US20100204327A1 - Methods for making retinoids and uses thereof - Google Patents

Methods for making retinoids and uses thereof Download PDF

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US20100204327A1
US20100204327A1 US11/661,030 US66103005A US2010204327A1 US 20100204327 A1 US20100204327 A1 US 20100204327A1 US 66103005 A US66103005 A US 66103005A US 2010204327 A1 US2010204327 A1 US 2010204327A1
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Wayne J. Brouillette
Donal D. Muccio
Venkatram Reddy Atigadda
John M. Ruppert
Susan M. Lobo Ruppert
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Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: THE UNIVERSITY OF ALABAMA AT BIRMINGHAM
Publication of US20100204327A1 publication Critical patent/US20100204327A1/en
Priority to US13/856,631 priority patent/US9169190B2/en
Priority to US14/859,824 priority patent/US20160106697A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH-DIRECTOR DEITR reassignment NATIONAL INSTITUTES OF HEALTH-DIRECTOR DEITR CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF ALABAMA AT BIRMINGHAM
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    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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Definitions

  • Retinoid receptors and other members of this superfamily of nuclear receptors which include the steroid, thyroid and vitamin D hormone receptors and other “orphan” receptors without known ligands, are new targets for drug development (1). It is thought that retinoic acid (RA) and synthetic retinoids act as ligand-dependent transcription factors with different members of nuclear retinoid receptors to control gene transcription responsible for cellular proliferation, differentiation, development and cell death (2).
  • RA retinoic acid
  • RARs and RXRs Two classes of nuclear retinoid receptors (RARs and RXRs) have been identified so far, and each has several different subtypes ( ⁇ , ⁇ , ⁇ ).
  • All-trans-retinoic acid is the first example of a FDA-approved agent used for differentiation therapy (rather than standard cytotoxic cancer chemotherapy) of patients with APL. Even though it has been shown to be highly effective in APL treatment, clinical resistance occurs frequently with pharmacological doses of ATRA and APL patients often relapse (4). In order to provide more effective therapies, new highly active retinoids need to be identified in the expectation that lower doses of these agents would not induce resistance as rapidly as ATRA.
  • Some of the most promising retinoids in cancer prevention are 9cRA and related analogs that bind to RXRs.
  • 9cRA When 9cRA is added to the diet of rats, the number of N-methyl-N-nitrosourea (MNU)-induced mammary cancers was reduced by 92% (30). Because of excessive toxicity, however, the usefulness of 9cRA for chemoprevention of cancer in the human is limited (31-33).
  • MNU N-methyl-N-nitrosourea
  • RXR-selective analogs of 9cRA 34, 35.
  • Our laboratory has described the synthesis of several such retinoids and showed that these compounds were effective for the prevention of skin tumors and had lower toxicity than natural retinoids (36).
  • Tamoxifen an estrogen antagonist
  • SARMs selective estrogen receptor modulators
  • retinoids In high yield and stereoselectivity, retinoids generally possess multiple carbon-carbon double bonds with either cis or trans stereochemistry. Thus, one retinoid can have several stereoisomers depending upon the number of carbon-carbon double bonds. Although synthetic routes to retinoids have been developed, they do not produce retinoids in high yield and stereoselectivity. The methods described herein address this need.
  • retinoids Described herein are methods for making retinoids. Also described herein are retinoids and methods of use thereof.
  • FIG. 1 shows a general reaction scheme for preparing retinoid compounds.
  • FIG. 2 shows a reaction scheme for preparing fused retinoid compounds.
  • FIG. 3 shows a reaction scheme for preparing non-fused retinoid compounds.
  • “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
  • the phrase “optionally substituted lower alkyl” means that the lower alkyl group can or can not be substituted and that the description includes both unsubstituted lower alkyl and lower alkyl where there is substitution.
  • R and R′ are, independently, hydrogen, methyl, or ethyl
  • any combination of R and R′ is contemplated.
  • R′ when R is hydrogen, R′ can be hydrogen, methyl, or ethyl.
  • Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
  • E,Z-stereochemistry about a carbon-carbon double bond refers to greater than 95%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or 100% of one stereoisomer (E or Z) over the other.
  • enantiomeric purity refers to greater than 95%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or 100% of one enantiomer with respect to the other enantiomer.
  • subject is meant an individual.
  • the subject can be a mammal such as a primate or a human.
  • the term “subject” can include domesticated animals including, but not limited to, cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.).
  • Treatment or “treating” means to administer a composition to a subject or a system with an undesired condition (e.g., cancer) or at risk for the condition.
  • the condition can include a disease or a predisposition to a disease.
  • the effect of the administration of the composition to the subject can have the effect of but is not limited to reducing or preventing the symptoms of the condition, a reduction in the severity of the condition, or the complete ablation of the condition.
  • an effective amount is meant a therapeutic amount needed to achieve the desired result or results, e.g., reducing or preventing the occurrence of a neoplastic condition.
  • alkyl group as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 15 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, or tetradecyl, and the like.
  • a “lower alkyl” group is an alkyl group containing from one to six carbon atoms.
  • cycloalkyl group is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • the term cycloalkyl group also includes a heterocycloalkyl group, where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.
  • aryl group as used herein is any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc.
  • aryl group also includes “heteroaryl group,” which is defined as an aryl group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy.
  • aralkyl as used herein is an aryl group having an alkyl group as defined above attached to the aryl group.
  • An example of an aralkyl group is a benzyl group.
  • These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein.
  • A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated.
  • each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
  • any subset or combination of these is also specifically contemplated and disclosed.
  • the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
  • This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions.
  • steps in methods of making and using the disclosed compositions are if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.
  • each and every combination of the variables in the formula is contemplated. For example, if an aryl ring is substituted with one or more C 1 -C 15 alkyl groups, then every possible substitution about the aryl ring with respect to the different alkyl groups is contemplated.
  • the reaction scheme depicted in FIG. 1 can be used to synthesize retinoid compounds.
  • the stereochemistry about each of the double bonds in each of the compounds in FIG. 1 is exemplary. It is contemplated that the stereochemistry about each double bond can vary depending upon the selection of the starting materials, reagents, and reaction conditions.
  • the synthesis starts with reacting the cyclic ketone I with compound II in the presence of a coupling agent to produce the spirolactone compound III.
  • R 1 and R 2 in formula I are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1 and R 2 collectively form a substituted or unsubstituted fused aryl group;
  • R 3 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; and n is from 0 to 3, wherein one or more carbon atoms in the ring in formula I can optionally be replaced with a heteroatom.
  • R 3 is not hydrogen, the cyclic ketone can be racemic or substantially enantiomerically pure. It is also contemplated that the cyclic ketone has one or more R 3 groups.
  • the groups can be the same or different. Additionally, when two different R 3 groups are present on the ring, they can be on the same carbon atom or on different carbon atoms of the ring. In other aspects, any of the carbon atoms in the cyclic ring of formula I can be replaced with a heteroatom (e.g., oxygen, sulfur, or nitrogen).
  • a heteroatom e.g., oxygen, sulfur, or nitrogen
  • n is 1, and R′ and R 2 are a C 1 -C 15 branched or straight chain alkyl group or a substituted or unsubstituted cycloalkyl group.
  • n is 1, R′ is a C 5 or greater branched or straight chain alkyl group or a substituted or unsubstituted cycloalkyl group, and R 2 is a C 1 -C 15 branched or straight chain alkyl group.
  • the cyclic ketone I has the formula XI
  • R 3 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group
  • R 9 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group
  • n is from 0 to 3, wherein one or more carbon atoms in the cycloalkyl ring and/or aryl ring in formula XI can optionally be replaced with a heteroatom.
  • n is 1 and (1) R 3 and R 9 are hydrogen; (2) R 3 is hydrogen and R 9 is one or more methyl groups; (3) R 9 is hydrogen and R 3 is one or more methyl groups; or (4) R 3 and R 9 is one or more methyl groups.
  • the cyclic ketone having the formula XI is 4-methyl-1-tetralone, 5-methyl-1-tetralone, 6-methyl-1-tetralone, 7-methyl-1-tetralone, 8-methyl-1-tetralone, or 7-isopropyl-1-tetralone.
  • R 4 -R 7 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group, and X is a halogen, wherein the stereochemistry about the carbon-carbon double bond in formula II is substantially E or Z.
  • R 4 in formula II is a methyl group and X is bromide or chloride.
  • R 4 in formula II is a methyl group
  • R 5 is an ethyl or methyl group
  • X is bromide or chloride
  • R 6 and R 7 are hydrogen.
  • the reaction between I and II is performed in the presence of a coupling agent, which is any compound that can facilitate the reaction between the two compounds.
  • the coupling agent comprises a zero-valent metal atom, a metal salt, or a mixture thereof, wherein the coupling agent is not zinc metal alone.
  • the coupling agent comprises a mixture of (1) a zinc compound and (2) a rhodium compound or iron compound.
  • the coupling agent comprises a mixture of a zinc compound and a copper compound.
  • the coupling agent comprises a mixture of zinc metal and a copper salt. Examples of copper salts include, but are not limited to, copper chloride, copper acetate, and the like.
  • the reaction between compounds I and II in the presence of the coupling agent is generally performed in the presence of a solvent.
  • a solvent such as, for example THF, can be used.
  • decomposition of compound III can be reduced relative to the reaction performed at elevated temperatures.
  • Compounds I, II, and the coupling agent can be added in any order. Reaction times and temperatures will vary depending upon the selection of compounds I, II, and the coupling agent.
  • Compound III can be purified and characterized using techniques known in the art.
  • eliminative ring-opening of compound III by reacting a compound III with a base produces compound IX, where R 1 -R 4 , R 6 , R 7 , and n are the same as defined above.
  • U.S. Pat. No. 6,172,112 which is incorporated by reference in its entirety, discloses methods for the eliminative ring-opening of spirolactones that can be used herein.
  • bases include, but are not limited to, NaOH, KOH, Ca(OH) 2 , K 2 CO 3 , or Na 2 CO 3 .
  • the conversion from compound III to compound IX can produce the E-isomer, the Z-isomer, or a mixture thereof.
  • compound III is produced in situ.
  • olefination reactions such as the Wittig, Horner-Wadsworth-Emmons, or Peterson olefinations are contemplated to convert compound I directly to compound IX, or to the ester derivative of IX.
  • compound IX is converted to the primary alcohol V, where R 1 -R 4 , R 6 , R 7 , and n are the same as defined above, by reacting compound a with a reducing agent in an alkyl ether.
  • reducing agents include, but are not limited to, LiAlH 4 , DIBAH, or diborane.
  • the alkyl ether is a lower alkyl ether such as, for example, diethyl ether.
  • a reducing agent such as, for example, a preformed ether solution of LiAlH 4 , to produce compound V that is substantially the Z-stereoisomer.
  • compound V is oxidized to the aldehyde VI, where R 1 -R 4 , R 6 , R 7 , and n are the same as defined above.
  • n is 1, and R 1 and R 2 are a C 1 -C 15 branched or straight chain alkyl group or a substituted or unsubstituted cycloalkyl group.
  • n is 1, R 1 is a C 5 or greater branched or straight chain alkyl group or a substituted or unsubstituted cycloalkyl group, and R 2 is a C 1 -C 15 branched or straight chain alkyl group.
  • R 6 and R 7 can be hydrogen.
  • compound V has the formula XII
  • R 3 , R 4 , R 6 , R 7 , R 9 , and n are the same as defined above.
  • n is 1 and (1) R 3 and R 9 are hydrogen; (2) R 3 is hydrogen and R 9 is one or more methyl groups; (3) R 9 is hydrogen and R 3 is one or more methyl groups; or (4) R 3 and R 9 is one or more methyl groups.
  • R 4 can be methyl.
  • R 6 and R 7 can be hydrogen.
  • compound V is (2Z,4E)-4-(3′,4′-dihydro-4′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-5′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-6′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-7′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-8′-methyl-1
  • the oxidant can be any compound capable of oxidizing a primary alcohol to the corresponding aldehyde.
  • the oxidant comprises H 2 CrO 4 , CrO 3 -pyridine, pyridinium chlorochromate, pyridinium dichromate, Fe(VI), a reagent for the Swern oxidation, dimethyl sulfide and N-chlorosuccinimide, tetramethyl piperidine nitroxide, acetic anhydride in DMSO, P 2 O 5 in DMSO, tosyl chloride/triethyl amine, or Dess-Martin reagent.
  • the oxidant is 2-iodoxybenzoic acid.
  • the oxidant is not MnO 2 .
  • Large amounts of MnO 2 and powdered molecular sieves are required to produce the aldehyde VI. Consequently, the isolation and purification of the aldehyde is extremely tedious. Isolation of the aldehyde requires washing the MnO 2 with a substantial amount of solvent, at which time a considerable amount of aldehyde will decompose and result in very low yields.
  • the oxidants used herein require a simple filtration of the aldehyde product and concentration of the filtrate, which results in minimal decomposition and isomerization of the product.
  • Reaction times and temperatures will vary depending upon the selection of compound V and the oxidant.
  • Compound VI can be purified and characterized using techniques known in the art.
  • R 8 , R 10 , and R 11 are, independently, hydrogen or a C 1 -C 15 branched or straight chain alkyl group, wherein the stereochemistry about the carbon-carbon double bond in formula VII is substantially E or Z, or an E,Z-mixture.
  • a solvent system comprising tetrahydrofuran and hexamethylphosphoramide, wherein the volumetric ratio of tetrahydrofuran to hexamethylphosphoramide is from 1:1 to 40:1.
  • n is 1, and R 1 and R 2 are a C 1 -C 15 branched or straight chain alkyl group.
  • n is 1, R 1 is a C 5 or greater branched or straight chain alkyl group, and R 2 is a C 1 -C 15 branched or straight chain alkyl group.
  • n is 1;
  • R 1 is an isopentyl group;
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl;
  • R 3 is hydrogen;
  • R 4 is methyl.
  • R 6 and R 7 are hydrogen
  • R 10 is methyl
  • R 11 is hydrogen or a C 1 -C 15 branched or straight chain alkyl group.
  • the compound having the formula VIa comprises the formula XV
  • R 3 , R 4 , R 6 , R 7 , R 9 , and n are the same as defined above.
  • n is 1 and (1) R 3 and R 9 are hydrogen; (2) R 3 is hydrogen and R 9 is one or more methyl groups; (3) R 9 is hydrogen and R 3 is one or more methyl groups; or (4) R 3 and R 9 is one or more methyl groups.
  • R 4 can be methyl.
  • R 6 and R 7 can be hydrogen.
  • R 4 and R 10 are methyl, R 6 and R 7 are hydrogen, and R 11 is hydrogen or a C 1 -C 15 branched or straight chain alkyl group.
  • compound VIII it is desirable to produce compound VIII as one stereoisomer or enriched with one stereoisomer.
  • ratio of tetrahydrofuran and hexamethylphosphoramide it is possible to produce compound VIII predominantly as one stereoisomer.
  • purification of the compound is also facilitated when predominantly one stereoisomer of compound VIII is present.
  • the volumetric ratio of tetrahydrofuran and hexamethylphosphoramide is 1:1 to 40:1; 1:1 to 30:1; 1:1 to 20:1; 1:1 to 10:1; 1:1 to 8:1; 1:1 to 6:1; or 1:1 to 4:1.
  • the starting material VIa and VIb can be isomerized to the other stereoisomer (i.e., Z to E or E to Z about the R 4 C ⁇ CR 6 bond) using techniques known in the art such as, for example, reacting compound VIa or VIb with iodine.
  • ester in the case when R 11 in compound VIII is not hydrogen, the ester can be converted to the corresponding acid using techniques known in the art. For example, treatment of the ester form of compound VIII with a base such as, for example, KOH, NaOH, Ca(OH) 2 , K 2 CO 3 , or Na 2 CO 3 can be used to convert the ester to the acid form.
  • a base such as, for example, KOH, NaOH, Ca(OH) 2 , K 2 CO 3 , or Na 2 CO 3 can be used to convert the ester to the acid form.
  • purification of compound VIII comprises
  • the method generally involves the recrystallization of compound VIII.
  • one stereoisomer of compound VIII can be crystallized from a mixture of two or more compounds.
  • organic solvents can be used to dissolve compound VIII.
  • the organic solvent comprises one or more branched or straight chain aliphatic compounds such as, for example, those derived from pentane, hexane, heptane, octane, or nonane.
  • the temperature and duration of the cooling step (b) will vary depending upon compound VIII and the solvent selected. In one aspect, the cooling step (b) is conducted at from 0° C. to ⁇ 78° C. In another aspect, the cooling step (b) is from 10 minutes to 48 hours.
  • R 8 and R 11 are, independently, a C 1 -C 15 branched or straight chain alkyl group, wherein the stereochemistry about the carbon-carbon double bond in formula XXVII is substantially E or Z, or an E,Z-mixture, in a solvent system comprising tetrahydrofuran and hexamethylphosphoramide, wherein the volumetric ratio of tetrahydrofuran to hexamethylphosphoramide is from 1:1 to 40:1 to produce a fifth compound having the formula XXVIII
  • R 1 is a C 5 or greater branched or straight chain alkyl group
  • R 2 is hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1 and R 2 collectively form a substituted or unsubstituted fused aryl group
  • R 3 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group
  • R 6 and R 7 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, or a substituted or unsubsti
  • R 11 is hydrogen or a C 1 -C 15 branched or straight chain alkyl group
  • n is from 0 to 3, wherein one or more carbon atoms in the ring in formula XXX can optionally be replaced with a heteroatom, or the pharmaceutically-acceptable salt or ester thereof, wherein the compound is not (2E,4E,6Z,8E)-8-(3′,4′-dihydro-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid or an ester thereof; (2E,4E,6E,8E)-8-(3′,4′-dihydro-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid or an ester thereof; (2E,4E,6Z,8E)-8-(3′,4′-dihydro-4′ methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-di
  • n is 1, and R 2 is a C 1 -C 15 branched or straight chain alkyl group.
  • R 1 is pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, or decyl.
  • n is 1;
  • R 1 is pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, or decyl; and
  • R 2 comprises a C 1 -C 15 branched or straight chain alkyl group.
  • R 1 is an isopentyl group
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl
  • R 6 , R 7 , and R 11 are hydrogen.
  • the compound having the formula XXX comprises the formula XXXI
  • R 3 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group;
  • R 6 and R 7 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group;
  • R 9 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group;
  • R 11 is hydrogen or a C 1 -C 15 branched or straight chain alkyl group;
  • n is 1 and (1) R 3 is hydrogen and R 9 is one or more methyl groups, or (2) R 9 is hydrogen and R 3 is one or more methyl groups.
  • R 6 , R 7 , and R 11 can be hydrogen.
  • compound XXXI is (2E,4E,6Z,8E)-8-(3′,4′-dihydro-5′-methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid (A); (2E,4E,6Z, 8E)-8-(3′,4′-dihydro-6′-methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid (B); (2E,4E,6Z,8E)-8-(3′,4′-dihydro-7′-methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid (C); (2E,4E,6Z,8E)-8-(3′,4′-dihydro-7′-
  • non-fused retinoid compounds having the formula XXX are depicted below, where R is ethyl, isopropyl, cyclopropyl, or phenyl.
  • R 1 and R 2 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1 and R 2 collectively form a substituted or unsubstituted fused aryl group;
  • R 3 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group;
  • R 4 , R 6 , and R 7 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, or a substituted or unsubstituted cycloal
  • any of the compounds synthesized by the methods described herein can exist or be converted to the pharmaceutically acceptable salt or ester thereof.
  • Pharmaceutically acceptable salts are prepared by treating the free acid with an appropriate amount of a pharmaceutically acceptable base.
  • Representative pharmaceutically acceptable bases are ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, and the like.
  • the reaction is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0° C. to about 100° C. such as at room temperature.
  • the molar ratio of the compound to base used is chosen to provide the ratio desired for any particular salts.
  • the starting material can be treated with approximately one equivalent of pharmaceutically acceptable base to yield a neutral salt.
  • Ester derivatives are typically prepared as precursors to the acid form of the compounds—as illustrated in the examples below—and accordingly can serve as prodrugs. Generally, these derivatives will be lower alkyl esters such as methyl, ethyl, and the like.
  • Amide derivatives —(CO)NH 2 , —(CO)NHR and —(CO)NR 2 , where R is an alkyl group defined above, can be prepared by reaction of the carboxylic acid-containing compound with ammonia or a substituted amine.
  • any of the compounds synthesized by the methods described herein can be formulated into a pharmaceutical composition.
  • a compound having the formula VIII, XXX, or XXXII can be combined with at least one pharmaceutically-acceptable carrier to produce a pharmaceutical composition.
  • the pharmaceutical compositions can be prepared using techniques known in the art.
  • the composition is prepared by admixing the compound with a pharmaceutically-acceptable carrier.
  • admixing is defined as mixing the two components together. Depending upon the components to be admixed the components may or may not chemically or physically interact with one another.
  • Pharmaceutically-acceptable carriers are known to those skilled in the art. These most typically would be standard carriers for administration to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.
  • Molecules intended for pharmaceutical delivery may be formulated in a pharmaceutical composition.
  • Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
  • the pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally, applied to the skin, etc.).
  • Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • the actual preferred amounts of active compound in a specified case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, and the particular situs and mammal being treated. Dosages for a given host can be determined using conventional considerations, e.g. by customary comparison of the differential activities of the subject compounds and of a known agent, e.g., by means of an appropriate conventional pharmacological protocol. Physicians and formulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining dose according to standard recommendations (Physicians Desk Reference, Barnhart Publishing (1999).
  • described herein are methods of treating a subject having a neoplastic condition or suspected of having a neoplastic or neoplastic-like condition by administering to the subject an effective amount of the compounds or compositions produced and disclosed herein.
  • the compounds and compositions produced and disclosed herein can also reduce or prevent the occurrence of a neoplastic condition in a subject.
  • the compound administered to the subject has the formula XXX or XXII.
  • the compound is further combined with 4-hydroxyphenylretinamide in the treatment.
  • two or more compounds produced or disclosed herein can be administered to the subject.
  • the neoplastic condition comprises breast cancer, lung cancer, colon cancer, or leukemia.
  • described herein is method for treating a subject having basal or squamous cell carcinoma comprising administering to the subject an effective amount of a compound having the formula VIII or a composition thereof
  • R 1 and R 2 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1 and R 2 collectively form a substituted or unsubstituted fused aryl group; and R 3 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; R 4 , R 6 , and R 7 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group
  • the compound has the formula XXXV
  • R 3 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group
  • R 4 , R 6 , and R 7 are, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group
  • R 9 is one or more groups comprising, independently, hydrogen, a C 1 -C 15 branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group
  • R 10 and R 11 are, independently, hydrogen or a C 1 -C 15 branche
  • n 1 and R 4 and R 10 are methyl. In another aspect, the compound is
  • described herein are methods for reducing serum triglycerides in a subject by administering to the subject an effective amount of the compounds or compositions produced and disclosed herein.
  • the compounds described herein can be used as hypolipidemic drugs.
  • the compounds herein can reduce serum triglycerides in a subject by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the compounds having the formula VIII can be used in these methods.
  • the compound is (2E,4E,6E,8E)-8-(3′,4′-dihydro-8′-methyl-V(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid and (2E,4E,6Z)-8-(3′-cyclopropyl-2′-(3-methylbutyl)-2′-cyclohexen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid.
  • the amount of compound administered to the subject will vary depending upon the subject, the malady to be treated, and the compound selected.
  • the dosage range is from about 1 mg/kg to about 300 mg/kg, 10 mg/kg to about 300 mg/kg, 1 mg/kg to about 250 mg/kg, 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, or 1 mg/kg to about 100 mg/kg of body weight.
  • the mode of administration can be oral or parenteral.
  • oral is used herein to encompass administration of the compounds via the digestive tract.
  • parenteral is used herein to encompass any route of administration, other than oral administration, by which the compound is introduced into the systemic circulation which includes, but is not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal, ocular, inhalable, rectal, vaginal, transdermal, topical, buccal, sublingual, or mucosal administration.
  • mucosal encompasses the administration of the compounds by methods that employ the mucosa (mucous membranes) of the human body such as, but not limited to, buccal, intranasal, gingival, vaginal, sublingual, pulmonary, or rectal tissue.
  • transdermal encompasses the administration of the compounds that go into the skin or go through the skin using formulations such as, but not limited to, transdermal formulations, buccal patches, skin patches, or transdermal patches.
  • topical encompasses administration by applying conventional topical preparations such as creams, gels, or solutions for localized percutaneous delivery and/or by solution for systemic and/or localized delivery to areas such as, but not limited to the eye, skin, rectum, and vagina.
  • reaction conditions e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.
  • Triethylphosphonosenecioate was prepared via the Arbusov reaction. Tetrahydrofuran was distilled from sodium metal/benzophenone ketyl. Diethyl ether, benzene, and dichloromethane were purchased from Fischer as anhydrous solvents. HMPA was distilled from calcium hydride.
  • the reaction mixture was cooled to room temperature, and water (200 mL) and HCl (2 N, 500 mL) were added.
  • the mixture was diluted with 1000 mL of ether, filtered, and the acid layer was separated.
  • the organic layer was washed with water (2 ⁇ 200 mL), NaOH (1 N, 2 ⁇ 250 mL), and brine (2 ⁇ 250 mL). It was then dried (Na 2 SO 4 ) and evaporated to give an oil.
  • This oil was subjected to distillation on a high vacuum pump (0.1 mm) at 60° C. The distillate was discarded, and the remaining thick oily residue solidified upon addition of hexanes.
  • 2-(3-Methylbutyl)-3-(2-methylpropyloxy)-2-cyclohexenone (8) A solution of ketoenol 7 (68.0 g, 374 mmol), isobutanol (83.0 g, 1120 mmol), and p-toluenesulfonic acid (1.0 g, 1.2 mmol) in anhydrous benzene (730 mL) was refluxed overnight with azeotropic removal of water (Dean-Stark trap).
  • the clumps of zinc were then carefully broken up with a stirring rod.
  • the cooled zinc was suspended in anhydrous dioxane (200 mL), and the stirred suspension was heated to 125° C. in an oil bath.
  • a solution of ketone 9 (47.0 g, 242 mmol), ethyl bromosenecioate (120 g, 579 mmol) and anhydrous dioxane (200 mL) was added to the reaction mixture dropwise over a period of 1 hour. The addition produced an exothermic reaction.
  • the final reaction mixture was stirred at this temperature for an additional 2.5 hours.
  • the reaction mixture was cooled to room temperature and water (100 mL) was added.
  • the wet precipitate was dissolved in ether (1000 mL), washed with brine (2 ⁇ 200 mL), dried (Na 2 SO 4 ) and concentrated to about 100 mL volume under vacuum. The mixture was diluted with hexanes (200 mL) and cooled in the freezer for 18 hours.

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US8475775B1 (en) 2012-08-24 2013-07-02 The Uab Research Foundation Retinoids and use thereof
WO2016004066A1 (en) * 2014-06-30 2016-01-07 The Uab Research Foundation Novel rexinoid compounds and methods of using rexinoid compounds for treating metabolic disorders and cancer

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US10328040B2 (en) 2014-01-17 2019-06-25 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic methods
WO2015130973A1 (en) 2014-02-26 2015-09-03 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
CN103936642B (zh) * 2014-04-25 2016-08-24 上虞新和成生物化工有限公司 一种维生素a母液中维生素a异构体的提纯方法
WO2016140979A1 (en) 2015-03-03 2016-09-09 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
MX2018011108A (es) * 2016-03-15 2019-06-03 Brickell Biotech Inc Proceso para sintesis de acido (2e,4e,6z,8e)-8-(3,4-dihidronaftale n-1(2h)-iliden)-3,7-dimetilocta-2,4,6-trienoico.
US10238655B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
US10238626B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
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

Citations (2)

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Publication number Priority date Publication date Assignee Title
US5094783A (en) * 1990-06-29 1992-03-10 Uab Research Foundation Retinoid compounds
US6172112B1 (en) * 1998-04-06 2001-01-09 Uab Research Foundation Retinoids and use thereof

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US4920123A (en) 1988-10-21 1990-04-24 Beyer Jr Karl H Method for controlling and/or lowering serum triglyceride and/or cholesterol levels in mammals
US5256410A (en) 1988-12-01 1993-10-26 Schering Corporation Treatment of squamous cell carcinoma intralesionally with recombinant human alpha interferon
US5635532A (en) 1991-10-21 1997-06-03 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Compositions and methods for therapy and prevention of pathologies including cancer, AIDS and anemia
US5976555A (en) * 1994-09-07 1999-11-02 Johnson & Johnson Consumer Products, Inc. Topical oil-in-water emulsions containing retinoids
US20040097587A1 (en) * 2002-03-27 2004-05-20 Arbiser Jack L Compositions and methods of treatment of ulcerating diseases, burns, and related conditions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5094783A (en) * 1990-06-29 1992-03-10 Uab Research Foundation Retinoid compounds
US6172112B1 (en) * 1998-04-06 2001-01-09 Uab Research Foundation Retinoids and use thereof

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US8475775B1 (en) 2012-08-24 2013-07-02 The Uab Research Foundation Retinoids and use thereof
WO2014031242A1 (en) * 2012-08-24 2014-02-27 The Uab Research Foundation Retinoids and use thereof
WO2016004066A1 (en) * 2014-06-30 2016-01-07 The Uab Research Foundation Novel rexinoid compounds and methods of using rexinoid compounds for treating metabolic disorders and cancer
US10800726B2 (en) 2014-06-30 2020-10-13 The Uab Research Foundation Rexinoid compounds and methods of using rexinoid compounds for treating metabolic disorders and cancer

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