WO1998007716A2 - Agents anticancereux hetero-arotinoides possedant une specificite en matiere de recepteurs et une activite de tgase - Google Patents

Agents anticancereux hetero-arotinoides possedant une specificite en matiere de recepteurs et une activite de tgase Download PDF

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WO1998007716A2
WO1998007716A2 PCT/US1997/014720 US9714720W WO9807716A2 WO 1998007716 A2 WO1998007716 A2 WO 1998007716A2 US 9714720 W US9714720 W US 9714720W WO 9807716 A2 WO9807716 A2 WO 9807716A2
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Kenneth Darrel Berlin
Shanker Subramanian
Eldon Carl Nelson
Matora May Madler
Manford Kenneth Patterson, Jr.
Paul Joseph Birckbichler
Doris Mangiaracina Benbrook
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Oklahoma State University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to anticancer compositions in terms of receptor binding and activation as well as activity in stimulating formation of the enzyme transglutaminase as a marker for anticancer activity. Specifically, the invention relates to certain heteroarotinoids and derivatives thereof.
  • Retinoids (vitamin A and derivatives thereof) is a name associated with a family of compounds both of natural and synthetic origin. There is significant interest in such molecules because of the observed strong anticancer activity in a number of assays including the hamster tracheal organ culture (TOC) assay, the ornithine decarboxylase (ODC) assay, and with HL-60 cells (human leukemic cell line).
  • Heteroarotinoids are a group of derivatives which contain an aromatic ring and at least one heteroatom in a fused, partially saturated ring bonded to an aromatic ring. Examples of heteroarotinoids and the activity of such in the assays cited above are found in several papers such as in the Journal of Medicinal Chemistry, 1985, Vol.
  • TGase transglutaminase
  • RAR- ⁇ Certain human retinoic acid receptors have been isolated and are labelled RAR- ⁇ , RAR- ⁇ , and RAR- ⁇ , There have also been identified rather non-specific retinoid receptors designated as RXR- ⁇ , RXR- ⁇ , and RXR- ⁇ . These receptors are proteins which, when bound to an active agent, elicit a specific biological response. The exact tissue distribution of RARs and RXRs is still under investigation [See "Regulation of Gene Expression by Vitamin A. The Role of Nuclear Retinoic Acid Receptors", published in Annual Reviews of Nutrition, 1992, Vol. 12, pages 443-471 , by D. L. Hill and C. J. Grubbs].
  • the present invention involves certain unusual heteroarotinoids and the identification of receptor specificity of action as well as the induction of TGase activity by the retinoids.
  • the receptor specificity is very important for the inducement of specific biological reponses such as in development of normal versus cancerous conditions in specific tissues.
  • Table I contains representative structures for certain heteroarotinoids in the TGase assay along with data for tr ⁇ ns-retinoic acid (1) as the standard for each individual test compound. The greater the R value for the heteroarotinoid the greater the degree of activity
  • G symbolizes a propenyl type double bond, such as in systems 3, 4, 7, 9, 10, 12, 14, 16, 18, 19, 22, 24, 25, 27, 28, 30, 33, 34, 36, 42, 43, 45, 93, and 94, an amide type bond, such as in 2, 6, 21, 23, 26, 29, 31, 32, 35, 38, 39, 41, 123, and 124, an acryloyl type bond as in 5 (see Table I), and an oxycarbonyl or carbonyloxy group as in 96-102, 104, 107, 114, 122, 126, 134, and 138.
  • the X is O, S, NCH 3 , NC 2 H 5 , NCH2CH2CH3, or NCH(CH 3 ) 2 .
  • Compound 1 is ./' ⁇ /15-retinoic acid (7-RA) and is the standard used in the experiments.
  • HETEROAROTINOIDS DECREASING BINDING POTENCY WITH SPECIFIC HUMAN RETINOIC ACID RECEPTORS 3
  • the systems possess a fused five-six or a fused six-six ring unit with a heteroatom in the partially saturated ring.
  • novel heteroarotinoid compositions are heteronuclear rings, organic compounds shown below with the letters A, G, L, M, Q, R, T, X, and Y representing the groups illustrated. Although these compounds are structurally related to .ra/..s--retinoic acid (1), they are also unique in that they possess a heteroatom as well as a least one aromatic ring and in some cases two aromatic rings as illustrated.
  • the connecting group G in fused six-six-membered ring systems 2, 6, 26, 29, 32, 35, 39, 123, and 124 is somewhat flexible amide bridge as is true for 21, 23, 38, and 41 in the fused five-six-membered ring systems. Systems 3, 4, 7, 9, 10, 11, 12, 13, 14-20, 22, 24, 25, 27, 28, 30, 33, 34, 36, 37, 40, 42 ⁇ 5, 93, and 94 have a propenyl or polyene link or side chain for G.
  • Retinoic acid receptors are proteins which are known to be expressed in vivo as RAR ⁇ (ubiquitous), RAR ⁇ (kidney, heart, and skeletal muscle), and RAR ⁇ (skin and bones), respectively.
  • RAR ⁇ ubiquitous
  • RAR ⁇ kidney, heart, and skeletal muscle
  • RAR ⁇ skin and bones
  • Table II data are given in terms of potency of the minimum concentration of the heteroarotinoid required to bind to the specific receptor as compared to the concentration required of the standard 9- -retinoic acid.
  • the concentration required for a heteroarotinoid to bind to a specific receptor type the more active the heteroarotinoid for binding purposes and for inducing a specific biological response such as the differentiation of normal cell development in the production of normal skin cells, liver cells, etc.
  • Table III Data in Table III were obtained from an assay which involved the treatment of a CC-B cervical tumor cell line, which contained stabilized, integrated copies of RAR ⁇ - RARE-tk-CAT reporter plasmid, with the test heteroarotinoid with a separate experiment with /ra/.s-retinoic acid (1) as a control.
  • the values in Table III refer to percent of control in terms of ability to activate endogenous nuclear receptors.
  • Table III also contains data on ability of the heteroarotinoids to inhibit growth of cervical carcinoma cells (CC- 1 or CC-B) as percentage relative to that of the control, and the data are influenced by the same parameters as cited above for the receptor activation.
  • Table I demonstrates that the compounds induce transglutaminase enzyme in leukemia tumor cells.
  • Transglutaminase is a marker of differentiation and apoptosis, two activities that induce anticancer effects.
  • the heteroarotinoids reverse the loss of normal differentiation which is characteristic of tumor cells and thus restorethe cells to a more natural state and reduce their ability to spread within the body.
  • Human cells have a natural mechanism whereby the detect and eliminate abnormal cells via a self-induced suicide event called apoptosis.
  • Heteroarotinoids reduce tumor growth (Table III) via stimulation of apoptosis.
  • heteroarotinoids regulate biological activities to a lesser extent but are more selective than rran.s'-retinoic acid (1) and are therefore more likely to exhibit improved therapeutic ratios compared to 1.
  • Table II there is shown a strong selectivity of the heteroarotinoids for individual nuclear receptors. Therefore, by exhibiting a preference for one or two of the three retinoic acid receptors, heteroarototinoids will effect a different profile of biological activities that will in turn influence the chemotherapeutic ratio.
  • Ketone 48 is the key precursor of 19, 20, 34, and 37 via Scheme III. Intermediates 60-63 are also unknown , but these compounds were fully characterized.
  • the thiosemicarbazone derivative 97 is also the first example of such a derivative in the family of heteroarotinoids.
  • Certain thiosemicabazones have displayed useful anticancer activity as found in an article in the Journal of Medicinal Chemistry, 1995, vol. 38, pages 4234-4243, entitled "Synthesis and Antitumor Activity of 4- and 5-Substituted Derivatives of Isoquinoline- 1 -carboxyaldehyde Thiosemicarbazone" by M. C. Lium, T. P. Lim, P. Penketh, and A. C. Sartorelli.
  • Esters 98-102 in Scheme XII possess a small variations in terminal functional groups with the basic heterocyclic skeletal unit intact.
  • Example 102 allowed appraisal of the effect of a fused five-six-membered ring system on the activity while the other examples of 98-101 possessed the six-six-membered groups in the basic structure.
  • Examples 99 and 100 allow an assessment of two different heterocyclic rings on activity as well as hydrophilicity which can be very beneficial in agent formulation.
  • anticancer activity of the agents will be regulated.
  • Scheme XVIII outlines the synthesis of a novel heteroarotinoid in which the heteroatom (oxygen in this case, but the sulfur atom could also be utilized) is repositioned at a new location in the cyclohexyl ring unit.
  • the method involves 127 ⁇ 128-.129 ⁇ 130 ⁇ 131 ⁇ 132 ⁇ 133 ⁇ 134, the latter being the target molecule.
  • Methylation alpha to the nitrile group in 127 gave 128 which, when subjecte to basic hydrolysis, gave 129. Reduction of the carboxyl group in 129 produced alcohol 130.
  • the defense for this type of heteroarotinoid is that the new position of the heteroatom in the cyclohexyl ring and the flexible linker group will influence receptor binding and anticancer activity.
  • Target system 138 in Scheme XIX was designed as a model system for 134 since the former does not possess a heteroatom in the cyclohexyl ring unit.
  • Ether 135 was acetylated under standard conditions to yield ketone 136.
  • Haloform type conditions converted 136 to 137 although the reaction had to be done with care.
  • Esterification of 137 paralleled the method used to obtain 134 illustrated previously.
  • 138 allows a comparison of the influence on anticancer activity by the absence of the heteroatom.
  • Ester 26 (0.15 g, 0.39 mmol) in 95% ethanol (7 mL) was treated with 2 N NaO ⁇ (10 eq, 3.9 mmol). After stirring the solution for 4 h, the mixture was acidified with 2 N ⁇ C1 (30 mL) which produced a white foam that was filtered, washed ( ⁇ 2O), dried, and recrystallized (EtOAc:hexane; 2: 1). The yield of 2 was 0.1 g (68%) with a mp of 208-209.5
  • Ester 26 was prepared from amine 56 which was synthesized as follows. Nitro- substituted compound 79 (0.69 g, 2.7 mmol) was dissolved in acetic acid (25 mL) and water (5 mL) with vigorous stirring. Then TiCl3/HCl (28.06 g, 18 mmol) was added dropwise, and the resultant mixture was stirred at RT (2 h). After being cooled to 0 °C, the mixture was treated slowly with 30% NaOH (1 10 mL). Extracts (ethyl acetate followed by H 2 CCI2) of the aqueous phase were combined with the organic layer and washed with water and saturated NaHCO3.
  • Nitro-substituted compound 79 was obtained from the reaction involving dropwise addition of a solution of cold cone HNO 3 (3 mL) with acetic anhydride (9 mL) into a solution of ether 78 (4.35 g, 21.0 mmol) dissolved in acetic anhydride (8 mL) at 0 °C. After stirring 1 h, the solution was poured into a saturated solution (-100 mL) of NaHCO3, and the resulting mixture was extracted (H2CCI2). The organic layer was washed with water and brine and then dried (Na2SO 4 ).
  • ester 12 (0.22 g, 0.57 mmol), ethanol (10 mL), water (10 mL), and NaO ⁇ (0.04 g, 1.9 mmol) was boiled for 6 h and then cooled slowly to RT.
  • the new solution was chilled to 0 °C and was then treated with cone ⁇ C1 ( ⁇ 8 mL, p ⁇ ⁇ 2) to yield a solid.
  • the solid was washed well with water, air dried, and then dried under vacuum to give acid (E)-9 as needles (0.17 g, 0.49 mmol, 63%) with a mp of 171-172 °C.
  • ester 14 (0.32 g, 0.80 mmol), 95% ethanol (20 mL), water (5 mL), and
  • Salt 84 was prepared as follows. A solution of 4-thia- ⁇ -ionone (54, 8.0 g, 0.38
  • ester 37 (0.150 g, 0.48 mmol), KOH (1 mL, 35% aqueous), and ethanol
  • ester 23 (0.56 g, 1.61 mmol) in absolute ethanol (20 mL) was added dropwise 2 N ⁇ aOH (10 eq., 16.1 mmol), and the solution was boiled for 4 h. After acidification of this solution with HCl (2 N, 0 °C, -50 mL), the resulting mixture was stored in a freezer for 12 h. A white solid formed and was filtered off, washed with water, dried, and recrystallized (hexane:EtOAc, 2: 1). The crystals of 21 were dried under vacuum for 12 h and had a mp of 219-220 °C.
  • Acid 59 was prepared as follows: Ketone 47 (1.0 g, 5.26 mmol), dissolved in ethanol (17 mL), was treated with commercial clorox (50 mL), and the resultant solution 5 was boiled with stirring for 5 h and then was stirred at RT (5 h). The cooled (0 °C) reaction mixture was cautiously treated with a 25% solution of sodium metabisulfite (-50 mL) followed by cone HCl (-10 mL). A white solid formed in the mixture, after which another 70 mL of sodium metasulfite solution was added. The solid was filtered, dried, and recrystallized (ethanol) to yield 59 (0.71 g, 3.69 mmol) with a mp of 175-175 ⁇ C. IR (KBr)
  • Phosphonium salt 71 was prepared as follows. A mixture of thiochroman-4-one (3 g, 18 mmol), toluene (75 mL), water (120 mL), cone HCl (60 mL), and the Clemmenson- Martin amalgam (50 g) [E. L. Martin, Journal of the American Chemical Society, volume 58, pages, 1438-1432 (1936)] was boiled for 72 h with additional cone HCl (-20 mL) being added every 6 h to maintain a total volume of about 500 mL. After the mixture had cooled to RT, it was filtered, and the aqueous layer was extracted (toluene). The combined organic phases were washed with saturated NaHCO3, water, and brine.
  • ester 33 (0.25 g, 0.54 mmol) in ethanol (10 mL), water (10 mL), and
  • Ester 35 (0.4 g, 1.0 mmol), 95% ethanol (5 mL), and 2 N ⁇ aO ⁇ (10 eq) were boiled for 1 h and then stirred at RT for 48 h. Acidification of the solution with 2 N ⁇ C1 (-50 mL) produced a white solid which was filtered, washed with water, dried, and recrystallized (95% ethanol) to give a flaky solid 32 (0.26 g, 65%) with a mp of 331-331.8 °C.
  • IR (KBr) 3380, 3350, 1700 c ⁇ r 1 ; ! ⁇ ⁇ MR (DMSO-t/ 6 ) ⁇ 1.37 [s, 6 H], 1.46 [s, 6 H], 2.31 [s, 2 HJ,
  • Salt 61 was obtained as follows. Ketone 48 (2.0 g, 1 1.2 mmol) in dry THF (20 mL) was added dropwsie to a suspension of LiAlH 4 (1.266 g, 33.3 mmol) in dry THF ( 10 mL) over 10 min. The resultant mixture was boiled for 24 h with aliquots of dry ether ( 10 mL each) being added to maintain volume after 8 and 16 h. The mixture was allowed to cool to RT, and then it was chilled in ice. Extremely cautious addition of water was initiated to destroy excess LiAlH 4 over 0.5 h. A white precipitate formed, and the mixture, while still cool, was treated slowly with 5% HCl (80 mL) with stirring over 80 min.
  • Acid 76 was prepared as follows. To a solution of ketone 52 (2.0 g. 8.0 mmol) in ethanol (20 mL) was added commercial clorox (150 L), and the turbid mixure was stirred
  • Salt 63 was obtained as follows. Ketone 48 (4.0 g, 22.4 mmol) in dry THF (25 mL) was added dropwise over 0.25 h to a vinylmagnesium bromide [obtained from reaction of vinyl bromide (20 g, 187.9 mmol) in dry THF (35 mL) by standard procedures] using a dry- ice condenser. After being held at reflux for 2 h, the reaction mixture was stirred at RT (10 h). The mixture was then cooled in a water bath, and a saturated NH 4 CI (20 mL) was added dropwise. Two layers formed and the aqueous layer was extracted (ether), and the combined extracts were washed with brine and then dried (Na 2 SO 4 ). Evaporation left an oil 62 (-4.78 g, qt) which was used directly to prepare salt 63. Alcohol 62 (1.01 g, 4.92 mmol)
  • Acid 77 was prepared as follows. To a solution of ketone 53 ( 1.0 g, 6.1 mmol) in ethanol (35 L) was added a commercial clorox ( 140 mL), and the turbid mixture was boiled (24 h). After cooling (0 °C) the clear solution, a 25% solution of sodium metabisulfite (-30 mL) was added very slowly followed by cone HCl (-50 mL). Another 70 mL of the sodium metabisulfite solution was added to complete the precipitation of a solid. The white solid was filtered and recrystallized (95% ethanol) to give colorless needles of acid 77 (0.91 g, 81 %) with a mp of 285.5-286.4 °C. IR (KBr) 3500, 1710 cm 1 ;
  • Amine 69 was obtained as follows. To a solution of benzodioxan (67, 4.35 g, 31.85 mmol) in acetic anhydride (8 mL) was added dropwise a solution of HNO3 (3 mL) and acetic anhydride (9 mL) at 0 °C over 10 min. A thick yellow suspension formed and was stirred at RT (4 h). This mixture was poured slowly and cautiously into saturated NaHCO 3 (-250 mL), and the resultant mixture was extracted (H 2 CCI 2 ). The organic layer was separated, washed with water and brine, and then dried (MgSO4). Evaporation of the
  • Extracts (EtOAc and HCCI 3 ) of the aqueous layer were combined, washed with water and saturated NaHCO3, dried (MgSO 4 ), and evaporated to give an oil which was chromatographed over silica gel (H2CCl 2 :ethyl acetate, 3: 1 ) and gave oil 69 (2.08 g, 62%) that was used directly to prepare 39.
  • Properties of 69 were as follows: ⁇ NMR (DCC1 3 ) ⁇ 3.36 [bs, 2 H
  • Salt 65 was prepared as follows. Ketone 49 (2.00 g, 12.2 mmol) in dry THF (35 mL) was added dropwise to a cooled (0 °C) solution of freshly prepared vinylmagnesium bromide [obtained from vinyl bromide (4.9 g, 46 mmol) and Mg (0.90 g, 37 mmol) in THF (25 mL)] over 0.5 h. The cold bath was removed, and the resultant mixture was stirred at RT (1 h). The mixture was cooled again and then quenched by slow addition of water and then ether (-100 mL) was added to form two layers. Extracts (ether and H2CCI 2 ) of the aqueous layer were combined, dried (Na 2 SO 4 ), and evaporated to a yellow oil 64 (2.32 g,
  • Ketone 90 was prepared as follows. 2-Octylthiochroman (89, 1.5 g, 6 mmol) in CS2:H 3 CNO2 (1 :5, 25 mL) was added to a stirred suspension of acetic anhydride (0.5 mL, 6 mmol), AICI 3 (11.4 g, 9 mmol) in nitromethane (50 mL) at 0 °C. After 1 h, the suspension was allowed to warm to RT and then was stirred for 48 h. The resultant soution was cooled (0 °C) and then quenched with water (50 mL). Extracts (HCCI 3 ) of the aqueous layer were combined and washed with NaHCO3, water, and brine. The dried (Na 2 SO 4 ) solution was evaporated to an oil (quantitative yield) which was used directly to make alcohol 91.
  • ketone 90 Properties of ketone 90 were: IR (neat) 1680 cm 1 ; J H NMR (DCCI3) ⁇ 0.9 [t, 3 H], 1.35-
  • TFAA trifluoroacetic anhydride
  • ketone 90 Properties of 89 were: ⁇ NMR (DCCI3) ⁇ 0.88 [t, 3 HJ, 1.2-1.5 [bs, 12 H], 1.6-
  • Sulfide 88 was prepared as follows. 3,4-Dihydro-2-n-octyl-2H-l-benzothiopyran-l- oxide (87, 5.72 g, 30 mmol) in dry T ⁇ F (50 mL) was added to a solution of lithium diisopropylamide (LDA) in dry T ⁇ F (50 mL) at -78 °C over 15 min.
  • LDA lithium diisopropylamide
  • Intermediate 87 was prepared according to a literature procedure [T. Takata, Y Mayuni, K. Fujimori, H. K. Young, T. Iyangi, and S. Oae, Bull. Chem. Soc. Jpn., volume 15 56, pages 2300-2310 ( 1983)].
  • the preparation of intermediate 86 (3,4-dihydro-2H-l - benzothiopyran) was described under Example XVI and was a modification of a reported procedure [T. Takata, Y Mayuni, K. Fujimori, ⁇ . K. Young, T. Iyangi, and S. Oae, Bull. Chem. Soc. Jpn., volume 56, pages 2300-2310 (1983)J.
  • lactol 105 (0.100 g, 0.42 mmol)
  • a catalytic amount of p-toluenesulfonic acid 0.025 g
  • 4 A molecular seives 1.0 g
  • toluene 5 mL
  • the mixture was boiled for 2 h (showed completion by TLC).
  • the mixture was allowed to cool to RT and filtered.
  • the filtrate was washed with saturated Na ⁇ C ⁇ 3 (10 mL) and brine (10 mL) and then dried (Na2SO 4) .
  • the solvent was evaporated in vacuo to give 106 as a light
  • the tetrahydroquinoline 111 ( 2.5 g 0.01 mol), ⁇ aHCO 3 ( 1.51 g 0.018 mol), and H2O (2 mL) were placed in a standard system. The system was then cooled to 15-18 °C, and the dimethyl sulfate ( 1.64 g 0.013 mol) was added dropwise. The cloudy light yellow mixture was stirred at RT until the evolution of CO 2 ceased (1 h). The flask was then maintained at 50° C until additional CO2 ceased to be released ( 1 h). The flask was then allowed to cool to RT. Chloroform (25 mL) was added, and the layers were separated.
  • the carboxylic acid 113 (0.174 g, 0.794 mmol) and ethyl 4-hydroxybenzoate (0.198 g, 1.08 mmol) were mixed with CH2CI2 (6 mL). To this cloudy mixture was added dicyclohexylcarbodiimide (-0.025 g, 7.9 mmol) and a catalytic amount of DMAP (7 mg).
  • Acid 129 was prepared from 128 by the literature procedure [K. Nakatani, S. Numata, T. Inoue, K. K. Fujisawa, T. I. Kawasaki, T. Toyama, H. Tachibana, T. Udagawa, and M.Gohbara, Chemical Abstracts, volume 97, page 5964e ( 1982)], mp 79-80 °C.
  • Bioguard-LiOCl (5 g; LiOCl-29%, inert ingredients-71%), Clorox (20 mL] and 95% ethanol ( 10 mL). The resulting mixture was boiled (24 h), and it was then allowed to cool to RT. Ether extracts were washed with water and brine and then were dried (MgSO 4 ). Separate extracts (ether) of the acidified (2 N HCl, pH ⁇ 3) aqueous layer were washed with water and brine and then were dried (MgSO4). Evaporation of the solvent gave a solid which was recrystallized (EtOAc) to white 133 (0.420 g, 21 %), mp 147-149 °C. IR (KBr) 3443-2538, 1691 cm" 1 ; »H ⁇ MR (DCC1 3 ) ⁇ 1.30 [s, 6 HJ, 1.54 [s, 6 H], 3.61 Is, 2 HJ, 4.07
  • Ether 135 was prepared from a literature procedure [M. F. Boehm, L. Zhang, B. A. Badea, S. K. White, D. E. Mais, E. Berger, M. C. Suto, M. E. Goldman, and R. A. Heyman, Journal of Medicinal Chemistiy, volume 37, pages 2930-2941 (1994)].
  • ketone 136 (0.900 g, 3.46 mmol), a solution of Bioguard-LiOCl/Clorox (40 g of LiOCl and 80 mL of Clorox), and 95% ethanol (45 mL). After boiling the above mixture (24 h), it was allowed to cool to RT and was then treated with an aqueous solution of 25% Na2S2 ⁇ s (35 mL). Extracts (ether) of the acidified (6 M HCl, pH ⁇ 3) aqueous solution were combined, washed with water and brine and were finally dried (MgSO 4 ). Evaporation of the solvent gave a light yellow solid 137 (0.420 g, 44%),
  • t-RA t-RA
  • vehicle alone control
  • heteroarotinoid The r-RA (Sigma, St. Louis, MO) was added to one flask in all experiments to ensure that transglutaminase induction occurred, and it was also used as the standard to which the heteroarotinoid induction was compared.
  • Cultures were covered with aluminum foil to protect them from light and then incubated at 37 °C for 48 h. Cells ( 10-40 x 10 6 ) were collected by centrifugation at 2000 rpm for 5 min. The resulting cell pellet was resuspended in 10 mL of Ca,Mg-free Earles solution, and the cell suspension was centrifuged at 2000 rpm for 3 min.
  • Retinoic Acid is a High Affinity Ligand for RXR'" Cell, 1992, 68, 397-406. Data are in
  • DMSO in control and treated cultures was 0.1%.
  • cell extracts were prepared and CAT activity was assayed as previously described [Sleigh, M. J. "A Nonchromatographic Assay for Expression of the Chloramphenicol Acetyltransferase Gene in Eukaryotic Cells". Anal. Biochem. 1986, 156, 251-256] with the exception that 3 H acetyl-CoA was used instead of 14 C acetyl-CoA.
  • Protein concentrations of the extracts were determined using the Bio-Rad Protein Assay (Bio-Rad, Richmond, VA). Transactivation activities were derived by dividing CAT activity per milligram of protein in the drug-treated culture by the activity in the control culture. The results, presented as percentages in Table II and III, are the average of three experiments.
  • cervical carcinoma cells (CC-1 or CC-B) were treated with the heteroarotinoids in Table III for seven days.
  • Control cultures were treated with the same volume of solvent as used with the treated cultures. The effect of the agents on growth was as cited above

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Compositions anticancéreuses ayant une spécificité en matière de récepteurs et manifestant une activité qui stimule la formation de l'enzyme transglutaminase servant de marqueur dans l'activité anticancéreuse. Les compositions comprennent certaines structures hétéro-arotinoïdes partiellement liées à l'acide transrétinoïque par le réseau de base à anneaux condensés.
PCT/US1997/014720 1996-08-23 1997-08-21 Agents anticancereux hetero-arotinoides possedant une specificite en matiere de recepteurs et une activite de tgase Ceased WO1998007716A2 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000475A1 (fr) * 1998-06-30 2000-01-06 Du Pont Pharmaceuticals Company Quinoline-2(1h)-ones substituees utiles comme inhibiteurs de la transcriptase inverse du vih
WO2000015612A1 (fr) * 1998-08-26 2000-03-23 Aventis Pharma Limited Bicycles aza modulant l'inhibition de l'adhesion cellulaire
US6586460B1 (en) 2001-04-02 2003-07-01 The Board Of Regents For Oklahoma State University Heteroarotinoids containing urea or thiourea linker
RU2226526C2 (ru) * 1998-08-26 2004-04-10 Авентис Фарма Лимитед Азабициклы, модулирующие ингибирование клеточной адгезии, фармацевтическая композиция на их основе и способ лечения
CN107250112A (zh) * 2014-10-10 2017-10-13 高力研究有限公司 荧光合成类视色素
US10231947B2 (en) * 2017-01-23 2019-03-19 Arizona Board Of Regents On Behalf Of Arizona State University Isochroman compounds and methods of use thereof
US10238626B2 (en) * 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
US10238655B2 (en) * 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
WO2024137738A1 (fr) * 2022-12-22 2024-06-27 The Board Of Regents Of The University Of Oklahoma Combinaisons d'inhibiteurs de poly (adp-ribose) polymérase (parp) et d'hétéroarotinoïdes et méthodes d'utilisation en tant que traitements du cancer

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LU77254A1 (fr) * 1977-05-04 1979-01-18
CH651034A5 (de) * 1982-05-12 1985-08-30 Hoffmann La Roche Chroman-, thiochroman- oder 1,2,3,4-tetrahydrochinolinderivate und ihre verwendung als arzneimittel-wirkstoffe.
ATE38835T1 (de) * 1983-07-05 1988-12-15 Pfizer Karbonsaeure-derivate verwendbar bei der verhuetung der zersetzung von knorpeln.
EP0155940A1 (fr) * 1983-08-08 1985-10-02 Sri International Analogues des acides benzonorbornenyle, benzopyranyle et benzothiopyranyle retinoiques
US4826984A (en) * 1984-04-09 1989-05-02 The Board Of Regents For The Oklahoma Agricultural And Mechanical College Acting For And On Behalf Of Oklahoma State University Heteroarotinoid compounds as anticancer agents
US4833254A (en) * 1987-05-11 1989-05-23 The Board Of Regents For The Oklahoma Agricultural And Mechanical Colleges Acting For And On Behalf Of Oklahoma State University Heteroarotinoids as anticancer agents
US4895868A (en) * 1988-06-29 1990-01-23 Allergan, Inc. Thiochroman esters of phenols and terephthallates having retinoid-like activity
AU626881B2 (en) * 1988-07-14 1992-08-13 F. Hoffmann-La Roche Ag Benzofused heterocyclics used as pharmaceuticals
US5006550A (en) * 1989-12-29 1991-04-09 Allergan, Inc. Chroman esters of phenols and benzoic acids having retinoid-like activity

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000475A1 (fr) * 1998-06-30 2000-01-06 Du Pont Pharmaceuticals Company Quinoline-2(1h)-ones substituees utiles comme inhibiteurs de la transcriptase inverse du vih
US6090821A (en) * 1998-06-30 2000-07-18 E. I. Dupont De Nemours And Company Substituted quinolin-2 (1H)-ones useful as HIV reverse transcriptase inhibitors
WO2000015612A1 (fr) * 1998-08-26 2000-03-23 Aventis Pharma Limited Bicycles aza modulant l'inhibition de l'adhesion cellulaire
AU754557B2 (en) * 1998-08-26 2002-11-21 Aventis Pharma Limited Aza-bicycles which modulate the inhibition of cell adhesion
US6608084B1 (en) 1998-08-26 2003-08-19 Aventis Pharma Ltd. Aza-bicycles which modulate the inhibition of cell adhesion
RU2226526C2 (ru) * 1998-08-26 2004-04-10 Авентис Фарма Лимитед Азабициклы, модулирующие ингибирование клеточной адгезии, фармацевтическая композиция на их основе и способ лечения
US6586460B1 (en) 2001-04-02 2003-07-01 The Board Of Regents For Oklahoma State University Heteroarotinoids containing urea or thiourea linker
JP2017537140A (ja) * 2014-10-10 2017-12-14 ハイ フォース リサーチ リミテッド 蛍光合成レチノイド
CN107250112A (zh) * 2014-10-10 2017-10-13 高力研究有限公司 荧光合成类视色素
US10759762B2 (en) * 2014-10-10 2020-09-01 High Force Research Limited Fluorescent synthetic retinoids
CN107250112B (zh) * 2014-10-10 2021-04-23 高力研究有限公司 荧光合成类视色素
JP7178781B2 (ja) 2014-10-10 2022-11-28 ハイ フォース リサーチ リミテッド 蛍光合成レチノイド
US10231947B2 (en) * 2017-01-23 2019-03-19 Arizona Board Of Regents On Behalf Of Arizona State University Isochroman compounds and methods of use thereof
US10238626B2 (en) * 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
US10238655B2 (en) * 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
WO2024137738A1 (fr) * 2022-12-22 2024-06-27 The Board Of Regents Of The University Of Oklahoma Combinaisons d'inhibiteurs de poly (adp-ribose) polymérase (parp) et d'hétéroarotinoïdes et méthodes d'utilisation en tant que traitements du cancer

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WO1998007716A3 (fr) 1998-03-26

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