阅读说明：本技术 μ阿片受体偏向性激动剂及其医药用途 (Mu opium receptor bias agonist and medical application thereof ) 是由 史卫国 马梦君 孙佳琳 仲伯华 李梦华 程京超 于 2019-01-04 设计创作，主要内容包括：本发明涉及式Ⅰ所示的μ阿片受体偏向性激动剂或其药学上可接受的盐,还涉及含有这些化合物或其药学上可接受的盐的药物组合物,以及所述化合物或其药学上可接受的盐用于制备镇痛药物的用途,<Image he="372" wi="700" file="DDA0001936059690000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a mu opioid receptor biased agonist shown in a formula I or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compounds or the pharmaceutically acceptable salt thereof, and application of the compounds or the pharmaceutically acceptable salt thereof in preparing analgesic drugs,)

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein:

(1)X₁is a nitrogen atom, X₂、X₃Is a carbon atom, R is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom (F, Cl, Br) or C₁-C₅Linear or branched alkyl of, X₄Is a nitrogen atom, an oxygen atom or a sulfur atom, the configuration of the chiral carbon 1 and the chiral carbon 2 is R type or S type,

(2)X₂is a nitrogen atom, X₁、X₃Is a carbon atom, R is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom (F, Cl, Br) or C₁-C₅Linear or branched alkyl of, X₄Is a nitrogen atom, an oxygen atom or a sulfur atom, and the configuration of the chiral carbon 1 and the chiral carbon 2 is R type or S type, or

(3)X₃Is a nitrogen atom, X₁、X₂Is a carbon atom, R is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom (F, Cl, Br) or C₁-C₅Linear or branched alkyl of, X₄Is a nitrogen atom, an oxygen atom or a sulfur atom, and the configuration of the chiral carbon 1 and the chiral carbon 2 is R type or S type.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound has a structure represented by formula Ia,

in the structural formula Ia, the substitution position of the naphthalene ring is 1 position or 2 position, the configuration of the chiral carbon 2 is R type or S type, R is C₁-C₅Linear or branched alkyl groups of (a).

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula Ib,

in the structural formula Ib, the substituted position of the naphthalene ring is 1 position or 2 position.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula Ic,

in the structural formula Ic, the substitution position of the naphthalene ring is 1 or 2.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

6. a pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients,

preferably, the pharmaceutical composition is a solution, tablet, capsule or injection,

preferably, the pharmaceutical composition is administered by injection or orally.

7. Use of a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a medicament for use as an analgesic.

Technical Field

The invention relates to novel mu opioid receptor biased agonists or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds as active ingredients, and the use of the derivatives or pharmaceutically acceptable salts thereof for the preparation of analgesic drugs.

Background

For a long time, the treatment of moderate to severe pain has relied on opioids. However, opioid administration causes side effects such as respiratory depression, gastrointestinal dysfunction, constipation, etc., and also causes adverse reactions such as tolerance and addiction after long-term administration.

In recent years, it has been found that some ligands of GPCRs exhibit an "unbalanced effect" in activating the signaling pathway, and they bind to specific receptor forms, or induce receptors to selectively bind to different types of G protein subunits, even β -arrestin, thereby biasing intracellular signaling towards a pathway, and such ligands have been termed "biased agonists", "selective functional ligands" or "biased ligands".

Studies have shown that the analgesic effect of opioid is generated by signaling through Gi protein in G protein, and many side effects, including respiratory depression and constipation, may be generated by signaling through β -arrestin pathway downstream of mu-opioid receptor (MOR) activation, it was confirmed that opioid analgesic effect and side effects disappear simultaneously in MOR knockout mice, and morphine analgesic experiments using β -arrestin-2 knockout mice showed that morphine has better analgesic effect, is less prone to drug tolerance and causes less respiratory depression and constipation than wild-type mice.

PZM21 is a MOR-biased agonist with a different morphine backbone.

Experiments prove that PZM21 can strongly activate Gi/o to only cause very low aggregation of β -arrestin, which indicates that PZM21 is a high-efficiency MOR biased agonist, has good analgesic effect, and has far lower induced side effects such as respiratory depression and constipation than morphine and no obvious addiction.

Disclosure of Invention

The present invention relates to compounds of formula I or a pharmaceutically acceptable salt thereof:

wherein:

(1)X₁is a nitrogen atom, X₂、X₃Is a carbon atom, R is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom (F, Cl, Br) or C₁-C₅Linear or branched alkyl of, X₄Is a nitrogen atom, an oxygen atom or a sulfur atom, the configuration of the chiral carbon 1 and the chiral carbon 2 is R type or S type,

(2)X₂is a nitrogen atom, X₁、X₃Is a carbon atom, R is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom (F, Cl, Br) or C₁-C₅Linear or branched alkyl of, X₄Is a nitrogen atom, an oxygen atom or a sulfur atom, and the configuration of the chiral carbon 1 and the chiral carbon 2 is R type or S type, or

(3)X₃Is a nitrogen atom, X₁、X₂Is a carbon atom, R is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom (F, Cl, Br) or C₁-C₅Linear or branched alkyl of, X₄Is a nitrogen atom, an oxygen atom or a sulfur atom, and the configuration of the chiral carbon 1 and the chiral carbon 2 is R type or S type.

In certain embodiments, the compounds of formula I, or pharmaceutically acceptable salts thereof, of the present invention have the structure of formula Ia,

in structural formula Ia:

the substitution position of the naphthalene ring is 1 position or 2 position,

the configuration of the chiral carbon 2 is R type or S type,

r is hydrogen atom, hydroxyl, methoxyl, ethoxyl, halogen atom (F, Cl, Br) or C₁-C₅Is preferably C₁-C₅Linear or branched alkyl groups of (a).

In certain embodiments, the compounds of formula I or pharmaceutically acceptable salts thereof, of the present invention, wherein the compounds have the structure of formula Ib,

in the structural formula Ib, the substituted position of the naphthalene ring is 1 position or 2 position.

In certain embodiments, the compounds of formula I or pharmaceutically acceptable salts thereof, of the present invention, wherein the compounds have the structure of formula Ic,

in the structural formula Ic, the substitution position of the naphthalene ring is 1 or 2.

In certain embodiments, the compounds of formula i, or pharmaceutically acceptable salts thereof, of the present invention are selected from:

the invention also relates to a pharmaceutical composition comprising a compound of formula i, formula Ia, formula Ib or formula Ic according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients. These pharmaceutical compositions may be solutions, tablets, capsules or injections. These pharmaceutical compositions may be administered by injection route or orally.

The invention also relates to the application of the compound shown in the formula I, the formula Ia, the formula Ib or the formula Ic or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing analgesics.

The compound shown as the formula Ia is synthesized by taking naphthylalanine (I-1) as an initial raw material, reacting with thionyl chloride and ammonia water to generate naphthylalanine amide (II-1), and carrying out reductive amination and borane reduction reaction on the II-1 to generate an intermediate (III-1); thiophene-3-formaldehyde (IV-1) and nitroethane generate nitro derivatives (V-1) through Henry reaction, the V-1 is reduced by lithium aluminum hydride to obtain an intermediate (VI-1), and the VI-1 can be resolved into an R type or an S type by p-methoxybenzoyl tartaric acid; VI-1 and p-nitro phenyl chloroformate react to generate an intermediate (VII-1), and VII-1 reacts with III-1 and triethylamine to obtain a target product Ia. The synthetic route for the compound of formula Ia is shown below:

in the structural formula Ia, the substitution position of the naphthalene ring is 1 position or 2 position, the configuration of the chiral carbon 2 is R type or S type, R is C₁-C₅Linear or branched alkyl groups of (a).

The compound shown as the formula Ib is synthesized by taking naphthylalanine (I-1) as an initial raw material, reacting with thionyl chloride and ammonia water to generate naphthylalanine amide (II-1), and carrying out reductive amination and borane reduction reaction on the II-1 to generate an intermediate (III-1); 3-aminoethyl thiophene (IV-1) and p-nitro phenyl chloroformate react to generate an intermediate (V-1), and the V-1 reacts with III-1 and triethylamine to obtain a target product Ib. The synthetic route for the compound of formula Ib is shown below:

in the structural formula Ib, the substituted position of the naphthalene ring is 1 position or 2 position.

The compound shown as the formula Ic is synthesized by taking naphthylalanine (I-1) as a starting material, reacting with thionyl chloride and ammonia water to generate naphthylalanine amide (II-1), and carrying out reductive amination and borane reduction reaction on the II-1 to generate an intermediate (III-1); 2-thiophene ethylamine (IV-1) reacts with p-nitro phenyl chloroformate to generate an intermediate (V-1), and the V-1 reacts with III-1 and triethylamine to obtain a target product Ic. The synthetic route for the compound of formula Ic is shown below:

in the structural formula Ic, the substitution position of the naphthalene ring is 1 or 2.

The invention has the beneficial technical effects

Biological evaluation results show that the compound shown in the formula I shows a remarkable analgesic effect on a mouse formalin-licking model after being injected subcutaneously.

Detailed Description

The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.