# US 9,433,604 B2 · Method for inhibiting growth of cancer cells

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- Number: US 9,433,604 B2
- Document ID: US9433604B2
- Status: Granted
- Kind: B2
- Application number: 14/497,816
- Filed: 2014-09-26
- Published: 2015-05-28
- Granted: 2016-09-06
- Earliest claimed: 2013-10-08
- Assignees: Pain Therapeutics, Inc.
- Applicants: Pain Therapeutics, Inc.
- Inventors: Hoau-Yan Wang; Lindsay Burns Barbier
- Web page: https://patentgrep.com/patent/US9433604B2

## CPC

- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/395: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/426: 1,3-Thiazoles
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/4741: condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/54: having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 31/625: having heterocyclic substituents, e.g. 4-salicycloylmorpholine, (sulfasalazine A61K31/635)
- A61P 35/00: Antineoplastic agents
- 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

A method of inhibiting the growth of cancer cells is disclosed in which cancer cells that contain an enhanced amount relative to non-cancerous cells of one or more of phosphorylated mTOR, Akt1, ERK2 and serine2152-phosphorylated filamin A are contacted with an FLNA-binding effective amount of a compound or a pharmaceutically acceptable salt thereof that binds to the pentapeptide of filamin A (FLNA) of SEQ ID NO: 1 and exhibits at least about 60 percent of the FITC-labeled naloxone binding amount when present at a 10 μM concentration and using unlabeled naloxone as the control inhibitor at the same concentration. A compound that binds to the FLNA pentapeptide preferably also contains at least four of the six pharmacophores of FIGS. 19-24.

## Claims

### Claim 1

A method of inhibiting the growth of cancerous cells that contain an enhanced amount of one or more of phosphorylated-mTOR, phosphorylated-Akt1, phosphorylated-ERK2 and serine2152-phosphorylated filamin A that comprises contacting said cancer cells with an FLNA-binding effective amount of a compound or a pharmaceutically acceptable salt thereof that binds in a solid phase assay to the pentapeptide of FLNA of SEQ ID NO: 1, said compound or salt exhibits at least about 60 percent of the FITC-labeled naloxone binding amount when present at a 10 μM concentration, using unlabeled naloxone as the control inhibitor at the same concentration as said compound or salt, said pentapeptide of FLNA being biotinylated at its N-terminal valine residue and bound to a streptavidin-coated solid support, wherein said enhanced amount of phosphorylated-mTOR, phosphorylated-Akt1, phosphorylated-ERK2 and serine2152-phosphorylated filamin A being an amount that is significantly greater than the amount present in a non-cancerous cell of the same type, wherein said compound is a compound of Series C-2 that corresponds in structure to the Formula I below:
wherein
J and F are the same or different and are CH2, CHD or CD2 (where D is deuterium);
Q is CHR9 or C(O), Z is CHR10 or C(O), and only one of Q and Z is C(O);
each of m, n and p is zero or one and the sum of m+n+p is 2;
W is selected from the group consisting of NR2, NR7, S and O, where R7 and R2 are the same or different and are H, C(H)v(D)h where each of v and h is 0, 1, 2 or 3 and v+h =3, C(H)q(D)r-aliphatic C1-C11 hydrocarbyl where each of q and r is 0, 1, or 2 and q+r =0, 1 or 2, aliphatic C1-C12 hydrocarbyl sulfonyl or aliphatic C1-C12 hydrocarboyl, and X-circle A-R1 is as defined hereinafter;
X is SO2 or CH2;
circle A is an aromatic or heteroaromatic ring system that contains a single ring or two fused rings;
R1 is H or represents up to three substituents, R1a, R1b, and R1c, that can be the same or different, wherein each of those three groups, R1a-c, is separately selected from the group consisting of H, C1-C6 hydrocarbyl, C1-C6 hydrocarbyloxy, C1-C6 hydrocarbyloxycarbonyl, trifluoromethyl, trifluoromethoxy, C1-C7 hydrocarboyl, hydroxy-, trifluoromethyl- or halogen-substituted C1-C7 hydrocarboyl, C1-C6 hydrocarbylsulfonyl, C1-C6 hydrocarbyloxysulfonyl, halogen, nitro, phenyl, cyano, carboxyl, C1-C7 hydrocarbyl carboxylate, carboxamide or sulfonamide,
wherein the amido nitrogen in either amide group has the formula NR3R4 in which R3 and R4 are the same or different and are H, C1-C4 hydrocarbyl, or R3 and R4 together with the amido nitrogen form a 5-7-membered ring that optionally contains 1 or 2 additional hetero atoms that independently are nitrogen, oxygen or sulfur,
MAr, where M is —CH2—, —O— or —N═N— and Ar is a single-ringed aryl or heteroaryl group and NR5R6 wherein R5 and R6 are the same or different and are H, C1-C4 hydrocarbyl, C1-C4 acyl, C1-C4 hydrocarbylsulfonyl, or R5 and R6 together with the nitrogen form a 5-7-membered ring that optionally contains 1 or 2 additional hetero atoms that independently are nitrogen, oxygen or sulfur; and
R8, R9, and R10 are each H, or two of R8, R9, and R10 are H and one is a C1-C8 hydrocarbyl group that is unsubstituted or is substituted with up to three atoms that are the same or different and are oxygen or nitrogen atoms.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said compound contains at least four of the six pharmacophores of FIGS. 19-24.

### Claim 3 (depends on 1)

The method according to claim 1, wherein said cancer cells are solid tumor cancer cells.

### Claim 4 (depends on 3)

The method according to claim 3, wherein said solid tumor cancer cells are selected from the group consisting of one or more of melanoma cells, glioblastoma cells, small cell lung carcinoma cells, breast cancer cells and pancreatic cancer cells.

### Claim 5 (depends on 1)

The method according to claim 1, wherein said compound corresponds in structure to the Formula II:
wherein J and F are the same or different and are CH2, CHD or CD2 (where D is deuterium).

### Claim 6 (depends on 1)

The method according to claim 1, wherein said compound corresponds in structure to the Formula III:
wherein J and F are the same or different and are CH2, CHD or CD2 (where D is deuterium); and
each of m and n is one.

### Claim 7 (depends on 6)

The method according to claim 6, wherein said compound corresponds in structure to a compound whose formula is selected from:

### Claim 8 (depends on 1)

The method according to claim 1, wherein said contacting is carried out a plurality of times.

### Claim 9 (depends on 8)

The method according to claim 8, wherein said contacting is carried out daily.

### Claim 10 (depends on 8)

The method according to claim 8, wherein said contacting is carried out multiple times daily.

### Claim 11 (depends on 1)

The method according to claim 1, wherein said contacting is carried out by contacting said cancer cells in vitro.

### Claim 12 (depends on 1)

The method according to claim 1, wherein said contacting is carried out by contacting said cancer cells in vivo.

### Claim 13 (depends on 12)

The method according to claim 12, wherein said contacting is carried out in the absence of a mu opioid receptor- (MOR-) binding effective amount of a separate MOR agonist or antagonist.

### Claim 14 (depends on 1)

The method according to claim 1, wherein said compound or a pharmaceutically acceptable salt thereof is present dissolved or dispersed in a pharmaceutically acceptable diluent as a pharmaceutical composition when administered.

### Claim 15 (depends on 1)

The method according to claim 1, wherein said cancer cells contain an elevated amount of serine2152-phosphorylated filamin A.

### Claim 16 (depends on 15)

The method according to claim 15, wherein said cancer cells additionally contain an enhanced amount of one or more of phosphorylated-mTOR, phosphorylated-Akt1 and phosphorylated-ERK2.

### Claim 17 (depends on 1)

The method according to claim 1, wherein said cancer cells are contacted a plurality of times with said compound or pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The method according to claim 1, wherein J and F are both CH2, p is one, and X is SO2.

### Claim 19 (depends on 18)

The method according to claim 18, wherein said compound corresponds in structure to a compound whose formula is selected from:

### Claim 20 (depends on 1)

The method according to claim 1, wherein J and F are both CH2, where R8 is H, one of n and m is zero and the remaining Z or Q is CH2, and X is SO2.

### Claim 21 (depends on 20)

The method according to claim 20, wherein said compound corresponds in structure to a compound whose formula is selected from:

### Claim 22

A method of inhibiting the growth of cancerous cells that contain an enhanced amount of serine2152-phosphorylated filamin A that comprises contacting said cancer cells with a FLNA-binding effective amount of a compound or a pharmaceutically acceptable salt thereof that binds in a solid phase assay to the pentapeptide of FLNA of SEQ ID NO: 1, said compound or salt exhibits at least about 60 percent of the FITC-labeled naloxone binding amount when present at a 10 μM concentration, using unlabeled naloxone as the control inhibitor at the same concentration as said compound or salt, said pentapeptide of FLNA being biotinylated at its N-terminal valine residue and bound to a streptavidin-coated solid support, wherein said enhanced amount of serine2152-phosphorylated filamin A being an amount that is significantly greater than the amount present in a non-cancerous cell of the same type, wherein said compound corresponds in structure to a compound whose formula is selected from: