CN116410214A - Novel cationic condensed ring conjugated pyrrole derivative and application thereof in medicine field - Google Patents

Novel cationic condensed ring conjugated pyrrole derivative and application thereof in medicine field Download PDF

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CN116410214A
CN116410214A CN202310190932.6A CN202310190932A CN116410214A CN 116410214 A CN116410214 A CN 116410214A CN 202310190932 A CN202310190932 A CN 202310190932A CN 116410214 A CN116410214 A CN 116410214A
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thiophene
bis
difluoro
boron
indenotetraene
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陈志龙
曹宁
江颖
严懿嘉
鲍蕾蕾
邱彦
金辉
吴晓锋
阮继武
可敢
梅金纳
特妮孔
山妮妮
首辛吴
刘世芳
张洪涛
吴丹
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SHANGHAI XIANHUI MEDICAL TECHNOLOGY CO LTD
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Abstract

Novel cationic condensed ring conjugated pyrrole derivative and application thereof in medicine field, and is characterized by comprisingThe following structures (I) and (II):

Description

Novel cationic condensed ring conjugated pyrrole derivative and application thereof in medicine field
Technical Field
The invention relates to the fields of cationic photosensitive medicaments, photodynamic Antibacterial (PACT) and photodynamic therapy (PDT), in particular to a novel cationic condensed ring conjugated pyrrole derivative which has the advantages of stable structure, difficult aggregation, good amphipathy, strong absorption in a near infrared region, high photodynamic activity, wide application and the like, and the application of the derivative in the field of medicines.
Background
Photodynamic therapy is now commonly used for photodynamic antibacterial therapy (Photodynamic Antibacteria Chemotherapy, PACT) and photodynamic antitumor therapy (Photodynamic therapy, PDT) as a novel treatment method combining photosensitizers (photosensitizing drugs) with visible light to generate high active oxygen for inactivation of pathogenic microorganisms or cancer tissues. Compared with the traditional therapy, the photodynamic therapy has the advantages of good selectivity, no toxicity, reusability, strong action effect and the like, wherein the photodynamic therapy is particularly important in that the photodynamic therapy generates oxidative damage to surrounding tissues through active oxygen and has non-specificity, so that microorganisms or pathological tissues cannot generate drug resistance to photosensitizing drugs. With the development of new photosensitizers and advances in laser technology, PACT and PDT have become the most promising new therapeutic technologies for some highly resistant bacteria, fungi, viruses, and refractory tumor eradication approaches (jpn.j. Cancer res., 2000, 91 (5): 560-565).
Photodynamic therapy has two mechanisms of action at the molecular level; type I (Type I) and Type II (Type II), the photosensitizer molecule, after being irradiated by a light source of a certain wavelength, first transitions from a ground state to a short-lived singlet excited state and then to a longer-lived triplet excited state by intersystem crossing. The triplet excited photosensitizer molecule directly reacts with a substrate in a hydrogen extraction reaction or an electron transfer reaction to generate free radicals or free radical ions, and the free radicals react with biomolecules and oxygen molecules to generate oxidation products, wherein the process is called a type I mechanism and also called a free radical mechanism; the triplet excited photosensitizer molecule can also generate energy transfer action with oxygen to generate singlet oxygen 1 O 2 ) High activity 1 O 2 The rapid reaction with neighboring biomolecules causes damage to the biomolecules, a process known as a type II mechanism, also known as a singlet oxygen mechanism. In the antibacterial or anticancer field, type I mechanisms mainly occur in cell membranes, such as hydrogen abstraction with unsaturated phospholipid molecules, followed by further reaction with oxygen to form lipid peroxides, which lead to disruption of the structural integrity of the cell membrane (j. Photochem. Photobiol. B., 1990, 6, 343-347); type II mechanisms, which can interact with other targeting molecules in bacteria or cancer cells, including some amino acids, polypeptides, enzymes, receptors, etc., are generally considered to be the primary pathways for photodynamic oxidative killing, and thus the singlet oxygen quantum yield of photosensitizer molecules is an important factor affecting their photodynamic effect.
In the past decades, PDT has been mainly focused on cancer treatment, which gradually evolves into a new generation of anticancer methods following radiotherapy and chemotherapy; in addition, PDT has been successfully applied to the clinical treatment of other diseases such as rheumatoid arthritis, atherosclerotic plaque, actinic keratosis and the like.
Bacterial and fungal infections can cause harm to human health, and bacteria are pathogens of many diseases, and can cause diseases such as tuberculosis, gonorrhea, anthracnose, syphilis, plague, trachoma and the like; fungi can invade human skin, mucous membranes and deep tissues to cause inflammation and even systemic disseminated infection. Antibiotics are currently used as a common treatment method, and the treatment effect of the antibiotics is remarkably reduced because bacteria and fungi can generate drug resistance to the antibiotics. There is a need for new methods, techniques and medicaments for killing bacteria and fungi. With the development of photosensitizers and advanced optical technology, PACT is considered one of the most promising antimicrobial treatments, especially against infections caused by highly resistant bacteria and fungi. PACT has various advantages such as non-invasive, broad antimicrobial spectrum, effectiveness against biofilm produced by microorganisms, effectiveness against deep gum infections resulting from dental implants, etc.
In the field of photodynamic antibacterial, photosensitizers represented by Toluidine Blue (TBO) or Methylene Blue (MB) are currently mostly selected. Both belong to the class of phenothiazine basic dyes, which have been found to be useful in photodynamic antimicrobial therapy. TBO-mediated PACT has begun to enter the in vivo research stage and achieves better therapeutic effects; however, its high permeability results in large side effects, limiting its use in vivo therapy (lasers. Med. Sci., 2009, 24 (4): 521-526). MB has been widely studied in the medical field and has been successfully applied to in vitro anti-phage and viral infections (proc. Soc. Exp. Biol. Med., 1928, 26, 100-101); furthermore Cragah et al report that high concentrations of MB can also be used to treat bladder cancer, but greatly limit its in vivo anti-tumor application due to its strong photobleaching phenomenon (Br. J. Urol., 1995, 75 (4): 477-479). At present, a multipurpose photosensitizer drug (which can be used for resisting tumor and microorganism) is not developed, and development of a photosensitizer with wide applicability (which can be used for PDT and PACT) is an important target pursued by pharmaceutical and technological workers.
Figure SMS_1
Because of the disadvantages of weak absorption strength, low singlet oxygen generation capacity, remarkable photobleaching phenomenon, large side effects and the like of the phenothiazine derivatives, researchers are paying attention to other types of photosensitizers. The BODIPY (C-BDP) is an organic fluorescent dye with the absorption wavelength of ultraviolet-visible light between 400 nm and 500 nm. In recent years, the research of the molecules is mainly focused on the fluorescence field, and the application of the molecules to photodynamic anticancer and antibacterial research is less. The structure of the BODIPY is modified by Banfi and the like, and a water-soluble BODIPY dye molecule (compound 1) is designed, the maximum absorption wavelength of the BODIPY dye molecule is 550nm, the oil-water partition coefficient log P value is-1.96, the BODIPY dye molecule shows better photodynamic activity and has better sterilization effect. However, the low maximum absorption wavelength of this molecule limits its application in the field of photodynamic antibacteria (j. Photo chem. Photo biol. B., 2012, 114, 44-51). Li Chaodeng the conjugation of BODIPY molecules is increased at the 3, 7 positions of the borofluoride by Heck reaction to prepare The conjugated pyridine salt BODIPY derivative (compound 2) enables the maximum absorption wavelength of the compound to be red shifted to 630nm, and has a certain sterilization effect; however, the stability of this molecule is poor and does not have the prospect of being used as photodynamic antibacterial (chem. Phys. Chem., 2012, 13, 2739). In addition, O ’ The Shea et al designs and synthesizes an aza-BODIPY photosensitive molecule (compound 3), the maximum absorption wavelength of the molecule is 643nm, two quaternary ammonium ions are introduced, the water solubility is obviously improved, the LogP value is-0.23, the amphipathy is good, and the compound has higher photodynamic antibacterial capability on gram-negative bacteria and gram-positive bacteria; however, this molecule also has the disadvantage of poor in vivo stability, greatly limiting its use in the field of photodynamic therapy (j. Med. Chem., 2010, 53 (20): 7337-7343).
Figure SMS_2
At present, BODIPY photosensitizers have a plurality of defects: such as unstable structure, weak absorption in near infrared region, poor photodynamic effect, easy aggregation, etc. Based on the past research, novel cation class thieno [3,2-b ] thiophene condensed ring BODIPY derivatives containing medium phenyl are innovatively designed and prepared. Due to the introduction of thiophene condensed rings, the BODIPY parent ring conjugated system is expanded, so that the maximum absorption wavelength region of the compound is improved to 650-730nm; cationic groups (such as quaternary ammonium, quaternary phosphonium and the like) are introduced to the periphery of the benzene ring, so that the water solubility and the fat solubility of the compound are obviously improved, the log P value interval (-0.1-7.5) of BODIPY photosensitive drug molecules is greatly expanded, and the novel cationic modified thieno [3,2-b ] thiophene condensed ring BODIPY derivatives can be flexibly used for cancer and antibacterial treatment. The photosensitive drug molecule designed and synthesized by the team has the advantages of higher photodynamic activity, strong repeatability, good amphipathy, wide application and the like, can be developed into photodynamic therapeutic drugs for treating diseases caused by microbial infection, and diseases such as tumors, macular degeneration of retina, actinic keratosis, nevus harlequin, condyloma acuminatum and the like, and is hopeful to develop into multipurpose photodynamic candidate drugs with PACT and PDT functions.
Disclosure of Invention
In order to overcome the defects of complex composition, unstable structure, easy aggregation, weak absorption in a near infrared region, poor amphipathy, insufficient application range and the like in the existing photosensitizer or photosensitive medicine, the invention adopts a full synthesis method to prepare a novel condensed ring conjugated derivative containing medium-pressure phenyl group and containing pyrrole, introduces a cationic group at the periphery of a benzene ring, and introduces halogen atoms at the periphery of a conjugated parent ring. The prepared novel compound has the advantages of remarkably enhanced absorption in the near infrared region, remarkably improved singlet oxygen yield, remarkably enhanced photodynamic effect and strong structural stability. After a great deal of creative work is done, the novel cation modified thieno [3,2-b ] thiophene condensed ring conjugated derivative is synthesized, and the invention is completed.
The invention relates to a novel cationic condensed ring conjugated pyrrole derivative which has the advantages of stable structure, difficult aggregation, good amphipathy, strong absorption in a near infrared region, high photodynamic activity, wide application and the like, and an application thereof in the field of medicines.
The invention is summarized as follows:
the novel cationic condensed ring conjugated pyrrole derivative has the advantages of stable structure, difficult aggregation, good amphipathy, strong absorption in a near infrared region, high photodynamic activity and wide application, and is characterized in that: the photosensitizer is a thieno [3,2-b ] thiophene condensed ring conjugated derivative (I) and (II) with intermediate cation modification:
Figure SMS_3
Wherein A is alkyl, alkyl containing N or O or S atoms, alkyl containing carbonyl alkyl and amide bond, and various alkyl containing alkyl, carboxyl (ester) group, hydroxyl or amino side chain;
R 1 =
Figure SMS_4
, />
Figure SMS_5
, />
Figure SMS_6
, />
Figure SMS_7
, />
Figure SMS_8
the method comprises the steps of carrying out a first treatment on the surface of the Wherein y=cl, br, I;
x is H, cl, br, I,
Figure SMS_9
or->
Figure SMS_10
Wherein z=o, S, se;
R 2 , R 3 ,R 4 = -H, -F, -Cl, -Br, -I, -OH, -O(CH 2 ) m CH 3 , -(CH 2 ) m CH 3 , -(CH 2 ) m O(CH 2 ) n C(CH 3 ) 3 ,
-(CH 2 ) m O(CH 2 ) n CH(CH 3 ) 2 ，-(CH 2 ) m COOH, -(CH 2 ) m CH(CH 3 )COOH，-(CH 2 ) m C(CH 3 ) 2 COOH，
-(CH 2 ) m OH, -(CH 2 ) m C 6 H 4 OH,-(CH 2 ) m CO(CH 2 ) n OH, -(CH 2 ) m O(CH 2 ) n OH, -(CH 2 ) m (OCH 2 CH 2 ) p OH, -(CH 2 ) m R 1 , -(CH 2 ) m C(CH 3 ) 2 R 1 , -(CH 2 ) m CH(CH 3 )R 1 , -(CH 2 ) m O(CH 2 ) n R 1 , -(CH 2 ) m S(CH 2 ) n R 1 ,
-(CH 2 ) m O(CH 2 ) m C(CH 3 ) 2 R 1 ，-(CH 2 ) m O(CH 2 ) m CH(CH 3 )R 1 ，-(CH 2 ) m S(CH 2 ) m C(CH 3 ) 2 R 1 ,
-(CH 2 ) m S(CH 2 ) m CH(CH 3 )R 1 ,-(CH 2 ) m (OCH 2 CH 2 ) p R 1 ，-(CH 2 ) m CO(CH 2 ) m C(CH 3 ) 2 R 1 ,
-(CH 2 ) m CO(CH 2 ) m CH(CH 3 )R 1 , -(CH 2 ) m CONH(CH 2 ) n R 1 , -(CH 2 ) m CONH(CH 2 ) n C(CH 3 ) 2 R 1 ,
-(CH 2 ) m CONH(CH 2 ) n CH(CH 3 )R 1 or amino acid derivatives, m=0-7, n=1-7, p=1-5.
The process according to claim 1, wherein
A is- (CH) 2 ) n -, -(CH 2 ) m C(CH 3 ) 2 -, -(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m O(CH 2 ) n -, -(CH 2 ) m S(CH 2 ) n -,
-(CH 2 ) m O(CH 2 ) m C(CH 3 ) 2 -,-(CH 2 ) m O(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m S(CH 2 ) m C(CH 3 ) 2 -,
-(CH 2 ) m S(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m (OCH 2 CH 2 ) p -，-(CH 2 ) m CO(CH 2 ) m C(CH 3 ) 2 -,
-(CH 2 ) m CO(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m CONH(CH 2 ) n -, -(CH 2 ) m CONH(CH 2 ) n C(CH 3 ) 2 -,
-(CH 2 ) m CONH(CH 2 ) n CH(CH 3 )-, -R 5 (CH 2 ) m C(CH 3 ) 2 -, -R 5 (CH 2 ) m CH(CH 3 )-, -R 5 O(CH 2 ) n -,
-R 5 O(CH 2 ) m C(CH 3 ) 2 -，-R 5 O(CH 2 ) m CH(CH 3 )-,-R 5 (OCH 2 CH 2 ) p -，-R 5 CO(CH 2 ) m CH(CH 3 )-,
-R 5 CO(CH 2 ) m C(CH 3 ) 2 -, m=0-7, n=1-7, p=1-5;
Wherein R is 5 is-CH [ (CH) 2 ) m CH 3 ], -CH[(CH 2 ) n OCH 3 ], -CH[(CH 2 ) n OH], -CH[(CH 2 ) m COOH],
-CH[(CH 2 ) m O(CH 2 ) n C(CH 3 ) 3 ], -CH[(CH 2 ) m COO(CH 2 ) m CH 3 ], -CH[(CH 2 ) m (OCH 2 CH 2 ) n CH 3 )],
-CH[(CH 2 ) m CO(CH 2 ) n C(CH 3 ) 3 ], -CH[(CH 2 ) m CO(CH 2 ) n CH(CH 3 ) 2 ],
-CH[(CH 2 ) m CONH(CH 2 ) n C(CH 3 ) 3 ] -CH((CH 2 ) m CONH[CH 2 ) n CH(CH 3 ) 2 ], m=0-7, n=1-7。
The amino acid derivative as claimed in claim 1, wherein the amino acid derivative is:
-(CH 2 ) m CONH(CH 2 ) n COOH, -(CH 2 ) m CONHCH(CH 3 )COOH,
-(CH 2 ) m CONH(CH 2 ) n CO(CH 2 ) p COOH, -(CH 2 ) m CONHCH[CH(CH 3 ) 2 ]COOH,
-(CH 2 ) m CONHCH[CH 2 CH(CH 3 ) 2 ]COOH, -(CH 2 ) m CONHCH[CH(CH 3 )CH 2 CH 3 ]COOH,
-(CH 2 ) m CONHCH(CH 2 C 6 H 5 )COOH, -(CH 2 ) m CON[(CH 2 ) n COOH] 2 ,
-(CH 2 ) m CONHCH(COOH)CH 2 COOH, m=0-7, n=1-7, p=1-5。
the novel cationic fused ring conjugated pyrrole derivatives (I) according to claim 1, wherein the compounds comprise the following compounds:
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_11
1 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_12
2 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_13
3 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ] ]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_14
4 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_15
5 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N, N-triethyl) ethoxy) phenyl group]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_16
6 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_17
7 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_18
8 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_19
9 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_20
10 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_21
11 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ] ]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_22
12 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_23
13 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_24
14 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_25
15 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N, N-triethyl) ethoxy) phenyl group]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_26
16 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethoxy) phenyl)]4-boron-3 a,4a-Diaza-s-indenotetraene
Figure SMS_27
17 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_28
18 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (quinolinyl) ethoxy) phenyl ] ]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_29
19 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_30
20 ）。
The novel cationic fused ring conjugated pyrrole derivatives (II) according to claim 1, wherein the compounds comprise the following compounds:
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 1 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 2 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 3 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2-quinolinyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 4 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (triphenylphosphonium) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 5 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 6 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 7 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 8 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 9 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 10 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 11 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 12 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (pyridinyl) ethoxy) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 13 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 14 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 15 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 16 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 17 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 18 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 19 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (triphenylphosphonium) ethyl) carbamoyl) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 20 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 21 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 22 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 23 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 24 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 25 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 26 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 27 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 28 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 29 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 30 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 31 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 32 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (pyridinyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 33 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 34 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 35 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 36 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 37 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 38 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 39 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 40 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 41 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 42 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (pyridinyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 43 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 44 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 45 ）
2,3, 5, 6-bis [ 2-bromo-Thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 46 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 47 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 48 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 49 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 50 ）。
The novel cationic condensed ring conjugated pyrrole derivatives (I) and (II) as claimed in claim 1 can be used as photosensitive drugs or reagents for diagnosing and treating microbial infection, tumors, macular degeneration of retina, actinic keratosis, nevus rubrum, condyloma acuminatum and other diseases, and can be used as fluorescent dyes and reagents for near infrared fluorescence imaging, fluorescent marking or photoelectric material fields.
Specific preparation scheme
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Example 1
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_31
1 ）
Figure SMS_32
Thiophene [3,2-b ]]Pyrrole III 1 (1.09 g,6.1 mmol) and 4- (3- (N, N, N-triethyl) propyl) carbamoyl benzaldehyde II 1 (500 mg,3.0 mmol) was sequentially added to a three-necked flask, DCM (100 mL) was added thereto, 1 drop of trifluoroacetic acid was added dropwise under argon, after stirring at room temperature for 24 hours, DDQ (1.04 g,4.5 mmol) was added thereto, stirring was continued for 1.5 hours, triethylamine (10 mL) and boron trifluoride diethyl ether solution (8 mL) were sequentially added thereto, stirring was continued for 1 hour, TLC detection reaction was completed, saturated brine (30 mL X3) was added thereto, washing was performed with dichloromethane (20 mL X3), the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness under reduced pressure, and the crude product was purified by column chromatography (DCM: meOH=20:1) to give a dark blue solid I 1 （462 mg，30.2 %）。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.99 - 7.93 (m, 2H), 7.45 - 7.39 (m, 2H), 7.30 (dd, J = 10.1, 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.75 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 3.64 (td, J = 6.9, 1.0 Hz, 2H), 3.54 (td, J = 6.9, 1.0 Hz, 2H), 3.28 (q, J = 8.0 Hz, 6H), 1.25 (t, J = 8.0 Hz, 9H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 168.55, 163.85, 162.49, 151.63, 150.53, 148.14, 145.92, 143.38, 143.33, 142.79, 139.03, 134.89, 129.85, 128.96, 128.57, 127.06, 123.30, 122.06, 102.71, 54.14, 53.55, 25.52, 9.32. MS (MALDI-TOF): calculated for C 32 H 30 BBrF 2 N 4 OS 4[M-Br+H]: 663.1379; found, 664.4567。
Example 2
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_33
11 ）
Figure SMS_34
Compound I 1 (500 mg,1 mmol) was dissolved in tetrahydrofuran (20 mL) mixed solvent, a methanol solution of NBS (150 mg,2 mmol) was slowly added dropwise, the reaction mixture was stirred at 0℃for 12 hours, TLC monitored the formation of the starting material disappeared product, and the reaction was quenched by the addition of sodium thiosulfate solution (5 mol/L, 5 mL). Evaporating the solvent under reduced pressure, and recrystallizing with dichloromethane and methanol to obtain dark green powder I 11 （600 mg，90.2 %）。 1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.40 (s, 1H), 8.12 (dd, J = 12.3, 6.3 Hz, 4H), 7.70 (d, J = 7.3 Hz, 2H), 7.22 (s, 2H). 13 C NMR (101 MHz, DMSO-d6): δ ppm 168.14, 167.94, 167.88, 167.83, 162.08, 161.85, 161.79, 161.74, 156.72, 156.67, 156.61, 151.68, 151.63, 151.57, 151.08, 150.59, 145.26, 144.81, 143.38, 129.51, 128.20, 128.16, 128.05, 122.90, 119.88, 117.08, 116.15, 101.85. HRMS (MALDI-TOF): calculated for C 32 H 28 BBr 3 F 2 N 2 O 2 S 4 [M-Br+H]: 821.3574.8045; found: 823.2043。
Example 3
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_35
3 ）
Figure SMS_36
Reference Compound I 1 The synthesis method of (2) prepares the compound I 3 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.38 (dt, J = 7.0, 1.4 Hz, 2H), 8.74 (t, J = 7.3, 1.5 Hz, 1H), 8.28 - 8.18 (m, 3H), 7.99 - 7.93 (m, 2H), 7.45 - 7.37 (m, 4H), 7.19 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.30 (s, 1H), 5.01 (t, J = 7.1 Hz, 2H), 3.48 (t, J = 7.1 Hz, 2H), 2.33 (p, J = 7.1 Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 168.55, 166.26, 162.49, 156.67, 156.46, 151.63, 150.59, 148.14, 146.47, 145.26, 144.56, 143.68, 143.38, 139.03, 136.07, 129.88, 128.93, 127.10, 127.07, 122.38, 116.62, 116.49, 101.85, 61.31, 39.36, 29.33. MS (MALDI-TOF): calculated for C 31 H 20 BBrF 2 N 4 OS 4 [M-Br+H]: 641.34; found, 642.60。
Example 4
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_37
4 ）
Figure SMS_38
Reference Compound I 1 The synthesis method of (2) prepares the compound I 4 。
1 H NMR (400 MHz, DMSO- d 6 ) δ ppm: 9.38 (dd, J = 7.4, 1.5 Hz, 1H), 8.65 – 8.57 (m, 2H), 8.42 (dt, J = 7.5, 1.6 Hz, 1H), 8.27 - 8.18 (m, 3H), 8.03 - 7.93 (m, 3H), 7.45 - 7.37 (m, 4H), 7.19 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.30 (s, 1H), 5.01 (t, J = 7.1 Hz, 2H), 3.48 (t, J = 7.1 Hz, 2H), 2.33 (p, J = 7.1 Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 168.55, 166.26, 162.49, 156.46, 151.63, 150.59, 148.14, 145.26, 143.68, 143.38, 142.57, 139.03, 138.97, 137.02, 136.07, 132.37, 129.88, 129.14, 128.93, 127.10, 127.07, 126.62, 126.40, 124.60, 122.38, 116.62, 116.49, 101.85, 59.08, 39.36, 29.14. MS (MALDI-TOF): calculated for C 35 H 22 BBrF 2 N 4 OS 4[M-Br+H]: 771.0366; found, 772.1276。
Example 5
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_39
5 ）
Figure SMS_40
Reference Compound I 1 The synthesis method of (2) prepares the compound I 5 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.20 (s, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.45 - 7.29 (m, 9H), 7.32 - 7.22 (m, 11H), 7.19 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.30 (s, 1H), 3.48 (t, J = 7.1 Hz, 2H), 1.60 (p, J = 7.0 Hz, 2H), 1.30 (dt, J = 14.0, 7.1 Hz, 2H).
13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 168.55, 166.26, 162.49, 156.67, 156.46, 151.63, 150.59, 148.14, 145.26, 143.68, 143.38, 139.03, 136.07, 133.47, 132.97, 131.66, 131.57, 129.88, 127.10, 127.07, 122.38, 119.79, 119.08, 116.62, 116.49, 101.85, 41.44, 41.29, 23.59, 23.18, 22.40. MS (MALDI-TOF): calculated for C 44 H 30 BBrF 2 N 3 OPS 4 [M-Br+H]: 824.1279; found, 824.2195。
Example 6
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N, N-triethyl) ethoxy) phenyl group]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_41
6 ）
Figure SMS_42
Reference Compound I 1 The synthesis method of (2) prepares the compound I 6 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.40 (t, J = 3.8 Hz, 2H), 7.35 – 7.29 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.79 - 6.73 (m, 2H), 6.30 (s, 1H), 4.38 (t, J = 7.1 Hz, 2H), 3.66 (t, J = 7.1 Hz, 2H), 3.28 (q, J = 8.0 Hz, 6H), 1.25 (t, J = 8.0 Hz, 9H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 166.26, 162.49, 157.48, 156.46, 151.63, 150.59, 148.14, 145.26, 143.38, 139.26, 136.07, 135.44, 127.07, 122.38, 116.62, 116.49, 113.47, 101.85, 66.01, 54.53, 53.55, 9.32. MS (MALDI-TOF): calculated for C 31 H 29 BBrF 2 N 3 OS 4 [M-Br+H]: 716.2128; found, 717.2512。
Example 7
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 1 ）
Figure SMS_43
Reference Compound I 1 The synthesis method of (2) prepares the compound II 1 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.34 (t, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 2H), 7.40 (t, J = 3.7 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.75 (s, 2H), 6.30 (s, 1H), 3.64 (td, J = 6.9, 1.0 Hz, 4H), 3.54 (td, J = 6.9, 1.0 Hz, 4H), 3.28 (q, J = 8.0 Hz, 12H), 1.25 (t, J = 8.0 Hz, 18H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 166.93, 156.46, 150.59, 148.14, 146.64, 143.38, 136.83, 136.07, 132.15, 130.83, 127.07, 126.34, 122.38, 116.62, 116.49, 101.85, 54.00, 53.55, 40.11, 9.32. MS (MALDI-TOF): calculated for C 41 H 49 BBr 2 F 2 N 6 O 2 S 4 [M-2Br+H]:834.2179; found, 835.2395。
Example 8
2,3, 5, 6-bis [ thiophene [3,2-b ] ]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 2 ）
Figure SMS_44
Reference Compound I 1 The synthesis method of (2) prepares the compound II 2 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.58 (t, J = 1.9 Hz, 1H), 8.31 (d, J = 2.0 Hz, 2H), 7.40 (s, 1H), 6.80 (d, J = 4.9 Hz, 2H), 6.30 (s, 1H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 167.94, 167.88, 167.83, 167.68, 162.08, 161.85, 161.79, 161.74, 156.72, 156.67, 156.61, 152.11, 152.05, 152.00 , 151.08, 150.59, 146.64, 143.38, 133.69, 131.49, 130.71, 130.15, 128.05, 122.90, 119.88, 117.08, 116.15, 101.85. MS (MALDI-TOF): calculated for C 39 H 45 BBr 2 F 2 N 6 O 2 S 4 [M-2Br+H]: 805.2127; found, 806.2387。
Example 9
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 3 ）
Figure SMS_45
Reference Compound I 1 The synthesis method of (2) prepares the compound II 3 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: δ 9.38 (dt, J = 7.1, 1.4 Hz, 4H), 8.74 (t, J = 7.3, 1.5 Hz, 2H), 8.34 (t, J = 2.0 Hz, 1H), 8.28 - 8.20 (m, 4H), 8.04 (d, J = 2.0 Hz, 2H), 7.40 (t, J = 3.8 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.75 (s, 2H), 6.30 (s, 1H), 5.33 (t, J = 7.1 Hz, 4H), 3.94 (t, J = 7.1 Hz, 4H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 166.93, 166.26, 162.49, 156.67, 156.46, 152.05, 150.59, 148.14, 146.64, 146.47, 143.36, 136.83, 136.07, 132.15, 130.83, 128.87, 127.07, 126.34, 122.38, 116.62, 116.49, 101.85, 60.84, 39.89. MS (MALDI-TOF): calculated for C 39 H 29 BBr 2 F 2 N 6 O 2 S 4 [M-2Br+H]: 790.1275; found, 790.7205。
Example 10
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 6 ）
Figure SMS_46
Reference Compound I 1 The synthesis method of (2) prepares the compound II 6 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.40 (t, J = 3.8 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 1.9 Hz, 2H), 6.30 (s, 2H), 4.38 (t, J = 7.1 Hz, 4H), 3.66 (t, J = 7.1 Hz, 4H), 3.28 (q, J = 8.0 Hz, 12H), 1.25 (t, J = 8.0 Hz, 18H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 162.40, 156.46, 150.59, 148.14, 146.64 , 143.38, 136.07, 133.24, 127.07, 122.38, 116.62, 116.49, 113.90, 105.60, 101.85, 66.01, 54.53, 53.55, 9.32. MS (MALDI-TOF): calculated for C 39 H 47 BBr 2 F 2 N 4 O 2 S 4 [M-2Br+H], 780.2176; found, 781.3212。
Example 11
2,3, 5, 6-bis [ 2-thienyl-thia-zolePheno [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 11 ）
Figure SMS_47
Reference Compound I 1 The synthesis method of (2) prepares the compound II 11 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.53 (dd, J = 7.5, 1.5 Hz, 1H), 7.17 (dd, J = 7.5, 1.5 Hz, 1H), 7.08 (d, J = 15.0 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.30 (s, 1H), 4.38 (t, J = 7.1 Hz, 2H), 3.66 (t, J = 7.1 Hz, 2H), 3.28 (q, J = 8.0 Hz, 6H), 1.25 (t, J = 8.0 Hz, 9H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 169.13, 162.40, 158.56, 150.59, 146.64, 143.38, 139.35, 134.26, 133.24, 127.90, 124.43, 124.07, 123.36, 117.14, 113.90, 107.73, 105.60, 101.85, 66.01, 54.53, 53.55, 9.32. MS (MALDI-TOF): calculated for C 47 H 51 BBr 2 F 2 N 4 O 2 S 6[M-2Br+H], 945.1212; found, 946.2109。
Example 12
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 21 ）
Figure SMS_48
Reference Compound I 1 、I 11 The synthesis method of (2) prepares the compound II 21 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 6.80 (d, J = 4.9 Hz, 1H), 6.61 (d, J = 1.9 Hz, 1H), 6.30 (s, 1H), 4.38 (t, J = 7.1 Hz, 2H), 3.66 (t, J = 7.1 Hz, 2H), 3.28 (q, J = 8.0 Hz, 6H), 1.25 (t, J = 8.0 Hz, 9H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 162.40, 162.08, 151.08, 150.59, 146.64, 143.38, 133.24, 128.05, 122.90, 119.88, 117.08, 116.15, 113.90, 105.60, 101.85, 66.01, 54.53, 53.55, 9.32. MS (MALDI-TOF): calculated for C 47 H 63 BBr 4 F 2 N 5 O 3 S 4 [M-2Br+H], 938.1191; found, 939.2281。
Example 13
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 27 ）
Figure SMS_49
Reference Compound I 1 、I 11 Synthetic method for preparing Compound II 27 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.34 (t, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 2H), 7.40 (s, 1H), 6.80 (d, J = 4.9 Hz, 2H), 6.75 (s, 2H), 6.30 (s, 1H), 3.64 (td, J = 6.9, 1.0 Hz, 4H), 3.54 (td, J = 6.9, 1.0 Hz, 4H), 3.32 - 3.24 (m, 14H), 1.25 (t, J = 8.0 Hz, 12H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 166.93, 162.08, 151.08, 150.59, 146.64, 143.38, 136.83, 132.15, 130.83, 128.05, 126.34, 122.90, 119.88, 117.08, 116.15, 101.85, 59.86, 56.48, 46.15, 39.98, 11.27. MS (MALDI-TOF): calculated for C 39 H 43 BBr 4 F 2 N 6 O 2 S 4 [M-2Br+H]: 964.3375; found, 964.4305。
Example 14
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 26 ）
Figure SMS_50
Reference Compound I 1 、I 11 The synthesis method of (2) prepares the compound II 26 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.08 (d, J = 15.0 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.30 (s, 1H), 4.38 (t, J = 7.1 Hz, 2H), 3.66 (t, J = 7.1 Hz, 2H), 3.28 (q, J = 8.0 Hz, 6H), 1.25 (t, J = 8.0 Hz, 9H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 169.13, 162.40, 158.56, 150.59, 146.64, 143.38, 138.78, 134.73, 133.24, 127.35, 125.16, 121.44, 117.14, 113.90, 110.55, 107.73, 105.60, 101.85, 66.01, 54.53, 53.55, 9.32. MS (MALDI-TOF): calculated for C 47 H 49 BBr 4 F 2 N 4 O 4 S 6 [M-2Br+H], 1102.91; found, 1102.81。
Example 15
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 31 ）
Figure SMS_51
Reference Compound I 1 The synthesis method of (2) prepares the compound II 31 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.40 (t, J = 3.8 Hz, 1H), 6.61 (s, 1H), 4.38 (t, J = 7.1 Hz, 3H), 3.66 (t, J = 7.1 Hz, 3H), 3.28 (q, J = 8.0 Hz, 9H), 1.25 (t, J = 8.0 Hz, 13H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 156.46, 153.85, 150.59, 148.14, 146.64, 143.38, 140.68, 136.07, 129.68, 127.07, 122.38, 116.62, 116.49, 111.58, 101.85, 67.36, 66.20, 54.53, 53.55, 9.32. MS (MALDI-TOF): calculated for C 47 H 65 BBr 3 F 2 N 5 O 3 S 4 [M-3Br+H], 925.3211; found, 926.3242。
Example 16
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 46 ）
Figure SMS_52
Reference Compound I 1 、I 11 The synthesis method of (2) prepares the compound II 46 。
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 6.80 (d, J = 4.9 Hz, 1H), 6.61 (s, 1H), 4.38 (t, J = 7.1 Hz, 3H), 3.66 (t, J = 7.1 Hz, 3H), 3.28 (q, J = 8.0 Hz, 9H), 1.25 (t, J = 8.0 Hz, 13H). 13 C NMR (101MHz, DMSO-d 6 ) δ ppm: 162.08, 153.85, 151.08, 150.59, 146.64, 143.38, 140.68, 129.68, 128.05, 122.90, 119.88, 117.08, 116.15, 111.58, 101.85, 67.36, 66.20, 54.53, 53.55, 9.32. MS (MALDI-TOF): calculated for C 47 H 63 BBr 5 F 2 N 5 O 3 S 4[M-3Br+H], 1082.2191; found, 1083.2181。
Example 17
Photodynamic anti-human esophageal cancer Eca-109 cell proliferation experiment
Test cells: human esophageal cancer cells Eca-109.
Light source: XD-650AB type laser; SD2490 type laser power meter.
Test drug: 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 1 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_53
2 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indeno-tetralinAlkene (/ ->
Figure SMS_54
3 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (+.>
Figure SMS_55
4 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (+.>
Figure SMS_56
5 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N, N-triethyl) ethoxy) phenyl group]-4-boron-3 a,4 a-diaza-s-indenotetraene (+.>
Figure SMS_57
6 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 1 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 6 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 7 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 16 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 17 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethyl)Oxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 26 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-triethyl) ethoxy) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 36 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 38 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 47 ）。
Control drug: temopofen.
Photodynamic anti-tumor cell proliferation assay:
the Eca-109 cells in logarithmic growth phase were collected by centrifugation at 5X 10 4 A density of/mL was inoculated into a 96-well plate, and cultured overnight to adhere. The following day old medium was aspirated, and the compound was added for further incubation 24 h, followed by using a 650 nm laser (power density 18 mW/cm 2 The light dose is 6J/cm respectively 2 ) And (5) performing light treatment. Before the end of the incubation, 20. Mu.L of MTT solution at a concentration of 5 mg/mL was added to each well of 4. 4 h, and finally 150. Mu.L of DMSO was added, and the absorbance at 570. 570 nm was measured by a microplate reader. The experiment was repeated three times. The experimental results are shown in Table 1, and the result shows that the compound I 1-4 、I 6 、II 1-2 、II 6-7 、II 16-17 、II 26 、II 36 、II 38 、II 47 Has remarkable photodynamic anti-human esophageal cancer cell activity, which is superior to that of a control drug temoporfin, wherein the compound II 7 Photodynamic anti-tumor is most remarkable, and the inhibition rate is as high as 97.54%.
Inhibition of human esophageal cancer cell Eca-109 proliferation by compounds of Table 1
Figure SMS_58
/>
In comparison to the control drug temopofen, * P<0.05， ** P<0.01， *** P<0.001。
example 18
Photodynamic in vitro anti-gram positive and gram negative bacteria
Test strain: gram positive bacteria: staphylococcus aureus
Gram-negative bacteria: coli bacterium
Light source: XD-650AB type laser; SD2490 type laser power meter.
Test drug: 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 1 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene ]
Figure SMS_59
2 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (+.>
Figure SMS_60
3 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (+.>
Figure SMS_61
4 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (triphenylphosphine) ethyl) carbamoyl) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (+.>
Figure SMS_62
5 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N, N-triethyl) ethoxy) phenyl group]-4-boron-3 a,4 a-diaza-s-indenotetraene (+.>
Figure SMS_63
6 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]4-boron-containing material3a,4 a-diaza-s-indenotetraene (II) 1 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 6 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 7 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 16 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 17 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 26 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 36 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 38 ) The method comprises the steps of carrying out a first treatment on the surface of the 2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 47 ）。
Control drug: methylene Blue (MB).
Photodynamic antibacterial proliferation assay:
staphylococcus aureus and escherichia coli stored at-80 ℃ are respectively taken in 10 mL of LB liquid medium, and are subjected to shaking culture at constant temperature of 37 ℃ and 120 rpm for overnight. Inoculating loop to obtain bacterial liquid, inoculating to agar medium, culturing in 37 deg.C incubator overnight, inoculating single colony to 20 mL LB liquid medium, and culturing at constant temperature of 37 deg.C and 120 rpm Shaking culture 7 h, regulating bacterial liquid concentration to 2×10 with LB liquid culture medium 6 CFU/mL, and the CFU/mL and the drug diluent are added into a 24-well plate in a volume ratio of 1:1, and the operation process is carried out in the dark. Incubating the 24-well plate in a 37℃constant temperature shaking incubator at 120 rpm for 30 min, and irradiating with 650 nm laser (irradiation dose 20J/cm) 2 The optical power density was 440 mW/cm 2 ) Then, the bacterial liquid is diluted 10 by distilled water 4 Doubling, uniformly mixing, uniformly coating a flat plate with 1mL of each coating rod, standing for 10min, inversely placing the flat plate into a bacteria incubator at 37 ℃ for culturing overnight, and taking photos and recording the bacterial count by using a colony counter. Experimental results show that I 1-2 、I 6 、II 1-2 、II 6-7 、II 16-17 、II 26 、II 36 、II 38 、II 47 Has obvious photodynamic inhibition effect on both gram positive bacteria (staphylococcus aureus) and gram negative bacteria (escherichia coli), wherein the compound II 7 The photodynamic antibacterial effect is most obvious.
TABLE 2 proliferation of novel photodynamic antibody-outside bacteria
Figure SMS_64
Staphylococcus aureus group: in comparison with the control drug methylene blue, a P<0.05， aa P<0.01， aaa P<0.001；
coli group: in comparison with the control drug methylene blue, b P<0.05， bb P<0.01， bbb P<0.001。

Claims (6)

1. novel cationic condensed ring conjugated pyrrole derivatives and application thereof in the field of medicines, and are characterized by having the following structures (I) and (II):
Figure QLYQS_1
Wherein A is alkyl, alkyl containing N or O or S atoms, alkyl containing carbonylalkyl, amide bondAlkyl groups of various types containing alkyl groups, carboxyl (ester) groups, hydroxyl groups or amino side chains at the same time;
R 1 =
Figure QLYQS_2
, />
Figure QLYQS_3
, />
Figure QLYQS_4
, />
Figure QLYQS_5
, />
Figure QLYQS_6
the method comprises the steps of carrying out a first treatment on the surface of the Wherein y=cl, br, I;
x is H, cl, br, I,
Figure QLYQS_7
or->
Figure QLYQS_8
Wherein z=o, S, se;
R 2 , R 3 ,R 4 = -H, -F, -Cl, -Br, -I, -OH, -O(CH 2 ) m CH 3 , -(CH 2 ) m CH 3 , -(CH 2 ) m O(CH 2 ) n C(CH 3 ) 3 , -(CH 2 ) m O(CH 2 ) n CH(CH 3 ) 2 ，-(CH 2 ) m COOH, -(CH 2 ) m CH(CH 3 )COOH，-(CH 2 ) m C(CH 3 ) 2 COOH，-(CH 2 ) m OH, -(CH 2 ) m C 6 H 4 OH,-(CH 2 ) m CO(CH 2 ) n OH, -(CH 2 ) m O(CH 2 ) n OH, -(CH 2 ) m (OCH 2 CH 2 ) p OH, -(CH 2 ) m R 1 , -(CH 2 ) m C(CH 3 ) 2 R 1 , -(CH 2 ) m CH(CH 3 )R 1 , -(CH 2 ) m O(CH 2 ) n R 1 , -(CH 2 ) m S(CH 2 ) n R 1 , -(CH 2 ) m O(CH 2 ) m C(CH 3 ) 2 R 1 ，-(CH 2 ) m O(CH 2 ) m CH(CH 3 )R 1 ，-(CH 2 ) m S(CH 2 ) m C(CH 3 ) 2 R 1 , -(CH 2 ) m S(CH 2 ) m CH(CH 3 )R 1 ,-(CH 2 ) m (OCH 2 CH 2 ) p R 1 ，-(CH 2 ) m CO(CH 2 ) m C(CH 3 ) 2 R 1 , -(CH 2 ) m CO(CH 2 ) m CH(CH 3 )R 1 , -(CH 2 ) m CONH(CH 2 ) n R 1 , -(CH 2 ) m CONH(CH 2 ) n C(CH 3 ) 2 R 1 , -(CH 2 ) m CONH(CH 2 ) n CH(CH 3 )R 1 or amino acid derivatives, m=0-7, n=1-7, p=1-5.
2. The process according to claim 1, wherein
A is- (CH) 2 ) n -, -(CH 2 ) m C(CH 3 ) 2 -, -(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m O(CH 2 ) n -, -(CH 2 ) m S(CH 2 ) n -, -(CH 2 ) m O(CH 2 ) m C(CH 3 ) 2 -,-(CH 2 ) m O(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m S(CH 2 ) m C(CH 3 ) 2 -, -(CH 2 ) m S(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m (OCH 2 CH 2 ) p -，-(CH 2 ) m CO(CH 2 ) m C(CH 3 ) 2 -, -(CH 2 ) m CO(CH 2 ) m CH(CH 3 )-, -(CH 2 ) m CONH(CH 2 ) n -, -(CH 2 ) m CONH(CH 2 ) n C(CH 3 ) 2 -, -(CH 2 ) m CONH(CH 2 ) n CH(CH 3 )-, -R 5 (CH 2 ) m C(CH 3 ) 2 -, -R 5 (CH 2 ) m CH(CH 3 )-, -R 5 O(CH 2 ) n -, -R 5 O(CH 2 ) m C(CH 3 ) 2 -，-R 5 O(CH 2 ) m CH(CH 3 )-,-R 5 (OCH 2 CH 2 ) p -，-R 5 CO(CH 2 ) m CH(CH 3 )-, -R 5 CO(CH 2 ) m C(CH 3 ) 2 -, m=0-7, n=1-7, p=1-5;
Wherein R is 5 is-CH [ (CH) 2 ) m CH 3 ], -CH[(CH 2 ) n OCH 3 ], -CH[(CH 2 ) n OH], -CH[(CH 2 ) m COOH], -CH[(CH 2 ) m O(CH 2 ) n C(CH 3 ) 3 ], -CH[(CH 2 ) m COO(CH 2 ) m CH 3 ], -CH[(CH 2 ) m (OCH 2 CH 2 ) n CH 3 )], -CH[(CH 2 ) m CO(CH 2 ) n C(CH 3 ) 3 ], -CH[(CH 2 ) m CO(CH 2 ) n CH(CH 3 ) 2 ], -CH[(CH 2 ) m CONH(CH 2 ) n C(CH 3 ) 3 ] -CH((CH 2 ) m CONH[CH 2 ) n CH(CH 3 ) 2 ], m=0-7, n=1-7。
3. The amino acid derivative as claimed in claim 1, wherein the amino acid derivative is:
-(CH 2 ) m CONH(CH 2 ) n COOH, -(CH 2 ) m CONHCH(CH 3 )COOH,
-(CH 2 ) m CONH(CH 2 ) n CO(CH 2 ) p COOH, -(CH 2 ) m CONHCH[CH(CH 3 ) 2 ]COOH,
-(CH 2 ) m CONHCH[CH 2 CH(CH 3 ) 2 ]COOH, -(CH 2 ) m CONHCH[CH(CH 3 )CH 2 CH 3 ]COOH,
-(CH 2 ) m CONHCH(CH 2 C 6 H 5 )COOH, -(CH 2 ) m CON[(CH 2 ) n COOH] 2 ,
-(CH 2 ) m CONHCH(COOH)CH 2 COOH, m=0-7, n=1-7, p=1-5。
4. the novel cationic fused ring conjugated pyrrole derivatives (I) according to claim 1, wherein the compounds comprise the following compounds:
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 1 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 2 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 3 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 4 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]4-boron-containing material3a,4 a-diaza-s-indenotetraene (I) 5 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N, N-triethyl) ethoxy) phenyl group]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 6 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 7 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 8 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 9 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 10 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 11 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 12 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 13 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 14 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 15 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (N, N, N-triethyl) ethoxy)) Phenyl group]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 16 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (4- (2- (N, N-diethyl-N-methyl) ethoxy) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 17 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 18 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S) ]-4, 4-difluoro-8- [4- (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 19 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [4- (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (I) 20 ）。
5. The novel cationic condensed ring conjugated pyrrole derivatives (II) according to claim 1, wherein the compounds comprise the following compounds:
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 1 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 2 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 3 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2-quinolinyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 4 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (triphenylphosphonium) ethyl) carbamoyl) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 5 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 6 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 7 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 8 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 9 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 10 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 11 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 12 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ] ]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 13 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 14 ）；
2,3, 5, 6-bis [ 2-thienyl-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 15 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-dinitrogenHetero-s-indenotetraene (II) 16 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 17 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (pyridinyl) ethyl) carbamoyl) phenyl)]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 18 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 19 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ] ]Thiophene (S)]-4, 4-difluoro-8- [ (3, 5-bis (2- (triphenylphosphonium) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 20 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 21 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 22 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 23 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 24 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 25 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-bis (2- (N, N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 26 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 27 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 28 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 29 ）；
2,3, 5, 6-bis [2- (2-bromo-thienyl) -thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 30 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 31 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 32 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (pyridinyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 33 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (quinolinyl) ethyl) carbamoyl) phenyl ] ]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 34 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 35 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 36 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 37 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 38 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 39 ）；
2,3, 5, 6-bis [ thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 40 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N, N-triethyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 41 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ] ]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (N, N-diethyl-N-methyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 42 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (pyridinyl) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 43 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (quinolinyl) ethyl) carbamoyl) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 44 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [ (3, 4, 5-tris (2- (triphenylphosphine) ethyl) carbamoyl) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 45 ）
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-triethyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 46 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (N, N-diethyl-N-methyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 47 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (pyridinyl) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 48 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ] ]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (quinolinyl) ethoxy) phenyl ]]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 49 ）；
2,3, 5, 6-bis [ 2-bromo-thiophene [3,2-b ]]Thiophene (S)]-4, 4-difluoro-8- [3,4, 5-tris (2- (triphenylphosphonium) ethoxy) phenyl]-4-boron-3 a,4 a-diaza-s-indenotetraene (II) 50 ）。
6. The novel cationic condensed ring conjugated pyrrole derivatives (I) and (II) as claimed in claim 1 can be used as photosensitive drugs or reagents for diagnosing and treating microbial infection, tumors, macular degeneration of retina, actinic keratosis, nevus rubrum, condyloma acuminatum and other diseases, and can be used as fluorescent dyes and reagents for near infrared fluorescence imaging, fluorescent marking or photoelectric material fields.
CN202310190932.6A 2023-03-02 2023-03-02 Novel cationic condensed ring conjugated pyrrole derivative and application thereof in medicine field Pending CN116410214A (en)

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