# US 10,117,943 B2 · Synthetic antibody mimetic compounds (SYAMS) targeting cancer, especially prostate cancer

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- Number: US 10,117,943 B2
- Document ID: US10117943B2
- Status: Granted
- Kind: B2
- Application number: 14/888,779
- Filed: 2013-05-03
- Published: 2016-03-24
- Granted: 2018-11-06
- Earliest claimed: 2013-05-03
- Assignees: Yale University
- Applicants: Yale University
- Inventors: David A. Spiegel; Patrick McEnaney; Kelly Fitzgerald
- Web page: https://patentgrep.com/patent/US10117943B2

## CPC

- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/54: the modifying agent being an organic compound
- A61P 5/28: Antiandrogens
- A61P 13/08: of the prostate
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D 249/06: with aryl radicals directly attached to ring atoms
- 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

The present invention relates to compounds which function as antibody mimetic compounds. These compounds are bifunctional/multifunctional compounds which contain at least one cancer cell binding moiety which selectively binds to prostate specific membrane antigen (PSMA) and a FC receptor binding moiety which modulates an FC immune receptor, preferably a FcγRI receptor. Compounds according to the present invention bind selectively to cancer cells which upregulate PSMA and through that interaction, place the Fc receptor binding moiety of the compound in proximity to a Fc receptor, preferably a FcγRI receptor, which can modulate (preferably, upregulate) a humoral response in a patient to cancer cells. Through this biological action of the compounds according to the present invention, cancer cells, including metastatic cancer cells, especially prostate cancer cells can be immune regulated, resulting in the favorable therapy of cancer in a patient. Methods of using these compounds to treat cancer and/or reduce the likelihood of metastatis of cancer are additional aspects of the present invention.

## Claims

### Claim 1

A compound according to the chemical structure:
where [IBT] is an FcγRI receptor binding moiety according the chemical structure:
[CBT] is a cell binding moiety which binds to prostate specific membrane antigen (PSMA) according to the chemical structure:
Where X1 and X2 are each independently CH2, O, NH or S;
X3 is O, CH2, NR1, S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
R1 is H, a C1-C3 alkyl group, or a —C(O)(C1-C3) group;
k is an integer from 0 to 20;
L1 and L2 are each independently linker groups, each of which groups optionally includes one or more bifunctional connector groups [CON};
[MULTICON} is a multifunctional connector group which, when present, connects at least one [IBT) group to at least one [CBT] group through said linker group;
MCON is 0, 1, 2 or 3;
N″ and n′″ are each independently 1, 2, 3
NL1 and NL2 are each an integer from 0 to 5, with the proviso that n″≥NL1 and n′″≥NL2 and at least one of MCON, NL1 and NL2 is at least 1, or
a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein MCON is 1, 2 or 3.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein MCON is 1.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein n″ is 1, 2 or 3 and n′″ is 1 or 2.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein said [IBT] group is CP33.

### Claim 6 (depends on 2)

The compound according to claim 2 wherein said [IBT] group is CP33.

### Claim 7 (depends on 3)

The compound according to claim 3 wherein said [IBT] group is CP33.

### Claim 8 (depends on 1)

The compound according to claim 1 wherein said [IBT] group is CP33.

### Claim 9 (depends on 1)

The compound according to claim 1 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 0 to 20, or a salt or enantiomer thereof.

### Claim 10 (depends on 2)

The compound according to claim 2 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.

### Claim 11 (depends on 3)

The compound according to claim 3 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.

### Claim 12 (depends on 4)

The compound according to claim 4 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.

### Claim 13 (depends on 5)

The compound according to claim 5 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.

### Claim 14 (depends on 6)

The compound according to claim 6 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.

### Claim 15 (depends on 7)

The compound according to claim 7 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.

### Claim 16 (depends on 8)

The compound according to claim 8 wherein said [CBT] group is a group according to the chemical structure:
Where k is an integer from 1 to 4, or a salt or enantiomer thereof.

### Claim 17 (depends on 4)

The compound according to claim 4 wherein said [CBT] group is a group according to the chemical structure:
Where k is 4, or a salt or enantiomer thereof.

### Claim 18 (depends on 1)

The compound according to claim 1 wherein at least one linker optionally contains a [CON] group according to the chemical structure:
Where X2 is O, S, NR4, S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
X3 is O, S or NR4; and
R4 is H, a C1-C3 alkyl or alkanol group, or a —C(O)(C1-C3) group.

### Claim 19 (depends on 1)

The compound according to claim 1 wherein at least one linker optionally contains a [CON] group wherein said [CON] group is according to the chemical structure;
Where CL is
m is an integer from 0 to 12;
and iL is 0 or 1.

### Claim 20 (depends on 1)

The compound according to claim 1 wherein said linker group L1 or L2 comprises polyethyleneglycol (PEG) linkages, polypropylene glycol linkages, or polyethyleneglycol-co-polypropylene polymers from 1 to 100 units in length;
a linker according to the structure:
Where Ra is H, C1-C3 alkyl, alkanol or forms a cyclic ring with R3 in the case of proline and R3 is a side chain derived from an amino acid;
m″ is an integer from 0 to 25; and
m is an integer from 1 to 100; wherein each of said groups is optionally further linked through amide groups, keto groups, amine groups or amino acids.

### Claim 21 (depends on 1)

The compound according to claim 1 wherein said linker group L1 or L2 comprises or a linker according to the structure:
where Ra is H or a C1-C3 alkyl;
m is an integer from 1 to 12;
m″ is an integer 1, 2, 3, 4, 5, or 6;
t is 0, 1, 2, 3, 4, 5 or 6; and
iL is 0 or 1, wherein said linker optionally contains a [CON] group and is linked to a [CBT] group at one end optionally through said [CON] group and a [MULTICON] group on the other end; or
a linker according to the structure:
Where q is an integer from 0-12; and
q′ is 1 to 12; or
a linker according to the chemical structure:
Where q is an integer from 0-12; and
q′ is 1 to 12;
iL is 0 or 1; and
RL is an amino acid or an oligopeptide or a
linker according to the chemical structure:
where each XS is independently S, O or N—RS;
RS is H or C1-C3 alkyl;
Sc is CH2; CH2O; or CH2CH2O;
i is 0 or 1; and
mS is 0, 1, 2, 3, 4, 5, or 6, or a
linker according to the chemical formula:
Where Z and Z′ are each independently a bond, —(CH2)i—O, —(CH2)i—S, —(CH2)i—N—R,
wherein said Z or Z′ group, is optionally bonded to another linker group, a connector group [CON], a [MULTICON] group, an IBT group or a CBT group;
each R is H, or a C1-C3 alkyl or alkanol group;
each R2 is independently H or a C1-C3 alkyl group;
each Y is independently a bond, O, S or N—R;
each i is independently 0 to 100;
D is
or a bond, or
D may be
or a polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 100 glycol units;
with the proviso that Z, Z′ and D are not each simultaneously bonds;
each i is independently 0 to 100;
j is 1 to 100;
m (within this context) is an integer from 1 to 100; and
n (within this context) is an integer from 1 to 100;
m′ is 1 to 100;
m″ is an integer between 0 to 25;
n′ is 1 to 100;
X1 is O, S or N—R;
R is H, or a C1-C3 alkyl or alkanol group; and
Ra is H, C1-C3 alkyl or alkanol or forms a cyclic ring with R3; and R3 is a side chain derived from an amino acid.

### Claim 22 (depends on 1)

The compound according to claim 1 wherein said [MULTICON] group is a
multifunctional connector group or molecule according to the chemical structure:
where Y4 is C—H or N; and
Each X″ is (CH2)n″O, (CH2)n″NRCON, (CH2)n″S,
(CH2)n″, (CH2)n″C═O or a [CON] group;
RCON is H or a C1-C3 alkyl;
n″ is 0, 1, 2 or 3;
r is an integer from 1 to 12; and
said [CON] group, if present, is a moiety according to the chemical structure:
Where X2 is O, S, NR4, S(O), S(O)2, —S(O)2O, —OS(O)2, or OS(O)2O;
X3 is NR4, O or S; and
R4 is H, a C1-C3 alkyl or alkanol group, or a —C(O)(C1-C3) group; or
a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

The compound according to claim 1 wherein L1 and/or L2 is a
group;
where Ra is H or CH3;
m is an integer from 1 to 12;
m″ is an integer 1, 2, 3, 4, 5, or 6;
t is 0, 1, 2, 3, 4, 5, or 6; and
iL is 0 or 1.

### Claim 24 (depends on 1)

The compound according to claim 1 wherein L1 and/or L2 is
where Ra is H;
m″ is 1, 2, 3, 4, 5 or 6 and
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

### Claim 25 (depends on 1)

The compound according to claim 1 wherein L1 and/or L2 is a polyethylene glycol linker between 1 and 12 glycol units in length or a polyethylene glycol linker extended to a second polyethylene glycol linker through a [CON] group, wherein said polyethylene glycol linker is from 1 to 12 glycol units in length and said second polyethylene glycol linker is from 1 to 12 glycol units in length.

### Claim 26 (depends on 25)

The compound according to claim 25 wherein said [CON] group is

### Claim 27

A compound according to the chemical structure:
Wherein each RISY is independently H, a C4-C12 alkyl group, an acyl group or a biotin group, and CP33 is a group according to the chemical structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 28 (depends on 27)

The compound according to claim 27 wherein RISY is a biotin group.

### Claim 29 (depends on 27)

The compound of claim 27 according to the chemical structure:
Wherein each RISY is independently H, a C4-C12 alkyl group, an acyl group or a biotin group, and CP33 is a group according to the chemical structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 30 (depends on 29)

The compound according to claim 29 wherein RISY is a biotin group.

### Claim 31 (depends on 1)

A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

### Claim 32 (depends on 1, 31)

The composition according to claim 31 wherein said composition further comprises an effective amount of an anticancer agent other than a compound according to claim 1.

### Claim 33 (depends on 32)

The composition according to claim 32 wherein said other anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.

### Claim 34 (depends on 32)

The composition according to claim 32 wherein said other anticancer agent is aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with polifeprosan 20 iplant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; darbepoetin alfa; daunorubicin liposomal; daunorubicin; denileukin diftitox; dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; domostanolone propionate (drostanolone propionate); epirubicin; epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; filgrastim; floxuridine (intraarterial); fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nfetumomab (ofatumumab); LOddC; oprelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; telbivudine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof.

### Claim 35 (depends on 31)

The composition according to claim 31 further comprising at least one antiandrogen compound.

### Claim 36 (depends on 31)

The composition according to claim 31 further comprising at least one GNRh modulator.

### Claim 37 (depends on 31)

The composition according to claim 31 further comprising at least one agent selected from the group consisting of flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, leuprolide, goserelin, triptorelin, buserelin, abiraterone acetate, sorafenib and mixtures thereof.

### Claim 38 (depends on 31)

The composition according to claim 31 further comprising at least one agent selected from the group consisting of an enlarged prostate agent; flutamide; goserelin; leuprolide; nilutamide; and mixtures thereof.

### Claim 39 (depends on 31)

The composition according to claim 31 in oral dosage form.

### Claim 40 (depends on 31)

The composition according to claim 31 in parenteral dosage form.

### Claim 41 (depends on 40)

The composition according to claim 40 wherein said parenteral dosage form is an intravenous dosage form.

### Claim 42 (depends on 31)

The composition according to claim 31 in topical dosage form.