NZ753549B2 - Combination comprising benzoheterocyclic compound and androgen receptor pathway modulator, application thereof and treatment method - Google Patents
Combination comprising benzoheterocyclic compound and androgen receptor pathway modulator, application thereof and treatment method Download PDFInfo
- Publication number
- NZ753549B2 NZ753549B2 NZ753549A NZ75354917A NZ753549B2 NZ 753549 B2 NZ753549 B2 NZ 753549B2 NZ 753549 A NZ753549 A NZ 753549A NZ 75354917 A NZ75354917 A NZ 75354917A NZ 753549 B2 NZ753549 B2 NZ 753549B2
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- NZ
- New Zealand
- Prior art keywords
- prednisone
- enzalutamide
- combination
- arn
- galeterone
- Prior art date
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Abstract
Provided are a composition, an application thereof and a treatment method. The composition comprises a benzoheterocyclic compound represented by general formula (I), one or more from among a pharmaceutically acceptable salt thereof, a solvate, a crystal form, a cocrystal, a stereoisomer, an isotope compound, a metabolite and a prodrug, and an androgen receptor pathway modulator and/or a hormone drug. The composition and treatment method may effectively inhibit the growth of prostate cancer cells. compound, a metabolite and a prodrug, and an androgen receptor pathway modulator and/or a hormone drug. The composition and treatment method may effectively inhibit the growth of prostate cancer cells.
Description
Combination comprising benzoheterocyclic compound and androgen receptor
pathway modulator, application thereof and treatment method
The present application claims the benefit of Chinese Patent Application No.
CN201611170723.1 filed on December 16, 2016, the contents of which are incorporated herein
by reference in their entireties.
Field of invention
The present invention relates to a combination, an application thereof and a treatment
method.
Prior art
Prostate cancer is a common malignancy in the male reproductive system. The statistics
which was made by the International Agency for Research on Cancer of World Health
Organization in 2012 showed that the number of newly diagnosed prostate cancer patients in
the world was 1.1 million in that year, accounting for about 15% of the total number of new
cancer cases, making it the second most common cancer in men worldwide. In the United
States, the incidence of prostate cancer ranks first in all malignancies, with the second highest
mortality rate, second only to lung cancer. Although the incidence of prostate cancer in China
is much lower than that in western countries, it has shown a significant growth trend in recent
years and ranks first among male urological tumors, and most of prostate cancer were
diagnosed in the terminal stage.
The growth of the prostate cancer cells requires the supporting of androgens including
testosterone. Therefore, the targeted treatment strategies for prostate cancer mainly focus on
the synthesis of androgen and the binding to the androgen receptor thereof. For example,
Enzalutamide, a prostate cancer drug marketed by the U.S. FDA in August 2012, is a small
molecule androgen receptor antagonist, which finally inhibits the androgen receptor pathway
by competitive inhibition of the binding of androgen to its receptor, thereby achieving the
effect of treating castration-resistant prostate cancer.
Enzalutamide also shows some side effects in clinical studies, such as weakness or fatigue,
lumbago, diarrhea, joint pain, hot flashes, tissue swelling, musculoskeletal pain, headache,
upper respiratory tract infection, dizziness, spinal cord compression and cauda equina
syndrome, muscle weakness, dyscoimesis, lower respiratory tract infection, hematuria, tingling,
anxiety and hypertension and so on.
For the treatment of cancer, the drug combination is often used in the clinical practice to
improve the treatment effect, for example, the combination of docetaxel and prednisone for use
in the treatment of prostate cancer. However, people have met great setbacks when exploring
new combination regimens. One of the typical examples is that although the combination of
docetaxel and prednisone can treat prostate cancer (Tannock et al. N. Eng. J. Med. (2004), 351,
1502-1512), the combination regimen of docetaxel, prednisone and lenalidomide failed in a
Phase III clinical trial involving more than 1000 prostate cancer patients (Petrylak et al. Lancet
Oncol. ( 2015) 16-4, 417-425). It should also be noted that, the results of several phase II
clinical studies also indicated that the clinical efficacy of lenalidomide alone in the treatment of
prostate cancer was not satisfying (Xing et al. Asian Pac. J. Cancer Prev. (2015) 16- 9,
3969-3972). Therefore, it has become an urgent technical problem to be solved in the art to
explore combination regimens of anti-prostate cancer drugs (including Enzalutamide etc.) to
improve the efficacy and reduce the toxic and side effect.
Summary of the present invention
The technical problem to be solved in the present invention is to improve the efficacy of
the present anti-prostate cancer drugs to achieve better clinical application effects. The present
invention relates to a combination, application thereof and treatment method. The combination
and treatment method of the present invention can inhibit the growth of prostate cancer cells
more effectively.
In a first aspect the invention relates to a combination comprising one or more
benzoheterocyclic compound(s), or a pharmaceutically acceptable salt, solvate, polymorph,
co-crystal, stereoisomer, isotope thereof, and an androgen receptor pathway modulator;
wherein the benzoheterocyclic compound is any one of the following compounds:
wherein the androgen receptor pathway modulator is selected from one or more of
Enzalutamide, ARN-509, Abiraterone acetate, Galeterone, and ODM-201.
In an embodiment the combination consists of the one or more benzoheterocyclic
compound(s) and the androgen receptor pathway modulator.
In an embodiment the androgen receptor pathway modulator is Enzalutamide, ARN-509,
Galeterone, ODM-201, Abiraterone acetate, Enzalutamide and Galeterone, Enzalutamide and
Abiraterone acetate, Enzalutamide and ODM-201, ARN-509 and Galeterone, ARN-509 and
Abiraterone acetate, ARN-509 and ODM-201, or ODM-201 and Abiraterone acetate.
In an embodiment the combination of the benzoheterocyclic compound and the androgen
receptor pathway modulator is B101 and Enzalutamide, B102 and Enzalutamide, B103 and
Enzalutamide, B104 and Enzalutamide, B105 and Enzalutamide, B106 and Enzalutamide,
C111 and Enzalutamide, B101 and ARN-509, B102 and ARN-509, B103 and ARN-509, B104
and ARN-509, B105 and ARN-509, B106 and ARN-509, C111 and ARN-509, B101 and
Abiraterone acetate, B105 and Abiraterone acetate, C111 and Abiraterone acetate, B101 and
Galeterone, B105 and Galeterone, C111 and Galeterone, B101 and ODM-201, B105 and
ODM-201, C111 and ODM-201, B101 and Enzalutamide and Galeterone, B105 and
Enzalutamide and Galeterone, C111 and Enzalutamide and Galeterone, B101 and
Enzalutamide and Abiraterone acetate, B105 and Enzalutamide and Abiraterone acetate, C111
and Enzalutamide and Abiraterone acetate, B101 and ARN-509 and Galeterone, B105 and
ARN-509 and Galeterone, C111 and ARN-509 and Galeterone, B101 and ARN-509 and
Abiraterone acetate, B105 and ARN-509 and Abiraterone acetate, or C111 and ARN-509 and
Abiraterone acetate.
In an embodiment the combination further comprises a hormone compound, and the
hormone compound is prednisone.
In an embodiment the combination consists of the one or more benzoheterocyclic
compound(s), the androgen receptor pathway modulator and the hormone compound
prednisone.
In an embodiment the combination of the androgen receptor pathway modulator and the
hormone compound is Galeterone and prednisone, prednisone and Abiraterone acetate,
Enzalutamide and prednisone, ARN-509 and prednisone, Enzalutamide and Galeterone and
prednisone, Enzalutamide and Abiraterone acetate and prednisone, ARN-509 and Galeterone
and prednisone, or ARN-509 and Abiraterone acetate and prednisone.
In an embodiment the combination of the benzoheterocyclic compound, the androgen
receptor pathway modulator and the hormone compound is B101 and Enzalutamide and
prednisone, B105 and Enzalutamide and prednisone, C111 and Enzalutamide and prednisone,
B101 and ARN-509 and prednisone, B105 and ARN-509 and prednisone, C111 and ARN-509
and prednisone, B101 and Galeterone and prednisone, B105 and Galeterone and prednisone,
C111 and Galeterone and prednisone, B101 and prednisone and Abiraterone acetate, B105 and
prednisone and Abiraterone acetate, C111 and prednisone and Abiraterone acetate, B101 and
Enzalutamide and Galeterone and prednisone, B105 and Enzalutamide and Galeterone and
prednisone, C111 and Enzalutamide and Galeterone and prednisone, B101 and Enzalutamide
and Abiraterone acetate and prednisone, B105 and Enzalutamide and Abiraterone acetate and
prednisone, C111 and Enzalutamide and Abiraterone acetate and prednisone, B101 and
ARN-509 and Galeterone and prednisone, B105 and ARN-509 and Galeterone and prednisone,
C111 and ARN-509 and Galeterone and prednisone, B101 and ARN-509 and Abiraterone
acetate and prednisone, B105 and ARN-509 and Abiraterone acetate and prednisone, or C111
and ARN-509 and Abiraterone acetate and prednisone.
In a second aspect the invention relates to a pharmaceutical composition comprising the
combination according to the first aspect of the invention or any embodiment thereof and one
or more pharmaceutically acceptable excipients.
In a third aspect the invention relates to the use of one or more benzoheterocyclic
compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer,
isotope thereof as defined the first aspect of the invention, in the manufacture of a medicament
for the prevention and/or treatment of prostate cancer in combination with an androgen
receptor pathway modulator as defined in the first aspect of the invention;
or, use of one or more benzoheterocyclic compounds, or a pharmaceutically acceptable
salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in the first aspect
of the invention, in the manufacture of a medicament for the prevention and/or treatment of
prostate cancer in combination with an androgen receptor pathway modulator as defined in the
first aspect of the invention, and the hormone compound prednisone;
or, use of an androgen receptor pathway modulator as defined in the first aspect of the
invention, in the manufacture of a medicament for the prevention and/or treatment of prostate
cancer in combination with one or more benzoheterocyclic compounds, or a pharmaceutically
acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in the
first aspect of the invention;
or, use of the androgen receptor pathway modulator as defined in the first aspect of the
invention, in the manufacture of a medicament for the prevention and/or treatment of prostate
cancer in combination with one or more benzoheterocyclic compounds, or a pharmaceutically
acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in the
first aspect of the invention, and the hormone compound prednisone;
or, use of the hormone compound prednisone, in the manufacture of a medicament for the
prevention and/or treatment of prostate cancer in combination with one or more
benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph,
co-crystal, stereoisomer, isotope thereof as defined in the first aspect of the invention, and an
androgen receptor pathway modulator as defined in the first aspect of the invention.
In an embodiment the prostate cancer is castration-resistant prostate cancer.
In another aspect the invention relates to kit comprising a pharmaceutical composition A
and a pharmaceutical composition B;
wherein, the pharmaceutical composition A comprises the benzoheterocyclic compound,
or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
thereof as defined in the first aspect of the invention and one or more pharmaceutically
acceptable excipients;
the pharmaceutical composition B comprises an androgen receptor pathway modulator as
defined in the first aspect of the invention and one or more pharmaceutically acceptable
excipients.
In an embodiment the kit further comprises a pharmaceutical composition C, which
comprises the hormone compound prednisone and one or more pharmaceutically acceptable
excipients;
and/or, the pharmaceutical compositions in the kit are administered simultaneously or
separately.
Another aspect of the invention disclosed herein relates to a combination, comprising one
or more of the benzoheterocyclic compound of formula (I), the pharmaceutically acceptable
salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug
thereof, and the androgen receptor pathway modulator;
in formula (I), n1 is 0 or 1;
L and L are independently CH , CHD or CD ;
1 2 2 2
X is NH, ND or O;
R and R are independently H or D;
R is H, D or halogen;
Z is ; wherein, R is H, D, CH , CH D, CHD or CD ; R , R , R , R and R
4 3 2 2 3 5 6 7 8 9
are independently H or D; the carbon marked with * is an asymmetric center;
R is H, D or , wherein, R ’, R ’, R ’ and R ’ are independently H, D,
1 2 3 4
halogen, cyano, hydroxyl, substituted or unsubstituted (C -C ) alkyl, substituted or
1 12
unsubstituted (C -C ) alkoxy, (C -C ) heterocycloalkyl or deuterated C -C
1 12 2 20 2 20
heterocycloalkyl ;
the substituent in the substituted (C -C ) alkoxy is one or more of the following groups:
1 12
D, halogen, hydroxyl, (C -C ) alkoxy, (C -C ) heterocycloalkyl and (C -C ) heterocycloalkyl
1 12 2 20 2 20
substituted by (C -C ) alkyl;
1 12
the substituent in the substituted (C -C ) alkyl is one or more of the following groups: D,
1 12
(C -C ) heterocycloalkyl, deuterated (C -C ) heterocycloalkyl, (C -C ) heterocycloalkyl
2 20 2 20 2 20
substituted by (C -C ) alkyl and (C -C ) heterocycloalkyl substituted by deuterated (C -C )
1 12 2 20 1 12
alkyl;
when there are a plurality of substituents in the substituted (C -C ) alkyl or the
1 12
substituted (C -C ) alkoxy, the substituents are the same or different;
1 12
in each of the above groups, the (C -C ) heterocycloalkyl which is refered in the (C -C )
2 20 2 20
heterocycloalkyl, deuterated (C -C ) heterocycloalkyl, (C -C ) heterocycloalkyl substituted
2 20 2 20
by (C -C ) alkyl and (C -C ) heterocycloalkyl substituted by deuterated (C -C ) alkyl is
1 12 2 20 1 12
independently a (C -C ) heterocycloalkyl wherein the heteroatom is one or more of O, N and
2 20
in the general formula (I), when n1 is 0, X is NH or ND, R is H or D, then R is F;
2
in the general formula (I), when n1 is 1, then R is ;
D represents deuterium-enriched hydrogen, and H represents non-deuterium-enriched
hydrogen;
the androgen receptor pathway modulator is one or more of Enzalutamide, ARN-509,
ODM-201, VT-464, Orteronel, EPI-001, Andarine, RD162, BMS-641988, CH5137291,
Flutamide, Hydroxy flutamide, RU58642, LG120907, LG105, Galeterone, Spironolactone,
MK-2866, AZD3514, Cyproterone acetate, ORM-15341, Bicalutamide, Nilutamide, Degarelix,
Goserelin acetate, Leuprolide acetat, Abiraterone and Abiraterone Acetate;
when the androgen receptor pathway modulator is selected from one of the above
compounds, the androgen receptor pathway modulator is not Bicalutamide, Nilutamide,
Leuprolide acetate, Cyproterone acetate or Spironolactone.
In the formula (I), the asymmetric center preferably refers to (S)-configured carbon,
(R)-configured carbon or racemate.
In the formula (I), the Z is preferably any one of the following structures:
, , , , , , ,
, , , , , , ,
, , , , , , ,
, , , , , , ,
, , , , , , ,
, , , , , , , ,
, , , , , , , ,
, , , , , , ,
, , , , , , ,
, , , , , , ,
, , , , , ,
, , , , , , ,
, , , , , ,
, , , , , ,
, , , , , and
; In some embodiments of the invention, Z is more preferably any one of the
following structures , , and , wherein, the
carbon marked with * is an asymmetric center, and the asymmetric center, H and D are defined
as described above.
In the formula (I), preferably, the (C -C ) heterocycloalkyl which is refered in the (C -C )
2 20 2 20
heterocycloalkyl, the deuterated (C -C ) heterocycloalkyl, the (C -C ) heterocycloalkyl
2 20 2 20
substituted by (C -C ) alkyl or the (C -C ) heterocycloalkyl substituted by deuterated (C -C )
1 12 2 20 1 12
alkyl independently refers to a (C -C ) heterocycloalkyl wherein the heteroatom is N or O and
the number of heteroatoms is 1-2. The (C -C ) heterocycloalkyl wherein the heteroatom is N or
O and the number of heteroatoms is 1-2 is preferably morpholinyl (e.g. ).
In the formula (I), preferably, the (C -C ) alkyl which is refered in the substituted or
1 12
unsubstituted (C -C ) alkyl, the (C -C ) heterocycloalkyl substituted by (C -C ) alkyl and the
1 12 2 20 1 12
(C -C ) heterocycloalkyl substituted by deuterated (C -C ) alkyl is independently a (C -C )
2 20 1 12 1 4
alkyl. The (C -C ) alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or
tertiary-butyl. The substituted (C -C ) alkyl is preferably , ,
1 12
or .
In the formula (I), preferably, the “(C -C ) alkoxy” which is refered in the (C -C )
1 12 1 12
alkoxy and the substituted or unsubstituted (C -C ) alkoxy is independently a (C -C ) alkoxy;
1 12 1 4
The (C -C ) alkoxy is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy
or tert-butoxy.
In the formula (I), the is preferably , ,
, , or .
In the combination, the one or more of the benzoheterocyclic compound of formula (I),
the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof is preferably any one of the following compounds:
the pharmaceutically acceptable salt and the stereoisomer thereof.
In the combination, the one or more of the benzoheterocyclic compound of formula (I),
the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof is more preferably any one of the following
compounds: B101, B102, B103, B104, B105, B106, C107, C108, C109, C110, C111, C112, the
pharmaceutically acceptable salt and the stereoisomer thereof. The one or more of the
benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof is
most preferably any one of the following compounds: B101, B102, B103, B104, B105, B106,
C111, the pharmaceutically acceptable salt and the stereoisomer thereof.
In the combination, the androgen receptor pathway modulator is preferably selected from
one or more of Enzalutamide, ARN-509, Abiraterone, Abiraterone acetate, Galeterone,
ODM-201 and ORM-15341.
In the combination, the androgen receptor pathway modulator is more preferably
Enzalutamide, ARN-509, Galeterone, ODM-201, ORM-15341, Abiraterone, Abiraterone
acetate, Enzalutamide and Galeterone, Enzalutamide and Abiraterone acetate, Enzalutamide
and Abiraterone, Enzalutamide and ODM-201, Enzalutamide and ORM-15341, ARN-509 and
Galeterone, ARN-509 and Abiraterone acetate, ARN-509 and Abirateron, ARN-509 and
ODM-201, ARN-509 and ORM-15341, ODM-201 and Galeterone, ODM-201 and Abiraterone
acetate, ODM-201 and Abiraterone, ORM-15341 and Galeterone, ORM-15341 and
Abiraterone acetate, or ORM-15341 and Abiraterone.
In the combination, the androgen receptor pathway modulator is most preferably
Enzalutamide, ARN-509, Galeterone, ODM-201, Abiraterone, Abiraterone acetate,
Enzalutamide and Galeterone, Enzalutamide and Abiraterone acetate, ARN-509 and
Galeterone, ARN-509 and Abiraterone acetate, ODM-201 and Enzalutamide, ODM-201 and
ARN-509, ODM-201 and Galeterone, ODM-201 and Abiraterone, or ODM-201 and
Abiraterone acetate.
In some embodiments, the combination of “one or more of the benzoheterocyclic
compound of formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal,
stereoisomer, isotope compound, metabolite and prodrug thereof” and the androgen receptor
pathway modulator is that: the “one or more of the benzoheterocyclic compound of formula (I),
the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof” is selected from B101, B102, B103, B104, B105,
B106, C107, C108, C109, C110, C111, C112, the pharmaceutically acceptable salt and the
stereoisomer thereof; the androgen receptor pathway modulator is selected from one or more of
Enzalutamide, ARN-509, Abiraterone, Abiraterone acetate, Galeterone, ODM-201 and
ORM-15341.
In some embodiments, the combination of “one or more of the benzoheterocyclic
compound of formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal,
stereoisomer, isotope compound, metabolite and prodrug thereof” and the androgen receptor
pathway modulator is that: the “one or more of the benzoheterocyclic compound of formula (I),
the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof” is selected from B101, B102, B103, B104, B105,
B106, C107, C108, C109, C110, C111, C112, the pharmaceutically acceptable salt and the
stereoisomer thereof; the androgen receptor pathway modulator is Enzalutamide, ARN-509,
Galeterone, ODM-201, ORM-15341, Abiraterone, Abiraterone acetate, Enzalutamide and
Galeterone, Enzalutamide and Abiraterone acetate, Enzalutamide and Abiraterone,
Enzalutamide and ODM-201, Enzalutamide and ORM-15341, ARN-509 and Galeterone,
ARN-509 and Abiraterone acetate, ARN-509 and Abirateron, ARN-509 and ODM-201,
ARN-509 and ORM-15341, ODM-201 and Galeterone, ODM-201 and Abiraterone acetate,
ODM-201 and Abiraterone, ORM-15341 and Galeterone, ORM-15341 and Abiraterone acetate,
or ORM-15341 and Abiraterone.
In some embodiments, the combination of “one or more of the benzoheterocyclic
compound of formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal,
stereoisomer, isotope compound, metabolite and prodrug thereof” and the androgen receptor
pathway modulator is that: the “one or more of the benzoheterocyclic compound of formula (I),
the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof” is selected from B101, B102, B103, B104, B105,
B106, C107, C108, C109, C110, C111, C112, the pharmaceutically acceptable salt and the
stereoisomer thereof; the androgen receptor pathway modulator is Enzalutamide, ARN-509,
Galeterone, ODM-201, Abiraterone, Abiraterone acetate, Enzalutamide and Galeterone,
Enzalutamide and Abiraterone acetate, ARN-509 and Galeterone, ARN-509 and Abiraterone
acetate, ODM-201 and Enzalutamide, ODM-201 and ARN-509, ODM-201 and Galeterone,
ODM-201 and Abiraterone, or ODM-201 and Abiraterone acetate.
In some embodiments, the combination of the benzoheterocyclic compound of formula (I)
and the androgen receptor pathway modulator is more preferably that: B101 and Enzalutamide,
B102 and Enzalutamide, B103 and Enzalutamide, B104 and Enzalutamide, B105 and
Enzalutamide, B106 and Enzalutamide, C111 and Enzalutamide, B101 and ARN-509, B102
and ARN-509, B103 and ARN-509, B104 and ARN-509, B105 and ARN-509, B106 and
ARN-509, C111 and ARN-509, B101 and Abiraterone, B102 and Abiraterone, B103 and
Abiraterone, B104 and Abiraterone, B105 and Abiraterone, B106 and Abiraterone, C111 and
Abiraterone, B101 and Abiraterone acetate, B102 and Abiraterone acetate, B103 and
Abiraterone acetate, B104 and Abiraterone acetate, B105 and Abiraterone acetate, B106 and
Abiraterone acetate, C111 and Abiraterone acetate, B101 and Galeterone, B102 and Galeterone,
B103 and Galeterone, B104 and Galeterone, B105 and Galeterone, B106 and Galeterone, C111
and Galeterone, B101 and ODM-201, B102 and ODM-201, B103 and ODM-201, B104 and
ODM-201, B105 and ODM-201, B106 and ODM-201, C111 and ODM-201, B101 and
Enzalutamide and Galeterone, B102 and Enzalutamide and Galeterone, B103 and
Enzalutamide and Galeterone, B104 and Enzalutamide and Galeterone, B105 and
Enzalutamide and Galeterone, B106 and Enzalutamide and Galeterone, C111 and
Enzalutamide and Galeterone, B101 and Enzalutamide and Abiraterone acetate, B102 and
Enzalutamide and Abiraterone acetate, B103 and Enzalutamide and Abiraterone acetate, B104
and Enzalutamide and Abiraterone acetate, B105 and Enzalutamide and Abiraterone acetate,
B106 and Enzalutamide and Abiraterone acetate, C111 and Enzalutamide and Abiraterone
acetate, B101 and ARN-509 and Galeterone, B102 and ARN-509 and Galeterone, B103 and
ARN-509 and Galeterone, B104 and ARN-509 and Galeterone, B105 and ARN-509 and
Galeterone, B106 and ARN-509 and Galeterone, C111 and ARN-509 and Galeterone, B101
and ARN-509 and Abiraterone acetate, B102 and ARN-509 and Abiraterone acetate, B103 and
ARN-509 and Abiraterone acetate, B104 and ARN-509 and Abiraterone acetate, B105 and
ARN-509 and Abiraterone acetate, B106 and ARN-509 and Abiraterone acetate, C111 and
ARN-509 and Abiraterone acetate, B101 and ODM-201 and Enzalutamide, B102 and
ODM-201 and Enzalutamide, B103 and ODM-201 and Enzalutamide, B104 and ODM-201
and Enzalutamide, B105 and ODM-201 and Enzalutamide, B106 and ODM-201 and
Enzalutamide, C111 and ODM-201 and Enzalutamide, B101 and ODM-201 and ARN-509,
B102 and ODM-201 and ARN-509, B103 and ODM-201 and ARN-509, B104 and ODM-201
and ARN-509, B105 and ODM-201 and ARN-509, B106 and ODM-201 and ARN-509, C111
and ODM-201 and ARN-509, B101 and ODM-201 and Galeterone, B102 and ODM-201 and
Galeterone, B103 and ODM-201 and Galeterone, B104 and ODM-201 and Galeterone, B105
and ODM-201 and Galeterone, B106 and ODM-201 and Galeterone, C111 and ODM-201 and
Galeterone, B101 and ODM-201 and Abiraterone, B102 and ODM-201 and Abiraterone, B103
and ODM-201 and Abiraterone, B104 and ODM-201 and Abiraterone, B105 and ODM-201
and Abiraterone, B106 and ODM-201 and Abiraterone, C111 and ODM-201 and Abiraterone,
B101 and ODM-201 and Abiraterone acetate, B102 and ODM-201 and Abiraterone acetate,
B103 and ODM-201 and Abiraterone acetate, B104 and ODM-201 and Abiraterone acetate,
B105 and ODM-201 and Abiraterone acetate, B106 and ODM-201 and Abiraterone acetate, or
C111 and ODM-201 and Abiraterone acetate.
In some embodiments, the combination of the pharmaceutically acceptable salt of the
benzoheterocyclic compound of formula (I) and the androgen receptor pathway modulator is
preferably as any one of the combinations described in the above paragraph, with the only
difference of replacing "the benzoheterocyclic compound of formula (I)" with "the
pharmaceutically acceptable salt of the benzoheterocyclic compound of formula (I)". For
example, the combination of B101 and Enzalutamide in the above paragraph corresponds to the
pharmaceutically acceptable salt of B101 and enzalutamide in this paragragh.
In some embodiments, the combination of the stereoisomers of the benzoheterocyclic
compound of formula (I) and the androgen receptor pathway modulator is preferably as any
one of the combinations described in the above paragraph, with the only difference of replacing
" the pharmaceutically acceptable salt of the benzoheterocyclic compound of the formula (I)"
with "the stereoisomers of the benzoheterocyclic compound of formula (I)". For example, the
combination of the pharmaceutically acceptable salt of B101 and Enzalutamide in the above
paragraph corresponds to the stereoisomers of B101 and enzalutamide in this paragragh.
The combination may further comprise hormone compound, the hormone compound is
one or more of prednisone, dexamethasone, dehydroepiandrosterone, isoandrosterone and
megestrol acetate. The hormone compound is preferably prednisone. Therefore, the
combination may comprise one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof, the androgen receptor pathway modulator and the
hormone compound.
In the combination, the combination of the androgen receptor pathway modulator and the
hormone compound is preferably Galeterone and prednisone, prednisone and Abiraterone
acetate, Enzalutamide and prednisone, ARN-509 and prednisone, Enzalutamide and
dexamethasone, Enzalutamide and Galeterone and prednisone, Enzalutamide and Galeterone
and dexamethasone, Enzalutamide and ODM-201 and prednisone, Enzalutamide and
ODM-201 and dexamethasone, Enzalutamide and ORM-15341 and prednisone, Enzalutamide
and ORM-15341 and dexamethasone, Enzalutamide and Abiraterone acetate and prednisone,
Enzalutamide and Abiraterone acetate and dexamethasone, Enzalutamide and Abiraterone and
prednisone, Enzalutamide and Abiraterone and dexamethasone, ARN-509 and dexamethasone,
ARN-509 and Galeterone and prednisone, ARN-509 and Galeterone and dexamethasone,
ARN-509 and ODM-201 and prednisone, ARN-509 and ODM-201 and dexamethasone,
ARN-509 and ORM-15341 and prednisone, ARN-509 and ORM-15341 and dexamethasone,
ARN-509 and Abiraterone acetate and prednisone, ARN-509 and Abiraterone acetate and
dexamethasone, ARN-509 and Abiraterone and prednisone, ARN-509 and Abiraterone and
dexamethasone, ODM-201 and prednisone, ODM-201 and dexamethasone, ODM-201 and
Galeterone and prednisone, ODM-201 and Galeterone and dexamethasone, ODM-201 and
Abiraterone acetate and prednisone, ODM-201 and Abiraterone acetate and dexamethasone,
ODM-201 and Abiraterone and prednisone, ODM-201 and Abiraterone and dexamethasone,
ORM-15341 and prednisone, ORM-15341 and dexamethasone, ORM-15341 and Galeterone
and prednisone, ORM-15341 and Galeterone and dexamethasone, ORM-15341 and
Abiraterone acetate and prednisone, ORM-15341 and Abiraterone acetate and dexamethasone,
ORM-15341 and Abiraterone and prednisone, ORM-15341 and Abiraterone and
dexamethasone, Galeterone and dexamethasone or Abiraterone acetate and dexamethasone.
In the combination, the combination of the androgen receptor pathway modulator and the
hormone compound is more preferably Galeterone and prednisone, prednisone and Abiraterone
acetate, Enzalutamide and prednisone, ARN-509 and prednisone, Enzalutamide and Galeterone
and prednisone, Enzalutamide and ODM-201 and prednisone, Enzalutamide and ORM-15341
and prednisone, Enzalutamide and Abiraterone acetate and prednisone, Enzalutamide and
Abiraterone and prednisone, ARN-509 and Galeterone and prednisone, ARN-509 and
ODM-201 and prednisone, ARN-509 and ORM-15341 and prednisone, ARN-509 and
Abiraterone acetate and prednisone, ARN-509 and Abiraterone and prednisone, ODM-201 and
prednisone, ODM-201 and Galeterone and prednisone, ODM-201 and Abiraterone acetate and
prednisone, ODM-201 and Abiraterone and prednisone, ORM-15341 and prednisone,
ORM-15341 and Galeterone and prednisone, ORM-15341 and Abiraterone acetate and
prednisone or ORM-15341 and Abiraterone and prednisone.
In the combination, the combination of the androgen receptor pathway modulator and the
hormone compound is most preferably Galeterone and prednisone, prednisone and Abiraterone
acetate, Enzalutamide and prednisone, ARN-509 and prednisone, Enzalutamide and Galeterone
and prednisone, Enzalutamide and Abiraterone acetate and prednisone, ARN-509 and
Galeterone and prednisone, ARN-509 and Abiraterone acetate and prednisone, ODM-201 and
prednisone, ODM-201 and Galeterone and prednisone, ODM-201 and Abiraterone acetate and
prednisone, ODM-201 and Abiraterone and prednisone, Enzalutamide and ODM-201 and
prednisone or ARN-509 and ODM-201 and prednisone.
In some embodiments of the invention, the combination of “one or more of the
benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof” and
the androgen receptor pathway modulator and the hormone compound is preferably that: the
“one or more of the benzoheterocyclic compound of formula (I), the pharmaceutically
acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound, metabolite
and prodrug thereof” is selected from B101, B102, B103, B104, B105, B106, C107, C108,
C109, C110, C111, C112, the pharmaceutically acceptable salt and the stereoisomer thereof;
The combination of the androgen receptor pathway modulator and the hormone compound is
Galeterone and prednisone, prednisone and Abiraterone acetate, Enzalutamide and prednisone,
ARN-509 and prednisone, Enzalutamide and Galeterone and prednisone, Enzalutamide and
Abiraterone acetate and prednisone, ARN-509 and Galeterone and prednisone, ARN-509 and
Abiraterone acetate and prednisone, ODM-201 and prednisone, ODM-201 and Galeterone and
prednisone, ODM-201 and Abiraterone acetate and prednisone, ODM-201 and Abiraterone and
prednisone, Enzalutamide and ODM-201 and prednisone, or, ARN-509 and ODM-201 and
prednisone.
In some embodiments of the invention, the combination of the benzoheterocyclic
compound of formula (I) and the androgen receptor pathway modulator and the hormone
compound is more preferably B101 and Enzalutamide and prednisone, B102 and Enzalutamide
and prednisone, B103 and Enzalutamide and prednisone, B104 and Enzalutamide and
prednisone, B105 and Enzalutamide and prednisone, B106 and Enzalutamide and prednisone,
C111 and Enzalutamide and prednisone, B101 and ARN-509 and prednisone, B102 and
ARN-509 and prednisone, B103 and ARN-509 and prednisone, B104 and ARN-509 and
prednisone, B105 and ARN-509 and prednisone, B106 and ARN-509 and prednisone, C111
and ARN-509 and prednisone, B101 and Galeterone and prednisone, B102 and Galeterone and
prednisone, B103 and Galeterone and prednisone, B104 and Galeterone and prednisone, B105
and Galeterone and prednisone, B106 and Galeterone and prednisone, C111 and Galeterone
and prednisone, B101 and ODM-201 and prednisone, B102 and ODM-201 and prednisone,
B103 and ODM-201 and prednisone, B104 and ODM-201 and prednisone, B105 and
ODM-201 and prednisone, B106 and ODM-201 and prednisone, C111 and ODM-201 and
prednisone, B101 and prednisone and Abiraterone acetate, B102 and prednisone and
Abiraterone acetate, B103 and prednisone and Abiraterone acetate, B104 and prednisone and
Abiraterone acetate, B105 and prednisone and Abiraterone acetate, B106 and prednisone and
Abiraterone acetate, C111 and prednisone and Abiraterone acetate, B101 and Enzalutamide and
Galeterone and prednisone, B102 and Enzalutamide and Galeterone and prednisone, B103 and
Enzalutamide and Galeterone and prednisone, B104 and Enzalutamide and Galeterone and
prednisone, B105 and Enzalutamide and Galeterone and prednisone, B106 and Enzalutamide
and Galeterone and prednisone, C111 and Enzalutamide and Galeterone and prednisone, B101
and Enzalutamide and Abiraterone acetate and prednisone, B102 and Enzalutamide and
Abiraterone acetate and prednisone, B103 and Enzalutamide and Abiraterone acetate and
prednisone, B104 and Enzalutamide and Abiraterone acetate and prednisone, B105 and
Enzalutamide and Abiraterone acetate and prednisone, B106 and Enzalutamide and
Abiraterone acetate and prednisone, C111 and Enzalutamide and Abiraterone acetate and
prednisone, B101 and ARN-509 and Galeterone and prednisone, B102 and ARN-509 and
Galeterone and prednisone, B103 and ARN-509 and Galeterone and prednisone, B104 and
ARN-509 and Galeterone and prednisone, B105 and ARN-509 and Galeterone and prednisone,
B106 and ARN-509 and Galeterone and prednisone, C111 and ARN-509 and Galeterone and
prednisone, B101 and ARN-509 and Abiraterone acetate and prednisone, B102 and ARN-509
and Abiraterone acetate and prednisone, B103 and ARN-509 and Abiraterone acetate and
prednisone, B104 and ARN-509 and Abiraterone acetate and prednisone, B105 and ARN-509
and Abiraterone acetate and prednisone, B106 and ARN-509 and Abiraterone acetate and
prednisone, C111 and ARN-509 and Abiraterone acetate and prednisone, B101 and ODM-201
and Enzalutamide and prednisone, B102 and ODM-201 and Enzalutamide and prednisone,
B103 and ODM-201 and Enzalutamide and prednisone, B104 and ODM-201 and
Enzalutamide and prednisone, B105 and ODM-201 and Enzalutamide and prednisone, B106
and ODM-201 and Enzalutamide and prednisone, C111 and ODM-201 and Enzalutamide and
prednisone, B101 and ODM-201 and ARN-509 and prednisone, B102 and ODM-201 and
ARN-509 and prednisone, B103 and ODM-201 and ARN-509 and prednisone, B104 and
ODM-201 and ARN-509 and prednisone, B105 and ODM-201 and ARN-509 and prednisone,
B106 and ODM-201 and ARN-509 and prednisone, C111 and ODM-201 and ARN-509 and
prednisone, B101 and ODM-201 and Galeterone and prednisone, B102 and ODM-201 and
Galeterone and prednisone, B103 and ODM-201 and Galeterone and prednisone, B104 and
ODM-201 and Galeterone and prednisone, B105 and ODM-201 and Galeterone and
prednisone, B106 and ODM-201 and Galeterone and prednisone, C111 and ODM-201 and
Galeterone and prednisone, B101 and ODM-201 and Abiraterone and prednisone, B102 and
ODM-201 and Abiraterone and prednisone, B103 and ODM-201 and Abiraterone and
prednisone, B104 and ODM-201 and Abiraterone and prednisone, B105 and ODM-201 and
Abiraterone and prednisone, B106 and ODM-201 and Abiraterone and prednisone, C111 and
ODM-201 and Abiraterone and prednisone, B101 and ODM-201 and Abiraterone acetate and
prednisone, B102 and ODM-201 and Abiraterone acetate and prednisone, B103 and ODM-201
and Abiraterone acetate and prednisone, B104 and ODM-201 and Abiraterone acetate and
prednisone, B105 and ODM-201 and Abiraterone acetate and prednisone, B106 and ODM-201
and Abiraterone acetate and prednisone, or, C111 and ODM-201 and Abiraterone acetate and
prednisone.
In some embodiments, the combination of the pharmaceutically acceptable salt of the
benzoheterocyclic compound of formula (I) and the androgen receptor pathway modulator and
the hormone compound is more preferably as any one of the combinations described in the
above paragraph, with the only difference of replacing "the benzoheterocyclic compound of
formula (I)" with "the pharmaceutically acceptable salt of the benzoheterocyclic compound of
formula (I)". For example, the combination of B101 and Enzalutamide and prednisone in the
above paragraph corresponds to the pharmaceutically acceptable salt of B101 and enzalutamide
and prednisone in this paragragh.
In some embodiments, the combination of the stereoisomers of the benzoheterocyclic
compound of formula (I) and the androgen receptor pathway modulator and the hormone
compound is more preferably as any one of the combinations described in the above paragraph,
with the only difference of replacing " the pharmaceutically acceptable salt of the
benzoheterocyclic compound of formula (I)" with "the stereoisomer of the benzoheterocyclic
compound of formula (I)". For example, the combination of the pharmaceutically acceptable
salt of B101 and Enzalutamide and prednisone in the above paragraph corresponds to the
stereoisomer of B101 and enzalutamide and prednisone in this paragragh.
Each of the components in the combination may be administered simultaneously or
separately (eg, sequentially); when the components in the combination are administered
simultaneously, the components in the combination may be uniformly mixed (ie, the mixture of
components).
The components in the combination may be formulated into a single pharmaceutical
composition for simultaneous administration, or each of the components may be individually
formulated into a single independent pharmaceutical composition which may be administered
simultaneously or separately (eg, sequentially).
In the invention, the term “component” refers to a component in the combination of the
invention, that is one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof, the androgen receptor pathway modulator or the
hormone compound.
The present invention further provides a pharmaceutical composition, comprising the
above combination and one or more pharmaceutically acceptable excipients.
In one aspect, the pharmaceutical composition of the invention may comprise the above
one or more of the benzoheterocyclic compound of formula (I), the pharmaceutically
acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound, metabolite
and prodrug thereof, the above androgen receptor pathway modulator, and one or more
pharmaceutically acceptable excipients.
In another aspect, the pharmaceutical composition of the invention may comprise the
above one or more of the benzoheterocyclic compound of formula (I), the pharmaceutically
acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound, metabolite
and prodrug thereof, the androgen receptor pathway modulator mentioned above, the above
hormone compound, and one or more pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients can be those widely used in drug manufacture
field. The excipient is mainly used to provide a safe, stable and functionalized pharmaceutical
composition, and can also provide a method which makes the active ingredients dissolved at a
desired rate after the subject receives administration or promotes the efficacy of absorbtion of
the active ingredients after the subject is administered with the composition. The excipient can
be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the
composition or preventing the degradation of the active ingredients of the composition. The
pharmaceutically acceptable excipient may comprise one or more of the following excipients:
binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrating
agent, lubricant, anti-adhesive agent, glidant, wetting agent, gelling agent, absorption retarder,
dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative,
colorant, flavoring agent and sweetening agent.
The pharmaceutical composition may consist of the combination and one or more
pharmaceutically acceptable excipients.
The methods of preparing pharmaceutical compositions known to people skilled in the art
include but not limited to conventional mixing, dissolving, granulating, emulsifying, grinding,
encapsulating, embedding or lyophilization. For example, the pharmaceutical composition of
the present invention can be prepared by mixing one or more of the benzoheterocyclic
compound of formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal,
stereoisomer, isotope compound, metabolite and prodrug thereof, the androgen receptor
pathway modulator and the pharmaceutically acceptable excipient, or by mixing one or more of
the benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof, the
androgen receptor pathway modulator, the hormonal compound and the pharmaceutically
acceptable excipient.
The pharmaceutical composition of the present invention may be formulated into any
form for administration, including injection (intravenous), mucosal, oral administration (solid
and liquid preparation), inhalation, ocular administration, rectal administration, topical or
parenteral (infusion, injection, implantation, subcutaneous, vein, artery, intramuscular)
administration. The pharmaceutical composition of the present invention can also be a
controlled release or delayed release preparation. Examples of solid oral preparations include
but not limited to powder, capsule, caplet, soft capsule, pill and tablet. Examples of liquid
preparations for oral or mucosal administration include but not limited to suspension, emulsion,
elixir and solution. Examples of preparations for topical administration include but not limited
to emulsion, gel, ointment, cream, patch, paste, foam, lotion, drops or serum preparation.
Examples of preparations for parenteral administration include but not limited to injection
solution, dry preparation which can be dissolved or suspended in a pharmaceutically acceptable
carrier, injection suspension and injection emulsion. Examples of other suitable preparations of
the pharmaceutical composition, include but not limited to eye drops and other ophthalmic
preparations; aerosol, such as nasal spray or inhalation; liquid dosage forms suitable for
parenteral administration; suppository and pastille.
In some embodiments, the pharmaceutical composition of the present invention relates to
a controlled release preparation. As used herein, "controlled release preparation" refers to a
preparation, wherein the therapeutic active ingredient of the pharmaceutical composition has a
controlled release rate, or a specific delay to control the release site of the therapeutic active
ingredient in the subject administered with the pharmaceutical composition. One controlled
release preparation may comprise a controlled release agent, such as a sustained release agent
(sustained release) and/or a delayed release agent (delayed release).
As used herein, the term "sustained release" refers to prolonging the release of the
therapeutic active ingredient from the pharmaceutical formulation. As used herein, the term
"delayed release" refers to that the therapeutic active ingredient releases from the
pharmaceutical composition at a specific site or in a desired environment when the
composition reaches the desired environment in the subject who has received administration or
after a specific period of time since the subject receives administration.
As used herein, the terms "sustained release agent" and "delayed release agent" refer to a
compound or an additive which controls the releasing of the therapeutic active ingredient from
the composition, so as to make the release gradually and prolong the time of release. The
sustained or delayed release agent may make the therapeutic active ingredient released within a
specific period of time after the compostion was administered to a subject.
The "controlled release" from the controlled release preparation of the pharmaceutical
composition of the present invention can be achieved by a variety of conditions, including but
not limited to pH, temperature, enzymes, water, or other physiological conditions or
compounds. The pharmaceutical composition of the present invention may further comprise an
enteric coating which controls the release of the active ingredient in the pharmaceutical
composition, making it released gradually and continuously from the composition in a desired
period of time, so that the active ingredient can play a therapeutic or preventive role for an
extended period of time. One skilled in the art may be familiar with those appropriate
controlled release agents, sustained and delayed release agents based on the disclosed contents.
Unrestrictive examples of the controlled release agents which can be incorporated into the
pharmaceutical composition of the present invention in order to provide a controlled release
composition include polymers (such as hydroxypropyl methyl cellulose), gel, permeable
membrane, particle, liposome, microsphere and the combination thereof. Any composition
described herein may be suitable for the controlled release preparation, such as tablet, capsule,
soft capsule and caplet.
In another aspect, the invention provides a kit, comprising pharmaceutical composition A
and pharmaceutical composition B;
The pharmaceutical composition A comprises one or more of the benzoheterocyclic
compound of formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal,
stereoisomer, isotope compound, metabolite and prodrug thereof and one or more
pharmaceutically acceptable excipients; The pharmaceutical composition B comprises the
androgen receptor pathway modulator and one or more pharmaceutically acceptable excipients.
The kit may consist of the pharmaceutical composition A and the pharmaceutical
composition B. The pharmaceutical composition A may consist of one or more of the
benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof and
one or more pharmaceutically acceptable excipients; The pharmaceutical composition B may
consist of the androgen receptor pathway modulator and one or more pharmaceutically
acceptable excipients. The one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof in the pharmaceutical composition A, the androgen
receptor pathway modulator in the pharmaceutical composition B, and the combination thereof
are preferably as described above.
The kit may further comprise a pharmaceutical composition C, which comprises the
hormone compound as described above and one or more pharmaceutically acceptable
excipients.
The kit may consist of the pharmaceutical composition A, the pharmaceutical composition
B and the pharmaceutical composition C. The pharmaceutical composition C may consist of
the hormone compound as described above and one or more pharmaceutically acceptable
excipients; Preferably, the one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof in the pharmaceutical composition A, the androgen
receptor pathway modulator in the pharmaceutical composition B, the hormone compound in
the pharmaceutical composition C, and the combination thereof are as described above.
The pharmaceutical compositions in the kit may be administered simultaneously or
separately (eg, sequentially).
In the kit, the term “pharmaceutically acceptable excipients” has the same definition as
above.
In the invention, the term "active ingredient" refers to the active ingredient in the
pharmaceutical composition or the kit of the invention, that is, one or more of the compound of
formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer,
isotope compound, metabolite and prodrug thereof, the androgen receptor pathway modulator,
the hormone compound, or the above combination thereof.
The above combination, the above pharmaceutical composition or the above kit can be
used for the prevention and/or treatment of prostate cancer. The prostate cancer is preferably
castration-resistant prostate cancer.
In another aspect, the invention provides use of the above one or more of the
benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof, in the
manufacture of a medicament for the prevention and/or treatment of prostate cancer in
combination with the above androgen receptor pathway modulator.
In another aspect, the invention provides use of the above one or more of the
benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof, in the
manufacture of a medicament for the prevention and/or treatment of prostate cancer in
combination with the above androgen receptor pathway modulator and the above hormone
compound.
The invention provides use of the above androgen receptor pathway modulator, in the
manufacture of a medicament for the prevention and/or treatment of prostate cancer in
combination with the above one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof.
The invention provides use of the above androgen receptor pathway modulator, in the
manufacture of a medicament for the prevention and/or treatment of prostate cancer in
combination with the above one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof and the above hormone compound.
The invention provides use of the above hormone compound, in the manufacture of a
medicament for the prevention and/or treatment of prostate cancer in combination with the
above one or more of the benzoheterocyclic compound of formula (I), the pharmaceutically
acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound, metabolite
and prodrug thereof and the above androgen receptor pathway modulator.
In the use of the invention, the above one or more of the benzoheterocyclic compound of
formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer,
isotope compound, metabolite and prodrug thereof, the above androgen receptor pathway
modulator and the above hormone compound may be administered simultaneously or
separately (eg, sequentially).
In the above use, the one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof, the androgen receptor pathway modulator, the
hormone compound and the combination thereof are as described above.
In another aspect, the invention provides a method of prevention and/or treatment of
prostate cancer, comprising administration of a therapeutically or prophylactically effective
amount of the above combination to the patients in need. The prostate cancer can be
castration-resistant prostate cancer.
In an embodiment, the method of prevention and/or treatment of prostate cancer,
comprises administration of a therapeutically or prophylactically effective amount of the above
one or more of the benzoheterocyclic compound of formula (I), the pharmaceutically
acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound, metabolite
and prodrug thereof and a therapeutically or prophylactically effective amount of the above
androgen receptor pathway modulator to the patients in need;
Wherein, the above one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof and the above androgen receptor pathway
modulator may be administered simultaneously or separately (eg, sequentially).
In some embodiments of the invention, the method of prevention and/or treatment of
prostate cancer preferably comprises administration of a therapeutically or prophylactically
effective amount of the above one or more of the benzoheterocyclic compound of formula (I),
the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof, a therapeutically or prophylactically effective
amount of the above androgen receptor pathway modulator and a therapeutically or
prophylactically effective amount of the above hormone compound to the patients in need.
Wherein, the above one or more of the benzoheterocyclic compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof, the above androgen receptor pathway modulator
and the above hormone compound may be administered simultaneously or separately (eg,
sequentially).
In the method of prevention and/or treatment of prostate cancer, the one or more of the
benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof, the
androgen receptor pathway modulator, the hormone compound and the combination thereof are
as described above.
In some embodiments, the therapeutically or prophylactically effective amount of the
compound (herein referred as to one or more of the benzoheterocyclic compound of formula (I),
the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope
compound, metabolite and prodrug thereof, the androgen receptor pathway modulator, or the
hormone compound) administered to each subject is from about 0.005 to about 1000 mg/day,
from about 0.01 to about 500 mg/day, from about 0.01 to about 250 mg/day, from about 0.01 to
about 100 mg/day, from about 0.1 to about 100 mg/day, from about 0.5 to about 100 mg/day,
from about 1 to about 100 mg/day, from about 0.01 to about 50 mg/day, from about 0.1 to
about 50 mg/day, from about 0.5 to about 50 mg/day, from about 1 to about 50 mg/day, from
about 0.02 to about 25 mg/day, or from about 0.05 to about 10 mg/day.
In some embodiments, the therapeutically or prophylactically effective amount (herein
referred as to the therapeutically or prophylactically effective amount of one or more of the
benzoheterocyclic compound of formula (I), the pharmaceutically acceptable salt, solvate,
polymorph, co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof, the
androgen receptor pathway modulator, or the hormone compound) is about 0.01, about 0.05,
about 0.1, about 0.2, about 0.3, about 0.4, about 0,5, about 0.6, about 0.8, about 1, about 2,
about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, About
60, about 70, about 80, about 90, about 100, about 150, about 200, about 250, about 300, about
350, about 400, about 450, about 500, about 550, about 600, about 650, about 700 About 750,
about 800, about 850, about 900, or about 1000 mg/day/subject.
In the combination, the pharmaceutical composition, the kit, the use or the method of
prevention and/or treatment of prostate cancer of the invention, the mole ratio of the
benzoheterocyclic compound of formula (I) and the androgen receptor pathway modulator, can
be selected in accordance with the conventional art, for example, 1:0.0002-1:300, for example,
1:0.0005-1:222 (1:0.0002, 1:0.0005, 1:0014, 1:0.0041, 1:0.012, 1:0.0037, 1:0.11, 1:0.33, 1:1,
1:3, 1:9, 1:27, 1:79, 1:222), for example, 1:0.1-1:222.
In the combination, the pharmaceutical composition, the kit, the use or the method of
prevention and/or treatment of prostate cancer of the invention, the amount of the
benzoheterocyclic compound of formula (I) and the androgen receptor pathway modulator is
not particularly limited, which can be selected in accordance with the conventional art, the
amount of the benzoheterocyclic compound of formula (I) can be for example, 0.001-300µM,
for example, 0.05-300µM (for example, 300.00µM, 100.00µM, 33.33µM, 11.11µM, 3.70µM,
1.23µM, 0.41µM, 0.14µM or 0.05µM); the amount of the androgen receptor pathway
modulator can be 0.01-300µM, for example, 0.05-50µM, for example, 0.05-11.11µM.
In the combination, the pharmaceutical composition, the kit, the use or the method of
prevention and/or treatment of prostate cancer of the invention, when the hormone compound
is further comprised, the amount of the hormone compound is not particularly limited, for
example, the mole ratio of the hormone compound and the androgen receptor pathway
modulator can be 1:0.01-1:100, for another example, 1:0.1-1:10 (for another example,1:0.1, 1:1,
2:1, 1:10).
In the combination, the pharmaceutical composition, the kit, the use or the method of
prevention and/or treatment of prostate cancer of the invention, when the hormone compound
is further comprised, the amount of the hormone compound is not particularly limited, for
example, the amount of the hormone compound and the androgen receptor pathway modulator
can be individually 0.01-300µM, for another example, 0.05-50µM, for another example,
0.1-10µM.
When each of the components in the combination of the present invention is administered
to a subject for the purpose of treating or preventing a disease, disorder or condition, each
component in the combination may be administered by the same route or by a different route.
The route of administration may be any route described herein, including but not limited to oral,
inhalation, injection, ophthalmic, mucosal, rectal, emulsion, liposome, long-acting implant or
sustained controlled release method. The specific route of administration will depend on the
therapeutic agent itself and the preparation, as well as the disease, disorder or condition to be
prevented or treated. According to the present disclosure, the skill level of an ordinary person
skilled in the art is sufficient to determine the route of administration. Each of the components
in the combination of the present invention may be administered to the subject within a period
of time (administration period) followed by a period of no administration of the compound
(non-administration period). The administration period and non-administration period can be
repeated for desired times. The desired length and times of the administration period or
non-administration period will depend on the type and/or severity of the disease, disorder or
condition being treated or prevented, as well as the sex, age, weight, and other parameters (e.g.
the individual subject’s biological, physical, and physiological status, etc.) of the individual
subject. Each of the components in the combination of the present invention may be
administered simultaneously to the subject in a period of time and may also be administered to
the subject sequentially in a period of time. According to the present disclosure, the skill level
of an ordinary person skilled in the art is sufficient to determine the appropriate length and
times of administration period and / or non-administration period.
The therapeutic method in the present invention comprises administering each of the
components in the combination of the present invention to a subject by any suitable methods,
such as injection, mucosal, oral, inhalation, ocular, rectal, long-acting implant, liposome,
emulsion or sustained release process.
One skilled in the art will understand that the therapeutically or prophylactically effective
amount of each of the components or the active ingredients in the combination, pharmaceutical
composition or the kit of the present invention may vary with factors, for a specific subject,
such as age, diet, health, etc., the symptom or disease to be treated or prevented, the severity of
the disorder or condition, and the complications and types, and the preparations used etc.
According to the disclosures in present invention, one skilled in the art can easily determine the
desired therapeutically or prophylactically effective amount administered to the subject, so as
to induce the desired biological or medical response in the subject.
The combined use of each of the components or the active ingredients in the combination,
pharmaceutical composition or the kit according to the present invention may play a synergistic
effect in the treatment or prevention of any disease, disorder or condition (such as prostate
cancer).
In any of the methods described herein, including but not limited to the above therapeutic
methods, applications etc., the combination, the pharmaceutical composition or the kit
according to the present invention may be used alone or in combination with ultrasound
therapy, radiation therapy (referred to as radiotherapy) or radioimmunotherapy etc., and may
also be used in combination with one or more of other pharmacologically active therapeutic
agents (hereinafter referred to as "other therapeutic agents"). The amount and type of other
therapeutic agents will depend on the disease, disorder or condition to be treated or prevented;
the severity of the disease, disorder or condition; factors of the subject administrated with the
composition, such as age, weight, physical conditions, etc.; the route of administration, and so
on. According to the embodiments of the present invention, the other therapeutic agent may be
a natural, semi-synthetic or synthetic compound. In another embodiment, the other therapeutic
agent may be a small molecule, such as a synthetic organic or inorganic molecule; or a larger
molecule or biomolecule, such as a protein or nucleic acid with pharmacological activity. In
another embodiment, the other therapeutic agent may be one or more of a chemotherapeutant,
an antiangiogenic drug (also known as an angiogenesis inhibitor), an immunomodulatory agent,
an immunotherapeutic agent, a monoclonal antibody, a polyclonal antibody, and a kinase
inhibitor.
The chemotherapeutant (chemotherapeutic agent), is a chemically synthesized drug.
Currently, the chemotherapeutant is the main drug in the treatment of cancer and some
autoimmune diseases, what commonly used are: epirubicin, doxorubicin, daunorubicin,
mitomycin, fluorouracil deoxynucleotides and so on.
The antiangiogenic drug inhibits angiogenesis by inhibiting pro-angiogenic growth factor,
growth factor receptor or signaling pathway downstream etc., so as to inhibit the growth and
metastasis of the tumors, and it mainly includes vascular endothelial growth inhibitor, receptor
tyrosine kinase inhibitor, PI3K/AKT/mTOR pathway inhibitor, recombinant fusion protein (e.g.
aflibercept) acting on VEGF-A, VEGF-B and placental growth factor, recombinant human
endostatin and so on.
The immunomodulatory agent is a drug which can enhance, promote and regulate immune
functions and have a certain effect on immune dysfunction, some secondary immunodeficiency
diseases and some malignant tumors. In accordance with the functions of the
immunomodulatory agent, the immunomodulatory agent is mainly divided into
immunosuppressant and immunopotentiator. The former is used for anti-inflammatory,
anti-autoimmune reactions, anti-allergy, anti-transplant rejection and anti-tumor, and the latter
is for anti-infection, anti-allergy, and anti-tumor. Various kinds of drugs belong to
immunosuppressant, including antimetabolic drugs(cyclosporin A, azathioprine,
cyclophosphamide, methotrexate, mycophenolate, tacrolimus, mizoribine etc.), glucocorticoid,
monoclonal antibody (anti-TNF-alpha/receptor, anti-IFN-γ, and anti-CD25 monoclonal
antibody, etc.), cytokines IFN-β, IL-10 and TGF-β, chemicals(leflunomide and 5-HT3 receptor
antagonist), non-steroid anti-inflammatory drugs, nucleic acids, statins anti-lipid drugs, HMG
coenzyme A reductase inhibitor, plants (Tripterygium wilfordii, extract of Cordyceps sinensis
FTY720, artemisinin and Parviline etc.) and other biological products (cholera toxin B subunit,
sNTB-A-Fc fusion protein, CMV-IkappaBa carrier inhibitor and B7-HI inhibitor etc.). There
are also various kinds of immunopotentiators, including cytokines(interferon α, interferon γ,
thymic peptide, Thymopentin, G-CSF/GM-CSF, IL-2, IL-12, recombinant human
erythropoietin, epidermal growth factor, chemokine intercellular adhesion molecule-1, vascular
cell adhesion molecule-1, P-selectin, and other intercellular adhesion molecules, etc.),
biological products [IVIG, transfer factor, immune riboncleic acid, bacteria and its extract
(Bacillus Calmette Guerin and its extract, defatted and deactivated mycobacterium vaccine,
other bacterial extracts, low calcium response V or V antigen LcrV, vibrio cholerae products
Zot and mycobacterium etc.)], plant drugs (polysaccharides, saponins and other plant
ingredients), chemicals (Levamisole, Tagamet, Pidotimod, NS-398 Imiquimod,
Propagermanium and liposome etc.), micronutrients (vitamin A/C/D, trace elements iron, zinc,
selenium) and others (macrolide antibiotics, aminophylline).
Immunotherapy refers to the modulation of the immune response of a subject to produce
the desired therapeutic effect, the immunotherapeutic agent refers to a drug that when
administered to a subject modulates the immune system of the subject so as to be sufficient to
ultimately reduce the symptoms associated with an adverse immune response or ultimately
reduce the symptoms caused by the increase of the required immune response.
The monoclonal antibody refers to a highly uniform antibody, produced by a single B cell
clone, targeting only a specific epitope.
The polyclonal antibody refers to different antibodies produced by using an antigen
immune receptor that contains multiple antigenic determinants to stimulate multiple B cell
clones in the body, targeting multiple antigenic epitopes.
In biochemistry, kinases are enzymes that transfer phosphate groups from high-energy
donor molecules (such as ATP) to specific target molecules (substrates); and this process is
called phosphorylation; the kinase inhibitor refers to a class of molecules that may bind with
kinases and reduce their activity.
The other therapeutic agent includes but not limited to one or more of daratumumab,
elotuzumab, palbociclib, panobinostat, nivolumab, pembrolizumab, pemetrexed, topotecan,
doxorubicin, bortezomib, gemcitabine, dacarbazine, biaxin, vincristine, azacitidine, CAR-T,
rituximab, trastuzumab, PD-1 inhibitor, PD-L1 inhibitor, HDAC inhibitor, androgen receptor
pathway regulators other than the aforementioned androgen receptor pathway regulators,
docetaxel, clofarabine injection, Ublituximab, romidepsin, BTK inhibitor, erythropoietin,
eltrombopag, minocycline and melphalan.
In another embodiment, the therapeutically or prophylactically effective amount of the
androgen receptor pathway modulator or the hormone compound in the pharmaceutical
composition or the kit of the present invention may be lower than the effective amount when
the compound of formula (I), the pharmaceutically acceptable salt, solvate, polymorph,
co-crystal, stereoisomer, isotope compound, metabolite and prodrug thereof of the present
invention is not administered.
In the present invention, the amount of the compound administered, the therapeutically or
prophylactically effective amount, the dosage, the starting dosage and the like are all referred
to the amount of a specific compound, for example, a specific heterocyclic compound of
formula (I), the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer,
isotope compound, metabolite and prodrug thereof, a specific androgen receptor pathway
modulator or a specific hormone, rather than a combination of multiple compounds.
In the present invention, the therapeutically or prophylactically effective amount of the
androgen receptor pathway modulator or the hormone compound in the method and the
guidance for administration can be found in the patents and published patent applications cited
herein, and Wells et al, eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,
Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe
Edition, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical literatures.
The term “androgen receptor pathway modulator” in the present invention comprises
androgen inhibitor, androgen receptor inhibitor, androgen biosynthesis inhibitor and other
drugs that affect the androgen receptor pathway.
The term “hormones” are a class of chemicals that are produced by certain tissues of a
normal body, and then diffuse into the blood, and are transported to other tissues in the body by
blood circulation to exert special physiological functions. Hormonal compounds include
synthetic or natural hormonal chemicals.
As used herein, when referring to a specific salt, composition, and excipient etc. as
"pharmaceutically acceptable", it means that the salt, the composition, the excipient etc. are
generally non-toxic, safe, and suitable for use in a subject, preferably a mammalian subject,
more preferably a human subject
The term “pharmaceutically acceptable salt” herein refers to a pharmaceutically
acceptable organic or inorganic salt. Examples of the salt include but are not limited to: sulfate,
citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrosulfate, phosphate, acid
phosphate, isonicotinic acid salt, lactate, salicylic acid salt, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucuronate, saccharate, formate, benzoate, glutamate, methane sulfonate, ethane sulfonate,
benzene sulfonate, p-toluene sulfonate, and embonate (i.e.
1methylene-bis(2-hydroxynaphthoate)). The compounds of the present invention may
form pharmaceutically acceptable salts with various amino acids. Suitable alkali salts include
but are not limited to, aluminum salt, calcium salt, lithium salt, magnesium salt, potassium salt,
sodium salt, zinc salt, bismuth salt and diethanolamine salt. For a review of the
pharmaceutically acceptable salts, see Handbook of Pharmaceutical Salts: Properties, Selection,
and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
As used herein, the term “metabolite” refers to an active substance produced by changes
in chemical structure that a drug molecule undergoes in vivo, the active substance is generally
a derivative of the aforementioned drug molecule, and can also be chemically modified.
As used herein, the term “polymorph” refers to one or more crystal structures formed by
the different arrangement of molecules in the lattice space when crystallized.
As used herein, the term “co-crystal” refers to a multi-component system comprising one
or more API (active pharmaceutical ingredient) molecules and one or more object (or ligand)
molecules. In the co-crystal, API molecules and object (or ligand) molecules exist as solids at
room temperature when they are used as their pure form alone (in order to distinguish
co-crystal from solvate or hydrate). From this particular definition, salts in which significant or
complete proton exchange occurs between API molecules and guest molecules are excluded. In
the co-crystal, API and ligands interact through hydrogen bonds and other possible
non-covalent interactions. It is noted that the co-crystal itself may form solvates, including
hydrates. The object (or ligand) refers to other physiologically acceptable acids, bases or
non-ionic compounds.
As used herein, the term “solvate” refers to a crystal form of the compound of formula (I),
the pharmaceutically acceptable salt, polymorph, co-crystal, stereoisomer, isotopic compound,
metabolite or prodrug thereof, which further comprises one or more solvent molecule(s)
incorporated into the crystal structure. The solvate may include a stoichiometric amount or a
non-stoichiometric amount of solvent, and the solvent molecule in the solvent may exist in an
ordered or non-ordered arrangement. The solvate containing a non-stoichiometric amount of
solvent molecules may be obtained by the loss of at least one solvent molecule (but not all)
from the solvate. In a particular embodiment, a solvate refers to a hydrate, which means the
crystal of the compound further comprises water molecules, with water molecules as the
solvent.
As used herein, the term “prodrug” refers to a derivative of the compound comprising a
biologically reactive functional group such that the biological reactive functional group can be
cleaved from the compound or react in other ways to give the compound under biological
conditions (in vivo or in vitro). Usually, the prodrug is inactive, or at least has lower activity
than the compound itself, so that the compound exhibits its activity until it is cleaved from the
biologically reactive functional group. The biologically reactive functional group can be
hydrolyzed or oxidized under biological conditions to give the compound. For instance, the
prodrug may contain a biologically hydrolysable group. Examples of the biologically
hydrolysable group include but are not limited to: a biologically hydrolysable phosphate, a
biologically hydrolysable ester, a biologically hydrolysable amide, a biologically hydrolysable
carbonic ester, a biologically hydrolysable carbamate and a biologically hydrolysable ureide.
For a review of the prodrug, see, for example, J. Rautio et al., Nature Reviews Drug Discovery
(2008) 7, 255-270 and Prodrugs: Challenges and Rewards (V. Stella et al. ed., Springer, 2007).
The compound of formula (I), the pharmaceutically acceptable salt, solvate, polymorph,
co-crystal, stereoisomer, isotope compound, metabolite or prodrug thereof in the combination
of the present invention, may contain one or more asymmetric centers (“stereoisomer”). As
used herein, the term “stereoisomer” refers to all stereoisomers including enantiomers,
diastereoisomers, epimers, endo-exo isomers, atropisomers, regioisomers, cis- and
trans-isomers. The “stereoisomer” herein also includes "pure stereoisomer" and "enriched
stereoisomer" or "racemic isomer" of the various aforementioned stereoisomers. These
stereoisomers can be prepared according to an asymmetric synthesis process, or separated,
purified and enriched by a chiral separation process (including but not limited to thin layer
chromatography, rotating chromatography, column chromatography, gas chromatography, high
pressure liquid chromatography, etc.), and can also be obtained through chiral separation by
means of bonding (chemical binding etc.) or salifying (physical binding etc.) with other chiral
compound(s). The term "pure stereoisomer" herein refers to a stereoisomer of the compound
with the mass content of no less than 95% relative to other stereoisomers of the compound. The
term "enriched stereoisomer" herein refers to a stereoisomer of the compound with the mass
content of no less than 50% relative to other stereoisomers of the compound. The term
"racemic isomer" herein refers to a stereoisomer of the compound with the mass content equal
to that of other stereoisomers of the compound.
As used herein, D represents deuterium-enriched hydrogen, and H represents
non-deuterium-enriched hydrogen. “Deuterium-enriched” compound means that abundance of
deuterium at any relevant site in the compound of formula (I), the pharmaceutically acceptable
salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound, metabolite or prodrug
thereof is greater than its natural abundance at that site (0.0156%). So, in the
“deuterium-enriched” compounds, the abundance of deuterium at any of its related sites may
be in the range of 0.0156% to 100%. An example of a process for obtaining
deuterium-enriched compounds is to exchange hydrogen with deuterium or to synthesize the
compound from deuterium-enriched starting material.
Based on the general knowledge in the art, the symbol H may be omitted in the
non-deuterium-enriched site. “Non-deuterium enriched” refers to hydrogen in nature, i.e., in
the form of isotopic mixture of H (hydrogen or protium), D ( H or deuterium) and T ( H or
tritium).
The term “isotopic compound” used herein refers to the compound as shown in formula
(I), the pharmaceutically acceptable salt, the solvate, the polymorph, the co-crystal, the
stereoisomer, the isotopic compound, the metabolite or the prodrug thereof containing one or
more atomic isotope(s) with natural or non-natural abundance. Atomic isotopes with
non-natural abundance include, but are not limited to: deuterium ( H or D), tritium ( H or T),
125 32 13 14
iodine-125 ( I), phosphorus-32 ( P), carbon-13 ( C) or carbon-14 ( C). The aforementioned
isotopic compound can also be used as a therapeutic or diagnostic agent (i.e., internal
developing agent) or a research tool. All the isotopic variants of the compound of the present
invention, whether radioactive or not, are included in the scope of the present invention.
The term “isotope enriched” used herein refers to the compound of formula (I), the
pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, metabolite or
prodrug thereof containing one or more atomic isotope(s) with non-natural abundance. The
term “isotope enriched” also refers to the compound as shown in formula (I), the
pharmaceutically acceptable salt, the solvate, the polymorph, the co-crystal, the stereoisomer,
the isotopic compound, the metabolite or the prodrug thereof containing at least one isotopic
atom with non-natural abundance.
As used herein, the term "subject" or “patient” refers to any animal to be treated or treated
with the compound or the composition according to the embodiments of the present invention,
preferably mammal, and most preferably human. The term "mammal" used herein includes any
mammal. Examples of mammals include but not limited to cattle, horse, sheep, pig, cat, dog,
mouse, rat, rabbit, guinea pig, monkey, human and the like, most preferably human. In an
embodiment, the terms "treat" and "treating" refers to an improvement, prevention or reversal
of a disease or condition or at least one of identifiable symptoms thereof, such as treating
cancer by reducing or stabilizing the symptoms of the cancer or the condition. In another
embodiment, "treat" or "treating" refers to an improvement, prevention or reversal of at least
one measurable body parameter of a disease or condition which is being treated, but may not
be identified in mammal. However, in another embodiment, the term “treat” or “treating” refers
to slowing the progression of a disease or condition, in physical, such as stabilizing identifiable
symptoms, or in physiological, such as stabilizing physical parameters, or in both. In another
embodiment, the term “treat” or “treating” refers to delaying the development of a disease or
symptom.
In some embodiments, the combination, pharmaceutical composition or kit is
administered for a prevention purpose. As used herein, "prevent" or "preventing" refers to a
reduction in a risk of obtaining a given disease or condition. In a preferred embodiment, the
designated combination, pharmaceutical composition or kit is administered for a prevention
purpose to a subject, such as a subject with family history or tendency of cancer or
autoimmune disease.
As used herein, “therapeutically effective amount” refers to an amount of the compound
or the composition (which is sought by researchers, veterinarians, physicians, or other
clinicians) that can cause a biological or medical response in a tissue system, an animal or a
person, which may include relieving symptoms of the disease or symptom which is being
treated. In a preferred embodiment, the therapeutically effective amount is an amount which is
enough to effectively treat, improve or prevent cancer, condition or undesirable angiogenesis.
The term “prophylactically effective amount” refers to an amount of the active compound
or medicament (sought by researchers, veterinarians, physicians or other clinicians) that can
inhibit the development of a disease in a subject. A prophylactically effective amount of the
compound refers to an amount of the therapeutic agent used alone or in combination with other
active compound, which can provide a therapeutic benefit for treating or preventing the disease,
condition or disorder.
Each preferred conditions aforementioned can be combined randomly without departing
from the common knowledge in the art thereby forming various preferred embodiments of the
present invention.
Unless otherwise specified, the singular form of the term used herein, "a" or "an", also
includes a plural meaning.
Unless otherwise specified, the term "or" or "and" used herein refers to "and/or".
Various publications, articles, and patents are cited or described herein. The citation or
description of these references or the incorporation in their entirety or the discussion about
them intends to illustrate the background of the present invention, but not to mean that the
contents thereof form a part of the prior art of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as commonly understood by an ordinary person skilled in the art to which this
invention belongs. Otherwise, the meaning of certain terms used herein has the meaning set
forth in this description.
In the present invention, the structures of the androgen receptor pathway modulator and
the hormone compound are as follows:
Enzalutamide
ARN-509 (Apalutamide)
ODM-201 (BAY-1841788)
VT-464
Orteronel (TAK-700)
EPI-001
Bicalutamide
Andarine (GTx-007)
RD162
BMS-641988
CH5137291
Flutamide
Hydroxyflutamide
Nilutamide
RU58642
LG120907
LG105
Galeterone (TOK-001)
Abiraterone acetate
Abiraterone
Spironolactone
MK-2866 (GTx-024)
AZD3514
Dehydroepiandrosterone
Epiandrosterone
Cyproterone Acetate
Megestrol Acetate
ORM-15341
Prednisone
Degarelix
Goserelin acetate
Leuprolide acetate
The reagents used in the present invention are all commercially available. The compound
of formula (I) and the androgen receptor pathway modulator in the present invention may be
prepared by people skilled in the art according to synthetic methods well known in the art, or
readily synthesized according to the published literatures or patents, such as WO2016065980,
WO9803502, WO2010056344, WO2012079022, WO2012015986, WO2011100380,
WO2014116573, WO2008039489, WO2014110558, WO2014039421, WO2006124118 and so
The positive effect of the present invention is that the combination of the present
invention can inhibit the growth of prostate cancer cells more effectively. There is a synergistic
effect between each of the components in the combination.
Detailed description of the embodiments
The invention will be further illustrated by the following examples, but it should not be
constructed that the invention is limited to the scope of the examples. The experimental
methods that are not specified in details in the following examples are those according to
conventional methods and conditions, or according to the product manuals.
Effect embodiment 1 CTG cell proliferation assay
In vitro test of the inhibition effect of the compound in combination with androgen
receptor pathway modulators on the prostate cancer cell proliferation.
Inhibition effect of the compounds such as B101, B102, B103, B104, B105, B106, C111
and the like, androgen receptor pathway modulators, hormone compounds, alone or in
combination with each other on the prostate cancer cell proliferation were tested on Vcap cells
(androgen receptor (+) prostate cancer cells) (ATCC, catalogue number CRL-2876). The
specific experimental operation was as follows: 5×10 Vcap cells per well were inoculated into
96-well plates with transparent bottom and white wall (Corning, catalogue number CLS3903)
containing the specific medium, and were cultured in a 37 °C, 5% CO incubator for 24 hours.
The tested compounds and the androgen receptor pathway modulators were prepared to a
150mM stocking solution with DMSO (Sigma, catalogue number 276855), diluted with culture
medium to the desired concentrations (the final concentration of DMSO is 0.2%), and then
added to each well, 2 wells/concentration, followed by being incubated in a 37 °C, 5% CO
incubator for 5 days. The tested compounds were used alone or in combination with other
androgen receptor pathway modulators and/or hormone compounds respectively. The
combination drugs were: Enzalutamide(Selleck, catalogue number S1250), ARN-509 (Selleck,
catalogue number S2840), Abiraterone acetate (Selleck, catalogue number S2246), Galeterone
(Selleck, catalogue number S2803), ODM-201 (Kangpu Biopharmaceuticals, Ltd.) or
Prednisone (Selleck, catalogue number S1622). The concentration setting of each drug was
shown in the following tables of experimental results. After that, 100 μl of CellTiter-Glo® cell
viability assay reagent (Promega, catalogue number G7570) was added to each well and mixed
well on a vibrator for 10 minutes to induce cell lysis. The 96-well plate was placed at room
temperature for 10 minutes, so as to stabilize its luminescence signal. A white bottom
membrane was pasted on the bottom of the plate and the plate was tested using EnSpire. The
data was processed by Graphpad/Prism and Calcusyn software to calculate the average cell
proliferation inhibition rate or survival rate for each compound or the synergism index of the
drug combination, and the specific experimental results were shown in Tables 1-12.
Table 1. Vcap cell proliferation inhibition rate: the combination of B105 and Enzalutamide
B105 (µM)
300.0 100.0 0.00
33.33 11.11 3.70 1.23 0.41 0.14 0.05
0 0
Enzalutamid 11.1 62.2 64.6 65.4 64.6 62.5 63.4 60.2 59.2 52.3 38.9
e (µM) 1 % % % % % % % % % %
65.8 67.7 67.3 67.8 67.0 64.5 63.9 59.8 53.4 38.2
3.70
% % % % % % % % % %
62.9 63.2 64.5 66.4 64.6 61.8 60.2 54.1 48.2 30.0
1.23
% % % % % % % % % %
0.41 55.4 51.9 53.0 52.3 50.5 49.7 48.1 45.4 37.1 29.5
% % % % % % % % % %
41.0 39.7 41.4 40.9 37.8 38.5 39.7 36.2 28.3 20.8
0.14
% % % % % % % % % %
33.3 29.5 34.6 33.8 32.2 33.5 33.6 31.9 25.8 17.7
0.05
% % % % % % % % % %
22.8 25.1 27.4 27.0 25.9 26.3 28.2 23.9 17.4 6.5%
0.00
% % % % % % % % %
Noes of table 1: The cell proliferation inhibition rate (%) was measured after processing the
Vcap cells with different concentrations of B105 and Enzalutamide alone or in combination for
days. The effect of drug combination was outstanding, for example, the inhibition rate on
Vcap cells was 26.3% when B105 was used alone (concentration of 1.23 μM), the inhibition
rate on Vcap cells was 30% when Enzalutamide was used alone (concentration of 1.23 μM),
and the inhibition rate on Vcap cells was 61.8% when the two were combined (1.23 μM B105
and 1.23 μM Enzalutamide).
Table 2. Synergism index of the combination of B105 and Enzalutamide (carrying out
synergism analysis on the experimental data of the drug combination in table 1)
B105 (µM)
300.00 100.00 33.33 11.11 3.70 1.23 0.41 0.14 0.05
Enzalutamide 11.11 0.018 0.011 0.01 0.011 0.017 0.014 0.027 0.033 0.126
(µM) 3.70 0.003 0.002 0.002 0.002 0.002 0.004 0.004 0.01 0.034
1.23 0.002 0.002 0.001 0.001 0.001 0.002 0.003 0.01 0.03
0.41 0.003 0.005 0.004 0.005 0.007 0.008 0.01 0.017 0.088
0.14 0.014 0.018 0.013 0.014 0.026 0.023 0.018 0.036 0.201
0.05 0.024 0.055 0.018 0.021 0.03 0.023 0.022 0.032 0.132
Notes of table 2: The synergism analysis was carried out on the experimental data of the
drug combination of B105 and Enzalutamide in table 1 to give the data in Table 2 which
showed a strong synergism when the two drugs are used in combination.
Notes of the synergism index of drug combination (the same below): <0.1: very strong
synergism; 0.1-0.3: strong synergism; 0.3-0.7: synergism; 0.7-0.85: mild synergism; 0.85-0.90:
slight synergism; 0.90-1.10: approximately additive action; 1.10- 1.20: slight antagonism;
1.20-1.45: mild antagonism; 1.45-3.3: antagonism; 3.3-10: strong antagonism; >10: very strong
antagonism.
Table 3: Vcap cell proliferation inhibition rate: the combination of C111 and Enzalutamide
C111(µM)
300. 100.0 0.00
33.33 11.11 3.70 1.23 0.41 0.14 0.05
00 0
Enzalutamid 68.8 64.2 62.8 58.3 57.0 55.7 54.0 53.5 53.3 36.6
11.11
e (µM) % % % % % % % % % %
70.7 64.4 58.5 57.5 55.2 52.9 54.3 51.6 51.9 37.0
3.70
% % % % % % % % % %
70.1 64.3 59.5 57.0 52.2 54.7 51.1 52.5 49.8 36.8
1.23
% % % % % % % % % %
61.6 53.1 48.3 47.5 45.5 42.1 44.9 40.7 41.1 33.9
0.41
% % % % % % % % % %
54.0 43.3 44.9 44.4 36.4 42.0 40.9 41.4 38.3 27.7
0.14
% % % % % % % % % %
44.4 38.4 37.9 33.8 34.6 34.7 30.2 31.7 29.8 17.0
0.05
% % % % % % % % % %
33.9 31.6 29.1 28.8 25.4 23.4 24.9 20.9 19.6 6.9%
0.00
% % % % % % % % %
Noes of table 3: The cell proliferation inhibition rate (%) was measured after processing the
Vcap cells with different concentrations of C111 and Enzalutamide alone or in combination for
days. The effect of drug combination was outstanding, for example, the inhibition rate on
Vcap cells was 23.4% when C111 was used alone (concentration of 1.23 μM), the inhibition
rate on Vcap cells was 36.8% when Enzalutamide was used alone (concentration of 1.23 μM),
and the inhibition rate on Vcap cells was 54.7% when the two were combined (1.23 μM C111
and 1.23 μM Enzalutamide).
Table 4. Synergism index of the combination of C111 and Enzalutamide (carrying out
synergism analysis on the experimental data of the drug combination in table 3)
C111(µM)
300.00 100.00 33.33 11.11 3.70 1.23 0.41 0.14 0.05
Enzalutamide
(µM) 11.11 0.001 0.005 0.007 0.02 0.028 0.038 0.056 0.063 0.066
3.70 0 0.002 0.006 0.008 0.014 0.024 0.018 0.033 0.031
1.23 0 0.001 0.002 0.003 0.009 0.005 0.012 0.009 0.017
0.41 0 0.003 0.008 0.009 0.015 0.034 0.017 0.047 0.043
0.14 0.001 0.011 0.006 0.007 0.049 0.012 0.015 0.014 0.029
0.05 0.006 0.036 0.023 0.065 0.033 0.027 0.092 0.057 0.094
Notes of table 4: The synergism analysis was carried out on the experimental data of the
drug combination of C111 and Enzalutamide in table 3 to give the data in Table 4 which
showed a strong synergism when the two drugs are used in combination.
Table 5: Survival rate of Vcap cells: tested compound alone, tested compound in combination
with Enzalutamide or ARN-509
tested compound in combination with 1µM in combination with 1µM
tested
alone Enzalutamide ARN-509
compound
10µM 1µM 0.1µM 10µM 1µM 0.1µM 10µM 1µM 0.1µM
52.3% 54.0% 74.5%
Enzalutamide
ARN-509 48.9% 52.2% 81.8%
B101 64.7% 65.4% 77.7% 24.4% 25.2% 30.6% 24.5% 24.3% 29.3%
B105 72.7% 72.5% 83.3% 27.5% 27.5% 31.6% 27.0% 28.0% 30.6%
C111 77.0% 81.0% 81.5% 36.6% 35.8% 36.3% 37.3% 35.6% 37.0%
Notes of table 5: The effect of the drug combination was outstanding, for example, the cell
survival rates were 65.4%, 72.5%, 81.0%, 54.0% and 52.2% when B101, B105, C111,
enzalutamide and ARN-509 were used alone respectively at 1.0 μM. The cell survival rates
were 25.2%, 27.5% and 35.8% when 1.0 μM B101, B105 or C111 was used in combination
with 1.0 μM enzalutamide respectively. The cell survival rates were 24.3%, 28.0% and 35.6%
when 1.0 μM B101, B105 or C111 was used in combination with 1.0 μM ARN-509
respectively.
Table 6: Survival rate of Vcap cells: tested compound alone, tested compound in
combination with Galeterone or Abiraterone acetate
in combination with in combination with 1µM
tested compound alone
tested
1µM Galeterone Abiraterone acetate
compound
10µM 1µM 0.1µM 10µM 1µM 0.1µM 10µM 1µM 0.1µM
B101 64.7% 65.4% 77.7% 32.5% 34.4% 38.6% 52.9% 56.6% 61.8%
B105 72.7% 72.5% 83.3% 36.3% 36.7% 40.9% 58.0% 57.1% 65.0%
C111 77.0% 81.0% 81.5% 47.8% 47.0% 46.6% 66.1% 68.5% 65.5%
Galeterone 19.3% 62.8% 95.9%
Abiraterone
31.4% 91.7% 106.3%
acetate
Notes of table 6: The effect of the drug combination was outstanding, for example, the cell
survival rates were 65.4%, 72.5%, 81.0%, 62.8% and 91.7% when B101, B105, C111,
Galeterone and Abiraterone acetate were used alone respectively at 1.0 μM. The cell survival
rates were 34.4%, 36.7% and 47.0% when 1.0 μM B101, B105 or C111 was used in
combination with 1.0 μM Galeterone respectively. The cell survival rates were 56.6%, 57.1%
and 68.5% when 1.0 μM B101, B105 or C111 was used in combination with 1.0 μM
Abiraterone acetate respectively.
Table 7: Survival rate of Vcap cells: tested compound alone, tested compound in combination
with ODM-201
tested compound alone in combination with 1µM ODM-201
tested compound
10µM 1µM 0.1µM 10µM 1µM 0.1µM
ODM-201 75.4% 69.0% 90.7%
B101 65.8% 71.1% 81.7% 32.5% 37.1% 43.8%
B105 65.5% 69.7% 77.9% 32.2% 36.6% 43.3%
C111 63.3% 72.0% 76.3% 37.2% 43.1% 45.9%
Notes of table 7: The effect of the drugs combination was outstanding, for example, the cell
survival rates were 69.0%, 71.1%, 69.7% and 72.0% respectively when ODM-201, B101,
B105 and C111 were used alone at 1.0 μM. The cell survival rates were 37.1%, 36.6% and 43.1%
when 1.0 μM B101, B105 or C111 was used in combination with 1.0 μM ODM-201
respectively.
Table 8: Survival rate of Vcap cells: B105 in combination with Enzalutamide, ARN-509,
Prednisone, Galeterone, or Abiraterone acetate respectively
Abirater
drug
B10 Predniso Gale
ARN-509
Enzalutamide one Cell
combinati
ne terone
acetate surviv
al rate
10µ 1µ 0.1µ 10µ 1µ 0.1µ
1µM M M M M M M 1µM 1µM 1µM
v v 51.8%
v v 54.5%
v v 84.6%
v v 50.9%
v v 52.4%
v v 59.5%
v v 51.7%
v v 50.7%
2-drug
v v 69.7%
combinati
v v 47.4%
v v 54.3%
v v 79.6%
v v 46.5%
v v 50.8%
v v 61.0%
v v 46.6%
v v 50.5%
v v 68.9%
3-drug
v v v 50.4%
combinati v v v 49.5%
v v v 54.3%
v v v 46.3%
v v v 45.9%
v v v 68.5%
v v v 46.2%
v v v 47.5%
v v v 58.3%
v v v 44.1%
v v v 46.1%
v v v 69.3%
v v v 35.6%
v v v 53.1%
v v v 23.9%
v v v 23.0%
v v v 24.5%
v v v 21.7%
v v v 22.8%
v v v 25.5%
v v v 22.8%
v v v 22.0%
v v v 22.6%
v v v 21.6%
v v v 22.7%
v v v 23.6%
v v v 27.6%
v v v 37.0%
v v v 46.4%
v v v 27.9%
v v v 32.5%
v v v 39.8%
v v v v 28.8%
4-drug
v v v v 27.3%
combinati
v v v v 23.8%
v v v v 22.2%
v v v v 25.5%
v v v v 25.9%
v v v v 25.5%
v v v v 23.4%
v v v v 28.8%
v v v v 38.8%
v v v v 27.1%
v v v v 32.7%
“V” refers to the components contained in the combination. The blank indicates the
component was not contained. The same below.
Notes of table 8: The effect of the drug combination was outstanding, for example, the cell
survival rate was 50.7% when 1.0µM Enzalutamide was used in combination with 1.0µM
Abiraterone acetate. The cell survival rate decreased to 22.0% when 1.0µM Enzalutamide was
used in combination with 1.0µM Abiraterone acetate and 1.0µM B105. The cell survival rate
was 45.9% when 1.0µM Enzalutamide was used in combination with 1.0µM Prednisone and
1.0µM Abiraterone acetate. The cell survival rate decreased to 25.9% when 1.0µM
Enzalutamide was used in combination with 1.0µM Prednisone and 1.0µM Abiraterone acetate
and 1.0µM B105.
Table 9. Survival rate of Vcap cells: C111 in combination with Enzalutamide, ARN-509,
Prednisone, Galeterone, or Abiraterone acetate respectively
Pred Abiratero
C11 Gale-
Drug ARN-509
Enzalutamide nison ne Cell
1 terone
combination
e acetate surviv
1µ 10µ 1µ 0.1µ 10µ 1µ 0.1µ
al rate
M M M M M M M 1µM 1µM 1µM
v v v 51.4%
v v v 52.8%
v v v 64.1%
3-drug
v v v 50.2%
combination
v v v 49.8%
v v v 68.1%
v v v 48.7%
v v v 54.0%
v v v 57.4%
v v v 48.4%
v v v 55.5%
v v v 66.5%
v v v 41.9%
v v v 64.9%
v v v 39.0%
v v v 38.4%
v v v 38.8%
v v v 34.3%
v v v 34.1%
v v v 35.4%
v v v 37.2%
v v v 40.1%
v v v 41.6%
v v v 39.5%
v v v 38.8%
v v v 38.8%
v v v 44.4%
v v v 49.6%
v v v 56.7%
v v v 42.6%
v v v 47.7%
v v v 60.0%
v v v v 36.3%
v v v v 38.1%
v v v v 34.5%
v v v v 33.2%
4-drug
v v v v 36.4%
combination
v v v v 35.3%
v v v v 34.9%
v v v v 33.2%
v v v v 35.8%
v v v v 40.8%
v v v v 34.1%
v v v v 41.3%
Notes of table 9: the effect of the drug combination was outstanding, for example, the cell
survival rate was 50.7% (in table 8) when 1.0µM Enzalutamide was used in combination with
1.0µM Abiraterone acetate. The cell survival rate decreased to 40.1% when 1.0µM
Enzalutamide was used in combination with 1.0µM Abiraterone acetate and 1.0µM C111. The
cell survival rate was 49.8% when 1.0µM Enzalutamide was used in combination with 1.0µM
Prednisone and 1.0µM Abiraterone acetate. The cell survival rate decreased to 35.3% when
1.0µM Enzalutamide was used in combination with 1.0µM Prednisone, 1.0µM Abiraterone
acetate and 1.0µM C111.
Table 10: Survival rate of Vcap cells: B101 in combination with Enzalutamide, ARN-509,
Prednisone, Galeterone, or Abiraterone acetate respectively
Gale
B10 Prednison Abirateron
Enzalutamide ARN-509 teron Cel l
Drug combination 1 e e acetate
e surviva
10µ 1µ 0.1µ 10µ 1µ 0.1µ l rate
1µM M M M M M M 1µM 1µM 1µM
v v v 56.1%
v v v 54.1%
v v v 60.1%
v v v 50.2%
v v v 51.3%
v v v 69.1%
3-drug v v v 49.8%
combination
v v v 51.8%
v v v 65.1%
v v v 47.6%
v v v 48.2%
v v v 71.8%
v v v 37.5%
v v v 57.6%
v v v 29.0%
v v v 26.2%
v v v 27.5%
v v v 24.3%
v v v 25.6%
v v v 26.6%
v v v 26.6%
v v v 26.7%
v v v 27.0%
v v v 25.8%
v v v 25.4%
v v v 24.9%
v v v 30.5%
v v v 40.1%
v v v 48.6%
v v v 32.3%
v v v 35.1%
v v v 45.3%
v v v v 28.3%
v v v v 29.3%
v v v v 22.5%
v v v v 21.7%
v v v v 27.4%
v v v v 27.2%
4-drug combination
v v v v 25.0%
v v v v 24.6%
v v v v 26.2%
v v v v 34.9%
v v v v 28.7%
v v v v 33.3%
Notes of table 10: the effect of the drug combination was outstanding, for example, the
cell survival rate was 50.7% (in table 8) when 1.0µM Enzalutamide was used in combination
with 1.0µM Abiraterone acetate. The cell survival rate decreased to 26.7% when 1.0µM
Enzalutamide was used in combination with 1.0µM Abiraterone acetate and 1.0µM B101. The
cell survival rate was 51.3% when 1.0µM Enzalutamide was used in combination with 1.0µM
Prednisone and 1.0µM Abiraterone acetate. The cell survival rate decreased to 27.2% when
1.0µM Enzalutamide was used in combination with 1.0µM Prednisone, 1.0µM Abiraterone
acetate and 1.0µM B101.
Table 11: Survival rate of Vcap cells: tested compound alone, tested compound in
combination with B101 or B105
in combination with in combination with
tested compound tested compound alone
1µM B101 1µM B105
Concentration of the tested
0.1µ
10µM 1µM 0.1µM 10µM 1µM 0.1µM 10µM 1µM
compound
B101 73.3% 77.9% 83.3% / / / / / /
B105 80.0% 79.1% 81.5% / / / / / /
99.4% 99.7% 99.1% 75.3 76.9 84.0% 79.7 80.6 87.5%
Prednisone
% % % %
92.0% 94.0% 99.2% 64.0 66.5 70.5% 63.4 67.3 75.9%
bicalutamide
% % % %
69.4% 77.4% 76.5% 52.7 63.6 61.4% 52.5 59.7 62.6%
MK-2866
% % % %
61.9% 70.4% 95.9% 38.4 39.2 42.7% 38.0 38.6 45.3%
ARN-509
% % % %
69.4% 82.7% 85.6% 53.8 65.5 69.8% 53.5 64.6 71.1%
Andarine
% % % %
73.1% 96.7% 105.4 42.8 65.1 80.4% 43.8 64.6 76.5%
Flutamide
% % % % %
Dehydroepiandrosteron 100.4 102.4 101.2 75.4 84.5 85.6% 72.9 78.6 84.2%
e % % % % % % %
90.4% 82.0% 87.3% 79.8 71.1 71.0% 77.4 64.6 71.5%
Epiandrosterone
% % % %
83.5% 96.0% 97.2% 78.9 85.0 85.0% 79.4 84.0 82.1%
Cyproterone Acetate
% % % %
88.9% 102.9 99.7% 75.2 83.1 85.2% 76.6 83.3 82.1%
Megestrol Acetate
% % % % %
72.5% 91.3% 100.2 65.9 77.3 85.3% 64.5 79.6 87.2%
Spironolactone
% % % % %
60.5% 97.0% 96.1% 66.7 70.5 72.2% 69.2 70.7 77.3%
Abiraterone acetate
% % % %
Table 12: Survival rate of Vcap cells: tested compound alone, tested compound in combination
with Enzalutamide or ARN-509
in combination with 1µM in combination with 1µM
tested compound tested compound alone
Enzalutamide ARN-509
Concentration of the
10µM 1µM 0.1µM 10µM 1µM 0.1µM 10µM 1µM 0.1µM
tested compound
B102 78.4% 80.9% 84.7% 40.1% 41.1% 46.3% 38.3% 40.2% 47.2%
B103 85.5% 84.1% 86.3% 42.9% 42.7% 50.2% 38.3% 41.7% 48.8%
B104 74.0% 77.4% 84.4% 38.8% 41.2% 47.1% 37.8% 40.5% 45.7%
B106 74.1% 79.0% 86.8% 38.2% 40.5% 50.6% 39.9% 41.1% 50.6%
58.4% 65.7% 85.9% / / / / / /
Enzalutamide
ARN-509 61.9% 70.4% 95.9% / / / / / /
Notes of table 12: The effect of the drugs combination was outstanding, for example, the cell survival
rates were 80.9%, 84.1%, 77.4%, 79%, 65.7% and 70.4% when B102, B103, B104, B106, Enzalutamide and
ARN-509 were used alone respectively. The cell survival rates were 41.1%, 42.7%, 41.2% and 40.5% when
1.0 μM B102, B103, B104 or B106 was used in combination with 1.0 μM Enzalutamide respectively. The
cell survival rates were respectively 40.2%, 41.7%, 40.5%, 41.1%, when 1.0 μM B102, B103, B104 or B106
was used in combination with 1.0 μM ARN-509 respectively.
Effect embodiment 2 PSA inhibition rate experiment
The purpose of this experiment was to test the change of the secretion level of PSA
(Prostate antigen) in the supernatant of VCap cells processed by the tested compounds in
combination with Enzalutamide for 5 days.
VCap cells were processed by 0.5 μM Enzalutamide alone, and by different
concentrations of 2 tested compounds in combination with 0.5 μM Enzalutamide for 5 days
respectively, then the PSA level of each treatment group was tested by
electrochemiluminescence immunoassay.
Experimental materials and methods
1. Cell line
Processing time
Type of tumor Name of cell Medium
(days)
prostate cancer VCap DMEM+10%FBS 5
The cell culture conditions were: 37°C, 5% CO and 95% humidity.
2. Reagents
1) DMEM medium (Thermo scientific, product number: SH30243.01)
2) FBS (Fetal Bovine Serum) (Gibco, product number: 10099-141)
3) 0.25% trypsin-EDTA (Gibco, product number: 25200-072)
4) DMSO (Sigma, product number: D2650)
) Prostate specific antigen reagent (Roche, product number: 04641655190) (provided by
Taicang First People's Hospital)
3. Equipments
1) Carbon dioxide incubator: SANYO Electric Co., Ltd. (Japan). (Equipment ID:
TAINC0490)
2) Microscope: Chongguang XDS-1B, Chongqing Guangdian Corp. (Chongqing,
P.R.China). (Equipment ID: TAMIC0130)
3) Refrigerator: Haier Z16TXZ (China). (Equipment ID: TAREF0490)
4) Electronic Balance: Mettlertoledo AL104. (Shanghai, China). (Equipment ID:
TBBAL0560)
) Automatic Electrochemical Immunoassay Analyzer: Roche Cobas e601 (Taicang First
People's Hospital)
4. Secretion inhibition rate of the tested compounds on VCap cell PSA
Cell inoculation
Cells were collected in exponential growth phase for viable cell count. The cell
suspension was adjusted to 4.17×10E4/ml with the medium mentioned above. 120μl of cell
suspension was added to each well of a 96-well cell culture plateat, a final concentration of
cells was 5000 cells/well. The cells were incubated overnight in a 37ºC, 5% CO incubator.
Dosing treatment
10mM stocking solution was prepared by dissolving each tested compound in DMSO. A
series of 4× serial gradient dilutions were prepared with the stocking solution and DMSO,
followed by being diluted with medium to be 10-fold dilutions respectively, and a 10-fold
solution of Enzalutamide was prepared meanwhile. Enzalutamide and the equivalent volume of
corresponding solution of the tested compound were added to each well for each cell line
respectively, and a duplicate well was set for each drug concentration. The final concentrations
of Enzalutamide and the tested compound used in the test are shown in Table 13. The final
concentration of DMSO per well was 0.2%. The cells were incubated for 5 days in a 37ºC, 5%
CO incubator.
Detection
After 5 days’ drug treatment, the cell supernatant of each well was collected, and
centrifuged at 2000 r/min for 5 minutes, then transferred to a clean EP tube for PSA detection.
. Data analysis
Calculation formula of PSA inhibition rate: (1-(V /V )) × 100%. Wherein, V
sample DMSO sample
is the PSA reading of the drug treatment group, and V is the average value of PSA of the
DMSO
solvent control group.
Table 13 PSA inhibition rate (%): 0.5 μM Enzalutamide used alone, and in combination with
different concentrations of the tested compound
Concentration of the tested compound (µM) 100 25 6.25 1.56 0.39 0.10 0.02 0.01
Enzalutamide (0.5µM) + B105 66.4 67.7 66.7 65.1 62.7 60.4 50.6 44
Enzalutamide (0.5µM) + C111 68 57.3 58.8 60.6 58.6 52.8 55.3 51.7
PSA inhibition rate was 30.7% when Enzalutamide (0.5µM) was used alone
Notes of Table 13: The PSA inhibition rate was 30.7% when 0.5µM Enzalutamide was used
alone. The PSA inhibition rates were 60.4% and 52.8% when 0.5µM Enzalutamide was used in
combination with 0.1µM B105 and C111 respectively. It can be seen that the effect of drug
combination was significantly enhanced compared with Enzalutamide used alone.
Effect embodiment 3
Referring to the method of Effect embodiment 1, the Vcap cells were replaced by LNCap
cells (androgen receptor (+) prostate cancer cells) (ATCC, catalog number CRL-1740), and the
results were as follows:
Table 14: Survival rate of LNCap cells: tested compound alone, tested compound in
combination with Enzalutamide or ARN-509
in combination with 1µM in combination with
tested compound alone
tested
1µM ARN-509
Enzalutamide
compound
10µM 1µM 0.1µM 10µM 1µM 0.1µM 10µM 1µM 0.1µM
Enzalutamide 59.3%
70.5% 101.5%
ARN-509
60.2%
86.7% 105.2%
B101 42.4%
63.0% 99.6% 27.1% 34.1% 59.3% 32.4% 46.3% 86.7%
B105
40.8% 61.5% 102.9% 25.8% 32.0% 57.5% 32.4% 44.7% 82.6%
Notes of table 14: The effect of the drug combination was outstanding, for example, the
cell survival rates were 63%, 61.5%, 70.5% and 86.7% when B101, B105, enzalutamide and
ARN-509 were used alone respectively at 1.0 μM. The cell survival rates were 34.1% and 32%
when 1.0 μM B101 or B105 was used in combination with 1.0 μM enzalutamide respectively.
The cell survival rates were 46.3% or 44.7% when 1.0 μM B101 or B105 was used in
combination with 1.0 μM ARN-509 respectively.
Table 15: Survival rate of LNCap cells: tested compound alone, tested compound in
combination with Galeterone or Abiraterone acetate
tested in combination with in combination with 1µM
tested compound alone
compound 1µM Galeterone Abiraterone acetate
10µM 1µM 0.1µM 10µM 1µM 0.1µM 10µM 1µM 0.1µM
B101 42.4% 31.4%
63.0% 99.6% 43.6% 76.3% 33.2% 46.2% 82.4%
B105
40.8% 61.5% 102.9% 30.6% 40.6% 73.4% 31.7% 47.9% 83.7%
Galeterone 24.2%
79.0% 104.9%
Abiraterone
45.2% 90.7% 109.2%
acetate
Notes of table 15: The effect of the drug combination was outstanding, for example, the cell
survival rates were 63%, 61.5%, 79% and 90.7% when B101, B105, Galeterone and
Abiraterone acetate were used alone respectively at 1.0 μM. The cell survival rates were 43.6%
and 40.6% when 1.0 μM B101 or B105 was used in combination with 1.0 μM Galeterone
respectively. The cell survival rates were 46.2% and 47.9% when 1.0 μM B101 or B105 was
used in combination with 1.0 μM Abiraterone acetate respectively.
Table 16: Survival rate of LNCap cells: B105 in combination with Enzalutamide,
ARN-509, Prednisone, Galeterone, or Abiraterone acetate respectively
Cell Cell
Cell
Enzalutam surviv surviva
Drug surviv
ide (0.1, ARN-509 Galeteron Abirateron al rate l rate
combination al rate
1.0, 10 (0.1, 1.0, B105 Prednison e e acetate (10 (0.1µM
(1 µM)
µM) 10µM) (1µM) e (1µM) (1 µM) (1 µM) µM) )
3-drug
v v v 44.5%
combination
3-drug
v v v 48.2%
combination
3-drug
v v v 51.5% 55.7% 68.8%
combination
3-drug
v v v 51.4% 56.7% 69.9%
combination
v v v 26.2% 28.8% 30.3%
3-drug
combination
3-drug
v v v 26.6% 29.0% 31.6%
combination
3-drug
v v v 28.4% 30.8% 41.0%
combination
4-drug
v v v v 25.2% 26.8% 29.5%
combination
4-drug
v v v v 26.5% 28.6% 32.8%
combination
3-drug
v v v 54.3% 65.7% 75.7%
combination
3-drug
v v v 51.3% 66.9% 77.4%
combination
3-drug
v v v 27.3% 30.9% 31.4%
combination
3-drug
v v v 26.1% 30.8% 35.5%
combination
3-drug
v v v 26.7% 35.1% 46.0%
combination
4-drug
v v v v 26.5% 30.6% 37.4%
combination
4-drug
v v v v 26.5% 31.2% 36.6%
combination
“V” refers to the components contained in the combination. The blank indicates the
component was not contained. The same below.
Notes of table 16: The effect of the drug combination was outstanding, for example, the
cell survival rate was 56.7% when 1.0µM Enzalutamide was used in combination with 1.0µM
Prednisone and 1.0µM Abiraterone acetate. The cell survival rate decreased to 28.6% when
1.0µM Enzalutamide was used in combination with 1.0µM Prednisone and 1.0µM Abiraterone
acetate and 1.0µM B105. The cell survival rate was 55.7% when 1.0µM Enzalutamide was
used in combination with 1.0µM Prednisone and 1.0µM Galeterone. The cell survival rate
decreased to 26.8% when 1.0µM Enzalutamide was used in combination with 1.0µM
Prednisone and 1.0µM Galeterone and 1.0µM B105.
Table 17: Survival rate of LNCap cells: B101 in combination with Enzalutamide,
ARN-509, Prednisone, Galeterone, or Abiraterone acetate respectively
Cell Cell
Cell
ARN-50 surviv surviva
Drug surviv
Enzalutami 9 B101 Galeteron Abirateron al rate l rate
combination al rate
de (0.1, 1.0, (0.1, 1.0, (1µM Prednison e e acetate (10 (0.1µM
(1 µM)
µM) 10µM) ) e (1µM) (1 µM) (1 µM) µM) )
3-drug
v v v
43.5%
combination
3-drug
v v v
49.8%
combination
3-drug
v v v
50.6% 53.4% 64.0%
combination
3-drug
v v v
50.5% 57.6% 69.5%
combination
3-drug
v v v
26.9% 28.6% 31.6%
combination
3-drug
v v v
27.4% 28.4% 33.8%
combination
3-drug
v v v
28.3% 29.3% 41.6%
combination
4-drug
v v v v
24.2% 26.6% 31.3%
combination
4-drug
v v v v
.4% 27.5% 32.5%
combination
3-drug
v v v
48.4% 66.2% 71.1%
combination
3-drug
v v v
50.1% 71.4% 79.0%
combination
3-drug
v v v
27.4% 32.4% 36.7%
combination
3-drug
v v v
26.6% 32.6% 36.9%
combination
3-drug
v v v
26.2% 36.8% 47.4%
combination
4-drug
v v v v
.1% 28.0% 32.5%
combination
4-drug
v v v v
.7% 31.5% 38.4%
combination
“V” refers to the components contained in the combination. The blank indicates the
component was not contained.
Notes of table 17: The effect of the drug combination was outstanding, for example, the
cell survival rate was 57.6% when 1.0µM Enzalutamide was used in combination with 1.0µM
Prednisone and 1.0µM Abiraterone acetate. The cell survival rate decreased to 27.5% when
1.0µM Enzalutamide was used in combination with 1.0µM Prednisone and 1.0µM Abiraterone
acetate and 1.0µM B101. The cell survival rate was 53.4% when 1.0µM Enzalutamide was
used in combination with 1.0µM Prednisone and 1.0µM Galeterone. The cell survival rate
decreased to 26.6% when 1.0µM Enzalutamide was used in combination with 1.0µM
Prednisone and 1.0µM Galeterone and 1.0µM B101.
Any reference to or discussion of any document, act or item of knowledge in this
specification is included solely for the purpose of providing a context for the present invention.
It is not suggested or represented that any of these matters or any combination thereof formed
at the priority date part of the common general knowledge, or was known to be relevant to an
attempt to solve any problem with which this specification is concerned.
For the avoidance of doubt, in this specification the terms ‘comprises’, ‘comprising’,
‘includes’, ‘including’, or similar terms are intended to be construed non-exclusively whereby
a list of elements does not include those elements solely, but may well include other elements
not listed, whereas the term 'consisting of' is intended to be construed exclusively to mean
'consisting only of'.
Although the embodiments of the invention were described above, it will be understood
by people skilled in the art that these are just examples. Many changes and modifications can
be made to these embodiments without departing from the principle and essence of the present
invention. Therefore, the protection scope of the present invention is defined by the claims
attached.
Claims (16)
1. A combination comprising one or more benzoheterocyclic compound(s), or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof, and an androgen receptor pathway modulator; wherein the benzoheterocyclic compound is any one of the following compounds: wherein the androgen receptor pathway modulator is selected from one or more of Enzalutamide, ARN-509, Abiraterone acetate, Galeterone, and ODM-201.
2. The combination according to claim 1, wherein the combination consists of the one or more benzoheterocyclic compound(s) and the androgen receptor pathway modulator.
3. The combination according to claim 1 or 2, wherein the androgen receptor pathway modulator is Enzalutamide, ARN-509, Galeterone, ODM-201, Abiraterone acetate, Enzalutamide and Galeterone, Enzalutamide and Abiraterone acetate, Enzalutamide and ODM-201, ARN-509 and Galeterone, ARN-509 and Abiraterone acetate, ARN-509 and ODM-201, or ODM-201 and Abiraterone acetate.
4. The combination according to claim 1 or 2, wherein the combination of the benzoheterocyclic compound and the androgen receptor pathway modulator is B101 and Enzalutamide, B102 and Enzalutamide, B103 and Enzalutamide, B104 and Enzalutamide, B105 and Enzalutamide, B106 and Enzalutamide, C111 and Enzalutamide, B101 and ARN-509, B102 and ARN-509, B103 and ARN-509, B104 and ARN-509, B105 and ARN-509, B106 and ARN-509, C111 and ARN-509, B101 and Abiraterone acetate, B105 and Abiraterone acetate, C111 and Abiraterone acetate, B101 and Galeterone, B105 and Galeterone, C111 and Galeterone, B101 and ODM-201, B105 and ODM-201, C111 and ODM-201, B101 and Enzalutamide and Galeterone, B105 and Enzalutamide and Galeterone, C111 and Enzalutamide and Galeterone, B101 and Enzalutamide and Abiraterone acetate, B105 and Enzalutamide and Abiraterone acetate, C111 and Enzalutamide and Abiraterone acetate, B101 and ARN-509 and Galeterone, B105 and ARN-509 and Galeterone, C111 and ARN-509 and Galeterone, B101 and ARN-509 and Abiraterone acetate, B105 and ARN-509 and Abiraterone acetate, or C111 and ARN-509 and Abiraterone acetate.
5. The combination according to any one of claims 1 or 3-4, wherein the combination further comprises a hormone compound, and the hormone compound is prednisone.
6. The combination according to claim 5, wherein the combination consists of the one or more benzoheterocyclic compound(s), the androgen receptor pathway modulator and the hormone compound prednisone.
7. The combination according to claim 5 or 6, wherein the combination of the androgen receptor pathway modulator and the hormone compound is Galeterone and prednisone, prednisone and Abiraterone acetate, Enzalutamide and prednisone, ARN-509 and prednisone, Enzalutamide and Galeterone and prednisone, Enzalutamide and Abiraterone acetate and prednisone, ARN-509 and Galeterone and prednisone, or ARN-509 and Abiraterone acetate and prednisone.
8. The combination according to claim 5 or 6, wherein the combination of the benzoheterocyclic compound, the androgen receptor pathway modulator and the hormone compound is B101 and Enzalutamide and prednisone, B105 and Enzalutamide and prednisone, C111 and Enzalutamide and prednisone, B101 and ARN-509 and prednisone, B105 and ARN-509 and prednisone, C111 and ARN-509 and prednisone, B101 and Galeterone and prednisone, B105 and Galeterone and prednisone, C111 and Galeterone and prednisone, B101 and prednisone and Abiraterone acetate, B105 and prednisone and Abiraterone acetate, C111 and prednisone and Abiraterone acetate, B101 and Enzalutamide and Galeterone and prednisone, B105 and Enzalutamide and Galeterone and prednisone, C111 and Enzalutamide and Galeterone and prednisone, B101 and Enzalutamide and Abiraterone acetate and prednisone, B105 and Enzalutamide and Abiraterone acetate and prednisone, C111 and Enzalutamide and Abiraterone acetate and prednisone, B101 and ARN-509 and Galeterone and prednisone, B105 and ARN-509 and Galeterone and prednisone, C111 and ARN-509 and Galeterone and prednisone, B101 and ARN-509 and Abiraterone acetate and prednisone, B105 and ARN-509 and Abiraterone acetate and prednisone, or C111 and ARN-509 and Abiraterone acetate and prednisone.
9. A pharmaceutical composition, comprising the combination according to any one of claims 1-8 and one or more pharmaceutically acceptable excipients.
10. Use of one or more benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in claim 1, in the manufacture of a medicament for the prevention and/or treatment of prostate cancer in combination with an androgen receptor pathway modulator as defined in claim 1 or 3; or, use of one or more benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in claim 1, in the manufacture of a medicament for the prevention and/or treatment of prostate cancer in combination with an androgen receptor pathway modulator as defined in claim 1 or 3, and a hormone compound as defined in claim 5; or, use of an androgen receptor pathway modulator as defined in claim 1 or 3, in the manufacture of a medicament for the prevention and/or treatment of prostate cancer in combination with one or more benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in claim 1; or, use of the androgen receptor pathway modulator as defined in claim 1 or 3, in the manufacture of a medicament for the prevention and/or treatment of prostate cancer in combination with one or more benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in claim 1, and a hormone compound as defined in claim 5; or, use of a hormone compound as defined in claim 5, in the manufacture of a medicament for the prevention and/or treatment of prostate cancer in combination with one or more benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in claim 1, and an androgen receptor pathway modulator as defined in claim 1 or 3.
11. The use according to claim 10, wherein the combination of the one or more benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof and the androgen receptor pathway modulator is as defined in claim 4; and/or, the combination of the androgen receptor pathway modulator and the hormone compound is as defined in claim 7; and/or, the combination of the one or more benzoheterocyclic compounds, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof, the androgen receptor pathway modulator and the hormone compound is as defined in claim 8.
12. The use according to claim 10 or 11 wherein the prostate cancer is castration-resistant prostate cancer.
13. A kit, comprising a pharmaceutical composition A and a pharmaceutical composition wherein, the pharmaceutical composition A comprises the benzoheterocyclic compound, or a pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof as defined in claim 1 and one or more pharmaceutically acceptable excipients; the pharmaceutical composition B comprises an androgen receptor pathway modulator as defined in claim 1 or 3 and one or more pharmaceutically acceptable excipients.
14. The kit according to claim 13, wherein the combination of the one or more benzoheterocyclic compounds, the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope thereof in the pharmaceutical composition A and the androgen receptor pathway modulator in the pharmaceutical composition B are as defined in claim 4.
15. The kit according to claim 13 or 14, further comprising a pharmaceutical composition C, which comprises a hormone compound according to claim 5 and one or more pharmaceutically acceptable excipients; and/or, the pharmaceutical compositions in the kit are formulated for simultaneous or separate administration
16. The kit according to claim 15, wherein the combination of the one or more of the benzoheterocyclic compound, the pharmaceutically acceptable salt, solvate, polymorph, co-crystal, stereoisomer, isotope compound thereof in the pharmaceutical composition A, the androgen receptor pathway modulator in the pharmaceutical composition B and the hormone compound in the pharmaceutical composition C is as defined in claim 8.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201611170723.1 | 2016-12-16 | ||
CN201611170723 | 2016-12-16 | ||
PCT/CN2017/116413 WO2018108147A1 (en) | 2016-12-16 | 2017-12-15 | Composition, application thereof and treatment method |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ753549A NZ753549A (en) | 2021-10-29 |
NZ753549B2 true NZ753549B2 (en) | 2022-02-01 |
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