- A high yield and pilot-scale process for the preparation of adapalene
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Strategies that were adopted during the process development of adapalene to achieve a cost-effective commercial-scale synthesis are described herein. These included (1) the use of AcOH/H2SO4 to afford 2-(1-adamantyl)-4-bromophenol in quantitative yield; (2) the dimethyl sulfate methylation to enhance the yield of methylation to 95%; (3) direct conversion of the Grignard reagent into methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2- naphthoate by the catalysis of both PdCl2-(PPh3) 2 and ZnCl2 in high yield; (4) the use of EDTA-disodium salt dihydrate to ensure the heavy metal's content within acceptable limits; (5) the use of toluene to simplify the original Chromatographic purification to recrystallization. The pilot-scale synthesis of adapalene is described in detail in the Experimental Section.
- Liu, Zhichang,Xiang, Jiannan
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Read Online
- Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors
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To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116.
- Cincinelli, Raffaella,Musso, Loana,Giannini, Giuseppe,Zuco, Valentina,De Cesare, Michelandrea,Zunino, Franco,Dallavalle, Sabrina
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supporting information
p. 251 - 259
(2014/05/06)
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- Ion-exchange-resin-catalyzed adamantylation of phenol derivatives with adamantanols: Developing a clean process for synthesis of 2-(1-adamantyl)-4- bromophenol, A key intermediate of adapalene
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A clean process has been developed for the synthesis of 2-adamantylphenol derivatives through adamantylation of substituted phenols with adamantanols catalyzed by commercially available and recyclable ion-exchange sulfonic acid resin in acetic acid.The sole byproduct of the adamantylation reaction,namely water,could be converted into the solvent acetic acid by addition of a slight excess of acetic anhydride during the work-up procedure,making the process waste-free except for regeneration of the ionexchange resin,and facilitating the recycling of the resin catalyst.The ion-exchange sulfonic acid resin catalyst could be readily recycled by filtration and directly reused at least ten times without a significant loss of activity.The key intermediate of adapalene,2-(1-adamantyl)-4-bromophenol,could be produced by means of this waste-free process.
- Wang, Nan,Wang, Ronghua,Shi, Xia,Zou, Gang
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experimental part
p. 227 - 233
(2012/04/10)
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- New synthesis of 6[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid and evaluation of the influence of adamantyl group on the DNA binding of a naphthoic retinoid
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6[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid (Adapalene), a synthetic aromatic retinoid specific for RARβ and RARγ receptors, has been prepared utilizing a Pd/C-mediated Suzuki coupling between 6-bromo-2-naphthoic acid and 4-methoxyphenyl boronic acid, followed by introduction of an adamantyl group in the position 3 of the formed 6-(4-methoxyphenyl)-2-naphthoic acid. The interaction of 6-(4-methoxyphenyl)-2- naphthoic acid/ethyl ester and the 3-adamantyl analogs with DNA was studied in aqueous solution at physiological conditions by UV-vis spectroscopy. The calculated binding constants Kligand-DNA ranged between 1.1 × 104 M-1 and 1.1 × 105 M-1, the higher values corresponding to those of the adamantylated compounds. Molecular modeling studies have emphasized that the intercalative binding of adapalene and its derivatives to DNA is mainly stabilized by hydrophobic interactions related to the presence of the adamantyl group.
- Milanese, Alberto,Gorincioi, Elena,Rajabi, Mehdi,Vistoli, Giulio,Santaniello, Enzo
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p. 151 - 158
(2011/11/07)
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- S1P RECEPTORS MODULATORS AND THEIR USE THEREOF
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The invention relates to novel compounds that have S1P receptor modulating activity. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, autoimmune response. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as autoimmune response.
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Page/Page column 80
(2010/04/30)
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- METHOD FOR PREPARATION OF 6-[3(1-ADAMANTYL) -4-METHOXYPHENYL]-2-NAPHTOIC ACID
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A method for preparation of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid is disclosed based on “one pot” synthesis approach including a direct synthesis of boronic acid derivative from 2-(1-adamantyl)-4-bromoanisole and cycloboranes with a subsequent Suzuki-Miyaura coupling with 6-halonaphthenoates and basic hydrolysis of the reaction product in ethylene glycol or 1,2-propanediol.
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Page/Page column 2
(2010/04/23)
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- PROCESS FOR PREPARATION OF 6-[3-(1-ADMANTYL)-4-METHOXYPHENYL]-2-NAPHTOIC ACID.
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A process for preparation of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid from 2-(1-adamantyl)-4-bromanisolee is disclosed, based on transformation of 2-(1-adamantyl)-4-bromanisole into a Grignard's reagent by using metallic magnesium, anhydrous lithium chloride and dibromoethane followed by transmetallation with borates to 3-(adamantyl)-4-methoxyphenylboronic acid, which is converted into 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid esters by Suzuki-Miyaura cross-coupling reaction with alkyl-6-halonaftoates catalyzed by Pd [0] or Pd/phosphine ligands and followed by basic hydrolysis in ethylene glycol or 1,2-propanediol of ester thus obtained into 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid.
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Page/Page column 3
(2010/07/04)
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- A PROCESS FOR PREPARATION OF ADAPALENE
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The present invention discloses a process for preparation of highly pure Adapalene, chemically designated as 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (I) comprising: a) reacting 1-adamantanol with 4-bromophenol (II) in presence of sulphonic acid with or without the use of organic solvent to give 2-(l-adamantyl)-4- bromophenol (III); b) alkylating compound of formula(III) with dimethylsulphate in presence of base in organic solvent to obtain 2-(l-adamantyl)-4-bromoanisole (IV); c) C-C coupling the compound of formula (IV) with methyl-6-bromo-2- naphthoate using magnesium, purified zinc chloride and NiCl2-DPPE in THF at a temperature of 40-60°C tO obtain methyl ester of 6-[3-(l- adamantyl)-4-methoxy phenyl] -2-naphthoic acid (V); d) purifying crude methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthoic acid (V) using a mixture of organic solvent to obtain pure compound (V); e) hydrolyzing the compound (V) with a solution of alkali in organic solvent to obtain metal salt of 6-[3-(l-adamantyl)-4-methoxy phenyl] -2-naphthoic acid (VI); f) acidifying metal salt of adapalene (VI) using organic or inorganic acid to obtain crude adapalene (I) and g) recrystallizing the crude adapalene (I) using a mixture of organic solvents to obtain pure adapalene (I).
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- Synthesis and structure-activity relationships of new antiproliferative and proapoptotic retinoid-related biphenyl-4-yl-acrylic acids
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Atypical retinoids, or retinoid-related molecules (RRMs), represent a class of proapoptotic agents with a promising potential in the treatment of neoplastic diseases. In the present work, the synthesis and structure-activity relationship of a series of 3′-adamantan-1-yl-biphenyl-4-yl-acrylic acids substituted in ring A were studied. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocitic leukemia cell line (NB4), and in an ovarian carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-resistant subline, IGROV-1/Pt-1. The presence of at least one oxygenated substituent in positions 4′ or 5′ appears determinant for the antiproliferative activity. With two substituents of this kind the activity increases, particularly in the case of alkylenedioxy compounds. The activation of DNA damage response as indicated by phosphorylation of H2AX histone, RPA-2 protein, and p53 at serine 15 by the most apoptotic compounds provides additional support to the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this group.
- Cincinelli, Raffaella,Dallavalle, Sabrina,Nannei, Raffaella,Merlini, Lucio,Penco, Sergio,Giannini, Giuseppe,Pisano, Claudio,Vesci, Loredana,Ferrara, Fabiana Fosca,Zuco, Valentina,Zanchi, Chiara,Zunino, Franco
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p. 4863 - 4875
(2008/03/15)
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- NOVEL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER, METABOLIC DISEASES AND SKIN DISORDERS
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The present invention is directed to novel compounds according to formula (I) wherein R1, R2, and X are as defined herein. The invention also discloses methods of preparation, pharmaceutical compositions, and methods of disease treatment utilizing pharmaceutical compositions comprising these compounds. The compounds of this invention are novel therapeutic agents for the treatment of cancer, diabetes, metabolic diseases and skin disorders in mammalian subjects. These compounds are also useful modulators of gene expression. They exert their activity by interfering with certain cellular signal transduction cascades. The compounds of the invention are thus also useful for regulating cell differentiation and cell cycle processes that are controlled or regulated by various hormones or cytokines. The invention also discloses pharmaceutical compositions and methods of treatment of disease in mammals.
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Page/Page column 50-51
(2008/06/13)
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- NOVEL THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER, METABOLIC DISEASES AND SKIN DISORDERS
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The present invention is directed to novel compounds according to formulae (I) wherein R1, R2, R3 and R4 are as defined herein. The invention also discloses methods of preparation, pharmaceutical compositions, and methods of disease treatment utilizing pharmaceutical compositions comprising these compounds. The compounds of this invention are novel therapeutic agents for the treatment of cancer, diabetes, metabolic diseases and skin disorders in mammalian subjects. These compounds are also useful modulators of gene expression. They exert their activity by interfering with certain cellular signal transduction cascades. The compounds of the invention are thus also useful for regulating cell differentiation and cell cycle processes that are controlled or regulated by various hormones or cytokines. The invention also discloses pharmaceutical compositions and methods of treatment of disease in mammals.
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Page/Page column 47
(2008/06/13)
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- Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes
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The retinoic acid receptors (RARs) transduce retinoid dependant gene regulation, and many biological effects of retinoids are mediated through binding and activation of three closely related receptor subtypes (RARα, RARβ, and RARγ). In order to investigate the role of receptor subtypes, we have carried out a chemical synthesis program to seek selective retinoids for these receptors. We measured receptor binding affinity using recombinant RARα, -β, and -γ proteins and assessed cellular differentiating activity in F9 murine teratocarcinoma cells (F9 cells). This research has identified the 4-substituted-3-(1-adamantyl)phenyl moiety as a new pharmacophore which can replace the β-cyclogeranylidene ring of the naturally ocurring all- trans-retinoic acid. Two chemical series derived from the general structures 6-(3-tertioalkyl-phenyl)-2-naphthoic acid (series I) and 4-[(E)-2-(3- tertioalkylphenyl)propenyl]benzoic acid (series II) were developed. In particular, we have obtained the RARγ selective derivatives 6-[3-(1- adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (7) [K(i)(RARα) = 6500 nM, Ki(RARβ) = 2480 nM, K(i)(RARγ) = 77 nM] and 4-[(E)-2-[3-(1-adamantyl)-4- hydroxyphenyl]propenyl]benzoic acid (19) [K(i)(RARα) = 1 144 nM, K(i)(RARβ) = 1245 nM, K(i)(RARγ) = 53 nM]. In series I, the presence of a phenol group, irrespective of the nature of tertioalkyl group, imparted at least partial RARγ selectivity, whereas in series II, the presence of both adamantyl and phenol groups is needed to confer RARγ selectivity. The RARγ selective ligands induce differentiation in F9 cells (7, AC50 = 33 nM; 19, AC50 = 66 nM). From series I, a mixed RARβ-γ agonist with potent cellular differentiating activity was selected for development as a topical antiacne agent, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (5, CD 271) [K(i)(RARα) = 1100 nM, K(i)-(RARβ) = 34 nM, K(i)(RARγ) = 130 nM, AC50(F9) = 37 nM]. Finally, from series II, we have obtained a weak antagonist in the F9 cellular differentiation assay, 4-[(E)-2-(3-tert-butyl- 4-hydroxyphenyl)propenyl]benzoic acid (15, IC50 = 700 nM).
- Charpentier,Bernardon,Eustache,Millois,Martin,Michel,Shroot
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p. 4993 - 5006
(2007/10/03)
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- Process for the preparation of 1-adamantane derivatives
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A process for the preparation of 1-adamantane derivatives characterized by the fact that a 1-acyloxyadamantane, in which the acyl group contains 1 to 4 carbon atoms, is reacted with a receptor compound in a linear aliphatic or cycloaliphatic type solvent in the presence of concentrated sulfuric acid and at ambient temperature.
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- Benzonaphthalene derivatives and compositions
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A benzonaphthalene compound has the formula STR1 wherein R1 represents (i) STR2 or (ii) --CH2 OH; R6 represents STR3 or OR7 wherein R7 represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' or r" represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl or a residue of an amino acid or a sugar, or together form a heterocycle; R2 represents hydrogen, alkyl having 1-15 carbon atoms, alkoxy having 1-4 carbon atoms or a cycloaliphatic radical; R3 represents hydrogen, hydroxy, alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphatic radical, a thiocycloaliphatic radical or --O--Si(CH3)2 --R8 wherein R8 represents lower alkyl; and R4 and R5 represent hydrogen, lower alkyl, hydroxy or lower acyloxy. This compound is useful in the topical and systemic treatment of dermatologic diseases and in the treatment of the degeneration of conjuctive tissues. The compound also possesses anti-tumor activity.
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