# US 12,600,724 B2 · Indole alkaloid and preparation method and use thereof

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- Number: US 12,600,724 B2
- Document ID: US12600724B2
- Status: Granted
- Kind: B2
- Application number: 18/264,435
- Filed: 2022-11-09
- Published: 2025-01-09
- Granted: 2026-04-14
- Earliest claimed: 2022-05-09
- Assignees: Nanjing University of Chinese Medicine; China Pharmaceutical University
- Applicants: Nanjing University of Chinese Medicine; China Pharmaceutical University
- Inventors: Xu Shen; Sheng Jiang; Kuojun Zhang; Jiaying Wang; He Tang; Yujie Huang; Tong Zhao; Minyi Qian
- Web page: https://patentgrep.com/patent/US12600724B2

## CPC

- C07D 471/22: in which the condensed systems contains four or more hetero rings
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/02: for peripheral neuropathies
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

A compound represented by formula (I) and a preparation method thereof, and a pharmaceutically acceptable salt thereof, a metabolic precursor thereof, a metabolite thereof, an isomer thereof or a prodrug thereof; experiments show that the indole alkaloid not only promotes axon growth of peripheral sensory neurons, improves the nerve conduction velocity and anesthesia symptom of diabetic rats, but also promotes healing of foot ulcer wounds of diabetic rats, thus having good therapeutic effects on diabetic complication peripheral neuropathy and diabetic feet; they also show that the indole alkaloid also obviously reduces a degree of pulmonary fibrosis induced by bleomycin in mice, and plays a role in protecting lung tissues.

## Claims

### Claim 1

A compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein the formula I is shown as follows:
in the formula:
X is O or −NR1;
R1 is hydrogen, unsubstituted or R1-1 substituted C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, and C3-10 cycloalkyl-(C1-4 alkyl)- or C6-12 aryl-(C1-4 alkyl)-;
R1-1 is halogen or hydroxyl;
Y is —(CH2) m-;
m is an integer from 1 to 6;
Z is a single bond,
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from hydrogen, unsubstituted or R3-1 substituted C1-6 alkyl, C6-10 aryl, unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, heteroaryl, or heteroaryl-(C1-4 alkyl)-; and the heteroaryl is 5-10 membered heteroaryl;
R3-1 is hydroxyl, carboxyl, amino, sulfhydryl, —(C═O)NR3-1-1, or —NH(C═NH)NH2;
R3-1-1 is hydrogen or C1-4 alkyl;
R3-2 is halogen or hydroxyl;
R is hydrogen, hydroxyl, C2-6 alkoxy or
R2 is C1-6 alkyl or hydrogen;
n is an integer from 1 to 500; and
is polyethylene glycol (PEG) with a linear, tree, star or hyperbranched structure comprising —(OCH2CH2)n—; wherein the tree-shaped PEG is a polymer with a highly symmetrical, tree-like architecture, synthesized layer by layer from a central core to form a precise, multi-branched structure; the star-shaped PEG is a branched polymer architecture in which multiple linear PEG chains emanate from a central core molecule, creating a star-like or radial topology; the hyperbranched PEG is a three-dimensional, globular polymer obtained through a one-step synthesis; it possesses a densely yet irregularly branched structure, lacking the perfect symmetry of dendritic polymers.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein when R1 is unsubstituted or R1-1 substituted C1-6 alkyl, the number of R1-1 is one or more, and when more R1-1 are provided, the R1-1 may be the same or different;
and/or, when R1 is unsubstituted or R1-1 substituted C1-6 alkyl, the C1-6 alkyl is C1-4 alkyl;
and/or, when R1 is C6-10 aryl, the C6-10 aryl is phenyl;
and/or, when R1 is C3-10 cycloalkyl, the C3-10 cycloalkyl is C3-6 cycloalkyl;
and/or, when R1 is C6-12 aryl-(C1-4 alkyl)-, the C6-12 aryl-(C1-4 alkyl)- is benzyl;
and/or, when R1 is C3-10 cycloalkyl-(C1-4 alkyl)-, the C3-10 cycloalkyl-(C1-4 alkyl)- is C3-6 cycloalkyl-(C1-2 alkyl);
and/or, when R1-1 is halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-1 substituted C1-6 alkyl, the number of R3-1 is one or more, and when more R3-1 are provided, the R3-1 may be the same or different;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-1 substituted C1-6 alkyl, the C1-6 alkyl is C1-4 alkyl;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, the number of R3-2 is one or more, and when more R3-2 are provided, the R3-2 may be the same or different;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-1 substituted C6-12 aryl-(C1-4 alkyl)-, the C6-12 aryl-(C1-4 alkyl)- is C6-12 aryl-(C1-2 alkyl)-;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from 5-10 membered heteroaryl-(C1-4 alkyl)-, the 5-10 membered heteroaryl-(C1-4 alkyl)- is 5-9 membered heteroaryl-(CH2)—;
and/or, when R3-1-1 is C1-4 alkyl, the C1-4 alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or, m is an integer from 1 to 4;
and/or, n is an integer from 0-1 to 400;
and/or,
is polyethylene glycol with a linear structure comprising —(OCH2CH2)n—;
and/or, when R2 is C1-6 alkyl, the C1-6 alkyl is C1-4 alkyl;
and/or, when R is C2-6 alkoxy, the C2-6 alkoxy is C1-4 alkoxy.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein when R1 is unsubstituted or R1-1 substituted C1-6 alkyl, the number of R1-1 is 1, 2 or 3;
and/or, when R1 is unsubstituted or R1-1 substituted C1-6 alkyl, the C1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tertiary butyl;
and/or, when R1 is C3-10 cycloalkyl, the C3-10 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or, when R1 is C3-10 cycloalkyl-(C1-4 alkyl)-, the C3-10 cycloalkyl-(C1-4 alkyl)- is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-1 substituted C1-6 alkyl, the number of R3-1 is 1, 2 or 3;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-1 substituted C1-6 alkyl, the C1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tertiary butyl;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, the number of R3-2 is 1, 2 or 3;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, the C6-12 aryl-(C1-4 alkyl)- is benzyl;
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from 5-10 membered heteroaryl-(C1-4 alkyl)-, the 5-10 membered heteroaryl-(C1-4 alkyl)- is indolylmethyl or imidazolylmethyl;
and/or, m is an integer from 1 to 2;
and/or, n is an integer from 1 to 100;
and/or, when R2 is C1-6 alkyl, the C1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tertiary butyl;
and/or, when R is C2-6 alkoxy, the C2-6 alkoxy is ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein when R1 is R1-1 substituted C1-6 alkyl, the R1-1 substituted C1-6 alkyl is trifluoromethyl, or
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from R3-1 substituted C1-6 alkyl, the R3-1 substituted C1-6 alkyl is
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, the R3-2 substituted C6-12 aryl-(C1-4 alkyl)- is
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from 5-10 membered heteroaryl-(C1-4 alkyl)-, the 5-10 membered heteroaryl-(C1-4alkyl)- is

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 is hydrogen, unsubstituted or R1-1 substituted C1-6 alkyl or C3-10 cycloalkyl;
and/or, R1-1 is hydroxyl;
and/or, m is an integer from 1 to 2;
and/or, Z is a single bond or
and/or, when R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from hydrogen, unsubstituted or R3-1 substituted C1-6 alkyl, unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, and heteroaryl-(C1-4 alkyl)-, the heteroaryl is 5-10 membered heteroaryl;
and/or, R3-1 is hydroxyl, carboxyl, amino, sulfhydryl, —(C═O)NR3-1-1, or —NH(C═NH)NH2;
and/or, R3-1-1 is hydrogen;
and/or, R3-2 is hydroxyl;
and/or, n is an integer from 1 to 400;
and/or,
is polyethylene glycol with a linear structure comprising —(OCH2CH2)n—.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein:
X is O or —NR1;
R1 is hydrogen, unsubstituted or R1-1 substituted C1-6 alkyl or C3-10 cycloalkyl;
R1-1 is hydroxyl;
Y is —(CH2)m—;
m is an integer from 1 to 2;
Z is a single bond or
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from hydrogen, unsubstituted or R3-1 substituted C1-6 alkyl, unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, or heteroaryl-(C1-4 alkyl)-, and the heteroaryl is 5-10 membered heteroaryl;
R3-1 is hydroxyl, carboxyl, amino, sulfhydryl, —(C═O)NR3-1-1, or —NH(C═NH)NH2;
R3-1-1 is hydrogen;
R3-2 is hydroxyl;
R is hydrogen, hydroxyl, C1-6 alkoxy or
R2 is C1-6 alkyl or hydrogen;
n is an integer from 1 to 400; and
is polyethylene glycol with a linear structure comprising —(OCH2CH2)n—.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein:
X is —NR1;
R1 is hydrogen;
Y is —(CH2)m—;
m is an integer from 1 to 2;
Z is a single bond or
R3 is hydrogen, or unsubstituted or R3-1 substituted C1-6 alkyl;
R3-1 is hydroxyl, carboxyl, amino, sulfhydryl, —(C═O)NR3-1-1, or —NH(C═NH)NH2;
R3-1-1 is hydrogen;
R is hydrogen, hydroxyl, C2-6 alkoxy or
R2 is C1-6 alkyl or hydrogen;
n is an integer from 0 to 100; and
is polyethylene glycol with a linear structure comprising —(OCH2CH2)n—.

### Claim 8

A compound for treating a disease, wherein the compound is selected from the group consisting of:
wherein the disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, diabetic peripheral neuropathy, diabetic foot and pulmonary fibrosis disease.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein the compound is prepared by the following step of: in a solvent, under the action of a base and a condensing agent, subjecting a compound as shown in formula II and a compound as shown in formula III to a condensation reaction as shown below;
wherein, L is —NHR1, hydroxyl

### Claim 10 (depends on 9)

The compound according to claim 9, wherein the solvent is an amide solvent or a halogenated alkane solvent;
and/or, the base is an organic base or an inorganic base;
and/or, the condensing agent is a carbodiimide, an organophosphorus salt or an onium salt.

### Claim 11

A pharmaceutical composition comprising a compound represented by formula I, or the pharmaceutically acceptable salt thereof, or ane isomer thereof, and a pharmaceutical excipient;
wherein the formula I is shown as follows:
in the formula:
X is O or —NR1;
R1 is hydrogen, unsubstituted or R1-1 substituted C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, and C3-10 cycloalkyl-(C1-4 alkyl)- or C6-12 aryl-(C1-4 alkyl)-;
R1-1 is halogen or hydroxyl;
Y is —(CH2)m—;
m is an integer from 1 to 6;
Z is a single bond,
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from hydrogen, unsubstituted or R3-1 substituted C1-6 alkyl, C6-10 aryl, unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, heteroaryl, or heteroaryl-(C1-4 alkyl)-; and the heteroaryl is 5-10 membered heteroaryl;
R3-1 is hydroxyl, carboxyl, amino, sulfhydryl, —(C═O)NR3-1-1, or —NH(C═NH)NH2;
R3-1-1 is hydrogen or C1-4 alkyl;
R3-2 is halogen or hydroxyl;
R is hydrogen, hydroxyl, C1-6 alkoxy or
R2 is C1-6 alkyl or hydrogen;
n is an integer from 0 to 500; and
is polyethylene glycol (PEG) with a linear, tree, star or hyperbranched structure comprising —(OCH2CH2)n; wherein the tree-shaped PEG is a polymer with a highly symmetrical, tree-like architecture, synthesized layer by layer from a central core to form a precise, multi-branched structure; the star-shaped PEG is a branched polymer architecture in which multiple linear PEG chains emanate from a central core molecule, creating a star-like or radial topology; the hyperbranched PEG is a three-dimensional, globular polymer obtained through a one-step synthesis; it possesses a densely yet irregularly branched structure, lacking the perfect symmetry of dendritic polymers.

### Claim 12

A method for treating a disease by administrating a compound represented by formula I or a pharmaceutically acceptable salt thereof or an isomer thereof to a subject in need, wherein the disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, diabetic peripheral neuropathy, diabetic foot and pulmonary fibrosis disease;
wherein the formula I is shown as follows:
in the formula:
X is O or —NR1;
R1 is hydrogen, unsubstituted or R1-1 substituted C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, and C3-10 cycloalkyl-(C1-4 alkyl)- or C6-12 aryl-(C1-4 alkyl)-;
R1-1 is halogen or hydroxyl;
Y is —(CH2)m—;
m is an integer from 1 to 6;
Z is a single bond,
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each independently selected from hydrogen, unsubstituted or R3-1 substituted C1-6 alkyl, C6-10 aryl, unsubstituted or R3-2 substituted C6-12 aryl-(C1-4 alkyl)-, heteroaryl, or heteroaryl-(C1-4 alkyl)-; and the heteroaryl is 5-10 membered heteroaryl;
R3-1 is hydroxyl, carboxyl, amino, sulfhydryl, —(CO)NR3-1-1, or —NH(C═NH)NH2;
R3-1-1 is hydrogen or C1-4 alkyl;
R3-2 is halogen or hydroxyl;
R is hydrogen, hydroxyl, C1-6 alkoxy or
R2 is C1-6 alkyl or hydrogen;
n is an integer from 0 to 500; and
is polyethylene glycol (PEG) with a linear, tree, star or hyperbranched structure comprising —(OCH2CH2)n; wherein the tree-shaped PEG is a polymer with a highly symmetrical, tree-like architecture, synthesized layer by layer from a central core to form a precise, multi-branched structure; the star-shaped PEG is a branched polymer architecture in which multiple linear PEG chains emanate from a central core molecule, creating a star-like or radial topology; the hyperbranched PEG is a three-dimensional, globular polymer obtained through a one-step synthesis; it possesses a densely yet irregularly branched structure, lacking the perfect symmetry of dendritic polymers.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the compound is prepared as a pharmaceutical composition with a pharmaceutical excipient.