CN105439928B - Prodrugs of retinoids and retinoid-like compounds - Google Patents
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- CN105439928B CN105439928B CN201510594392.3A CN201510594392A CN105439928B CN 105439928 B CN105439928 B CN 105439928B CN 201510594392 A CN201510594392 A CN 201510594392A CN 105439928 B CN105439928 B CN 105439928B
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Abstract
The invention relates to the design and synthesis of prodrugs of positively charged retinoids and retinoid-like compounds having the general formula (31) 'Structure 31'. The compounds can be obtained by reacting retinoic acid and related compounds with suitable alcohols, thiols, or amines via coupling reagents. Experimental results indicate that more than 90% of the prodrug can change back to the parent drug within minutes. In therapy, these prodrugs can be administered transdermally for any kind of treatment, avoiding most of the side effects of retinoids and retinoid-like compounds. The controlled-release transdermal drug delivery system of the prodrug can stabilize the concentration of the vitamin A acids and the retinoid acid compounds in blood at the optimal treatment concentration, improve the curative effect and reduce the side effects of the vitamin A acids and the retinoid acid compounds. Another great benefit of transdermal administration of these prodrugs is that it is more convenient to use, especially for children.
Description
The present application is a divisional application of the chinese patent application No. 200780049882.9. The filing date of the original application is 2007, 01, 15 and the name of the invention is 'positively charged water-soluble prodrugs of retinoids and retinoid-like compounds with rapid skin penetration rate'.
Technical Field
The present invention relates to positively charged and water-soluble prodrugs of retinoids and retinoid-like compounds and their use in treating any therapeutic condition of humans or animals. In particular, the present invention allows retinoids and retinoid-like compounds to penetrate the skin quickly.
Background
Retinoic acid is a class of compounds whose structure contains four isoprenoid building blocks joined in a head-to-tail fashion. The vitamin A acids include all-trans-vitamin A acid (retinoic acid), cis-isovitamin A acid, such as 13-cis-vitamin A acid (isoretinoic acid), 9-cis-vitamin A acid (alitretinoic acid), vitamin A (vitamin A), 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl]Benzoic acid (Bexarotene, tazarotene retinaldehyde, Ratifolio)
(E, E, E) -7- (2-n-propoxy-5, 5, 8, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octenoic acid, adapalene (6- [3- (1-adamantyl) -4-methoxyphenyl]-2-naphthoic acid), acyclic retinoic acid [ (2E, 4E, 6E, 10E) -3, 7, 11, 15-tetramethyl-2, 4, 6, 10, 14-hexadecapentaenoic acid (hexadececapenenoic acid)]Ethyl (E, E) -7- (2-n-propoxy-5, 5, 8, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octtrienoate, and their natural and synthetic derivatives. Various synthetic retinoids and retinoid compounds having retinoid activity are reported in various patents (U.S. Pat. Nos. 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). Retinoids play a very important role in many life processes, including patterns of vision, reproduction, metabolism, differentiation, skeletal development and embryonic development stagesAnd (pattern formation). Vitamin a (vitamin a) and retinal are in chemical equilibrium in the body and have equivalent anti-dry eye activity. Vitamin a combines with opsin, i.e., rod cytochrome in the retina, to form rhodopsin, which is important for the dark adaptation of vision. Deficiency in vitamin A causes night blindness, keratomalacia, keratinization and dry skin, reduced infection resistance, slower growth, thickened bone, reduced corticosteroid production, and fetal malformations (PDR genetics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 3094).
Topical application of retinoic acid (all-trans-retinoic acid) can reduce adhesion of follicular epithelial cells, reduce the formation of fine comedones and stimulate mitosis, increase follicular epithelial cell turnover and cause the discharge of comedones. Topical administration of retinoic acid can treat acne vulgaris, photoaging, pigmented macules (liver spots) and early wrinkles, drug-induced photosensitivity, psoriasis, epidermal scar healing, xerophthalmia, keloids, and cutaneous epidermal keratosis (PDR genetics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 2981). Isoretinoic acid inhibits sebaceous gland function and keratinization. Isoretinoic acid is indicated for the treatment of severe refractory cystic acne, basal cell carcinoma, cervical cancer, mycosis fungoides (cutaneous T-cell lymphoma), darrieus disease, ichthyosis lamellar, pityriasis rubra pilaris, herpes simplex infections, Grover disease, lichen planus, stubborn rosacea, palmoplantar keratosis, leukoplakia mucosae, leukoplakia, and herpes simplex infections,
Squamous basal cell carcinoma and xeroderma pigmentosum. Alitretinoin (9-cis-retinoic acid) is a natural endogenous retinoic acid that binds to and activates all known intracellular retinoic acid receptor subtypes (RAR, RXR, and RXR). These receptors, once activated, act as transcription factors that regulate the expression of genes that control cell differentiation and proliferation in normal and cancer cells. Aliretinoin can inhibit the growth of Kaposi's Sarcoma (KS) cells in vitro. Use of alflavonoic acid for treating Kaposi's Sarcoma (KS) and myelodysplastic disordersSyndrome (I). Rotiferol derivatives are useful in the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, keratinization and keratosis disorders, neoplastic disorders, sebaceous gland disorders such as acne and seborrhea, conditions associated with photodamage, sun-induced skin damage, wrinkles, elastosis and premature aging (Hilpert, et al, u.s.pat.no. 6437142). Adapalene can be used for external treatment of acne vulgaris. Acyclic retinoic acid is used to prevent secondary cancers (Yasutoshi Muto, et al, the New England Journal of Medicine, 340, 1046 (1999)). (E, E, E) -7- (2-n-propoxy-5, 5, 8, 8-tetramethyl-5, 6,7, 8-tetrahydro-naphthalen-3-yl) -6-fluoro-3-methyl-2, 4, 6-octenoic acid may be used in the treatment of type II diabetes and other metabolic diseases (Deng T, et al, biol. pharm. Bull.28(7), 1192, 2005). Taleather ranine
The oral preparation can be used for treating cutaneous T-cell lymphoma (CTCL), head and neck cancer, systemic Kaposi's sarcoma, lung cancer, ovarian cancer, prostate cancer and renal cell carcinoma. Topical administration of tazarotene can be used to treat cutaneous T-cell lymphoma (CTCL).
An alternative mode of administration is topical administration. Topical drug delivery systems have several advantages. This approach helps to avoid first pass metabolism of the drug in the liver and gastrointestinal tract. It can deliver appropriate concentrations of drugs locally to the site of action of interest without systemic exposure. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) states that another problem associated with oral administration is that the concentration of the drug in the blood circulation must be high in order to effectively treat pain or inflammation at the distal site. These concentrations are often much higher than is actually necessary given the direct targeting of the drug to the site of pain or injury. Yeager attempts to administer PGE through penetration enhancers1For the treatment of male erectile dysfunction (Yeager, James L. U.S. Pat. No.6,693,135). Susan Miloovich et al designed and synthesized testosterone 4-dimethylaminobutyrate hydrochloride (TSBH) having a lipid soluble portion and a tertiary amine structure that exists in protonated form at physiological pH. He has a main bodyIt was found that the pro-drug (TSBH) penetrates human skin approximately 60 times faster than the parent drug (TS) [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993)]。
Technical problem
Retinoids and retinoid-like 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 regions on both sides. Retinoids can enter the lipid layer of the membrane, but for similar compatibility reasons they will stay in the membrane as part of it, and not efficiently enter the inner cytoplasm. Since retinoids have highly unsaturated structures, retinoids are very sensitive to ultraviolet rays, air and oxidizing agents. After the vitamin A acid is externally applied, the vitamin A acid can enter a biological membrane but cannot enter the inside of a cell. Sunlight, air or oxidants chemically react with retinoids, causing redness, burning, sloughing, cracking, blistering, or itching of the skin. When they are administered orally, they are destroyed and inactivated within minutes by the first pass effect, i.e. chemical degradation of the compound by the liver and the gastrointestinal tract. Oral administration of retinoids causes unnecessary systemic exposure and causes many side effects.
Solution scheme
The invention relates to design and synthesis of novel vitamin A acids with positive charges and prodrugs of retinoid acid compounds, and medical application thereof. Prodrugs of 9-cis-retinoic acid (alitretinol), 13-cis-retinoic acid (isoretinoic acid), all-trans-retinoic acid (retinoic acid), vitamin a (vitamin a), raloxil (retiferol), adapalene, acyclic retinoic acid, and retinoid compounds have the general formula (1 to 27) "structures 1 to 27":
in the structural formulae 1 to 27, R represents a straight chain or a branched chain, - (CH)2)n-, where n is 0, 1, 2, 3, 4,5, 6,7, 8, 9, 10 … …, in- (CH)2)nIn, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl or other ring system group substitution; r1And R2Each independently may represent the same or different groups and may be H, any alkyl, alkoxy, alkenyl, or alkynyl group of 1 to 12 carbon atoms, aryl, or heteroaryl, or together in combination represent- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl or other ring system groups; r3Represents H, any alkyl, alkoxy, alkenyl or alkynyl group of 1 to 12 carbon atoms, an aryl or heteroaryl group, wherein any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl or other ring system groups; x represents O, S or NH; x1Represents H, OH, Cl, Br, F, I, NO2、NO、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6', alkyl of 1 to 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 alkoxy of 1 to 6 carbon atoms; x2Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 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 alkoxy of 1 to 6 carbon atoms; x3Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms; x4Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkene of 1-6 carbon atomsA group, alkynyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms; x5Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 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 alkoxy of 1 to 6 carbon atoms; x6Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 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 alkoxy of 1 to 6 carbon atoms; r4Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 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 haloalkyl of 1 to 6 carbon atoms; r5Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R6、COR6、COOR6、NR6COR4、SOR6、SR6、PO3R6R6′、SOR6、SR6Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 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 haloalkyl of 1 to 6 carbon atoms; r11Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 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 haloalkyl of 1 to 6 carbon atoms; r12Represents H, OH, Cl, Br, F, I, NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 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 haloalkyl of 1 to 6 carbon atoms; r6And R6' independently of one another may represent the same or different radicals and may be H, Cl, Br, F, I, OH, NO2、CN、SO2R5、COR5、COOR5、NR7COR5、SOR5、SR5、PO3R7R7′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, or haloalkyl, or together represent oxygen (═ O) or- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR7R7', aryl or heteroaryl, or other ring system group substitution; r7And R7Each independently of the others may represent the same or different radicals, and may be H, Cl, Br, F, I, OH, NO2、CN、SO2R5、COR5、COOR5、NR6COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, or haloalkyl, or together represent oxygen (═ O) or- (CH)2)n-, where n ═ 2, 3, 4, and,5. 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; r8And R8' independently of one another may represent the same or different radicals and may be H, Cl, Br, F, I, OH, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, or haloalkyl, or together represent oxygen (═ O) or- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl or other ring system group substitution; r9And R9' independently of one another may represent the same or different radicals and may be H, Cl, Br, F, I, OH, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR5Alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, or haloalkyl, or together represent oxygen (═ O) or- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 1O … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6' aryl or heteroaryl, or other ring system group substitution; r10And R10' independently of one another may represent the same or different radicals and may be H, Cl, Br, F, I, OH, NO2、CN、SO2R5、COR5、COOR5、NR4COR5、SOR5、SR5、PO3R6R6′、SOR5、SR51-6 carbon atomsAlkyl of a sub-group, alkoxy of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, or haloalkyl, or together represent oxygen (═ O) or- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; t represents CH2＝C，CH＝CH，C(CH3)＝CH，C≡C，C＝O、C＝S、CONH，CSNH，COO，OCO，COS，COCH2Or CH2CO；A-Represents Cl-，Br-，F-，I-，AcO-Citrate, or any negative ion; the double bond on the side chain may be in the Z or E configuration; all of R, R1，R2，R3，R4Or is- (CH)2)nThe group may be branched or straight-chain, may contain C, H, O, S, N and other atoms, may contain single, double, triple and cyclic systems.
Absorption of drugs, whether via the gastrointestinal tract or other routes, requires the passage of the drug in a molecular form across a barrier membrane. The drug must first be dissolved and, if the drug has the desired 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 biofilms contain lipids as a major component. The molecules that play a dominant role in 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 regions on both sides. Very hydrophilic drugs cannot pass through the lipid layer of the biofilm while very hydrophobic drugs stay in the biofilm as part of the biofilm for similar compatibility reasons and thus cannot effectively enter the inner cytoplasm.
The invention aims to improve the solubility of the vitamin A acid and related compounds in the moisture on the surface of the skin and improve the penetration rate of the vitamin A acid and related compounds to biological membranes and skin barriers, so that the vitamin A acid and related compounds can be applied through the skin (external application). These novel vitaminsProdrugs of the class of the acids A and related compounds have two identical structural features: they have a lipophilic moiety and a primary, secondary, or tertiary amine group (water-soluble moiety) in the protonated form at physiological pH. Such a water-oil balance is necessary for the drug to be able to effectively cross 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. Retinoids and related compounds have very low solubility in skin surface moisture and do not pass the skin barrier effectively in molecular form. After they have entered the biological membrane of the skin, they remain therein as part of the membrane for similar compatibility reasons and thus do not effectively enter the cytoplasm, a semi-liquid concentrated aqueous solution or suspension inside the cell. When these novel prodrugs are administered transdermally in a dosage form such as a solution, spray, lotion, ointment, emulsion, or gel, they dissolve rapidly in the moisture on the skin surface. The positive charge on the amino group of these pro-drugs will combine with the negative charge on the phosphate head group of the cell membrane. Thus, the local concentration of the drug outside the membrane is high and thus helps the pro-drugs pass from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drug into the cytoplasm. Because of the short residence time of these pro-drugs on the outer side of the biofilm on the skin surface, it does not cause burning, pain, itching or swelling of the skin, and the skin is not sensitive to sunlight. The penetration rate of these prodrugs in human skin isolated from human skin tissue (360-400 microns thick) anterior or posterior to the thigh region was measured in vitro by a modified Franz cell. 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 cross the skin versus time was determined using a specific high performance liquid chromatography method. The donor solution consists of a solution containing 5% of some of the pro-drugs of retinoids, or a suspension of 5% of retinoids, all dissolved in 0.The results are shown in FIG. 1 for a mixture of 2 ml ethanol and pH7.4 phosphate buffer (0.2M) (v/v, 70/30). Calculating the apparent penetration value of human skin to obtain N, N-diethylaminoethyl 9-cis-vitamin A acid ester hydrobromide, N-diethylaminoethyl 13-cis-vitamin A acid ester hydrobromide, N-diethylaminoethyl all-trans vitamin A acid ester hydrobromide, retinyl N, N-dimethyl-2-amino acetate hydrochloride, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl acetate hydrochloride]Benzoate hydrochloride, 9-cis vitamin A acid (Alivitamin A acid), 13-cis vitamin A acid (Isovitamin A acid), all-trans vitamin A acid (vitamin A acid), vitamin A (vitamin A) and Bexarotene
Has an apparent penetration value of 0.72 mg, 0.85 mg, 1.25 mg, 1.21 mg, 0.35 mg, 0.005 mg and 0.001 mg/cm, respectively2In terms of hours. These prodrugs diffuse in human skin about 350 times faster than the vitamin a class drugs. The results demonstrate that the positive charge on the dialkylaminoethyl group is important for the drug to cross biological membranes and skin barriers.
The irritation or adverse response of these novel prodrugs to mouse skin was evaluated by topically applying 0.1 ml of each test drug dissolved in 1% ethanolIn thatThe novel prodrugs were evaluated on the back of nude mice, twice daily, one week later, for irritation or adverse reaction to the mouse skin. p-N, N-diethylaminoethyl-9-cis-retinoate hydrobromide, N, N-diethylaminoethyl-13-cis-retinoate hydrobromide, N, N-diethylaminoethyl all-trans-retinoate hydrobromide, retinyl N, N-dimethyl-2-aminoethyl ester hydrochloride, N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl]No irritation or discomfort was observed with benzoate hydrochloride.
A good prodrug should easily change back to the parent drug structure. In vitro plasma hydrolysis experiments were performed on these prodrugs as follows. 10 mg of the prodrug was dissolved in 0.1 ml of 0.2M phosphate buffered saline pH 7.4. 1 ml of human plasma was preheated to 37 ℃ and added to the mixture. The mixture was incubated in a water bath at 37 ℃. At two minute intervals, 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 hydrolysis of the hydrobromide salt of N, N-diethylaminoethyl 9-cis-retinol ester is 10. + -.1 min, the half-life of hydrolysis of the hydrobromide salt of N, N-diethylaminoethyl 13-cis-retinol ester is 8. + -.2 min, the half-life of hydrolysis of the hydrobromide salt of N, N-diethylaminoethyl all-trans retinol ester is 9. + -.1 min, the half-life of hydrolysis of the hydrochloride salt of retinyl N, N-dimethyl-2-aminoacetic acid ester is 13. + -.2 min, and the half-life of hydrolysis of the hydrochloride salt of N, N-diethylaminoethyl-4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl ] benzoic acid ester is 11. + -.2 min.
Taleather ranine
(Bexarotene) selectively activates a subset of the vitamin A acid receptors known as RXR, which play a central role in the activity of many cells. One of the most important roles is programmed cell death, or "apoptosis," the natural process by which the body removes cells that are not needed for itself. The company Ligand is developing topical and oral formulations of tazarotene. Topical application of tazarotene can be used for treating cutaneous T-cell lymphoma (CTCL). In addition, the oral preparation of tazarotene can be used for treating cutaneous T-cell lymphoma (CTCL), head and neck cancer, systemic Kaposi's sarcoma, lung cancer, ovarian cancer, prostate cancer and renal cell carcinoma. Alitretinoin (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). These receptors, once activated, act as transcription factors that regulate gene expression in normal and tumor cells that control cellular differentiation and proliferation processes. Alivitamin A acid can be used for treatingKaposi's sarcoma, aids-related kaposi's sarcoma, 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 per mouse) were used3Tumor tissue) was implanted subcutaneously in nude mice (BALB). After 1 day, 50. mu.l of 1% N, N-diethylaminoethyl 9-cis-retinoic acid ester hydrobromide and 50. mu.l of 1% N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl ] was applied externally to the area (near the front leg) where the human breast cancer cells were implanted]Benzoate hydrochloride, each dissolved in ethanol/0.2 MpH phosphate buffer solution (v/v, 70/30) at a value of 7.4, was applied twice daily. After 28 days, the tumor incidence in the control nude mice (N ═ 7) was 100% (mean tumor size 13 ± 2 mm × 12 ± 2 cm), and N, N-diethylaminoethyl 9-cis-vitamin a acid ester hydrobromide or N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl ] was administered]No tumors were observed in the treated group of benzoate hydrochloride (n ═ 7) in nude mice. Most importantly, no discomfort or irritation was observed after administration to nude mice. The average body weight of the nude mice in the treatment group is 25 + -2 g, and the average body weight of the nude mice in the blank group is 23 + -3 g. The results of the experiments demonstrate that the side effects of these prodrugs are very slight.
In another experiment, human colon cancer cells (LS174J, 3-4 mm per mouse were used3Tumor tissue) was implanted subcutaneously in nude mice (BALB). After 1 day, 50. mu.l of 1% N, N-diethylaminoethyl 9-cis-retinoic acid ester hydrobromide and 50. mu.l of 1% N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl ] was applied topically to the area (near the front leg) where the human colon cancer cells were implanted]Benzoate hydrochloride, each dissolved in ethanol/0.2M phosphate buffer pH7.4 (v/v, 70/30), was applied twice daily. After 28 days, the tumor incidence in the control group (N ═ 7) was 100% (mean tumor size 22 ± 4 mm × 20 ± 3 mm), and N, N-diethylaminoethyl 9-cis-retinoic acid ester hydrobromide or N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-penta-aminoethylMethyl-2-naphthyl) ethenyl]No tumors were observed in the benzoate hydrochloride treatment group (n ═ 7).
All retinoids are commercially available. The compound represented by the 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 vitamin A acid 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 '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N '-tetramethyluronium tetrafluoroborate, O- (benzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, and the like.
Wherein R represents a linear or branched chain, - (CH)2)n-, where n is 0, 1, 2, 3, 4,5, 6,7, 8, 9, 10 … …, in- (CH)2)nIn, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; r1And R2Each independently may represent the same or different groups and may be H, any alkyl, alkoxy, alkenyl, or alkynyl group of 1 to 12 carbon atoms, aryl or heteroaryl, or together represent- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl or other ring system group substitution; x represents O, S or NH.
The compounds of the general formula (4, 13, 14, 15, 20 or 21) "structural formula 4, 13, 14, 15, 20 or 21" indicated above can be obtained by reacting vitamin A and related compounds thereof with the compounds of the general formula (29) "structural formula 29",
wherein R represents a linear or branched chain, - (CH)2)n-, where n is 0, 1, 2, 3, 4,5, 6,7, 8, 9, 10 … …, in- (CH)2)nIn, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; r1And R2Each independently may represent the same or different groups and may be H, any alkyl, alkoxy, alkenyl, or alkynyl group of 1 to 12 carbon atoms, aryl or heteroaryl, or together represent- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; r3Represents H, any alkyl, alkoxy, alkenyl or alkynyl group of 1 to 12 carbon atoms, an aryl or heteroaryl group, wherein any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; z represents F, Cl, Br or I; a. the-Represents Cl-，Br-，F-，I-，AcO-Citrate, or any negative ion.
When X represents O, the compound represented by the 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 linear or branched chain, - (CH)2)n-, where n is 0, 1, 2, 3, 4,5, 6,7, 8, 9, 10 … …, in- (CH)2)nIn, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; r1And R2Each independently may represent the same or different groups and may be H, any alkyl, alkoxy, alkenyl, alkynyl, aryl or heteroaryl group of 1 to 12 carbon atoms, or together represent- (CH)2)n-, where n ═ 2, 3, 4,5, 6,7, 8, 9, 10 … …, any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6' aryl or heteroaryl, or other ring system group substitution; r3Represents H, any alkyl, alkoxy, alkenyl or alkynyl group of 1 to 12 carbon atoms, an aryl or heteroaryl group, wherein any CH2Can be O, S, CH ═ CH, C ≡ C, CR6R6', aryl or heteroaryl, or other ring system group substitution; z represents F, Cl, Br or I, or p-toluenesulfonyl; a. the-Represents Cl-，Br-，F-，I-，AcO-Citrate, or any negative ion.
Advantages of the invention
The pro-drugs of retinoids and retinoid-like compounds of the invention have a lipid soluble portion and a water soluble portion (amine groups that exist in protonated form at physiological pH). The positively charged amino groups of these prodrugs have two major advantages. First, it greatly increases the solubility of the prodrug in water, which rapidly mixes with surface moisture on the skin, eyes, genital sites, mouth, nose, or other body parts when the prodrug is administered transdermally in the form of a solution, spray, lotion, ointment, emulsion, or gel. Second, the positive charge on the amino group of these pro-drugs can bind to the negative charge on the phosphate head structure of the membrane. Thus, the local concentration outside the membrane will be high, facilitating the penetration of these pro-drugs from regions of high concentration to regions of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the drug into the cytoplasm, a concentrated semi-liquid aqueous solution or suspension. Due to the short residence time on the skin, eyes, genital site, mouth, nose or other body parts, the pro-drugs do not cause itching, burning or pain. Experimental results show that more than 90% of the prodrug returns to the parent drug in a few minutes. These prodrugs are more potent than retinoids and retinoid-like compounds at equivalent doses because of their higher absorption and transdermal delivery to avoid first-pass metabolism. Another great benefit of transdermal administration of these pro-drugs is the ease of administration, particularly to children.
Drawings
FIG. 1: n, N-diethylaminoethyl 9-cis-vitamin a acid ester hydrobromide (5% solution, a), N-diethylaminoethyl 13-cis-vitamin a acid ester hydrobromide (5% solution, B), N-diethylaminoethyl all-trans-vitamin a acid ester hydrobromide (5% solution, C), retinyl N, N-dimethyl-2-aminoacetate hydrochloride (5% solution, D), N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl ] benzyl ester hydrochloride (5% solution, E), 9-cis-vitamin a acid (5% suspension, F) 13-cis-retinoic acid (5% suspension, G), all-trans-retinoic acid (5% suspension, H), vitamin a (5% suspension, I), and beaxarotene (5% suspension, J). In each case, the carrier solution was ethanol/phosphate buffered saline (0.2M) at pH7.4 (v/v, 70/30).
FIG. 2: structure 31, wherein Ret represents a vitamin a acid or a retinoid-like compound; r represents a linear or branched chain, - (CH)2)n-, where n ═ 0, 1, 2, 3, 4,5, 6,7, 8, 9, 10 … …, aryl or heteroaryl; r1And R2Each independently of the other may represent the same or different radicals and may be H, any alkyl, alkoxy, alkenyl or alkynyl group of 1 to 12 carbon atoms, aryl or heteroaryl, or together represent- (CH)2)n-, where n is 2, 3, 4,5, 6,7, 8, 9, 10 … …Any CH2Can be O, S, CH ═ CH, C ≡ C, CR4R3Aryl or heteroaryl, or other ring system group substitution; r3Represents H, any alkyl, alkoxy, alkenyl or alkynyl group of 1 to 12 carbon atoms, or an aryl or heteroaryl group; r4Represents H, any alkyl, alkoxy, alkenyl or alkynyl group of 1 to 12 carbon atoms, or an aryl or heteroaryl group; x represents O, S or NH; a. the-Represents Cl-、Br-、F-、I-、AcO-Citrate, or any negative ion; all R, R1、R2、R3Or- (CH)2)nThe radicals-are branched or unbranched, may contain C, H, O, S or N atoms, and may have single, double and triple bonds.
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-retinol are dissolved in 100 ml of acetonitrile. 26.1 g (0.1 mol) of 2-bromo-N, N-diethylethylamine 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 solid was removed by filtration. The filtrate was evaporated to dryness. 100 ml of ethyl acetate were added to the reaction mixture. 100 ml of hexane were added. The solid product was collected by filtration. Drying gave 36 g of the expected product (75% yield). An easy-to-absorb product; elemental analysis: c26H42BrNO2(ii) a Molecular weight: 480.52. theoretical value% C: 64.99 of the total weight of the powder; h: 8.81; br; 16.63; n: 2.91; o: 6.66; found% C: 65.03; h: 8.80; br: 16.60 parts of; n: 2.89; o: 6.68.
detailed description of the preferred embodiments
Preparation of N, N-diethylaminoethyl 13-cis-vitamin A acid ester hydrobromide
32.2 g (0.1 mol) of sodium 13-cis-retinol are dissolved in 100 ml of acetonitrile. 26.1 g (0.1 mol) of 2-bromo-N, N-diethylethylamine 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 are added to the evaporatedAnd (3) mixing. The solid was removed by filtration. The filtrate was evaporated to dryness. 100 ml of ethyl acetate were added to the reaction mixture. 100 ml of hexane were added. The solid product was collected by filtration. Drying gave 38 g of the expected product (yield 79.1%). An easy-to-absorb product; elemental analysis: c26H42BrNO2(ii) a Molecular weight: 480.52. theoretical value% C: 64.99 of the total weight of the powder; h: 8.81; br: 16.63; n: 2.91; o: 6.66; found% C: 65.03; h: 8.80; br: 16.60 parts of; n: 2.89; o: 6.68.
preparation of N, N-diethylaminoethyl all-trans-vitamin A acid ester hydrobromide
32.2 g (0.1 mol) of sodium all-trans-retinol are dissolved in 100 ml of acetonitrile. 26.1 g (0.1 mol) of 2-bromo-N, N-diethylethylamine 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 solid was removed by filtration. The filtrate was evaporated to dryness. 100 ml of ethyl acetate were added to the reaction mixture. 100 ml of hexane were added. The solid product was collected by filtration. Drying gave 35 g of the expected product (yield 72.9%). An easy-to-absorb product; elemental analysis: c26H42BrNO2(ii) a Molecular weight: 480.52. theoretical value% C: 64.99 of the total weight of the powder; h: 8.81; br: 16.63; n: 2.91; o: 6.66; found% C: 65.03; h: 8.80; br: 16.60 parts of; n: 2.89; o: 6.68.
preparation of N, N-dimethylamino acetic acid retinol (vitamin A) ester hydrochloride
28.6 g (0.1 mol) of vitamin A are dissolved in 100 ml of acetonitrile. 25 ml 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 solid was removed by filtration. The filtrate was evaporated to dryness. 500 ml of ethyl acetate were added to the residue. To the mixture was added 200 ml of 5% sodium carbonate solution with stirring. The organic solution was collected and washed with water (31 g of the expected product after evaporation to dryness (yield 75.5%). hygroscopic product; elemental analysis; C24H38ClNO2(ii) a A molecular weight; 408.02. theoretical value% C; 70.65; h; 9.39; cl; 8.69; n: 3.43; o: 7.84; found% C: 70.60, respectively;H：9.46；Cl：8.71；N：3.42；O：7.81。
preparation of hydrochloride salt of N, N-diethylaminoethyl 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl ] benzoate
34.9 g (0.1 mol) of 4- [1- (5, 6,7, 8-tetrahydro-3, 5,5, 8, 8-pentamethyl-2-naphthyl) vinyl]Benzoic acid (bexarotene, tazarotene) was dissolved in 300 ml chloroform. 20.6 g (0.1 mol) of N, N' -dicyclohexylcarbodiimide were 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 solid was removed by filtration. Chloroform solution with 5% NaHCO3(2X 100 ml) and water (3X 100 ml). The organic solution was dried over anhydrous sodium sulfate. The 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 easy-to-absorb product; elemental analysis: c30H42ClNO2(ii) a Molecular weight: 484.11. theoretical value% C: 74.43, respectively; h: 8.74 of; cl: 7.32 of; n: 2.89; o: 6.61; found% C: 74.39, respectively; h: 8.76; cl: 7.29; n: 2.91; o: 6.65.
industrial applicability
These prodrugs, represented by the general formulae (1-27) 'structures 1-27', are superior to retinoids and retinoid-like compounds. They may be used to treat any condition of the human or animal body which is treatable with retinoids and retinoid-like compounds. They can be used for the treatment of acne, acne scars, psoriasis, ichthyosis, eczema, keratinization disorders, precancerous lesions, drug prophylaxis, warts, sarcoidosis, treatment of photoaging of the skin, prevention of photoaging of the skin, treatment of chronic skin aging, hair loss and various cancers.
Claims (19)
1. A compound represented by the structural formula 1,
wherein the content of the first and second substances,
r represents a linear- (CH)2)n-, where n is 1, 2, 3, 4,5, 6,7, 8, 9, or 10;
R1and R2Each independently may represent the same or different groups and may be H, any alkyl group of 1 to 12 carbon atoms, an alkenyl or alkynyl group of 1 to 12 carbon atoms;
R3represents H;
x represents O, S or NH;
X1represents H; x2Represents H; x3Represents H; x4Represents H; x5Represents H; x6Represents H;
A-represents Cl-、Br-、F-、I-、AcO-Or citrate;
with the proviso that the alkenyl group does not comprise an alkenyl group of 1 carbon atom and the alkynyl group does not comprise an alkynyl group of 1 carbon atom.
2. The compound of claim 1 which is N, N-diethylaminoethyl 9-cis-vitamin a acid ester, HA, wherein a-Represents Cl-、Br-、F-、I-、AcO-Or citrate.
3. A compound represented by the structural formula 2,
wherein the content of the first and second substances,
r represents a linear- (CH)2)n-, where n is 1, 2, 3, 4,5, 6,7, 8, 9, or 10;
R1and R2Each independently may represent the same or different groups and may be H, any alkyl or alkoxy group of 1 to 12 carbon atoms, an alkenyl or alkynyl group of 1 to 12 carbon atoms;
R3representsH；
X represents O, S or NH;
X1represents H; x2Represents H; x3Represents H; x4Represents H; x5Represents H; x6Represents H;
A-represents Cl-、Br-、F-、I-、AcO-Or citrate;
with the proviso that the alkenyl group does not comprise an alkenyl group of 1 carbon atom and the alkynyl group does not comprise an alkynyl group of 1 carbon atom.
4. The compound of claim 3 which is N, N-diethylaminoethyl 13-cis-vitamin A acid ester HA, wherein A is-Represents Cl-、Br-、F-、I-、AcO-Or citrate.
5. A compound represented by the structural formula 3,
wherein the content of the first and second substances,
r represents a linear- (CH)2)n-, where n is 1, 2, 3, 4,5, 6,7, 8, 9 or 10;
R1and R2Each independently may represent the same or different groups and may be H, any alkyl or alkoxy group of 1 to 12 carbon atoms, an alkenyl or alkynyl group of 1 to 12 carbon atoms;
R3represents H;
x represents O, S or NH;
X1represents H; x2Represents H; x3Represents H; x4Represents H; x5Represents H; x6Represents H;
A-represents Cl-、Br-、F-、I-、AcO-Or citrate;
with the proviso that the alkenyl group does not comprise an alkenyl group of 1 carbon atom and the alkynyl group does not comprise an alkynyl group of 1 carbon atom.
6. The compound of claim 5 which is N, N-diethylaminoethyl all-trans-vitamin A acid ester HA, wherein A-Represents Cl-、Br-、F-、I-、AcO-Or citrate.
7. The method for synthesizing a compound represented by structural formula 1, 2 or 3 according to claim 1, 2, 3, 4,5 or 6, wherein the compound can be prepared by reacting retinoic acid and related compounds with a compound represented by structural formula 28 under the action of at least one coupling agent selected from the group consisting of: n, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N '-tetramethyluronium tetrafluoroborate, O- (benzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium Hexafluorophosphate (HBTU);
wherein the content of the first and second substances,
r represents a linear- (CH)2)n-, where n is 0, 1, 2, 3, 4,5, 6,7, 8, 9 or 10;
R1and R2Each independently may represent the same or different groups and may be H, any alkyl or alkoxy group of 1 to 12 carbon atoms, an alkenyl or alkynyl group of 1 to 12 carbon atoms;
x represents O, S or NH;
with the proviso that the alkenyl group does not comprise an alkenyl group of 1 carbon atom and the alkynyl group does not comprise an alkynyl group of 1 carbon atom.
8. The method for synthesizing a compound represented by structural formula 1, 2 or 3 according to claim 1, 2, 3, 4,5 or 6, wherein when X represents O, the compound can be prepared by reacting a metal salt, an organic base salt or an immobilized base salt of retinoic acid or a related compound thereof with a compound represented by structural formula 30:
wherein the content of the first and second substances,
r represents a linear- (CH)2)n-, where n is 1, 2, 3, 4,5, 6,7, 8, 9 or 10;
R1and R2Each independently may represent the same or different groups and may be H, any alkyl or alkoxy group of 1 to 12 carbon atoms, an alkenyl or alkynyl group of 1 to 12 carbon atoms;
R3represents H;
z represents halogen, or p-toluenesulfonyl;
A-represents Cl-、Br-、F-、I-、AcO-Or citrate;
with the proviso that the alkenyl group does not comprise an alkenyl group of 1 carbon atom and the alkynyl group does not comprise an alkynyl group of 1 carbon atom.
9. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 6.
10. Use of a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of conditions treatable with retinoids and retinoid-like compounds in humans or animals, wherein the medicament is administered orally or transdermally.
11. The use according to claim 10, wherein the states treatable with retinoids and retinoid-like compounds include: acne, acne scars, psoriasis, ichthyosis, eczema, keratosis, precancerous lesions, pharmacotherapy against warts, sarcoidosis, treatment of skin photoaging, prevention of skin photoaging, treatment of chronic skin aging, hair loss and various cancers.
12. The use of claim 11, wherein the medicament is in the form of a solution, spray, lotion, ointment, emulsion or gel that is administered transdermally to any part of the body to achieve a therapeutically effective plasma concentration.
13. The use according to claim 11, wherein the medicament is administered topically in the specific disease area.
14. A product for transdermal therapeutic use comprising the pharmaceutical composition according to claim 9.
15. A product for transdermal therapeutic application according to claim 14 wherein the product is a bandage or patch comprising a matrix layer containing the active substance and a non-permeable protective layer.
16. A product for transdermal therapeutic application according to claim 14 wherein the product comprises an active agent reservoir comprising a permeable skin facing base.
17. The transdermal therapeutic application product of claim 14, wherein the product stabilizes the vitamin a acid and retinoid acid compound at optimal therapeutic blood levels by controlling the release rate to enhance therapeutic effects and reduce side effects of the vitamin a acid and retinoid acid compound.
18. The transdermal therapeutic application product of claim 15 wherein the product stabilizes the vitamin a acid and retinoid acid compound at optimal therapeutic blood levels by controlling the release rate to enhance therapeutic efficacy and reduce side effects of the vitamin a acid and retinoid acid compound.
19. The transdermal therapeutic application product of claim 16 wherein the product stabilizes the vitamin a acid and retinoid compound at optimal therapeutic blood levels by controlling the release rate to enhance therapeutic efficacy and reduce side effects of the vitamin a acid and retinoid compound.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4326055A (en) * | 1977-12-22 | 1982-04-20 | Hoffmann-La Roche Inc. | Stilbene derivatives |
| US4656310A (en) * | 1973-03-30 | 1987-04-07 | Hoffmann-La Roche Inc. | Substituted triarylphosphonium derivatives |
| US5972323A (en) * | 1996-08-06 | 1999-10-26 | Wella Ag | Hydrolytically cleavable active ingredient derivative compounds, hair treatment compositions containing them and hair treatment methods |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3950418A (en) * | 1970-02-02 | 1976-04-13 | Hoffmann-La Roche Inc. | Vitamin A acid amides |
| US4588525A (en) * | 1984-02-27 | 1986-05-13 | Molecular Biosystems, Inc. | Prodrug compounds for dermal application |
| JP2672363B2 (en) * | 1989-03-29 | 1997-11-05 | 帝人株式会社 | Organic nonlinear optical material |
| AU2002347747A1 (en) * | 2002-07-23 | 2004-02-09 | Ardenia Investments Ltd. | Retinol derivatives, their use in the treatment of cancer and for potentiating the efficacy of other cytotoxic agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4656310A (en) * | 1973-03-30 | 1987-04-07 | Hoffmann-La Roche Inc. | Substituted triarylphosphonium derivatives |
| US4326055A (en) * | 1977-12-22 | 1982-04-20 | Hoffmann-La Roche Inc. | Stilbene derivatives |
| US5972323A (en) * | 1996-08-06 | 1999-10-26 | Wella Ag | Hydrolytically cleavable active ingredient derivative compounds, hair treatment compositions containing them and hair treatment methods |
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