94497-51-5

Usage

Uses

Used in Pharmaceutical Industry:
Tamibarotene is used as an antineoplastic agent for the treatment of acute promyelocytic leukemia (APL). It is a selective agonist of the retinoic acid receptor and has been approved for the treatment of relapsed or refractory APL in Japan. It has shown high remission rates among patients who have recurrent disease after all-trans retinoic acid therapy.
Used in Alzheimer's Disease Treatment:
Tamibarotene is used as a potential treatment for Alzheimer's disease, as it has shown to have potential anti-neoplastic activity.
Used in Multiple Myeloma Treatment:
Tamibarotene is used as a potential treatment for multiple myeloma, a type of blood cancer.
Used in Crohn's Disease Treatment:
Tamibarotene is used as a potential treatment for Crohn's disease, a chronic inflammatory bowel disease.

References

https://en.wikipedia.org/wiki/Tamibarotene https://www.drugbank.ca/drugs/DB04942

Originator

Toko Yakuhin Kogyo (Japan)

Biological Activity

Retinoic acid receptor α (RAR α ) agonist that induces differentiation (ED 50 = 0.79 nM) and apoptosis of HL-60 cells in vitro . Exhibits antiproliferative effects against a variety of human tumor cells lines (mean values of 35, 40 and 60% growth inhibition at 0.1, 1 and 10 μ M respectively) and displays anticancer activity against acute promyelocytic leukemia in vivo .

Biochem/physiol Actions

Tamibarotene (Am80) is a RAR α agonist. Tamibarotene was developed to overcome resistance to ATRA and is currently approved in Japan for treatment of recurrent acute promyelocytic leukemia (APL). The compound induces HL-60 cells differentiation and apoptosis. Similarly to TTNPB, the compound neither binds to nor transactivates the RXRs. In contrast to TTNPB (pan RAR agonist), Tamibarotene is rather specific toward RAR α. The compound is approximate 10 times more potent than ATRA.

Synthesis

Several synthesis of tamibarotene have been disclosed in the literature including the process scale synthesis as shown in the scheme. The synthesis started with preparation of dichloride 134 in 82% yield from diol 133 by treating with concentrated HCL in DCM. Friedal Crafts reaction of dichloride 134 with acetanilide in the presence of aluminum chloride at -15°C for 2h provided acetanilide derivative 136 in 78% yield. In a single pot, the acetanilide was reacted with PCl5 and dimethylaniline at -25°C for 1.5h followed by quenching the reaction with methanol for 2h after addition at -25°C. Addition of dimethylaniline and terepthalic chloride mono-methylester at -30 - - 20°C for 1 hr provided the tamibarotene methyl easter 137 in 81% yield. Hydrolysis of the ester by heating with sodium hydroxide in MeOH:water mixture for 1h followed isolation and crystallization gave tamibarotene (XIX) in 92% yield.

InChI:InChI=1/C22H25NO3/c1-21(2)11-12-22(3,4)18-13-16(9-10-17(18)21)23-19(24)14-5-7-15(8-6-14)20(25)26/h5-10,13H,11-12H2,1-4H3,(H,23,24)(H,25,26)

Upstream product

• 102121-55-1 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene 
• 27452-17-1 6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene 
• 7377-26-6 4-Methoxycarbonylbenzoyl chloride 
• 1679-64-7 Monomethyl terephthalate 
• 1446134-13-9 ethyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylcarbamoyl)benzenecarboxylate 
• 6683-46-1 1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphthalene 
• 6223-78-5 2,5-dichloro-2,5-dimethyl hexane 
• 110-03-2 2,5-dimethyl-2,5-hexanediol 
• 94497-53-7 methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-carbamoyl]benzoate 
• 92050-16-3 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine 

Downstream Products

• 102121-51-7 methyl 4-benzoate 

Relevant academic research and scientific papers

Synthesis of Tamibarotene via Ullmann-Type Coupling

An effective process was developed for the preparation of tamibarotene via an Ullmann-type coupling in a nonpressurized l-proline/DMSO system. Notable features were the telescoping of reactions, avoiding environmentally hazardous materials, and an accepta

Design, synthesis and biological evaluation of novel tamibarotene derivative as multitarget anticancer agent

A novel tamibarotene derivative was synthesized by coupling cytotoxic agent 5-Fluorouracil (5-FU) with tamibarotene via ester. This hybrid drug (compound 10) was evaluated for its antiproliferative activities against human leukemic U937, HL-60 and K562 cell lines in vitro. Results showed that compound 10 exhibited more potent anti-leukemic activity than the positive control tamibarotene. Furthermore, the preliminary stability test of compound 10 revealed that it could release tamibarotene and 5-FU significantly in vitro. These interesting results would be meaningful to develop more potent drugs for the treatment of human leukemia.

Highly efficient aminocarbonylation of iodoarenes at atmospheric pressure catalyzed by a robust acenaphthoimidazolyidene allylic palladium complex

A robust allylic palladium-NHC complex was developed and exhibited extremely high catalytic activity toward aminocarbonylation of various (hetero)aryl iodides under atmospheric carbon monoxide pressure, in which a broad range of secondary and primary amines were well tolerated. In addition, the concise synthesis of an anticancer drug tamibarotene was accomplished even in a gram scale, further highlighting the practical applicability of the protocol.

PROCESS FOR IDENTIFYING RAR-RECEPTOR-ANTAGONIST COMPOUNDS

The present invention relates to a process for identifying RAR-antagonist molecules, characterized in that it comprises the following steps: (i) a sufficient amount of an RAR-agonist molecule is applied topically to a part of the skin of a mammal, (ii) a molecule capable of having an RAR-antagonist activity is administered systemically or topically to this same mammal, or to this same part of the skin of the mammal, before, during or after step (i) , and (iii) the response on that part of the skin of the mammal thus treated is evaluated.

Method of treating bone disease with pyridine, carboxamide and carboxylic derivatives

Treatment of osteopathic comprising administering as an active ingredient a compound represented by the following formula (I), (II) or (III): STR1

Method for preparing benzoic acid derivatives

This invention relates to a synthesis method favorable for the industrial production of a benzoic acid derivative having a retinoid activity of the general formula: STR1 wherein the derivative can be obtained by a simple procedure in safety with high yield.Specifically, this invention relates to a synthesis method characterized in that only one vessel is needed for several reactions in the different steps of subjecting acetanilide as a starting material, which is readily available and safe to handle, to Friedel-Crafts reaction with 2,5-dimethyl-2,5-dichlorohexane; subjecting the thus obtained compound to acyl exchange reaction with monomethyl ester terephthalic chloride, followed by hydrolysis; and recrystallizing from a mixture of methanol and water.Moreover, the crystals in novel form obtained by the synthesis method of this invention are suitable for formulation, because the amount of solvents remaining therein after recrystallization is small and the grain size thereof is uniform.

Retinobenzoic Acids. 1. Structure-Activity Relationships of Aromatic Amides with Retinoidal Activity

Two types of aromatic amides, terephthalic monoanilides and (arylcarboxamido)benzoic acids, have been shown to possess potent retinoidal activities and can be classified as retinoids.The structure-activity relationships of these amides are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60.In generic formula 4 (X = NHCO or CONH), the necessary factors to elicit the retinoidal activities are a medium-sized alkyl group (isopropyl, tert-butyl, etc.) at the meta position and a carboxyl group at the para position of the other benzene ring.The bonding of the amide structure can be reversed, this moiety apparently having the role of locating the two benzene rings at suitable positions with respect to each other.Substitution at the ring position ortho to the amide group or N-methylation of the amido group caused loss of activity, presumably owing to the resultant change of conformation.It is clear that the mutual orientation of the benzylic methyl group(s) and the carboxyl group and their distance apart are essential factors determining the retinoidal activity.Among the synthesized compounds, 4-benzoic acid (Am80) and 4-benzoic acid (Am580) were several times more active than retinoic acid in the assay.They are structurally related to retinoic acid, as is clear from the biological activity of the hybrid compounds (M2 and R2).