CN114478396A - Dihydropyrimidine (thio) ketone compound and preparation method and application thereof - Google Patents
Dihydropyrimidine (thio) ketone compound and preparation method and application thereof Download PDFInfo
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- CN114478396A CN114478396A CN202210267572.0A CN202210267572A CN114478396A CN 114478396 A CN114478396 A CN 114478396A CN 202210267572 A CN202210267572 A CN 202210267572A CN 114478396 A CN114478396 A CN 114478396A
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- -1 Dihydropyrimidine (thio) ketone compound Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 230000006378 damage Effects 0.000 claims abstract description 17
- 230000006750 UV protection Effects 0.000 claims abstract 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000003368 amide group Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000003172 aldehyde group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 208000027418 Wounds and injury Diseases 0.000 claims description 5
- 208000014674 injury Diseases 0.000 claims description 5
- 229910052717 sulfur Chemical group 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- NPSJHQMIVNJLNN-UHFFFAOYSA-N 2-ethylhexyl 4-nitrobenzoate Chemical group CCCCC(CC)COC(=O)C1=CC=C([N+]([O-])=O)C=C1 NPSJHQMIVNJLNN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 230000004224 protection Effects 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims 1
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- 235000021436 nutraceutical agent Nutrition 0.000 claims 1
- 230000005855 radiation Effects 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 5
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
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- 125000000217 alkyl group Chemical group 0.000 description 7
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 7
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KQJQICVXLJTWQD-UHFFFAOYSA-N N-Methylthiourea Chemical compound CNC(N)=S KQJQICVXLJTWQD-UHFFFAOYSA-N 0.000 description 2
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methylthiourea Natural products CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
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- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
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- ADPUQRRLAAPXGT-UHFFFAOYSA-M sodium;2-formylbenzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC=C1C=O ADPUQRRLAAPXGT-UHFFFAOYSA-M 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
- C09D5/32—Radiation-absorbing paints
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Ophthalmology & Optometry (AREA)
- Toxicology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Materials Engineering (AREA)
- Wood Science & Technology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses dihydropyrimidine (thio) ketone compounds and a preparation method and application thereof, wherein the compounds are shown as a formula (I). The compound has stronger effect of resisting ultraviolet radiation damage, and can be applied to preparation of ultraviolet damage resisting compoundsOr an ultraviolet protection product.
Description
Technical Field
The invention relates to dihydropyrimidine (thio) ketone compounds or medicinal salts thereof, a preparation method thereof, a pharmaceutical composition containing the same and application thereof.
Background
Most of the ultraviolet rays in nature come from sunlight and can be divided into UV-A (320-400nm), UV-B (280-320nm) and UV-C (200-280nm) according to the wavelength bands. UV-C is absorbed by the ozone layer in the atmosphere, only a very small part reaches the earth's surface, the UV exposed in the environment is mainly UV-A (97%) and UV-B (3%), the shorter the wavelength the stronger the damage capability, so UV-B is the main band causing ultraviolet damage, and the skin and the ocular surface are the two main sites of damage. The damage caused by ultraviolet rays to the skin mainly comprises acute phototoxic reaction (erythema), often accompanied by skin fading and burning pain; a large amount of melanin is deposited in the epidermal layer (blackening); collagen and elastin degradation and denaturation (skin aging), and the like. Unlike the skin, the ocular surface cornea lacks the protection of the thicker epithelial layer, stratum corneum and melanocytes, and is therefore more fragile.
UV wavelength determines its penetration ability, and thus the UV damaged ocular tissue: the cornea absorbs predominantly UV-B radiation below 300 nm; the lens absorbs mainly UV-a radiation below 370 nm. The cornea and lens are the major ocular tissues affected by UV radiation, and a small amount of UV radiation can penetrate the retina to impair photoreceptor cell and pigment epithelial function. Excessive UV radiation can cause severe eye diseases-pterygium, keratoconjunctivitis, cataracts, macular degeneration, retinal burns, snow blindness, and the like. Meanwhile, the damage of the ozone layer, strong UV radiation in areas such as plateaus and low latitudes, strong UV reflection in places such as snowfields and seasides, special industries such as electric welding and the like, and UV radiation generated in the use process of modern electronic products increase the risk of UV exposure of eyes in modern life.
Deep research on UV damage mechanism and development of related medicines or protection technologies have important significance for caring eyes and protecting skin health.
Disclosure of Invention
The invention aims to provide a compound shown in formula (I) or a medicinal salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof.
The compound of the general formula (I) of the invention, or a pharmaceutically acceptable salt thereof;
wherein, in formula (I):
r1 is selected from optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group; the substituent is a sulfonic group;
r2 is one or more of hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, aldehyde group, sulfonic group, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group; n is 0 or an integer of 1 to 5; the substituent is a sulfonic group; when n is greater than 1, R2 are the same or different;
r3 is selected from hydrogen, C1-C10 alkyl or C1-C10 alkylamide;
r4 is selected from hydrogen, C1-C10 alkyl or C1-C10 alkylamido;
r5 is selected from C1-C10 alkyl;
x is selected from oxygen or sulfur;
at least one sulfonic acid group is contained in R1 and R2;
or R1 and R2 do not contain sulfonic acid groups, but R1 and R2 at least contain one C6-C10 alkyl ester group or at least contain one C6-C10 alkyl amide group.
In some specific embodiments, n is 0 or an integer from 1 to 3; more preferably n is 0, 1 or 2.
In some embodiments, R2 is optionally selected from one or more of hydrogen, hydroxyl, carboxyl, amino, nitro, aldehyde, sulfonic acid, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester, or optionally substituted C1-C10 alkyl amide.
In some embodiments, no sulfonic acid group is present in R1 and R2, but at least one of R1 and R2 comprises a hexanoloxy group, a heptanoloxy group, an octanoyloxy group, an isooctanoyloxy group, a trimethylcyclohexyloxy group, a menthoxyacyl group, a hexylamido group, a heptylamido group, an octylamido group, an isooctylamido group, a trimethylcyclohexylamido group, a menthylamido group, or the like.
In a more specific embodiment, R1 represents
R2 represents hydrogen.
In another specific embodiment, R1 represents a methoxyacyl group, and R2 represents a sulfonic acid group.
In another embodiment, R1 represents a 2-ethylhexyl ester group and R2 represents hydrogen.
In some preferred embodiments, in said formula (I): r3 represents hydrogen, C1-C6 alkyl or C1-C6 alkanoyl; in some more particular embodiments, R3 represents hydrogen, methyl, or ethyl; in a particular embodiment, R3 represents hydrogen.
In some preferred embodiments, in said formula (I): r4 represents hydrogen, C1-C6 alkyl or C1-C6 alkanoyl; in some more particular embodiments, R4 represents hydrogen, methyl, or ethyl; in a particular embodiment, R4 represents methyl.
In some preferred embodiments, in said formula (I): r5 represents C1-C6 alkyl; in some more particular embodiments, R5 represents methyl or ethyl; in a particular embodiment, R5 represents methyl.
In some preferred embodiments, in said formula (I): x represents oxygen or sulfur; in a particular embodiment, X represents sulfur.
In some embodiments, the present invention also provides a compound of formula (I-a), or a pharmaceutically acceptable salt thereof;
wherein R1 in the formula (I-a) is selected from an optionally substituted C1-C10 alkyl ester group or an optionally substituted C1-C10 alkyl amide group; the substituent is a sulfonic group; r2 is one or more of hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, aldehyde group, sulfonic group, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group; n is 0 or an integer of 1 to 5; the substituent is a sulfonic group; when n is greater than 1, R2 are the same or different;
at least one sulfonic acid group is contained in R1 and R2;
or R1 and R2 do not contain sulfonic acid groups, but R1 and R2 at least contain one C6-C10 alkyl ester group or at least contain one C6-C10 alkyl amide group.
In some specific embodiments, n is 0 or an integer from 1 to 3; more preferably n is 0, 1 or 2.
In some embodiments, R2 is optionally selected from one or more of hydrogen, hydroxyl, carboxyl, amino, nitro, aldehyde, sulfonic acid, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester, or optionally substituted C1-C10 alkyl amide.
In some embodiments, no sulfonic acid group is present in R1 and R2, but at least one of R1 and R2 comprises a hexanoloxy group, a heptanoloxy group, an octanoyloxy group, an isooctanoyloxy group, a trimethylcyclohexyloxy group, a menthoxyacyl group, a hexylamido group, a heptylamido group, an octylamido group, an isooctylamido group, a trimethylcyclohexylamido group, a menthylamido group, or the like.
In a more specific embodiment, R1 represents
R2 represents hydrogen.
In another specific embodiment, R1 represents a methoxyacyl group, and R2 represents a sulfonic acid group.
In another embodiment, R1 represents a 2-ethylhexyl ester group and R2 represents hydrogen.
The invention also provides a compound represented by any one of the following structures or a pharmaceutically acceptable salt thereof:
in another aspect, the present invention also relates to a process for the preparation of a compound of formula (I) as defined above:
wherein X, R1, R2, R3, R4 and R5 are as previously described.
In some embodiments, the present invention also provides methods for preparing specific compounds selected from reaction scheme one or reaction scheme two:
the first reaction scheme is as follows:
the second reaction scheme is as follows:
the invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of ultraviolet injury resistant or ultraviolet ray resistant products.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing products for resisting corneal ultraviolet injury or skin ultraviolet injury.
The products of the present invention may include, but are not limited to, pharmaceuticals, medical devices, health products, chemical coatings or skin care products, and the like.
The compounds or compositions of the present invention may be prepared in any pharmaceutically acceptable dosage form, for example, in a formulation suitable for any mode of intraocular, topical, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, topical, subcutaneous, intralipid, intraarticular, intraperitoneal or intrathecal administration.
In a preferred embodiment, the compound or composition of the present invention is in the form of drops, paste, liniment, spray, gel, patch, aqua, tablet, granule, oral liquid, capsule, drop pill, enema, film or injection.
The compound can be used alone or in combination with other products, and provides a new product for treating the diseases.
Unless otherwise specified, the groups according to the invention are defined as follows:
"optionally substituted" includes substituted or unsubstituted, and when substituted, the substituent may be one or more. When substituted, it is understood that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and may be synthesized by techniques and methods of the art from available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
"C1-C10 alkyl ester group" means
Wherein R6 is C1-C10 alkyl.
"C1-C10 Alkylamido" means
Wherein R7 is C1-C10 alkyl.
"alkyl" means a saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, including straight chain alkyl, branched chain alkyl, cycloalkyl, and cycloalkyl groups with straight or/and branched chain alkyl groups, and reference to a numerical range in this application, such as "1 to 10", means that the group, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and the like, up to and including 10 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, octyl, isooctyl, trimethylcyclohexyl, menthyl and the like. Alkyl groups may be substituted or unsubstituted. Menthyl radical representation
The resulting radical.
"alkoxy" means-O- (unsubstituted alkyl) or-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, hexyloxy, cyclohexyloxy, heptyloxy, octyloxy, isooctyloxy, trimethylcyclohexyloxy, menthyloxy and the like.
For chiral problems involved in the molecule, the compounds may be chiral compounds or racemates.
The invention has the beneficial effects that: the compound has better water solubility or fat solubility, strong ultraviolet radiation absorbing capacity and stronger ultraviolet radiation resisting effect.
Drawings
FIG. 1 is of DT1H-NMR；
FIG. 2 shows DT13C-NMR；
FIG. 3 is a diagram of a DS1H-NMR；
FIG. 4 is a diagram of a DS13C-NMR；
FIG. 5 is DO1H-NMR；
FIG. 6 is DO13C-NMR；
FIG. 7 is the UV absorption spectra of DT and DS in PBS solution (20. mu.g/mL);
FIG. 8 shows the cytotoxic effect of DT and DS after 24h incubation with HCE-2 cells, respectively;
FIG. 9 shows the effect of different concentrations of DT or DS (0.1, 0.2, 0.5mg/mL) against UV-B induced HCE-2 cell damage (Control group did not receive UV-B radiation, the remaining groups received UV-B radiation; UV-B: 302nm, 0.2J/cm2)；
FIG. 10 is Calcein AM/PI double staining: control group no UV-B radiation; the other groups were subjected to UVB irradiation, the UVB group was irradiated only, and the DT0.2 and DS0.2 groups were pretreated with 0.2mg/mL DT or DS, respectively, simultaneously with the UVB irradiation (UVB: 302nm, 0.1J/cm)2)。
Detailed Description
The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Example 1 preparation of compound DT:
wherein: (a)20 mol% MgCl2,AcOH,100℃；(b)NaOH；(c)Taurine,HATU,DIEA,DMF.
(1) Methyl acetoacetate 1(580mg, 5.0mmol), benzaldehyde 2(530mg, 5.0mmol), N-methylthiourea 3(675mg, 7.5mmol), anhydrous magnesium sulfate (95mg, 1.0mmol) and glacial acetic acid (5.0mL) are subjected to tube sealing reaction at 100 ℃ for 2 hours, after the reaction is finished, the reaction solution is cooled, poured into crushed ice, stirred vigorously and filtered, and the crude product is washed by water and ether to obtain 1.2g of a white solid, namely a compound 4. HRMS calcd for C14H17N2O2S[M+H]+277.1005,found277.1011；1H NMR(400MHz,DMSO-d6):δ9.87(d,J＝4.8Hz,1H),7.36-7.18(m,5H),5.21(d,J＝4.8Hz,1H),3.64(s,3H),3.48(s,3H),2.53(s,3H)；13C NMR(100MHz,DMSO-d6):δ150.4,140.5,126.5,121.5,110.8(2C),110.0,108.7(2C),92.0,49.6,49.1,36.8,20.9.
(2) Compound 4(552mg, 2.0)mmol) was added to a mixed solution of methanol (5mL) and 1N aqueous sodium hydroxide solution (10mL) under reflux for 1 hour, cooled to room temperature and poured into crushed ice, acidified with 1N aqueous hydrochloric acid solution, filtered and dried to obtain 430mg of a white solid, i.e., Compound 5. HRMS calcd for C14H17N2O2S[M+H]+263.0849,found263.0850；1H NMR(400MHz,DMSO-d6):δ12.56(s,1H),9.78(d,J＝3.6Hz,1H),7.36-7.31(m,2H),7.28-7.20(m,3H),5.21(d,J＝3.6Hz,1H),3.47(s,3H),2.52(s,3H)；13C NMR(100MHz,DMSO-d6):δ178.1,167.1,147.4,142.2,128.6(2C),127.6,126.0(2C),106.2,52.3,36.1,16.2.
(3) Dissolving compound 5(500mg, 1.91mmol), taurine (356mg, 2.85mmol) and HATU (1.1g, 2.89mmol) in DMF (10mL), adding DIEA (660. mu.L, 3.80mmol) dropwise into the above solution, stirring at room temperature for 2 hr, concentrating under reduced pressure after reaction, preparing white solid (400mg, 56.8%) from liquid phase, namely compound DT,1H-NMR and13the C-NMR is shown in FIGS. 1 and 2. ESI-MS: [ M + H ]]+m/z 370.1；1HNMR(400MHz,DMSO-d6):δ9.44(d,J＝3.6Hz,1H),7.97(t,J＝5.2Hz,1H),7.36-7.30(m,2H),7.29-7.22(m,1H),7.21-7.16(m,2H),7.08(br s,4H),5.12(d,J＝4.0Hz,1H),3.42(s,3H),3.41-3.33(m,2H),2.58-2.51(m,2H),2.17(s,3H)；13C NMR(100MHz,DMSO-d6):δ177.8,165.9,142.1,136.6,128.5,127.5,125.9,112.6,53.3,50.1,35.9,35.8,16.5.
Example 2 preparation of compound DS:
wherein: (a)20 mol% MgCl2,AcOH,100℃.
Benzaldehyde-2 sulfonic acid 6(930mg, 5.0mmol), methyl acetoacetate 2(580mg, 5.0mmol), N-methylthiourea 3(675mg, 7.5mmol), anhydrous magnesium sulfate (95mg, 1.0mmol) and glacial acetic acid (5.0mL) were reacted at 100 ℃ for 2 hours in a sealed tube, after the reaction was completed, the solution was cooled, concentrated under reduced pressure, and a white solid (700mg, 39.1%) was prepared as compound DS in a liquid phase,1H-NMR and13C-NMRas shown in fig. 3 and 4. ESI-MS: [ M + H ]]+m/z 357.4；1HNMR(400MHz,CD3OD):δ8.02(dd,J＝7.6,1.6Hz,1H),7.45(dd,J＝7.6,1.6Hz,1H),7.37(dd,J＝7.6,1.6Hz,1H),7.28(dd,J＝7.6,1.6Hz,1H),6.43(s,3H),3.63(s,3H),3.58(s,3H),2.71(s,3H)；1.93(s,3H)；13C NMR(150MHz,CD3OD):δ179.9,167.7,150.9,144.1,138.7,132.1,129.2,129.0,128.1,105.7,52.0,51.0,37.0,16.8.
Example 3 preparation of compound DO:
wherein: (a)2-Ethylhexanol, PPh3,DIAD,THF,MW.
In a 10mL microwave reaction tube, compound 5(100mg, 0.38mmol), 2-ethylhexanol (74mg, 0.57mmol), triphenylphosphine (150mg, 0.57mmol) and DIAD (116mg, 0.57mmol) were dissolved in anhydrous THF (2mL), and the above reaction solution was stirred for 10min, followed by microwave reaction at 25 ℃ for 30 min. After the reaction, the solvent was evaporated to dryness, and column chromatography was performed to obtain compound DO (90mg, 63%).1H-NMR and13C-NMR is shown in FIGS. 5 and 6. ESI-MS: [ M + H ]]+m/z 375.1；1HNMR(400MHz,CDCl3):δ7.47-7.35(m,1H),7.34-7.27(m,3H),7.24-7.18(m,2H),5.38(d,J＝4.0Hz,1H),4.02(dd,J＝13.6,5.6Hz,2H),3.62(s,3H),2.55(s,3H),1.51(m,1H),1.30-1.10(m,8H),0.90-0.75(m,6H)；13C NMR(100MHz,CDCl3):δ166.0,157.7,141.5,129.1(2C),128.3,126.2(2C),107.6,102.3,67.1(2C),54.0,38.9,37.2,30.6,30.5,29.0,28.9,24.0,23.9,23.0,17.0,14.2,11.1.
Example 4 solubility and UV absorption Spectroscopy
The research proves that: the solubility of DT in PBS is more than 6.0mg/mL, and the solubility of DS in PBS is more than 50mg/mL, and the solubility of DT in PBS and DS in PBS are both better water solubility, especially the compound DS; the UV absorption spectra of DT and DS (20. mu.g/mL) in PBS are shown in FIG. 7: both DT and DS can effectively absorb the ultraviolet radiation in the UV-B (280-320nm) and UV-C (200-280nm) wave bands. The compound DS has better absorption in the UV-B band than DT.
EXAMPLE 5 biocompatibility assay
To evaluate the biocompatibility of the compounds, their cytotoxic effect in the absence of UV radiation was examined by the CCK-8 method. Human corneal epithelial cells (HCE-2, 1X 10) were selected in logarithmic growth phase4cells/well), seeded in 96-well plates, placed at 37 ℃ with 5% CO2The incubator is incubated for 24 hours, so that the growth of the culture medium is performed adherent. The culture was removed and fresh medium containing different concentrations of DHPM-1(0, 1, 2, 5mg/mL) was added and incubation continued for 24 h. The absorbance at 450nm is measured by a CCK-8 method, and the cell survival rate is calculated according to the following formula:
cell survival rate ═ aExperimental group-ABlank group)/(AControl group-ABlank group)×100％
The results are shown in FIG. 8: incubation of DT with HCE-2 cells at the tested maximum concentration of 5mg/mL for 24h in the absence of UV radiation showed no significant cytotoxic effect (96%); DS is also very biocompatible at 1mg/mL (94%), and at 2mg/mL (85%).
Example 6 anti-UV-B Damage assay
To evaluate the UV-B damage resistance of DT and DS, the cell viability of DT and DS after UV-B irradiation was examined by CCK-8 method. Selection of HCE-2 cells (1X 10) in logarithmic growth phase4cells/well), seeded in 96-well plates, placed at 37 ℃ with 5% CO2The incubator is incubated for 24 hours, so that the growth of the culture medium is performed adherent. The culture medium was removed, fresh culture medium containing different concentrations of DT or DS (0, 0.1, 0.2 or 0.5mg/mL) was added, and UV-B irradiation (0.2J/cm)2) Inducing HCE-2 cell apoptosis, and culturing for 24h after irradiation. The absorbance at 450nm is measured by a CCK-8 method, and the cell survival rate is calculated according to the following formula:
cell viability ═ aExperimental group-ABlank group)/(AControl group-ABlank group)×100％
The results are shown in FIG. 9: UV-B (0.2J/cm)2) Can induce 83% HCE-2 cell apoptosis, DT and DS have already shown obvious protective effect at the concentration of 0.1mg/mL, cell activity is improvedHigh approaching 50% (cell viability: DT 66%, DS 63%); when the concentration of the compound DT or DS reaches 0.2mg/mL, the cell viability is 93 percent and 96 percent respectively, which are already equivalent to the level of the Control group; further increase the compound concentration to 0.5mg/mL, cell viability for DT and DS was 98% and 95%, respectively.
Meanwhile, the results of example 4 show that DT and DS have no obvious cytotoxic effect on HCE-2 cells at the concentrations of 5mg/mL and 1mg/mL respectively, and the compounds have good biocompatibility and excellent effect of resisting UV-B radiation damage.
Example 7Calcein-AM/PI double staining
Selection of HCE-2 cells (5X 10) in logarithmic growth phase4cells/well), inoculated in a 35mm laser confocal culture dish, placed at 37 ℃ in 5% CO2The incubator is incubated for 24 hours, so that the growth of the culture medium is performed adherent. The culture was removed, fresh culture containing different concentrations of DT or DS (0 or 0.2mg/mL) was added, and UV-B irradiation (0.1J/cm)2) Inducing HCE-2 cell apoptosis, and culturing for 24h after irradiation. The culture medium was discarded and washed 3 times with PBS. Adding culture solution containing Calcein-AM (2 μ M) and PI (4.5 μ M), placing in incubator, culturing for 7min, washing with PBS buffer solution for 1 time, and adding live cell imaging solution. Microscopic observation was carried out by laser confocal microscope (live cells Calcein-AM. lamda. ex: 488nm,. lamda. em: 500-530 nm; dead cells PI. lamda. ex: 561nm,. lamda. em: 600-700nm) with the UV-free group as a control.
The results are shown in FIG. 10: the Control group cells without UV-B radiation are stained by Calcein-AM and become normal living cells; UVB radiation group (0.1J/cm)2) Most cells are stained by PI, and only a small part of cells can be stained by Calcein-AM, which shows that UVB can remarkably induce HCE-2 cell apoptosis; DT0.2 group HCE-2 cells were pretreated with 0.2mg/mL and then subjected to UVB radiation (0.1J/cm)2) After further post-culture for 24h, the cells were basically stained by Calcein-AM, and the fluorescence of dead cells stained by PI was very weak; as with DT0.2, HCE-2 cells in DS0.2 were substantially stained by Calcein-AM. The above data indicate that 0.2mg/mL DT or DS are both effective against UVB (0.1J/cm)2) Induced HCE-2 cell damage.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;
wherein, in formula (I):
r1 is selected from optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group; the substituent is a sulfonic group;
r2 is one or more selected from hydrogen, halogen, hydroxyl, carboxyl, amino, nitryl, aldehyde group, sulfonic group, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group; n is 0 or an integer of 1 to 5; the substituent is a sulfonic group; when n is greater than 1, R2 are the same or different; preferably, n is 0 or an integer of 1 to 3; more preferably n is 0, 1 or 2; preferably, R2 is one or more selected from hydrogen, hydroxyl, carboxyl, amino, nitro, aldehyde group, sulfonic group, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group;
r3 is selected from hydrogen, C1-C10 alkyl or C1-C10 alkylamide;
r4 is selected from hydrogen, C1-C10 alkyl or C1-C10 alkylamide;
r5 is selected from C1-C10 alkyl; preferably, R5 represents C1-C6 alkyl; more preferably, R5 represents methyl or ethyl; most preferably, R5 represents methyl;
x is selected from oxygen or sulfur; preferably, X represents sulfur;
at least one sulfonic acid group is contained in R1 and R2;
or R1 and R2 do not contain sulfonic acid groups, but R1 and R2 at least contain one C6-C10 alkyl ester group or at least contain one C6-C10 alkyl amide group; preferably, R1 and R2 do not contain a sulfonic acid group, but R1 and R2 contain at least one of a hexanoyloxy group, a heptanoyloxy group, an octanoyloxy group, an isooctyloxy group, a trimethylcyclohexyloxy group, a menthoxy acyl group, a hexylamido group, a heptylamido group, an octylamido group, an isooctylamido group, a trimethylcyclohexylamido group, or a menthylamido group.
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 represents
R2 represents hydrogen; or R1 represents a methoxyacyl group, R2 represents a sulfonic acid group; or R1 represents a 2-ethylhexyl ester group and R2 represents hydrogen.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R3 and R4 are independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkylacyl; preferably, R3 and R4 are independently selected from hydrogen, methyl or ethyl; more preferably, R3 represents hydrogen; more preferably, R4 represents methyl.
4. A compound of formula (I-a) or a pharmaceutically acceptable salt thereof:
wherein R1 in the formula (I-a) is selected from an optionally substituted C1-C10 alkyl ester group or an optionally substituted C1-C10 alkyl amide group; the substituent is a sulfonic group; r2 is one or more of hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, aldehyde group, sulfonic group, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group; n is 0 or an integer of 1 to 5; the substituent is a sulfonic group; when n is greater than 1, R2 are the same or different; preferably, n is 0 or an integer of 1 to 3; more preferably n is 0, 1 or 2; preferably, R2 is one or more selected from hydrogen, hydroxyl, carboxyl, amino, nitro, aldehyde group, sulfonic group, optionally substituted C1-C10 alkoxy, optionally substituted C1-C10 alkyl ester group or optionally substituted C1-C10 alkyl amide group;
at least one sulfonic acid group is contained in R1 and R2;
or R1 and R2 do not contain sulfonic acid groups, but R1 and R2 at least contain one C6-C10 alkyl ester group or at least contain one C6-C10 alkyl amide group; preferably, R1 and R2 do not contain a sulfonic acid group, but R1 and R2 contain at least one of a hexanoyloxy group, a heptanoyloxy group, an octanoyloxy group, an isooctyloxy group, a trimethylcyclohexyloxy group, a menthoxy acyl group, a hexylamido group, a heptylamido group, an octylamido group, an isooctylamido group, a trimethylcyclohexylamido group, or a menthylamido group.
5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R1 represents
R2 represents hydrogen; or R1 represents a methoxyacyl group, R2 represents a sulfonic acid group; or R1 represents a 2-ethylhexyl ester group and R2 represents hydrogen.
6. A compound represented by any one of the following structures:
7. a process for the preparation of a compound of formula (I):
wherein X, R1, R2, R3, R4, and R5 are as recited in claim 1.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8 for the manufacture of a product for protection against uv damage or uv protection; preferably, the application in preparing products for resisting corneal ultraviolet injury or skin ultraviolet injury.
10. The use according to claim 9, wherein the product is a pharmaceutical, medical device, nutraceutical, chemical coating or skin care product.
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