CN117986173A - Prodrugs of retinoic acid and retinoid compounds - Google Patents
Prodrugs of retinoic acid and retinoid compounds Download PDFInfo
- Publication number
- CN117986173A CN117986173A CN202311850135.2A CN202311850135A CN117986173A CN 117986173 A CN117986173 A CN 117986173A CN 202311850135 A CN202311850135 A CN 202311850135A CN 117986173 A CN117986173 A CN 117986173A
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- Prior art keywords
- acid
- retinoid
- carbon atoms
- tetrahydro
- cis
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- -1 retinoid compounds Chemical class 0.000 title claims abstract description 65
- 229930002330 retinoic acid Natural products 0.000 title claims abstract description 45
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- 125000000217 alkyl group Chemical group 0.000 claims description 28
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 28
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Abstract
The present invention relates to prodrugs of retinoic acid and retinoid compounds. Specifically, the present invention relates to the design and synthesis of positively charged prodrugs of retinoids and retinoid-like compounds having the structure of the general formula (31) 'Structure 31'. The compounds may be obtained by reacting retinoic acid and related compounds with suitable alcohols, thiols, or amines via coupling agents. Experimental results indicate that more than 90% of the prodrug can be converted back to the parent drug in a matter of minutes. In therapy, these prodrugs can be transdermally administered for any kind of medical treatments and avoid most of the side effects of retinoids and retinoid compounds. The controlled release transdermal drug delivery system of the prodrug can stabilize the concentration of the vitamin A acid and the retinoid in blood at the optimal therapeutic concentration, improve the curative effect and reduce the side effects of the vitamin A acid and the retinoid. Another great benefit of transdermal administration of these prodrugs is that they are more convenient to use, especially for children.
Description
The application is a divisional application of Chinese patent application 202110941855.4. The application date of the original application is 1 month 15 of 2007, and the application is named as a prodrug of the vitamin A acid and the retinoid compound.
Technical Field
The present invention relates to positively charged and water-soluble prodrugs of retinoids and retinoid compounds and their use in treating any retinoid and retinoid compound treatable conditions in humans or animals. In particular, the present invention provides for rapid penetration of retinoids and retinoid compounds through the skin.
Background
Retinoic acid is a class of compounds whose structure contains four isoprenoid building blocks joined in a head-to-tail fashion. The retinoic acid includes all-trans retinoic acid (retinoic acid), cis-isomerised retinoic acid such as 13-cis retinoic acid (isotretinoin), 9-cis-retinoic acid (alpha Li Weisheng retinoic acid), vitamin A (retinol), 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoic acid (Besalutin, taleather Lei Ting retinol, lei Tifei roto)(E, E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid, adapalene (6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid), acyclic vitamin A acid [ (2E, 4E,6E, 10E) -3,7, 11, 15-tetramethyl-2, 4,6, 10, 14-hexadecano-pentaenoic acid (hexadecapentaenoic acid) ], ethyl (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoate, and natural and synthetic derivatives thereof. Several patents report that various synthetic retinoic acids and retinoid compounds having retinoic acid activity (U.S. Pat. No. :5,648,563;5,648,385;5,618,839;5,559,248;5,616,712;5,616,597;5,602,135;5,599,819;5,556,996;5,534,516;5,516,904;5,498,755;5,470,999;5,468,879;5,455,265;5,451,605;5,426,118;5,407,937;5,399,586;5,399,561;5,391,753). retinoic acid plays a very important role in many life processes, including pattern formation during vision, reproduction, metabolism, differentiation, skeletal development and embryonic development (pattern formation), vitamin A (vitamin A) and retinoids are in a state of chemical equilibrium in vivo and have equivalent anti-dry eye activity vitamin A combines with an opsin, i.e., rod-like cytochrome in the retina to form retinal purple, which is very important for visual accommodation darkness, lack of vitamin A causes night blindness, keratosis, keratitis and skin dryness, reduced antiinfective ability, reduced growth, bone thickening, reduced corticosteroid production, topical administration of retinoic acid (Abiral retinoic acid) can treat acne vulgaris, photoaging, pigment macula (liver spots) and early wrinkles, drug-induced photoallergence, psoriasis, cutaneous wound healing, xerophthalmia, keloids, cutaneous epidermolysis (PDR GENERICS,1996,SECOND EDITION,MEDICAL ECONOMICS,MONTVALE,NEW JERSEY,PG 2981), and isotretinoin can inhibit sebaceous gland function and keratinization, basal cell carcinoma, cervical cancer, mycosis fungoides (cutaneous T-lymphomas), darier disease, ichthyosis lamellaris, pityriasis pilaris, infection with herpes simplex, grover disease, lichen planus, refractory rosacea, palmoplantar keratosis, leukoplakia, squamous basal cell carcinoma, and xeroderma pigmentosum. The acil Li Weisheng retinoic acid (9-cis retinoic acid) is a natural endogenous retinoic acid that binds to and activates all known intracellular retinoic acid receptor subtypes (RAR, RAR, RAR, RXR, RXR, and RXR). These receptors, once activated, act as transcription factors, regulating the expression of genes that control cell differentiation and proliferation in normal and cancer cells. The a Li Weisheng acid inhibited the growth of Kaposi's Sarcoma (KS) cells in vitro experiments. The A Li Weisheng acid is used for treating Kaposi's Sarcoma (KS) and myelodysplastic syndrome. The Ratifluo (retiferol) derivatives are useful in the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, keratinization and keratosis disorders, tumour epilepsy, sebaceous gland disorders such as acne and seborrheic dermatitis, conditions associated with photodamage, sun-induced skin damage, wrinkles, elastosis and premature ageing (Hilpert, et al, U.S. Pat.No. 6437142). Adapalene can be used for external treatment of acne vulgaris. Acyclic vitamin a acids are useful for preventing secondary cancers (Yasutoshi Muto, et al, THE NEW ENGLAND Journal of Medic ine,340, 1046 (1999)). (E, E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid may be useful in the treatment of type II diabetes and other metabolic disorders (Deng T, et al, biol. Pharm. Bull.28 (7), 1192, 2005). Tower leather Lei Ting/>The oral formulations can be used for the treatment of cutaneous T-lymphomas (CTCL), head and neck cancers, systemic kaposi's sarcoma, lung cancer, ovarian cancer, prostate cancer and renal cell carcinoma. External administration of tara Lei Ting can be used to treat cutaneous T-cell lymphoma (CTCL).
An alternative mode of administration is topical administration. There are several advantages to topical drug delivery systems. This approach helps to avoid first pass metabolism of the drug in the liver and gastrointestinal tract. It can deliver a proper concentration of drug locally to the site of action of interest without the need for systemic exposure. Fishman (Fishman; robert, U.S. Pat. No. 7,052,715) teaches that another problem associated with oral administration is that the concentration of drug in the blood circulation must be high in order to effectively treat pain or inflammation at the distal site. These concentrations are often far higher than actually required assuming that the drug is directly targeted to the pain or injury site. Yeager attempts to administer PGE1 via permeation enhancers for the treatment of male erectile dysfunction (Yeager, james L. U.S. Pat. No. 6,693,135). Susan Milosovich et al designed and synthesized testosterone 4-dimethylaminobutyrate hydrochloride (TSBH) having a fat-soluble moiety and a tertiary amine structure in protonated form at physiological pH. They found that this prodrug (TSBH) penetrated human skin at a rate nearly 60 times that of the parent drug (TS) [ Susan Milosovich, et a1., J.Pharm. Sci.,82, 227 (1993) ].
Technical problem
Retinoids and retinoid compounds have been used to treat a variety of health conditions including acne, photoaging, psoriasis, ichthyosis, alopecia and a wide variety of cancers.
However, retinoids and retinoid-like compounds are too fat-soluble and completely insoluble in water. The biofilm has a bilayer structure with a hydrophilic head structure facing the aqueous phase region on both sides. The retinoids are able to enter the lipid layer of the biofilm, but for similar compatibility reasons they stay there as part of the biofilm and do not effectively enter the internal cytoplasm. Since retinoids have highly unsaturated structures, retinoids are very sensitive to ultraviolet light, air and oxidizing agents. After topical administration, the retinoid may enter the biofilm but not the interior of the cells. Sunlight, air or oxidants can chemically react the retinoids, causing redness, burning, molting, cracking, foaming, or itching of the skin. When they are administered orally, they are destroyed and deactivated within a few minutes by the first pass effect, i.e. chemical degradation of the compound by the liver and the gastrointestinal tract. Oral administration of retinoids can cause unnecessary systemic exposure and result in a number of side effects.
Solution scheme
The invention relates to design and synthesis of novel pro-drugs of retinoids and retinoid compounds with positive charges and medical application thereof. The prodrugs of 9-cis-retinoic acid (aci Li Weisheng retinoic acid), 13-cis retinoic acid (isotretinoin), all-trans retinoic acid (retinoic acid), vitamin a (retinol), lei Tifei ro (retiferol), adapalene, acyclic retinoic acids, and retinoid compounds have the general formula (1 to 27) 'structures 1 to 27':
In formulae 1-27, R represents a straight or branched chain, - (CH 2)n -, wherein n=0, 1, 2,3, 4, 5, 6, 7, 8, 9, 10 … …, in- (CH 2)n -, any CH 2 may be replaced by O, S, CH =ch, c≡ C, CR 6R6 ', aryl or heteroaryl or other cyclic system groups; R 1 and R 2 each independently may represent the same or different groups and may be H, any alkyl, alkoxy, alkenyl, or alkynyl of 1 to 12 carbon atoms, aryl, or heteroaryl, or taken together represent- (CH 2)n -, wherein n=2, 3, 4, 5, 6, 7, 8, 9, 10 … …, any CH 2 may be substituted with O, S, CH =CH, C≡ C, CR 6R6 ', aryl, or heteroaryl or other cyclic groups, R 3 represents H, any alkyl, alkoxy, alkenyl, or alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl, wherein any CH 2 may be substituted with O, S, CH =CH, C≡ C, CR 6R6 ', aryl or heteroaryl or other cyclic groups, X represents O, S, or NH, X 1 represents alkyl of H、OH、Cl、Br、F、I、NO2、NO、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、1-6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms of alkyl of 1 to 6 carbon atoms, alkynyl, and alkynyl of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms; x 3 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R5、COR5、COOR5、NRCOR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms; x 4 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms; x 5 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms; x 6 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R5、COR5、COOR5、NRCOR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms; r 4 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or a haloalkyl group of 1 to 6 carbon atoms; r 5 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R6、COR6、COOR6、NR6COR4、SOR6、SR6、PO3R6R6′、SOR6、SR6、1-6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or a haloalkyl group of 1 to 6 carbon atoms; r 11 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or a haloalkyl group of 1 to 6 carbon atoms; r 12 represents an alkyl group of H、OH、Cl、Br、F、I、NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, a perfluoroalkyl group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or a haloalkyl group of 1 to 6 carbon atoms; r 6 and R 6 ' independently of one another may represent the same or different radicals, and R 7 and R 7 independently of one another may represent the same or different radicals, and may be an alkyl radical of H、Cl、Br、F、I、OH、NO2、CN、SO2R5、COR5、COOR5、NR7COR5、SOR5、SR5、PO3R7R7′、SOR5、SR6、1-6 carbon atoms, an alkenyl radical of 1 to 6 carbon atoms, an alkynyl radical of 1 to 6 carbon atoms, or a haloalkyl radical, or together represent oxygen (=O) or- (CH 2)n -, where n=2, 3, 4, 5, 6, 7, 8, 9, 10 … …, any CH 2 may be replaced by O, S, CH =CH, C≡ C, CR 7R7 ' aryl or heteroaryl radicals, or other cyclic system groups, and R 7 and R 7 independently of one another may represent the same or different radicals, and may be an alkyl radical of H、Cl、Br、F、I、OH、NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, an alkoxy radical of 1 to 6 carbon atoms, an alkenyl radical of 1 to 6 carbon atoms, an alkynyl radical of 1 to 6 carbon atoms, or a haloalkyl radical, or together represent oxygen (=O) or- (CH 2)n -, where n=2, 3, 4, 5, 6, 7, 8, 9, 10, … …, and any CH=7, C≡may be replaced by an aryl radical of O, S, CH =CH, C≡ C, CR 7R7 ', or a cyclic system group of the same or different radicals, and R 7 and R 7 independently of one another may represent an alkyl radical of 1 to 6 carbon atoms, an alkynyl radical of 1 to 6 carbon atoms, or a haloalkyl radical, or together represent oxygen (=O) or a group, or may represent oxygen (=O) or a group, or may alternatively may represent a cyclic radical, or may be taken 7. 8, 9, 10 … …, any CH 2 may be substituted with O, S, CH =ch, c≡ C, CR 6R6', aryl or heteroaryl or other cyclic system groups; r 9 and R 9 ' may each independently represent the same or different groups, may be an alkyl group of H、Cl、Br、F、I、OH、NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or a haloalkyl group, or together represent oxygen (=O) or- (CH 2)n -, wherein n=2, 3, 4, 5, 6, 7, 8, 9, 10 … …, any CH 2 may be replaced by O, S, CH =CH, C≡ C, CR 6R6 ', aryl or heteroaryl groups, or other cyclic system groups, R 10 and R 10 ' may each independently represent the same or different groups, may be an alkyl group of H、Cl、Br、F、I、OH、NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5、1-6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, an alkenyl group of 1 to 6 carbon atoms, an alkynyl group of 1 to 6 carbon atoms, or a haloalkyl group, or together represent oxygen (=O) or- (CH 2)n -, wherein n=2, 3, 4, 5, 6, 7, 8, 9, 10, and/or CH … … may be replaced by any CH.69=CH.7 ', aryl group or heteroaryl groups, or any cyclic system groups, R 10 and R 10 ' may represent a single bond, CH 9762, a triple bond, a straight chain, a C.p.t may be replaced by a C.t.c.t. or a cyclic system, and may represent any other cyclic system, such as may be a straight chain, such as a bond, or a bond, and may be used.
Drugs, whether absorbed through the gastrointestinal tract or other pathways, need to traverse the barrier membrane in molecular form. The drug must first dissolve and if the drug has desirable biopharmaceutical properties, it will diffuse from a region of high concentration to a region of low concentration across the cell membrane into the blood or systemic circulatory system. All biological membranes contain lipids as the main component. The dominant molecules in the biofilm structure all have a highly polar head structure containing phosphate and, in most cases, two highly hydrophobic hydrocarbon tails. The biofilm has a bilayer structure with a hydrophilic head structure facing the aqueous phase region on both sides. Very hydrophilic drugs cannot pass through the lipid layer of the biofilm and very hydrophobic drugs stay in it as part of the biofilm for similar compatibility reasons, thus not effectively entering the inner cytoplasm.
The object of the present invention is to make it possible to administer vitamin a acids and related compounds transdermally (for external use) by increasing their solubility in the moisture of the skin surface and increasing their penetration rate into biological membranes and skin barriers. Prodrugs of these novel retinoids and related compounds have two identical structural features: they have a lipophilic moiety and a primary, secondary, or tertiary amine group (water-soluble moiety) that exists in protonated form at physiological pH. Such water-oil solubility balance is necessary for the drug to pass effectively through the biofilm [ Susan Milosovich, et al, j.pharm.sci.,82, 227 (1993) ]. The positively charged amino groups greatly increase the solubility of the drug in water. In many cases, dissolution of the drug is the slowest or rate limiting step in the absorption process. The retinoids and their related compounds have low solubility in skin surface moisture and cannot pass through the skin barrier effectively in molecular form. After they enter the biological membrane of the skin, they remain as part of the biological membrane for similar reasons of compatibility and thus do not effectively enter the cytoplasm, i.e. a semi-liquid concentrated aqueous solution or suspension inside the cell. When these novel prodrugs are transdermally administered in a dosage form such as a solution, spray, emulsion, ointment, emulsion or gel, they dissolve rapidly in the moisture present on the skin surface. The positive charge on the amino group in these pro-drug molecules will combine with the negative charge on the phosphate head group of the cell membrane. Thus, the local concentration of the drug outside the biofilm is high to facilitate passage of these prodrugs through the high concentration region to the low concentration region. After these prodrug molecules enter the biofilm, the hydrophilic moiety pushes the prodrug into the cytoplasm. Because of the short residence time of these prodrugs outside the biofilm on the skin surface, they do not cause skin burning, pain, itching or swelling and are not sensitive to sunlight when applied to the skin. The penetration rate of these prodrugs in human skin was measured in vitro by a modified Franz cell, wherein human skin was isolated from human skin tissue (360-400 microns thick) either in front of or behind the thigh area. The receiving solution consisted of 2 ml of physiological saline containing 2% bovine serum globulin and was stirred at 600 rpm. The cumulative total amount of these prodrugs and their parent drugs that pass through the skin is determined by specific high performance liquid chromatography. The donor solution consisted of a solution containing 5% of some retinoid prodrug, or a suspension of 5% retinoid, each dissolved in a mixture of 0.2 ml ethanol and pH7.4 phosphate buffer solution (0.2M) (v/v, 70/30), the results are shown in FIG. 1. Calculating apparent penetration values of the penetration into human skin to obtain N, N-diethylaminoethyl 9-cis-retinoic acid ester hydrobromide, N-diethylaminoethyl 13-cis-retinoic acid ester hydrobromide, N-diethylaminoethyl all-trans-retinoic acid ester hydrobromide, retinyl N, N-dimethyl-2-amino acetic acid ester hydrochloride, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride, 9-cis-retinoic acid (aci Li Weisheng-retinoic acid), 13-cis-retinoic acid (isotretinoin), all-trans-retinoic acid (retinoic acid), retinol (retinol) and betasalbutamolThe apparent penetration values of the penetration through human skin were 0.72 mg, 0.85 mg, 1.25 mg, 1.21 mg, 0.35 mg, 0.005 mg and 0.001 mg/cm 2/hr, respectively. These prodrugs diffuse 350 times faster in human skin than retinoids. The results demonstrate that the positive charge on the dialkylaminoethyl group is very important for the drug to cross the biological membrane and skin barrier.
The effect of these novel prodrugs on the skin of mice was evaluated by applying o.1 ml of 1% of each test drug dissolved in ethanol to the back of nude mice twice daily and evaluating the effect of these novel prodrugs on the skin of mice after one week. No irritation or discomfort was found to be observed with N, N-diethylaminoethyl-9-cis-retinoic acid ester hydrobromide, N, N-diethylaminoethyl-13-cis-retinoic acid ester hydrobromide, N, N-diethylaminoethyl all-trans-retinoic acid ester hydrobromide, retinyl N, N-dimethyl-2-aminoethyl hydrochloride, N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride.
A good prodrug should be easily changed back to the parent drug structure. These prodrugs were subjected to in vitro plasma hydrolysis experiments according to the following procedure. 10mg of the prodrug was dissolved in 0.1 ml of 0.2M phosphate buffer pH 7.4. 1 ml of human plasma was preheated to 37℃and added to the mixture. The mixture was incubated in a 37℃water bath. At intervals of two minutes, 0.2 ml of sample was removed and 0.4 ml of methanol was added to precipitate plasma proteins. The samples were centrifuged for 5 minutes and analyzed by high performance liquid chromatography. The half-life of the hydrolysis of N, N-diethylaminoethyl 9-cis-vitamin A acid ester hydrobromide is 10+ -1 min, the half-life of the hydrolysis of N, N-diethylaminoethyl 13-cis-vitamin A acid ester hydrobromide is 8+ -2 min, the half-life of the hydrolysis of N, N-diethylaminoethyl all-trans vitamin A acid ester hydrobromide is 9+ -1 min, the half-life of the hydrolysis of retinyl N, N-dimethyl-2-amino acetate hydrochloride is 13+ -2 min, and the half-life of the hydrolysis of N, N-diethylaminoethyl-4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride is 11+ -2 min.
Tower leather Lei Ting(Besalutin) selectively activates a subset of the vitamin A acid receptors called RXR, which play an important role in the activity of many cells. One of the most important effects is programmed cell death, or "apoptosis", the natural process by which the body removes unwanted cells from itself. Ligand corporation is developing topical and oral formulations of Taiger Lei Ting. The external use of Taiger Lei Ting can be used for treating cutaneous T-lymphomas (CTCL). In addition, the oral formulation of Takara Lei Ting is useful for the treatment of cutaneous T-lymphomas (CTCL), head and neck cancers, systemic Kaposi's sarcoma, lung cancer, ovarian cancer, prostate cancer and renal cell carcinoma. The acil Li Weisheng retinoic acid (9-cis retinoic acid) is a natural endogenous retinoic acid that binds to and activates all known intracellular retinoic acid receptor subtypes (RARa, RARb, RARg, RXRa, RXRb and RXRg). Once activated, these receptors can act as transcription factors to regulate gene expression in normal cells and tumor cells that can control the processes of cell differentiation and proliferation. The A-acid of the A Li Weisheng can be used for treating Kaposi's sarcoma, kaposi's sarcoma related to AIDS, other skin cancers, breast cancer and other cancers.
To evaluate the anticancer activity of these prodrugs, human breast cancer cells (BCAP-37, 3-4 mm 3 tumor tissue was used per mouse) were implanted subcutaneously in nude mice (BALB). After 1 day, 50. Mu.l of 1% N, N-diethylaminoethyl 9-cis-retinoate hydrobromide and 50. Mu.l of 1% N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride were applied to the area (near the foreleg) where the human breast cancer cells were implanted, both dissolved in ethanol/0.2 MpH.4 in phosphate buffer (v/v, 70/30) and applied twice daily. After 28 days, the tumor incidence of control nude mice (n=7) was 100% (semi-average tumor size 13±2mm×12±2 cm), whereas no tumor was observed in the treated group of nude mice (n=7) dosed with N, N-diethylaminoethyl 9-cis-retinoate hydrobromide or N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride. Most importantly, the nude mice did not show any discomfort or irritation after administration. The average body weight of the nude mice in the treatment group was 25+ -2 g, and the average body weight of the nude mice in the blank group was 23+ -3 g. The experimental results demonstrate that these prodrugs have very mild side effects.
In another experiment, human colon cancer cells (LS 174J, 3-4 mm 3 tumor tissue was used per mouse) were implanted subcutaneously in nude mice (BALB). After 1 day, 50. Mu.l of 1% N, N-diethylaminoethyl 9-cis-retinoate hydrobromide and 50. Mu.l of 1% N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride were applied to the area (near the foreleg) where human colon cancer cells were implanted, both in ethanol/O.2M phosphate buffer (v/v, 70/30) pH 7.4, twice daily. After 28 days, the control group (n=7) had a tumor incidence of 100% (average tumor size of 22±4 mm×20±3 mm), whereas no tumor was observed in the treatment group (n=7) to which N, N-diethylaminoethyl 9-cis-retinoate hydrobromide or N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride was administered.
All retinoids are commercially available. The compound represented by the above general formula (1, 2, 3,5, 6, 7, 8, 9, 10, 11, 12, 16, 17, 22, 23, 24, 25, 26 or 27) "structural formula 1, 2, 3,5, 6, 7, 8, 9, 10, 11, 12, 16, 17, 22, 23, 24, 25, 26 or 27" may be prepared by reacting a retinoid or a related compound thereof with a compound represented by the general formula (28) "structural formula 28" under the action of a coupling agent. Coupling agents such as: n, N '-dicyclohexyl-carbodiimide, N, N' -diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea tetrafluoroborate, O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, and the like.
Wherein R represents a straight or branched chain, - (CH 2)n -, where n=0, 1, 2,3, 4, 5, 6, 7, 8, 9, 10 … …, in- (CH 2)n -, any CH 2 may be replaced by O, S, CH =ch, c≡ C, CR 6R6 ', aryl or heteroaryl, or other cyclic system groups, R 1 and R 2 each independently may represent the same or different groups, may be H, alkyl, alkoxy, alkenyl, or alkynyl of any 1-12 carbon atoms, aryl or heteroaryl, or together represent- (CH 2)n -, where n=2, 3, 4, 5, 6, 7, 8, 9, 10 … …, any CH 2 may be replaced by O, S, CH =ch, c≡ C, CR 6R6' aryl or heteroaryl or other cyclic system groups, and X represents O, S or NH.
The compound represented by the above general formula (4, 13, 14, 15, 20 or 21) 'structural formula 4, 13, 14, 15, 20 or 21' can be obtained by reacting vitamin A and its related compound with the compound represented by the general formula (29) 'structural formula 29',
Wherein R represents a straight or branched chain, - (CH 2)n -, wherein n=O, 1,2,3,4,5,6, 7,8, 9, 10 … …, in- (CH 2)n -, any CH 2 may be replaced by O, S, CH =CH, C≡ C, CR 6R6 ', aryl or heteroaryl, or other cyclic system groups, R 1 and R 2 each independently may represent the same or different groups, may be H, any alkyl, alkoxy, alkenyl or alkynyl group of 1-12 carbon atoms, aryl or heteroaryl, or together represent- (CH 2)n -, wherein n=2, 3,4,5,6, 7,8, 9, 10 … …, any CH 2 may be replaced by O, S, CH =CH, C≡ C, CR 6R6 ', aryl or heteroaryl, or other cyclic system groups, R 3 represents H, any alkyl, alkoxy, alkenyl, or alkynyl group of 1-12 carbon atoms, aryl or heteroaryl, wherein any CH 2 may be replaced by C O, S, CH =CH 7 ', or heteroaryl, or any cyclic system groups, Z.6, N.7, C.ident. C, CR 6R6 ', aryl or heteroaryl, or any other cyclic system groups, R 3 represents H, C.ident.7, C.ident.35 ', aryl or heteroaryl, R..
When X represents O, the compound represented by the above-mentioned general formula (1, 2,3, 5,6, 7, 8, 9, 10, 11, 12, 16, 17, 22, 23, 24, 25, 26 or 27) 'structural formula 1,2, 3, 5,6, 7, 8, 9, 10, 11, 12, 16, 17, 22, 23, 24, 25, 26 or 27' can be obtained by reacting a metal salt, an organic base salt or an immobilized base salt of a retinoid or a related compound thereof with the compound represented by the general formula (30) 'structural formula 30'.
Wherein R represents a straight or branched chain, - (CH 2)n -, wherein n=O, 1, 2, 3,4, 5, 6, 7, 8, 9, 10 … …, in- (CH 2)n -, any CH 2 may be replaced by O, S, CH =CH, C≡ C, CR 6R6 ', aryl or heteroaryl, or other cyclic system groups, R 1 and R2 each independently may represent the same or different groups, may be H, any alkyl, alkoxy, alkenyl, alkynyl, aryl or heteroaryl of 1-12 carbon atoms, or together represent- (CH 2)n -, wherein n=2, 3,4, 5, 6, 7, 8, 9, 10 … …, any CH 2 may be replaced by O, S, CH =CH, C≡ C, CR 6R6' aryl or heteroaryl, or other cyclic system groups, R 3 represents H, any alkyl, alkoxy, alkenyl or alkynyl of 1-12 carbon atoms, aryl or heteroaryl, wherein any CH 2 may be replaced by 3526=CH 35 ', C≡35, Z≡35', or heteroaryl, or any cyclic system group, and F, cl, or other groups, and represents a negative ion, such as Cl, or a salt thereof.
Advantages are that
The pro-drugs of the retinoids and retinoid-like compounds of the invention have a lipid-soluble moiety and a water-soluble moiety (amine groups present in protonated form at physiological pH). Positively charged amino groups in these prodrugs have two major advantages. First, it greatly enhances the solubility of the prodrugs in water, and when the prodrugs are transdermally administered in the form of solutions, sprays, lotions, ointments, emulsions or gels, they can be rapidly mixed with moisture on the skin, eyes, genital area, mouth, nose or other parts of the body. Second, the positive charge on the amino groups of these prodrugs can combine with the negative charge on the phosphate head structure of the biofilm. Thus, the local concentration outside the biofilm may be high, thereby facilitating penetration of these prodrugs from high concentration regions to low concentration regions. When these prodrugs enter the biological membrane, the hydrophilic moiety pushes the drug into the cytoplasm, a concentrated semi-liquid aqueous solution or suspension. The prodrug does not cause itching, burning or pain due to the short residence time in the skin, eyes, genital area, mouth, nose or other parts of the body. Experimental results showed that more than 90% of the prodrug could be returned to the parent drug within a few minutes. Because prodrugs have higher absorption rates and transdermal delivery avoids first pass metabolism, these prodrugs are more potent than retinoids and retinoid-like compounds at equal doses. Another great benefit of transdermal administration of these prodrugs is the ease of administration, particularly to children.
Drawings
Fig. 1: n, N-diethylaminoethyl 9-cis-retinoic acid ester hydrobromide (5% solution, A), N, N-diethylaminoethyl 13-cis-retinoic acid ester hydrobromide (5% solution, B), N, N-diethylaminoethyl all-trans-retinoic acid ester hydrobromide (5% solution, C), retinyl N, N-dimethyl-2-aminoacetic acid ester hydrochloride (5% solution, D), N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphtyl) vinyl ] benzyl hydrochloride (5% solution, E), 9-cis-retinoic acid (5% suspension, F), 13-cis-retinoic acid (5% suspension, G), all-trans-retinoic acid (5% suspension, H), retinol (5% suspension, I), and salubriol (5% suspension J) isolated from human skin tissue in Franz (n=5). In each case, the carrier solution was ethanol/phosphate buffer (0.2M) at pH 7.4 (v/v, 70/30).
Fig. 2: structure 31 wherein Ret represents retinoids and retinoid-like compounds; r represents a straight or branched chain, - (CH 2)n -, wherein n=0, 1,2, 3, 4, 5,6, 7, 8, 9, 10 … …, aryl or heteroaryl, R 1 and R 2 independently may represent the same or different groups and may be H, alkyl, alkoxy, alkenyl or alkynyl of any 1 to 12 carbon atoms, aryl or heteroaryl, or together represent- (CH 2)n -, wherein n=2, 3, 4, 5,6, 7, 8, 9, 10 … …, any CH 2 may be replaced by O, S, CH =CH, C≡ C, CR 4R3, aryl or heteroaryl, or other ring system groups, R 3 represents H, alkyl, alkoxy, alkenyl or alkynyl of any 1 to 12 carbon atoms, or aryl or heteroaryl, R 4 represents H, alkyl, alkoxy, alkenyl, or alkynyl of any 1 to 12 carbon atoms, or aryl or heteroaryl, X represents O, S or NH, A - represents -、Br-、F-、I-、AcO-, citrate, or any negative ion, and may contain a single bond, C may be a single bond, C, or a branched chain, or a triple bond, and N may contain a triple bond, or a triple bond.
Best mode for carrying out the invention
Preparation of N, N-diethylaminoethyl 9-cis-vitamin A acid ester hydrobromide
32.2 G (0.1 mol) of sodium 9-cis-retinoate are dissolved in 100ml of acetonitrile. 26.1 g (0.1 mol) of 2-bromo-N, N-diethylamine hydrobromide was added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. 200ml of ethanol were added to the evaporated mixture. The solids were removed by filtration. The filtrate was evaporated to dryness. 100ml of ethyl acetate was added to the reaction mixture. 100ml of hexane was added. The solid product was collected by filtration. Drying gave 36 g of the expected product (75% yield). An easily hygroscopic product; elemental analysis: c 26H42BrNO2; molecular weight: 480.52. theoretical% C:64.99; h:8.81; br:16.63; n:2.91;0:6.66; measured value% C:65.03; h:8.80; br:16.60; n:2.89;0:6.68.
Description of the embodiments
Preparation of N, N-diethylaminoethyl 13-cis-retinoic acid ester hydrobromide
32.2 G (0.1 mol) of sodium 13-cis-retinoate are dissolved in 100 ml of acetonitrile. 26.1 g (0.1 mol) of 2-bromo-N, N-diethylamine hydrobromide was added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. 200 ml of ethanol were added to the evaporated mixture. The solids were removed by filtration. The filtrate was evaporated to dryness. 100 ml of ethyl acetate was added to the reaction mixture. 100 ml of hexane was added. The solid product was collected by filtration. Drying gave 38 g of the expected product (79.1% yield). An easily hygroscopic product; elemental analysis: c 26H42BrNO2; molecular weight: 480.52. theoretical% C:64.99; h:8.81; br:16.63; n:2.91;0:6.66; measured value% C:65.03; h:8.80; br:16.60; n:2.89;0:6.68.
Preparation of N, N-diethylaminoethyl all-trans-vitamin A acid ester hydrobromide
32.2 G (0.1 mol) of all-trans-vitamin A acid sodium are dissolved in 100ml of acetonitrile. 26.1 g (0.1 mol) of 2-bromo-N, N-diethylamine hydrobromide was added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. 200ml of ethanol were added to the evaporated mixture. The solids were removed by filtration. The filtrate was evaporated to dryness. 100ml of ethyl acetate was added to the reaction mixture. 100ml of hexane was added. The solid product was collected by filtration. Drying gave 35 g of the expected product (yield 72.9%). An easily hygroscopic product; elemental analysis: c 26H42BrNO2; molecular weight: 480.52. theoretical% C:64.99; h:8.81; br:16.63; n:2.91;0:6.66; measured value% C:65.03; h:8.80; br:16.60; n:2.89;0:6.68.
Preparation of N, N-dimethylaminoacetic acid retinyl (vitamin A) ester hydrochloride
28.6 G (0.1 mol) of vitamin A are dissolved in 100 ml of acetonitrile. 25ml of triethylamine was added to the reaction solution. 16 g of N, N-dimethylaminoacetyl chloride hydrochloride are added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The solids were removed by filtration. The filtrate was evaporated to dryness. 500 ml of ethyl acetate was added to the residue. 200 ml of 5% sodium carbonate solution was added to the mixture with stirring. The organic solution was collected and washed with water (after evaporation to dryness 31 g of the expected product (75.5% yield.) were obtained, elemental analysis: C 24H38ClNO2; molecular weight: 408.02. Theoretical% C:70.65; H:9.39; cl:8.69; N:3.43;0:7.84; observed% C:70.60; H:9.46; cl:8.71; N:3.42; O: 7.81).
Preparation of N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoate hydrochloride
34.9 G (0.1 mol) of 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoic acid (Besalobuty, takara Lei Ting) were dissolved in 300ml of chloroform. 20.6 g (O.1 mol) of N, N' -dicyclohexylcarbodiimide was added to the reaction mixture. 11.6 g of dimethylaminoethanol was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solids were removed by filtration. The chloroform solution was washed with 5% nahco 3 (2×100 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 3.6 g of HCl gas dissolved in 100 ml of diethyl ether are added to the reaction mixture with stirring. The solid product was collected by filtration. After drying, 40 g of the expected product are obtained (yield 85.8%). An easily hygroscopic product; elemental analysis: c 30H42ClNO2; molecular weight: 484.11. theoretical% C:74.43; h:8.74; cl:7.32; n:2.89;0:6.61; measured value% C:74.39; h:8.76; cl:7.29; n:2.91;0:6.65.
Industrial applicability
These prodrugs of general formula (1-27) 'Structure 1-27' are superior to retinoids and retinoid-like compounds. They can be used to treat any condition of the human or animal that can be treated with retinoids and retinoid-like compounds. They are useful in the treatment of acne, acne scars, psoriasis, ichthyosis, eczema, keratinization disorders, precancerous lesions, drug prophylaxis, warts, sarcoidosis, treatment of photoaging of skin, prevention of photoaging of skin, treatment of chronic skin aging, hair loss and various cancers.
Claims (16)
1. The compound represented by "structural formula 7",
Wherein,
R represents a straight or branched chain- (CH 2)n -, where n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R 1 and R 2 each independently represent the same or different groups selected from H and alkyl groups of 1 to 12 carbon atoms;
r 3 represents H;
X represents O, S or NH;
x 1-X6 each independently represents H or alkyl of 1 to 6 carbon atoms;
R 4、R5、R6 and R 6'、R7 and R 7'、R8 and R 8' each independently represent the same or different groups selected from H and alkyl groups of 1 to 6 carbon atoms;
r 9-R11 each independently represents H;
a - represents negative ions; the double bond on the side chain may be in the Z or E configuration.
2. The compound represented by "structural formula 20",
Wherein,
R represents a straight or branched chain- (CH 2)n -, where n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R 1 and R 2 each independently represent the same or different groups selected from H and alkyl groups of 1 to 12 carbon atoms;
r 3 represents H;
X represents O, S or NH;
x 1-X6 each independently represents H or alkyl of 1 to 6 carbon atoms;
r 4 and R 5 each independently represent H;
a - represents negative ions; the double bond on the side chain may be in the Z or E configuration.
3. A compound as claimed in claim 1 or 2 wherein a - represents Cl -、Br-、F-、I-、AcO- or citrate.
4. A pharmaceutical composition comprising at least one compound according to any one of claims 1-3.
5. Use of a pharmaceutical composition according to claim 4 for the preparation of a medicament for the treatment of a condition treatable with a retinoid compound in a human or animal, wherein the medicament is administered orally or transdermally, and
Wherein the retinoid is selected from all-trans retinoic acid, cis-isomeric retinoic acids, retinol, 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoic acid, (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid, adapalene, (2E, 4E,6E, 10E) -3,7, 11, 15-tetramethyl-2, 4,6, 10, 14-hexadecano-c-ylic acid, and ethyl (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid ester.
6. The use of claim 5, wherein the cis-isomerised retinoic acid is selected from the group consisting of 13-cis retinoic acid and 9-cis retinoic acid.
7. The use of claim 5 or 6, wherein the condition treatable with a retinoid compound comprises: acne, acne scar, psoriasis, ichthyosis, eczema, keratosis disorder, precancerous lesions, drug prophylaxis, warts, sarcoidosis, treatment of skin photoaging, prevention of skin photoaging, treatment of chronic skin aging, hair loss and various cancers.
8. The use according to claim 5 or 6, wherein the medicament is in the form of a solution, spray, emulsion, ointment, emulsion or gel, which is treated by transdermal administration to any part of the body to achieve a therapeutically effective plasma concentration.
9. The use of claim 8, wherein the medicament is administered topically to the area of the particular disease.
10. A transdermal therapeutic application product comprising the pharmaceutical composition of claim 4.
11. A transdermal therapeutic application product according to claim 10, wherein the product is a bandage or patch comprising a matrix layer comprising the active substance and an impermeable protective layer.
12. A transdermal therapeutic application product according to claim 10, wherein the product comprises an active substance reservoir comprising a permeable skin-facing base.
13. A transdermal therapeutic application product according to claim 10, wherein the release rate is controlled so that the vitamin a acid compound is stabilized at an optimal therapeutic blood level to increase the therapeutic effect and reduce the side effects of the vitamin a acid compound, and
Wherein the retinoid is selected from all-trans retinoic acid, cis-isomeric retinoic acids, retinol, 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoic acid, (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid, adapalene, (2E, 4E,6E, 10E) -3,7, 11, 15-tetramethyl-2, 4,6, 10, 14-hexadecano-c-ylic acid, and ethyl (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid ester.
14. A transdermal therapeutic application product according to claim 11, wherein the release rate is controlled so that the vitamin a acid compound is stabilized at an optimal therapeutic blood level to increase the therapeutic effect and reduce the side effects of the vitamin a acid compound, and
Wherein the retinoid is selected from all-trans retinoic acid, cis-isomeric retinoic acids, retinol, 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoic acid, (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid, adapalene, (2E, 4E,6E, 10E) -3,7, 11, 15-tetramethyl-2, 4,6, 10, 14-hexadecano-c-ylic acid, and ethyl (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid ester.
15. A transdermal therapeutic application product according to claim 12 wherein the release rate is controlled to stabilize the retinoid at an optimal therapeutic blood level to increase efficacy and reduce side effects of the retinoid, and
Wherein the retinoid is selected from all-trans retinoic acid, cis-isomeric retinoic acids, retinol, 4- [1- (5, 6,7, 8-tetrahydro-3, 5, 8-pentamethyl-2-naphthyl) vinyl ] benzoic acid, (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid, adapalene, (2E, 4E,6E, 10E) -3,7, 11, 15-tetramethyl-2, 4,6, 10, 14-hexadecano-c-ylic acid, and ethyl (E, E) -7- (2-n-propoxy-5, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octatrienoic acid ester.
16. The transdermal therapeutic application product of any one of claims 13-15, wherein the cis-isomerised retinoic acid is selected from the group consisting of 13-cis retinoic acid and 9-cis retinoic acid.
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