Purpurin analog for use in photodynamic therapy

Abstract

The present invention relates to purpurin analogs and pharmaceutically acceptable salts thereof, and to compositions comprising purpurin analogs and pharmaceutically acceptable salts thereof. Purpurin analogs and pharmaceutically acceptable salts thereof are suitable for use, for example, in photodynamic therapy, cell luminescence therapy and photodynamic diagnostics for the treatment or detection of tumors or for antiviral treatment. The present invention also relates to the use of purpurin analogs and pharmaceutically acceptable salts thereof in the manufacture of phototherapy agents or photodiagnostic agents, and to methods for photodynamic therapy, cell luminescence therapy or photodynamic diagnostics for, for example, in the treatment or detection of tumors or for antiviral treatment. [Formula 1] JPEG2026519098000056.jpg66162

Claims

[Claim 1] A compound of formula (I) or a complex of formula (II), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, -R １ is -CH ２ OR ２ 、-CH ２ SR ２ 、-CH ２ S(O)R ２ 、-CH ２ S(O) ２ R ２ 、-CH ２ N(R ２ ) ２ 、-R ２ 、-C(O)-OR ３ 、-C(O)-SR ３ 、-C(O)-N(R ３ ) ２ 、-C(S)-OR ３ 、-C(S)-SR ３ or -C(S)-N(R ３ ) ２ selected from; -R ２ is, independently of each other, -H, -C(O)R ４ , -C(O)-OR ４ , -C(O)-SR ４ , -C(O)-N(R ４ ), -C(S)-OR ２ , -C(S)-SR ４ , -C(S)-N(R ４ ), -R ４ -H, -R ２ , -R α -R β , -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O) ２ R β , -R α -NH ２ , -R α -NH(R β ), -R α -N(R β ), -R ２ , -R α -X, -R α -[N(R ５ ), -R ３ -[P(R α ), -R ５ ), -R ３ -[R α , -R ７ -[N(R α ), -R ５ ), -R ２ (R ５’ ), -R α -[P(R ５ ), -R ２ (R ５’ ), or -R α -[R ７’ and is selected from; -R ３ and -R ４ are each independently, -H, -R α -H, -R β , -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O) ２ R β , -R α -NH ２ , -R α -NH(R β ), -R α -N(R β ) ２ , -R α -X, -R α -[N(R ５ ) ３ Y, -R α -[P(R ５ ) ３ Y, -R α -[R ７ Y, -R α -[N(R ５ ) ２ (R ５’ )], -R α -[P(R ５ ) ２ (R ５’ )] or R α -[R ７’ and are selected from; -R α - are independent of each other, C １ -C ４２ Selected from alkylene groups, the alkylene group is one or more C １ -C ４ Alkyl, C １ -C ４ The alkylene group may be optionally substituted with a haloalkyl or halo group, and one or more carbon atoms in the alkylene group skeleton may be optionally substituted with a heteroatom or group independently selected from O, S, NH, or NMe; -R β Each of these is independently a saturated or unsaturated hydrocarbyl group, the hydrocarbyl group may be linear or branched, or a cyclic group, or may contain a cyclic group, the hydrocarbyl group may optionally be substituted, and the hydrocarbyl group may optionally contain one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -R ５ Each of them is independent of C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, -(CH ２ CH ２ O) ｎ -H, -(CH ２ CH ２ O) ｎ -CH ３ , phenyl or C ５ -C ６ Selected from heteroaryls, in which case the phenyl or C ５ -C ６ A heteroaryl is optional, with one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ It may be substituted by the element; -R ５’ C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, -(CH ２ CH ２ O) ｎ -H, -(CH ２ CH ２ O) ｎ -CH ３ , phenyl or C ５ -C ６ Selected from heteroaryls, each being -CO ２ － Substituted with, in which case, the phenyl or C ５ -C ６ The heteroaryl may optionally also contain one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ It may be substituted by the element; -R ６ is, -OR ２ , -N(R ２ ) ２ , -SR ２ , -S(O)R ２ , -S(O) ２ R ２ , or -X selected; -R ７ is 1 or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ Substituted arbitrarily by the base - [NC ５ H ５ ] and; -R ７’ is, -CO ２ － Replaced by and optionally one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ Substituted with -[NC ５ H ５ ] and; -R ９ is -H, -C(O)R ４ -C(O)-OR ４ -C(O)-SR ４ -C(O)-N(R ４ ) ２ -C(S)-OR ４ -C(S)-SR ４ -C(S)-N(R ４ ) ２ -R α -H, -R β -R α -R β -R α -OH, -R α -OR β -R α -SH, -R α -SR β -R α -S(O)R β -R α -S(O) ２ R β -R α -NH ２ -R α -NH(R β )、-R α -N(R β ) ２ -R α -X、-R α -[N(R ５ ) ３ Y、-R α -[P(R ５ ) ３ Y、-R α -[R ７ Y、-R α -[N(R ５ ) ２ (R ５’ )]、-R α -[P(R ５ ) ２ (R ５’ )]または-R α -[R ７’ and is selected from; -R ２６ is, -CH ２ R ６ ien-CH ２ CH ３ ien-CH=CH ２ or selected from -C(O)H; -R ２９ - is -N(R ９ )-,-N(OR ９ ) -, -O-, -S- or -Se- are selected; n is 1, 2, 3, 4, 5, or 6; X is a halo group; Y is the opposite anion; Z is a countercation; and M ２＋ It is a metal cation; However, if the compound of formula (I) or the complex of formula (II) is -R α - [P(R ５ ) ３ ]Y, -R α - [R ７ ]Y, -R α - [P(R ５ ) ２ (R ５’ ) ] or -R α - [R ７’ The compound or complex having the condition that it contains at least one group selected from ]. [Claim 2] Each -R α - became independent, C １ -C ６ A compound or complex according to claim 1, selected from alkylenes. [Claim 3] -R ６ However, -O-C(O)R １４ , -N(R １２ )-C(O)R １４ , -O-C(O)-OR １４ , -N(R １２ )-C(O)-OR １４ , -O-C(O)-N(R １２ ) (Caution １４ ), or -N(R １２ )-C(O)-N(R １２ ) (Caution １４ ) selected from; -R １２ is hydrogen or C １ -C ３ Selected from alkyl groups; -R １４ However, -R α - [P(R ５ ) ３ ]Y, -R α - [R ７ ]Y, -R α - [P(R ５ ) ２ (R ５’ )], or -R α - [R ７’ Selected from ]; each -R ５ C １ -C ４ Selected from alkyl or phenyl, where the phenyl is optionally 1, 2, or 3 C １ -C ４ Alkyl or C １ -C ４ Substituted with an alkoxy group; each -R ５’ However, C １ -C ４ Selected from alkyl or phenyl, respectively -CO ２ － Substituted with, in which case the phenyl is optionally further with 1, 2 or 3 C １ -C ４ Alkyl or C １ -C ４ Substituted with an alkoxy group; -R ７ is C 1, 2 or 3 １ -C ４ Alkyl or C １ -C ４ -[NC] optionally substituted with an alkoxy group ５ H ５ ] is; -R ７’ is, -CO ２ － Replaced with, and optionally 1, 2, or 3 C １ -C ４ Alkyl or C １ -C ４ -[NC] substituted with an alkoxy group ５ H ５ ] is; -R α - is C １ -C １２ A compound or complex according to any of the prior claims, selected from an alkylene group, wherein 1, 2, 3, or 4 carbon atoms in the skeleton of the alkylene group may be independently substituted with heteroatoms or groups selected from O, S, NH, or NMe; and Y is a counterion. [Claim 4] -R １ is -C(O)-OR ３ And, -R ３ ga-R β And, -R β C １ -C ４ A compound or complex according to any of the prior claims, wherein the compound is an alkyl group. [Claim 5] The aforementioned compound or complex 【Chemistry 2】 【change】 【change】 The compound or complex according to claim 1, which is a metal cation complex thereof, or a pharmaceutically acceptable salt thereof. [Claim 6] A compound or complex according to any of the prior claims, for use in pharmaceuticals. [Claim 7] A compound or complex according to any of the prior claims, for use in photodynamic therapy or cell luminescence therapy. [Claim 8] Atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacteria or parasitic infections; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or herpes zoster infections; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; hyperplasia of benign or malignant cells or A compound or complex according to any of the prior claims for use in the treatment of cancers of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectal, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas. [Claim 9] A compound or complex according to any of the prior claims, for use in the treatment of a disease characterized by benign or malignant cell overgrowth or by areas of angiogenesis. [Claim 10] A compound or complex according to any of the prior claims, for use in the treatment of benign or malignant tumors. [Claim 11] A compound or complex according to any of the prior claims for use in the treatment of cancers of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile duct, intestine, colon, colorectal, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas. [Claim 12] A compound or complex according to any of the prior claims, for use in photodynamic diagnostics. [Claim 13] The compound or complex according to any of the prior claims, wherein the compound is suitable for administration before the administration of radiation. [Claim 14] The compound or complex according to claim 13, wherein the radiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm. [Claim 15] A pharmaceutical composition comprising a compound or complex described in any of the prior claims and a pharmaceutically acceptable carrier or diluent. [Claim 16] The pharmaceutical composition according to claim 15, further comprising polyvinylpyrrolidone. [Claim 17] The pharmaceutical composition according to claim 15 or 16, further comprising an immune checkpoint inhibitor. [Claim 18] The pharmaceutical composition according to claim 17, wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, semiprimab, atezolizumab, avelumab, durvalumab, or ipilimumab. [Claim 19] The pharmaceutical composition according to any one of claims 15 to 18, wherein the pharmaceutical composition is in a form suitable for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intratumoral, intraarticular, intraabdominal, intracranial and epidural), transdermal, respiratory (aerosol), rectal, vaginal, or topical (including cheek, mucous membrane and sublingual) administration. [Claim 20] The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is in a form suitable for oral or parenteral administration. [Claim 21] A combination of medications or a kit, (a) A compound or complex according to any one of claims 1 to 14, (b) The combination drug or kit comprising a co-drug that is an immune checkpoint inhibitor. [Claim 22] The combination of pharmaceuticals or kit according to claim 21, wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, semiprimab, atezolizumab, avelumab, durvalumab, or ipilimumab.

Images