WO1998045242A1 - Regulateurs d'activite des retinoides - Google Patents

Regulateurs d'activite des retinoides Download PDF

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Publication number
WO1998045242A1
WO1998045242A1 PCT/JP1998/001211 JP9801211W WO9845242A1 WO 1998045242 A1 WO1998045242 A1 WO 1998045242A1 JP 9801211 W JP9801211 W JP 9801211W WO 9845242 A1 WO9845242 A1 WO 9845242A1
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Prior art keywords
group
compound
tetrahydro
mhz
hexane
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PCT/JP1998/001211
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English (en)
Japanese (ja)
Inventor
Hiroyuki Kagechika
Koichi Shudo
Tatsuo Sugioka
Tomomi Sotome
Yuki Nakayama
Kazuyuki Doi
Original Assignee
Hiroyuki Kagechika
Koichi Shudo
Tatsuo Sugioka
Tomomi Sotome
Yuki Nakayama
Kazuyuki Doi
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Application filed by Hiroyuki Kagechika, Koichi Shudo, Tatsuo Sugioka, Tomomi Sotome, Yuki Nakayama, Kazuyuki Doi filed Critical Hiroyuki Kagechika
Priority to AU64206/98A priority Critical patent/AU6420698A/en
Publication of WO1998045242A1 publication Critical patent/WO1998045242A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/33—Polycyclic acids
    • C07C63/49—Polycyclic acids containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/17—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C07C65/26—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel compound, and more particularly to a novel compound which regulates a physiological action of a nuclear receptor monoligand represented by a compound having a retinoic acid-like retinoic acid-like physiological activity (retinoide). .
  • the compound of the present invention is useful as an active ingredient of a medicament such as a retinoid action regulator.
  • Retinoic acid is an active metabolite of vitamin A. It acts to differentiate developing immature cells into mature cells with unique functions, promote cell growth, It has extremely important physiological functions such as life support.
  • vitamin A derivatives synthesized so far, for example, benzoic acid derivatives described in JP-A-61-22047 and JP-A-61-76440, and journals' Ob 'Medicinal' Chemistry (Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p. 2182) have been shown to have similar physiological effects.
  • Such compounds having retinoic acid and retinoic acid-like biological activity are collectively referred to as "retinoides”.
  • all-trans 'retinoic acid is a nuclear receptor present in the cell nucleus', a retinoic acid receptor belonging to the superfamily (Evans, RM, Science, 240, p. 889, 1988).
  • RAR retinoic acid receptor
  • retinoic acid-like biological activity for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyDcarbamoyl] benzoic acid: Am80, etc.
  • retinoic acid Similar to retinoic acid, it has been suggested that it binds to RAR and exerts physiological activity (Hashimoto, Y., Cell struct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Co., Ltd., 166, pp.
  • An object of the present invention is to provide a compound having an action of regulating the action of retinoid such as retinoic acid. More specifically, it is capable of enhancing the action of retinoids such as retinoic acid, despite having no retinoide action or having a weak retinoide action, or It is an object of the present invention to provide a compound capable of suppressing the action of retinoid.
  • the present inventor has made intensive efforts to solve the above-described problems, and as a result, is represented by the following general formula. These compounds have been found to have an effect of regulating the action of retinoids such as retinoic acid, and have completed the present invention.
  • R 1 represents a hydrogen atom or a _ 6 alkyl group
  • R 2, R d, and R 4 are each independently a hydrogen atom, an alkyl group, or either an alkoxy group, or a ⁇ and R 3 are adjacent 2 1 or on them, may form a 5- to 6-membered ring together with the carbon atoms on Fuweniru groups bonded together such connection ⁇ and R u (above rings the ring in the case of X may be -C (R 5 ) (R D, which may have one of the above-mentioned alkyl groups or one condensed benzene ring which may have one or more substituents).
  • )-Or -NR 7- represents a divalent group (wherein IT represents a hydrogen atom or a hydroxyl group; RD represents a phenyl group which may have a substituent, or may have a substituent. It is 5 shows the saturated or heterocyclic group unsaturated nitrogen-containing 6-membered; R 7 is a hydrogen atom, on one or two or more non Also c 2 alkyl group having a sum bond, (:.
  • the present invention provides a compound represented by the formula And a pharmaceutically acceptable salt thereof, and a drug comprising as an active ingredient a substance selected from the group consisting of hydrates and solvates thereof.
  • a nuclear receptor belonging to the nuclear receptor / superfamily type is used.
  • the above-mentioned compounds and physiologically acceptable salts thereof for the manufacture of the above-mentioned medicament, preferably for the manufacture of a medicament in the form of a pharmaceutical composition, and water thereof.
  • a method for regulating the action of retinoid in a living body of a mammal, including human comprising the compound and a physiologically acceptable substance.
  • a method comprising administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of a salt thereof, and hydrates and solvates thereof.
  • This method includes, for example, vitamin A deficiency; keratosis of epithelial tissue and skin diseases such as psoriasis; allergic diseases; immunological diseases such as rheumatism; bone diseases such as osteoporosis and fractures; Alzheimer's disease; Or a method for preventing and / or treating a disease such as cancer, and preventing and / or treating a disease such as diabetes, arteriosclerosis, hyperlipidemia, hypercholesterolemia, bone disease, rheumatism, or immune disease. Available as a method.
  • a pharmaceutical composition comprising a compound selected from the group consisting of the above compound, a physiologically acceptable salt thereof, a hydrate thereof, and a solvate thereof, and a retinoid. Things are provided. BEST MODE FOR CARRYING OUT THE INVENTION
  • R 1 is a hydrogen atom or an alkyl group (rc ⁇
  • alkyl group means that the group contains from 1 to 6 carbon atoms in total, as well as other similar expressions used herein.
  • the alkyl group may be straight-chain or branched, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, etc. be able to.
  • a methyl group, an ethyl group, or the like can be used.
  • R 2, R J s and R 4 each independently represent a hydrogen atom, - shows a 6 alkoxy group - 6 alkyl group, or.
  • the alkyl group may be linear or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, A tert-butyl group or the like can be used. Among these, it is preferable to use a bulky alkyl group such as an isopropyl group and a tert-butyl group.
  • the 6- alkoxy group may be straight-chain or branched, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, etc. Can be used.
  • the substitution position of R 2 and R 3 is not particularly limited, but can be substituted in any position independently, it is preferred that ⁇ Oyobi is substituted at adjacent positions with each other. For example, it is particularly preferred that R 2 and R 3 are at the para and meta positions, respectively, with respect to X.
  • R 2 and R 3 When R 2 and R 3 are substituted at adjacent positions, they together form a 5- or 6-membered ring, preferably a 6-membered ring, with the carbon atom on the phenyl group to which R 2 and R 3 are attached. May be. It thus 5 are formed in the 6-membered ring, the ring on the one or more ( ⁇ - 4 alkyl groups may have, for example, 2-4-methylcarbamoyl group, preferably it may have 4 methyl groups.
  • a 5- to 6-membered ring preferably a 6-membered ring formed by combining R 2 and R 3 may have one fused benzene ring.
  • one or more C 1 _ / (alkyl groups may be present on the 5- or 6-membered ring formed by combining R 2 and R 3 , for example, 2 Up to 4 methyl groups, preferably 4 methyl groups, may be present on each ring, and the condensed benzene ring may be unsubstituted, but may be an alkyl group or an alkoxy group.
  • R 4 is It is preferably a hydrogen atom or an alkyl group.
  • nitrogen-containing heterocyclic groups may contain one or more hetero atoms other than nitrogen, for example, an oxygen atom or a sulfur atom.
  • nitrogen-containing heterocyclic group may be unsubstituted, but for example, alkyl group, 6 alkoxy group, a hydroxyl group, a halogen atom, a halogenated alkyl group, a carboxyl group, 6 alkoxycarbonyl group, - 6 alkyl It may have one or two or more substituents such as a hydroxyl group or a substituted or unsubstituted amino group.
  • the bonding mode between the nitrogen-containing heterocyclic group and the carbon atom to which R 5 and R 6 are bonded is not particularly limited, but the nitrogen atom constituting the nitrogen-containing hetero ring and the above carbon atom may be bonded. preferable.
  • R ' is a hydrogen atom, one or two or more are also 12 alkyl Le group having an unsaturated bond, c 3 - 12 cycloalkyl group, - ⁇ cycloalkyl-substituted alkyl group, it may have a substituent Ararukiru And a c 2 alkanol group, an optionally substituted aryloyl group, or an optionally substituted phenyl group.
  • the alkyl group may be linear or branched, and may have one or more unsaturated groups. May have a match.
  • the unsaturated bond may have one or more double bonds and one or more triple bonds in combination.
  • the double bond may be either Z- or E-type.
  • aralkyl group examples include a benzyl group, a naphthylmethyl group, a biphenylmethyl group, a phenethyl group and the like.
  • the one or more substituent groups present on Ariru ring in substituent Ararukiru group for example, ( ⁇ -6 alkyl group, an alkoxy group, a hydroxyl group, a halogen atom, a halogenated alkyl group, a force Rupokishiru group, alkoxycarbonyl group, - 6 alkylcarbonyl group, a substituted young properly may be used as the unsubstituted ⁇ Mi cyano group.
  • the c M 2 Arukanoiru group for example, Asechiru group, Puropanoiru group, can be used as the pig Noiru group, the Aroiru group, for example, it can be used as Benzoiru group, naphthoyl group.
  • the one or more substituent groups present on ⁇ Li Ichiru ring in substituent Aroiru group e.g., p-alkyl group, ( ⁇ _ 6 alkoxy group, a hydroxyl group, a halogen atom, a halogenated alkyl group, a carboxyl group , _ 6 alkoxycarbonyl group, a (. alkylcarbonyl group, such as ⁇ Mi amino group substituted or Mu ⁇ conversion may be used.
  • R 7 represents a substituted phenyl group, two alkyl groups at adjacent positions
  • the compound of the present invention may have one or more asymmetric carbons, and any optical isomer based on such asymmetric carbon, any mixture of optical isomers, racemate, two or more Any of the diastereoisomers, arbitrary mixtures of diastereoisomers, and the like based on the asymmetric carbon are included in the scope of the present invention. Also, any geometric isomer based on one or more double bonds is included in the scope of the present invention. Further, any hydrate or solvate of the compound in the form of a free compound or a salt is also included in the scope of the present invention.
  • compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups.
  • Pharmaceutical compositions suitable for parenteral administration include Examples thereof include injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, and patches.
  • Examples of pharmacologically and pharmaceutically acceptable additives for pharmaceuticals used in the production of the above pharmaceutical composition include excipients, disintegrants or disintegrants, binders, lubricants, —Tinting agents, pigments, diluents, bases, solubilizers or solubilizers, tonicity agents, pH regulators, stabilization And
  • M014 was obtained according to the method described in Example 1 using compound 1-2 and 4-bromo-N, N-dimethylaniline as starting materials.
  • Example 6 4- [3,4-methylenedi Preparation of oxyphenyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) methyl] benzoic acid (M015)
  • DM021 was obtained according to the method described in Example 8 using compound I-2 and morpholine as starting materials.
  • DM022 was obtained according to the method described in Example 8 using compound ⁇ -2 and 1-methylbiperazine as starting materials.
  • Example 11 4-[ (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)-(1,2,4-triazol-1-yl) methyl] Preparation of benzoic acid (M030) (Scheme 3) 1,2,4-Triazole (0.17 g) was added to a solution of sodium hydride (60% in oil, 0.11 g) in anhydrous MF (20 ml) under a dry nitrogen atmosphere.
  • M036 (1.10 g) was obtained by hydrolyzing the highly polar ester (1.40 g) in the same manner.
  • Example 13 4-[(5,6,7,8 tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) (imidazole- 1-yl) Methyl] benzoic acid (DM032)
  • Example 34 4-[N-cyclohexylmethyl-N- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl) Production of tylnaphthalene 2-yl) amino] benzoic acid (DA036)
  • Example 38 4-[N- (4-ethoxy-2,3,5,6-tetrafluorobenzyl) -N (5,6,7,8 Production of tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl) amino] benzoic acid (DA045)
  • DA045 4- [N- (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthale-yl) amino] ethyl benzoate (VI-2) and odor
  • the DA045 was synthesized according to the method of Example 20 using fluorinated benzene (fluorobenzene).
  • the ester (79 mg) was dissolved in ethanol (4 ml), a 5% aqueous NaOH solution (1 ml) was added, and the mixture was stirred at room temperature for 5 hours.
  • the reaction solution was poured into 1N hydrochloric acid and extracted with methylene chloride.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 77 mg (quantitative) of DA055.
  • Example 43 4- [N- (4-carboxybenzoyl) -N- (5,6,7,8-tetrahydro-5,5,8 8 Preparation of tetramethylnaphthalene-2-yl) amino] benzoic acid (DA058)
  • DA113 was synthesized according to the method of Example 44 using compound VII-4 and n-propyl iodide.
  • Table 1 concentration dependent differentiation inducing ability of each compound alone, and showed a concentration-dependent effects on Rechinoi phosphate (RA) or inducing the differentiation of Am80 the lxl (T 9 M, 1 x 10
  • Table 2 shows the concentration-dependent effects of each compound on the differentiation-inducing ability of 10 Am80.
  • Table 3 shows the concentration-dependent differentiation-inducing ability of each compound alone and the concentration of 1 x 10-1 () M Am80 on the differentiation-inducing ability. The percentage (%) of the differentiated cells shown in the following tables was calculated from the NBT reducing ability, the concentration was shown as a logarithmic value, and 1 means not measured.
  • Table 1 compound 1 x 10- 9 M Am80 coexistence lxl (T a 9M induced to differentiate at 3 ⁇ 4 RA and coexistence differentiation induction were derived differentiated during cell cells alone
  • mice Blood was collected from the tail vein of KK mice that developed diabetes at the age of 4 to 5 months, and their blood glucose levels were measured. Next, the mice were divided into groups so that the average of the blood glucose levels of the mice in each group was the same (one group, four mice), and a mouse powder prepared so as to contain the test substance at 0.01% to 0.03%.
  • the diet (F-1, Funabashi Farm) was given to each group of mice for 3 days. As a control, a powder diet containing no drug was administered to control mice. Three days later, blood was collected from the tail vein of the mouse, and the glucose concentration in the plasma obtained by centrifugation was measured using a glucose analyzer-1 and Glucoda-F (A & T).

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  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
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Abstract

Cette invention se rapporte à des composés représentés par la formule générale (I), dans laquelle R1 est hydrogène ou alkyle C¿1-6?; R?2, R3 et R4¿ sont hydrogène, alkyle C¿1-6?, etc.; et X représente un groupe divalent -C(R?5)(R6¿)- ou -NR?7 (où R5¿ est hydrogène ou hydroxy; R6 est phényle ou un hétérocycle contenant de l'azote, saturé ou insaturé, à 5 ou 6 éléments; et R7 est hydrogène, alkyle C¿1-12? possédant éventuellement une ou plusieurs liaisons insaturées, etc.).En raison de l'effet de régulation qu'ils produisent sur l'expression des activités physiologiques de rétinoïdes tels que l'acide rétinoïque, ces composés s'avèrent utiles en tant que régulateurs d'activité des rétinoïdes.
PCT/JP1998/001211 1997-04-08 1998-03-20 Regulateurs d'activite des retinoides WO1998045242A1 (fr)

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AU64206/98A AU6420698A (en) 1997-04-08 1998-03-20 Retinoid activity regulators

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JP8945097 1997-04-08
JP9/89450 1997-04-08
JP10041490A JPH10338658A (ja) 1997-04-08 1998-02-24 レチノイド作用調節剤
JP10/41490 1998-02-24

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029324A1 (fr) * 1997-12-05 1999-06-17 Institute Of Medicinal Molecular Design. Inc. Agents preventifs/medicaments contre le diabete
US6093838A (en) * 1999-08-16 2000-07-25 Allergan Sales, Inc. Amines substituted with a dihydro-benzofuranyl or with a dihydro-isobenzofuranyl group, an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity
US6127382A (en) * 1999-08-16 2000-10-03 Allergan Sales, Inc. Amines substituted with a tetrahydroquinolinyl group an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity
WO2000066595A1 (fr) * 1999-04-28 2000-11-09 Institute Of Medicinal Molecular Design. Inc. Derives d'acides carboxyliques heterocycliques
US6613917B1 (en) 2000-03-23 2003-09-02 Allergan, Inc. Amines substituted with a dihydronaphthalenyl, chromenyl, or thiochromenyl group, an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity
US7199140B2 (en) 2001-06-26 2007-04-03 Astrazeneca Ab Vinyl phenyl derivatives as GLK activators
WO2009067315A1 (fr) * 2007-11-16 2009-05-28 Chemtura Corporation Dérivés d'amine diaromatique comme anti-oxydants
EP1733722A4 (fr) * 2004-03-10 2010-07-14 Res Found Itsuu Lab Accelerateur de la fixation en memoire
WO2011101787A1 (fr) * 2010-02-16 2011-08-25 Università Degli Studi Di Siena Inhibiteurs non peptidiques des protéines 14-3-3 et leur utilisation
JP2017502999A (ja) * 2014-01-14 2017-01-26 コネクシャス ライフ サイエンシス ピーヴィティー リミテッドＣｏｎｎｅｘｉｏｓ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｐｖｔ． Ｌｔｄ． Ｒｘｒアゴニストとしての置換二環式ヘテロアリール化合物
US9908856B2 (en) 2014-02-26 2018-03-06 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
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
US10328040B2 (en) 2014-01-17 2019-06-25 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic methods

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US20070161105A1 (en) 2003-03-20 2007-07-12 Reasearch Foundation Itsuu Laboratory Method of forming organ
US8389538B2 (en) 2007-02-27 2013-03-05 National University Corporation Okayama University Rexinoid compound having alkoxy group
US9520569B2 (en) 2011-10-17 2016-12-13 Sumitomo Chemical Company, Limited Aryl compounds for application in a highly polar solvent
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US6127382A (en) * 1999-08-16 2000-10-03 Allergan Sales, Inc. Amines substituted with a tetrahydroquinolinyl group an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity
US6093838A (en) * 1999-08-16 2000-07-25 Allergan Sales, Inc. Amines substituted with a dihydro-benzofuranyl or with a dihydro-isobenzofuranyl group, an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity
US6613917B1 (en) 2000-03-23 2003-09-02 Allergan, Inc. Amines substituted with a dihydronaphthalenyl, chromenyl, or thiochromenyl group, an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity
US7026487B2 (en) 2000-03-23 2006-04-11 Allergan, Inc. Amines substituted with a dihydronaphthalenyl, chromenyl, or thiochromenyl group, a pyridyl group and an alkyl group, having retinoid-like biological activity
US7199140B2 (en) 2001-06-26 2007-04-03 Astrazeneca Ab Vinyl phenyl derivatives as GLK activators
US8431613B2 (en) 2004-03-10 2013-04-30 Research Foundation Itsuu Laboratory Memory fixation accelerator
EP1733722A4 (fr) * 2004-03-10 2010-07-14 Res Found Itsuu Lab Accelerateur de la fixation en memoire
US8198329B2 (en) 2004-03-10 2012-06-12 Research Foundation Itsuu Laboratory Memory consolidation promoting agent and method of use
WO2009067315A1 (fr) * 2007-11-16 2009-05-28 Chemtura Corporation Dérivés d'amine diaromatique comme anti-oxydants
JP2011500729A (ja) * 2007-11-16 2011-01-06 ケムチュア コーポレイション 酸化防止剤としての二環芳香族アミン誘導体
WO2011101787A1 (fr) * 2010-02-16 2011-08-25 Università Degli Studi Di Siena Inhibiteurs non peptidiques des protéines 14-3-3 et leur utilisation
US8895600B2 (en) 2010-02-16 2014-11-25 Università Degli Studi Di Siena Non peptidic 14-3-3 inhibitors and the use thereof
JP2017502999A (ja) * 2014-01-14 2017-01-26 コネクシャス ライフ サイエンシス ピーヴィティー リミテッドＣｏｎｎｅｘｉｏｓ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｐｖｔ． Ｌｔｄ． Ｒｘｒアゴニストとしての置換二環式ヘテロアリール化合物
CN107074800A (zh) * 2014-01-14 2017-08-18 康内克斯生命科学私人有限公司 经取代的双环杂芳基化合物作为rxr促效剂
US10328040B2 (en) 2014-01-17 2019-06-25 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic methods
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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

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