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Naphthalene-containing melanocortin receptor-specific small molecule

A compound and stereoisomer technology, applied in the field of 3/061660, can solve the problems of not disclosing the structure of a single substituent, not disclosing the structure of piperazine, etc.

Inactive Publication Date: 2006-08-09
PALATIN TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] WO 02 / 085925 of Proctor & Gamble Company, "Melanocortin receptor ligand" discloses the structure of ketopiperazine and its synthesis method, but does not disclose the structure of piperazine. The structure of piperazine with four substituents is synthesized A method of piperazine structure, a method of synthesizing a piperazine or ketopiperazine structure having four substituents, or a method of synthesizing an optically pure structure, and also no disclosure of a structure having a single substituent which is a D-Phe residue , or a derivative or analogue thereof, optionally having an amino terminal group

Method used

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  • Naphthalene-containing melanocortin receptor-specific small molecule
  • Naphthalene-containing melanocortin receptor-specific small molecule
  • Naphthalene-containing melanocortin receptor-specific small molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 31、32、33 and 34

[0594] The alkyl group on the amino group of the D-4-Cl-phenylalanine moiety in Examples 31, 32, 33 and 34 was introduced by reductive amination as described for the synthesis of mixtures 3-4.

[0595] Route 6: Another Synthesis of Tetra-Substituted Piperazines

[0596]

[0597] To a solution of compound 5-3 and TEA (1 eq) in DCM was slowly added benzyl chloroformate (1 eq) at 0 °C. The reaction was carried out overnight. The product was purified on a chromatographic column after evaporation of the solvent to give 6-1.

[0598] Compound 6-1 was dissolved in anhydrous THF, and borane in THF (1M solution, 5 eq. in total) was added thereto. The solution was stirred for 16 hours. The reaction was quenched with 1N HCl and then the reaction was neutralized with 1N NaOH. The product was extracted with EtOAc and the organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated and the dried product 6-2 was used in the next reaction.

[0...

Embodiment 1

[0642] Example 1 N-3-[1-[2(R)-amino-3-(2,4-dichloro-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalene -2-yl-ethyl)-piperazin-2(S)-yl]-propyl-guanidine

[0643] The following compounds were obtained by the method of Route 3, using 2-naphthylacetic acid as J-COOH, (S)-(+)-1-amino-2-propanol as NH 2 -CH(R 5 )-CH(R 4)-OH, Fmoc-L-Arg(Boc) 2 -OH as Prt-NH-C(R 2 )-COOH and Boc-D-2,4-dichloro-Phe-OH were synthesized as Q-COOH. Test according to the above method and give the result. Mass spectral analysis: 569.4 (M+H).

[0644]

[0645] Inhibition at 1 μM

[0646] MC1-R MC3-R MC4-R MC5-R

[0647] 14 32 95 36

[0648] Ki(nM)

[0649] MC1-R MC3-R MC4-R MC5-R

[0650] 1309 366 15 727 The compound of example 1 was not intrinsically active at a concentration of 1 μM in the cAMP assay using MC4-R.

Embodiment 2

[0651] Example 2 N-{3-[1-[2(R)-amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2- Naphthalene-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0652] The following compounds are obtained via two routes 3 and 5, using 2-naphthylacetic acid as J-COOH and (R)-(-)-2-amino-1-propanol as NH 2 -CH(R 5 )-CH(R 4 )-OH, Fmoc-LArg(Boc) 2 -OH as Prt-NH-C(R 2 )-COOH, D-alanine methyl ester as NH 2 -CH(R 5 )-COOCH 3 and Boc-D-2,4-dichloro-Phe-OH were synthesized as Q-COOH. Test according to the above method and give the result. Mass spectral analysis: 569.3 (M+H).

[0653]

[0654] Inhibition at 1 μM

[0655] MC1-R MC3-R MC4-R MC5-R

[0656] 20 72 99 65

[0657] Ki(nM)

[0658] MC1-R MC3-R MC4-R MC5-R

[0659] 1134 95 2 362

[0660] In the cAMP assay to determine agonist / antagonist status, compounds other than the ones described were determined to be antagonists of MC4-R.

[0661] At the 1 nmol dose level...

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Abstract

A melanocortin receptor-specific compound of the general formula of structure I: where X, R1, R2a, R2b, R3, R4a, R4b, R5a and R5b are as defined in the specification, which compound binds with high affinity to one or more melanocortin receptors and is optionally an agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist, and may be employed for treatment of one or melanocortin receptor-associated conditions or disorders, and methods for the use of the compounds of the invention.

Description

Background of the invention [0001] Field of invention (technical field): [0002] The present invention relates to tetra- and penta-substituted piperazines and piperazine-derived ring compounds, optionally containing C=O or C=S units, which bind one or more melanocortin receptors body and is optionally an agonist, antagonist, mixed agonist-antagonist or inverse agonist for one or more melanocortin receptors and is useful in the treatment of metabolic, immune, infection-related and melanocortin receptor-mediated diseases. [0003] Related prior art: [0004] Note that the following discussion refers to documents by a number of authors and years of origin, as well as their most recent publication dates, some of which are not considered prior art to the present invention. The discussion of these documents provides a more complete technical background and should not be construed as prior art for purposes of determining patentability. [0005] Piperazines are an important class...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/495A61K31/496C07D241/04C07D241/08C07D403/04
Inventor S·D·夏尔马施亦群吴志骏R·拉普罗特A·M·沙迪克P·普尔马K·D·伯里斯
Owner PALATIN TECH INC
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