Novel tetrapyrrole derivatives and application thereof
阅读说明：本技术 一类新型四吡咯衍生物及其应用 (Novel tetrapyrrole derivatives and application thereof ) 是由 陈志龙 李慢一 糜乐 严懿嘉 梁宏玉 韩一平 邱彦 金辉 鲍蕾蕾 陈婷 山妮妮 于 2021-10-11 设计创作，主要内容包括：本发明涉及一类性能稳定、亲水性好、不易聚集的新型中介二(二取代)苯基二卤代卟吩衍生物及应用,该化合物具有下述结构(I)和(II)：其中：X为Cl,Br或I；A和Y相同或不同且独立地为CH-(2)或O；R-(1)与R-(2)不同、R-(3)与R-(4)相同或不同且至少有一个含有极性基团,且独立地为烷基、含N或O原子的烷基、含羰基烷基或者含酰胺键的烷基或烷基羧酸、烷基醇、含N或O原子的烷基羧酸、含N或O原子的烷基醇、含羰基烷基羧酸、含羰基烷基醇、含有酰胺键的烷基羧酸、同时含有羰基和酰胺键的烷基羧酸；本发明制备的中介二卤代二苯基卟吩光敏剂具有显著的光动力活性,可作为光动力诊治肿瘤、视网膜黄斑变性、光化性角化病、鲜红斑痣、尖锐湿疣等疾病的药物。(The invention relates to a novel intermediate di (disubstituted) phenyl dihalogen porphin derivative with stable performance, good hydrophilicity and difficult aggregation and application thereof, wherein the compound has the following structures (I) and (II): wherein: x is Cl, Br or I; a and Y are the same or different and are independently CH 2 Or O; r 1 And R 2 Different, R 3 And R 4 The same or different and at least one of which contains a polar group and is independently an alkyl group, an alkyl group containing an N or O atom, an alkyl or alkylcarboxylic acid containing a carbonylalkyl group or an amide bond, an alkyl alcohol, an alkylcarboxylic acid containing an N or O atom, an alkyl alcohol containing an N or O atom, an alkylcarboxylic acid containing a carbonylalkyl alcohol, an alkylcarboxylic acid containing an amide bond, an alkylcarboxylic acid containing both a carbonyl group and an amide bond; the intermediate dihalogeno-diphenporphin photosensitizer prepared by the invention has obvious photodynamic activity, and can be used as a medicament for photodynamic diagnosis and treatment of diseases such as tumor, macular degeneration of retina, actinic keratosis, nevus flammeus, condyloma acuminatum and the like.)
1. a novel intermediate di (disubstituted) phenyl dihalogen porphin tetrapyrrole photosensitive compound with good stability, good hydrophilicity and difficult aggregation is characterized in that: the photosensitive compounds are intermediate di [3, 4-disubstituted ] phenyl dihaloporphin derivatives (I) and intermediate di (3, 5-disubstituted) phenyl dihaloporphin derivatives (II):
wherein:
x is Cl, Br or I;
a and Y are the same or different and are independently CH2Or O;
when R is1When it is an alkyl group, an alkyl group containing an N or O atom, a carbonylalkyl group or an alkyl group containing an amide bond, R2Is alkyl carboxylic acid, alkyl alcohol, alkyl carboxylic acid containing N or O atoms, alkyl alcohol containing N or O atoms, alkyl carboxylic acid containing carbonyl group, alkyl alcohol containing carbonyl group, alkyl carboxylic acid containing amido bond or alkyl carboxylic acid containing carbonyl group and amido bond;
or when R is1When R is an alkyl carboxylic acid, an alkyl alcohol, an alkyl carboxylic acid containing an N or O atom, an alkyl alcohol containing an N or O atom, an alkyl carboxylic acid containing a carbonyl group, an alkyl alcohol containing a carbonyl group, an alkyl carboxylic acid containing an amide bond or an alkyl carboxylic acid containing both a carbonyl group and an amide bond2Is alkyl, alkyl containing N or O atoms, alkyl containing carbonyl group or alkyl containing amido bond;
R3and R4The same or different and at least one of which contains a polar group (e.g., a carboxyl group, an alcohol, or an amino group) and is independently an alkyl group, an alkyl group containing a N or O atom, an alkyl group containing a carbonylalkyl group or an amide bond, an alkyl carboxylic acid, an alkyl alcohol, an alkyl carboxylic acid containing a N or O atom, an alkyl alcohol containing a N or O atom, a carbonylalkyl carboxylic acid, a carbonylalkyl alcohol, an alkyl carboxylic acid containing an amide bond, or an alkyl carboxylic acid containing both a carbonyl group and an amide bond.
2. The formula (I) according to claim 1, wherein
When R is1Is- (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,-(CH2)mCONH(CH2)nC(CH3)3Where m is 0 to 7, n is 1 to 7, and p is 1 to 3,
R2is- (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH or an amino acid derivative, m-1-7, n-2-7, p-1-3;
when R is1Is- (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH or an amino acid derivative, where m is 1-7, n is 2-7, and p is 1-3,
R2is- (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,-(CH2)mCONH(CH2)nC(CH3)3,m＝0-7,n＝1-7,p＝1-3。
3. A compound of formula (II), R according to claim 13And R4Identical or different and at least one contains a polar group (e.g., carboxyl, alcohol or amino), wherein:
the nonpolar group being- (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2Or- (CH)2)mCONH(CH2)nC(CH3)3,m＝0-7,n＝1-7,p＝1-3；
The polar group is (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH or an amino acid derivative, m-1-7, n-2-7, p-1-3.
4. The amino acid derivative as set forth in claims 2 and 3, wherein the amino acid derivative is:
-(CH2)mCONH(CH2)mCOOH,-(CH2)mCONHCH(CH3)COOH,-(CH2)mCONH(CH2)mCO(CH2)pCOOH,-(CH2)mCONHCH[CH(CH3)2]COOH,-(CH2)mCONHCH[CH2CH(CH3)2]COOH,-(CH2)mCONHCH[CH(CH3)CH2CH3]COOH,-(CH2)mCONHCH(CH2C6H5)COOH,-(CH2)mCON[(CH2)mCOOH]2,-(CH2)mCONHCH(COOH)CH2COOH,m＝1-7,p＝1-3。
5. a novel class of intermediate bis (3, 4-disubstituted) phenyl dihaloporphin compounds and their amino acid condensates (I) as claimed in claim 1 wherein said compounds include the following:
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)1)；
5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dichloroporphin (I)2)；
5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)3)；
5, 15-bis [ (3-carboxymethoxy-4-ethoxy) phenyl)]-10, 20-dichloroporphin (I)4)；
5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)5)；
5, 15-bis [ (3-carboxymethoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)6)；
5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)7)；
5, 15-bis [ (3-carboxybutoxy-4-methoxy) phenyl)]-10, 20-dichloroporphin (I)8)；
5, 15-bis [ (3-ethoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)9)；
5, 15-bis [ (3-carboxybutoxy-4-ethoxy) phenyl)]-10, 20-dichloroporphin (I)10)；
5, 15-bis [ (3-propoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)11)；
5, 15-bis [ (3-carboxybutoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)12)；
5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)13)；
5, 15-bis [ (3-hydroxyethoxy-4-methoxy) phenyl]-10, 20-dichloroporphin (I)14)；
5, 15-bis [ (3-ethoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)15)；
5, 15-bis [ (3-hydroxyethoxy-4-ethoxy) phenyl]-10, 20-dichloroporphin (I)16)；
5, 15-bis [ (3-propoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)17)；
5, 15-bis [ (3-hydroxyethoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)18)；
5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)19)；
5, 15-bis [ (3-hydroxypropoxy-4-methoxy) phenyl]-10, 20-dichloroporphin (I)20)；
5, 15-bis [ (3-ethoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)21)；
5, 15-bis [ (3-hydroxypropoxy-4-ethoxy) phenyl]-10, 20-dichloroporphin (I)22)；
5, 15-bis [ (3-propoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)23)；
5, 15-bis [ (3-hydroxypropoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)24)；
5, 15-bis [ [ 3-methoxy-4- (2-oxo-2-carboxymethylamino) ethoxy ] ethoxy]Phenyl radical]-10, 20-dichloroporphin (I)25)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)26)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)27)；
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)28)；
5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)29)；
5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)30)；
5, 15-bis [ (3-carboxymethoxy-4-ethoxy) phenyl)]-10, 20-dibromoporphine (I)31)；
5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)32)；
5, 15-bis [ (3-carboxymethoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)33)；
5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoPorphine (I)34)；
5, 15-bis [ (3-carboxybutoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)35)；
5, 15-bis [ (3-ethoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)36)；
5, 15-bis [ (3-carboxybutoxy-4-ethoxy) phenyl)]-10, 20-dibromoporphine (I)37)；
5, 15-bis [ (3-propoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)38)；
5, 15-bis [ (3-carboxybutoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)39)；
5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)40)；
5, 15-bis [ (3-hydroxyethoxy-4-methoxy) phenyl]-10, 20-dibromoporphine (I)41)；
5, 15-bis [ (3-ethoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)42)；
5, 15-bis [ (3-hydroxyethoxy-4-ethoxy) phenyl]-10, 20-dibromoporphine (I)43)；
5, 15-bis [ (3-propoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)44)；
5, 15-bis [ (3-hydroxyethoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)45)；
5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)46)；
5, 15-bis [ (3-hydroxypropoxy-4-methoxy) phenyl]-10, 20-dibromoporphine (I)47)；
5, 15-bis [ (3-ethoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)48)；
5, 15-bis [ (3-hydroxypropoxy-4-ethoxy) phenyl]-10, 20-dibromoporphine (I)49)；
5, 15-bis [ (3-propoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)50)；
5, 15-bis [ (3-hydroxypropoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)51)；
5, 15-bis [ [ 3-methoxy ] methyl ester4- (2-oxo-2-carboxymethylamino) ethoxy]Phenyl radical]-10, 20-dibromoporphine (I)52)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)53)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)54)。
6. The novel hydrophilic, non-aggregating intermediary di (3, 5-disubstituted) phenyldihaloporphin compounds and their amino acid condensates (II) as claimed in claim 1, wherein the compounds include:
5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dichloroporphin (II)1)；
5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dichloroporphin (II)2)；
5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dichloroporphin (II)3)；
5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dichloroporphin (II)4)；
5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)5)；
5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)6)；
5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)7)；
5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)8)；
5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10, 20-dichloroporphin (II)9)；
5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)10)；
5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)11)；
5, 15-di[ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dibromoporphine (II)12)；
5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dibromoporphine (II)13)；
5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dibromoporphine (II)14)；
5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dibromoporphine (II)15)；
5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)16)；
5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)17)；
5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)18)；
5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)19)；
5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10, 20-dibromoporphine (II)20)；
5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)21)；
5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)22)。
7. The use of the novel hydrophilic, non-aggregating intermediary di (disubstituted) phenyl dihaloporphine and its amino acid condensates (I) and (II) as claimed in claim 1 in the preparation of photodynamic medicaments for the diagnosis and treatment of tumors, macular degeneration, actinic keratosis, nevus flammeus, condyloma acuminatum, and the like.
Technical Field
The invention relates to the field of photosensitive drugs and photodynamic therapy, in particular to a novel intermediate di (disubstituted) phenyl dihalogen porphin tetrapyrrole derivative with good stability, simple and convenient preparation process, good hydrophilicity, difficult aggregation, good photodynamic effect and small skin phototoxic side effect and application thereof.
Background
Photodynamic therapy (PDT) is a promising new approach to the diagnosis and treatment of tumors, following traditional surgical, chemotherapy, and radiation therapy. The principle is that after the photosensitizer is injected into human body intravenously, it can be selectively gathered or retained in the focus (such as malignant tumor), after the photosensitizer concentration reaches a certain extent, it adopts the light with specific wavelength to make directional irradiation, and the photosensitizer can produce photochemical reaction after being excited, and finally produce active oxygen (such as singlet oxygen) to kill tumor or other pathologic hyperplasia tissue.
Photosensitizers, light of specific wavelengths and oxygen molecules are three essential elements essential for photodynamic therapy, wherein photosensitizers play a dominant role in the overall PDT as the core of the three main components of photodynamic therapy. Most of the current market uses porphin-like tetrapyrrole photosensitizers. The porphin photosensitizer mainly comprises a heme derivative (also called hematoporphyrin derivative) and a tetraphenylporphin derivative. Porfimer sodium (photosensitizer II) is used as a heme derivative, is a photosensitive drug which is applied to clinic at the earliest and achieves remarkable treatment effect, but the drug is a mixture consisting of a plurality of compounds, the content of each component is difficult to control in the preparation process, the retention time of some components in the skin is long, and the drugs need to be protected from light for more than 4 weeks, so that patients are difficult to tolerate (foreign medicines-synthetic medicines, biochemical medicines, preparation books, 1998,19, 32-34; world clinical medicines, 2018,39, 285-; the photosensitive drug Verteporfin (Verteporfin) approved by the United states FDA in 2000 for clinical treatment of tumor, macular degeneration and other diseases also belongs to a heme derivative, the maximum absorption wavelength of the heme derivative can reach 689nm, the thickness of a penetrating tissue is twice of that of porfimer sodium, and the heme derivative can be rapidly eliminated from cells, but the synthetic raw material of the heme derivative is derived from a natural product protoporphyrin, belongs to a semi-synthetic product, has complex synthetic process, multiple isomers, difficult separation and purification and low total yield (China New medicine journal, 2005,14, 785-. In addition, the photosensitizer Temoporfin (Temoporfin) which is marketed belongs to tetraphenyl porphin derivatives, and has the disadvantages of easy oxidation, poor stability, weak solubility in water, high price and the like (chem. Soc. Rev.,1995,24, 19-33), and the clinical application is limited. The discovery of the novel high-efficiency photosensitizer is a great challenge for domestic and foreign scientists, and has important scientific significance and application value.
The intermediate diphenyl porphin is a tetrapyrrole compound with a novel structure, and only a few scholars have conducted preliminary research on the intermediate diphenyl porphin. 5, 15-bis (3-hydroxyphenyl) porphine (compound 1) synthesized by Arno Wiehe et al has a good photodynamic action, but is unstable in structure and easily oxidized due to two phenolic hydroxyl groups on the peripheral benzene ring structure (J.Porphyr.Phenaloya., 2001,5, 758-. Biaryl chlorin derivatives were synthesized from 5, 15-bis (4-carboxyphenyl) porphin (compound 2) as an intermediate by Makino stone, etc., but no study of photodynamic therapeutic action was carried out on compound 2 (CN 1382493A). The company Designy Pharma, UK developed photosensitizer XF-73 (Exeporphium Chloride, Compound 3), which has the effect of resisting staphylococcus aureus infection and can be used as a photoactivation antibacterial disinfectant, but is not suitable for treating diseases such as tumor, macular degeneration and the like (anti. agents Chemothermy, 2005,49, 1542-one 1552; CN 101389631A). Yamada et al prepared 5, 15-bis (4-tert-butylphenyl) -10, 20-dibromoporphin (compound 4), which was used as an intermediate for the preparation of double-peptide chain-linked polyporphin compounds for which no photodynamic activity evaluation was performed (J.am. chem. Soc.,2014,136, 6505-. Kazuya et al prepared 5, 15-bis (4-formylethylphenyl) -10, 20-dibromoporphin (compound 5), which was used as an intermediate for the preparation of polyporphyrin conjugated supramolecular compounds, which were not evaluated for photodynamic activity (J.Porphyr.Phthalocyya., 2007,11, 359-367). Christina et al prepared 5, 15-bis (4-carboxyphenyl) -10, 20-dibromoporphin zinc (Compound 6), which was incorporated into a batteryHas certain photoelectric conversion efficiency and potential of becoming a photoelectric material of a solar cell (Eur.J.Inorg.chem.,2013, 1275-one 1286), but does not develop the research of the effect of photodynamic therapy. Wu et al prepared 5, 15-bis [ (4-acetoacetylmethoxy) phenyl]10, 20-dibromoporphine (compound 7) and 5, 15-bis (4-ethylcarboxyphenyl) -10, 20-dibromoporphine (compound 8), which were used as intermediates for the preparation of acetylene-bridged tripartite porphine compounds (bioconjugate. chem.,2005,16, 542-. Julia (Julia)Et al prepared 5, 15-bis (3, 5-di-tert-butylphenyl) -10, 20-dibromoporphine (compound 9), which was used as an intermediate for the preparation of diphorphin compounds and was not evaluated for photodynamic activity (chem. Takuji et al prepared 5, 15-bis (3, 5-dihydroxyphenyl) -10, 20-dibromoporphin zinc (compound 10) and used it as an intermediate for the preparation of porphin supramolecular compounds (JP2004063421), nor did they have been studied for photodynamic activity.
The tetrapyrrole macrocyclic compound is easy to generate self-aggregation or self-assembly phenomena, so that the solubility of the compound is greatly reduced, the compound is difficult to be dissolved in various solvents and is difficult to be prepared into preparations for use, and in addition, the photodynamic activity can be influenced, so that the drug forming property and the application in photodynamic therapy are seriously influenced (acta. pharm. sin. B.,2018,8, 137-146-).
In order to find a novel photosensitive drug with novel structure, good optical property and good pharmacy, a novel intermediate diphenyl dihalogen porphin tetrapyrrole compound is designed and prepared. Activity evaluation research shows that compared with a control compound 1, a compound 2, a compound 3, a compound 4, a compound 5, a compound 6, a compound 7, a compound 8, a compound 9 and a compound 10, the photosensitizer designed and synthesized by the group has higher photodynamic pharmacological activity and smaller skin phototoxic side effect, has the advantages of stable structure, simple and feasible preparation process, good hydrophilicity, capability of preventing aggregation and the like, and can be developed into photodynamic treatment medicines for diseases such as tumors, macular degeneration of retina, actinic keratosis, nevus flammeus, condyloma acuminatum and the like.
Disclosure of Invention
In order to overcome the defects of complex composition, unstable structure, difficult preparation, higher cost, easy aggregation, poor water solubility, strong skin light toxic and side effects and the like in the conventional photosensitive drug, the invention introduces a polar group as a hydrophilic group and introduces an alkyl group as a hydrophobic group into the phenyl group of the intermediate diphenyl dihalogenated porphin compound, thereby improving the hydrophilicity of the compound and inhibiting the aggregation capability of the compound; in addition, halogen is introduced into intermediate positions of the compound, the generation capability of active free radicals and the photodynamic biological activity are improved, the prepared novel compound has the advantages of stable structure, good hydrophilicity, difficult aggregation, simple preparation process, low production cost, strong photodynamic use and small skin photo-toxic side effect, and a series of intermediate diphenyl dihalogenated porphin and amino acid condensate derivatives thereof are synthesized after a large amount of creative work is paid, thereby completing the invention.
The invention relates to an intermediate diphenyl dihalogen porphin tetrapyrrole compound with the advantages of high photodynamic activity, small skin light toxic and side effects, stable property, good hydrophilicity, difficult aggregation, easy preparation of injection and the like and the application thereof.
The invention is summarized as follows:
a novel intermediate di (disubstituted) phenyl dihalogen porphin derivative with good stability, good hydrophilicity and difficult aggregation is characterized in that: the photosensitizer is intermediate di [3, 4-disubstituted ] phenyl dihaloporphin derivative (I) and intermediate di (3, 5-disubstituted) phenyl dihaloporphin derivative (II):
wherein:
x is Cl, Br or I;
a and Y are the same or different and are independently CH2Or O;
when R is1When it is an alkyl group, an alkyl group containing an N or O atom, a carbonylalkyl group or an alkyl group containing an amide bond, R2Is alkyl carboxylic acid, alkyl alcohol, alkyl carboxylic acid containing N or O atoms, alkyl alcohol containing N or O atoms, alkyl carboxylic acid containing carbonyl group, alkyl alcohol containing carbonyl group, alkyl carboxylic acid containing amido bond or alkyl carboxylic acid containing carbonyl group and amido bond;
or when R is1When R is an alkyl carboxylic acid, an alkyl alcohol, an alkyl carboxylic acid containing an N or O atom, an alkyl alcohol containing an N or O atom, an alkyl carboxylic acid containing a carbonyl group, an alkyl alcohol containing a carbonyl group, an alkyl carboxylic acid containing an amide bond or an alkyl carboxylic acid containing both a carbonyl group and an amide bond2Is alkyl, alkyl containing N or O atoms, alkyl containing carbonyl group or alkyl containing amido bond;
R3and R4The same or different and at least one of which contains a polar group (e.g., a carboxyl group, an alcohol, or an amino group) and is independently an alkyl group, an alkyl group containing a N or O atom, an alkyl group containing a carbonylalkyl group or an amide bond, an alkyl carboxylic acid, an alkyl alcohol, an alkyl carboxylic acid containing a N or O atom, an alkyl alcohol containing a N or O atom, a carbonylalkyl carboxylic acid, a carbonylalkyl alcohol, an alkyl carboxylic acid containing an amide bond, or an alkyl carboxylic acid containing both a carbonyl group and an amide bond.
The formula (I) according to claim 1, wherein
When R is1Is- (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,-(CH2)mCONH(CH2)nC(CH3)3Where m is 0 to 7, n is 1 to 7, and p is 1 to 3,
R2is- (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH or an amino acid derivative, m-1-7, n-2-7, p-1-3;
when R is1Is- (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH or an amino acid derivative, where m is 1-7, n is 2-7, and p is 1-3,
R2is- (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2,-(CH2)mCONH(CH2)nC(CH3)3,m＝0-7,n＝1-7,p＝1-3。
A compound of formula (II), R according to claim 13And R4Identical or different and at least one contains a polar group (e.g. carboxyl, alcohol or amino), of which
The nonpolar group being- (CH)2)mCH3,-(CH2)mCH(CH3)2,-(CH2)mC(CH3)3,-(CH2)mN[(CH2)mCH3]2,-(CH2)mO(CH2)mCH3,-(CH2)mO(CH2)mCH(CH3)2,-(CH2)mO(CH2)mC(CH3)3,-(CH2)m(OCH2CH2)pCH3,-(CH2)mCO(CH2)mCH3,-(CH2)mCO(CH2)mCH(CH3)2,-(CH2)mCO(CH2)mC(CH3)3,-(CH2)mCONH(CH2)nCH3,-(CH2)mCONH(CH2)nCH(CH3)2Or- (CH)2)mCONH(CH2)nC(CH3)3,m＝0-7,n＝1-7,p＝1-3；
The polar group is (CH)2)mCOOH,-(CH2)mCH(CH3)COOH,-(CH2)mOH,-(CH2)mCH(CH3)OH,-(CH2)mC6H4OH,-(CH2)mN[(CH2)mCOOH]2,-(CH2)mN[(CH2)nOH]2,-(CH2)mO(CH2)mCOOH,-(CH2)mO(CH2)nOH,-(CH2)m(OCH2CH2)pOH,-(CH2)mCO(CH2)mCOOH,-(CH2)mCO(CH2)mOH or an amino acid derivative, m-1-7, n-2-7, p-1-3.
The amino acid derivative according to claim 2 or 3, wherein
-(CH2)mCONH(CH2)mCOOH,-(CH2)mCONHCH(CH3)COOH,-(CH2)mCONH(CH2)mCO(CH2)pCOOH,-(CH2)mCONHCH[CH(CH3)2]COOH,-(CH2)mCONHCH[CH2CH(CH3)2]COOH,-(CH2)mCONHCH[CH(CH3)CH2CH3]COOH,-(CH2)mCONHCH(CH2C6H5)COOH,-(CH2)mCON[(CH2)mCOOH]2,-(CH2)mCONHCH(COOH)CH2COOH,m＝1-7,p＝1-3。
A novel class of intermediate bis (3, 4-disubstituted) phenyl dihaloporphin compounds and their amino acid condensates (I) as claimed in claim 1 wherein said compounds include the following:
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)1)；
5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dichloroporphin (I)2)；
5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)3)；
5, 15-bis [ (3-carboxymethoxy-4-ethoxy) phenyl)]-10, 20-dichloroporphin (I)4)；
5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)5)；
5, 15-bis [ (3-carboxymethoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)6)；
5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)7)；
5, 15-bis [ (3-carboxybutoxy-4-methoxy) phenyl)]-10, 20-dichloroporphin (I)8)；
5, 15-bis [ (3-ethoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)9)；
5, 15-bis [ (3-carboxybutoxy-4-ethoxy) phenyl)]-10, 20-dichloroporphin (I)10)；
5, 15-bis [ (3-propoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)11)；
5, 15-bis [ (3-carboxybutoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)12)；
5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)13)；
5, 15-bis [ (3-hydroxyethoxy-4-methoxy) phenyl]-10, 20-dichloroporphin (I)14)；
5, 15-bis [ (3-ethoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)15)；
5, 15-bis [ (3-hydroxyethoxy-4-ethoxy) phenyl]-10, 20-dichloroporphin (I)16)；
5, 15-bis [ (3-propoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)17)；
5, 15-bis [ (3-hydroxyethoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)18)；
5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)19)；
5, 15-bis [ (3-hydroxypropoxy-4-methoxy) phenyl]-10, 20-dichloroporphin (I)20)；
5, 15-bis [ (3-ethoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)21)；
5, 15-bis [ (3-hydroxypropoxy-4-ethoxy) phenyl]-10, 20-dichloroporphin (I)22)；
5, 15-bis [ (3-propoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)23)；
5, 15-bis [ (3-hydroxypropoxy-4-propoxy) phenyl]-10, 20-dichloroporphin (I)24)；
5, 15-bis [ [ 3-methoxy-4- (2-oxo-2-carboxymethylamino) ethoxy ] ethoxy]Phenyl radical]-10, 20-dichloroporphin (I)25)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)26)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)27)；
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)28)；
5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)29)；
5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)30)；
5, 15-bis [ (3-carboxymethoxy-4-ethoxy) ethyl esterRadical) phenyl]-10, 20-dibromoporphine (I)31)；
5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)32)；
5, 15-bis [ (3-carboxymethoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)33)；
5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)34)；
5, 15-bis [ (3-carboxybutoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)35)；
5, 15-bis [ (3-ethoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)36)；
5, 15-bis [ (3-carboxybutoxy-4-ethoxy) phenyl)]-10, 20-dibromoporphine (I)37)；
5, 15-bis [ (3-propoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)38)；
5, 15-bis [ (3-carboxybutoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)39)；
5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)40)；
5, 15-bis [ (3-hydroxyethoxy-4-methoxy) phenyl]-10, 20-dibromoporphine (I)41)；
5, 15-bis [ (3-ethoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)42)；
5, 15-bis [ (3-hydroxyethoxy-4-ethoxy) phenyl]-10, 20-dibromoporphine (I)43)；
5, 15-bis [ (3-propoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)44)；
5, 15-bis [ (3-hydroxyethoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)45)；
5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)46)；
5, 15-bis [ (3-hydroxypropoxy-4-methoxy) phenyl]-10, 20-dibromoporphine (I)47)；
5, 15-bis [ (3-ethoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)48)；
5, 15-bis [ (3-hydroxypropoxy-4-ethoxy) phenyl]-10, 20-dibromoporphine (I)49)；
5, 15-bis [ (3-propoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)50)；
5, 15-bis [ (3-hydroxypropoxy-4-propoxy) phenyl]-10, 20-dibromoporphine (I)51)；
5, 15-bis [ [ 3-methoxy-4- (2-oxo-2-carboxymethylamino) ethoxy ] ethoxy]Phenyl radical]-10, 20-dibromoporphine (I)52)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)53)；
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)54)。
The novel class of hydrophilic, non-aggregating intermediary di (3, 5-disubstituted) phenyldihaloporphin derivatives (I) as claimed in claim 1, characterized in that the following compounds are included in the class of compounds:
5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dichloroporphin (II)1)；
5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dichloroporphin (II)2)；
5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dichloroporphin (II)3)；
5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dichloroporphin (II)4)；
5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)5)；
5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)6)；
5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)7)；
5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)8)；
5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10,20-dichloroporphin (II)9)；
5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)10)；
5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)11)；
5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dibromoporphine (II)12)；
5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dibromoporphine (II)13)；
5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dibromoporphine (II)14)；
5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dibromoporphine (II)15)；
5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)16)；
5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)17)；
5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)18)；
5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)19)；
5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10, 20-dibromoporphine (II)20)；
5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)21)；
5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)22)。
The intermediate di (disubstituted) phenyl dihalogen porphin derivatives (I) and (II) are prepared for the first time, and have novelty.
The intermediate di (disubstituted) phenyl dihalogen porphin derivatives (I) and (II) have the advantages of high photodynamic activity, small skin light toxic and side effect, stable property, good hydrophilicity, difficult aggregation, easy preparation of injection and the like, overcome the defects of complex composition, unstable structure, difficult preparation, higher cost, easy aggregation, poor hydrophilicity, strong skin light toxic and side effect and the like in the conventional photosensitive compound and photosensitive medicine, and have substantial progress and creativity.
The intermediate di (disubstituted) phenyl dihalogenated porphin derivatives (I) and (II) have obvious photodynamic activity and small skin toxic and side effects, can be used as a medicament for photodynamic diagnosis and treatment of diseases such as tumors, macular degeneration of retina, actinic keratosis, nevus flammeus, condyloma acuminatum and the like, and has practicability.
Specific preparation scheme
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
General scheme 1
R5And R6R is an ester-or acetyl-containing protecting group1And R2。
In the step (i), the compound (III) and dipyrromethane are dissolved in dichloromethane, a catalytic amount of trifluoroacetic acid is dropwise added under the protection of nitrogen, the mixture is stirred and reacted at room temperature, thin-layer chromatography (TLC) is used for monitoring that the raw materials disappear, dichlorodicyanoquinone and triethylamine are added, the stirring and the reaction are continued, and the oxidation is completely monitored by TLC. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to give a magenta powder (IV).
In step (ii), the compound (IV) is dissolved in a mixed solvent of dichloromethane and methanol, and a halogenating agent [ e.g.: a solution of N-chlorobutyrylimine (NCS), or N-bromobutyrylimine (NBS), or N-bromobutyrylimine (NIS) ] in methanol, the reaction mixture was stirred at 0 ℃, TLC monitored for the disappearance of starting material and the reaction quenched by addition of acetone. The solvent was distilled off under reduced pressure and recrystallized from methylene chloride and methanol to give a magenta powder (V).
In step (ii), the compound (V) is dissolved in tetrahydrofuran, an aqueous solution of potassium hydroxide is added, and the reaction mixture is stirred under reflux under a nitrogen atmosphere. The reaction solution was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and the residue was diluted with water and adjusted to pH 5-6 with dilute hydrochloric acid. Filtering under reduced pressure to collect a filter cake, and drying the filter cake in vacuum to obtain a mauve solid (I).
General scheme 2
R7And R8R is an ester-or acetyl-containing protecting group3And R4。
In the step (iv), the compound (VI) and dipyrromethane are dissolved in dichloromethane, a catalytic amount of trifluoroacetic acid is dropwise added under the protection of nitrogen, the mixture is stirred and reacted at room temperature, TLC monitors that the product is generated after the disappearance of the raw materials, dichlorodicyanobenzoquinone and triethylamine are added, the stirring and the reaction are continued, and TLC monitors that the oxidation is complete. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to give a magenta powder (VII).
In step (v), the compound (VII) is dissolved in a mixed solvent of dichloromethane and methanol, and a halogenating agent [ e.g.: a solution of N-chlorobutyrylimine (NCS), or N-bromobutyrylimine (NBS), or N-bromobutyrylimine (NIS) ] in methanol, the reaction mixture was stirred at 0 ℃, TLC monitored for the disappearance of starting material and the reaction quenched by addition of acetone. The solvent was distilled off under reduced pressure and recrystallized from methylene chloride and methanol to give a magenta solid (VIII).
In step (vi), the compound (VIII) is dissolved in tetrahydrofuran, an aqueous potassium hydroxide solution is added, and the reaction mixture is stirred under reflux under a nitrogen atmosphere. The reaction solution was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and the residue was diluted with water and adjusted to pH 5-6 with dilute hydrochloric acid. Filtering under reduced pressure to collect a filter cake, and drying the filter cake in vacuum to obtain a mauve solid (II).
[ example 1]
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)1)
Ethyl 2- (4-formyl-2-methoxyphenoxy) acetate (643mg,2.7mmol) and dipyrromethane (392mg,2.7mmol) were dissolved in DCM (500mL), and trifluoroacetic acid (0.12mL,1.7mmol) was added dropwise under nitrogen, and the reaction was stirred at room temperature for 12 hours. Dichlorodicyanobenzoquinone DDQ (0.735g,3.24mmol) and triethylamine (4mL) were added and the reaction was stirred for an additional 1 hour. Evaporating under reduced pressure to remove solvent, and purifying the residue by column chromatography (eluting with dichloromethane) to obtain mauve powder IV1(434.4mg,44.3％)。1H NMR(400MHz,CDCl3):δppm 10.32(s,2H),9.41(d,J＝4.6Hz,4H),9.15(d,J＝4.6Hz,4H),7.89(d,J＝2.0Hz,2H),7.80(dd,J＝8.0,2.1Hz,2H),7.29(s,2H),5.05(s,4H),4.48(q,J＝7.1Hz,4H),4.06(s,6H),1.47(t,J＝7.1Hz,6H),-3.06(s,2H).MS(MALDI-TOF):m/z＝727.3[M+H]+。
5, 15-bis [ (3-methoxy-4-ethoxycarbonylmethoxy) phenyl]Porphine (600mg,0.82mmol) dissolved in DCM/MeOH (200mL, V)DCM/VMeOH9/1), NCS (309mg,1.73mmol) in methanol was added dropwise, the reaction mixture was stirred at 0 ℃ for 5 hours, TLC monitored for disappearance of the product, and acetone (5mL) was added to quench the reaction. The solvent was removed under reduced pressure and recrystallized from DCM and MeOH to give a magenta powder V1(698mg,96％)。1H NMR(400MHz,CDCl3):δppm 9.63(d,J＝4.3Hz,4H),8.91(brs,4H),7.76(s,2H),7.69(d,J＝8.1Hz,2H),7.22(d,J＝8.1Hz,2H),5.04(s,4H),4.48-4.43(m,4H),4.04(s,6H),1.48-1.43(m,6H),-2.72(s,2H).
5, 15-bis [ (3-methoxy-4-ethoxycarbonylmethoxy) phenyl]-10, 20-Dichloroporphin (400mg,0.45mmol) dissolved in THF/MeOH (200mL, V)THF/VMeOH1/1), followed by addition of KOH solution (2mol/L,50mL), and heating of the reaction mixture back under nitrogen atmosphereThe flow was stirred for 6 hours, the reaction was monitored by TLC for completion, the organic solvent was removed under reduced pressure, water (30mL) was added and the pH was adjusted to 5-6 with dilute hydrochloric acid solution (2 mol/L). Filtering, collecting filter cake, and vacuum drying the filter cake to obtain mauve solid I1(352mg，94％)。1H NMR(400MHz,DMSO-d6):δppm 12.45(s,2H),8.96(brs,4H),8.62(brs,4H),7.70(s,2H),7.63(s,2H),7.18(s,2H),4.36(s,4H),3.92(s,6H),-2.73(s,2H).13C NMR(101MHz,DMSO-d6):δppm 171.80,152.24,150.67,145.65,145.44,145.01,144.71,144.40,143.71,140.60,132.93,132.08,131.14,130.53,129.62,124.20,122.05,120.78,118.74,115.36,114.82,114.13,109.39,66.21,56.83.HRMS(MALDI-TOF):calculated for C38H28Cl2N4O8[M+H]+:738.13；found 739.0918。
[ example 2]
5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)13)
Reference Compound I1The synthesis method of (1) prepares the compound I13。1H NMR(400MHz,DMSO-d6):δppm 8.86(brs,4H),8.15(d,J＝7.9Hz,4H),7.96(d,J＝8.0Hz,2H),7.74(d,J＝7.5Hz,2H),7.43(d,J＝7.8Hz,2H),4.97(t,J＝5.6Hz,2H),4.25(d,J＝5.2Hz,4H),3.97(s,6H),3.75-3.70(m,4H),-2.73(s,2H).13C NMR(101MHz,DMSO-d6):δppm 151.12,150.91,145.65,145.44,145.01,144.71,144.40,143.71,140.60,132.93,131.96,131.14,130.53,130.00,124.20,122.05,120.78,118.74,115.34,114.86,114.13,109.39,70.25,60.89,56.83.HRMS(MALDI-TOF):calculated for C38H32Cl2N4O6[M+H]+,710.17；found 711.3284。
[ example 3]
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)26)
Reference Compound I1The synthesis method of (1) prepares the compound I26。1H NMR(400MHz,DMSO-d6):δppm 12.55(s,2H),10.25(s,2H),9.58(d,J＝4.5Hz,4H),8.99(brs,4H),7.73(s,2H),7.69(s,2H),7.20(d,J＝7.3Hz,2H),4.85(s,4H),4.28(d,J＝4.6Hz,4H),3.85(s,6H),2.82-2.71(m,8H),-2.73(s,2H).13C NMR(101MHz,DMSO-d6):δppm 204.48,175.89,169.81,152.24,150.67,145.65,145.01,144.71,144.40,143.71,140.60,132.93(s),131.14,130.53,129.62,124.20,122.05,120.78,118.74,115.36,114.82,114.13,109.39,68.20,56.83,47.38,37.95,31.19.HRMS(MALDI-TOF):calculated for C48H42Cl2N6O12[M+H]+,965.79；found 966.1093。
[ example 4]
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)28)
Reference Compound I1The synthesis method of (1) prepares the compound I28。1H NMR(400MHz,DMSO-d6):δppm 12.58(s,2H),9.66(brs,4H),8.99(brs,4H),7.79(s,2H),7.64(s,2H),7.17(d,J＝7.8Hz,2H),4.38(s,4H),3.91(s,6H),-2.83(s,2H).13C NMR(101MHz,DMSO-d6):δppm 170.72,158.51,136.02,133.55,121.67,113.71,103.50,79.76,79.43,79.10,65.43.HRMS(MALDI-TOF):calculated for C38H28Br2N4O8[M+H]+:826.03；found 827.2019。
[ example 5]
5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)29)
Reference Compound I1The synthesis method of (1) prepares the compound I29。1H NMR(400MHz,DMSO-d6):δppm 9.78(d,J＝4.8Hz,4H),9.10(d,J＝4.8Hz,4H),8.09(d,J＝1.9Hz,2H),7.84(dd,J＝8.1,1.9Hz,2H),7.38(d,J＝8.2Hz,2H),5.18(s,4H),4.08(s,6H),-2.53(s,2H).13C NMR(101MHz,DMSO-d6):δppm 171.80,151.90,149.46,147.57,146.75,145.01,143.71,140.60,133.74,132.63,130.86,128.49,127.21,125.86,124.25,122.22,118.58,115.74,115.11,112.97,110.59,105.56,66.21,56.83.HRMS(MALDI-TOF):calculated for C38H28Br2N4O8[M+H]+:826.03；found 827.1175。
[ example 6]
5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)34)
Reference Compound I1The synthesis method of (1) prepares the compound I34。1H NMR(400MHz,Pyr):δppm 11.30(d,J＝2.6Hz,4H),10.58(s,4H),9.43(s,2H),9.30(s,2H),8.91(d,J＝8.3Hz,2H),5.94(s,4H),5.72(d,J＝7.1Hz,4H),5.47(s,6H),3.97–3.92(m,4H),-0.95(s,2H)..13C NMR(101MHz,Pyr):δppm177.25,151.12,150.91,147.57,146.75,145.01,143.71,140.60,133.74,132.63,131.96,131.14,130.00,128.49,127.21,125.86,124.25,122.22,118.58,115.34,114.91,110.59,105.56,69.99,56.83,31.84,24.05.HRMS(MALDI-TOF):calculated for C42H36Br2N4O8[M+H]+:882.09；found 883.3643。
[ example 7]
5, 15-bis [ (3-carboxybutoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)35)
Reference Compound I1The synthesis method of (1) prepares the compound I35。1H NMR(400MHz,DMSO-d6):δppm 9.77(d,J＝4.6Hz,4H),9.09(s,4H),8.09(s,2H),7.84(d,J＝7.9Hz,2H),7.39(d,J＝8.2Hz,2H),5.18(s,4H),4.17(d,J＝7.1Hz,4H),4.09(s,4H),4.08(s,6H),-2.54(s,2H).13C NMR(101MHz,DMSO-d6):δppm 177.25,152.90,150.34,147.57,146.75,145.01,143.71,140.60,133.74,132.63,131.14,130.60,129.81,128.49,127.21,125.86,124.25,122.22,118.58,115.11,112.74,110.59,105.56,69.99,56.83,31.84,24.05.HRMS(MALDI-TOF):calculated for C42H36Br2N4O8[M+H]+:882.09；found,883.0923。
[ example 8]
5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)53)
Reference Compound I1The synthesis method of (1) prepares the compound I53。1H NMR(400MHz,DMSO-d6):δppm 12.64(s,2H),10.35(s,2H),9.62(d,J＝4.5Hz,4H),8.96(brs,4H),7.83(s,2H),7.66(s,2H),7.20(d,J＝7.5Hz,2H),4.82(s,4H),4.35(d,J＝4.6Hz,4H),3.98(s,6H),2.82-2.60(m,8H),-2.75(s,2H).13C NMR(101MHz,DMSO-d6):δppm 204.48,175.89,171.66,147.57,145.01,143.14,136.36,132.63,131.14,128.49,125.86,124.25,119.28,118.50,115.11,105.56,55.23,47.38,44.50,37.95,31.19.HRMS(MALDI-TOF):calculated for C48H42Br2N6O12[M+H]+,1052.12；found 1053.1233。
[ example 9]
5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dichloroporphin (II)1)
Reference Compound I1The synthesis method of (2) prepares a compound II1。1H NMR(400MHz,DMSO-d6):δppm 12.43(s,2H),9.67(brs,4H),8.83(brs,4H),7.73(s,2H),7.57(s,2H),7.38(s,2H)1.58(s,9H),1.37(s,9H),-2.82(d,J＝18.7Hz,2H).13C NMR(101MHz,DMSO-d6):δppm 167.64,152.62,145.65,145.44,145.01,144.70,144.40,141.13,140.27,132.93,132.04,131.39,130.53,130.20,124.20,122.05,120.78,118.82114.82,114.13,109.39,35.51,31.36.HRMS(MALDI-TOF):calculated for C42H36Cl2N4O4[M+H]+,730.21；found,731.6385。
[ example 10]
5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)5)
Reference Compound I1The synthesis method of (2) prepares a compound II5。1H NMR(400MHz,DMSO-d6):δppm 8.84(brs,4H),8.18(d,J＝7.9Hz,4H),7.99(d,J＝8.1Hz,2H),7.74(d,J＝7.9Hz,2H),7.43(d,J＝7.5Hz,2H),4.97(t,J＝5.5Hz,2H),4.23(d,J＝5.2Hz,4H),3.97(s,6H),3.73-3.70(m,4H),-2.93(s,2H).13C NMR(101MHz,DMSO-d6):δppm 160.98,159.59,145.65,145.44,145.01,144.70,144.40,141.13,140.23,132.93,131.14,130.53,124.20,122.05,120.78,118.82,118.00,116.89,114.77,109.39,105.35,69.84,60.89,56.08.HRMS(MALDI-TOF):calculated for C38H32Cl2N4O6[M+H]+,710.17；found 711.2912。
[ example 11]
5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)7)
Reference Compound I1The synthesis method of (2) prepares a compound II7。1H NMR(400MHz,DMSO-d6):δppm 8.94(brs,4H),8.21(d,J＝6.9Hz,4H),7.87(d,J＝8.5Hz,2H),7.71(d,J＝7.7Hz,2H),7.53(d,J＝7.4Hz,2H),4.99(s,4H),4.23(d,J＝5.1Hz,8H),3.75-3.69(m,8H),-2.93(s,2H).13C NMR(101MHz,DMSO-d6):δppm 159.24,145.65,145.44,145.01,144.70,141.13,138.79,132.93,131.14,130.53,124.20,122.05,120.78,118.82,116.83(s),114.82,109.39,107.33,69.84,60.89.HRMS(MALDI-TOF):calculated for C40H36Cl2N4O8[M+H]+,770.19；found 771.2536。
[ example 12]
5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)10)
Reference Compound I1The synthesis method of (2) prepares a compound II10。1H NMR(400MHz,DMSO-d6):δppm 12.58(s,2H),9.66(s,4H),8.85(s,4H),8.64(t,J＝5.6Hz,2H),8.13(d,J＝7.9Hz,2H),7.77(d,J＝8.0Hz,2H),4.16(d,J＝5.5Hz,4H),3.91(s,4H),2.76(t,J＝6.5Hz,4H),1.61(s,18H),-2.95(s,2H).13C NMR(101MHz,DMSO-d6):δppm 204.48,175.89,166.93,152.81,145.65,145.44,144.70,141.06,138.35,134.21,132.93,131.13,130.53,129.96,124.20,122.05,120.78,118.82,118.00,114.82,114.13,109.39,49.27,37.95,35.51,31.28.HRMS(MALDI-TOF):calculated for C52H50Cl2N6O8[M+H]+,956.31；found 957.1026。
[ example 13]
5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)11)
Reference Compound I1The synthesis method of (2) prepares a compound II11。1H NMR(400MHz,DMSO-d6):δppm 12.61(s,4H),9.63(d,J＝3.7Hz,4H),8.97(brs,4H),7.79(d,J＝7.2Hz,2H),7.62(d,J＝7.9Hz,4H),4.38(s,4H),4.22(s,4H),1.61(s,18H),-2.87(s,2H).13C NMR(101MHz,DMSO-d6):δppm 172.28,153.54,145.65,145.44,145.01,144.70,144.40,141.13,140.07,138.72,133.22,132.93,131.65,131.14,130.53,129.34,124.20,122.05,120.78,118.82,118.00,114.82,114.13,109.39,47.56,35.51,31.36.HRMS(MALDI-TOF):calculated for C50H46Cl2N6O10[M+H]+,960.27；found 961.1324。
[ example 14]
5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dibromoporphine (II)12)
Reference Compound I1The synthesis method of (2) prepares a compound II12。1H NMR(400MHz,DMSO-d6):δppm 12.52(s,2H),9.70(brs,4H),8.84(brs,4H),8.66(s,2H),8.48(s,2H),8.38(s,2H)1.55(s,9H),1.36(s,9H),-2.90(d,J＝18.7Hz,2H).13C NMR(101MHz,DMSO-d6):δppm 172.82,157.76,142.71,128.09,127.74,123.74,122.71,121.66,121.45,114.81,103.89,67.38,60.20,41.89,41.00,31.12,29.79,28.93.24.98,14.05.HRMS(MALDI-TOF):calculated for C42H36Br2N4O4[M+H]+,818.11；found,819.6385。
[ example 15]
5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)16)
Reference Compound I1The synthesis method of (2) prepares a compound II16。1H NMR(400MHz,DMSO-d6):δppm 8.88(brs,4H),8.07(d,J＝8.4Hz,4H),7.93(s,2H),7.78(d,J＝7.5Hz,2H),7.49(d,J＝7.2Hz,2H),4.98(t,J＝5.1Hz,2H),4.23(d,J＝4.8Hz,4H),4.01(s,6H),3.75-3.70(m,4H),-2.82(s,2H).13C NMR(101MHz,DMSO-d6):δppm 160.98,159.59,147.57,146.75,145.01,144.70,141.13,140.23,133.74,132.63,131.14,128.49,127.21,125.86,124.25,122.22,118.50,116.89,115.11,114.73,110.59,105.56,105.35,69.84,60.89,56.08.HRMS(MALDI-TOF):calculated for C38H32Br2N4O6[M+H]+,798.07；found 799.3214。
[ example 16]
5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)18)
Reference Compound I1The synthesis method of (2) prepares a compound II18。1H NMR(400MHz,DMSO-d6):δppm 8.93(brs,4H),8.12(d,J＝8.5Hz,4H),7.87(s,2H),7.65(d,J＝7.2Hz,2H),7.44(d,J＝7.1Hz,2H),4.93(S,4H),4.23(d,J＝4.8Hz,8H),3.71-3.63(m,8H),-2.82(s,2H).13C NMR(101MHz,DMSO-d6):δppm 159.24,147.57,146.75,145.01,144.70,141.13,138.79,133.74,132.63,131.14,128.49,127.21,125.86,124.25,122.22,118.50,118.00,116.83,115.11,110.59,107.33,105.56,69.84,60.89.HRMS(MALDI-TOF):calculated for C40H36Br2N4O8[M+H]+,858.09；found 859.0256。
[ example 17]
5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)21)
Reference Compound I1The synthesis method of (2) prepares a compound II21。1H NMR(400MHz,DMSO-d6):δppm 12.24(s,2H),9.54(s,4H),8.82(s,4H),8.56(s,2H),8.13(d,J＝6.4Hz,2H),7.96(s,2H),4.11(d,J＝4.9Hz,4H),2.72(t,J＝6.1Hz,4H),2.47(t,J＝6.0Hz,4H),1.68(s,18H),-3.20(s,2H).13C NMR(101MHz,DMSO-d6):δppm 204.48,175.89,166.93,152.81,147.57,146.75,145.01,144.70,141.06,138.35,134.21,133.74,132.63,131.13,129.96,128.49,127.21,125.86,124.25,122.22,118.50,115.11,110.59,105.56,49.27,37.95,35.51,31.28.HRMS(MALDI-TOF):calculated for C50H46Br2N6O10[M+H]+,1044.21；found 1045.0122。
[ example 18]
5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)22)
Reference Compound I1The synthesis method of (2) prepares a compound II22。1H NMR(400MHz,DMSO-d6):δppm 12.59(s,4H),9.64(d,J＝3.7Hz,4H),8.85(brs,4H),8.10(d,J＝7.9Hz,4H),7.67(d,J＝8.0Hz,2H),4.34(s,4H),4.11(s,4H),1.58(s,9H),1.53(s,9H),-3.00(s,2H).13C NMR(101MHz,DMSO-d6):δppm 172.28,153.54,147.57,146.75,145.01,144.70,141.13,140.07,138.72,133.74,133.22,132.63,131.14,129.34,128.49,127.21,125.86,124.25,122.22,118.50,118.00,115.11,110.59,105.56,47.56,35.51,31.36.HRMS(MALDI-TOF):calculated for C50H46Br2N6O10[M+H]+,1048.16；found 1049.1078。
[ example 19]
Photodynamic antiproliferation experiment of photosensitizer on human esophageal cancer Eca-109 cells
Test cells:
human esophageal cancer cell Eca-109.
Light source:
XD-650AB laser; model SD2490 laser power measuring instrument.
The tested drugs are:
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)1) (ii) a 5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dichloroporphin (I)2) (ii) a 5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)3) (ii) a 5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)5) (ii) a 5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)7) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)13) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)19) (ii) a 5, 15-bis [ [ 3-methoxy-4- (2-oxo-2-carboxymethylamino) ethoxy ] ethoxy]Phenyl radical]-10, 20-dichloroporphin (I)25) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)26) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)27) (ii) a 5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)28) (ii) a 5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)29) (ii) a 5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)30) (ii) a 5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)32) (ii) a 5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)34) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)40) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)46) (ii) a 5, 15-bis [ [ 3-methoxy-4- (2-oxo-2-carboxymethylamino) ethoxy ] ethoxy]Phenyl radical]-10, 20-dibromoporphine (I)52) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)53) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)54) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dichloroporphin (II)1) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dichloroporphin (II)2) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dichloroporphin (II)3) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dichloroporphin (II)4) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)5) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)6) (ii) a 5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)7) (ii) a 5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)8) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10, 20-dichloroporphin (II)9) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)10) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)11) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dibromoporphine (II)12) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dibromoporphine (II)13) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dibromoporphine (II)14) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dibromoporphine (II)15) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)16) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)17) (ii) a 5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)18) (ii) a 5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)19) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10, 20-dibromoporphine (II)20) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)21) (ii) a 5, 15-bis [ [ 3-tert-butyl ] butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)22)。
Control compound:
compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10.
Control drugs:
and (4) the helmofofen.
Experiment of photodynamic anti-tumor cell proliferation:
after trypsinizing the cells in logarithmic growth phase, the complete medium was resuspended to a cell suspension, which was then seeded into 96-well plates at 100. mu.L per well in 5% CO at 37 ℃2Culturing in an incubator, and adding a photosensitizer after 24 hours; after 12 hours, the mixture was irradiated with light (power 18 mW/cm)2Wavelength of 650nm, light dose of 4J/cm2) Adding culture medium for continuous culture; MTT assay was performed after 24 hours. 20 mu L of 5mg/mL MTT was added 4 hours before the termination of the culture, 150 mu L of DMSO was added after the aspiration of the culture medium to terminate the reaction, and the OD value was measured at 570nm with a microplate reader. The experiment was repeated three times. The results are shown in Table 1, and the intermediate diphenyl dihalo-porphin derivative I is found1-3,I5,I7,I13,I19,I25-30,I32,I34,I40,I46,I52-54And II1-22Has antiproliferative effect on human esophageal cancer cells, and the photodynamic activity is obviously superior to that of a control compound 1-10 and a control drug, i.e. the hamporfin.
TABLE 1 inhibition of Eca-109 human esophageal cancer cell proliferation by novel compounds
Compared to control compound 8, which had the best antitumor effect in control compounds 1-10,ΔP<0.05，ΔΔP<0.01，ΔΔΔP<0.001; p compared to the control drug Helipofen<0.05，**P<0.01，***P<0.001。
[ example 20]
Evaluation experiment of phototoxicity of photosensitizer to mouse skin
The test animals were:
kunming mice, 5 weeks old (22. + -.2 g).
Light source:
230 V.E 27/ES Oseland simulated solar light; YK-PDT-300 type power density meter.
The tested drugs are:
5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)1) (ii) a 5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dichloroporphin (I)2) (ii) a 5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)3) (ii) a 5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dichloroporphin (I)5) (ii) a 5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dichloroporphin (I)7) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (I)13) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (I)19) (ii) a 5, 15-bis [ [ 3-methoxy-4- (2-oxo-2-carboxymethylamino) ethoxy ] ethoxy]Phenyl radical]-10, 20-dichloroporphin (I)25) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)26) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dichloroporphin (I)27) (ii) a 5, 15-bis [ (3-methoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)28) (ii) a 5, 15-bis [ (3-carboxymethoxy-4-methoxy) phenyl)]-10, 20-dibromoporphine (I)29) (ii) a 5, 15-bis [ (3-ethoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)30) (ii) a 5, 15-bis [ (3-propoxy-4-carboxymethoxy) phenyl]-10, 20-dibromoporphine (I)32) (ii) a 5, 15-bis [ (3-methoxy-4-carboxybutoxy) phenyl]-10, 20-dibromoporphine (I)34) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (I)40) (ii) a 5, 15-bis [ (3-methoxy-4-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (I)46) (ii) a 5, 15-bis [ [ 3-methoxy-4- (2-oxo-2-carboxymethylamino) ethoxy ] ethoxy]Phenyl radical]-10, 20-dibromoporphine (I)52) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (2-oxo-4-carboxy) butylamino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)53) (ii) a 5, 15-bis [ [ 3-methoxy-4- [ 2-oxo-2- (N, N-dicarboxymethyl) amino]Ethoxy radical]Phenyl radical]-10, 20-dibromoporphine (I)54) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dichloroporphin (II)1) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dichloroporphin (II)2) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dichloroporphin (II)3) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dichloroporphin (II)4) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)5) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)6) (ii) a 5, 15-bis [ (3, 5-dihydroxyethoxy) phenyl]-10, 20-dichloroporphin (II)7) (ii) a 5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dichloroporphin (II)8) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10, 20-dichloroporphin (II)9) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)10) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dichloroporphin (II)11) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxy) phenyl]-10, 20-dibromoporphine (II)12) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethyl) phenyl]-10, 20-dibromoporphine (II)13) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxymethoxy) phenyl]-10, 20-dibromoporphine (II)14) (ii) a 5, 15-bis [ (3-tert-butyl-5-carboxypropoxy) phenyl]-10, 20-dibromoporphine (II)15) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)16) (ii) a 5, 15-bis [ (3-methoxy-5-hydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)17) (ii) a 5, 15-bis [ (3, 5-bis ]Hydroxyethoxy) phenyl]-10, 20-dibromoporphine (II)18) (ii) a 5, 15-bis [ (3, 5-dihydroxypropoxy) phenyl]-10, 20-dibromoporphine (II)19) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- (carboxymethylamino) formyl group]Phenyl radical]-10, 20-dibromoporphine (II)20) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- [ (2-oxo-4-carboxy) butylamino]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)21) (ii) a 5, 15-bis [ [ 3-tert-butyl-5- [ (N, N-dicarboxymethyl) amino group]Formyl radical]Phenyl radical]-10, 20-dibromoporphine (II)22)；
Control drugs:
a photosensitizer II.
Mouse model skin phototoxicity evaluation experiment:
mice were randomly grouped into groups of 8 mice, each half of the mice was male and female, and the back hair of the mice was shaved 24h before the experiment. The tested drugs are administered to the tail vein of 1 time in each group, the injection dose is 10mg/kg, the drugs are irradiated for 10min by simulated sunlight 4h after administration, and the illumination intensity is 10mW/cm2. Before irradiation, 5% chloral hydrate is needed to be injected into the abdominal cavity for anaesthetizing the mice, and the anaesthetization dosage is 0.06mL/10 g. The mouse is fixed on a self-made fixer in a prone position, and the mouse is placed in a dark room and is illuminated at a position 45cm below a light source. The mice need to be strictly protected from light after being irradiated, and the physiological conditions of the animals are strictly observed and recorded after being irradiated. The mouse is killed by cervical dislocation after being irradiated by simulated sunlight for 24 hours, the back skin is taken by an 8mm puncher, weighed by an electronic analytical balance, and the back skin index is calculated according to the formula of the back skin index which is the weight (mg) of the back skin/the weight (g) multiplied by 100. The smaller difference between the index of the back skin of the test drug group and the index of the back skin of the control group indicates that the skin is less phototoxic. The results are shown in Table 2 and show that the mediated diphenyl dihaloporphin derivative I1-3,I5,I7,I13,I19,I25,I27-30,I32,I34,I40,I46,I52,I54,II1,II3,II5-9,II11-19,II21-22The dorsal skin index of the treated mice was significantly lower than that of the photosensitizer II treated group, indicating that the tested compounds all had lower skin phototoxic side effects.
Table 2 table for calculating index of new compound to dorsal skin of mouse in back illumination area
P <0.05, P <0.01, P <0.001 compared to the blank;
compared with the control drug of the photosensitizer II,ΔP<0.05，ΔΔP<0.01，ΔΔΔP<0.001。
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