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Flufenoxine derivatives for the treatment and prevention of amiloyd pathologies

A technology for pathological states and symptoms, applied in the field of flufenoxine derivatives, can solve problems such as no revelation

Inactive Publication Date: 2013-04-03
飞思药物有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In Orjales et al. J.Med.Chem, 2003, 46, 5512-5532, it is described that flufenacine derivatives are compounds with high affinity for serotonin transporters (transporters) (most of them for norepinephrine transporters with high affinity), but there is no suggestion that these compounds would be useful in the treatment of amyloid pathological states such as Alzheimer's disease

Method used

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  • Flufenoxine derivatives for the treatment and prevention of amiloyd pathologies
  • Flufenoxine derivatives for the treatment and prevention of amiloyd pathologies
  • Flufenoxine derivatives for the treatment and prevention of amiloyd pathologies

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Experimental program
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Embodiment approach

[0065] According to one embodiment of the present invention, A is -C(H)- and B is -O-.

[0066] According to one embodiment of the present invention, C is a phenyl group optionally substituted with one or more groups independently selected from: -F, -Cl, -Br, -I, C 1 -C 3 Alkyl (such as methyl), C 1 -C 3 Alkenyl, C 1 -C 3 Perfluoroalkyl, -O-C 1 -C 3 -Alkyl (such as methoxy), -O-C 1 -C 3 -Alkenyl, -CN, C 6 -C 10 Aryl, C 7 -C 10 Aralkyl, wherein the C 1 -C 3 Alkyl and the O-C 1 -C 3 The alkyl group of the alkyl group can be -O-C 6 -C 10 Heteroaryl substitution. According to another embodiment, C is a phenyl substituted at least with -F, -Cl, -Br or -I, in particular a phenyl substituted with -F or -Cl.

[0067] According to another embodiment, C is a phenyl group of formula (VII)

[0068]

[0069] Of which halogen, R 3 And m are as defined above.

[0070] According to one embodiment of the invention, Ar is phenyl. According to an embodiment of the present invention, Ar is selected from...

specific Embodiment approach

[0135] Can follow in N 0 The general methods described in 9802420, EP1002794A1, US 6,518,284 or PCT / EP2007 / 053582 prepare the compounds of the present invention, including compounds of formula (II), (III), (IV) or (V).

[0136] And, according to the following plan 1, by using Me 3 S(O)I or MeOCH 2 PPh 3 (P.J.Gilliagan et al. J.Med.Chem.1992,35,23,4349) treat the corresponding ketone, and then reduce it to prepare the compound of formula (V) or related compounds. The resulting alcohol can be alkylated with the corresponding benzyl or phenyl derivatives.

[0137]

[0138] plan 1

[0139] Representative examples will be given below.

Embodiment 1

[0141] (+ / -)-4-[(naphthalene-1-oxy)(4-chlorophenyl)methyl]piperidine hemisulfate compound 31

[0142] The following procedure is similar to the preparation of compound 15au described in J. Med. Chem. 2003. Vol 46, 25, 5512-5532.

[0143] J Med 2003, vol 46, 25, 5512-5532 compound 14b (1.6g, 4.8mmol) was added in multiple portions to hexane washed NaH (0.2g 60% oil dispersion) / 10ml anhydrous DMSO in a stirred suspension. The reaction was stirred at room temperature for 30 minutes, potassium benzoate (0.7 g) was added, and stirring continued for 30 minutes, naphthalene (5.9 mmol) was added, and the reaction mixture was heated at 85°C for 15 hours, and then cooled to room temperature. A mixture of water and brine was added and the oil was extracted with ether. The organic layer was concentrated in vacuo, stirred with methanol (35 ml) and 10% aqueous HCl and refluxed for 1.5 hours. After removing the solvent, the residue is partitioned into 10% aqueous HCl and CHCl 3 between. Treat...

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Abstract

The present invention is directed to a compound of formula (I) for use in a method to treat or ameliorate amyloid or tau pathologies, such as Alzheimer's disease, or symptoms thereof. The invention is also directed to new compounds of formula (I), of subformula (II), (III), (IV), or (V).

Description

Technical field [0001] The present invention relates to a flufenoxine derivative useful for treating amyloid or tau pathological conditions (such as Alzheimer's disease) and / or improving the symptoms thereof. Background technique [0002] Alzheimer's disease (AD) is the most widely studied amyloid pathology and the most common cause of Alzheimer's disease. It is estimated to affect 15 million people and 40% of the population over 85 years old worldwide. The disease is characterized by a gradual loss of memory, language, and movement, with the patient’s overall disability and eventually death. [0003] The pathological state of amyloid cannot be cured at this stage. Nowadays, drug treatment is at best focused on controlling this symptom and its various stages. For example, mild to moderate AD can include the use of biliary lipid inhibitors such as Yizhi Capsules (R) (9-aminotetrahydroacridine), Aricept (donepezil), Eisner (R) (Rivas Ming), or Razadyne (R) (galantamine) treatment....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22C07D211/24C07D401/12C07D405/12C07D409/06A61K31/4462A61K31/4465A61K31/4545A61P25/28
CPCA61K31/4535C07D401/12A61K31/4525C07D211/24A61K31/4465C07D405/12C07D211/22A61K31/496A61K31/445C07D409/06A61P25/28A61P43/00
Inventor 弗朗西斯科·莱多·戈麦斯阿尼娅·穆尼奥斯·穆尼奥斯卡门·普马尔·杜兰
Owner 飞思药物有限公司
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