- Process for the preparation of tazarotene intermediates and use thereof for the preparation of tazarotene
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The present invention provides a novel intermediate of ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl] nicotinate or a pharmaceutically acceptable salt thereof and a process for its preparation. The present invention also provides for the preparation of ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl] nicotinate of Formula I or a pharmaceutically acceptable salt thereof using the intermediate.
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Page/Page column 8
(2010/11/28)
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- PROCESS FOR THE PREPARATION OF ACETYLENIC RETINOID
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A process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4- dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1,comprising, (a) cyclizing phenyl-3-methylbut-2-enylsulfide, a compound of formula 6, in presence of an acid selected from sulfuric acid or p-toluenesulfonic acid to yield 4,4-dimethylthiochroman, a compound of formula 2; (b)acetylating the compound of formula 2, to 4,4 -dimethyl-6-acetylthiochroman, a compound of formula 3; (c)(i) reacting the compound of formula 3 with hydrazine;(ii) reacting resultant product of step (i) with iodine; (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6- ethynyl thiochroman, a compound of formula 4 and (d) reacting the compound of formula 4 with ethyl-6-halonicotinate, a compound of formula 5, wherein X is Cl or Br, in presence of cuprous halide, a transition metal and an inorganic base.
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Page/Page column 19
(2008/06/13)
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- Disubstituted chalcone oximes as selective agonists of RAR retinoid receptors
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Compounds of the formula where the variables are as defined in the specification, are useful for preventing or treating emphysema and related pulmonary conditions of mammals and other diseases and conditions which are responsive to RARγ agonist retinoids, such as skin related diseases, including but not limited to acne and psoriasis.
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Page/Page column 19
(2008/06/13)
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- Process for the preparation of 4,4-dimethyl-6-ethynylthiochroman
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An improved process for the preparation of key intermediates for tazarotene, 4,4-dimethyl-6-ethynylthiochroman, is provided comprising (a) reacting 4,4-dimethyl-6-acetylthiochroman of the formula with an acid chloride and an amido-group containing compound of the general formula wherein R is hydrogen or a hydrocarbyl of from 1 to 15 carbon atoms and R1 and R2 can be the same or different and are hydrocarbyls of from 1 to 15 carbon atoms or R1 and R2 together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms, or one of R1 and R2 together with the nitrogen atom to which it bonded are joined together with the carbonyl radical to form a heterocyclic group, optionally containing one or more additional heterocyclic atoms to form a β-chloro vinyl carbonyl compound intermediate of the general formula wherein R has the aforestated meanings; and (b) reacting the β-chloro vinyl carbonyl compound intermediate with an alkali metal to provide the 4,4-dimethyl-6-ethynylthiochroman.
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- PROCESS FOR THE PREPARATION OF DISUBSTITUTED ACETYLENES BEARING HETEROAROMATIC AND HETEROBICYCLIC GROUPS
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A process for the preparation of a disubstituted acetylene bearing heteroaromatic and heterobicyclic groups of formula I is provided wherein X is S, O, or NR1 wherein R1 is hydrogen or a C1-C6 straight or branched alkyl group; R is hydrogen or a C1-C6 straight or branched alkyl group; A is a substituted or unsubstituted pyridinyl, thienyl, furyl, pyridazinyl, pyrimidinyl or pyrazinyl group; n is 0--4; and B is H2 -COOH, -CH2OH, -CHO or a C1-C6 alkyl acetal derivative, -COR2or a C1-C6 alkyl ketal derivative where R2 is -(CH2),,,CH3 where m is 0-4 or COOR3 wherein R3 is a straight or branched C1-C30 alkyl group, a substituted or unsubstituted C6-C30 aromatic group, a substituted or unsubstituted C3-C30 cycloalkyl, a substituted or unsubstituted C3-C30 cycloalkylalkyl, a substituted or unsubstituted C3-C30 cycloalkenyl, a substituted or unsubstituted C5-C30 aryl, a substituted or unsubstituted C5-C30 arylalkyl, a substituted or unsubstituted C5-C30heteroaryl, a substituted or unsubstituted C3-C30 heterocyclic ring, a substituted or unsubstituted C4-C30 heterocyclylalkyl, a substituted or unsubstituted C6-C30 heteroarylalkyl, the process comprising a Sonogashira coupling reaction between a compound of formula II wherein X and R have the aforestated meanings, with a compound of formula III wherein X' is a halogen and A, n and B have the aforestated meanings, in the presence of a base and a transition metal catalyst and in a polar aprotic solvent.
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Page/Page column 9-10
(2010/02/15)
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- Heteroarotinoids as anticancer agents
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Novel heteroarotinoid compositions characterized by the formulae: STR1 where: X is S or O; OAc is the acetate group STR2 and R is --H, --OH, --OCH3, or --OC2 H5 and includes STR3 for formulae (1) and (2). Such compositions exhibit activity as anticancer agents.
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- Heteroarotinoid compounds as anticancer agents
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Novel heteroarotinoid compositions characterized by the formulae: STR1 where R is H, CH3 or C2 H5 and X is S, S O, O, NCH3, Si(CH3)2, N+ (H)CH3 [Cl- ], N+ (H)CH3 [Br- ] or N+ (alkyl) CH3 [Cl- or Br-) where alkyl is CH3, C2 H5, CH2 =CHCH2 or C6 H5 CH2. Such compositions exhibit activity as anticancer agents.
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- Heteroarotinoids as anticancer agents
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Novel heteroarotinoid compositions characterized by the formulae: STR1 where: X is S or O; OAc is the acetate group STR2 and R is --H, --OH, --OCH3, or --OC2 H5 and includes STR3 for formulae (1) and (2). Such compositions exhibit activity as anticancer agents.
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- Heterocyclic compounds
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Novel p-[2(4,4-dimethyl-6-heterophenyl)substituted phenyl derivatives and salts thereof which are useful for combatting neoplasms and dermatoses including oral and topical compositions containing said derivatives which are suitable for such uses.
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- Synthesis and Characterization of Selected Heteroarotinoids. Pharmacological Activity as Assessed in Vitamin A Deficient Hamster Tracheal Organ Cultures. Single-Crystal X-ray Diffraction Analysis of 4,4-Dimethylthiochroman-6-yl Methyl Ketone 1,1-Dioxide and Ethyl (E)-p-<2-(4,4-Dimeth...
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There is reported the first four members of heteroarotinoids, the names of which are ethyl (E)-p-benzoate (1b), ethyl (E)-p-benzoate (1c), ethyl (E)-p-benzoate (1d), and (E)-p-benzoic acid (1e).IR, 1H NMR and 13C NMR data have been recorded for each compound and support the structural assignments.To provide a firm basis for comparison purposes of future analogues, an X-ray analysis was performed on asingle crystal of ethyl (E)-p-benzoate (1b) and a precursor 4,4-dimethylthiochroman-6-yl methyl ketone 1,1-dioxide (18).These data for the heteroarotinoid 1b revealed that the two aryl ring systems were nearly perpendicular in each of the two molecules present in the unit cell (86.37 deg and 84.17 deg, respectively).The space group for both molecules was P1 in triclinic systems.Unit cell dimensions (at 15 deg C) are as follows: for 1b, a = 20.568 (6) Angstroem, b = 14.760 (3) Angstroem, c = 7.679 (2) Angstroem, α = 113.33 (2) deg, β = 79.45 (2) deg, γ = 79.98 (2) deg, Z = 4; for 18, a = 9.292 (5) Angstroem, b = 9.291 (5) Angstroem, c = 7.951 (3) Angstroem, α = 102.16 (3) deg, β = 77.49 (3) deg, γ = 79.60 (4) deg, Z = 2.The sulfur containing ring is in a distorted half-chair in 1b and the methyl carbon C(12) is shown to be trans to H(13) at the C(11)-C(13) bond.The biological activity of these arotinoids was determined in the tracheal organ culture asssay and compared with trans-retinoic acid for ability to reverse keratinization in vitamin A deficient hamsters.The ester 1b displayed activity about one-half log unit less than of the ref erence while 1c and 1e had activity nearly one log until less than trans-retinoic acid.The sulfoxide was the least active of the heteroretinoids.
- Waugh, Kristy M.,Berlin, K. Darrell,Ford, Warren T.,Holt, Elizabeth M.,Carrol, John P.,et al.
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p. 116 - 124
(2007/10/02)
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- Conformationally Restricted Retinoids
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A series of conformationally restricted retinoids was synthesized and screened in two assays used to measure the ability of retinoids to control cell differentiation, namely, the reversal of keratinization in tracheal organ culture from vitamin A deficient hamsters and the inhibition of the induction of mouse epidermal ornithine decarboxylase by a tumor promoter.These compounds had bonds corresponding to selected bonds of the E-tetraene chain of retinoic acid (1) held in a planar cisoid conformation by inclusion in an aromatic ring.The meta-substituted analogue 3 of 4-benzoic acid (2) was far less active than 2 in both assays.In contrast, the vinyl homologue of 2 (4) and the 7,8-dihydro and 7,8-methano analogues (5 and 6) had activity comparable to that of 2.Analogues of 4-benzoic acid (7) were also screened.Replacement of the tetrahydronaphthalene ring of 7 by a benzonorbornenyl group (9) significantly reduced activity, as did removal of the vinylic methyl group from 9 (10).Replacement of the propenyl group of 9 by a cyclopropane ring (12) also reduced activity.Replacement of the tetrahydronaphthalene ring of 7 by 4,4-dimethyl-3,4-dihydro-2H-1-benzopyran and -benzothiopyran rings (13 and 14) also decreased activity.Inclusion of the 7,9 double bond system of 1 in an aromatic ring (15 and 16) reduced activity, whereas inclusion of the 5,7 double bond system in an aromatic ring enhanced activity (7 and 19).Inclusion of the 11,13 and 9,11,13 double bond systems in aromatic rings (2 and 18) also reduced activity below that of 1.Retinoic acid, 7, 13, 14, and 19 inhibited papilloma tumor formation in mice.Toxicity testing indicated that 7 was more toxic than 1, 13, 14, and 19, 19 was more toxic than 1, and 13 and 14 were less toxic than 1.
- Dawson, Marcia I.,Hobbs, Peter D.,Derdzinski, Krzysztof,Chan, Rebecca L.-S.,Gruber, John,et al.
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p. 1516 - 1531
(2007/10/02)
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