# US 10,500,198 B2 · Bis-benzylidine piperidone proteasome inhibitor with anticancer activity

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,500,198 B2
- Document ID: US10500198B2
- Status: Granted
- Kind: B2
- Application number: 15/876,880
- Filed: 2018-01-22
- Published: 2019-06-13
- Granted: 2019-12-10
- Earliest claimed: 2013-05-08
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Richard B. Roden; Ravi K. Anchoori; Balasubramanyam Karanam
- Web page: https://patentgrep.com/patent/US10500198B2

## CPC

- A61K 31/45: having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- 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 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 38/05: Dipeptides
- A61P 35/00: Antineoplastic agents
- C07D 211/74: Oxygen atoms
- C07D 213/68: attached in position 4
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 451/06: Oxygen atoms
- C07D 471/08: Bridged systems
- C07D 475/04: with a nitrogen atom directly attached in position 2
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

We describe a bis-benzylidine piperidone, RA190, which covalently binds to the ubiquitin receptor RPN13 (ADRM1) in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma lines, even those resistant to bortezomib, were sensitive to RA190 via ER stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After p.o. or i.p. dosing of mice, RA190 distributed to plasma and major organs excepting brain, and potently inhibited proteasome function in skin and muscle. RA190 administration i.p. profoundly reduced growth of multiple myeloma and ovarian cancer xenografts, and oral RA190 treatment retarded HPV+ syngeneic mouse tumor growth, without impacting spontaneous HPV-specific CD8+ T cell responses, suggesting its therapeutic potential. The bis-benzylidine piperidone RA190 is a new orally-available proteasome inhibitor. Multiple myeloma, cervical and ovarian cancers are particularly sensitive to RA190.

## Claims

### Claim 1

A method of inhibiting proteasomes in a mammal by administering to the mammal an effective amount of a compound of formula I,
wherein each pair of As is one of:
(i) phenyl, optionally substituted with 1-5 substituents selected from the group consisting of R1, OR1, NR1R2, S(O)qA1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3;
(ii) naphthyl, optionally substituted with 1-5 substituents selected from the consisting of R1, OR1, NR1R2, S(O)qA1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3;
(iii) a 5 or 6 membered monocyclic heteroaryl group, having 1-3 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with 1-3 substituents selected from the group consisting of R1, OR1, NR1R2, S(O)qA1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3; and
(iv) an 8 to 10 membered bicyclic heteroaaryl group containing 1-3 heteroatoms selected from the group consisting of O, N, and S; and the second ring is fused to the first ring using 3 to 4 carbon atoms, and the bicyclic hetero aryl group is optionally substituted with 1-3 substituents selected from the group consisting of R1, OR1, NR1R2, S(O)qA1, SO2NR1R2, NR1SO2R2, C(O)R1, C(O)OR1, C(O)NR1R2, NR1C(O)R2, NR1C(O)OR2, CF3, and OCF3;
wherein X is OR1 or NP, wherein P is selected from the group consisting of R1, C(O)R1, C(O)OR1, C(O)NR1R2, S—N(R1)COOR1, and S—N(R1),
wherein Y is selected from the group consisting of O, S, NR1 and CR1R2,
wherein R1 and R2 are selected from the group consisting of hydrogen, nitro; hydroxyl; carboxy; amino; halogen; cyano; and C1-C14 linear or branched alkyl groups, that are optionally substituted with 1-3 substituents selected from the group consisting of C1-C14 linear or branched alkyl, up to perhalo substituted C1-C14 linear or branched alkyl, C1-C14 alkoxy, hydrogen, nitro, hydroxyl, carboxy, amino, C1-C14 alkylamino, C1-C14 dialkylamino, halogen, and cyano; and
wherein Z is selected from the group consisting of hydrogen; C1 to C14 linear, branched, or cyclic alkyls; phenyl; benzyl; 1-5 substituted benzyl; C1 to C3 alkyl-phenyl, wherein the alkyl moiety is optionally substituted with halogen up to perhalo; up to perhalo substituted C1 to C14 linear or branched alkyls; and —(CH2)q—K, where K is a 5 or 6 membered monocyclic heterocyclic ring, containing 1 to 4 atoms selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or an 8 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S, wherein said alkyl moiety is optionally substituted with halogen up to perhalo; and wherein the variable q is an integer ranging from 0 to 4; and
wherein inhibiting the proteasomes comprises inhibiting a ubiquitin proteasome system.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mammal is a human.

### Claim 3 (depends on 1)

The method of claim 1, wherein the method treats a condition or a disease in the mammal.

### Claim 4 (depends on 3)

The method of claim 3, wherein the mammal is a human.

### Claim 5 (depends on 3)

The method of claim 3, wherein the condition or disease is a type of cancer.

### Claim 6 (depends on 5)

The method of claim 5, wherein the type of cancer is selected from the group consisting of breast cancer, cervical cancer, ovarian cancer, multiple myeloma, breast cancer and pancreatic cancer.

### Claim 7 (depends on 5)

The method of claim 5, wherein the type of cancer is associated with Human Papilloma Virus (HPV).

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is administered in combination with at least one other therapeutic agent.

### Claim 9 (depends on 8)

The method of claim 8, wherein the at least one other therapeutic agent is a proteasome inhibitor.

### Claim 10 (depends on 8)

The method of claim 8, wherein the at least one other therapeutic agent is bortezomib.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound binds to RPN13.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound is orally administered.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is intraperitoneally administered.

### Claim 14 (depends on 1)

The method compound of claim 1, wherein the compound is topically applied.

### Claim 15 (depends on 1)

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

### Claim 16

A method of inhibiting proteasomes in a mammal by administering to the mammal an effective amount of a compound having the structure:

### Claim 17 (depends on 1)

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