# US 11,028,098 B2 · 4-phenylpiperidines, their preparation and use

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- Number: US 11,028,098 B2
- Document ID: US11028098B2
- Status: Granted
- Kind: B2
- Application number: 16/151,019
- Filed: 2018-10-03
- Published: 2019-01-31
- Granted: 2021-06-08
- Earliest claimed: 2013-03-14
- Assignees: The Trustees of Columbia University in the City of New York
- Applicants: The Trustees of Columbia University in the City of New York
- Inventors: Konstantin Petrukhin; Christopher Cioffi; Graham Johnson; Nicoleta Dobri; Emily Freeman; Ping Chen; Michael Conlon; Lei Zhu
- Web page: https://patentgrep.com/patent/US11028098B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 27/02: Ophthalmic agents
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 491/052: the oxygen-containing ring being six-membered
- C07D 495/04: 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 provide a compound having the structure: (structurally represented) wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl; R6 is H, OH, or halogen; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterocycle is other than chloro substituted indole; and the pyrazole, when substituted, is substituted with other than trifluoromethyl, or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a mammal afflicted therewith comprising administering to the mammal an effective amount of a compound having the structure:
R1, R2, R3, and R4, are each independently H, halogen, CF3 or C1-C4 alkyl, and wherein R5 is CF3;
R6 is H, OH, or halogen;
B is a substituted or unsubstituted pyridazine, pyrimidine, pyrazine, or B has the structure:
wherein
n is 1;
R7 is H, C1-C4 alkyl, or oxetane;
Y1 and Y4 are each CH2; and
one of Y2 or Y3 is CH2 and the other of Y2 or Y3 is O, SO2, or N—R10,
wherein
R10 is H, C1-C4 alkyl, C1-C4 cycloalkyl, (C1-C4 alkyl)-CF3, (C1-C4 alkyl)-OCH3, (C1-C4 alkyl)-halogen, SO2—(C1-C4 alkyl), SO2—(C1-C4 alkyl)-CF3, SO2—(C1-C4 alkyl)-OCH3, SO2—(C1-C4 alkyl)-halogen, C(O)—(C1-C4 alkyl), C(O)—(C1-C4 alkyl)-CF3, C(O)—(C1-C4 alkyl)-OCH3, C(O)—(C1-C4 alkyl)-halogen, C(O)—NH—(C1-C4 alkyl), C(O)—N(C1-C4 alkyl)2, C1-C4 alkyl)-C(O)OH, or oxetane;
or B has the structure:
wherein
R7 is H, C1-C4 alkyl, or oxetane; and
Y1, Y2, Y3 and Y4 are each independently CR8 or N,
wherein each R8 is independently H, halogen, C1-C4 alkyl, C1-C4 cycloalkyl, O—(C1-C4 alkyl), C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3, NHC(O)—N(CH3)2, CN, or CF3;
or B has the structure:
wherein
Y1, Y2, Y3 and Y4 are each independently CR8 or N,
wherein each R8 is independently H, halogen, C1-C4 alkyl, C1-C4 cycloalkyl, O—(C1-C4 alkyl), C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3NHC(O)—N(CH3)2, CN, or CF3;
and
wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration, dry Age-Related Macular Degeneration, Geographic atrophy, Stargardt Disease, Best disease, adult vitelliform maculopathy, or Stargardt-like macular dystrophy;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound has the structure:

### Claim 4

A method of lowering the serum or plasma concentration of RBP4 in a mammal comprising administering to the mammal an effective amount of a compound having the structure:
R1, R2, R3, and R4, are each independently H, halogen, CF3 or C1-C6 alkyl, and wherein R5 is CF3;
R6 is H, OH, or halogen;
B is a substituted or unsubstituted pyrimidine, pyridazine, pyrazine, or B has the structure:
wherein
n is 1;
R7 is H, C1-C4 alkyl, or oxetane;
Y1 and Y4 are each CH2; and
one of Y2 or Y3 is CH2 and the other of Y2 or Y3 is O, SO2, or N—R10,
wherein
R10 is H, C1-C4 alkyl, C1-C4 cycloalkyl, (C1-C4 alkyl)-CF3, (C1-C4 alkyl)-OCH3, (C1-C4 alkyl)-halogen, SO2—(C1-C4 alkyl), SO2—(C1-C4 alkyl)-CF3, SO2—(C1-C4 alkyl)-OCH3, SO2—(C1-C4 alkyl)-halogen, C(O)—(C1-C4 alkyl), C(O)—(C1-C4 alkyl)-CF3, C(O)—(C1-C4 alkyl)-OCH3, C(O)—(C1-C4 alkyl)-halogen, C(O)—NH—(C1-C4 alkyl), C(O)—N(C1-C4 alkyl)2, C1-C4 alkyl)-C(O)OH, or oxetane;
or B has the structure:
wherein
R7 is H, C1-C4 alkyl, or oxetane; and
Y1, Y2, Y3 and Y4 are each independently CR8 or N,
wherein each R8 is independently H, halogen, C1-C4 alkyl, C1-C4 cycloalkyl, O—(C1-C4 alkyl), C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3, NHC(O)—N(CH3)2, CN, or CF3;
or B has the structure:
wherein
Y1, Y2, Y3 and Y4 are each independently CR8 or N,
wherein each R8 is independently H, halogen, C1-C4 alkyl, C1-C4 cycloalkyl, O—(C1-C4 alkyl), C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3NHC(O)—N(CH3)2, CN, or CF3;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein B has the structure:
wherein
n is 1;
R7 is H, C1-C4 alkyl, or oxetane;
Y1 and Y4 are each CH2; and
one of Y2 or Y3 is CH2 and the other of Y2 or Y3 is O, SO2, or N—R10,
wherein
R10 is H, C1-C4 alkyl, C1-C4 cycloalkyl, (C1-C4 alkyl)-CF3, (C1-C4 alkyl)-OCH3, (C1-C4 alkyl)-halogen, SO2—(C1-C4 alkyl), SO2—(C1-C4 alkyl)-CF3, SO2—(C1-C4 alkyl)-OCH3, SO2—(C1-C4 alkyl)-halogen, C(O)—(C1-C4 alkyl), C(O)—(C1-C4 alkyl)-CF3, C(O)—(C1-C4 alkyl)-OCH3, C(O)—(C1-C4 alkyl)-halogen, C(O)—NH—(C1-C4 alkyl), C(O)—N(C1-C4 alkyl)2, (C1-C4 alkyl)-C(O)OH, or oxetane.

### Claim 6 (depends on 5)

The method of claim 5, wherein B has the structure:

### Claim 7 (depends on 6)

The method of claim 6, wherein B has the structure:
wherein
n is 1;
R7 is H, C1-C4 alkyl, or oxetane;
Y1 and Y4 are each CH2 or C(CH3)2; and
one of Y2 or Y3 is CH2, and the other of Y2 or Y3 is N—R10; and
R10 is C(O)—CH3, C(O)—CH2CH3, C(O)—CH2CH2CH3, C(O)—CH(CH3)2, C(O)—CH2CH(CH3)2, C(O)-t-Bu, C(O) CH2OCH3, C(O) CH2CF3, C(O)—CH2Cl, C(O)—CH2F, C(O)—CH2CH2OCH3, C(O)—CH2CH2CF3, C(O)—CH2CH2Cl, C(O)—CH2CH2F,

### Claim 8 (depends on 4)

The method of claim 4, wherein B has the structure:
wherein
R7 is H, C1-C4 alkyl, or oxetane; and
Y1, Y2, Y3 and Y4 are each independently CR8 or N,
wherein each R8 is independently H, halogen, C1-C4 alkyl, C1-C4 cycloalkyl, O—(C1-C4 alkyl), C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3, NHC(O)—N(CH3)2, CN, or CF3.

### Claim 9 (depends on 4)

The method of claim 4, wherein B has the structure:
wherein
Y1, Y2, Y3 and Y4 are each independently CR8 or N,
wherein each R8 is independently H, halogen, C1-C4 alkyl, C1-C4 cycloalkyl, O—(C1-C4 alkyl), C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3NHC(O)—N(CH3)2, CN, or CF3.

### Claim 10 (depends on 4)

The method of claim 4, wherein B is pyridazine, pyrazine, or pyrimidine.

### Claim 11 (depends on 10)

The method of claim 10, wherein B has the structure:
wherein R19 is H, halogen CN, CF3, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, O(C1-C4 alkyl), C(O)NH2, C(O)NH(C1-C4 alkyl), C(O)N(C1-C4 alkyl)2, C(O)OH, C(O)O(C1-C4 alkyl), C(O) (C1-C4 alkyl), C(O)NH(SO2)—(C1-C4 alkyl), C(O)NH(SO2)—(C3-C6 cycloalkyl), C(O)NH(SO2)-(aryl), O(SO2)—NH2, NHC(O)—NH(C1-C4 alkyl), NHC(O)—N(C1-C4 alkyl)2, SO2—(C1-C4 alkyl), or tetrazole.

### Claim 12 (depends on 10)

The method of claim 10, wherein B has the structure:
wherein R21, R22, R23, R24, and R25 are each independently H, halogen, CN, CF3, OH, NH2, C1-C10 alkyl, C3-C6 cycloalkyl, O(C1-C4 alkyl), C(O)NH2, C(O)NH(C1-C10 alkyl), C(O)N(C1-C4 alkyl)2, C(O)OH, C(O)O(C1-C10 alkyl), C(O) (C1-C10 alkyl), C(O)NH(SO2)—(C1-C4 alkyl), C(O)NH(SO2)—(C3-C6 cycloalkyl), C(O)NH(SO2)-(aryl), O(SO2)—NH2, NHC(O)—NH(C1-C10 alkyl), NHC(O)—N(C1-C4 alkyl)2, SO2—(C1-C10 alkyl), or
B has the structure:
wherein R21, R22, R24, and R25 are each independently H, halogen, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, O(C1-C4 alkyl), C(O)NH2, C(O)NH(C1-C4 alkyl), C(O)N(C1-C4 alkyl)2, C(O)OH, C(O)O(C1-C4 alkyl), C(O) (C1-C4 alkyl), C(O)NH(SO2)—(C1-C4 alkyl), C(O)NH(SO2)—(C3-C6 cycloalkyl), C(O)NH(SO2)-(aryl), O(SO2)—NH2, NHC(O)—NH(C1-C4 alkyl), NHC(O)—N(C1-C4 alkyl)2, or SO2—(C1-C4 alkyl).

### Claim 13 (depends on 12)

The method of claim 12, wherein B has the structure:

### Claim 14 (depends on 4)

The method of claim 4, wherein the compound is administered to the mammal intravenously, intravitreally, or orally.

### Claim 15 (depends on 4)

The method of claim 4, wherein the compound is administered in an oral dosage form as a tablet, capsule, or liquid suspension.

### Claim 16

A method for lowering the serum or plasma concentration of RBP4 in a mammal comprising administering to the mammal an effective amount of a compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The method of claim 1, wherein the disease characterized by excessive lipofuscin accumulation in the retina is dry Age-Related Macular Degeneration.

### Claim 18 (depends on 1)

The method of claim 1, wherein the disease characterized by excessive lipofuscin accumulation in the retina is Geographic atrophy.

### Claim 19 (depends on 1)

The method of claim 1, wherein the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt Disease or Best disease.

### Claim 20 (depends on 1)

The method of claim 1, wherein the disease characterized by excessive lipofuscin accumulation in the retina is adult vitelliform maculopathy or Stargardt-like macular dystrophy.