# US 10,870,642 B2 · Biheterocyclic compound

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- Number: US 10,870,642 B2
- Document ID: US10870642B2
- Status: Granted
- Kind: B2
- Application number: 16/392,732
- Filed: 2019-04-24
- Published: 2019-10-10
- Granted: 2020-12-22
- Earliest claimed: 2016-01-15
- Assignees: Sumitomo Dainippon Pharma Co., Ltd.
- Applicants: Sumitomo Dainippon Pharma Co., Ltd.
- Inventors: Hitoshi Watanabe; Yoshiaki Isobe; Hidenori Kimura; Yuji Fujiwara
- Web page: https://patentgrep.com/patent/US10870642B2

## CPC

- C07D 405/14: containing three or more hetero rings
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- 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
- A61P 27/04: Artificial tears; Irrigation solutions
- C07D 311/22: with oxygen or sulfur atoms directly attached in position 4
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- 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

## Abstract

The present invention provides a compound of formula (1) and a pharmaceutical composition comprising the compound useful as a nerve regeneration promoter wherein R1-L- is R1—OC(O)—, or the like, R1 is hydrogen atom, optionally-substituted C1-6 alkyl group, optionally-substituted 3- to 8-membered cycloalkyl group, or the like, R2 is hydrogen atom or the like, Ring A is formula (2) or formula (3) wherein R3 is hydrogen atom, optionally-substituted C1-6 alkyl group, or the like, the part of X, Y, and Z is X═Y—Z, X—Y═Z, or X—Y—Z, X is nitrogen atom, NR4 (R4 is hydrogen atom, optionally-substituted C1-6 alkyl group, or the like), or the like, Y is carbon atom or the like, and Z is carbon atom, nitrogen atom or the like.

## Claims

### Claim 1

A compound selected from the group consisting of:
a) N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
b) N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
c) N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid and
d) N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising as an active ingredient a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

### Claim 3 (depends on 1)

A method
for treating and/or preventing a disease associated with neurodegeneration or neurological disorder, or
for treating and/or preventing a neurological disease associated with ischemic damage, or
for treating and/or preventing corneal disease
comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the method is a method for treating and/or preventing corneal disease; and the corneal disease is dry eye.

### Claim 5 (depends on 3)

The method of claim 3, wherein the method is a method for treating and/or preventing corneal disease; and the corneal disease is a disease associated with neurodegeneration or neurological disorder.

### Claim 6

A method for treating and/or preventing a disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (7):
wherein
Ring B is a group of formula (8), (9), or (10);
R1 is
(i) hydrogen atom,
(ii) C1-3 alkyl group
which is unsubstituted or substituted with one or more substituents selected independently from the group consisting of
(a) hydroxy group,
(b) methoxy group,
(c) ethoxy group,
(d) carboxyl group,
(e) carbamoyl group which is unsubstituted or independently substituted with one or two C1-3 alkyl,
(f) NR5R6 wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group,
(g) 3- to 6-membered cycloalkyl group which is unsubstituted or substituted with one or more substituents selected independently from the group consisting of amino group which is unsubstituted or independently substituted with one or two C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group,
(h) 4- to 6-membered saturated aliphatic heterocyclyl group which is unsubstituted or substituted with one or more substituents selected independently from the group consisting of amino group which is unsubstituted or independently substituted with one or two C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group, and
(i) 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one or more substituents selected independently from amino group which is unsubstituted or independently substituted with one or two C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group,
(iii) the group of formula (4):
wherein m is 1, 2, 3, 4, or 5, R7 is C1-3 alkoxy group, amino acid group which binds to C(O) at its N terminus, or peptide consisting of 2-3 amino acid residues which binds to C(O) at its N terminus,
(iv) the group of formula (5):
R8-L2-(CH2CH2O)qCH2CH2→ (5)
wherein q is 1, 2, 3, 4, or 5, L2 is single bond or C(O), R8 is hydroxy group, C1-3 alkoxy group, amino group which is unsubstituted or independently substituted with one or two C1-3 alkyl, amino acid group which binds to L2 at its N terminus, or peptide consisting of 2-3 amino acid residues which binds to L2 at its N terminus, or
(v) the group of formula (6):
wherein L3 is CH2 or C(O), and R9 is hydroxy group, C1-3 alkoxy group, amino group which is unsubstituted or independently substituted with one or two C1-3 alkyl, amino acid group which binds to L3 at its N terminus, or peptide consisting of 2-3 amino acid residues which binds to L3 at its N terminus;
X1 is 0 or NR14; and
R13 and R14 are independently hydrogen atom, C1-3 alkyl group, or 3- to 6-membered cycloalkyl group,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The method of claim 6, wherein the disease or disorder is
a disease associated with neurodegeneration or neurological disorder,
a neurological disease associated with ischemic damage,
corneal disease,
a disease associated with degeneration or damage of the central nerve or peripheral nerve, or
dysosmia, traumatic neurological disorder, cerebral-infarct neurological disorder, facial palsy, diabetic neurosis, glaucoma, retinitis pigmentosa, dry eye, Alzheimer's disease, Parkinson's disease, neurodegenerative disease, muscular dysgenic lateral sclerosis, amyotrophic lateral sclerosis, Huntington's disease, cerebral infarct, or traumatic neurodegenerative disease.

### Claim 8 (depends on 6)

The method of claim 6, wherein Ring B is the group of formula (8).

### Claim 9 (depends on 6)

The method of claim 6, wherein R1 is the group of formula (4), (5), or (6).

### Claim 10 (depends on 6)

The method of claim 6, wherein
R1 is hydrogen or the group of formula (6), and
in formula (6), L3 is C(O) and R9 is an amino acid group which binds to L3 at its N terminus.

### Claim 11 (depends on 6)

The method of claim 6, wherein L2 and L3 are each C(O).

### Claim 12 (depends on 6)

The method of claim 6, wherein R7, R8, or R9 is an amino acid group which binds to C(O), L2, or L3 at its N terminus.

### Claim 13 (depends on 8)

The method of claim 8, wherein R7, R8, or R9 is L-glutamic acid which binds to C(O), L2, or L3 at its N terminus.

### Claim 14 (depends on 6)

The method of claim 6, wherein R13 is hydrogen atom.

### Claim 15 (depends on 6)

The method of claim 6, wherein X1 is NR14.

### Claim 16 (depends on 6)

The method of claim 6, wherein R14 is methyl group.

### Claim 17 (depends on 6)

The method of claim 6, wherein the compound of formula (7) is selected from the following compounds:
3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid;
N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
N2-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine;
3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid;
N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylic acid;
N-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-glutamic acid;
N2-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-arginine;
3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid;
N-({4-[({[3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinol in-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic acid;
N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid;
N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid;
3-[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoic acid;
N-{3-[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoyl}-L-glutamic acid;
2,2′-{[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethyl]imino}-diacetic acid;
2,3-dihydroxypropyl 3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate;
(trans-4-aminocyclohexyl)methyl 3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate;
O-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-homoserine;
14-hydroxy-3,6,9,12-tetraoxatetradec-1-yl 3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate; and
2-amino-2-oxoethyl 3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate.

### Claim 18 (depends on 7)

The method of claim 7, wherein the disease or disorder is a neurological disease associated with ischemic damage; and the patient has experienced or is experiencing ischemia or ischemic cerebrovascular disease.

### Claim 19 (depends on 18)

The method of claim 18, wherein the ischemic cerebrovascular disease is cerebral emboli, transient cerebral ischemia, subclavian steal syndrome, Wallenberg's syndrome, cerebral thrombosis, lacunar infarct, reversible ischemic neurological deficit, cerebral infarct, moyamoya disease, cerebral hypoxia, sinus thrombosis, or postoperative spinal cord ischemia.

### Claim 20 (depends on 7)

The method of claim 7, wherein the disease or disorder is corneal disease; and the patient is experiencing or has experienced neurodegeneration or a neurological disorder.

### Claim 21 (depends on 7)

The method of claim 7, wherein the disease or disorder is corneal disease; and the corneal disease is dry eye, keratitis, leukoma, corneal infection, corneal degeneration, corneal dystrophy, corneal stromal dystrophy, bullous keratopathy, keratoconus, corneal endothelial decompensation, corneal ulcer, nerve-paralytic keratopathy, diabetic keratopathy, chemical ocular injury or corneal burn.

### Claim 22 (depends on 7)

The method of claim 7, wherein the disease or disorder is corneal disease; and the corneal disease is dry eye, keratitis, bullous keratopathy, corneal ulcer, nerve-paralytic keratopathy, or diabetic keratopathy.

### Claim 23 (depends on 7)

The method of claim 7, wherein the disease or disorder is corneal disease; and the corneal disease is dry eye.

### Claim 24 (depends on 6)

The method of claim 6, wherein the disease or disorder is glaucoma, central retinal artery occlusion, central branch retinal artery occlusion, central retinal vein occlusion, central branch retinal vein occlusion, ischemic optic neuropathy, diabetic retinopathy, diabetic keratopathy, macular degeneration, or retinopathy of prematurity.

### Claim 25 (depends on 6)

The method of claim 6, wherein the disease or disorder is diabetic retinopathy or macular degeneration.

### Claim 26 (depends on 3)

The method of claim 3, wherein the method is a method for treating and/or preventing a neurological disease associated with ischemic damage; and the patient has experienced or is experiencing ischemia or ischemic cerebrovascular disease.

### Claim 27 (depends on 26)

The method of claim 26, wherein the ischemic cerebrovascular disease is cerebral emboli, transient cerebral ischemia, subclavian steal syndrome, Wallenberg's syndrome, cerebral thrombosis, lacunar infarct, reversible ischemic neurological deficit, cerebral infarct, moyamoya disease, cerebral hypoxia, sinus thrombosis, or postoperative spinal cord ischemia.

### Claim 28 (depends on 3)

The method of claim 3, wherein the corneal disease is dry eye, keratitis, leukoma, corneal infection, corneal degeneration, corneal dystrophy, corneal stromal dystrophy, bullous keratopathy, keratoconus, corneal endothelial decompensation, corneal ulcer, nerve-paralytic keratopathy, diabetic keratopathy, chemical ocular injury or corneal burn.

### Claim 29 (depends on 3)

The method of claim 3, wherein the corneal disease is dry eye, keratitis, bullous keratopathy, corneal ulcer, nerve-paralytic keratopathy, or diabetic keratopathy.

### Claim 30 (depends on 6)

The method of claim 6, wherein the compound of formula (7) is selected from the following compounds:
a) N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
b) N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid;
c) N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic acid and
d) N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic acid,
or a pharmaceutically acceptable salt thereof.

### Claim 31 (depends on 30)

The method of claim 30, wherein the disease or disorder is glaucoma, central retinal artery occlusion, central branch retinal artery occlusion, central retinal vein occlusion, central branch retinal vein occlusion, ischemic optic neuropathy, diabetic retinopathy, diabetic keratopathy, macular degeneration, or retinopathy of prematurity.

### Claim 32 (depends on 30)

The method of claim 30, wherein the disease or disorder is diabetic retinopathy or macular degeneration.

### Claim 33 (depends on 30)

The method of claim 30, wherein the disease or disorder is a disease associated with degeneration or damage of the central nerve or peripheral nerve.

### Claim 34 (depends on 30)

The method of claim 30, wherein the disease or disorder is dysosmia, traumatic neurological disorder, cerebral-infarct neurological disorder, facial palsy, diabetic neurosis, glaucoma, retinitis pigmentosa, dry eye, Alzheimer's disease, Parkinson's disease, neurodegenerative disease, muscular dysgenic lateral sclerosis, amyotrophic lateral sclerosis, Huntington's disease, cerebral infarct, or traumatic neurodegenerative disease.