# US 2013/0156761 A1 · Compounds Useful for Inhibiting Metastasis from Cancer and Methods Using Same

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- Number: US 2013/0156761 A1
- Document ID: US20130156761A1
- Status: Published application
- Kind: A1
- Application number: 13/776,220
- Filed: 2013-02-25
- Published: 2013-06-20
- Earliest claimed: 2010-12-07
- Assignees: Alliance Discovery, Inc.; Philadelphia Health & Education Corporation d/b/a Drexel University College of Medicine
- Inventors: Alessandro Fatatis; Joseph M. Salvino; Olimpla Meucci; Whitney L. Jamieson
- Web page: https://patentgrep.com/patent/US20130156761A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 31/453: containing a six-membered ring with oxygen as a ring hetero atom
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 19/00: Drugs for skeletal disorders
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention includes compositions that are useful in preventing or treating metastasis in a subject diagnosed with cancer. The present invention also includes methods of preventing or treating metastasis in a subject diagnosed with cancer, wherein the method comprises administering to the subject in need thereof an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one CX3CR1 or fractalkine antagonist.

## Claims

### Claim 1

A composition comprising at least one agent selected from the group consisting of:
(i) a compound of Formula (I):
wherein in (I):
A1 is CH2 or cyclopentane-1,3-diyl;
n is 0, 1, 2, 3, 4 or 5 if A is CH2, or n is 0, 1, or 2 if A is cyclopentane-1,3-diyl;
A2 and A3 are both H, or A2 and A3 combine to form a divalent radical selected from the group consisting of methanediyl, ethane-1,2-diyl, or propane-1,3-diyl;
A4 is CH2, CH(CF3), or CF2;
R1 and R2 are both H, and R3 is selected from the group consisting of:
wherein ring A is selected from the group consisting of phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, thiophenyl, substituted thiophenyl, 1H-pyrazole, and 1-(C1-C6) alkyl-1H-pyrazole;
R4 is nil or (C1-C6)alkyl, wherein if R4 is (C1-C6)alkyl, compound of Formula (I) is a quaternary ammonium salt;
R5 is (C1-C6)alkyl, substituted (C1-C6)alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;
R6 is H, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl or substituted aryl; and,
R7 is OH, CH2OH, or C(═O)OR6;
(ii) a compound of Formula (IX):
RA—RB (IX),
wherein:
RA is a group selected from the group consisting of:
and,
RB is a group selected from the group consisting of:
(iii) a compound of Formula (X):
wherein R1 is (C1-C8) alkyl, substituted (C1-C8) alkyl, phenyl, substituted phenyl, (C1-C8) cycloalkyl or substituted (C1-C8) cycloalkyl;
(iv) a compound of Formula (XI):
wherein
R is selected from the group consisting of:
each occurrence of R1 and R4 is independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, or substituted (C1-C6) cycloalkyl; and,
R2 and R3 are independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, substituted (C1-C6) cycloalkyl, halo, OR4, N(R4)(R4), NO2, or NHAc;
(v) a compound of Formula (XII):
wherein
R is selected from the group consisting of:
each occurrence of R1, R4 and R5 is independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, or substituted (C1-C6) cycloalkyl; and,
R2 and R3 are independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, substituted (C1-C6) cycloalkyl, halo, OR4, N(R4)(R4), NO2, or NHAc;
(vi) a CX3CR1 or fractalkine antibody; and
combinations thereof, and a pharmaceutically acceptable salt thereof.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The composition of claim 1, further comprising at least one pharmaceutically acceptable carrier.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the antibody comprises an antibody selected from a polyclonal antibody, a monoclonal antibody, a humanized antibody, a synthetic antibody, a heavy chain antibody, a human antibody, a biologically active fragment of an antibody, and combinations thereof.

### Claim 5

A method of preventing or treating metastasis in a subject diagnosed with cancer, wherein the method comprises administering to the subject in need thereof an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one CX3CR1 or fractalkine antagonist.

### Claim 6 (depends on 5)

The method of claim 5, wherein the subject is subjected to primary surgery related to the cancer.

### Claim 7 (depends on 6)

The method of claim 6, wherein administering the pharmaceutical formulation takes place before, during or after the primary surgery.

### Claim 8 (depends on 5)

The method of claim 5, wherein the cancer comprises a solid cancer.

### Claim 9 (depends on 8)

The method of claim 8, wherein the solid cancer is selected from the group consisting of breast cancer and prostate cancer.

### Claim 10 (depends on 5)

The method of claim 5, wherein the metastasis comprises bone metastasis.

### Claim 11 (depends on 7)

The method of claim 7, wherein the administering starts at least 6 months before the primary surgery.

### Claim 12 (depends on 11)

The method of claim 11, wherein the administering starts at least 3 months before the primary surgery.

### Claim 13 (depends on 12)

The method of claim 12, wherein the administering starts at least 1 month before the primary surgery.

### Claim 14 (depends on 7)

The method of claim 7, wherein the administering starts within 1 week after the surgery.

### Claim 15 (depends on 5)

The method of claim 5, wherein the at least one CX3CR1 or fractalkine inhibitor comprises an agent selected from the group consisting of an antibody, siRNA, ribozyme, antisense, aptamer, peptidomimetic, small molecule, and combinations thereof.

### Claim 16 (depends on 15)

The method of claim 15, wherein the antibody comprises an antibody selected from a polyclonal antibody, monoclonal antibody, humanized antibody, synthetic antibody, heavy chain antibody, human antibody, a biologically active fragment of an antibody, and combinations thereof.

### Claim 17 (depends on 15)

The method of claim 15, wherein the small molecule is selected from the group consisting of:
(i) a compound of Formula (I),
wherein in (I):
A1 is CH2 or cyclopentane-1,3-diyl;
is 0, 1, 2, 3, 4 or 5 if A is CH2, or n is 0, 1, or 2 if A is cyclopentane-1,3-diyl;
A2 and A3 are both H, or A2 and A3 combine to form a divalent radical selected from the group consisting of methanediyl, ethane-1,2-diyl, or propane-1,3-diyl;
A4 is CH2, CH(CF3), or CF2;
R1 is H, CN, CO2R6, (C1-C6)CH2NH2, or (C1-C6)CH2NHC(═O)NH(4-piperidinyl);
R2 and R3, are independently aryl or substituted aryl; or R2 and R3 combine to form a divalent fragment (a), wherein X is selected from the group consisting of —S—, —O—, —CH2S—, —CH2S(═O)—, —CH2S(═O)2—, —SCH2—, —S(═O)CH2—, —S(═O)2CH2—, —CH2CH2—, —CH═CH—, —CH2O—, —OCH2—, —N(CH3)C(═O)—, and —C(═O)N(CH3)—;
or R1 and R2 are both H, and R3 is selected from the group consisting of:
wherein ring A is selected from the group consisting of phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, thiophenyl, substituted thiophenyl, 1H-pyrazole, and 1-(C1-C6) alkyl-1H-pyrazole;
R4 is nil or (C1-C6)alkyl, wherein if R4 is (C1-C6)alkyl, compound of Formula (I) is a quaternary ammonium salt;
R5 is (C1-C6)alkyl, substituted (C1-C6)alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;
R6 is H, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl or substituted aryl; and,
R7 is OH, CH2OH, or C(═O)OR6;
(ii) a compound of Formula (II):
wherein:
A is a ring of formula (a), (b) or (c):
R1 and R2 independently represent H, C1-C8 alkyl, C2-C8 alkenyl, C2-C5 alkynyl or C3-C7 saturated or partially unsaturated cycloalkyl,
wherein in R1 or R2 the alkyl, alkenyl, alkynyl and cycloalkyl groups are optionally and independently further substituted with one or more substituents selected independently from the group consisting of OH, C1-C6 alkoxy, CH2OR4, NR5R6, CO2R7 and CONR8R9;
R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C7 saturated or partially unsaturated cycloalkyl;
wherein in R3:
the alkyl, alkenyl and alkynyl chains independently and optionally include a O, NR10 or S atom in the chain;
the alkyl, alkenyl, alkynyl and cycloalkyl groups are independently and optionally further substituted by phenyl or a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected independently from the group consisting of O, S and N;
the phenyl or heteroaromatic groups are independently and optionally further substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, OH, C1-C4 alkoxy, CN, CO2R11, NR12R13, C(═O)NR14R15, SO2R16, NR17R18 and SO2N19R20
X is O, S or S(O);
R21 is H, CH2OR24, CH2NR24R25, CO2R24 or C(═O)NR24R25;
n is 0, 1 or 2;
R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R24, R25 and R26 are independently H or C1-C6 alkyl;
(iii) a compound of Formula (VI):
wherein:
R1 is CH3 or CH3CH2;
R2 is H, 2-F, 2—Cl, 3-F, 3-OCH3, 3-CN, 3-CF3, 3-CONH2 or 3-SO2CH3;
R3 is H or CH3;
R4 is H or CH3 and
R5 is H; or, when R4 is CH3, R5 is H or F;
(iv) a compound of Formula (VII):
wherein:
R1 is CH3 or CH3CH2;
R2 is H or CH3;
R3 is H or CH3;
R4, R5, R6 and R7 are independently H, CH3 or CH2CH3;
(v) a compound of Formula (VIII):
wherein:
R1 is CH3 or CF3;
R2 is halo, CN or C1-C6 alkyl;
R3 and R4 are independently H or CH3;
n is 0, 1 or 2;
(vi) a compound of Formula (IX):
RA—RB (IX),
wherein:
RA is a group selected from the group consisting of:
and,
RB is a group selected from the group consisting of:
(vii) a compound of Formula (X):
wherein R1 is (C1-C8) alkyl, substituted (C1-C8) alkyl, phenyl, substituted phenyl, (C1-C8) cycloalkyl or substituted (C1-C8) cycloalkyl;
(viii) a compound of Formula (XI):
wherein
R is selected from the group consisting of:
each occurrence of R1 and R4 is independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, or substituted (C1-C6) cycloalkyl; and,
R2 and R3 are independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, substituted (C1-C6) cycloalkyl, halo, OR4, N(R4)(R4), NO2, or NHAc;
(ix) a compound of Formula (XII):
wherein
R is selected from the group consisting of:
each occurrence of R1 and R4 and R5 is independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, or substituted (C1-C6) cycloalkyl; and,
R2 and R3 are independently H, (C1-C6) alkyl, substituted (C1-C6) alkyl, phenyl, substituted phenyl, (C1-C6) cycloalkyl, substituted (C1-C6) cycloalkyl, halo, OR4, N(R4)(R4), NO2, or NHAc;
(x) a compound selected from the group:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein the compound of Formula (I) is a compound of Formula (Ia):
wherein in (Ia):
n is 0, 1, 2, 3, 4 or 5;
R1 is H, CN, CO2R6, (C1-C6)CH2NH2, or (C1-C6)CH2NHC(═O)NH(4-piperidinyl);
R2 and R3 are independently aryl or substituted aryl; or R2 and R3 combine to form a divalent fragment (a), wherein X is selected from the group consisting of S, O, CH2S, CH2S(═O), CH2S(═O)2, SCH2, S(═O)CH2, S(═O)2CH2, CH2CH2, CH═CH, CH2O, OCH2, N(CH3)C(═O), and C(═O)N(CH3);
R4 is no atom or (C1-C6)alkyl, wherein if R4 is (C1-C6)alkyl, compound (I) is a quaternary ammonium salt;
R5 is (C1-C6)alkyl, substituted (C1-C6)alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl;
R6 is H, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl or substituted aryl; and,
R7 is OH, CH2OH, or C(═O)OR6.

### Claim 19 (depends on 17)

The method of claim 17, wherein in Formula (I) R2 and R3 are independently phenyl, substituted phenyl, naphthryl or substituted naphthryl.

### Claim 20 (depends on 17)

The method of claim 17, wherein the compound of Formula (II) is:
(i) a compound of Formula (III):
(b) a compound of Formula (IV):
(c) a compound of Formula (V):
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 17)

The method of claim 17, wherein in Formula (X) R1 is n-hexyl, phenyl or cyclopentyl.

### Claim 22 (depends on 17)

The method of claim 17, wherein the small molecule is selected from the group consisting of:
5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile,
N-(1-benzylpiperidin-4-yl)-9H-xanthene-9-carboxamide,
5-(3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one,
5-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one, combinations thereof, and a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 5)

The method of claim 5, wherein the subject is a mammal.

### Claim 24 (depends on 23)

The method of claim 23, wherein the mammal is human.

### Claim 25 (depends on 5)

The method of claim 5, wherein the composition is administered by an administration route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, and combinations thereof.