# US 10,441,565 B2 · Conjugate of memantine and arctigenin, and composition and use thereof

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- Number: US 10,441,565 B2
- Document ID: US10441565B2
- Status: Granted
- Kind: B2
- Application number: 15/756,342
- Filed: 2015-08-31
- Published: 2018-10-04
- Granted: 2019-10-15
- Earliest claimed: 2015-08-31
- Assignees: Shenzhen Qingyaqirui Bio-Tech Co., Ltd.
- Applicants: Shenzhen Qingyaqirui Bio-Tech Co., Ltd.
- Inventors: Haifeng Sun; Zhiyuan Zhu; Jun Liu; Wei Yan; Ding Zhang; Jing Yang
- Web page: https://patentgrep.com/patent/US10441565B2

## CPC

- A61K 31/365: Lactones
- A61K 31/13: Amines {(A61K31/04 takes precedence)}
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/4748: forming part of bridged ring systems (strychnine A61K31/475; morphinan derivatives A61K31/485)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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

## Abstract

Provided are a conjugate of memantine and arctigenin, and a pharmaceutical composition comprising the conjugate. The conjugate can treat diseases associated with Aβ or Tau protein pathways, such as Alzheimer's disease or Parkinson's disease.

## Claims

### Claim 1

A conjugate comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof:
wherein:
Linker 1 is selected from the group consisting of —C(O)—, —C(O)L1C(O)—, —C(O)OL1C(O)—, —C(O)OL1OC(O)—, —C(O)OQ1L2Q2-, —C(O)Q1L2Q2N(R1)C(O)—, —C(O)Q1L2Q2OC(O)—, —C(O)Q1L2Q2C(O)—, —C(O)OQ1L2Q2OC(O)—, —C(O)OQ1L1Q2N(R1)C(O)—, —C(O)OQ1L2Q2N(R1)C(O)— and —C(O)OQ1L2Q2C(O)—;
L1 is a direct bond, or is selected from the group consisting of —O—, —S—, —NR2—, substituted or unsubstituted C1-C6 straight or branched alkylene, substituted or unsubstituted C2-C6 straight or branched alkenylene, substituted or unsubstituted C2-C6 straight or branched alkynylene, substituted or unsubstituted C3-C10 cyclrejectionlkylene, substituted or unsubstituted C3-C10 non-aromatic heterocyclylene, substituted or unsubstituted C6-C14 arylene, substituted or unsubstituted C6-C14 heterrectionrylene, and substituted or unsubstituted C6-C20 aralkylene;
L2 is a direct bond, or is selected from the group consisting of —NR2—, —O—, —C(O)—, —N(R3)C(O)—, —C(O)N(R3)—, —C(O)O—, —OC(O)—, —N(R3)Q3O—, —N(R3)C(O)Q3O—, —N(R3)C(O)Q3C(O)—, —N(R3)C(O)Q3N(R3)—, —N(R3)C(O)Q3C(O)N(R3)—, —N(R3)C(O)Q3N(R3)C(O)—, —N(R3)C(O)Q3C(O)O—, —N(R3)C(O)Q3OC(O)—, —C(O)N(R3)Q3C(O)N(R3)—, —C(O)N(R3)Q3C(O)O—, —C(O)N(R3)Q3N(R3)C(O)—, —C(O)N(R3)Q3OC(O)—, —N(R3)Q3C(O)N(R3)—, —N(R3)Q3C(O)O—, —N(R3)Q3N(R3)C(O)—, —N(R3)Q3OC(O)—, —OQ3N(R3)—, —OQ3C(O)N(R3)—, —OQ3C(O)O—, —OQ3N(R3)C(O)—, —OQ3OC(O)—, —OC(O)Q3-, —OC(O)Q3C(O)N(R3)—, —OC(O)Q3C(O)O—, —OC(O)Q3N(R3)—, —OC(O)Q3N(R3)C(O)—, —OC(O)Q3N(R3)L1O—, —OC(O)Q3OC(O)—, —C(O)OQ3-, —C(O)OQ3O—, —C(O)OQ3C(O)N(R3)—, —C(O)OQ3C(O)O—, —C(O)OQ3N(R3)C(O)— or —C(O)OQ3OC(O)—;
Q1, Q2 and Q3 are each independently selected from the group consisting of substituted or unsubstituted C1-C6 straight or branched alkylene, substituted or unsubstituted C3-C10 cyclrejectionlkylene, substituted or unsubstituted C2-C6 straight or branched alkenylene, substituted or unsubstituted C2-C6 straight or branched alkynylene, substituted or unsubstituted C3-C10 non-aromatic heterocyclylene, substituted or unsubstituted C6-C14 arylene, substituted or unsubstituted C6-C14 heterrejectionrylene, and substituted or unsubstituted C6-C20 aralkylene; and
R1, R2 and R3 are each independently selected from the group consisting of H and C1-C6 alkyl.

### Claim 2 (depends on 1)

The conjugate according to claim 1, which is a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof:
wherein:
Linker 2 is selected from the group consisting of -L1-, -L1O—, -Q1L1Q2N(R1)—, -Q1L2Q2N(R1)—, -Q1L2Q2O— or -Q1L2Q2-;
L1 is selected from the group consisting of substituted or unsubstituted C1-C6 straight or branched alkylene, substituted or unsubstituted C2-C6 straight or branched alkenylene, substituted or unsubstituted C2-C6 straight or branched alkynylene, substituted or unsubstituted C3-C10 cyclrejectionlkylene, substituted or unsubstituted C3-C10 non-aromatic heterocyclylene, substituted or unsubstituted C6-C14 arylene, substituted or unsubstituted C6-C14 heterrejectionrylene, and substituted or unsubstituted C6-C20 aralkylene; and
L2, Q1, Q2, Q3, R1, R2 and R3 are as defined in claim 1.

### Claim 3 (depends on 2)

The conjugate according to claim 2, which is a compound of formula (III), or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvate thereof:
Linker 3 is a direct bond, or is selected from the group consisting of —C(O)Q3N(R3)Q2-, —C(O)Q3N(R3)Q2N(R1)—, —C(O)Q2O—, —C(O)Q2N(R1)—, —C(O)Q3N(R3)L1OQ2N(R1)— and —C(O)Q3Q2N(R1)—;
L1, Q2, Q3, R1 and R3 are as defined in claim 2; and
R is selected from the group consisting of H or C1-C6 alkyl.

### Claim 4 (depends on 1)

The conjugate according to claim 1, which is selected from the group consisting of conjugates A01 to A55 and pharmaceutically acceptable salts, stereoisomers, polymorphs, and solvates thereof:
No.
Conjugate Structure
A01
A02
A03
A04
A05
A06
A07
A08
A09
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
A30
A31
A32
A33
A34
A35
A36
A37
A38
A39
A40
A41
A42
A43
A44
A45
A46
A47
A48
A49
A50
A51
A52
A53
A54
A55

### Claim 5 (depends on 1)

A pharmaceutical composition comprising the conjugate according to claim 1 and one or more pharmaceutically acceptable carriers.

### Claim 6 (depends on 5)

The pharmaceutical composition according to claim 5, further comprising one or more additional agents for the treatment of a disease associated with the Aβ or Tau protein pathway.

### Claim 7 (depends on 1)

A method for treating a disease associated with the Aβ or Tau protein pathway, comprising administering to a subject in need thereof a therapeutically effective amount of the conjugate according to claim 1, wherein the disease is a neurodegenerative disease.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the disease is Alzheimer's disease or Parkinson's disease.

### Claim 9 (depends on 7)

The method according to claim 7, further comprising administering to a subject in need thereof an additional agent for the treatment of a disease associated with the Aβ or Tau protein pathway.

### Claim 10 (depends on 6)

The pharmaceutical composition according to claim 6, wherein the additional agent for the treatment of a disease associated with the Aβ or Tau protein pathway is an acetylcholinesterase inhibitor.

### Claim 11 (depends on 10)

The pharmaceutical composition according to claim 10, wherein the acetylcholinesterase inhibitor is donepezil, huperzine A, or tacrine.

### Claim 12 (depends on 5)

A method for treating a disease associated with the Aβ or Tau protein pathway, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 5, wherein the disease is a neurodegenerative disease.

### Claim 13 (depends on 9)

The method according to claim 9, wherein the additional agent for the treatment of a disease associated with the Aβ or Tau protein pathway is an acetylcholinesterase inhibitor.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the acetylcholinesterase inhibitor is donepezil, huperzine A, or tacrine.