Long-acting potassium opioid receptor agonists

Abstract

The present invention provides a long-acting K-opioid receptor agonist. This long-acting K-opioid receptor agonist is used to alleviate moderate to severe itching in patients and for postoperative pain relief.

Claims

1. K opioid receptor agonists having the following structural formula I: [Structural formula I] D-Phe-AA1-AA2-D-Lys-4-aminopiperidine-4-carboxylic acid-AA3-AA4(R)-AA5 -Tyr(Et)、--4yrr(9pr)、-m Phe(20)、D-heee(4_00)、--P he(2--3l)、D-heee(4-3l)、､- Phe(2mBrr)、--heeer(4-3)、 -Phe(2-9)、D-hheeh(4-9)、D -Phe(-Meee)、--heee(4Ett)、 -Phe(4-ｩprr)、--heeeh(4-8ｨ ２ )、D-Phee(4-(((H ３ )、D-Phee(4-(((H ２ 38 ３ )、D-Phe(4-8) ３ ) ) ２ )、D-Phe(4-8(3) ３ ) ) ２ )、またはD-Phe(4-8(3) ３ )32 ２ 38 ３ )であり; In structural formula I, AA2 is D-Leu or D-cyclopropylalanine; In structural formula I, AA3 is (PEG ｍ１ (CH ２ ) ｍ２ CO) ｍ３－ , or (AA6) ｍ１ Either it exists or it does not exist (where m1 is an integer from 1 to 10, m2 is an integer from 1 to 5, m3 is an integer from 1 to 5, and AA6 is Gly, D-type or L-type Ala, D-type or L-type Leu, D-type or L-type Phe, D-type or L-type Ser, D-type or L-type Thr, D-type or L-type Tyr, D-type or L-type Asp, D-type or L-type Glu, D-type or L-type Gln, D-type or L-type Lys, D-type or L-type Arg, or D-type or L-type His); AA4 in structural formula I is (AA7) ｎ Either it exists or does not exist (where n is an integer from 1 to 10, and AA7 is a D-type or L-type Lys, a D-type or L-type Dap, a D-type or L-type Dab, a D-type or L-type Orn, a D-type or L-type Dah, or a D-type or L-type Dao); In structural formula I, AA5 is either OH or NH ２ And; In structural formula I, R is HO ２ C (CH ２ ) ｎ１ CO-(AA8) ｎ２ - (PEG ｎ３ (CH ２ ) ｎ４ CO) ｎ５－ or HO ２ C (CH ２ ) ｎ１ CO-(AA8) ｎ２ - (AA9) ｎ６－ (wherein n1 is an integer from 10 to 20, n2 is an integer from 1 to 5, n3 is an integer from 1 to 30, n4 is an integer from 1 to 5, n5 is an integer from 1 to 5, n6 is an integer from 1 to 10, AA8 is γGlu, εLys, β-Ala, γ-aminobutyric acid, or 5-Ava, and AA9 is Ala, Gly, Leu, Phe, Ser, Thr, Tyr, Asp, Glu, Gln, Lys, D-Lys, Arg, or His)).

2. A long-acting K-opioid receptor agonist according to claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex formed from the analog, a prodrug based on the compound, or any mixture of the above forms.

3. A long-acting K-opioid receptor agonist according to claims 1 and 2, used for manufacturing a pharmaceutical composition for treating a disease.

4. The long-acting K-opioid receptor agonist according to claim 3, wherein the pharmaceutical composition is used for the relief of moderate to severe itching in patients and for postoperative pain relief.

5. A pharmaceutical composition characterized by comprising a long-acting K-opioid receptor agonist according to any one of claims 1 to 4.

6. Use of a long-acting K-opioid receptor agonist according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for manufacturing a pharmaceutical product for the relief of moderate to severe itching in patients and for postoperative pain relief.

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