Compounds containing acyclic N-N bonds for phototherapy
View Patent ↗The invention relates generally to optical agents for biomedical applications, including phototherapy. The invention includes optical agents, and related therapeutic methods, comprising compounds with an acyclic N—N bond having at least one aromatic and/or heterocyclic aromatic group providing phototherapeutic agents, including Type 1 phototherapeutic agents. In some embodiments, for example, the invention provides compounds for phototherapeutic methods having one or more photolabile acyclic N—N bonds capable of undergoing photoactivated cleavage to produce reactive species, such as radicals, ions, etc., that achieve a desired therapeutic effect, such as selective and/or localized tissue damage and/or cell death.
1. A method of performing a phototherapy procedure, the method comprising:
(i) administering to a patient in need thereof, a therapeutically effective amount of a phototherapeutic composition to a target tissue, wherein, the phototherapeutic composition comprises a compound of formula (FX1) or (FX2); and
(ii) exposing the administered phototherapeutic composition to electromagnetic radiation having wavelengths selected over the range of 350 nm and 1300 nm sufficient to result in injury or death to cells at the target tissue
wherein:
each of L 1 , L 2 , L 3 and L 4 , if present, is independently C 1 -C 10 alkylene, C 3 -C 10 cycloalkylene, C 2 -C 10 alkenylene, C 3 -C 10 cycloalkenylene, C 2 -C 10 alkynylene, ethenylene, ethynylene, phenylene, 1-aza-2,5-dioxocyclopentylene, —(CH 2 CH 2 O) b —, —(CHOH) a —, or 1,4-diazacyclohexylene;
each of W 1 , W 2 , W 3 and W 4 is independently a single bond, a double bond, —(CH 2 ) c —, —(HCCH) c —, —O—, —S—, —SO—, —SO 2 —, —SO 3 —, —OSO 2 —, —NR 5 —, —CO—, —COO—, —OCO—, —OCOO—, —CONR 6 —, —NR 7 CO—, —OCONR 8 —, —NR 9 COO—, —NR 10 CONR 11 —, or —NR 12 CSNR 13 —;
each of R 1 , R 2 , R 3 and R 4 is independently hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 5 -C 30 aryl, C 5 -C 30 heteroaryl, C 1 -C 20 acyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 20 alkylaryl, C 1 -C 6 alkoxycarbonyl, halo, halomethyl, dihalomethyl, trihalomethyl, —CN, —CO 2 R 14 , —CONR 15 R 16 , —COR 17 , —NO 2 , —SOR 18 , —OSR 19 , —SO 2 R 20 , —SO 2 OR 21 , —SO 2 NR 22 R 23 , —PO 3 R 24 R 25 , —OR 26 , —SR 27 , —NR 28 R 29 , —NR 30 COR 31 , —(CHOH) a R 32 , —(CH 2 CH 2 O) b R 33 , —CH(R 34 )CO 2 H, —CH(R 35 )NH 2 , or wherein at least one of: R 1 , R 2 , W 1 , W 2 , and L 1 and L 2 , if present; and R 3 , R 4 , W 3 , W 4 , and L 3 and L 4 , if present; together with the atoms to which they are attached combine to form one or more alicyclic 4, 5, 6, 7, 8 or 9 membered rings;
wherein at least one of R 1 , R 2 , R 3 and R 4 is C 5 -C 30 aryl or C 5 -C 30 heteroaryl, or wherein at least one of: R 1 , R 2 , W 1 , W 2 , and L 1 and L 2 , if present, and R 3 , R 4 , W 3 , W 4 , and L 3 and L 4 , if present; together with the atoms to which they are attached combine to form a C 5 -C 30 aryl or C 5 -C 30 heteroaryl;
wherein R 1 -R 4 do not include an azide group;
each of a and b is independently an integer selected from the range of 1 to 100;
each c is independently an integer selected from the range of 1 to 10;
each of e, f, g and j is independently 0 or 1;
each of R 5 -R 31 is independently hydrogen, C 1 -C 20 alkyl, C 5 -C 30 aryl or C 5 -C 30 heteroaryl;
each of R 32 and R 33 is independently hydrogen or C 1 -C 10 alkyl;
each of R 34 and R 35 is independently a side chain residue of a natural α-amino acid.
2. The method of claim 1 , wherein the compound absorbs the electromagnetic radiation having wavelengths selected over the range of 350 nanometers to 1300 nanometers.
3. The method of claim 1 , wherein R 1 is C 5 -C 30 aryl or C 5 -C 30 heteroaryl, and R 2 , R 3 and R 4 are independently hydrogen, C 1 -C 20 alkyl, C 5 -C 30 aryl, C 5 -C 30 heteroaryl, a or wherein R 2 is C 5 -C 30 aryl or C 5 -C 30 heteroaryl, and R 1 , R 3 and R 4 are independently hydrogen, C 1 -C 20 alkyl, C 5 -C 30 aryl, C 5 -C 30 heteroaryl, or or wherein R 3 is C 5 -C 30 aryl or C 5 -C 30 heteroaryl, and R 1 , R 2 and R 4 are independently hydrogen, C 1 -C 20 alkyl, C 5 -C 30 aryl, C 5 -C 30 heteroaryl, or wherein R 4 is C 5 -C 30 aryl or C 5 -C 30 heteroaryl, and R 1 , R 2 and R 3 are independently hydrogen, C 1 -C 20 alkyl, C 5 -C 30 aryl, C 5 -C 30 heteroaryl.
4. The method of claim 1 , wherein at least one of R 1 , R 2 , R 3 and R 4 is independently a group corresponding to benzene, naphthalene, naphthoquinone, diphenylmethane, fluorene, anthracene, anthraquinone, phenanthrene, tetracene, naphthacenedione, pyridine, quinoline, isoquinoline, indole, isoindole, pyrrole, imidazole, oxazole, thiazole, pyrazole, pyrazine, pyrimidine, purine, benzimidazole, furan, benzofuran, dibenzofuran, carbazole, acridine, acridone, phenanthridine, thiophene, benzothiophene, dibenzothiophene, xanthene, xanthone, flavone, coumarin, azulene, azaazulene or anthracycline.
5. The method of claim 1 ,
wherein each of R 1 , R 2 , R 3 , and R 4 Ar 1 , Ar 2 , Ar 3 and Ar 4 is independently a group corresponding to benzene, naphthalene, naphthoquinone, diphenylmethane, fluorene, anthracene, anthraquinone, phenanthrene, tetracene, naphthacenedione, pyridine, quinoline, isoquinoline, indole, isoindole, pyrrole, imidazole, oxazole, thiazole, pyrazole, pyrazine, pyrimidine, purine, benzimidazole, furan, benzofuran, dibenzofuran, carbazole, acridine, acridone, phenanthridine, thiophene, benzothiophene, dibenzothiophene, xanthene, xanthone, flavone, coumarin, azulene, azaazulene or anthracycline; and wherein R 1 -R 4 Ar 1 -Ar 4 do not include an azide group.
6. The method of claim 1 , wherein at least one of R 1 -R 4 is independently a group corresponding to naphthalene, diphenylmethane, fluorene, anthracene, phenanthrene, tetracene, naphthoquinone, anthraquinone, naphthacenedione, azulene, azaazuleneor anthracycline.
7. The method of claim 1 , wherein at least one of R 1 -R 4 is independently a group corresponding to pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, purine, acridine, acridone, or phenanthridine.
8. The method of claim 1 , wherein at least one of R 1 -R 4 is independently a group corresponding to pyrrole, pyrazole, indole, isoindole, imidazole, oxazole, thiazole, purine, benzimidazole, or carbazole.
9. The method of claim 1 , wherein at least one of R 1 -R 4 is independently a group corresponding to furan, oxazole, benzofuran, dibenzofuran, xanthene, xanthone, flavone, or coumarin.
10. The method of claim 1 , wherein at least one of R 1 -R 4 is independently a group corresponding to thiophene, thiazole, benzothiophene, or dibenzothiophene.
11. The method of claim 1 , wherein said compound is of the formula (FX21), (FX22), (FX23), (FX24) or (FX25):
12. The method of claim 1 , wherein said procedure is a Type 1 phototherapy procedure.
13. The method of claim 1 , wherein exposing the administered phototherapeutic agent to the electromagnetic radiation cleaves an N—N bond of the compound.
14. The method of claim 1 , further comprising contacting the target tissue of the subject with the administered phototherapeutic agent.
15. The method of claim 1 , wherein the target tissue is a colon, prostate, gastric, esophageal, uterine, endometrial, pancreatic, breast, cervical, brain, skin, gallbladder, lung, throat, kidney, testicular, prostate, gastric, or ovary tissue.
16. The method of claim 1 , wherein the target tissue is cancerous tissue or a tumor.
17. The method of claim 1 for use in treatment of cancer, a cancer-associated disorder, inflammation or an inflammation-associated disorder.