U.S. patent application number 17/045916 was filed with the patent office on 2021-12-09 for method of modulating tigit and pd-1 signalling pathways using 1,2,4-oxadiazole compounds.
The applicant listed for this patent is AURIGENE DISCOVERY TECHNOLOGIES LIMITED. Invention is credited to Gundala Chennakrishnareddy, Seetharamaiah Setty Sudarshan NAREMADDEPALLI, Muralidhara RAMACHANDRA, Pottayil Govindan Nair SASIKUMAR.
Application Number | 20210379024 17/045916 |
Document ID | / |
Family ID | 1000005807885 |
Filed Date | 2021-12-09 |
United States Patent
Application |
20210379024 |
Kind Code |
A1 |
SASIKUMAR; Pottayil Govindan Nair ;
et al. |
December 9, 2021 |
METHOD OF MODULATING TIGIT AND PD-1 SIGNALLING PATHWAYS USING
1,2,4-OXADIAZOLE COMPOUNDS
Abstract
The present invention relates to method of modulating TIGIT
signaling pathway and PD-1 signaling pathway. The invention also
encompasses the use of the compound of formula (I) or a
stereoisomer thereof or a pharmaceutically acceptable salt thereof
for the treatment of diseases or disorders mediated by both TIGIT
signaling pathway and PD-1 signaling pathway.
Inventors: |
SASIKUMAR; Pottayil Govindan
Nair; (Bangalore, IN) ; RAMACHANDRA; Muralidhara;
(Bangalore, IN) ; NAREMADDEPALLI; Seetharamaiah Setty
Sudarshan; (Bangalore, IN) ; Chennakrishnareddy;
Gundala; (Bangalore, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AURIGENE DISCOVERY TECHNOLOGIES LIMITED |
|
|
|
|
|
Family ID: |
1000005807885 |
Appl. No.: |
17/045916 |
Filed: |
March 13, 2019 |
PCT Filed: |
March 13, 2019 |
PCT NO: |
PCT/IB2019/052039 |
371 Date: |
October 7, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4245 20130101;
A61P 35/00 20180101 |
International
Class: |
A61K 31/4245 20060101
A61K031/4245; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 14, 2018 |
IN |
201841009306 |
Claims
1. A method of modulating T cell immunoreceptor with Ig and ITIM
domains (TIGIT) signaling pathway and programmed cell death 1
(PD-1) signaling pathway in a subject, comprising administering to
the subject with compound of formula (I), or a stereoisomer thereof
or a pharmaceutically acceptable salt thereof: ##STR00082##
wherein, R.sub.1 represents hydrogen, --(C.sub.1-C.sub.6)alkyl
optionally substituted with --OH, --COOH, aryl, heteroaryl, or
aryl-OH; R.sub.2 represents hydrogen, --(C.sub.1-C.sub.6)alkyl
optionally substituted with --OH, --SH, C(O)NH.sub.2, --COOH, aryl,
heteroaryl, or aryl-OH; R.sub.a represents hydrogen; or R.sub.a and
R.sub.2 taken together with the atom to which they are attached
form a pyrrolidine ring; R.sub.3 represents hydrogen or a group
represented by formula (I'), ##STR00083## represents point of
attachment; R.sub.b represents hydrogen; or R.sub.b and R.sub.c
taken together with the atoms to which they are attached form a
pyrrolidine ring; R.sub.c represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH,
--C(O)NH.sub.2, COOH, aryl, or aryl-OH.
2. The method of claim 1, wherein R.sub.1 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
phenyl, imidazolyl, or (p-OH)phenyl.
3-8. (canceled)
9. The method of claim 1, wherein R.sub.3 represents ##STR00084##
wherein represents point of attachment; R.sub.b represents
hydrogen; or R.sub.b and R.sub.c taken together with the atoms to
which they are attached form a pyrrolidine ring; R.sub.c represents
hydrogen, --(C.sub.1-C.sub.6)alkyl optionally substituted with
--OH, --C(O)NH.sub.2, COOH, phenyl, or (p-OH)phenyl.
10. (canceled)
11. The method of claim 1, wherein the compound is represented by
compound of formula (IA), ##STR00085## wherein, R.sub.1, R.sub.2,
R.sub.a, R.sub.b, and R.sub.c are as defined in claim 1.
12. The method of claim 11, wherein R.sub.1 represents
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
imidazolyl, phenyl, or (p-OH)phenyl; R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl substituted with --OH, --SH, --COOH,
phenyl, imidazolyl, or (p-OH)phenyl; R.sub.a represents hydrogen;
or R.sub.a and R.sub.2 taken together with the atom to which they
are attached form a pyrrolidine ring; R.sub.b represents hydrogen;
or R.sub.b and R.sub.c taken together with the atoms to which they
are attached form a pyrrolidine ring; R.sub.c represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH,
--C(O)NH.sub.2, --COOH, phenyl, or (p-OH)phenyl.
13. (canceled)
14. The method of claim 1, wherein the compound is represented by
compound of formula (IB), ##STR00086## wherein, R.sub.1, R.sub.2
and R.sub.a, are as defined in claim 1.
15. The method of claim 14, wherein R.sub.1 represents
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH or
(p-OH)phenyl; R.sub.2 represents hydrogen, --(C.sub.1-C.sub.6)alkyl
substituted with phenyl or (p-OH)phenyl; R.sub.a and R.sub.2 taken
together with the atom to which they are attached form a
pyrrolidine ring.
16. The method of claim 1, wherein the compound is TABLE-US-00010
Compound No. Structure 1 ##STR00087## 2 ##STR00088## 3 ##STR00089##
4 ##STR00090## 5 ##STR00091## 6 ##STR00092## 7 ##STR00093## 8
##STR00094## 9 ##STR00095## 10 ##STR00096## 11 ##STR00097## 12
##STR00098## 13 ##STR00099## 14 ##STR00100## 15 ##STR00101## 16
##STR00102## 17 ##STR00103## 18 ##STR00104## 19 ##STR00105## 20
##STR00106##
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
17.-18. (canceled)
19. The method of claim 1, wherein the subject is suffering from a
disease or disorder selected from cancer, immune disorders,
immunodeficiency disorders, inflammatory disorders, infectious
diseases, and transplant rejection.
20. The method of claim 19, wherein the disease or disorder is
cancer.
21-23. (canceled)
24. The method of claim 19, wherein the disease is an infectious
disease.
25. The method of claim 24, wherein the infectious disease is a
bacterial infection, a viral infection, a fungal infection, or a
parasitic infection.
26-36. (canceled)
37. A method of treating a disease or disorder mediated by both
TIGIT signalling pathway and PD-1 signalling pathway comprising
administering a therapeutically effective amount of compound of
formula (I) or a stereoisomer thereof or a pharmaceutically
acceptable salts thereof as defined in claim 1.
38. The method of claim 37, wherein the disease or disorder is
selected from cancer, immune disorders, immunodeficiency disorders,
inflammatory disorders, infectious diseases, and transplant
rejection.
39. The method of claim 38, wherein the cancer is selected from
blastoma, breast cancer, epithelial cancer, colon cancer, lung
cancer, melanoma, prostate cancer, renal cancer, bone cancer,
pancreatic cancer, skin cancer, cancer of the head or neck, uterine
cancer, ovarian cancer, colorectal cancer, rectal cancer, cancer of
the anal region, cancer of the peritoneum, stomach cancer,
testicular cancer, carcinoma of the fallopian tubes, carcinoma of
the endometrium, cervical cancer, vaginal cancer, vulval cancer,
cancer of the esophagus, cancer of the small intestine, cancer of
the endocrine system, cancer of the thyroid gland, cancer of the
parathyroid gland, cancer of the adrenal gland, sarcoma, cancer of
the urethra, cancer of the penis, chronic or acute leukemia, solid
tumors of childhood, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
cutaneous T cell lymphoma, mesothelioma, thymic carcinoma, myeloma,
cancer of the bladder, cancer of the ureter, carcinoma of the renal
pelvis, liver cancer, pancreatic cancer, post-transplant
lymphoproliferative disorder (PTLD), neoplasm of the central
nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain
stem glioma, pituitary adenoma, epidermoid cancer, salivary gland
carcinoma, squamous cell cancer, abnormal vascular proliferation
associated with phakomatoses, edema (such as that associated with
brain tumors), Meigs' syndrome, Merkel cell carcinoma, and
environmentally induced cancers.
40. The method of claim 38, wherein the infectious disease is a
bacterial infection, a viral infection, a fungal infection, or a
parasitic infection.
41-48. (canceled)
49. A method of modulating T cell immunoreceptor with Ig and ITIM
domains (TIGIT) signaling pathway in a subject, comprising
administering to the subject with compound of formula (I), or a
stereoisomer thereof or a pharmaceutically acceptable salt thereof:
##STR00107## wherein, R.sub.1 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
aryl, heteroaryl, or aryl-OH; R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --SH,
C(O)NH.sub.2, --COOH, aryl, heteroaryl, or aryl-OH; R.sub.a
represents hydrogen; or R.sub.a and R.sub.2 taken together with the
atom to which they are attached form a pyrrolidine ring; R.sub.3
represents hydrogen or a group represented by formula (I'),
##STR00108## represents point of attachment; R.sub.b represents
hydrogen; or R.sub.b and R.sub.c taken together with the atoms to
which they are attached form a pyrrolidine ring; R.sub.c represents
hydrogen, --(C.sub.1-C.sub.6)alkyl optionally substituted with
--OH, --C(O)NH.sub.2, COOH, aryl, or aryl-OH.
50-61. (canceled)
62. The method of claim 37, wherein the treatment of a disease or
disorder is inhibiting growth of tumor cells and/or metastasis.
63. The method of claim 62, wherein the tumor cells are of a cancer
selected from small cell lung cancer, multiple myeloma, bladder
carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's
lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic
cancer.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of Indian provisional
application number 201841009306, filed on Mar. 14, 2018; the
specifications of which are hereby incorporated by reference in
their entirety.
TECHNICAL FIELD
[0002] The present invention relates to methods for modulating T
cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed
cell death-1 (PD-1) signaling pathways in a subject comprising
administering compound of formula (I) or a pharmaceutically
acceptable salt thereof.
BACKGROUND OF THE INVENTION
[0003] Immunotherapies that harness the activity of the immune
system against tumors are proving to be an effective therapeutic
approach in multiple malignancies. Indeed, through accumulation of
genetic mutations, many tumors express antigens that can
potentially elicit specific tumor immunity. However, tumors can
also suppress these responses by activating negative regulatory
pathways and checkpoints such as PD-1/PD-L1 and CTLA-4.
[0004] TIGIT (T cell immunoreceptor with Ig and ITIM domains) is an
inhibitory receptor expressed by activated T cells, Tregs, and NK
cells, also known as WUCAM, Vstm3 or Vsig9. TIGIT has an
immunoglobulin variable domain, a transmembrane domain, and an
immunoreceptor tyrosine-based inhibitory motif (ITIM), and contains
signature sequence elements of the PVR protein family. It is known
to interact with poliovirus receptor (PVR; CD155) and with nectin2
(CD112) (Stengel et al. (2012) Proc. Nat'l Acad. Sci. (USA)
19:5399). TIGIT suppresses T cell activation by promoting the
generation of mature immunoregulatory dendritic cells. TIGIT and
other such co-inhibitory molecules (e.g. CTLA-4, PD-1, Lag3 and
BTLA) may play a role in evasion of immunosurveillance by tumour
cells. Experiments have shown that PVR/CD155 is over-expressed on
melanoma cells (Inozume et al. (2014) J. Invest. Dermatol.
134:S121-Abstract 693) and various other tumors. It is possible
that the TIGIT/PVR interaction can shield such tumour cells from
immune-mediated eradication by inhibiting anti-tumour responses of
T and NK cells (Stanietsky et al. (2009) Proc. Nat'l Acad. Sci.
(USA) 106:17858 and Lozano et al. (2012) J. Immunol. 188:3869). The
TIGIT pathway has been known to negatively regulating NK-cell
Function as indicated by reduced killing by either human
(Stanietsky et al. (2009) Proc. Nat'l Acad. Sci. (USA); 106:17858)
or mouse (Stanietsky et al. (2013) Eur J Immunol. 43:2138) primary
NK cells due to CD155/TIGIT interaction. Additionally, MDSC-induced
suppression of NK-cell function (degranulation, IFN-7 production)
was shown to be dependent on CD155-TIGIT interaction and greater
functional suppression observed by TIGIThigh NK cells (Sarhan et
al. (2016) Cancer Res 2016; 76:5696). Other experiments have
identified a TIGIT subset of regulatory T cells (Tregs) that
selectively suppress Th1 and Th17 responses (Joller et al. (2014)
Immunity 40:569), suggesting an alternative mechanism by which
TIGIT-blocking agents may enhance anti-tumour immune response.
[0005] TIGIT may act to `turn off` the immune response similarly to
other co-inhibitory receptors such as CTLA-4, PD-1 and BTLA.
Antibodies targeting CTLA-4 (ipilimumab) and PD-1 (nivolumab,
pembrolizumab) have been approved for the treatment of human
cancers, validating this therapeutic approach. Antibodies or other
agents that bind to human TIGIT might also find use in treatment of
cancers. In mouse models, antibody blockade of both PD-L1 and TIGIT
leads to a synergistic enhancement of CD8<+> T cell mediated
tumour rejection (Grogan et al. (2014) J. Immunol. 192(1) Suppl.
203.15; Johnston et al. (2014) Cancer Cell 26:1-15). Similar
results have been obtained in animal models of melanoma (Inozume et
al. (2014) J. Invest. Dermatol. 134:S121-Abstract 693).
[0006] Some experiments suggest that TIGIT blockade is effective to
enhance anti-tumour CD8<+> T cell response only in the
presence of the co-activating receptor DNAM-1/CD226, which competes
with TIGIT for binding to PVR/CD155 (Johnston et al. (2014) Cancer
Cell 26:1-15). Further experiments have explained that mAbs
(monoclonal antibodies) acting for dual TIGIT and PD-1 blockade
enhance CD8.sup.+ T cell responses to melanoma and improve the
clinical efficacy of PD-1 blockade for patients with advanced
melanoma (Joe-Marc Chauvin et al., (2015), J Clin Invest. May 1;
125(5): 2046-2058).
[0007] Thus, in view of the fact that the use of TIGIT blockade in
combination with PD-1 blockade in potentiating immune related
diseases such as cancers is not explored much, there is an unmet
need exists to develop potent therapeutic agents that exhibit dual
inhibition of TIGIT and PD-1 signaling pathway.
SUMMARY OF THE INVENTION
[0008] The present invention relates to methods of modulating T
cell immunoreceptor with Ig and ITIM domains (TIGIT) signaling
pathway and programmed cell death 1 (PD-1) signaling pathway using
1,2,4-oxadiazole compounds or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof.
[0009] In one aspect, the present disclosure provides a method of
modulating T cell immunoreceptor with Ig and ITIM domains (TIGIT)
signaling pathway and programmed cell death 1 (PD-1) signaling
pathway in a subject, comprising contacting the subject with
compound of formula (I), or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof:
##STR00001##
wherein, [0010] R.sub.1 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
aryl, heteroaryl, or aryl-OH; [0011] R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --SH,
C(O)NH.sub.2, --COOH, aryl, heteroaryl, or aryl-OH; [0012] R.sub.a
represents hydrogen; or R.sub.a and R.sub.2 taken together with the
atom to which they are attached form a pyrrolidine ring; [0013]
R.sub.3 represents hydrogen or a group represented by formula
(I'),
##STR00002##
[0013] represents point of attachment; [0014] R.sub.b represents
hydrogen; or R.sub.b and R.sub.c taken together with the atoms to
which they are attached form a pyrrolidine ring; [0015] R.sub.c
represents hydrogen, --(C.sub.1-C.sub.6)alkyl optionally
substituted with --OH, --C(O)NH.sub.2, COOH, aryl, or aryl-OH.
BRIEF DESCRIPTION OF FIGURE
[0016] FIG. 1: Antitumor effect of Compound 19 in CT26 tumor
bearing mice
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention provides a method of modulating TIGIT
signaling pathway and PD-1 signaling pathways using
1,2,4-oxadiazole compounds or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof. This invention also
provides a method for treatment of diseases or disorders mediated
by both TIGIT and PD-1 comprising administering a compound of
formula (I), or a stereoisomer thereof or a pharmaceutically
acceptable salt thereof.
[0018] Each embodiment is provided by way of explanation of the
invention, and not by way of limitation of the invention. In fact,
it will be apparent to those skilled in the art that various
modification and variations can be made in the present invention
without departing from the scope or spirit of the invention. For
instance, features illustrated or described as part of one
embodiment can be used on another embodiment to yield a still
further embodiment. Thus it is intended that the present invention
cover such modifications and variations as come within the scope of
the appended claims and their equivalents. Other objects, features,
and aspects of the present invention are disclosed in, or are
obvious from, the following detailed description. It is to be
understood by one of ordinary skill in the art that the present
discussion is a description of exemplary embodiments only, and is
not to be construed as limiting the broader aspects of the present
invention.
[0019] In certain embodiments, the present invention provides a
method of modulating T cell immunoreceptor with Ig and ITIM domains
(TIGIT) signaling pathway and programmed cell death 1 (PD-1)
signaling pathway in a subject, comprising contacting the subject
with compound of formula (I), or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof:
##STR00003##
wherein, [0020] R.sub.1 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
aryl, heteroaryl, or aryl-OH; [0021] R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --SH,
C(O)NH.sub.2, --COOH, aryl, heteroaryl, or aryl-OH; [0022] R.sub.a
represents hydrogen; or R.sub.a and R.sub.2 taken together with the
atom to which they are attached form a pyrrolidine ring; [0023]
R.sub.3 represents hydrogen or a group represented by formula
(I'),
##STR00004##
[0023] represents point of attachment; [0024] R.sub.b represents
hydrogen; or R.sub.b and R.sub.c taken together with the atoms to
which they are attached form a pyrrolidine ring; [0025] R.sub.c
represents hydrogen, --(C.sub.1-C.sub.6)alkyl optionally
substituted with --OH, --C(O)NH.sub.2, COOH, aryl, or aryl-OH.
[0026] In certain embodiments, R.sub.1 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
phenyl, imidazolyl, or (p-OH)phenyl.
[0027] In certain embodiments, R.sub.1 represents
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
imidazolyl, phenyl, or (p-OH)phenyl.
[0028] In certain embodiments, R.sub.1 represents
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
imidazolyl, or (p-OH)phenyl.
[0029] In certain embodiments, R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --SH,
--C(O)NH.sub.2, --COOH, phenyl, imidazolyl, or (p-OH)phenyl.
[0030] In certain embodiments, R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with
--C(O)NH.sub.2, phenyl, or (p-OH)phenyl.
[0031] In certain embodiments, R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl substituted with --OH, --SH, --COOH,
phenyl, imidazolyl, or (p-OH)phenyl.
[0032] In certain embodiments, R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl substituted with --OH, --COOH, phenyl,
imidazolyl, or (p-OH)phenyl.
[0033] In certain embodiments, R.sub.a represents hydrogen.
[0034] In certain embodiments, R.sub.a and R.sub.2 taken together
with the atom to which they are attached form a pyrrolidine
ring.
[0035] In certain embodiments, R.sub.3 represents
##STR00005## [0036] wherein [0037] represents point of attachment;
[0038] R.sub.b represents hydrogen; or R.sub.b and R.sub.c taken
together with the atoms to which they are attached form a
pyrrolidine ring; [0039] R.sub.c represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH,
--C(O)NH.sub.2, COOH, phenyl, or (p-OH)phenyl.
[0040] In certain embodiments, R.sub.b and R.sub.c taken together
with the atoms to which they are attached form a pyrrolidine
ring.
[0041] In certain embodiments, the compounds described in the
present invention is represented by compound of formula (IA),
##STR00006##
[0042] wherein, R.sub.1, R.sub.2, R.sub.a, R.sub.b, and R.sub.c are
as defined in compound of formula (I).
[0043] In certain embodiments, the compounds described in the
present invention is represented by compound of formula (IA), or a
stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein
[0044] R.sub.1 represents --(C.sub.1-C.sub.6)alkyl optionally
substituted with --OH, --COOH, imidazolyl, phenyl, or
(p-OH)phenyl;
[0045] R.sub.2 represents hydrogen, --(C.sub.1-C.sub.6)alkyl
substituted with --OH, --SH, --COOH, phenyl, imidazolyl, or
(p-OH)phenyl;
[0046] R.sub.a represents hydrogen; or R.sub.a and R.sub.2 taken
together with the atom to which they are attached form a
pyrrolidine ring;
[0047] R.sub.b represents hydrogen; or R.sub.b and R.sub.c taken
together with the atoms to which they are attached form a
pyrrolidine ring; and
[0048] R.sub.c represents hydrogen, --(C.sub.1-C.sub.6)alkyl
optionally substituted with --OH, --C(O)NH.sub.2, --COOH, phenyl,
or (p-OH)phenyl.
[0049] In certain embodiments, the compounds described in the
present invention is represented by compound of formula (IA), or a
stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein R.sub.1 represents --(C.sub.1-C.sub.6)alkyl optionally
substituted with --OH, --COOH, imidazolyl, or (p-OH)phenyl; and
R.sub.2 represents hydrogen, --(C.sub.1-C.sub.6)alkyl substituted
with --OH, --COOH, phenyl, imidazolyl, or (p-OH)phenyl.
[0050] In certain embodiments, the compounds described in the
present invention is represented by compound of formula (IB),
##STR00007##
[0051] wherein, R.sub.1, R.sub.2 and R.sub.a, are as defined in
compound of formula (I).
[0052] In certain embodiments, the compounds described in the
present invention is represented by compound of formula (IB), or a
stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein
[0053] R.sub.1 represents --(C.sub.1-C.sub.6)alkyl optionally
substituted with --OH or (p-OH)phenyl;
[0054] R.sub.2 represents hydrogen, --(C.sub.1-C.sub.6)alkyl
substituted with phenyl or (p-OH)phenyl; and
[0055] R.sub.a and R.sub.2 taken together with the atom to which
they are attached form a pyrrolidine ring.
[0056] In certain embodiments, the term `aryl` indicates
phenyl.
[0057] In certain embodiments, the term `heteroaryl` indicates
imidazole.
[0058] In certain embodiments, the dual modulators of TIGIT
signalling pathway and PD-1 signalling pathway is compound of
formula (I):
##STR00008##
wherein, [0059] R.sub.1 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, COOH,
aryl, heteroaryl, or aryl-OH; [0060] R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --SH,
C(O)NH.sub.2, --COOH, aryl, heteroaryl, or aryl-OH; [0061] R.sub.a
represents hydrogen; or R.sub.a and R.sub.2 taken together with the
atom to which they are attached form a pyrrolidine ring; [0062]
R.sub.3 represents hydrogen or a group represented by formula
(I'),
[0062] ##STR00009## [0063] represents point of attachment to
--N--R.sub.a group; [0064] R.sub.b represents hydrogen; or R.sub.b
and R.sub.c taken together with the atoms to which they are
attached form a pyrrolidine ring; [0065] R.sub.c represents
hydrogen, --(C.sub.1-C.sub.6)alkyl substituted with --OH,
--C(O)NH.sub.2, --COOH, aryl, or aryl-OH.
[0066] In certain embodiments, the present invention provides a
method of modulating T cell immunoreceptor with Ig and ITIM domains
(TIGIT) signaling pathway and programmed cell death 1 (PD-1)
signaling pathway in a subject, comprising contacting the subject
with compound of formula (I), or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof:
##STR00010##
[0067] R.sub.1 represents hydrogen, --CH.sub.2-aryl-OH,
--CH.sub.2--COOH, --CH.sub.2-imidazolyl, --(CH.sub.2).sub.2--COOH,
--CH(CH.sub.3).sub.2, --CH.sub.2-aryl, --CH(CH.sub.3)OH, or
--CH.sub.2(CH)(CH.sub.3).sub.2;
[0068] R.sub.2 represents hydrogen, --CH(CH.sub.3)OH,
--CH.sub.2-aryl-OH, --CH.sub.2--SH, --CH.sub.2-imidazolyl,
--CH(CH.sub.3).sub.2, --(CH.sub.2).sub.2--COOH,
--(CH.sub.2).sub.2--CONH.sub.2, or --CH.sub.2-aryl;
[0069] R.sub.a represents hydrogen; or R.sub.a and R.sub.2 taken
together with the atom to which they are attached form a
pyrrolidine ring;
[0070] R.sub.3 represents hydrogen or a group represented by
formula (I'),
##STR00011##
[0071] represents point of attachment to --N--R.sub.a group;
[0072] R.sub.b represents hydrogen; or R.sub.b and R.sub.c taken
together with the atoms to which they are attached form a
pyrrolidine ring;
[0073] R.sub.c represents hydrogen, --CH.sub.2--COOH,
--CH(CH.sub.3)OH, --CH.sub.2-aryl-OH, --CH.sub.2-aryl,
--(CH.sub.2).sub.2--CONH.sub.2, or
--CH(CH.sub.3)CH.sub.2CH.sub.3.
[0074] In certain embodiments, R.sub.1 represents hydrogen or
--CH(CH.sub.3)OH.
[0075] In certain embodiments, R.sub.2 represents
--(CH.sub.2).sub.2--COOH.
[0076] In certain embodiments, the present invention provides a
method of modulating T cell immunoreceptor with Ig and ITIM domains
(TIGIT) signaling pathway and programmed cell death 1 (PD-1)
signaling pathway in a subject, comprising contacting the subject
with compound of formula (I), or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof: wherein the compound
is:
TABLE-US-00001 Compound No. Structure 1 ##STR00012## 2 ##STR00013##
3 ##STR00014## 4 ##STR00015## 5 ##STR00016## 6 ##STR00017## 7
##STR00018## 8 ##STR00019## 9 ##STR00020## 10 ##STR00021## 11
##STR00022## 12 ##STR00023## 13 ##STR00024## 14 ##STR00025## 15
##STR00026## 16 ##STR00027## 17 ##STR00028## 18 ##STR00029## 19
##STR00030## 20 ##STR00031##
[0077] or a pharmaceutically acceptable salt or a stereoisomer
thereof.
[0078] In certain embodiments, the present invention provides a
method of modulating T cell immunoreceptor with Ig and ITIM domains
(TIGIT) signaling pathway and programmed cell death 1 (PD-1)
signaling pathway in a subject, comprising contacting the subject
with compound of formula (I), or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof: wherein the compound
is:
TABLE-US-00002 Compound No. Structure 1 ##STR00032## 2 ##STR00033##
3 ##STR00034## 4 ##STR00035## 5 ##STR00036## 6 ##STR00037## 7
##STR00038## 14 ##STR00039## 19 ##STR00040## 20 ##STR00041##
or a pharmaceutically acceptable salt thereof.
[0079] In certain embodiments, compounds of the invention may be
prodrugs of the compounds of formula (I), e.g., wherein a hydroxyl
in the parent compound is presented as an ester or a carbonate or
carboxylic acid present in the parent compound is presented as an
ester. In a further embodiment, the prodrug is metabolized to the
active parent compound in vivo (e.g., the ester is hydrolyzed to
the corresponding hydroxyl or carboxylic acid).
[0080] In certain embodiments, the compounds of the present
invention can also contain unnatural proportions of atomic isotopes
at one or more of the atoms that constitute such compounds. For
example, the present invention also embraces isotopically-labeled
variants of the present invention which are identical to those
recited herein, but for the fact that one or more atoms of the
compound are replaced by an atom having the atomic mass or mass
number different from the predominant atomic mass or mass number
usually found in nature for the atom. All isotopes of any
particular atom or element as specified are contemplated within the
scope of the compounds of the invention and their uses. Exemplary
isotopes that can be incorporated in to compounds of the invention
include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, sulfur, fluorine, chlorine and iodine, such as .sup.2H
("D"), .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.35S, .sup.18F, .sup.36Cl,
.sup.123I and .sup.125I. Isotopically labeled compounds of the
present inventions can generally be prepared by following
procedures analogous to those disclosed in the schemes and/or in
the examples herein below, by substituting an isotopically labeled
reagent for a non-isotopically labeled reagent.
[0081] The methods of the present invention may be utilized to
treat a subject in need thereof. In certain embodiments, the
individual is a mammal such as a human or a non-human mammal. When
administered to an animal, such as a human, the compound is
preferably administered as a pharmaceutical composition comprising,
for example, a compound of the invention and a pharmaceutically
acceptable carrier. Pharmaceutically acceptable carriers are well
known in the art and include, for example, aqueous solutions such
as water or physiologically buffered saline or other solvents or
vehicles such as glycols, glycerol, oils such as olive oil or
injectable organic esters. In a preferred embodiment, when such
pharmaceutical compositions are for human administration,
particularly for invasive routes of administration (i.e., routes,
such as injection or implantation, that circumvent transport or
diffusion through an epithelial barrier), the aqueous solution is
pyrogen-free or substantially pyrogen-free. The excipients can be
chosen, for example, to effect delayed release of an agent or to
selectively target one or more cells, tissues or organs. The
pharmaceutical composition can be in dosage unit form such as
tablet, capsule (including sprinkle capsule and gelatin capsule),
granule, lyophile for reconstitution, powder, solution, syrup,
suppository, injection or the like. The composition can also be
present in a transdermal delivery system, e.g., a skin patch. The
composition can also be present in a solution suitable for topical
administration, such as an eye drop.
[0082] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0083] The phrase "pharmaceutically acceptable carrier" as used
herein means a pharmaceutically acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material. Each carrier must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as pharmaceutically
acceptable carriers include: (1) sugars, such as lactose, glucose
and sucrose; (2) starches, such as corn starch and potato starch;
(3) cellulose and its derivatives, such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; (4) powdered
tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such
as cocoa butter and suppository waxes; (9) oils, such as peanut
oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil
and soybean oil; (10) glycols, such as propylene glycol; (11)
polyols, such as glycerin, sorbitol, mannitol and polyethylene
glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13)
agar; (14) buffering agents, such as magnesium hydroxide and
aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water;
(17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol;
(20) phosphate buffer solutions; and (21) other non-toxic
compatible substances employed in pharmaceutical formulations.
[0084] In certain embodiments, the present disclosure provides a
method of modulating T cell immunoreceptor with Ig and ITIM domains
(TIGIT) signaling pathway and programmed cell death 1 (PD-1)
signaling pathway (e.g., PD-1, PD-L1, or PD-L2) in a subject,
comprising contacting the subject with compound of formula (I), or
a stereoisomer thereof or a pharmaceutically acceptable salt
thereof, according to any of the above embodiments.
[0085] In certain embodiments, the present disclosure provides a
method of modulating T cell immunoreceptor with Ig and ITIM domains
(TIGIT) signaling pathway comprising contacting the subject with
compound 19 disclosed herein or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof.
[0086] In certain embodiments, the present disclosure provides a
method of modulating T cell immunoreceptor with Ig and ITIM domains
(TIGIT) signaling pathway comprising contacting the subject with
compound 20 disclosed herein or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof.
[0087] In accordance with any of the foregoing embodiments, in
certain embodiments, contacting the cell occurs in a subject in
need thereof, thereby treating a disease or disorder selected from
cancer, immune disorders, immunodeficiency disorders, inflammatory
disorders, infectious diseases, and transplant rejection.
[0088] In certain embodiments, the disease or disorder is
cancer.
[0089] In certain embodiments, the present disclosure provides
method for inhibiting growth of tumor cells and/or metastasis
comprising administering a therapeutically effective amount to the
subject in need thereof a TIGIT/PD-1 dual pathway inhibitor.
[0090] In certain embodiments, the tumor cells are from a cancer
selected from small cell lung cancer, multiple myeloma, bladder
carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's
lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic
cancer.
[0091] In certain embodiments, the tumor cells are from a cancer
selected from blastoma, breast cancer, epithelial cancer, colon
cancer, lung cancer, melanoma, prostate cancer, renal cancer, bone
cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
uterine cancer, ovarian cancer, colorectal cancer, rectal cancer,
cancer of the anal region, cancer of the peritoneum, stomach
cancer, testicular cancer, carcinoma of the fallopian tubes,
carcinoma of the endometrium, cervical cancer, vaginal cancer,
vulval cancer, cancer of the esophagus, cancer of the small
intestine, cancer of the endocrine system, cancer of the thyroid
gland, cancer of the parathyroid gland, cancer of the adrenal
gland, sarcoma, cancer of the urethra, cancer of the penis, chronic
or acute leukemia, solid tumors of childhood, Hodgkin's lymphoma,
non-Hodgkin's lymphoma, cutaneous T cell lymphoma mesothelioma,
thymic carcinoma, myeloma, cancer of the bladder, cancer of the
ureter, carcinoma of the renal pelvis, liver cancer, pancreatic
cancer, post-transplant lymphoproliferative disorder (PTLD),
neoplasm of the central nervous system (CNS), tumor angiogenesis,
spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid
cancer, salivary gland carcinoma, squamous cell cancer, abnormal
vascular proliferation associated with phakomatoses, edema (such as
that associated with brain tumors), Meigs' syndrome, Merkel cell
carcinoma, and environmentally induced cancers.
[0092] In certain embodiments, the present invention provides a
method for inhibiting growth of tumor cells and/or metastasis in a
subject, comprising administering to the subject in need thereof a
TIGIT/PD-1 dual pathway inhibitor.
[0093] In certain embodiments, the tumor cells are of a cancer
selected from small cell lung cancer, multiple myeloma, bladder
carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's
lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic
cancer.
[0094] In certain embodiments, the tumor cells are of a cancer
selected from blastoma, breast cancer, epithelial cancer, colon
cancer, lung cancer, melanoma, prostate cancer, renal cancer, bone
cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
uterine cancer, ovarian cancer, colorectal cancer, rectal cancer,
cancer of the anal region, cancer of the peritoneum, stomach
cancer, testicular cancer, carcinoma of the fallopian tubes,
carcinoma of the endometrium, cervical cancer, vaginal cancer,
vulval cancer, cancer of the esophagus, cancer of the small
intestine, cancer of the endocrine system, cancer of the thyroid
gland, cancer of the parathyroid gland, cancer of the adrenal
gland, sarcoma, cancer of the urethra, cancer of the penis, chronic
or acute leukemia, solid tumors of childhood, Hodgkin's lymphoma,
non-Hodgkin's lymphoma, cutaneous T cell lymphoma, mesothelioma,
thymic carcinoma, myeloma, cancer of the bladder, cancer of the
ureter, carcinoma of the renal pelvis, liver cancer, pancreatic
cancer, post-transplant lymphoproliferative disorder (PTLD),
neoplasm of the central nervous system (CNS), tumor angiogenesis,
spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid
cancer, salivary gland carcinoma, squamous cell cancer, abnormal
vascular proliferation associated with phakomatoses, edema (such as
that associated with brain tumors), Meigs' syndrome, Merkel cell
carcinoma, and environmentally induced cancers.
[0095] In certain embodiments, the present invention provides
methods for treating cancer, wherein the method comprises
administration to the subject in need thereof a TIGIT/PD-1 dual
pathway inhibitor.
[0096] In accordance with any of the foregoing embodiments, in
certain embodiments, TIGIT/PD-1 dual pathway inhibitor is compound
of formula (I) or a stereoisomer thereof or a pharmaceutically
acceptable salts thereof.
[0097] In accordance with any of the foregoing embodiments, in
certain embodiments, TIGIT/PD-1 dual pathway inhibitor is compound
of formula (IA) or a stereoisomer thereof or a pharmaceutically
acceptable salts thereof.
[0098] In accordance with any of the foregoing embodiments, in
certain embodiments, TIGIT/PD-1 dual pathway inhibitor is compound
of formula (IB) or a stereoisomer thereof or a pharmaceutically
acceptable salts thereof.
[0099] In certain embodiments, the present invention provides
methods for treating cancer, mediated by TIGIT, wherein the method
comprises administration to the subject in need thereof compound 19
or 20, or a stereoisomer thereof or a pharmaceutically acceptable
salt thereof.
[0100] In certain embodiments, the present invention provides
methods for inhibiting growth of tumor cells and/or metastasis in a
subject, comprising administering to the subject in need thereof,
the compound of formula (I) or a pharmaceutically acceptable salts,
capable of inhibiting the T cell immunoreceptor with Ig and ITIM
domains (TIGIT) pathway and programmed cell death 1 (PD1) signaling
pathway.
[0101] In certain embodiments, the present invention provides
methods for inhibiting growth of tumor cells and/or metastasis in a
subject, comprising administering to the subject in need thereof,
the compound of formula (IA) or a pharmaceutically acceptable
salts, capable of inhibiting the T cell immunoreceptor with Ig and
ITIM domains (TIGIT) pathway and programmed cell death 1 (PD1)
signaling pathway.
[0102] In certain embodiments, the present invention provides
methods for inhibiting growth of tumor cells and/or metastasis in a
subject, comprising administering to the subject in need thereof,
the compound of formula (IB) or a pharmaceutically acceptable
salts, capable of inhibiting the T cell immunoreceptor with Ig and
ITIM domains (TIGIT) pathway and programmed cell death 1 (PD1)
signaling pathway.
[0103] In view of the upregulation of TIGIT on CD8+ T cells upon
activation (Joller et al. (2011) J Immunol. 186:1338), a large
number of cancer indications are expected to respond to
TIGIT-blocking agents. Available data also indicate high level of
expression of TIGIT on CD8+ TILs in non-small cell lung cancer,
colon cancer, and melanoma (Chauvin et al. (2015) Clin Investig.
125:2046; Johnston et al. (2014) Cancer Cell. 26:923), on T cells
in chronic lymphocytic leukemia (Catakovic et al., (2017)
Oncoimmunology 7(1):e1371399) and follicular lymphoma (Josefsson et
al. (2018) Clin Cancer Res. 24:870) and in the peripheral blood
mononuclear cells (PBMCs) of acute myelogenous leukemia (AML)
patients (Kong et al. (2016) Clin Cancer Res. 22:3057).
[0104] Representative tumor cells disclosed therein include cells
of a cancer such as, but not limited to, blastoma (e.g.,
glioblastoma), breast cancer (e.g., breast carcinoma, primary
ductal carcinoma, triple negative breast cancer, estrogen receptor
positive (ER+), progesterone receptor positive (PR+), and/or human
epidermal growth factor receptor 2 positive (HER2+)), epithelial
cancer (e.g., carcinomas), colon cancer, lung cancer (e.g., small
cell lung cancer, non-small cell lung cancer (NSCLC), lung
adenocarcinoma, and lung squamous cell carcinoma), melanoma (e.g.,
cutaneous melanoma, ocular melanoma, cutaneous or intraocular
malignant melanoma, and lymph node-associated melanoma), prostate
cancer (e.g., prostate adenocarcinoma), renal cancer (e.g., renal
cell cancer (RCC) and kidney cancer), bone cancer (e.g.,
osteosarcoma), pancreatic cancer (e.g., pancreatic adenocarcinoma),
skin cancer, cancer of the head or neck (e.g., head and neck
squamous cell carcinoma), uterine cancer, ovarian cancer (e.g.,
ovarian carcinoma), colorectal cancer (e.g., microsatellite
instability high colorectal cancer and colorectal adenocarcinoma),
rectal cancer, cancer of the anal region, cancer of the peritoneum,
stomach cancer (e.g., gastric carcinoma and gastrointestinal
cancer), testicular cancer, carcinoma of the fallopian tubes,
carcinoma of the endometrium, cervical cancer (e.g., carcinoma of
the cervix), vaginal cancer (e.g., carcinoma of the vagina), vulval
cancer (e.g., carcinoma of the vulva), cancer of the esophagus,
cancer of the small intestine, cancer of the endocrine system,
thyroid cancer (e.g., cancer of the thyroid gland), cancer of the
parathyroid gland, cancer of the adrenal gland, sarcoma (e.g.,
sarcoma of soft tissue and Kaposi's sarcoma), cancer of the
urethra, cancer of the penis, chronic or acute leukemia, (e.g.,
acute myeloid leukemia, chronic myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, Hairy cell
leukemia, and chronic myeloblastic leukemia,), solid tumors of
childhood, Hodgkin's lymphoma (HL) (e.g., lymphocyte-rich (LRCHL),
nodular sclerosis (NSHL), mixed cellularity (MCHL) and lymphocyte
depleted (LDHL)), B-cell lymphomas (e.g., diffuse large B-cell
lymphoma (DLBCL)), non-Hodgkin's lymphoma (NHL) (e.g., low
grade/follicular non-Hodgkin's lymphoma, small lymphocytic (SL)
NHL, intermediate grade/follicular NHL, intermediate grade diffuse
NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL,
high grade small non-cleaved cell NHL, bulky disease NHL, Burkitt's
lymphoma, mantle cell lymphoma), AIDS-related lymphoma, cutaneous
T-cell lymphoma (e.g., mycosis fundoides) and Waldenstrom's
Macroglobulinemia, post-transplant lymphoproliferative disorder
(PTLD), lymphocytic lymphoma, primary CNS lymphoma, and T-cell
lymphoma), mesothelioma, thymic carcinoma, myeloma (e.g., multiple
myeloma), cancer of the bladder (e.g., bladder carcinoma), cancer
of the ureter, carcinoma of the renal pelvis, liver cancer (e.g.,
hepatocellular cancer, hepatic carcinoma, hepatoma), pancreatic
cancer, post-transplant lymphoproliferative disorder (PTLD),
neoplasm of the central nervous system (CNS), tumor angiogenesis,
spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid
cancer, salivary gland carcinoma, squamous cell cancer, abnormal
vascular proliferation associated with phakomatoses, edema (such as
that associated with brain tumors), Meigs' syndrome, Merkel cell
carcinoma, environmentally induced cancers (including those induced
by asbestos), and combinations of said cancers.
[0105] In other embodiments, for example, the tumor cells may
include cells of a cancer selected from prostate cancer, melanoma,
breast cancer, colon cancer, prostate cancer, lung cancer, renal
cancer, pancreatic cancer, gastric carcinoma, bladder cancer,
esophageal cancer, mesothelioma, thyroid cancer, thymic carcinoma,
sarcoma, glioblastoma, chronic or acute leukemia, lymphoma,
myeloma, Merkel cell carcinoma, epithelial cancer, colorectal
cancer, vaginal cancer, cervical cancer, ovarian cancer, and cancer
of the head and neck.
[0106] In other embodiments, for example, the tumor cells may
include cells of a cancer selected from melanoma, triple negative
breast cancer, non-small cell lung cancer, renal cell carcinoma,
pancreatic cancer, gastric carcinoma, bladder cancer, mesothelioma,
Hodgkins's lymphoma, cervical cancer, ovarian cancer, and head and
neck squamous cell carcinoma. In other embodiments, for example,
the tumor cells may include cells of a cancer selected from
prostate cancer, melanoma, breast cancer, colon cancer, prostate
cancer, lung cancer, renal cancer, pancreatic cancer, gastric
carcinoma, bladder cancer, esophageal cancer, mesothelioma, thyroid
cancer, thymic carcinoma, sarcoma, glioblastoma, chronic or acute
leukemia, lymphoma, myeloma, Merkel cell carcinoma, epithelial
cancer, colorectal cancer, vaginal cancer, cervical cancer, ovarian
cancer, and cancer of the head and neck.
[0107] In other embodiments, for example, the tumor cells may
include cells of a cancer selected from melanoma, triple negative
breast cancer, non-small cell lung cancer, renal cell carcinoma,
pancreatic cancer, gastric carcinoma, bladder cancer, mesothelioma,
Hodgkins's lymphoma, cervical cancer, ovarian cancer, and head and
neck squamous cell carcinoma.
[0108] In some embodiments, the tumor cells are, and/or the subject
is, naive to immunooncology therapy. Immunooncology uses the
subject's immune system to help fight cancer. For example, an
immunooncology therapy includes, but is not limited to,
atezolizumab (human monoclonal antibody that targets PD-L1),
avelumab (human monoclonal antibody that targets PD-L1),
brentuximab vedotin (antibody-drug conjugate that targets CD30),
rituximab (antibody that targets CD20), durvalamab (human monocle
nal antibody that targets PD-L1), ipilimumab (human monoclonal
antibody that targets CTLA-4), nivolumab (human monoclonal antibody
that targets PD-L1), pembrolizumab (also referred to as
lambrolizumab, human monoclonal antibody that targets PD-L1),
tremelimumab (human monoclonal antibody that targets CTLA-4),
CT-011 (antibody that targets PD-1), MDX-1106 (antibody that
targets PD-1), MK-3475 (antibody that targets PD-1), YW243.55.S70
(antibody that targets PD-L1), MPDL3280A (antibody that targets
PD-L1), MDX-1105 (antibody that targets PD-L1), and MEDI4736
(antibody that targets PD-L1). In some embodiments, the
immunooncology therapy is selected from an anti-CTLA-4 antibody, an
anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody,
an anti-TIGIT antibody (e.g., antibodies disclosed in WO
2015/009856).
[0109] In further embodiments, the present disclosure provide a
method of treatment of infection by blockade of the TIGIT signaling
pathway and PD-1 signalling pathway, for example inhibiting an
immunosuppressive signal induced by PD-1, (e.g., PD-1, PD-L1, or
PD-L2) and TIGIT, wherein the method comprises administration of a
therapeutically effective amount of a compound of Formula (I) to
the subject in need thereof.
[0110] In some embodiments, the infectious disease is a bacterial
infection, a viral infection, a fungal infection, or a parasitic
infection, as well as methods of administering a therapeutically
effective amount of a compound of Formula (I) for the treatment of
a bacterial infection, a viral infection, a fungal infection, or a
parasitic infection.
[0111] In view of the upregulation of TIGIT on CD8+ T cells upon
activation (Joller et al. (2011) J Immunol. 186:1338)
TIGIT-blocking agents are expected to be effective in a larger
number of infectious diseases. TIGIT has been reported to enforce
CD8+ T cell exhaustion in chronic infections caused by LCMV
(Johnston et al. (2014) Cancer Cell. 26) and HIV (Tauriainen et al.
(2017) Sci Rep. 7:40354).
[0112] In some embodiments, for example, bacterial infection may be
caused by at least one bacterium selected from Chlamydia, Bacilli,
Bordetella, botulism, Campylobacter, Burkholderia, anthrax,
cholera, Clostridium, Listeria, Conococcus, Corynebacterium,
diptheria, Treponema, Brucella, Enterococcus, Mycoplasma, Borrelia,
Erwinia, Escherichia, Francisella, Haemophilus, Heliobacter,
Klebsiella, Xanthomonas Legionella, Leptospira, leptospirosis,
Lyme's disease, meningococcus, Pneumonococcus, Mycobacterium,
Neisseria, Vibrio, Pasteurella, Pelobacter, Serratia, plague,
Streptococcus, Proteus, Enterobacter, Pseudomonas, Rickettsia,
Salmonella, Shigella, Staphylococcus tetanus, and Yersinia.
[0113] In other embodiments, for example, viral infection may be
caused by at least one virus selected from arboviral encephalitis
virus, adenovirus, herpes simplex type I, herpes simplex type 2,
Varicella-zoster virus, Epstein-barr virus, cytomegalovirus,
herpesvirus type 8, papillomavirus, BK virus, coronavirus,
echovirus, JC virus, smallpox, Hepatitis B, bocavirus, parvovirus
B19, astrovirus, Norwalk virus, coxsackievirus, Hepatitis A,
poliovirus, rhinovirus, severe acute respiratory syndrome virus,
Hepatitis C, yellow fever, dengue virus, West Nile virus, rubella,
Hepatitis E, human immunodeficiency virus (HIV), human T-cell
lymphotropic virus (HTLV), influenza, guanarito virus, Junin virus,
Lassa virus, Machupo virus, Sabia virus, Crimean-Congo hemorrhagic
fever virus, ebola virus, Marburg virus, measles virus, molluscum
virus, mumps virus, parainfluenza, respiratory syncytial virus,
human metapneumovirus, Hendra virus, Nipah virus, rabies, Hepatitis
D, rotavirus, orbivirus, coltivirus, vaccinia virus, and Banna
virus.
In other embodiments, for example, fungal infection may be selected
from thrush, Coccidioides immitis, Blastomyces dermatitidis,
otomycosis, Candida (albicans, krusei, glabrata, tropicalis, etc.),
Tinea capitis, Tinea barbae, Tinea corporis, Tinea cruris, Tinea
nigra, Sporothrix schenkii, zygomycosis, chromoblastomycosis,
Cryptococcus (neoformans, etc.), Histoplasma capsulatum, Tinea
pedis, Paracoccidioides brasiliensis, phaeohyphomycosis, Tinea
favosa, Mucorales (mucor, absidia, rhizophus), sporotrichosis,
Aspergillus (fumigatus, niger, etc.), lobomycosis, mycetoma,
onychomycosis, piedra pityriasis versicolor, and
rhinosporidiosis.
[0114] In some embodiments, for example, parasitic infection may be
caused by at least one parasite selected from Ascaris lumbricoides,
Balantidium coli, Entamoeba hystolytica, Giardia lamblia, Naegleria
fowleri, Necator americanus, Nippostrongylus brasiliensis,
Strongyloides stercoralis, Cryptosporidium muris, Trypanosomatida
gambiense, Trypanosomatida rhodesiense, Babesia microti,
Trypanosoma cruzi, Leishmania mexicana, Leishmania braziliensis,
Leishmania tropica, Leishmania donovani, Wuchereria bancrofti,
Dracunculus medinensis, Toxoplasma gondii, Fasciola gigantica,
Heterophyes heterophyes, Plasmodium vivax, Trypanosoma brucei,
Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum,
Pneumocystis carinii, Trichomonas vaginalis, Histomonas
meleagridis, Secementea, Trichuris trichiura, Acanthamoeba,
Enterobius vermicularis, Ancylostoma duodenale, blood flukes, liver
flukes, intestinal flukes, lung flukes, Schistosoma mansoni,
Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica,
and Paragonimus westermani.
[0115] In certain embodiments, the present invention provides
methods for treating cancer, wherein the cancer is selected from
lung cancer, breast cancer, colon cancer, renal cancer, bladder
cancer, thyroid cancer, prostate cancer, osteosarcoma and Hodgkin's
lymphoma.
[0116] In certain embodiments, the present invention provides
methods of modulating an immune response in a subject, comprising
exposing a biological sample of the subject overexpressing T cell
immunoreceptor with Ig and ITIM domains (TIGIT) and at least one of
PD-L1 or PD-L2, to compound of formula (I) or a stereoisomer
thereof or a pharmaceutically acceptable salt.
[0117] In certain embodiments, the present invention provides
methods of modulating an immune response in a subject, comprising
a) determining whether a biological sample from a subject
overexpresses TIGIT; and b) if the sample overexpresses TIGIT,
contacting the subject with a compound of formula (I) or a
stereoisomer thereof or a pharmaceutically acceptable salt.
[0118] In certain embodiments, the present invention provides
methods of modulating an immune response in a subject, further
comprising: [0119] a) determining whether the sample overexpresses
PD-L1 or PD-L2; and [0120] b) if the sample overexpresses TIGIT and
either PD-L1 or PD-L2, contacting the subject with the compound of
formula (I) or a stereoisomer thereof or a pharmaceutically
acceptable salt.
[0121] In certain embodiments, the biological sample is selected
from whole blood, plasma, serum, cells (e.g., tumor cells), saliva,
urine, stool and tissue.
[0122] In certain embodiments, subject has a cancer, and,
optionally, the sample comprises one or more cells from the
cancer.
[0123] In certain embodiments, the subject has an infectious
disease selected from a bacterial infection, a viral infection, a
fungal infection, and a parasitic infection.
[0124] In certain embodiments, the control sample is obtained
before the subject has received a compound of Formula (I) and the
subject sample is obtained after the subject has received a
compound of Formula (I).
[0125] The compounds of the present invention may be used as single
drugs (monotherapy) or conjointly with one or more other agents
(conjoint therapy). The compounds may be used by themselves or,
preferably, in a pharmaceutical composition in which the compound
is mixed with one or more pharmaceutically acceptable
materials.
[0126] In certain embodiments, the prevention invention provides
compounds for use in modulating an immune response mediated by both
TIGIT signalling pathway and PD-1 signalling pathway in a
subject.
[0127] In certain embodiments, immune response is modulated to
treat diseases or disorders mediated by both TIGIT signalling
pathway and PD-1 signalling pathway.
[0128] In certain embodiments, the cancer, according to this
present disclosure, is selected from blastoma, breast cancer,
epithelial cancer, colon cancer, lung cancer, melanoma, prostate
cancer, renal cancer, bone cancer, pancreatic cancer, skin cancer,
cancer of the head or neck, uterine cancer, ovarian cancer,
colorectal cancer, rectal cancer, cancer of the anal region, cancer
of the peritoneum, stomach cancer, testicular cancer, carcinoma of
the fallopian tubes, carcinoma of the endometrium, cervical cancer,
vaginal cancer, vulval cancer, cancer of the esophagus, cancer of
the small intestine, cancer of the endocrine system, cancer of the
thyroid gland, cancer of the parathyroid gland, cancer of the
adrenal gland, sarcoma, cancer of the urethra, cancer of the penis,
chronic or acute leukemia, solid tumors of childhood, Hodgkin's
lymphoma, non-Hodgkin's lymphoma, cutaneous T cell lymphoma,
mesothelioma, thymic carcinoma, myeloma, cancer of the bladder,
cancer of the ureter, carcinoma of the renal pelvis, liver cancer,
pancreatic cancer, post-transplant lymphoproliferative disorder
(PTLD), neoplasm of the central nervous system (CNS), tumor
angiogenesis, spinal axis tumor, brain stem glioma, pituitary
adenoma, epidermoid cancer, salivary gland carcinoma, squamous cell
cancer, abnormal vascular proliferation associated with
phakomatoses, edema (such as that associated with brain tumors),
Meigs' syndrome, Merkel cell carcinoma, and environmentally induced
cancers.
[0129] In certain embodiments, the present invention provides a
compound of formula (I) or a stereoisomer thereof or a
pharmaceutically acceptable salt thereof, for use in modulating T
cell immunoreceptor with Ig and ITIM domains (TIGIT) signaling
pathway and programmed cell death 1 (PD-1) signaling pathway in a
subject;
##STR00042##
wherein, [0130] R.sub.1 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --COOH,
aryl, heteroaryl, or aryl-OH; [0131] R.sub.2 represents hydrogen,
--(C.sub.1-C.sub.6)alkyl optionally substituted with --OH, --SH,
C(O)NH.sub.2, --COOH, aryl, heteroaryl, or aryl-OH; [0132] R.sub.a
represents hydrogen; or R.sub.a and R.sub.2 taken together with the
atom to which they are attached form a pyrrolidine ring; [0133]
R.sub.3 represents hydrogen or a group represented by formula
(I'),
[0133] ##STR00043## [0134] represents point of attachment; [0135]
R.sub.b represents hydrogen; or R.sub.b and R.sub.c taken together
with the atoms to which they are attached form a pyrrolidine ring;
[0136] R.sub.c represents hydrogen, --(C.sub.1-C.sub.6)alkyl
optionally substituted with --OH, --C(O)NH.sub.2, COOH, aryl, or
aryl-OH.
[0137] In certain embodiments, the present invention provides
compound of formula
##STR00044##
(compound 1) or a stereoisomer thereof or a pharmaceutically
acceptable salt thereof, for use in modulating T cell
immunoreceptor with Ig and ITIM domains (TIGIT) signaling pathway
and programmed cell death 1 (PD-1) signaling pathway in a
subject.
[0138] In certain embodiments, the present invention provides a
compound of formula
##STR00045##
(compound 2) or a stereoisomer thereof or a pharmaceutically
acceptable salt thereof, for use in modulating T cell
immunoreceptor with Ig and ITIM domains (TIGIT) signaling pathway
and programmed cell death 1 (PD-1) signaling pathway in a
subject.
[0139] In certain embodiments, the present invention provides a
compound of formula
##STR00046##
(compound 3) or a stereoisomer thereof or a pharmaceutically
acceptable salt thereof, for use in modulating T cell
immunoreceptor with Ig and ITIM domains (TIGIT) signaling pathway
and programmed cell death 1 (PD-1) signaling pathway in a
subject.
[0140] In certain embodiments, the present invention provides a
compound of formula
##STR00047##
(compound 19) or a stereoisomer thereof or a pharmaceutically
acceptable salt thereof, for use in modulating T cell
immunoreceptor with Ig and ITIM domains (TIGIT) signaling pathway
and programmed cell death 1 (PD-1) signaling pathway in a
subject.
[0141] Unless otherwise specified here within, the terms "antibody"
and "antibodies" broadly encompass naturally-occurring forms of
antibodies (e.g. IgG, IgA, IgM, IgE) and recombinant antibodies
such as single-chain antibodies, chimeric and humanized antibodies
and multi-specific antibodies, as well as fragments and derivatives
of all of the foregoing, which fragments and derivatives have at
least an antigenic binding site. Antibody derivatives may comprise
a protein or chemical moiety conjugated to an antibody.
[0142] The term "antibody" as used herein also includes an
"antigen-binding portion" of an antibody (or simply "antibody
portion"). The term "antigen-binding portion", as used herein,
refers to one or more fragments of an antibody that retain the
ability to specifically bind to an antigen (e.g., a biomarker
polypeptide or fragment thereof). It has been shown that the
antigen-binding function of an antibody can be performed by
fragments of a full-length antibody.
[0143] The term "control" refers to any reference standard suitable
to provide a comparison to the expression products in the test
sample. In certain embodiments, the control comprises obtaining a
"control sample" from which expression product levels are detected
and compared to the expression product levels from the test sample.
Such a control sample may comprise any suitable sample, including
but not limited to a sample from a control subject (can be stored
sample or previous sample measurement) with a known outcome; normal
tissue or cells isolated from a subject, cultured primary
cells/tissues isolated from a subject, adjacent normal
cells/tissues obtained from the same organ or body location of the
subject, a tissue or cell sample isolated from a normal subject, or
a primary cells/tissues obtained from a depository. In certain
embodiments, the control may comprise a reference standard
expression product level from any suitable source, including but
not limited to housekeeping genes, an expression product level
range from normal tissue (or other previously analyzed control
sample), a previously determined expression product level range
within a test sample from a group of patients, or a set of patients
with a certain outcome or receiving a certain treatment. It will be
understood by those of skill in the art that such control samples
and reference standard expression product levels can be used in
combination as controls in the methods of the present
invention.
[0144] The "normal" level of expression of TIGIT is the level of
expression of TIGIT in cells of a subject, e.g., a human patient,
not in need of immune response modulation. An "over-expression" or
"significantly higher level of expression" of a biomarker refers to
an expression level in a test sample that is greater than the
standard error of the assay employed to assess expression, and is
preferably at least about 10%, and more preferably about 1.2, 1.3,
1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1, 2.2, 2.3, 2.4, 2.5,
2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5,
9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or
more higher than the expression activity or level of TIGIT in a
control sample (e.g., sample from a healthy subject not in need of
immune modulation, or from a healthy tissue sample obtained from
the same subject) and preferably, the average expression level of
the biomarker in several control samples. A "significantly lower
level of expression" of a biomarker refers to an expression level
in a test sample that is at least about 10%, and more preferably
about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5,
7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20 times or more lower than the expression level of the
biomarker in a control sample (e.g., sample from a healthy subject
not in need of immune modulation) and preferably, the average
expression level of the biomarker in several control samples.
[0145] The term "sample" used for detecting or determining the
presence or level of the TIGIT gene is typically whole blood,
plasma, serum, saliva, urine, stool (e.g., feces), tears, and any
other bodily fluid (e.g., as described above under the definition
of "body fluids"), or a tissue sample (e.g., biopsy) such as a
small intestine, colon sample, or surgical resection tissue. In
some embodiments, the disclosed methods further comprise obtaining
the sample from the subject prior to detecting or determining the
presence or level of the TIGIT gene.
[0146] The pharmaceutical composition may be administered by oral
or inhalation routes or by parenteral administration route. For
example, compositions can be administered orally, by intravenous
infusion, topically, intraperitoneally, intravesically or
intrathecally. Examples of parenteral administration includes but
not limited to intraarticular (in the joints), intravenous,
intramuscular, intradermal, intraperitoneal and subcutaneous
routes. Suitable liquid compositions may be aqueous or non-aqueous,
isotonic sterile injection solutions and may contain antioxidants,
buffers, bacteriostats and solutes that render the formulation
isotonic with the blood of the intended recipient and aqueous and
non-aqueous sterile suspensions that can include suspending agents,
solubilizers, thickening agents, stabilizers and preservatives.
Oral administration, parenteral administration, subcutaneous
administration and intravenous administration are preferred methods
of administration.
[0147] The dosage of the compounds of the present invention varies
depending on a patient's age, weight or symptoms, as well as the
compound's potency or therapeutic efficacy, the dosing regimen
and/or treatment time. Generally, suitable routes of administration
may, for example, include oral, eyedrop, rectal, transmucosal,
topical or intestinal administration; parenteral delivery,
including intramuscular, subcutaneous, intramedullary injections,
as well as intrathecal, direct intraventricular, intravenous,
intraperitoneal, intranasal or intraocular injections. The
compounds of the invention may be administered in an amount of 0.5
mg or 1 mg up to 500 mg, 1 g or 2 g per dosage regimen. The dosage
may be administered once per week, once per three days, once per
two days, once per day, twice per day, three times per day or more
often. In alternative embodiments, in certain adults the compound
can be continuously administered by intravenous administration for
a period of time designated by a physician. Since the dosage is
affected by various conditions, an amount less than or greater than
the dosage ranges contemplated about may be implemented in certain
cases. A physician can readily determine the appropriate dosage for
a patient undergoing therapeutic treatment.
Combination Therapy
[0148] The compounds of the present disclosure may be administered
in combination with one or more other drugs (1) to complement
and/or enhance effect of the compound of Formula (I), (2) to
modulate pharmacodynamics, improve absorption, or reduce dosage of
the compound of Formula (I), and/or (3) to reduce or ameliorate the
side effects of the compound Formula (I). As used herein, the
phrase "conjoint administration" refers to any form of
administration of two or more different therapeutic compounds such
that the second compound is administered while the previously
administered therapeutic compound is still effective in the body
(e.g., the two compounds are simultaneously effective in the
patient, which may include synergistic effects of the two
compounds). For example, the different therapeutic compounds can be
administered either in the same formulation or in a separate
formulation, either concomitantly or sequentially. In certain
embodiments, the different therapeutic compounds can be
administered within one hour, 12 hours, 24 hours, 36 hours, 48
hours, 72 hours, or a week of one another. Thus, an individual who
receives such treatment can benefit from a combined effect of
different therapeutic compounds. The respective compounds may be
administered by the same or different route and the same or
different method. In some embodiments, the combined effect of
conjoint therapy is detectable through immune effects.
[0149] The dosage of the other drug can be a dosage that has been
clinically used, or may be an altered dosage such that the dosage
is effective when administered in combination with a compound of
the present disclosure. The ratio of the compound of the present
disclosure and the other drug can vary according to age and weight
of a subject to be administered, administration method,
administration time, disorder to be treated, symptom and
combination thereof. For example, the other drug may be used in an
amount of 0.01 to 100 parts by mass, based on 1 part by mass of the
compound of the present disclosure.
[0150] Conjoint therapy can be employed to treat any diseases
discussed herein. In certain embodiments, a compound of Formula (I)
of the disclosure may be conjointly administered with another
therapeutic agent, e.g., an anti-cancer agent, an anti-viral agent,
a cytokine or an immune agonist. In some embodiments, the other
therapeutic agent is selected from CTLA-4 antagonists, PD-1
antagonists, PD-L1 antagonists, or PD-L2 antagonists, and EGFR
antagonists.
[0151] TIGIT antagonizing agents are expected to rescue NK cell
function from the TIGIT-mediated suppression. Since NK cells
contribute to the efficacy of many of the antibodies targeting
cancer cell surface proteins (such as HER2, EGFR, CD38 and CD20
antibodies) through antibody-mediated cellular cytotoxicity (ADCC),
TIGIT agents are expected to work synergistically in combination
with many of the anti-cancer antibodies such as anti-HER2
antibodies, anti-EGFR antibodies, anti-CD38 antibodies and
anti-CD20 antibodies.
Agents for Combination Therapies
[0152] In certain embodiments, a compound of Formula (I) can be
conjointly administered with another therapeutic agent, e.g.,
1) an aldosterone synthase inhibitor; 2) an ALK inhibitor; an
apoptosis inducer; 3) an aromatase inhibitor; 4) a CART cell (e.g.,
a CART cell targeting CD19); 5) a BCR-ABL inhibitor; 6) a BRAF
inhibitor; 7) a CDK4/6-inhibitor; 8) a CEACAM (e.g., CEACAM-1, -3
and/or -5) inhibitor; 9) a c-KIT inhibitor; 10) a c-MET inhibitor;
10) a cRAP inhibitor; 11) a CTLA4 inhibitor; 12) a cytochrome P450
inhibitor (e.g., a CYP17 inhibitor); 13) an EGF inhibitor; 14) an
ERK1/2 ATP inhibitor; 15) an FGF inhibitor (e.g., a FGFR2 or FGFR4
inhibitor); 16) a Flt3 inhibitor (e.g., FLK2/STK1); 17) a
P-Glycoprotein 1 inhibitor; 18) a HDAC inhibitor; 19) a HDM2
inhibitor; 20) a HER3 inhibitor; 21) a histamine release inhibitor;
22) an HSP90 inhibitor; 23) an IAP inhibitor; 24) an IDH inhibitor;
25) an IDO inhibitor 26) an IGF-1R inhibitor; 27) an iron chelating
agent; 28) a Janus inhibitor; 29) a LAG-3 inhibitor; 30) an M-CSF
inhibitor; 31) a MEK inhibitor; 32) an mTOR inhibitor; 33) a p53
inhibitor (e.g., an inhibitor of a p53/Mdm2 interaction); 34) a
PDGFR.beta. inhibitor; 35) a PKC inhibitor; 36) a PI3K inhibitor;
37) a PIM inhibitor; 38) a PRLR inhibitor; 39) a Raf kinase C
inhibitor; 40) a smoothened (SMO) receptor inhibitor; 41) a
somatostatin agonist and/or a growth hormone release inhibitor; 42)
a transduction modulator and/or angiogenesis inhibitor; 43) a
VEGFR-2 inhibitor (e.g., FLK-1/KDR); 44) a tyrosine kinase
inhibitor (e.g., CSF-1R tyrosine kinase); 45) a Wnt signaling
inhibitor 46) a Bcl-2 inhibitor; 47) a Mcl-1 inhibitor; 48) a BTK
inhibitor; 49) dual active molecules such as CUDC-907 (a dual
PJ3K/HDAC inhibitor); and 50) BET bromodomain inhibitor.
[0153] Additional therapeutic agents suitable for conjoint
administration with the compounds and compositions disclosed herein
have been described, for example, in the following publications:
WO2016/100882; WO2016/054555; WO2016/040892; WO2015/097536;
WO2015/088847; WO2015/069770; WO2015/026634; WO 2015/009856; EP
1377609 B1; Antonia, et al. Clin. Cancer Res. 2014 20:6258-6268;
and Melero, et al. Nature Reviews Cancer 2015 15:457-472. Each
publication is incorporated herein by reference in its
entirety.
[0154] For example, in the methods of the disclosure directed to
the treatment of cancer, the compound of the present disclosure can
be used with another chemotherapeutic conjointly as a single
pharmaceutical composition or a combination of different
pharmaceutical compositions. Non-limiting examples of the
chemotherapeutic agent include an alkylation agent, nitrosourea
agent, antimetabolites, anticancer antibiotics, vegetable-origin
alkaloids, topoisomerase inhibitors, hormone drugs, hormone
antagonists, leucopenia (neutropenia) treatment drugs,
thrombocytopenia treatment drugs, antiemetics, aromatase
inhibitors, P-glycoprotein inhibitors, platinum complex
derivatives, other immunotherapeutic drugs and other anticancer
drugs.
[0155] Exemplary cytotoxic agents that can be administered
conjointly include antimicrotubule agents, topoisomerase
inhibitors, anti-metabolites, mitotic inhibitors, alkylating
agents, anthracyclines, vinca alkaloids, intercalating agents,
agents capable of interfering with a signal transduction pathway,
agents that promote apoptosis, proteosome inhibitors, and radiation
(e.g., local or whole body irradiation).
[0156] Non-limiting examples of additional therapeutic agents
include, but are not limited to, peptides, polypeptides, proteins,
fusion proteins, nucleic acid molecules, small molecules, mimetic
agents, synthetic drugs, inorganic molecules, and organic
molecules.
[0157] The conjoint therapy can include, other compatible agents,
e.g., a chemotherapeutic agent, a cytokine therapy, an interferon
therapy (e.g., interferon-.alpha., .beta., or .gamma.; interferon
.alpha.-2a; interferon .alpha.-2b; interferon .alpha.-m; interferon
.alpha.-n3; interferon .beta.-Ia; and interferon .gamma.-Ib), an
interlukin therapy (e.g., IL-1, IL-2, IL-2R.beta., IL-2R.gamma.,
IL-3, IL-7, IL7R.alpha., IL-11, IL-12, IL-15, and IL-21), a cluster
of differentiation (CD) protein (e.g., CD2, CD4, CD7, CD8.alpha.,
CD8.beta., CD11a/CD18, CD11b, CD11c, CD11d, CD18, CD19, CD19a,
CD20, CD27, CD28, CD29, CD30, CD40, CD40L, CD49a, CD49D, CD49f,
CD69, CD84, CD96, CD100, CD103, CD137, CD160, CD226, CD229, CD278)
a co-stimulatory modulator, e.g., an agonist (e.g., an agonistic
antibody or antigen-binding fragment thereof, or soluble fusion) of
an MHC class I molecule, a TNF receptor protein, an
immunoglobulin-like protein, a Toll ligand receptor, a CD83 ligand,
a cytokine receptor, an integrin, signaling lymphocytic activation
molecules (SLAM proteins), an activating NK cell receptor, an
antibody therapy, a viral therapy, gene therapy or a combination
thereof.
[0158] Chemotherapeutic and other therapeutic agents that may be
conjointly administered with compounds of the disclosure include,
but are not limited to: abiraterone, abraxane, aceglatone,
acivicin, aclacinomysin, actimid, actinomycin, aflibercept,
aldesleukin, aldophosphamide glycoside alectinib, alendronate,
alitretinoin, altretamine, aminoglutethimide, aminolevulinic acid,
aminopterin, amsacrine, anastrozole, ancitabine, angiostatin,
angiozyme, anguidine, ansamitocin, anthramycin, antithrombin III,
apatinib, arabinoside, arboplatin, asparaginase, authramycin,
axitinib, azacitidine, azaserine, azetepa, azotomycin,
6-azauridine, baricitinib, batimastat, bendamustine, benimetinib,
benzodopa, bestrabucil, bexarotene, bicalutamide, bisantrene,
bleomycin, bortezomib, bosutinib, brequinar, brivanib, bryostatin,
bropirimine, bullatacin, bullatacinone, buserelin, busulfan,
cactinomycin, calicheamicin, callystatin, calusterone, caminomycin,
campothecin, capecitabine, carabicin, carboplatin, carboquone,
carfilzomib, carmofur, carmustine, carubicin, carzelesin,
carzinophilin, cedefingol, cediranib, chlomaphazine, chlorambucil,
chloroquine, chlorozotocin, cholophosphamide, chromomycin,
cirolemycin, cisplatin, cisdichlorodiamine platinum (II),
cisplatin, cladribine, clodronate, cobimetinib, colchicine,
crisnatol, crizotinib, cryptophycin 1, cryptophycin 8,
cyclophosphamide, cyproterone, cytarabine, cytochalasin B, cytosine
arabinoside, dabrafenib, dacarbazine, dactinomycin, danoprevir,
dasatinib, diaziquone, dibromomannitol, daunorubicin, decitabine,
defofamine, degarelix, 1-dehydrotestosterone, delanzomib,
demecolcine, demethoxyviridin, denileukin, denenicokin, denopterin,
desacetylravidomycin, detorubicin, dexamethasone, dexormaplatin,
dezaguanine, diaziquone, 6-diazo-5-oxo-L-norleucine,
dichloroacetate, dideoxyuridine, dienestrol, diethylstilbestrol,
diftitox, difluoromethylomithine, dihydroxyanthracindione,
dinaciclib, docetaxel, dolastatin, dovitinib, doxifluridine,
doxorubicin, doxycycline, droloxifene, dromostanolone, duazomycin,
duocarmycin, dynemicin, edatrexate, eflomithine, elliptinium
acetate, eleutherobin, emetine, emsirolimus, encorafenib,
enloplatin, enocitabine, enpromate, epipropidine, epirubicin,
epithilone, epitiostanol, erbulozole, erismodegib, erlotinib,
esorubicin, esperamicin, estradiol, estramustine, etanidazole,
ethidium bromide, 2-ethylhydrazide, etidronate, etoglucid,
etoposide, everolimus, exemestane, fadrozole, fazarabine,
fenretinide, filgrastim, floxuridine, fludarabine, fludrocortisone,
fluorouracil, fluoxymesterone, flurocitabine, flutamide, foretinib,
formestane, fosquidone, fotemustine, frolinic acid, gacytosine,
gallium nitrate, galunisertib, gandotinib, gefitinib, geldanamycin,
gemcitabine, genistein, glucocorticoids, goserelin, gramicidin D,
herbimycin, hiltonol, 4-hydroxytamoxifen, hydroxyurea, ibandronate,
idarubicin, ifosfamide, ilmofosine, imatinib, imiquimod,
improsulfan, indoximod, interferon, iproplatin, irinotecan,
ironotecan, ixazomib, keoxifene, laherparepvec, lameotide,
lapatinib, lenalidomide, lestaurtinib, letrozole, leucovorin,
leuprolide, lentinan, levamisole, liarozole, lidocaine, linifanib,
lometrexo, lomustine, lonidamine, losoxantrone, marcellomycin,
marizomib, masitinib, masoprocol, maytansyne, maytansinol,
mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine,
medroxyprogesterone, megestrol, melengestrol, menogaril, melphalan,
mepitiostane, mercaptopurine, mesna, metformin, methotrexate,
metoprine, meturedopa, mithramycin, mitobronitol, mitoguazone,
mitolactol, mitomycin, mitosper, mitotane, mitoxantrone,
momelotinib, montanide, mopidamol, motesanib, motolimod,
mycophenolic acid, mylotarg, nab-paclitaxel, navelbine, neratinib,
nilotinib, nilutamide, nimustine, nitracrine, nocodazole,
nogalamycin, novantrone, novembichin, obinutuzumab, octreotide,
olivomycin, onapristone, ormaplatin, oxaliplatin, paclitaxel,
pacritinib, palbociclib, pamidronate, pancratistatin, panobinostat,
pazopanib, pegaptanib, pegaspargase, pegfilgrastim, peginterferon
.alpha.-2b, pelitinib, pemetrexed, pentostatin,
N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, peplomycin,
perifosine, phenamet, phenesterine, pimasertib, pipobroman,
piposulfan, pirarubicin, plicamycin, podophyllinic acid,
polifeprosan, pomalidomide, porfimer, porfromycin, potfiromycin,
prednimustine, procaine, procarbazine, propranolol, pteropterin,
puromycin, quelamycin, raltitrexed, raloxifene, ranimustine,
rapamycin, ravidomycin, razoxane, regorafenib, risedronate,
resiquimod, rituximab, rodorubicin, rogletimide, roridin,
ruxolitinib, safingol, sarcodictyin, selumetinib, semaxanib,
semustine, simapimod, simtrazene, sirolimus, sizofiran, sorafenib,
sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin,
spongistatin, streptonigrin, streptozocin, sulofenur, sunitinib,
suramin, talisomycin, tamoxifen, talimogene, tasocitinib, taxol,
tegafur, telatinib, teloxantrone, temoporfin, temozolomide,
temsirolimus, teniposide, tenuazonic acid, teroxirone,
testolactone, testosterone, tetracaine, tezacitibine, thalidomide,
thiamiprine, thioguanine, thiotepa, tiazofurin, tiludronate,
tirapazamine, titanocene, tivozanib, toceranib, tofacitinib,
topoisomerase inhibitor RFS 2000, topotecan, toremifene,
tozasertib, trametinib, trastuzumab, triaziquone, tretinoin,
2,2',2''-trichlorotriethylamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphaoramide,
trilostane, trimethylolomelamine, trimetrexate, triptorelin,
trofosfamide, tubercidin, tuvizanib, uracil mustard, ubenimex,
uredopa, urethane, vandetanib, vapreotide, vargatef, vatalanib,
vemurafenib, verracurin, verteporfin, vinblastine, vincristine,
vindesine, vinepidine, vinglycinate, vinleurosine, vinorelbine,
vinrosidine, vinzolidine, vorozole, vismodegib, xeloda, zactima,
zeniplatin, zinostatin, Ziv-aflibercept, zoledronate, and
zorubicin.
[0159] In certain embodiments, exemplary chemotherapeutic agents
include, but are not limited to, cytokines such as ABT-869,
ACP-196, ADXS11-001, ADXS31-142, AEE788, AG-490, AM0010, AMN-107,
AMP-224, AMP-514, AP24534, ARRY-142886, AST-6, AZD1480, AZD4547,
AZD6094, AZD6244, AZD8055, AZD9291, B7-H3, BAFFR, 4-1BB, BEZ235,
BGT 226, BHG712, BIBF 1120, BIBW2992, BIX 02188, BJG398, BKM-120,
BMS-599626, BMS-690154, BMS-777607, BMS-911543, BMS-936558,
BMS-936559, BMS-986016, BRAF V600E, BTLA, BUW078, BYL719, CAL-101,
CAL-263, CBI-TMI, CC-1065, CC-4047, CC-5013, CDS, CDX-1127,
CEACAM1, CEP-701, CEP-11981, CGM097, Chi Lob 7/4, CI-1040, CO-1686,
CP-673451, CP-870,893, CpG 7909, CPT-11, CRTAM, CT-011, CTL019,
CTLA-4, CUDC-101, CYC116, CYT 387, DCC-2036, DNAM1, E6201, E7080,
EGF816, FOLFOX6, G02443714, G-38963, GADS, GC1008, G-CSF, GDC-0032,
GDC-0973, GDC-0980, GITR, GM CSF, GR-MD-02, GSK1059615, GVAX, HVEM
(LIGHTR), IA4, ICAM-1, ICOS, IMC-TR1, IMP321, INC280, INC424,
INCB18424, INCB024360, INCB028050, IPH2012, IPI926, IRX-2, ISA
51VG, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB1,
ITGB2, ITGB7, JNJ-26483327, Ki8751, KIRDS2, KU-0063794, KW-289LAT,
LBH589, LCL161, LGH447, LTBR, LDK378, LEE011, LGX818, LIGHT,
LJM716, LY117018, LY2157299, LY294002, LY2940680, M-CSF, MARTI,
MDX-1105, MDX-1106, MEDI0562, MEDI4736, MEDI4737, MEDI6383,
MEDI6469, MEK162, MG-132, MGCD265, MK-3475, MK 4166, MM-121,
MOXR0916, MP470, MPDL3280A, MSB-0010718C, NKG2C, NKG2D, NKp30,
NKp44, NKp46, NKp80 (KLRF1), NY-ESO-1, ODC-0879, ODC-0980,
ONX-0912, ODC-0941, OSI-027, OSI-930, OSK-1120212, OSK 2118436, OSK
2126458, OX40, P529, PAG/Cbp, PD153035, PD173074, PD0325901,
PF-299804, PF-02341066, PF-04217903, PF-046915032, PF-05082566,
PD98059, Poly(I:C), PKI-587, PLX4032, PLX4720, PSGL1, PSK, PX-886,
Rad-001, RAF265, rHIgM12B7, R07204, RO4987655, RO6895882,
RO7009789, SAR 245408, SAR 245409, SB-1317, SB-1518, SB-1578,
SELPLG, SF1126, SGX523, SLAM, SLAMF4, SLAMF6, SLAMF7, SLAML_BLAME,
SLP-76, SU 5402, T2 toxin, TEW 7197, TGN1412, TNFR2, TRANCE/RANKL,
TriMix-DC, TRP-2, TRX518, TSU-68, VLA1, VLA-6, WYE-354, WZ3146,
WZ4002, WZ8040, XL-147, XL-184, XL-228, XL-281, XL-647, XL-756,
XL-765, XL-880, Yttrium90/MX-DTPA, and YW243.55.S70.
[0160] Exemplary paclitaxel agents that can be used conjointly with
compounds disclosed herein include, but are not limited to,
nanoparticle albumin-bound paclitaxel (ABRAXANE, marketed by
Abraxis Bioscience), docosahexaenoic acid bound-paclitaxel
(DHA-paclitaxel, Taxoprexin, marketed by Protarga), polyglutamate
bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103,
XYOTAX, marketed by Cell Therapeutic), the tumor-activated prodrug
(TAP), ANG 105 (Angiopep-2 bound to three molecules of paclitaxel,
marketed by ImmunoGen), paclitaxel-EC-1 (paclitaxel bound to the
erbB2-recognizing peptide EC-1; see Li et al., Biopolymers (2007)
87:225-230), and glucose-conjugated paclitaxel (e.g., 2'paclitaxel
methyl 2-glucopyranosyl succinate, see Liu et al., Bioorganic &
Medicinal Chemistry Letters (2007) 17:617-620).
[0161] In certain embodiments, exemplary chemotherapeutic agents
include, but are not limited to: [0162] 1)
(S)--N--((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrro-
lidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide; [0163] 2)
((1R,9S,12S,15R,16E,18R,19R,21R, 23S, 24E, 26E, 28E, 30S, 32S,
35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxyc-
yclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,-
36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,-
10,14,20-pentaone); [0164] 3)
(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-
-oxopiperazin-1-yl)-trans-cyclohexylmethyl]-amino}phenyl)-1,4-dihydro-2H-i-
soquinolin-3one; [0165] 4)
N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro
phenyl)-5-fluoropicolinamide; [0166] 5) anti-HER3 monoclonal
antibody or antigen binding fragment thereof, that comprises a VH
of SEQ ID NO: 141 and VL of SEQ ID NO: 140, as described in U.S.
Pat. No. 8,735,551; [0167] 6)
(E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phe-
nyl) acrylamide; [0168] 7)
(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-y-
l]propanenitrile; and/or [0169] 8)
8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid
(4-dimethylaminomethyl-1H-imidazol-2-yl)-amide.
[0170] In other embodiments, exemplary chemotherapeutic agents
include, but are not limited to, [0171] 1)
3-(1H-indol-3-yl)-4-[2-(4-methyl-1-piperazinyl)-4-quinazolinyl]-1H-pyrrol-
e-2,5-diane; [0172] 2)
5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)
phenyl)isoxazole-3-carboxamide; [0173] 3)
2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,-
5-c]quinolin-1-yl)phenyl)propanenitrile (dactolisib); [0174] 4)
Compound D (CYP17 inhibitor); [0175] 5)
4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]-benzoic acid
(defeasirox); [0176] 6)
4,4'-(1H-1,2,4-triazol-1-ylmethylene)bis-benzonitrile (letrozole);
[0177] 7)
(4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidi-
n]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one; [0178] 8)
(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl-
)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imi-
dazol-4(1H)-one; [0179] 9)
4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyri-
midinyl]amino]phenyl]-methanesulfonate-benzamide; [0180] 10)
4-[(R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile
(osilodrostat); [0181] 11)
N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4'(tri
fluoromethoxy)-[1,1'-biphenyl]-3-carboxamide, diphosphate
(sonidegib phosphate); [0182] 12)
(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)
pyrazin-2-yl)propan-2-ol; [0183] 13) Compound M (human monoclonal
antibody to PRLR); [0184] 14)
2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)
acetamide; [0185] 15)
7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diaza
bicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine--
6-carboxamide; [0186] 16) Compound P (FGFR2 and/or FGFR4 antibody
drug conjugate, mAb 12425); [0187] 17) Compound Q (monoclonal
antibody of Fab to M-CSF); [0188] 18)
N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9-
,13-epoxy-1H,9H-diindolo[1,2,3m]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N--
methyl-benzamide (midostaurin); [0189] 19)
1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N--
(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine; [0190] 20)
cyclo((4R)-4-(2-aminoethylcarbamoyloxy)-L-prolyl-L-phenylglycyl-D-tryptop-
hyl-L-lysyl-4-0-benzyl-L-tyrosyl-L-phenylalanyl-) (pasireotide
diaspartate); [0191] 21)
1-amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2(1H-
)-quinolinone (dovitinib); [0192] 22)
8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-
-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; [0193] 23)
N6-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopro-
pylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine;
[0194] 24)
3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amin-
o)-5-fluoro-2-methylphenyl)piperidin-1-yl)thietane 1,1-dioxide;
[0195] 25)
5-chloro-N2-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-
-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
[0196] 26)
5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-
-methyl-1Hpyrazol-3-yl)pyrimidine-2,4-diamine; [0197] 27)
6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]cyclo
sporine D. Amdray, PSC833,
[3'-Desoxy-3'-oxo-MeBmt]l-[Val]2-cyclosporin (valspodar); [0198]
28) N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-phthalazinamine
succinate (vatalanib succinate); [0199] 29) Compound CC (IDH
inhibitor); [0200] 30)
(R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(-
1H-pyrazol-5-yl)nicotinamide; [0201] 31) Compound EE (cRAF
inhibitor); [0202] 32) Compound FF (ERK1/2 ATP competitive
inhibitor); and [0203] 33)
4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-met-
hylpicolinamide. See, e.g., WO2016/100882, which is incorporated
herein by reference in its entirety.
[0204] In certain embodiments, exemplary therapeutic agents for
conjoint administration are monoclonal antibodies or fragments
thereof (see e.g., Bolliger (1993) Proc. Natl. Acad. Sci. USA
90:6444-6448; Poljak (1994) Structure 2:1121-1123). These
therapeutic monoclonal antibodies and/or fragments thereof include,
but are not limited to, anti-LAG-3 monoclonal antibody, anti-PD-1
antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-TIM-3
antibody, anti-CTLA-4 antibody, anti-TIGIT antibody, anti-OX40
antibody, anti-GITR antibody, adalimumab, afatinib, afutuzumab,
alemtuzumab, atezolizumab, avelumab, axitinib, basiliximab,
bavituximab, belimumab, bevacizumab, brentuximab, canakinumab,
certolizumab, cetuximab, daclizumab, denosumab, durvalamab,
eculizumab, efalizumab, elotuzumab, fostamatinib, gemtuzumab
ozogamicin, golimumab, ibritumomab tiuxetan, infliximab,
ipilimumab, lambrolizumab, lapatinib, lenvatinib, lirilumab,
mogamulizumab, motavizumab, mubritinib, natalizumab, nivolumab,
obinutuzumab, ofatumumab, omalizumab, palivizumab, panitumumab,
pegaptani, pembrolizumab, pertuzumab, pidilizumab, ranibizumab,
raxibacumab, rilotumumab, rituximab, tocilizumab, tositumomab-I-13,
trastuzumab, tremelimumab, urelumab, ustekinumab, and
varlilumab.
[0205] Combination therapies can also include administration of
bispecific antibodies. Bispecific antibodies can be used to target
two separate antigens. For example anti-Fc receptor/anti-tumor
antigen (e.g., Her-2/neu) bispecific antibodies have been used to
target macrophages to sites of tumor. This targeting may more
effectively activate tumor specific responses. The T cell arm of
these responses would by augmented by the use of PD-1 blockade.
Alternatively, antigen may be delivered directly to DCs by the use
of bispecific antibodies which bind to tumor antigen and a
dendritic cell specific cell surface marker.
[0206] Other antibodies which may be used to activate host immune
responsiveness can be used in combination with the combination
therapies described herein. These include molecules on the surface
of dendritic cells which activate DC function and antigen
presentation. Anti-CD40 antibodies are able to substitute
effectively for T cell helper activity (Ridge, J. et al. (1998)
Nature 393: 474-478) and can be used in conjunction with PD-1
antibodies (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40).
Antibodies to T cell costimulatory molecules such as CTLA-4 (e.g.,
U.S. Pat. No. 5,811,097), OX-40 (Weinberg, A. et al. (2000) Immunol
164: 2160-2169), 4-1BB (Melero, I. et al. (1997) Nature Medicine 3:
682-685 (1997), and ICOS (Hutloff, A. et al. (1999) Nature 397:
262-266) may also provide for increased levels of T cell
activation.
[0207] Immunomodulatory agents and therapies that are suitable for
use in the compositions and conjoint methods described herein
include, but are not limited to, anti-T cell receptor antibodies
such as anti-CD3 antibodies (e.g., Nuvion (Protein Design Labs),
OKT3 (Johnson & Johnson), or anti-CD20 antibodies Rituxan
(IDEC)), antiCD52 antibodies (e.g., CAMPATH 1H (Ilex)), anti-CD11a
antibodies (e.g., Xanelim (Genentech)); anti-cytokine or
anti-cytokine receptor antibodies and antagonists such as anti-IL-2
receptor antibodies (Zenapax (Protein Design Labs)), anti-IL-6
receptor antibodies (e.g., MRA (Chugai)), and anti-IL-12 antibodies
(CNT01275 (Janssen)), anti-TNFalpha antibodies (Remicade (Janssen))
or TNF receptor antagonist (Enbrel (Immunex)), anti-IL-6 antibodies
(BE8 (Diaclone) and siltuximab (CNT032 (Centocor)), and antibodies
that immunospecifically bind to tumor-associated antigens (e.g.,
trastuzimab (Genentech)).
[0208] The combination therapies disclosed herein can be further
combined with an immunogenic agent, such as cancerous cells,
purified tumor antigens (including recombinant proteins, peptides,
and carbohydrate molecules), cells, and cells transfected with
genes encoding immune stimulating cytokines (He et al. (2004) J.
Immunol. 173:4919-28). Non-limiting examples of tumor vaccines that
can be used include peptides of melanoma antigens, such as peptides
of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor
cells transfected to express the cytokine GM-CSF.
[0209] Compounds disclosed herein can be used in conjunction with a
collection of recombinant proteins and/or peptides expressed in a
tumor in order to generate an immune response to these proteins.
These proteins are normally viewed by the immune system as self
antigens and are therefore tolerant to them. The tumor antigen may
also include the protein telomerase, which is required for the
synthesis of telomeres of chromosomes and which is expressed in
more than 85% of human cancers and in only a limited number of
somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013).
(These somatic tissues may be protected from immune attack by
various means). Tumor antigens may also be "neo-antigens" expressed
in cancer cells because of somatic mutations that alter protein
sequence or create fusion proteins between two unrelated sequences
(ie. bcr-abl in the Philadelphia chromosome), or idiotype from B
cell tumors.
[0210] Compounds disclosed herein can be combined with a
vaccination protocol. Many experimental strategies for vaccination
against tumors have been devised (see Rosenberg, S., 2000,
Development of Cancer Vaccines, ASCO Educational Book Spring:
60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300-302;
Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K.
2000, ASCO Educational Book Spring: 730-738; see also Restifo, N.
and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V.
et al. (eds.), 1997, Cancer: Principles and Practice of Oncology.
Fifth Edition). In one of these strategies, a vaccine is prepared
using autologous or allogeneic tumor cells. These cellular vaccines
have been shown to be most effective when the tumor cells are
transduced to express GM-CSF. GM-CSF has been shown to be a potent
activator of antigen presentation for tumor vaccination (Dranoff et
al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43). In some
embodiments, vaccination with immunoglobulin idiotype produced by
malignant plasma cells is used. Other therapeutic vaccines include,
but are not limited to, sipuleucel-T, gp100 vaccine, HPV-16
vaccination, and GVAX pancreas vaccine.
[0211] Other tumor vaccines may include the proteins from viruses
implicated in human cancers such a Human Papilloma Viruses (HPV),
Hepatitis Viruses (HBV and HCV), Kaposi's Herpes Sarcoma Virus
(KHSV) and Preferentially Expressed Antigen In Melanoma (PRAME). In
certain embodiments, the vaccine is selected from a viral vector
vaccine, bacterial vaccine, cell-based vaccine, DNA vaccine, RNA
vaccine, peptide vaccine, or protein vaccine. See, e.g., Jeffrey
Schlom, "Therapeutic Cancer Vaccines: Current Status and Moving
Forward," J Natl Cancer Inst; 104:599-613 (2012). Another form of
tumor specific antigen which may be used in conjunction with PD-1
blockade is purified heat shock proteins (HSP) isolated from the
tumor tissue itself. These heat shock proteins contain fragments of
proteins from the tumor cells and these HSPs are highly efficient
at delivery to antigen presenting cells for eliciting tumor
immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588;
Tamura, Y. et al. (1997) Science 278:117-120).
[0212] Exemplary agents that can be conjointly administered with
compounds disclosed herein include a therapeutic cancer vaccine or
adoptive T cell therapy. In certain embodiments, the therapeutic
cancer vaccine is a dendritic cell vaccine. The dendritic cell
vaccine can be composed of autologous dendritic cells and/or
allogeneic dendritic cells. In certain embodiments, the autologous
or allogeneic dendritic cells are loaded with cancer antigens prior
to administration to the subject. In certain embodiments, the
autologous or allogeneic dendritic cells are loaded with cancer
antigens through direct administration to the tumor. In certain
embodiments, the adoptive T cell therapy comprises autologous
and/or allogenic T-cells. In certain embodiments, the autologous
and/or allogenic T-cells are targeted against tumor antigens.
[0213] In certain embodiments, non-limiting examples of cancer
vaccines include tumor cell vaccines, antigen vaccines, dendritic
cell vaccines, DNA vaccines, and vector based vaccines. Antigen
vaccines boost the immune system by using one or more antigens,
such as peptides. Antigen vaccines may be specific for a certain
type of cancer because each tumor type may be identified by
specific antigen profiles. Dendritic cell vaccines are often
autologous vaccines, and must often be made individually for each
subject. Non-limiting examples of dendritic vaccines are
Sipuleucel-T and DCvax. For preparing DNA vaccines, vectors can be
engineered to contain specific DNAs that can be injected into a
subject which leads to the DNA being taken up by cells. Once the
cells take up the DNA, the DNA will program the cells to make
specific antigens, which can then provoke the desired immune
response.
Pancreatic Cancer
[0214] Exemplary agents that that can be used conjointly with
compounds disclosed herein for the treatment of pancreatic cancer
include, but are not limited to, TAXOL, an albumin-stabilized
nanoparticle paclitaxel formulation (e.g., ABRAXANE) or a liposomal
paclitaxel formulation); gemcitabine (e.g., gemcitabine alone or in
combination with AXP107-11); other chemotherapeutic agents such as
oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicin
hydrochloride, NC-6004, cisplatin, docetaxel (e.g., TAXOTERE),
mitomycin C, ifosfamide; interferon; tyrosine kinase inhibitor
(e.g., EGFR inhibitor (e.g., erlotinib, panitumumab, cetuximab,
nimotuzumab); HER2/neu receptor inhibitor (e.g., trastuzumab); dual
kinase inhibitor (e.g., bosutinib, saracatinib, lapatinib,
vandetanib); multikinase inhibitor (e.g., sorafenib, sunitinib,
XL184, pazopanib); VEGF inhibitor (e.g., bevacizumab, AV-951,
brivanib); radioimmunotherapy (e.g., XR303); cancer vaccine (e.g.,
GVAX, survivin peptide); COX-2 inhibitor (e.g., celecoxib); IGF-1
receptor inhibitor (e.g., AMG 479, MK-0646); mTOR inhibitor (e.g.,
everolimus, temsirolimus); IL-6 inhibitor (e.g., CNTO 328);
cyclin-dependent kinase inhibitor (e.g., P276-00, UCN-01); Altered
Energy Metabolism-Directed (AEMD) compound (e.g., CPI-613); HDAC
inhibitor (e.g., vorinostat); TRAIL receptor 2 (TR-2) agonist
(e.g., conatumumab); MEK inhibitor (e.g., AS703026, selumetinib,
GSK1120212); Raf/MEK dual kinase inhibitor (e.g., R05126766); Notch
signaling inhibitor (e.g., MK0752); monoclonal antibody-antibody
fusion protein (e.g., L191L2); curcumin; HSP90 inhibitor (e.g.,
tanespimycin, STA-9090); riL-2; denileukin diftitox; topoisomerase
1 inhibitor (e.g., irinotecan, PEP02); statin (e.g., simvastatin);
Factor VIla inhibitor (e.g., PCI-27483); AKT inhibitor (e.g.,
RX-0201); hypoxia-activated prodrug (e.g., TH-302); metformin
hydrochloride, gamma-secretase inhibitor (e.g., R04929097);
ribonucleotide reductase inhibitor (e.g., 3-AP); immunotoxin (e.g.,
HuC242-DM4); PARP inhibitor (e.g., KU-0059436, veliparib); CTLA-4
inhibitor (e.g., CP-675,206, ipilimumab); AdVtk therapy; proteasome
inhibitor (e.g., bortezomib (Velcade), NPI-0052); thiazolidinedione
(e.g., pioglitazone); NPC-1C; Aurora kinase inhibitor (e.g.,
R763/AS703569), CTGF inhibitor (e.g., FG-3019); siG 12D LODER; and
radiation therapy (e.g., tomotherapy, stereotactic radiation,
proton therapy), surgery, and a combination thereof.
Small Cell Lung Cancer
[0215] Exemplary agents that that can be used conjointly with
compounds disclosed herein to treat small cell lung cancer include,
but are not limited to, etoposide, carboplatin, cisplatin,
irinotecan, topotecan, gemcitabine, liposomal SN-38, bendamustine,
temozolomide, belotecan, NK012, FR901228, flavopiridol); tyrosine
kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib, gefitinib,
cetuximab, panitumumab); multikinase inhibitor (e.g., sorafenib,
sunitinib); VEGF inhibitor (e.g., bevacizumab, vandetanib); cancer
vaccine (e.g., GVAX); Bcl-2 inhibitor (e.g., oblimersen sodium,
ABT-263); proteasome inhibitor (e.g., bortezomib (Velcade),
NPI-0052), paclitaxel or a paclitaxel agent; docetaxel; IGF-1
receptor inhibitor (e.g., AMG 479); HGF/SF inhibitor (e.g., AMG
102, MK-0646); chloroquine; Aurora kinase inhibitor (e.g.,
MLN8237); radioimmunotherapy (e.g., TF2); HSP90 inhibitor (e.g.,
tanespimycin, STA-9090); mTOR inhibitor (e.g., everolimus);
Ep-CAM-/CD3-bispecific antibody (e.g., MT110); CK-2 inhibitor
(e.g., CX-4945); HDAC inhibitor (e.g., belinostat); SMO antagonist
(e.g., BMS833923); peptide cancer vaccine, and radiation therapy
(e.g., intensity-modulated radiation therapy (IMRT),
hypofractionated radiotherapy, hypoxia-guided radiotherapy),
surgery, and combinations thereof.
Non-Small Cell Lung Cancer
[0216] Exemplary agents that that can be used conjointly with
compounds disclosed herein to treat non-small cell lung cancer
include, but are not limited to, vinorelbine, cisplatin, docetaxel,
pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal
SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium,
azacitidine, irinotecan, tegafurgimeracil-oteracil potassium,
sapacitabine); tyrosine kinase inhibitor (e.g., EGFR inhibitor
(e.g., erlotinib, gefitinib, cetuximab, panitumumab, necitumumab,
PF-00299804, nimotuzumab, R05083945), MET inhibitor (e.g.,
PF-02341066, ARQ 197), PI3K kinase inhibitor (e.g., XL147,
GDC-0941), Raf/MEK dual kinase inhibitor (e.g., R05126766),
PI3K/mTOR dual kinase inhibitor (e.g., XL765), SRC inhibitor (e.g.,
dasatinib), dual inhibitor (e.g., BIBW 2992, GSK1363089, ZD6474,
AZD0530, AG-013736, lapatinib, MEHD7945A, linifanib), multikinase
inhibitor (e.g., sorafenib, sunitinib, pazopanib, AMG 706, XL184,
MGCD265, BMS-690514, R935788), VEGF inhibitor (e.g., endostar,
endostatin, bevacizumab, cediranib, BIBF 1120, axitinib, tivozanib,
AZD2171), cancer vaccine (e.g., BLP25 liposome vaccine, GVAX,
recombinant DNA and adenovirus expressing L523S protein), Bcl-2
inhibitor (e.g., oblimersen, sodium), proteasome inhibitor (e.g.,
bortezomib, carfilzomib, NPI-0052, ixazomid), paclitaxel or a
paclitaxel agent, docetaxel, IGF-1 receptor inhibitor (e.g.,
cixutumumab, MK-0646, OSI906, CP-751,871, BIIB022),
hydroxychloroquine, HSP90 inhibitor (e.g., tanespimycin, STA-9090,
AUY922, XL888), mTOR inhibitor (e.g., everolimus, temsirolimus,
ridaforolimus), Ep-CAM-/CD3-bispecific antibody (e.g., MT110), CK-2
inhibitor (e.g., CX-4945), HDAC inhibitor (e.g., MS 275, LBH589,
vorinostat, valproic acid, FR901228), DHFR inhibitor (e.g.,
pralatrexate), retinoid (e.g., bexarotene, tretinoin),
antibody-drug conjugate (e.g., SGN-15), bisphosphonate (e.g.,
zoledronic acid), cancer vaccine (e.g., belagenpumatucel-L), low
molecular weight heparin (LMWH) (e.g., tinzaparin, enoxaparin),
GSK1572932A, melatonin, talactoferrin, dimesna, topoisomerase
inhibitor (e.g., amrubicin, etoposide, karenitecin), nelfinavir,
cilengitide, ErbB3 inhibitor (e.g., MM-121, U3-1287), survivin
inhibitor (e.g., YM155, LY2181308), eribulin mesylate, COX-2
inhibitor (e.g., celecoxib), pegfilgrastim, Polo-like kinase 1
inhibitor (e.g., BI 6727), TRAIL receptor 2 (TR-2) agonist (e.g.,
CS-1008), CNGRC peptide-TNF alpha conjugate, dichloroacetate (DCA),
HGF inhibitor (e.g., SCH 900105), SAR240550, PPAR-gamma agonist
(e.g., CS-7017), gamma-secretase inhibitor (e.g., R04929097),
epigenetic therapy (e.g., 5-azacitidine), nitroglycerin, MEK
inhibitor (e.g., AZD6244), cyclin-dependent kinase inhibitor (e.g.,
UCN-01), cholesterol-Fus1, antitubulin agent (e.g., E7389),
farnesyl-OHtransferase inhibitor (e.g., lonafarnib), immunotoxin
(e.g., BB-10901, SS1 (dsFv) PE38), fondaparinux,
vascular-disrupting agent (e.g., A VE8062), PD-L1 inhibitor (e.g.,
MDX-1105, MDX-1106), beta-glucan, NGR-hTNF, EMD 521873, MEK
inhibitor (e.g., GSK1120212), epothilone analog (e.g.,
ixabepilone), kinesin-spindle inhibitor (e.g., 4SC-205), telomere
targeting agent (e.g., KML-001), P70 pathway inhibitor (e.g.,
LY2584702), AKT inhibitor (e.g., MK-2206), angiogenesis inhibitor
(e.g., lenalidomide), Notch signaling inhibitor (e.g., OMP-21M18),
radiation therapy, surgery, and combinations thereof.
Ovarian Cancer
[0217] Exemplary agents that that can be used conjointly with
compounds disclosed herein to treat ovarian cancer include, but are
not limited to, a chemotherapeutic agent (e.g., paclitaxel or a
paclitaxel agent; docetaxel; carboplatin; gemcitabine; doxorubicin;
topotecan; cisplatin; irinotecan, TLK286, ifosfamide, olaparib,
oxaliplatin, melphalan, pemetrexed disodium, SJG-136,
cyclophosphamide, etoposide, decitabine); ghrelin antagonist (e.g.,
AEZS-130), immunotherapy (e.g., APC8024, oregovomab, OPT-821),
tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib),
dual inhibitor (e.g., E7080), multikinase inhibitor (e.g., AZD0530,
JI-101, sorafenib, sunitinib, pazopanib), ON 01910.Na), VEGF
inhibitor (e.g., bevacizumab, BIBF 1120, cediranib, AZD2171), PDGFR
inhibitor (e.g., IMC-303), paclitaxel, topoisomerase inhibitor
(e.g., karenitecin, Irinotecan), HDAC inhibitor (e.g., valproate,
vorinostat), folate receptor inhibitor (e.g., farletuzumab),
angiopoietin inhibitor (e.g., AMG 386), epothilone analog (e.g.,
ixabepilone), proteasome inhibitor (e.g., carfilzomib), IGF-1
receptor inhibitor (e.g., OSI 906, AMG 479), PARP inhibitor (e.g.,
veliparib, AG014699, iniparib, MK-4827), Aurora kinase inhibitor
(e.g., MLN8237, ENMD-2076), angiogenesis inhibitor (e.g.,
lenalidomide), DHFR inhibitor (e.g., pralatrexate),
radioimmunotherapeutic agnet (e.g., Hu3S 193), statin (e.g.,
lovastatin), topoisomerase 1 inhibitor (e.g., NKTR-102), cancer
vaccine (e.g., p53 synthetic long peptides vaccine, autologous
OC-DC vaccine), mTOR inhibitor (e.g., temsirolimus, everolimus),
BCR/ABL inhibitor (e.g., imatinib), ET-A receptor antagonist (e.g.,
ZD4054), TRAIL receptor 2 (TR-2) agonist (e.g., CS-1008), HGF/SF
inhibitor (e.g., AMG 102), EGEN-001, Polo-like kinase 1 inhibitor
(e.g., BI 6727), gamma-secretase inhibitor (e.g., R04929097), Wee-1
inhibitor (e.g., MK-1775), antitubulin agent (e.g., vinorelbine,
E7389), immunotoxin (e.g., denileukin diftitox), SB-485232,
vascular-disrupting agent (e.g., A VE8062), integrin inhibitor
(e.g., EMD 525797), kinesin-spindle inhibitor (e.g., 4SC-205),
revlimid, HER2 inhibitor (e.g., MGAH22), ErrB3 inhibitor (e.g.,
MM-121), radiation therapy; and combinations thereof.
Myeloma
[0218] Exemplary agents that that can be conjointly administered
with compounds disclosed herein to treat myeloma include, but are
not limited to, thalidomide analogs, (e.g., lenalidomide), HSCT
(Cook, R. (2008) J Manag Care Pharm. 14(7 Suppl):19-25), an
anti-TIM-3 antibody (Hallett, W H D et al. (2011) J of American
Society for Blood and Marrow Transplantation 17 (8): 1133-145),
tumor antigen-pulsed dendritic cells, fusions (e.g.,
electrofusions) of tumor cells and dendritic cells, or vaccination
with immunoglobulin idiotype produced by malignant plasma cells
(reviewed in Yi, Q. (2009) Cancer J. 15(6):502-10).
Renal Cell Carcinoma
[0219] Exemplary agents that that can be conjointly administered
with compounds disclosed herein to treat renal cell carcinoma
include, but are not limited to, interleukin-2 or
interferon-.alpha., a targeted agent (e.g., a VEGF inhibitor such
as a monoclonal antibody to VEGF, e.g., bevacizumab (Rini, B. I. et
al. (2010) J. Clin. Oncol. 28(13):2137-2143)); a VEGF tyrosine
kinase inhibitor such as sunitinib, sorafenib, axitinib and
pazopanib (reviewed in Pal S. K. et al. (2014) Clin. Advances in
Hematology & Oncology 12(2):90-99)); an RNAi inhibitor), or an
inhibitor of a downstream mediator of VEGF signaling, e.g., an
inhibitor of the mammalian target of rapamycin (mTOR), e.g.,
everolimus and temsirolimus (Hudes, G. et al. (2007) N. Engl. J.
Med. 356(22):2271-2281, Motzer, R. J. et al. (2008) Lancet 372:
449-456).
Chronic Myelogenous Leukemia
[0220] Exemplary agents that that can be conjointly administered
with compounds disclosed herein to treat chronic myelogenous
leukemia (CML) include, but are not limited to, a chemotherapeutic
(e.g., cytarabine, hydroxyurea, clofarabine, melphalan, thiotepa,
fludarabine, busulfan, etoposide, cordycepin, pentostatin,
capecitabine, azacitidine, cyclophosphamide, cladribine,
topotecan), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor
(e.g., imatinib, nilotinib), a dual inhibitor (e.g., dasatinib,
bosutinib), multikinase inhibitor (e.g., DCC-2036, ponatinib,
sorafenib, sunitinib, RGB-286638)), interferon alfa, steroids,
apoptotic agent (e.g., omacetaxine mepesuccinat), immunotherapy
(e.g., allogeneic CD4+ memory Th1-like T cells/microparticle-bound
anti-CD3/anti-CD28, autologous cytokine induced killer cells (CIK),
AHN-12), CD52 targeting agent (e.g., alemtuzumab), HSP90 inhibitor
(e.g., tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor
(e.g., everolimus), SMO antagonist (e.g., BMS 833923),
ribonucleotide reductase inhibitor (e.g., 3-AP), JAK-2 inhibitor
(e.g., INCB018424), hydroxychloroquine, retinoid (e.g.,
fenretinide), cyclin-dependent kinase inhibitor (e.g., UCN-01),
HDAC inhibitor (e.g., belinostat, vorinostat, JNJ-26481585), PARP
inhibitor (e.g., veliparib), MDM2 antagonist (e.g., R05045337),
Aurora B kinase inhibitor (e.g., TAK-901), radioimmunotherapy
(e.g., actinium-225-labeled anti-CD33 antibody HuM195), Hedgehog
inhibitor (e.g., PF-04449913), STAT3 inhibitor (e.g., OPB-31121),
KB004, cancer vaccine (e.g., AG858), bone marrow transplantation,
stem cell transplantation, radiation therapy, and combinations
thereof.
Chronic Lymphocyic Leukemia
[0221] Exemplary agents that that can be conjointly administered
with compounds disclosed herein to treat chronic lymphocyic
leukemia (CLL) include, but are not limited to, a chemotherapeutic
agent (e.g., fludarabine, cyclophosphamide, doxorubicin,
vincristine, chlorambucil, bendamustine, chlorambucil, busulfan,
gemcitabine, melphalan, pentostatin, mitoxantrone, 5-azacytidine,
pemetrexed disodium), tyrosine kinase inhibitor (e.g., EGFR
inhibitor (e.g., erlotinib), BTK inhibitor (e.g., PCI-32765),
multikinase inhibitor (e.g., MGCD265, RGB-286638), CD-20 targeting
agent (e.g., rituximab, ofatumumab, R05072759, LFB-R603), CD52
targeting agent (e.g., alemtuzumab), prednisolone, darbepoetin
alfa, lenalidomide, Bcl-2 inhibitor (e.g., ABT-263), immunotherapy
(e.g., allogeneic CD4+ memory Th1-like T cells/microparticle-bound
anti-CD3/anti-CD28, autologous cytokine induced killer cells
(CIK)), HDAC inhibitor (e.g., vorinostat, valproic acid, LBH589,
JNJ-26481585, AR-42), XIAP inhibitor (e.g., AEG35156), CD-74
targeting agent (e.g., milatuzumab), mTOR inhibitor (e.g.,
everolimus), AT-101, immunotoxin (e.g., CAT-8015, anti-Tac(Fv)-PE38
(LMB-2)), CD37 targeting agent (e.g., TRU-5016), radioimmunotherapy
(e.g., 131-tositumomab), hydroxychloroquine, perifosine, SRC
inhibitor (e.g., dasatinib), thalidomide, PI3K delta inhibitor
(e.g., CAL-101), retinoid (e.g., fenretinide), MDM2 antagonist
(e.g., R05045337), plerixafor, Aurora kinase inhibitor (e.g.,
MLN8237, TAK-901), proteasome inhibitor (e.g., bortezomib), CD-19
targeting agent (e.g., MEDI-551, MOR208), MEK inhibitor (e.g.,
ABT-348), JAK-2 inhibitor (e.g., INCB018424), hypoxia-activated
prodrug (e.g., TH-302), paclitaxel or a paclitaxel agent, HSP90
inhibitor, AKT inhibitor (e.g., MK2206), HMG-CoA inhibitor (e.g.,
simvastatin), GNKG 186, radiation therapy, bone marrow
transplantation, stem cell transplantation, and combinations
thereof.
Acute Lymphocyic Leukemia
[0222] Exemplary agents that that can be conjointly administered
with compounds disclosed herein to treat acute lymphocyic leukemia
(ALL) include, but are not limited to, a chemotherapeutic agent
(e.g., prednisolone, dexamethasone, vincristine, asparaginase,
daunorubicin, cyclophosphamide, cytarabine, etoposide, thioguanine,
mercaptopurine, clofarabine, liposomal annamycin, busulfan,
etoposide, capecitabine, decitabine, azacitidine, topotecan,
temozolomide), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor
(e.g., imatinib, nilotinib), ON 01910.Na, multikinase inhibitor
(e.g., sorafenib)), CD-20 targeting agent (e.g., rituximab), CD52
targeting agent (e.g., alemtuzumab), HSP90 inhibitor (e.g.,
STA-9090), mTOR inhibitor (e.g., everolimus, rapamycin), JAK-2
inhibitor (e.g., INCB018424), HER2/neu receptor inhibitor (e.g.,
trastuzumab), proteasome inhibitor (e.g., bortezomib),
methotrexate, asparaginase, CD-22 targeting agent (e.g.,
epratuzumab, inotuzumab), immunotherapy (e.g., autologous cytokine
induced killer cells (CIK), AHN-12), blinatumomab, cyclin-dependent
kinase inhibitor (e.g., UCN-01), CD45 targeting agent (e.g., BC8),
MDM2 antagonist (e.g., R05045337), immunotoxin (e.g., CAT-8015,
DT2219ARL), HDAC inhibitor (e.g., JNJ-26481585), JVRS-100,
paclitaxel or a paclitaxel agent, STAT3 inhibitor (e.g.,
OPB-31121), PARP inhibitor (e.g., veliparib), EZN-2285, bone marrow
transplantation, stem cell transplantation, radiation therapy, and
combinations thereof.
Acute Myeloid Leukemia
[0223] Exemplary agents that that can be conjointly administered
with compounds disclosed herein to treat acute myeloid leukemia
(AML) include, but are not limited to, a chemotherapeutic agent
(e.g., cytarabine, daunorubicin, idarubicin, clofarabine,
decitabine, vosaroxin, azacitidine, clofarabine, ribavirin,
CPX-351, treosulfan, elacytarabine, azacitidine), tyrosine kinase
inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON
01910.Na, multikinase inhibitor (e.g., midostaurin, SU 11248,
quizartinib, sorafinib)), immunotoxin (e.g., gemtuzumab
ozogamicin), DT388IL3 fusion protein, HDAC inhibitor (e.g.,
vorinostat, LBH589), plerixafor, mTOR inhibitor (e.g., everolimus),
SRC inhibitor (e.g., dasatinib), HSP90 inhibitor (e.g., STA-9090),
retinoid (e.g., bexarotene, Aurora kinase inhibitor (e.g., BI
811283), JAK-2 inhibitor (e.g., INCB018424), Polo-like kinase
inhibitor (e.g., BI 6727), cenersen, CD45 targeting agent (e.g.,
BC8), cyclin-dependent kinase inhibitor (e.g., UCN-01), MDM2
antagonist (e.g., R05045337), mTOR inhibitor (e.g., everolimus),
LY573636-sodium, ZRx-101, MLN4924, lenalidomide, immunotherapy
(e.g., AHN-12), histamine dihydrochloride, bone marrow
transplantation, stem cell transplantation, radiation therapy, and
combinations thereof.
Multiple Myeloma
[0224] Exemplary agents that can be conjointly administered with
compounds disclosed herein to treat multiple myeloma include, but
are not limited to, a chemotherapeutic agent (e.g., melphalan,
amifostine, cyclophosphamide, doxorubicin, clofarabine,
bendamustine, fludarabine, adriamycin, SyB L-0501), thalidomide,
lenalidomide, dexamethasone, prednisone, pomalidomide, proteasome
inhibitor (e.g., bortezomib, carfilzomib, ixazomid), cancer vaccine
(e.g., GVAX), CD-40 targeting agent (e.g., SGN-40, CHIR-12.12),
perifosine, zoledronic acid, immunotherapy (e.g., MAGE-A3,
NY-ESO-1, HuMax-CD38), HDAC inhibitor (e.g., vorinostat, LBH589,
AR-42), aplidin, cycline-dependent kinase inhibitor (e.g.,
PD-0332991, dinaciclib), arsenic trioxide, CB3304, HSP90 inhibitor
(e.g., KW-2478), tyrosine kinase inhibitor (e.g., EGFR inhibitor
(e.g., cetuximab), multikinase inhibitor (e.g., AT9283)), VEGF
inhibitor (e.g., bevacizumab), plerixafor, MEK inhibitor (e.g.,
AZD6244), IPH2101, atorvastatin, immunotoxin (e.g., BB-10901),
NPI-0052, radioimmunotherapeutic (e.g., yttrium Y 90 ibritumomab
tiuxetan), STAT3 inhibitor (e.g., OPB-31121), MLN4924, Aurora
kinase inhibitor (e.g., ENMD-2076), IMGN901, ACE-041, CK-2
inhibitor (e.g., CX-4945), bone marrow transplantation, stem cell
transplantation, radiation therapy, and combinations thereof.
Prostate Cancer
[0225] Exemplary agents that can be conjointly administered with
compounds disclosed herein to treat prostrate cancer include, but
are not limited to, a chemotherapeutic agent (e.g., docetaxel,
carboplatin, fludarabine), abiraterone, hormonal therapy (e.g.,
flutamide, bicalutamide, nilutamide, cyproterone acetate,
ketoconazole, aminoglutethimide, abarelix, degarelix, leuprolide,
goserelin, triptorelin, buserelin), tyrosine kinase inhibitor
(e.g., dual kinase inhibitor (e.g., lapatanib), multikinase
inhibitor (e.g., sorafenib, sunitinib)), VEGF inhibitor (e.g.,
bevacizumab), TAK-700, cancer vaccine (e.g., BPX-101, PEP223),
lenalidomide, TOK-001, IGF-1 receptor inhibitor (e.g.,
cixutumumab), TRC105, Aurora A kinase inhibitor (e.g., MLN8237),
proteasome inhibitor (e.g., bortezomib), OGX-011,
radioimmunotherapy (e.g., HuJ591-GS), HDAC inhibitor (e.g.,
valproic acid, SB939, LBH589), hydroxychloroquine, mTOR inhibitor
(e.g., everolimus), dovitinib lactate, diindolylmethane, efavirenz,
OGX-427, genistein, IMC-303, bafetinib, CP-675,206, radiation
therapy, surgery, or a combination thereof.
Hodgkin's Lymphomas
[0226] Exemplary agents that that can be used conjointly with
compounds disclosed herein for the treatment of Hodgkin's lymphomas
include, but are not limited to, chemotherapeutics such as
Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine
(Velban, Velsar), dacarbazine, etoposide (Toposar, VePesid),
cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS,
Oncovin), procarbazine (Matulane), prednisone, Ifosfamide (Ifex),
carboplatin (Paraplatin), Mechlorethamine, Chlorambucil,
methylprenisolone (Solu-Medrol), cytarabine (Cytosar-U), cisplatin
(Platinol), Gemcitabine (Gemzar), vinorelbine (Navelbine),
oxaliplatin (Eloxatin), Lomustine, Mitoxantrone, carmustine,
melphalan, Bendamustine, Lenalidomide, and vinorelbine; either
alone or in combinations; Brentuximab vedotin (Adcetris--a CD30
anti-body drug conjugate); Iodine131-CHT25 antibody conjugate; HDAC
inhibitors (e.g., vorinostat); m-TOR inhibitors (e.g., everolimus,
temsirolimus); PI3K inhibitors (e.g., CAL-101, BAY80-6946,
TGR-1202, BKM-120, AMG-319); JAK/STAT pathway inhibitors; Bcl-2
inhibitors (e.g., venetoclax); Mcl-1 inhibitors; multikinase
inhibitors such as BAY 43-9006 (sorafenib); proteasome inhibitors
(e.g., bortezomib (Velcade), NPI-0052); dual PI3K/HDAC targeted
inhibitors (e.g., CUDC-907); NF-kB inhibitors; anti-PD-1 antibodies
(e.g., nivolumab, pembrolizumab); anti-CTLA-4 antibodies (e.g.,
ipilimumab); anti-CD-20 antibodies (e.g., rituximab); anti-CD40
antibodies; anti-CD80 antibodies; and radiation therapy (e.g.,
tomotherapy, stereotactic radiation, proton therapy), surgery, and
a combination thereof.
Non-Hodgkin's Lymphomas
[0227] Exemplary agents that that can be used conjointly with
compounds disclosed herein for the treatment of Hodgkin's lymphomas
include, but are not limited to, chemotherapeutics such as
Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine
(Velban, Velsar), dacarbazine, etoposide (Toposar, VePesid),
cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS,
Oncovin), procarbazine (Matulane), prednisone, Ifosfamide (Ifex),
carboplatin (Paraplatin), Mechlorethamine, Chlorambucil,
methylprenisolone (Solu-Medrol), cytarabine (Cytosar-U), cisplatin
(Platinol), Gemcitabine (Gemzar), vinorelbine (Navelbine),
oxaliplatin (Eloxatin), Lomustine, Mitoxantrone, methotrexate,
carmustine, melphalan, Bendamustine, Lenalidomide, and vinorelbine;
either alone or in combinations; tyrosine kinase inhibitors (e.g.,
EGFR inhibitor (e.g., erlotinib, panitumumab, cetuximab,
nimotuzumab); HDAC inhibitors (e.g., vorinostat); IRAK-4
inhibitors; HSP90 inhibitors (e.g., tanespimycin, STA-9090,
CUDC-305); m-TOR inhibitors (e.g., everolimus, temsirolimus); PI3K
inhibitors (e.g., CAL-101, BAY80-6946, TGR-1202, BKM-120, AMG-319);
JAK/STAT pathway inhibitors; AKT inhibitors (e.g., RX-0201); Bcl-2
inhibitors (e.g., venetoclax); Mcl-1 inhibitors; multikinase
inhibitors such as BAY 43-9006 (sorafenib); proteasome inhibitors
(e.g., bortezomib (Velcade), NPI-0052); dual PI3K/HDAC targeted
inhibitors (e.g., CUDC-907); NF-kB inhibitors; BTK inhibitors
(e.g., ibrutinib); BET bromodomain inhibitors; anti-PD-1 antibodies
(e.g., nivolumab, pembrolizumab); anti-CTLA-4 antibodies (e.g.,
ipilimumab); anti-CD-20 antibodies (e.g., rituximab); anti-CD40
antibodies; anti-CD80 antibodies; and radiation therapy (e.g.,
tomotherapy, stereotactic radiation, proton therapy), surgery, and
a combination thereof.
[0228] In certain embodiments, a compound of Formula (I) of the
disclosure may be conjointly administered with non-chemical methods
of cancer treatment. In a further embodiment, a compound of Formula
(I) of the disclosure may be conjointly administered with radiation
therapy. In a further embodiment, a compound of Formula (I) of the
disclosure may be conjointly administered with surgery, with
thermoablation, with focused ultrasound therapy, with cryotherapy,
or with any combination of these.
[0229] In certain embodiments, different compounds of the
disclosure may be conjointly administered with one or more other
compounds of the disclosure. Moreover, such combinations may be
conjointly administered with other therapeutic agents, such as
other agents suitable for the treatment of cancer, immunological or
neurological diseases, such as the agents identified above. In
certain embodiments, conjointly administering one or more
additional chemotherapeutic agents with a compound of Formula (I)
of the disclosure provides a synergistic effect. In certain
embodiments, conjointly administering one or more additional
chemotherapeutics agents provides an additive effect.
Pharmaceutical Compositions
[0230] In certain embodiments, the present disclosure provides a
pharmaceutical composition comprising a compound of Formula (I) as
disclosed herein, optionally admixed with a pharmaceutically
acceptable carrier or diluent.
[0231] The present disclosure also provides methods for formulating
the disclosed compounds of Formula (I) for pharmaceutical
administration.
[0232] The compositions and methods of the present disclosure may
be utilized to treat an individual in need thereof. In certain
embodiments, the individual is a mammal such as a human, or a
non-human mammal. When administered to an animal, such as a human,
the composition or the compound is preferably administered as a
pharmaceutical composition comprising, for example, a compound of
Formula (I) of the disclosure and a pharmaceutically acceptable
carrier. Pharmaceutically acceptable carriers are well known in the
art and include, for example, aqueous solutions such as water or
physiologically buffered saline or other solvents or vehicles such
as glycols, glycerol, oils such as olive oil, or injectable organic
esters. In a preferred embodiment, when such pharmaceutical
compositions are for human administration, particularly for
invasive routes of administration (i.e., routes, such as injection
or implantation, that circumvent transport or diffusion through an
epithelial barrier), the aqueous solution is pyrogen-free, or
substantially pyrogen-free. The excipients can be chosen, for
example, to effect delayed release of an agent or to selectively
target one or more cells, tissues or organs. The pharmaceutical
composition can be in dosage unit form such as tablet, capsule
(including sprinkle capsule and gelatin capsule), granule, lyophile
for reconstitution, powder, solution, syrup, suppository, injection
or the like. The composition can also be present in a transdermal
delivery system, e.g., a skin patch. The composition can also be
present in a solution suitable for topical administration, such as
an eye drop.
[0233] A pharmaceutically acceptable carrier can contain
physiologically acceptable agents that act, for example, to
stabilize, increase solubility or to increase the absorption of a
compound such as a compound of Formula (I) of the disclosure. Such
physiologically acceptable agents include, for example,
carbohydrates, such as glucose, sucrose or dextrans, antioxidants,
such as ascorbic acid or glutathione, chelating agents, low
molecular weight proteins or other stabilizers or excipients. The
choice of a pharmaceutically acceptable carrier, including a
physiologically acceptable agent, depends, for example, on the
route of administration of the composition. The preparation of
pharmaceutical composition can be a self-emulsifying drug delivery
system or a self-microemulsifying drug delivery system. The
pharmaceutical composition (preparation) also can be a liposome or
other polymer matrix, which can have incorporated therein, for
example, a compound of Formula (I) of the disclosure. Liposomes,
for example, which comprise phospholipids or other lipids, are
nontoxic, physiologically acceptable and metabolizable carriers
that are relatively simple to make and administer.
[0234] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0235] The phrase "pharmaceutically acceptable carrier" as used
herein means a pharmaceutically acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material. Each carrier must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as pharmaceutically
acceptable carriers include: (1) sugars, such as lactose, glucose
and sucrose; (2) starches, such as corn starch and potato starch;
(3) cellulose, and its derivatives, such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; (4) powdered
tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such
as cocoa butter and suppository waxes; (9) oils, such as peanut
oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil
and soybean oil; (10) glycols, such as propylene glycol; (11)
polyols, such as glycerin, sorbitol, mannitol and polyethylene
glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13)
agar; (14) buffering agents, such as magnesium hydroxide and
aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water;
(17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol;
(20) phosphate buffer solutions; and (21) other non-toxic
compatible substances employed in pharmaceutical formulations.
[0236] A pharmaceutical composition (preparation) can be
administered to a subject by any of a number of routes of
administration including, for example, orally (for example,
drenches as in aqueous or non-aqueous solutions or suspensions,
tablets, capsules (including sprinkle capsules and gelatin
capsules), boluses, powders, granules, pastes for application to
the tongue); absorption through the oral mucosa (e.g.,
sublingually); anally, rectally or vaginally (for example, as a
pessary, cream or foam); parenterally (including intramuscularly,
intravenously, subcutaneously or intrathecally as, for example, a
sterile solution or suspension); nasally; intraperitoneally;
subcutaneously; transdermally (for example as a patch applied to
the skin); and topically (for example, as a cream, ointment or
spray applied to the skin, or as an eye drop). The compound may
also be formulated for inhalation. In certain embodiments, a
compound may be simply dissolved or suspended in sterile water.
Details of appropriate routes of administration and compositions
suitable for same can be found in, for example, U.S. Pat. Nos.
6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970
and 4,172,896, as well as in patents cited therein.
[0237] The formulations may conveniently be presented in unit
dosage form and may be prepared by any methods well known in the
art of pharmacy. The amount of active ingredient which can be
combined with a carrier material to produce a single dosage form
will vary depending upon the host being treated, the particular
mode of administration. The amount of active ingredient that can be
combined with a carrier material to produce a single dosage form
will generally be that amount of the compound which produces a
therapeutic effect. Generally, out of one hundred percent, this
amount will range from about 1 percent to about ninety-nine percent
of active ingredient, preferably from about 5 percent to about 70
percent, most preferably from about 10 percent to about 30
percent.
[0238] Methods of preparing these formulations or compositions
include the step of bringing into association an active compound,
such as a compound of Formula (I) of the disclosure, with the
carrier and, optionally, one or more accessory ingredients. In
general, the formulations are prepared by uniformly and intimately
bringing into association a compound of the present disclosure with
liquid carriers, or finely divided solid carriers, or both, and
then, if necessary, shaping the product.
[0239] Formulations of the disclosure suitable for oral
administration may be in the form of capsules (including sprinkle
capsules and gelatin capsules), cachets, pills, tablets, lozenges
(using a flavored basis, usually sucrose and acacia or tragacanth),
lyophile, powders, granules, or as a solution or a suspension in an
aqueous or non-aqueous liquid, or as an oil-in-water or
water-in-oil liquid emulsion, or as an elixir or syrup, or as
pastilles (using an inert base, such as gelatin and glycerin, or
sucrose and acacia) and/or as mouth washes and the like, each
containing a predetermined amount of a compound of the present
disclosure as an active ingredient. Compositions or compounds may
also be administered as a bolus, electuary or paste.
[0240] To prepare solid dosage forms for oral administration
(capsules (including sprinkle capsules and gelatin capsules),
tablets, pills, dragees, powders, granules and the like), the
active ingredient is mixed with one or more pharmaceutically
acceptable carriers, such as sodium citrate or dicalcium phosphate,
and/or any of the following: (1) fillers or extenders, such as
starches, lactose, sucrose, glucose, mannitol, and/or silicic acid;
(2) binders, such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia;
(3) humectants, such as glycerol; (4) disintegrating agents, such
as agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate; (5) solution
retarding agents, such as paraffin; (6) absorption accelerators,
such as quaternary ammonium compounds; (7) wetting agents, such as,
for example, cetyl alcohol and glycerol monostearate; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
a talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof; (10)
complexing agents, such as, modified and unmodified cyclodextrins;
and (11) coloring agents. In the case of capsules (including
sprinkle capsules and gelatin capsules), tablets and pills, the
pharmaceutical compositions may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
[0241] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0242] The tablets, and other solid dosage forms of the
pharmaceutical compositions, such as dragees, capsules (including
sprinkle capsules and gelatin capsules), pills and granules, may
optionally be scored or prepared with coatings and shells, such as
enteric coatings and other coatings well known in the
pharmaceutical-formulating art. They may also be formulated so as
to provide slow or controlled release of the active ingredient
therein using, for example, hydroxypropylmethyl cellulose in
varying proportions to provide the desired release profile, other
polymer matrices, liposomes and/or microspheres. They may be
sterilized by, for example, filtration through a bacteria-retaining
filter, or by incorporating sterilizing agents in the form of
sterile solid compositions that can be dissolved in sterile water,
or some other sterile injectable medium immediately before use.
These compositions may also optionally contain opacifying agents
and may be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain portion of the
gastrointestinal tract, optionally, in a delayed manner. Examples
of embedding compositions that can be used include polymeric
substances and waxes. The active ingredient can also be in
micro-encapsulated form, if appropriate, with one or more of the
above-described excipients.
[0243] Liquid dosage forms useful for oral administration include
pharmaceutically acceptable emulsions, lyophiles for
reconstitution, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active ingredient, the liquid dosage
forms may contain inert diluents commonly used in the art, such as,
for example, water or other solvents, cyclodextrins and derivatives
thereof, solubilizing agents and emulsifiers, such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
oils (in particular, cottonseed, groundnut, corn, germ, olive,
castor and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and
mixtures thereof.
[0244] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0245] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0246] Formulations of the pharmaceutical compositions for rectal,
vaginal, or urethral administration may be presented as a
suppository, which may be prepared by mixing one or more active
compounds with one or more suitable nonirritating excipients or
carriers comprising, for example, cocoa butter, polyethylene
glycol, a suppository wax or a salicylate, and which is solid at
room temperature, but liquid at body temperature and, therefore,
will melt in the rectum or vaginal cavity and release the active
compound.
[0247] Formulations of the pharmaceutical compositions for
administration to the mouth may be presented as a mouthwash, or an
oral spray, or an oral ointment.
[0248] Alternatively or additionally, compositions can be
formulated for delivery via a catheter, stent, wire, or other
intraluminal device. Delivery via such devices may be especially
useful for delivery to the bladder, urethra, ureter, rectum, or
intestine.
[0249] Formulations which are suitable for vaginal administration
also include pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing such carriers as are known in the art
to be appropriate.
[0250] Dosage forms for the topical or transdermal administration
include powders, sprays, ointments, pastes, creams, lotions, gels,
solutions, patches and inhalants. The active compound may be mixed
under sterile conditions with a pharmaceutically acceptable
carrier, and with any preservatives, buffers, or propellants that
may be required.
[0251] The ointments, pastes, creams and gels may contain, in
addition to an active compound, excipients, such as animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0252] Powders and sprays can contain, in addition to an active
compound, excipients such as lactose, talc, silicic acid, aluminum
hydroxide, calcium silicates and polyamide powder, or mixtures of
these substances. Sprays can additionally contain customary
propellants, such as chlorofluorohydrocarbons and volatile
unsubstituted hydrocarbons, such as butane and propane.
[0253] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present disclosure to the
body. Such dosage forms can be made by dissolving or dispersing the
active compound in the proper medium. Absorption enhancers can also
be used to increase the flux of the compound across the skin. The
rate of such flux can be controlled by either providing a rate
controlling membrane or dispersing the compound in a polymer matrix
or gel.
[0254] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this disclosure. Exemplary ophthalmic formulations are described in
U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and
2005/004074 and U.S. Pat. No. 6,583,124, the contents of which are
incorporated herein by reference in its entirety. If desired,
liquid ophthalmic formulations have properties similar to that of
lacrimal fluids, aqueous humor or vitreous humor or are compatible
with such fluids. A preferred route of administration is local
administration (e.g., topical administration, such as eye drops, or
administration via an implant).
[0255] A suppository also is contemplated as being within the scope
of this disclosure.
[0256] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0257] Pharmaceutical compositions suitable for parenteral
administration comprise one or more active compounds in combination
with one or more pharmaceutically acceptable sterile isotonic
aqueous or nonaqueous solutions, dispersions, suspensions or
emulsions, or sterile powders which may be reconstituted into
sterile injectable solutions or dispersions just prior to use,
which may contain antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0258] Examples of suitable aqueous and nonaqueous carriers that
may be employed in the pharmaceutical compositions of the
disclosure include water, ethanol, polyols (such as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable
mixtures thereof, vegetable oils, such as olive oil, and injectable
organic esters, such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of coating materials, such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0259] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents that delay
absorption such as aluminum monostearate and gelatin.
[0260] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution, which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0261] Injectable depot forms are made by forming microencapsulated
matrices of the subject compounds in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions that are
compatible with body tissue.
[0262] For use in the methods of this disclosure, active compounds
can be given per se or as a pharmaceutical composition containing,
for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active
ingredient in combination with a pharmaceutically acceptable
carrier.
[0263] Methods of introduction may also be provided by rechargeable
or biodegradable devices. Various slow release polymeric devices
have been developed and tested in vivo in recent years for the
controlled delivery of drugs, including proteinaceous
biopharmaceuticals. A variety of biocompatible polymers (including
hydrogels), including both biodegradable and non-degradable
polymers, can be used to form an implant for the sustained release
of a compound at a particular target site.
[0264] Actual dosage levels of the active ingredients in the
pharmaceutical compositions may be varied so as to obtain an amount
of the active ingredient that is effective to achieve the desired
therapeutic response for a particular patient, composition, and
mode of administration, without being toxic to the patient.
[0265] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound or
combination of compounds employed, or the ester, salt or amide
thereof, the route of administration, the time of administration,
the rate of excretion of the particular compound(s) being employed,
the duration of the treatment, other drugs, compounds and/or
materials used in combination with the particular compound(s)
employed, the age, sex, weight, condition, general health and prior
medical history of the patient being treated, and like factors well
known in the medical arts.
[0266] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the therapeutically effective
amount of the pharmaceutical composition required. For example, the
physician or veterinarian could start doses of the pharmaceutical
composition or compound at levels lower than that required in order
to achieve the desired therapeutic effect and gradually increase
the dosage until the desired effect is achieved. By
"therapeutically effective amount" is meant the concentration of a
compound that is sufficient to elicit the desired therapeutic
effect. It is generally understood that the effective amount of the
compound will vary according to the weight, sex, age, and medical
history of the subject. Other factors which influence the effective
amount may include, but are not limited to, the severity of the
patient's condition, the disorder being treated, the stability of
the compound, and, if desired, another type of therapeutic agent
being administered with the compound of Formula (I) of the
disclosure. A larger total dose can be delivered by multiple
administrations of the agent. Methods to determine efficacy and
dosage are known to those skilled in the art (Isselbacher et al.
(1996) Harrison's Principles of Internal Medicine 13 ed.,
1814-1882, herein incorporated by reference).
[0267] In general, a suitable daily dose of an active compound used
in the compositions and methods of the disclosure will be that
amount of the compound that is the lowest dose effective to produce
a therapeutic effect. Such an effective dose will generally depend
upon the factors described above.
[0268] If desired, the effective daily dose of the active compound
may be administered as one, two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms. In certain
embodiments of the present disclosure, the active compound may be
administered two or three times daily. In preferred embodiments,
the active compound will be administered once daily.
[0269] The patient receiving this treatment is any animal in need,
including primates, in particular humans, and other mammals such as
equines, cattle, swine and sheep; and poultry and pets in
general.
[0270] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0271] Examples of pharmaceutically acceptable antioxidants
include: (1) water-soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal-chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
Definitions and Abbreviations
[0272] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning and the meaning of such terms is
independent at each occurrence thereof and is as commonly
understood by one of skill in art to which the subject matter
herein belongs. That notwithstanding and except where stated
otherwise, the following definitions apply throughout the
specification and claims. Chemical names, common names and chemical
structures may be used interchangeably to describe the same
structure. If a chemical compound is referred to using both a
chemical structure and a chemical name and an ambiguity exists
between the structure and the name, the structure predominates.
These definitions apply regardless of whether a term is used by
itself or in combination with other terms, unless otherwise
indicated. Hence, the definition of "alkyl" applies to "alkyl" as
well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl,"
"--O-alkyl," etc.
[0273] The term "compound(s) of the present invention", unless
otherwise specifically stated, comprises compounds of formula (I)
or formula (IA) or formula (IB) or a pharmaceutical acceptable salt
thereof and stereoisomers thereof.
[0274] As used herein, the terms "optional" or "optionally" mean
that the subsequently described event or circumstance may occur or
may not occur and that the description includes instances where the
event or circumstance occurs as well as instances in which it does
not. For example, "optionally substituted alkyl" refers to the
event or circumstance where alkyl is substituted as well as the
event or circumstance where the alkyl is not substituted.
[0275] The term "substituted", unless the substituents are
specifically mentioned, refers to moieties having substituents
replacing hydrogen on one or more carbons of the backbone. It will
be understood that "substitution" or "substituted with" includes
the implicit proviso that such substitution is in accordance with
permitted valence of the substituted atom and the substituent and
that the substitution results in a stable compound, e.g., which
does not spontaneously undergo transformation such as by
rearrangement, cyclization, elimination, etc. As used herein, the
term "substituted" is contemplated to include all permissible
substituents of organic compounds. In a broad aspect, the
permissible substituents include acyclic and cyclic, branched and
unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic
substituents of organic compounds. The permissible substituents can
be one or more and the same or different for appropriate organic
compounds. For purposes of this invention, the heteroatoms such as
nitrogen may have hydrogen substituents and/or any permissible
substituents of organic compounds described herein which satisfy
the valences of the heteroatoms. Substituents can include any
substituents described herein, for example, a halogen, a hydroxyl,
a carbonyl (such as a carboxyl, an alkoxyl, an oxo, an amino, an
amido, an amidine, a nitro, an azido, a heteroaryl, an aralkyl or
an aromatic or heteroaromatic moiety. It will be understood by
those skilled in the art that substituents can themselves be
substituted, if appropriate.
[0276] As used herein, the term "alkyl" refers to saturated
aliphatic groups, including but not limited to C.sub.1-C.sub.1o
straight-chain alkyl groups or C.sub.3-C.sub.10 branched-chain
alkyl groups. Preferably, the "alkyl" group refers to
C.sub.1-C.sub.6 straight-chain alkyl groups or C.sub.3-C.sub.6
branched-chain alkyl groups. Most preferably, the "alkyl" group
refers to C.sub.1-C.sub.4 straight-chain alkyl groups or
C.sub.3-C.sub.8 branched-chain alkyl groups. Examples of "alkyl"
include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,
n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl,
neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl,
3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl and 4-octyl. The
"alkyl" group may be optionally substituted.
[0277] The term "aryl" as used herein include substituted or
unsubstituted single-ring aromatic groups in which each atom of the
ring is carbon. Preferably the ring is a 5- to 7-membered ring,
more preferably a 6-membered ring. Particularly, the term `aryl`
includes phenyl.
[0278] As used herein, the expression "(p-OH)aryl" means aryl group
which is para-substituted with hydroxyl (--OH) group, wherein the
aryl group is as defined above.
[0279] The term "heteroaryl" includes substituted or unsubstituted
aromatic single ring structures, preferably 5- to 7-membered rings,
more preferably 5- to 6-membered rings, whose ring structures
include at least one heteroatom, preferably one to four
heteroatoms, more preferably one or two heteroatoms. Particularly,
the term `heteroaryl` includes imidazole. A heteroaryl group may be
substituted at one or more positions, as permitted by valence, with
any optional substituents described herein.
[0280] As used herein, the term "aralkyl" includes an aryl group
substituted with alkyl radical(s) by replacing one or more hydrogen
atom(s).
[0281] As used herein, the term "aryloxy" refers to the group
--O-aryl, where aryl group is as defined above.
[0282] As used herein, the term "heteroarylalkyl" refers to a alkyl
group, attached to heteroaryl group, wherein `alkyl` and
`heteroaryl` groups are as defined above.
[0283] As used herein, a therapeutic that "prevents" a disorder or
condition refers to a compound that, in a statistical sample,
reduces the occurrence of the disorder or condition in the treated
sample relative to an untreated control sample or delays the onset
or reduces the severity of one or more symptoms of the disorder or
condition relative to the untreated control sample.
[0284] The term "treating" includes prophylactic and/or therapeutic
treatments. The term "prophylactic or therapeutic" treatment is
art-recognized and includes administration to the host of one or
more of the subject compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or
other unwanted state of the host animal) then the treatment is
prophylactic (i.e., it protects the host against developing the
unwanted condition), whereas if it is administered after
manifestation of the unwanted condition, the treatment is
therapeutic, (i.e., it is intended to diminish, ameliorate or
stabilize the existing unwanted condition or side effects
thereof).
[0285] The term "prodrug" is intended to encompass compounds which,
under physiologic conditions, are converted into the
therapeutically active agents of the present invention (e.g., a
compound of formula (I)). A common method for making a prodrug is
to include one or more selected moieties which are hydrolyzed under
physiologic conditions to reveal the desired molecule. In other
embodiments, the prodrug is converted by an enzymatic activity of
the host animal. For example, esters or carbonates (e.g., esters or
carbonates of alcohols or carboxylic acids) are preferred prodrugs
of the present invention. In certain embodiments, some or all of
the compounds of formula (I) in a formulation represented above can
be replaced with the corresponding suitable prodrug, e.g., wherein
a hydroxyl in the parent compound is presented as an ester or a
carbonate or carboxylic acid present in the parent compound is
presented as an ester.
[0286] As used herein, the term "comprise" or "comprising" is
generally used in the sense of include, that is to say permitting
the presence of one or more additional (unspecified) features or
components.
[0287] As used herein, the term "including" as well as other forms,
such as "include", "includes," and "included," is not limiting.
[0288] Throughout this specification and claims, the `L-threonine
residue` structurally mentioned in compounds of the present
invention and/or preparation thereof can be represented by any one
of the following formulae. This representation may be interpreted
to other compounds having similar structural motifs.
##STR00048##
[0289] This invention includes pharmaceutically acceptable salts of
compounds of the invention and their use in the compositions and
methods of the present invention. In certain embodiments,
contemplated salts of the invention include, but are not limited
to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In
certain embodiments, contemplated salts of the invention include,
but are not limited to, L-arginine, benenthamine, benzathine,
betaine, calcium hydroxide, choline, deanol, diethanolamine,
diethylamine, 2-(diethylamino)ethanol, ethanolamine,
ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole,
lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine,
piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium,
triethanolamine, tromethamine and zinc salts. In certain
embodiments, contemplated salts of the invention include, but are
not limited to, Na, Ca, K, Mg, Zn or other metal salts.
[0290] The pharmaceutically acceptable acid addition salts can also
exist as various solvates, such as with water, methanol, ethanol,
dimethylformamide and the like. Mixtures of such solvates can also
be prepared. The source of such solvate can be from the solvent of
crystallization, inherent in the solvent of preparation or
crystallization or adventitious to such solvent.
[0291] The term "stereoisomers" refers to any enantiomers,
diastereoisomers or geometrical isomers, such as of the compounds
of the invention. When compounds of the invention are chiral, they
can exist in racemic or in optically active form. Since the
pharmaceutical activity of the racemates or stereoisomers of the
compounds according to the invention may differ, it may be
desirable to use compounds that are enriched in one of the
enantiomers. In these cases, the end product or even the
intermediates can be separated into enantiomeric compounds by
chemical or physical measures known to the person skilled in the
art or even employed as such in the synthesis. In the case of
racemic amines, diastereomers are formed from the mixture by
reaction with an optically active resolving agent. Examples of
suitable resolving agents are optically active acids such as the R
and S forms of tartaric acid, diacetyltartaric acid,
dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid,
suitable N-protected amino acids (for example N-benzoylproline or
N-benzenesulfonylproline) or the various optically active
camphorsulfonic acids. Also advantageous is chromatographic
enantiomer resolution with the aid of an optically active resolving
agent (for example dinitrobenzoylphenylglycine, cellulose
triacetate or other derivatives of carbohydrates or chirally
derivatised methacrylate polymers immobilised on silica gel).
[0292] In certain embodiments, compounds of the invention may be
racemic. In certain embodiments, compounds of the invention may be
enriched in one enantiomer. For example, a compound of the
invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70%
ee, 80% ee, 90% ee or even 95% or greater ee. In certain
embodiments, compounds of the invention may have more than one
stereocenter. In certain such embodiments, compounds of the
invention may be enriched in one or more diastereomer. For example,
a compound of the invention may have greater than 30% de, 40% de,
50% de, 60% de, 70% de, 80% de, 90% de or even 95% or greater
de.
[0293] The term "subject" includes mammals (especially humans) and
other animals, such as domestic animals (e.g., household pets
including cats and dogs) and non-domestic animals (such as
wildlife).
[0294] The abbreviations used in the entire specification may be
summarized herein below with their particular meaning.
[0295] .degree. C. (degree Celsius); % (percentage); brine (NaCl
solution); Boc (Tert-butyloxycarbonyl); DIC:
N,N'-Diisopropylcarbodiimide; DIPEA (N,N-Diisopropylethylamine);
DMF (Dimethyl formamide); EtOH (Ethanol); EtOAc (Ethyl Acetate);
Fmoc (9-Fluorenylmethyloxycarbonyl); g or gr (gram); HOBt
(1-Hydroxy benzotriazole); h or hr (Hours); HPLC (High-performance
liquid chromatography); LCMS (Liquid chromatography mass
spectroscopy); mmol (Millimoles); M (Molar); .mu.l (Microlitre); mL
(Millilitre); mg (Milligram); min (Minutes); NaHCO.sub.3 (Sodium
bicarbonate); NMM (N-Methylmorpholine); Na.sub.2SO.sub.4 (Sodium
sulphate); NH.sub.2OH.HCl (Hydroxylamine hydrochloride);
prep-HPLC/preparative HPLC (Preparative High-performance liquid
chromatography); TEA/Et.sub.3N (Triethylamine); TLC (Thin Layer
Chromatography); THF (Tetrahydrofuran); TIPS (Triisopropylsilane);
t.sub.R (Retention time); etc.
EXPERIMENTAL
Analytical HPLC Methods:
Method-1: Hilic Method
Column: ZIC-HILLIC (Sequant), C18 (4.6.times.250 mm, 5 .mu.m)
200A.degree.
[0296] Flow: 1.0 mL/min; Column Temp: 25.0.degree. C. Mobile phase:
A=5 mM Ammonium Acetate PH-4.0 (Acetic Acid), B=ACN
Gradient (Time/% B): 0/85, 2/85, 20/40, 20.1/85, 30/85.
Method 2: DiBoc Method
[0297] Column: PhenomenexAeris peptide C18 (2) 100A (250.times.4.6
mm, 3.6.mu.) Flow: 1.0 mL/min; Column Temp: 25.0.degree. C.
Mobile Phase: A=0.1% TFA (Aq), B=ACN
Gradient (Time/% B): 0/2, 2/2, 15/70, 20/95, 25/100, 30/100, 32/2,
42/2
Preparative HPLC Method:
[0298] Preparative HPLC was performed on SeQuant ZIC HILIC 200
A.degree.column (10 mm.times.250 mm, 5 .mu.m), Flow rate: 5.0
mL/min. The elution conditions used are: Buffer A: 5 mmol ammonium
acetate (adjust to pH-4 with Acetic Acid), Buffer B: Acetonitrile,
Equilibration of the column with 90% buffer B and elution by a
gradient of 90% to 40% buffer B during 20 min.
[0299] LCMS was performed on AP1 2000 LC/MS/MS triple quad (Applied
biosystems) with Agilent 1100 series HPLC with G1315 B DAD, using
Mercury MS column or using Agilent LC/MSD VL single quad with
Agilent 1100 series HPLC with G1315 B DAD, using Mercury MS column
or using Shimadzu LCMS 2020 single quad with Prominence UFLC system
with SPD-20 A DAD.
Example 1:
((S)-2-(3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-1,2,4-oxadiazo-
l-5-yl)pyrrolidine-1-carbonyl)-L-aspartic acid (Compound 1)
##STR00049##
[0300] Step 1a: Synthesis of Compound 1b
##STR00050##
[0302] Ethylchloroformate (4.8 g, 44.4 mmol) and NMM (4.5 g, 44.4
mmol) were added to a solution of compound 1a (10.0 g, 29.63 mmol)
in THF (120 mL) and stirred at -20.degree. C. for 20 min. After 20
minutes, 25% of aqueous ammonia (30 mL) was added to the active
mixed anhydride and stirred at 0-5.degree. C. for 30 min. The
completeness of the reaction was confirmed by TLC analysis. The
volatiles were evaporated under reduced pressure and partitioned
between water and ethyl acetate. The organic layer was washed with
NaHCO.sub.3 solution followed by citric acid solution and brine
solution. The separated organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
yield 8.9 g of compound 1b. LCMS: 337.4 [M+H].sup.+.
Step 1b: Synthesis of Compound 1c
##STR00051##
[0304] Trifluroacetic anhydride (TFAA) (14.2 g, 67.77 mmol) was
added to a solution of compound 1b (7.6 g, 22.59 mmol) in pyridine
(9.92 mL, 112.96 mmol) and stirred at room temperature for 2 h. The
completion of the reaction was confirmed by TLC analysis. The
volatiles were evaporated under reduced pressure and partitioned
between water and ethyl acetate. The organic layer was washed with
NaHCO.sub.3 solution followed by citric acid and brine solution.
The separated organic layer was dried over Na.sub.2SO.sub.4,
filtered and evaporated under reduced pressure to yield 5.5 g of
compound 1c, which was used for next step directly.
Step 1c: Synthesis of Compound 1d
##STR00052##
[0306] Hydroxylamine hydrochloride (1.62 g, 23.56 mmol), water (9.4
mL) and potassium carbonate (2.17 g, 15.7 mmol) were added to a
solution of compound 1c (2.5 g, 7.8 mmol) in EtOH (28 mL) and
stirred at 86.degree. C. for 4 h. The completion of the reaction
was confirmed by TLC analysis. The volatiles were evaporated under
reduced pressure and partitioned between water and ethyl acetate.
The organic layer was washed with brine solution, dried over
Na.sub.2SO.sub.4 then filtered and evaporated under reduced
pressure to yield 2.4 g of compound 1d. LCMS: 351.8
[M+H].sup.+.
Step-1d: Synthesis of Compound 1e
##STR00053##
[0308] To a solution of Fmoc-Pro-OH (1.5 g, 4.5 mmol) in DMF (20
mL) were added HOBt (1.92 g, 14.23 mmol) and DIC (1.8 g, 14.23
mmol) at 0.degree. C. and stirred for 15 min. Then compound 1d (2
g, 5.7 mmol) was added at the same temperature and continued
stirring for 1 h and then at room temperature for 2 h. The
completion of the reaction was confirmed by TLC analysis. The
reaction mixture was quenched with ice water, the precipitated
white solid was filtered, washed with water (150 mL) and dried
under high reduced pressure. The solid was stirred with diethyl
ether (250 mL) for 15 min, filtered and dried to yield 3.2 g of
compound 1e. LCMS: 671.1 [M+H]+.
Step 1e: Synthesis of Compound 1f
##STR00054##
[0310] To a solution of compound 1e (3.2 g, 4.7 mmol) in
acetonitrile (30 ml) was added acetic acid (3.2 mL) at room
temperature and refluxed at 90.degree. C. for 12 h. The completion
of the reaction was confirmed by TLC analysis. The volatiles were
evaporated under reduced pressure to obtain crude semi solid which
was diluted with water and ethyl acetate. The organic layer was
washed with NaHCO.sub.3 solution followed by citric acid and brine
solution. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and evaporated under reduced pressure to get crude solid
which was diluted with 10% acetonitrile in hexane (50 ml) and
stirred for 2 h to afford white solid. The obtained white solid was
filtered and washed with n-pentane (50 mL) and dried to yield 0.9 g
of compound 1f. LCMS: 653.4 [M+H].sup.+.
Step 1f: Synthesis of Compound 1g
##STR00055##
[0312] To a solution of 20% piperidine in DCM (15 mL) was added
compound if (1.2 g, 1.83 mmol) at 0.degree. C. and stirred at same
temperature for 1 h. The completion of the reaction was confirmed
by TLC analysis. The reaction mixture was concentrated under
reduced pressure and diluted with hexane, stirred and filtered. The
filtered solid was dissolved in EtOAc and washed with sat.
NaHCO.sub.3 solution, brine solution, dried over Na.sub.2SO.sub.4
filtered and evaporated to yield 0.65 g of compound 1g. LCMS 431.1
[M+H].sup.+.
Step 1g: Synthesis of Compound 1i
##STR00056##
[0314] DIPEA (0.19 g, 1.5 mmol) was added to a solution of compound
1h (0.74 g, 1.81 mmol, prepared as per the procedure given below)
and compound 1g (0.65 g, 1.5 mmol) in EtOH (10 mL) was stirred at
RT for 3 h. The volatiles were evaporated and partitioned between
ethyl acetate and water. The organic layer was washed with
saturated NaHCO.sub.310% citric acid, brine solution, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude
compound was purified by column chromatography over neutral alumina
using 25% ethyl acetate in hexane to yield 0.75 g compound 1i.
LCMS: 702.4 [M+H].sup.+.
Step 1h: Synthesis of Compound 1
##STR00057##
[0316] A solution of compound 1i (0.75 g, 1.06 mmol) was added 7.5
mL of cocktail mixture of and trifluoroacetic:TIPS:water
(95:2.5:2.5) and was stirred at RT for 2 h. The resulting reaction
mixture was evaporated under reduced pressure, diluted with diethyl
ether and filtered to yield 0.4 g of crude compound 1. The crude
solid material was purified by preparative HPLC method described
under experimental conditions. LCMS: 434.3 [M+H].sup.+. HPLC RT
(min): 11.1
Synthesis of Compound 1h:
##STR00058##
[0318] To a solution of H-Asp(O'Bu)-O'Bu (1.0 g, 3.54 mmol) in
CH.sub.2Cl.sub.2 (20 mL) was added pyridine (0.55 g, 7.08 mmol) and
the solution was stirred at room temperature for 10 min. To this
mixture was added a solution of 4-nitrophenyl chloroformate (0.86
g, 4.25 mmol) in CH.sub.2Cl.sub.2 (20 mL) and the resultant mixture
was stirred at room temperature for 1 h. After completion of
reaction (confirmed by TLC) it was diluted with CH.sub.2Cl.sub.2
(50 mL) and washed with 1.0 M of sodium bisulphate solution (50
mL.times.2) followed by 1.0 M sodium carbonate solution (50
mL.times.2). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and evaporated under reduced pressure to yield crude
compound 1h, which was purified by silica gel column chromatography
(eluent: 0-20% ethyl acetate in hexane) and yields 0.75 g of
compound.
[0319] The below compounds were prepared by procedure similar to
the one described in Example 1 (compound 1) with appropriate
variations in reactants, quantities of reagents, solvents and
reaction conditions. The characterization data of the compounds are
summarized herein below table.
TABLE-US-00003 HPLC Compound (t.sub.R in min) LCMS No. Structure
Method 2 [M + H].sup.+ 2 ##STR00059## 13.1 331.6 3 ##STR00060##
14.7 460.1 4 ##STR00061## 13.15 498.1 5 ##STR00062## 9.90 387.3 6
##STR00063## 14.22 422.0 7 ##STR00064## 10.37 460.12 8 ##STR00065##
8.86 346.2 9 ##STR00066## 12.06 408.25 10 ##STR00067## 12.51 372.35
11 ##STR00068## 10.71 408.3 12 ##STR00069## 9.52 406.2 13
##STR00070## 14.37 345.5
Example 2:
4-((S)-2-amino-2-(5-((S)-pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)-
ethyl)phenol (Compound 14)
##STR00071##
[0320] Step 2a: Synthesis of Compound 2a
##STR00072##
[0322] The Compound 2a was synthesized as per the similar procedure
described in steps 1a to 1c of Example 1 (Compound 1) by using
Boc-Tyr(.sup.tBu)-OH.
Step 2b: Synthesis of Compound 2b
##STR00073##
[0324] To a solution of Boc-Pro-OH (0.86 g, 3.41 mmol) in DMF (20
mL) were added HOBt (1.4 g, 10.6 mmol) and DIC (1.7 mL, 10.6 mmol)
at 0.degree. C. and stirred for 30 minutes. Then compound 2a (1.8
g, 5.12 mmol) was added at the same temperature and continued
stirring for 10 min and then at room temperature for 1 h. The
completion of the reaction was confirmed by TLC analysis. The
reaction mixture was quenched with ice water, the precipitated
white solid was filtered, washed with water and dried under high
under reduced pressure. The solid was stirred with diethyl ether
(50 mL) for 15 min, filtered and dried to yield 1.8 g of compound
2b. LCMS: 549.5 [M+H].sup.+.
Step 2c: Synthesis of Compound 2c
##STR00074##
[0326] To a solution of compound 2b (1.8 g, 3.3 mmol) in
acetonitrile (35 mL) was added acetic acid (1.8 mL) at room
temperature and refluxed at 85.degree. C. for 12 h. The competition
of the reaction was confirmed by TLC analysis. The volatiles were
evaporated under reduced pressure to obtain crude semi solid which
was diluted with water and ethyl acetate. The organic layer was
washed with NaHCO.sub.3 solution followed by citric acid solution
and brine solution. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
get crude. The crude compound was purified by column chromatography
over silica gel using 20% ethyl acetate in hexane to yield 0.5 g
compound 2c. LCMS: 531.3 [M+H].sup.+.
Step 2d: Synthesis of Compound 14
##STR00075##
[0328] A solution of compound 2c (0.5 g, 0.94 mmol) was added 5 mL
of cocktail mixture of and trifluoroacetic:TIPS:water (95:2.5:2.5)
and was stirred at rt for 2 h. The resulting reaction mixture was
evaporated under reduced pressure, diluted with diethyl ether and
filtered to yield 0.45 g of crude compound 14. The crude solid
material was purified by preparative HPLC method described under
experimental conditions. HPLC (t.sub.R in min): 9.99; LCMS: 275.4
[M+H].sup.+.
[0329] The below compounds were prepared by procedure similar to
the one described in Example 2 (Compound 14) with appropriate
variations in reactants, quantities of reagents, solvents and
reaction conditions. The characterization data of the compounds are
summarized herein below table.
TABLE-US-00004 HPLC Compound (t.sub.R in min) LCMS No. Structure
Method 2 [M + H].sup.+ 15 ##STR00076## 9.72 279.4 16 ##STR00077##
10.79 263.4 17 ##STR00078## 10.8 341.3 18 ##STR00079## 11.9
324.9
[0330] The synthetic procedures for the preparation of compounds 19
and 20 of the present invention were described in WO2016142833
A1.
TABLE-US-00005 Compound No. Structure 19 ##STR00080## 20
##STR00081##
Example 3: Rescue of Mouse Splenocyte Proliferation in the Presence
of Recombinant PD-L1/PD-L2
[0331] Recombinant mouse PD-L1 (rm-PDL-1, cat no: 1019-B7-100;
R&D Systems) were used as the source of PD-L1.
Requirements:
[0332] Mouse splenocytes harvested from 6-8 weeks old C57 BL6 mice;
RPMI 1640 (GIBCO, Cat #11875); DMEM with high glucose (GIBCO, Cat
#D6429); Fetal Bovine Serum [Hyclone, Cat #SH30071.03]; Penicillin
(10000 unit/mL)-Streptomycin (10,000 .mu.g/mL) Liquid (GIBCO, Cat
#15140-122); MEM Sodium Pyruvate solution 100 mM (100.times.),
Liquid (GIBCO, Cat #11360); Nonessential amino acid (GIBCO, Cat
#11140); L-Glutamine (GIBCO, Cat #25030); Anti-CD3 antibody
(eBiosciences--16-0032); Anti-CD28 antibody
(eBiosciences--16-0281); ACK lysis buffer (1 mL) (GIBCO, Cat
#-A10492); Histopaque (density-1.083 gm/mL) (SIGMA 10831); Trypan
blue solution (SIGMA-T8154); 2 mL Norm Ject Luer Lock
syringe-(Sigma 2014-12); 40 .mu.m nylon cell strainer (BD FALCON
35230); Hemacytometer (Bright line-SIGMA Z359629); FACS Buffer
(PBS/0.1% BSA): Phosphate Buffered Saline (PBS) pH 7.2 (HiMedia
TS1006) with 0.1% Bovine Serum Albumin (BSA) (SIGMA A7050) and
sodium azide (SIGMA 08591); 5 mM stock solution of CFSE: CFSE stock
solution was prepared by diluting lyophilized CFSE with 180 .mu.L
of Dimethyl sulfoxide (DMSO C.sub.2H.sub.6SO, SIGMA-D-5879) and
aliquoted in to tubes for further use. Working concentrations were
titrated from 10 .mu.M to 1 .mu.M. (eBioscience-650850-85); 0.05%
Trypsin and 0.02% EDTA (SIGMA 59417C); 96-well format ELISA plates
(Corning CLS3390); BD FACS caliber (E6016); Recombinant mouse
B7-H1/PDL1 Fc Chimera, (rm-PD-L1 cat no: 1019-B7-100).
Protocol
Splenocyte Preparation and Culturing:
[0333] Splenocytes harvested in a 50 mL falcon tube by mashing
mouse spleen in a 40 .mu.m cell strainer were further treated with
1 mL ACK lysis buffer for 5 min at room temperature. After washing
with 9 mL of RPMI complete media, cells were re-suspended in 3 mL
of 1.times.PBS in a 15 mL tube. 3 mL of Histopaque was added
carefully to the bottom of the tube without disturbing overlaying
splenocyte suspension. After centrifuging at 800.times.g for 20 min
at room temperature, the opaque layer of splenocytes was collected
carefully without disturbing/mixing the layers. Splenocytes were
washed twice with cold 1.times.PBS followed by total cell counting
using Trypan Blue exclusion method and used further for cell based
assays.
[0334] Splenocytes were cultured in RPMI complete media (RPMI+10%
fetal bovine serum+1 mM sodium pyruvate+10,000 units/mL penicillin
and 10,000 .mu.g/mL streptomycin) and maintained in a CO.sub.2
incubator with 5% CO.sub.2 at 37.degree. C.
CFSE Proliferation Assay:
[0335] CFSE is a dye that passively diffuses into cells and binds
to intracellular proteins. 1.times.10.sup.6 cells/mL of harvested
splenocytes were treated with 5 .mu.M of CFSE in pre-warmed
1.times.PBS/0.1% BSA solution for 10 min at 37.degree. C. Excess
CFSE was quenched using 5 volumes of ice-cold culture media to the
cells and incubated on ice for 5 min. CFSE labelled splenocytes
were further given three washes with ice cold complete RPMI media.
CFSE labelled 1.times.10.sup.5 splenocytes added to wells
containing either MDA-MB231 cells (1.times.10.sup.5 cells cultured
in high glucose DMEM medium) or recombinant human PDL-1 (100 ng/mL)
and test compounds. Splenocytes were stimulated with anti-mouse CD3
and anti-mouse CD28 antibody (1 .mu.g/mL each), and the culture was
further incubated for 72 h at 37.degree. C. with 5% CO.sub.2. Cells
were harvested and washed thrice with ice cold FACS buffer and %
proliferation was analysed by flow cytometry with 488 nm excitation
and 521 nm emission filters.
Data Compilation, Processing and Inference:
[0336] Percent splenocyte proliferation was analysed using cell
quest FACS program and percent rescue of splenocyte proliferation
by compound was estimated after deduction of % background
proliferation value and normalising to % stimulated splenocyte
proliferation (positive control) as 100%.
Stimulated splenocytes: Splenocytes+anti-CD3/CD28 stimulation
Background proliferation: Splenocytes+anti-CD3/CD28+PD-L1 Compound
proliferation: Splenocytes+anti-CD3/CD28+PD-L1+Compound Compound
effect is examined by adding required conc. of compound to
anti-CD3/CD28 stimulated splenocytes in presence of ligand (PDL-1).
The results are given in the following table.
TABLE-US-00006 Compound Percent rescue of splenocyte proliferation
No. at 100 nM PD-L1 based assay 1 17 2 84 3 11 4 22 5 27 6 15 7 39
19 99 20 35
Example-4: Rescue of the Mouse CD8.sup.+ T-Cell Proliferation in
the Presence of Recombinant mPVR
Reagents:
[0337] 96-well plates, Corning; RPMI, Cat No. R6504, Sigma; Easy
Sep magnet, Cat No. 18000, Stem Cell; Easy Sep Mouse CD8 T Cell
isolation kit, Cat No. 19853, Stem Cell; Corning.RTM. cell
strainer, (70 .mu.m) Cat No. 431751, Corning; Purified anti-mouse
CD3 Abs, Cat No. 100201, Biolegend; Recombinant mouse PVR, Cat No.
6909-CD-050, R&D Systems; Recombinant mouse anti-TIGIT Ab, Cat
No. 142101, Biolegend; FBS, Cat No. SH30070.03, Hyclone; Mouse IL-2
ELISA Kit, R&D System Cat no DY402; Mouse IFN-.gamma. ELISA Kit
R&D Systems Cat no. DY485; Sterile PBS; FicollHistopaque, Cat
No. 10831-6X100ML, Sigma
Protocol:
[0338] Spleen was collected from C57BL/6 male mice with 6-8 weeks
of age. Splenocytes were isolated by slowly crushing the spleen
between the sterile glass slides in RPMI+10% FBS and passing it
through the 70 .mu.m strainer. Cell suspension was centrifuged at
912.times.g for 10 minutes at room temperature and discarded the
supernatant. Splenocytes were resuspended in RPMI+10% FBS (Complete
RPMI). Resuspended splenocytes were overlaid on Ficoll
Histopaque-1083 in a 50 ml Tarson tubes. Overlaid cells were
centrifuged at 584.times.g for 30 minutes at room temperature
without break. A clear buffy coat was carefully aspirated into
sterile PBS. Isolated cells were washed using PBS and resuspended
in complete RPMI medium to get a suspension of about
5.times.10.sup.7 cells/ml. Mouse CD8.sup.+ T cell were isolated by
using EasySep Mouse CD8+ T Cell Isolation kit, as per manufacturers
instruction.
[0339] 96-well cell culture plate was coated with Purified
anti-mouse CD3, 1 .mu.g/mL (50 .mu.L/well) and Recombinant Mouse
PVR Fe Chimera, 0.5 .mu.g/mL (50 ul/well) for 4 hours at 37.degree.
C. After 4 hours, the coated plate was washed with sterile PBS.
Mouse CD8+ T cells isolated from spleen were added at 0.2
million/well (180 .mu.L) concentration into a 96-well cell culture
plate. Test compound at various concentrations prepared in water or
DMSO was added in respective wells (20 .mu.L/well) so as to make
the total volume 200 .mu.L/well. The plates were incubated in
37.degree. C. CO.sub.2 incubator for 3 days. On the 3.sup.rd day,
cell supernatant was collected to determine cytokine levels (IL-2
or IFN-7) using ELISA. The extent of CD8.sup.+ T cell proliferation
in presence or absence of test compound was measured by analysing
the amount of IL-2 or IFN-.gamma. in the culture supernatants using
mouse IL-2 or IFN-.gamma. ELISA kits as per manufacture
instructions. Recombinant mouse anti-TIGIT antibody was used as
positive control to determine the increased proliferation of
CD8.sup.+ T cells.
Data Compilation, Processing and Inference:
[0340] Percent CD8.sup.+ T cell proliferation was analysed by
measuring IL-2 levels using IL-2 ELISA kit and percent rescue of
CD8.sup.+ T cell by test compound was estimated after deduction of
% background proliferation value and normalising to % stimulated
CD8.sup.+ T cell proliferation by anti-TIGIT antibody (positive
control) as 100%. The results are given in following table.
TABLE-US-00007 Compound Percent rescue of CD8.sup.+T-cell
proliferation No. at 100 nM mPVR based assay 1 98 2 14 3 59 5 (17 @
1000 nM) 8 14.6 9 56.9 16 72 (@ 1000 nM) 19 72
Example-5: Efficacy Study of Compound 19 in the CT-26 Syngeneic
(Balb/c Male) Mouse Tumor Model
[0341] The objective of this study was to evaluate anti-tumor
activity of Compound 19 in a CT26 syngeneic colon adenocarcinoma
model.
Reagents and Materials
TABLE-US-00008 [0342] Name of the Reagent/Chemical Source Catalogue
No. Media - RPMI Sigma Aldrich R-6504 Fetal bovine serum (FBS)
Invitrogen 10437 028 Penicillin Streptomycin Invitrogen 15140122
CT26 Cell Line ATCC NA Anti-PD1 antibody BioXcell BE0033-2 TIGIT
antibody BioXcell BE027-4 Tween .RTM. 80 Sigma Aldrich P4780
2-Hydroxypropyl-beta- Sigma Aldrich 54290 cyclodextrin HP.beta.CD
Citric Acid Fisher Scientific 22595 Dipotassium EDTA salt dihydrate
Sigma Aldrich 332593 Capmul .RTM. PG-8 NF Abitec Corporation Not
available
Cell Line Propagation and Inoculation
[0343] CT26 cell line was procured from ATCC, maintained and stored
at ADTL-Bangalore cell line repository. One vial of CT26 cell line
was thawed and revived in T-150 cm.sup.2 flask with RPMI medium
supplemented with 10% FBS (Gibco), 10 mM
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 1 mM
sodium pyruvate, 4.5 g/L Glucose, 1% penicillin streptomycin
(Sigma) and 1.5 g/L sodium bicarbonate. The flask with CT26 cells
at cell density 0.25 million/ml was incubated at 37.+-.1.degree. C.
incubator supplied with 5% carbon dioxide. Cell expansion was
carried out in T-150 cm.sup.2 flasks and cell density was
maintained between 0.25 million/flask to 1.2 million/flask, with
cell splitting every alternate day. After the final step of
splitting, cells were processed for injection when the cells
reached exponential phase. Cells in the T-150 cm.sup.2 flask were
trypsinized and transferred to 50 ml tubes and centrifuged at 1200
rpm for 5 minutes at controlled room temperature to obtain cell
pellet. Supernatant was discarded and cell pellets were suspended
in media and counted using hemocytometer. Cell pellet was
re-suspended in RPMI media at a final concentration of
10.times.10.sup.6 cells/ml. To establish tumors, 1.times.10.sup.6
cells (0.1 ml of cell suspension) were injected subcutaneously into
the right flank region of mice.
Grouping and Allocation of Animals
[0344] When the mean tumor volumes reached approximately 30.+-.5
mm.sup.3, the animals were randomized based on tumor volumes into
five groups (G1 to G5) of ten animals (N=10) each as mentioned
below. The treatment was continued for a period of 14 days after
which the overall efficacy and tolerability were evaluated based on
tumor volume and body weight changes observed during the treatment
period. On treatment day 14, animals from all groups were
sacrificed at 0.5 hour, 1 hour and 4 hour after last dose
administration.
Grouping, Dose and Dosing Regimen (Dosing Starts after
Randomization)
TABLE-US-00009 Route of Group Compound Dose Frequency
Administration 1 Vehicle control 0 mg/kg qd Oral 2 Anti-mouse PD1
10 Once I.P antibody .mu.g/animal weekly 3 Anti-mouse TIGIT 500
twice I.P antibody .mu.g/animal weekly 4 Compound 19 10 mg/kg qd
Oral 5 Compound 19 30 mg/kg qd Oral
[0345] There was no impact on body weight in any of the treatment
in this study indicating excellent tolerability of the test agents
at the dosage administered. Treatment with Compound 19 resulted in
a dose dependent tumor growth inhibition (42% at 10 mg/kg (qd) and
53% at 30 mg/kg (qd) doses). Percent tumor growth inhibition
observed with 30 mg/kg (qd) dose was statistically significant
compared to vehicle treated animals. The result of the study is
graphically represented in FIG. 1.
* * * * *