.86 (64H, m) 2.5 (4H, broad) 2.26 (6H, d) -3,68 (2H, s) Example 4 HPDG4200■ obtained in Example 1 was mixed with pyridine 100,
Reflux for 1915 minutes and reduce to 20- and 4% water)
Add 20rnl of IJum aqueous solution and reflux for 15 minutes, then add 20ml of water. Add nl and reflux for 15 minutes. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved by adding 50% of water, 4% of acetic acid was added under cooling with water, and the precipitated crystals were collected by centrifugation to give 187μ of dark brown 7.12-bis(1-( 2-(2-hydroxyethyloxy)ethyloxy)ethyl)-3,8,13,
17-tetramethyl-21H,23H-porphine-2
, 18-cyfuropionic acid (hereinafter abbreviated as HPDG) was obtained.
IR(KBr) crl-1; 3380, 3300, 2960, 2910, 2
850, 171ONMR (CF3CO20) δ; 6.38 (2H, broad) 4.64 (4H, broad) 4.3-3.9 (16H, m) 3.80 (12H, s) 3.36, 3. 35 (4H, broad) 2.21
．． 2.20 (6H, d) Example 5 Using 200μ of HPTrGn obtained in Example 2, the same operation as in Example 4 was carried out to obtain dark brown 7.12-bis(
1-(2-(2-(2-hydroxyethyloxy)ethyloxy)ethyloxy)ethyl)-3,8,13,1
7-tetramethyl-2LH923H-porphine-2,
190 ml of 18-dipropion ugly (hereinafter abbreviated as HPTrG) was obtained.
ｍ、ｐ、 ８８°Ｃ
可視吸収スペクトル（ＤＭＦ）ｎｍ；
４００ 、４９８ 、５３１ 、５６７．５ 、５９５
、６２２ＩＲ（ＫＢｒ ）Ｃ１ｍ−’ ＋
３３９０ 、３３００ 、２９６０ 、２９００ 、２
８５０ 、１７２ＯＮＭＲ（ＣＦ３ＣＯ２Ｄ ）δ；
６．３９（２Ｈ，ｂｒｏａｄ）
４．６７ （４Ｈ、ｂｒｏａｄ ）
４．３−３．９（２４Ｈ，ｍ）
３．８０（１２Ｈ，ｓ）
３．３８ （４Ｈ、ｂｒｏａｄ ）
２．１９（６Ｈ，ｄ）
実施例６
実施例３で得たＨＰＴｅＧ４２００■を用い、実施例４
と同様の操作を行なって黒褐色の７，１２−ビス（１−
（２−（２−（２−（２−ヒドロキシエチルオキシ）エ
チルオキシ）エチルオキシ）エチルオキシ）エチル）−
３，８，１３，１７−テトラメチル−２１８，２３Ｈ−
ポルフィン−２，１８−ジプロピオン酸（以下ＨＰＴｅ
Ｇと略する。m, p, 88°C visible absorption spectrum (DMF) nm; 400, 498, 531, 567.5, 595
, 622IR(KBr)C1m-' + 3390, 3300, 2960, 2900, 2
850, 172ONMR (CF3CO2D) δ; 6.39 (2H, broad) 4.67 (4H, broad) 4.3-3.9 (24H, m) 3.80 (12H, s) 3.38 (4H, broad ) 2.19 (6H, d) Example 6 Using HPTeG4200■ obtained in Example 3, Example 4
Perform the same operation as above to obtain a dark brown 7,12-bis(1-
(2-(2-(2-(2-hydroxyethyloxy)ethyloxy)ethyloxy)ethyloxy)ethyl)-
3,8,13,17-tetramethyl-218,23H-
Porphine-2,18-dipropionic acid (hereinafter referred to as HPTe)
Abbreviated as G.
）を７０η得た。) was obtained for 70η.
ｍ、ｐ、 ３３℃
可視吸収スペクトル（ＤＭＦ ） ｎｍ ；４００ 、
４９８ 、５３１ 、５６７．５ 、５９５ 、６２２
Ｉ Ｒ（ＫＢｒ ）ＣＩｌ＋−’ ；
３４００ 、３２９０ 、２９５０ 、２９００ 、２
８５０ 、１７２ＯＮＭＲ（ＣＦ３ＣＯ２Ｄ）δ；
６．３６ （２Ｈ、ｂｒｏａｄ ）
４．６４ （４）１． ｂｒｏａｄ ）４．２−３．９
（３２Ｈ、ｍ）
３．８０（１２Ｈ，ａ）
３．３４ （４Ｈ、ｔ ）
２．１８ 、２．１５（６Ｈ、ｄ ）
参考例
癌細胞親和性
生後３凋のＢａ１ｂ／ｃマウスの背部にマウスの腎Ｉｆ
Ａ稚肉ｊル由来のＭＫＳＡ細胞１×１０ 個を移植し、
２〜３週間後本発明で得られたポルフィリン誘導体を５
０μｍｏ ｌ ｅ ｌｋｑ腹腔内投与した。２４時間後
に各臓器及び癌細胞を摘出しそこから発するポルフィリ
ン誘導体に由来する螢光をレーザーお断装置（會沢勝夫
ら、レーザー医学会誌、５巻、６３−６８頁（１９８４
））を用いて測定した。m, p, 33°C visible absorption spectrum (DMF) nm; 400,
498, 531, 567.5, 595, 622
IR(KBr)CIl+-'; 3400, 3290, 2950, 2900, 2
850, 172ONMR (CF3CO2D) δ; 6.36 (2H, broad) 4.64 (4)1. broad ) 4.2-3.9
(32H, m) 3.80 (12H, a) 3.34 (4H, t) 2.18, 2.15 (6H, d) Reference example Cancer cell affinity On the back of a Ba1b/c mouse at 3 days old Mouse kidney If
1 x 10 MKSA cells derived from A young meat were transplanted,
After 2 to 3 weeks, the porphyrin derivative obtained in the present invention was
0 μmol elkq was administered intraperitoneally. After 24 hours, each organ and cancer cell was removed and the fluorescence derived from the porphyrin derivative emitted from the organ was removed using a laser cutting device (Katsuo Aizawa et al., Journal of the Laser Medical Society, Vol. 5, pp. 63-68 (1984).
)).
その結果を腫瘍部位での螢光強度に対する正常部位での
螢光強度の比、及び腫瘍部位での螢光強度で表わし表２
にまとめた。The results are expressed as the ratio of the fluorescence intensity at the tumor site to the fluorescence intensity at the normal site, and the fluorescence intensity at the tumor site. Table 2
summarized in.
（発明の効果）
本発明化合物は癌細胞への集積性を有し、光を照射する
ことにより螢光を発する。また、酸素の存在下これに光
を照射することにより１０□を発生し、この１０□は癌
細胞殺傷作用を有している。このため本発明化合物は癌
の診断、治療薬として有用な化合物である。(Effects of the Invention) The compound of the present invention has the ability to accumulate in cancer cells, and emits fluorescence when irradiated with light. Furthermore, by irradiating it with light in the presence of oxygen, 10□ is generated, and this 10□ has a cancer cell killing effect. Therefore, the compound of the present invention is a useful compound as a diagnostic and therapeutic drug for cancer.
また、本発明化合物は現在医薬品として用いられ大量に
製造されているプロトポルフィリンを原料として用いる
ことができるため安定した供給が可能である有用な化合
物である。Furthermore, the compound of the present invention is a useful compound that can be stably supplied because protoporphyrin, which is currently used as a pharmaceutical and is produced in large quantities, can be used as a raw material.
Claims (2)
、ｎは２〜６の整数を示す。］で表わされるポルフィリ
ン誘導体。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is a hydrogen atom, (CH_2CH_2O)_nH
, n represents an integer of 2 to 6. ] A porphyrin derivative represented by.
トラメチル−２１Ｈ，２３Ｈ−ポルフィン−２，１８−
ジプロピオン酸を臭化水素の酢酸溶液で処理した後 一般式ＨＯ（ＣＨ＿２ＣＨ＿２Ｏ）＿ｎＨ （式中、ｎは２〜６の整数を示す。）で表わされる化合
物と反応させて 一般式 ▲数式、化学式、表等があります▼ （式中、ｎは前記と同義）で表わされるポルフィリン誘
導体を製造し、このポルフィリン誘導体を加水分解して 一般式 ▲数式、化学式、表等があります▼ （式中、ｎは前記と同義）で表わされるポルフィリン誘
導体を製造する方法。(2) 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-
After treating dipropionic acid with an acetic acid solution of hydrogen bromide, it is reacted with a compound represented by the general formula HO(CH_2CH_2O)_nH (in the formula, n represents an integer from 2 to 6) to form the general formula ▲mathematical formula, chemical formula , tables, etc.▼ (In the formula, n has the same meaning as above) are produced, and this porphyrin derivative is hydrolyzed to produce the general formula ▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, n is the same meaning as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4599986A JPS62205081A (en) | 1986-03-03 | 1986-03-03 | Porphyrin derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4599986A JPS62205081A (en) | 1986-03-03 | 1986-03-03 | Porphyrin derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62205081A true JPS62205081A (en) | 1987-09-09 |
Family
ID=12734792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4599986A Pending JPS62205081A (en) | 1986-03-03 | 1986-03-03 | Porphyrin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62205081A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02138280A (en) * | 1988-07-14 | 1990-05-28 | Toyo Hatsuka Kogyo Kk | Porphyrin derivative |
| US5211938A (en) * | 1989-07-28 | 1993-05-18 | Queen's University At Kingston | Method of detection of malignant and non-malignant lesions by photochemotherapy of protoporphyrin IX percursors |
| US5234940A (en) * | 1989-07-28 | 1993-08-10 | Queen's University | Photochemotherapeutic method using 5-aminolevulinic acid and precursors thereof |
-
1986
- 1986-03-03 JP JP4599986A patent/JPS62205081A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02138280A (en) * | 1988-07-14 | 1990-05-28 | Toyo Hatsuka Kogyo Kk | Porphyrin derivative |
| US5211938A (en) * | 1989-07-28 | 1993-05-18 | Queen's University At Kingston | Method of detection of malignant and non-malignant lesions by photochemotherapy of protoporphyrin IX percursors |
| US5234940A (en) * | 1989-07-28 | 1993-08-10 | Queen's University | Photochemotherapeutic method using 5-aminolevulinic acid and precursors thereof |
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