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Piperidinyl nociceptin receptor compounds

A technology for compounds and hydrates, applied in the fields of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve the problems of poor duration, short clinical effect, limited treatment options, etc.

Pending Publication Date: 2018-11-23
ASTRAEA THERAPEUTICS +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For dyskinesias, treatment options are very limited and the only anti-dyskinesia drugs on the market, i.e., amantadine, glutamate antagonists, have poor and very short-lasting clinical effects

Method used

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  • Piperidinyl nociceptin receptor compounds
  • Piperidinyl nociceptin receptor compounds
  • Piperidinyl nociceptin receptor compounds

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0138] Compound preparation

[0139] Those of ordinary skill in the art understand that the piperidinyl nociceptin receptor compound containing formula (I) and the embodiments represented by formula (II), formula (III) and formula (IV) can be synthesized by various synthetic routes . Exemplary syntheses of compounds of formula (II) are shown in Figures 1 to 6 and 10 and described in Examples 1 to 6 and 10 below. Table 1 also provides the compounds of formula II 1 H NMR or TLC data.

[0140] Exemplary syntheses of compounds of formula (III) are shown in Figures 7 and 8 and described in Examples 7 and 8 below. Regarding the compound of formula (III), Table 2 provides the 1 H NMR or TLC data.

[0141] An exemplary route to a compound of formula (IV) is shown in Figure 9 and described in Example 9 below. For compounds of formula (IV), Table 3 provides where indicated 1 H NMR data.

[0142] Composition and method of application

[0143] Compositions provided herein contai...

example 1

[0236] Example 1: 1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole (61) and 1-(1-((1s, Synthesis of 4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indole-3-carbaldehyde oxime (81)

[0237] Scheme I depicts this synthesis.

[0238] Option I

[0239]

[0240] Scheme I materials and conditions: a) AcOH, sodium triacetoxyborohydride (STAB), MgSO 4 , DCE, room temperature (general process step A); b) i.TFA, CH 2 Cl 2 , ii.4-isopropyl-cyclohexanone, STAB, AcOH, DCE (general process step B, 2 steps); c) MnO 2 、CH 2 Cl 2 ; d) POCl 3 , DMF; and e) NH 2 OH·HCl, NaOAc·3H 2 O, EtOH:H 2 O(2:1), 110°C.

[0241] General Process Step A: Reductive Amination Using N-Boc-Piperidone : A round bottom flask was charged with aniline substrate (1.00 equiv) and N-Boc-piperidone (1.05 to 1.50 equiv). 1,2-DCE (0.25M) was added, and the mixture was stirred until both components were dissolved. Add MgSO to this solution at ambient temperature 4 (100 wt% of the limiting age...

example 2

[0250] Example 2: Benzyl ((1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methyl base) carbamate (17) and (1-(1-((1s,4s)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanamine (3) Synthesis

[0251] Scheme II depicts this synthesis.

[0252] Scheme II

[0253]

[0254] Scheme II materials and conditions: a) i.N-Boc piperidone, AcOH, STAB, MgSO 4 , DCE, room temperature (general process step A), ii. TFA, CH 2 Cl 2 , iii. 4-isopropyl-cyclohexanone, STAB, AcOH, DCE (general process step B, 2 steps); b) i. benzyl prop-2-yn-1-ylcarbamate, catalyst PdCl 2 (PPh 3 ) 2 , catalyst cuprous iodide (CuI), DMF: iso-Pr 2 NEt(3:1), ii. Catalyst Cu(OAc) 2 , PhMe, reflux (general process step C, 2 steps); and c) H 2 Airbag, Catalyst 10%Pd / C, NH 3 / MeOH.

[0255] syn-N-(2-iodophenyl)-1-(4-isopropylcyclohexyl)piperidin-4-amine (II-1) :

[0256] i. See General Process Step A. 2-iodoaniline (15.0g, 63.3mmol, 1.00eq), N-Boc-piperidone (18.5g, 95.0mm...

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Abstract

The present invention provides novel piperidinyl-containing nociceptin receptor ligand compounds and pharmaceutical compositions useful in the treatment of neurological diseases and conditions where such ligands mediate the negative effects of the condition. Such neurological diseases and conditions include acute and chronic pain, substance abuse / dependence, alcohol addiction, anxiety, depression,sleep disorders, gastrointestinal disorders, renal disorders, cardiovascular disorders and Parkinson's disease.

Description

[0001] Statement Regarding Federally Funded Research [0002] This invention was made with Government support under Project Grant Nos. R01DA014026, R01DA027811, R43NS070664, R43HL115984, HHSN275201300005C, and HHSN27520150005C awarded by the U.S. Department of Human Health and Services, National Institutes of Health. The US Government has certain rights in this invention. [0003] Priority Claim Based on 35 U.S.C. §119(e) [0004] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 261,871, filed December 2, 2015, which is hereby incorporated by reference in its entirety. technical field [0005] The present invention provides novel compounds and pharmaceutical compositions thereof that modulate nociceptin receptors. These compounds are useful in the treatment of acute and chronic pain, substance abuse / dependence, alcohol addiction, anxiety, depression, sleep disorders, gastrointestinal disorders, renal disease, cardiovascul...

Claims

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Application Information

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IPC IPC(8): A61K31/44A01N43/42
CPCC07D401/04C07D471/10C07D401/14C07D405/14C07D471/04A61P1/00A61P25/16A61P25/20A61P25/22A61P25/24A61P25/30A61P25/32A61P29/00A61P43/00A61P9/00A01N43/42A61K31/454A61K31/4747
Inventor N·T·扎维里M·梅耶V·B·乔尼根D·亚苏达
Owner ASTRAEA THERAPEUTICS
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