U.S. patent application number 10/140843 was filed with the patent office on 2003-05-15 for use of neurokinin receptor antagonists to treat androgen-dependent diseases.
This patent application is currently assigned to Schering Corporation. Invention is credited to Berardi, Mark R., Cartwright, Mark E., Leach, Michael W., Mirro, Elmer J., Pachter, Jonathan A., Reichard, Gregory A., Sinha, Dineshwar.
Application Number | 20030092602 10/140843 |
Document ID | / |
Family ID | 23111765 |
Filed Date | 2003-05-15 |
United States Patent
Application |
20030092602 |
Kind Code |
A1 |
Leach, Michael W. ; et
al. |
May 15, 2003 |
Use of neurokinin receptor antagonists to treat androgen-dependent
diseases
Abstract
Use of an antagonist selected from the group consisting of: (a)
antagonists of neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and
neurokinin-3 (NK.sub.3) receptors, (b) antagonists of NK.sub.1 and
NK.sub.2 receptors, (c) antagonists of NK.sub.2 and NK.sub.3
receptors, (d) antagonists of NK.sub.1 and NK.sub.3 receptors, (e)
antagonists of NK.sub.1 receptors, and (f) antagonists of NK.sub.2
to treat symptoms and disorders associated with a production and/or
secretion of androgen. One aspect of the invention relates to the
use of antagonists to suppress production/secretion of androgens in
mammals suffering from an androgen-dependent disease, such as
benign prostatic hyperplasia and prostatic carcinoma.
Inventors: |
Leach, Michael W.;
(Shrewsbury, MA) ; Berardi, Mark R.; (Sussex,
NJ) ; Mirro, Elmer J.; (Wantage, NJ) ; Sinha,
Dineshwar; (Newton, NJ) ; Pachter, Jonathan A.;
(Maplewood, NJ) ; Cartwright, Mark E.; (Sparta,
NJ) ; Reichard, Gregory A.; (Morris Plains,
NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
23111765 |
Appl. No.: |
10/140843 |
Filed: |
May 7, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60289491 |
May 8, 2001 |
|
|
|
Current U.S.
Class: |
514/1 |
Current CPC
Class: |
A61K 31/4545 20130101;
A61P 13/10 20180101; A61P 17/10 20180101; A61P 15/10 20180101; A61P
17/14 20180101; A61P 15/08 20180101; A61P 5/28 20180101; A61K 31/00
20130101; A61P 35/00 20180101 |
Class at
Publication: |
514/1 |
International
Class: |
A61K 031/00 |
Claims
What is claimed is:
1. A method of treating a symptom or disorder associated with a
production and/or secretion of androgen comprising administering to
a patient in need of such treatment a therapeutically effective
amount of an antagonist selected from the group consisting of: (a)
antagonists of neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and
neurokinin-3 (NK.sub.3) receptors, (b) antagonists of NK.sub.1 and
NK.sub.2 receptors, (c) antagonists of NK.sub.2 and NK.sub.3
receptors, (d) antagonists of NK.sub.1 and NK.sub.3 receptors, (e)
antagonists of NK.sub.1 receptors, and (f) antagonists of NK.sub.2
receptors.
2. The method of claim 1, wherein the antagonist administered to
the patient is (a) the antagonist of NK.sub.1, NK.sub.2 and
NK.sub.3 receptors.
3. The method of claim 1, wherein the antagonist administered to
the patient is (b) the antagonist of NK.sub.1and NK.sub.2
receptors.
4. The method of claim 1, wherein the antagonist administered to
the patient is (c) the antagonist of NK.sub.2 and NK.sub.3
receptors.
5. The method of claim 1, wherein the antagonist administered to
the patient is (d) the antagonist of NK.sub.1and NK.sub.3
receptors.
6. The method of claim 1, wherein the antagonist administered to
the patient is (e) the antagonist of NK.sub.1 receptors.
7. The method of claim 1, wherein the antagonist administered to
the patient is (f) the antagonist of NK.sub.2 receptors.
8. The method of claim 1 wherein the antagonist administered to the
patient is a compound represented by the structural formula 1: 18or
a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2
or 3; R is H, C.sub.1-6 alkyl, --OH or C.sub.2-C.sub.6
hydroxyalkyl; A is an optionally substituted oxime, optionally
substituted hydrazone or optionally substituted olefin; X is a
bond, --C(O)--, --O--, --NR.sup.6--, --S(O).sub.e--,
--N(R.sup.6)C(O)--, --C(O)N(R.sup.6)-- --OC(O)NR.sup.6--,
--OC(.dbd.S)NR.sup.6--, --N(R.sup.6)C(.dbd.S)O--,
--C(.dbd.NOR.sup.1)--, --S(O).sub.2N(R.sup.6)--,
--N(R.sup.6)S(O).sub.2--- , --N(R.sup.6)C(O)O-- or --OC(O)--; b, d
and e are each independently 0, 1 or 2; T is H, phthalimidyl, aryl,
heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl; Q
is --SR.sup.6, --N(R.sup.6)(R.sup.7), --OR.sup.6, phenyl, naphthyl
or heteroaryl; R.sup.6a, R.sup.7a, and R.sup.8a are each
independently H, C.sub.1-6 alkyl, C.sub.2-C.sub.6 hydroxyalkyl,
C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkyl, phenyl or benzyl;
R.sup.6 and R.sup.7 are each independently H, C.sub.1-6 alkyl,
C.sub.2-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6
alkoxy-C.sub.1-C.sub.6 alkyl, phenyl or benzyl; or R.sup.6 and
R.sup.7, together with the nitrogen to which they are attached,
form a ring; R.sup.9a is R.sup.6 or --OR.sup.6; Z is morpholinyl,
optionally N-substituted piperazinyl, optionally substituted 19 ,
or substituted 20g is 0-3; h is 1-4, provided the sum of h and g is
1-7; wherein each aryl, heterocycloalkyl, heteroaryl, cycloalkyl
and bridged cycloalkyl groups are all optionally substituted.
9. The method of claim 1 wherein the antagonist is a compound
represented by the structural formula 2: 21or a pharmaceutically
acceptable salt thereof, wherein: T is 1) phenyl, substituted with
two or three substituents independently selected from the group
consisting of: a) chloro; b) methyl, and c) methoxy; or 2) pyridyl,
substituted with two or three substituents independently selected
from the group consisting of: a) chloro, and b) methyl; R.sup.1 is
H, methyl, ethyl, --CH.sub.2CN, --CH.sub.2C(O)NH.sub.2,
--(CH.sub.2).sub.3SO.sub.3H, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2C(O)NHOH, --CH.sub.2C(O)NHOCH.sub.3,
--CH.sub.2C(O)NHCH.sub.2CN, --CH.sub.2F,
--CH.sub.2C(O)NHCH.sub.2SO.sub.3- H, 22R.sup.4 is methyl or ethyl;
and Z is 23
10. The method of claim 9 wherein, for the compound, T is phenyl,
substituted with two or three substituents independently selected
from the group consisting of: a) chloro; b) methyl, and c) methoxy;
R.sup.1 is H, methyl, --CH.sub.2F, --CH.sub.2CN,
--(CH.sub.2).sub.3SO.sub.3H, 24R.sup.4 is methyl, and Z is 25
11. The method of claim 9 wherein, for the compound, T is phenyl,
substituted with 2 chloro substituents; R.sup.1 is H or methyl;
R.sup.4 is methyl, and Z is 26
12. The method of claim 1 wherein the antagonist is selected from
the group consisting of: 27
13. The method of claim 1 wherein the symptom or disorder is
associated with an overproduction of androgen or excessive androgen
stimulation.
14. The method of claim 1 wherein the symptom or disorder is
selected from the group consisting of benign prostatic hyperplasia,
metastatic carcinoma, testicular cancer, androgen dependent acne,
male pattern baldness, precocious puberty in boys,
hyperandrogenism, hirsutism, virilization, PCOS, HAIR-AN syndrome,
ovarian hyperthecosis, follicular maturation arrest, atresia,
anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility, and androgen-producing tumors.
15. A method of treating a symptom or disorder associated with a
production and/or secretion of androgen comprising administering to
a patient in need of such treatment a therapeutically effective
amount of a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and an antagonist selected from
the group consisting of: (a) antagonists of neurokinin-1
(NK.sub.1), neurokinin-2 (NK.sub.2) and neurokinin-3 (NK.sub.3)
receptors, (b) antagonists of NK.sub.1 and NK.sub.2 receptors, (c)
antagonists of NK.sub.2 and NK.sub.3 receptors, (d) antagonists of
NK.sub.1 and NK.sub.3 receptors, (e) antagonists of NK.sub.1
receptors, and (f) antagonists of NK.sub.2 receptors.
16. A method of treating a symptom or disorder associated with a
production and/or secretion of androgen comprising administering to
a patient in need of such treatment a therapeutically effective
amount of a pharmaceutical composition comprising the antagonist of
formula 1 as defined in the method of claim 8 and a
pharmaceutically acceptable carrier.
17. A method of treating a symptom or disorder associated with a
production and/or secretion of androgen comprising administering to
a patient in need of such treatment a therapeutically effective
amount of a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and an antagonist selected from
the group consisting of: 28
18. The method of claim 15, wherein the symptom or disorder is
selected from the group consisting of benign prostatic hyperplasia,
metastatic carcinoma, testicular cancer, androgen dependent acne,
male pattern baldness, precocious puberty in boys,
hyperandrogenism, hirsutism, virilization, PCOS, HAIR-AN syndrome,
ovarian hyperthecosis, follicular maturation arrest, atresia,
anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility, and androgen-producing tumors.
19. The method of claim 16, wherein the symptom or disorder is
selected from the group consisting of benign prostatic hyperplasia,
metastatic carcinoma, testicular cancer, androgen dependent acne,
male pattern baldness, precocious puberty in boys,
hyperandrogenism, hirsutism, virilization, PCOS, HAIR-AN syndrome,
ovarian hyperthecosis, follicular maturation arrest, atresia,
anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility, and androgen-producing tumors.
20. The method of claim 17, wherein the symptom or disorder is
selected from the group consisting of benign prostatic hyperplasia,
metastatic carcinoma, testicular cancer, androgen dependent acne,
male pattern baldness, precocious puberty in boys,
hyperandrogenism, hirsutism, virilization, PCOS, HAIR-AN syndrome,
ovarian hyperthecosis, follicular maturation arrest, atresia,
anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility, and androgen-producing tumors.
21. A method of treating a symptom or disorder associated with a
production and/or secretion of luteinizing hormone (LH) comprising
administering to a patient in need of such treatment a
therapeutically effective amount of an antagonist selected from the
group consisting of: (a) antagonists of neurokinin-1 (NK.sub.1),
neurokinin-2 (NK.sub.2) and neurokinin-3 (NK.sub.3) receptors, (b)
antagonists of NK.sub.1 and NK.sub.2 receptors, (c) antagonists of
NK.sub.2 and NK.sub.3 receptors, (d) antagonists of NK.sub.1 and
NK.sub.3 receptors, (e) antagonists of NK.sub.1 receptors, and (f)
antagonists of NK.sub.2 receptors.
22. A method of treating a symptom or disorder selected from the
group consisting of benign prostatic hyperplasia, metastatic
carcinoma, testicular cancer, androgen dependent acne, male pattern
baldness, precocious puberty in boys, hyperandrogenism, hirsutism,
virilization, PCOS, HAIR-AN syndrome, ovarian hyperthecosis,
follicular maturation arrest, atresia, anovulation, dysmenorrhea,
dysfunctional uterine bleeding, infertility, and androgen-producing
tumors, by modulating a production and/or secretion of androgen
and/or luteinizing hormone, comprising administering to a patient
in need of such treatment a therapeutically effective amount of an
antagonist selected from the group consisting of: (a) antagonists
of neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and
neurokinin-3 (NK.sub.3) receptors, (b) antagonists of NK.sub.1 and
NK.sub.2 receptors, (c) antagonists of NK.sub.2 and NK.sub.3
receptors, (d) antagonists of NK.sub.1 and NK.sub.3 receptors, (e)
antagonists of NK.sub.1 receptors, and (f) antagonists of NK.sub.2
receptors.
23. A method of inhibiting a production and/or secretion of an
androgen in a mammal, comprising administering to the mammal an
inhibitory amount of the compound of formula 1 as defined in the
method of claim 8.
24. A method of inhibiting a production and/or secretion of an
androgen in a mammal, comprising administering to the mammal an
inhibitory amount of the compound of formula 2 as defined in the
method of claim 9.
25. A method of inhibiting a production and/or secretion of
luteinizing hormone (LH) in a mammal, comprising administering to
the mammal an inhibitory amount of the compound of formula 1 as
defined in the method of claim 8.
26. A method of inhibiting a production and/or secretion of
luteinizing hormone (LH) in a mammal, comprising administering to
the mammal an inhibitory amount of the compound of formula 2 as
defined in the method of claim 9.
27. A method of modulating the level of an androgen in a mammal,
comprising administering to the mammal an effective amount of the
compound of formula 1 as defined in the method of claim 8.
28. A method of modulating the level of an androgen in a mammal,
comprising administering to the mammal an effective amount of the
compound of formula 2 as defined in the method of claim 9.
29. A method of modulating the level of luteinizing hormone in a
mammal, comprising administering to the mammal an effective amount
of the compound of formula 1 as defined in the method of claim
8.
30. A method of modulating the level of luteinizing hormone in a
mammal, comprising administering to the mammal an effective amount
of the compound of formula 2 as defined in the method of claim 9.
Description
RELATED APPLICATION
[0001] The application claims priority to U.S. Provisional
Application No. 60/289,491, filed May 8, 2001.
FIELD OF THE INVENTION
[0002] The invention is directed to a method of treating an
androgen-dependent disease in mammals, e.g., humans, with
antagonists of neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2)
and/or neurokinin-3 (NK.sub.3) receptors. The invention further
relates to the use of these antagonists for purposes of
prophylactic modulation.
BACKGROUND OF THE INVENTION
[0003] An androgen-dependent disease is one which is exacerbated
by, or caused by, excessive, inappropriate or unregulated androgen
production. Examples of such diseases in men include, but are not
limited to, benign prostatic hyperplasia (BPH), metastatic
prostatic carcinoma, testicular cancer, androgen dependent acne,
male pattern baldness and precocious puberty in boys. Examples of
such diseases in women include, but are not limited to,
hyperandrogenism, hirsutism, virilization, polycystic ovary
syndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin
resistance and acanthosis nigricans), ovarian hyperthecosis
(HAIR-AN with hyperplasia of luteinized theca cells in ovarian
stroma), other manifestations of high intraovarian androgen
concentrations (e.g., follicular maturation arrest, atresia,
anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility) and androgen-producing tumors (virilizing ovarian or
adrenal tumor).
[0004] Benign prostatic hyperplasia and prostatic carcinoma are
among the most common afflictions of aging men.
[0005] Benign prostatic hyperplasia is often treated surgically
with a procedure known as transurethral resection of the prostate
(TURP). Other surgical procedures performed to release the
obstruction of urine include incision or stents. Castration has
also resulted in regression of prostatic enlargement. Drug therapy
for BPH has included alpha-1 blockers which treat the symptoms of
the disease by alleviating obstructive symptoms, but do not affect
the underlying cause of the disease, the enlarged prostate gland.
Representative alpha-1 blockers used in the treatment of BPH
include: prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.
These drugs relax prostatic smooth muscle tone, decreasing
intraurethral pressure without affecting bladder pressure. Common
side effects of these agents are dizziness, headache and
fatigue.
[0006] Both prostatic carcinoma and BPH have been treated with
antiandrogens. A principal mediator of androgenic activity in the
prostate is 5.alpha.-dihydrotestosterone (DHT), formed locally in
the prostate by the action of testosterone-5.alpha.-reductase.
Inhibitors of testosterone-5.alpha.-reductase inhibit the
conversion of testosterone (T) to DHT and serve to prevent or
lessen symptoms of hyperandrogenic stimulation in the prostate.
Non-steroidal antiandrogens such as flutamide and Casodex compete
with DHT for androgen receptor sites in the prostrate cells. These
non-steroidal antiandrogens do not substantially change sexual
potency and libido as the gonadotrophin releasing hormone agonists
and progestogens do; however, these non-steroidal antiandrogens
often exhibit the undesirable tendency to feminize the male host
(gynaecomastia) or initiate feed-back effects which would cause
hyperstimulation of the testes.
[0007] Luteinizing hormone (LH), under control of Gonadotropin
Releasing Hormone (GnRH), is released by the pituitary gland and
stimulates the production of androgens by the gonads. Androgens,
the principle one being testosterone, are secreted mainly by the
testes and, to a lesser degree, by the adrenal cortex and ovary.
Suppression of gonadotropin production and/or secretion results in
the suppression of androgen production and/or secretion.
[0008] Gonadotropin-releasing hormone (GnRH) agonists such as
nafarelin, buserelin, goserelin and leuprorelin, reduce the release
of luteinizing hormone (LH) by desensitizing the GnRH receptors in
the anterior pituitary gland. GnRH agonists are able to reduce the
production of testosterone, induce shrinkage of prostate volume and
reduce the severity of urinary symptoms of BPH. Unfortunately,
these drugs have adverse effects such as impotence and flushing,
which discourage a majority of patients from continuing with the
drugs. These androgen-suppressing agents are thus of
inconsequential significance in BPH treatment, but are of major
importance in the treatment of patients with advanced prostatic
cancer. These initially can cause increased androgen production
before desensitization occurs, which is a major side effect.
[0009] Progestogens, such as megestrol acetate, hydroxyprogesterone
and medrogestone depress testosterone by inhibiting LH release and
blocking androgen receptors, causing a reduction in prostatic
volume. Adverse effects such as decreased libido and impotence have
limited progestogens from common use in BPH treatment.
[0010] Thus, there remains a need for improved therapies for BPH
and prostatic carcinoma, as well as other androgen-dependent
diseases. There also remains a need for an additional method for
the treatment of androgen-dependent diseases which utilizes
non-steroidal compounds that possess different pharmacological
properties from steroids.
[0011] Neurokinin receptors can be found in the nervous system,
circulatory system and peripheral tissues of mammals. Consequently,
the modulation of these types of receptors have been studied to
potentially treat or prevent various mammalian disease states.
Representative types of neurokinin receptor antagonists and the
disorders that can be treated with them can be found in: U.S. Pat.
No. 6,329,401 (2001) (sleep), U.S. Pat. No. 5,760,018 (1998) (pain,
inflammation, migraine and emesis), U.S. Pat. No. 5,620,989 (1997)
(pain, nociception and inflammation), WO 95/19344 (same), WO
94/13639 (same) and WO 94/10165 (same).
[0012] NK.sub.1 and NK.sub.2 receptor antagonists have also been
disclosed in U.S. Pat. No. 5,350,852 and WO 94/29309.
[0013] WO 00/43008 discloses a method of suppressing gonadotropin
and/or androgen production with specific NK.sub.3 receptor
antagonists.
SUMMARY OF THE INVENTION
[0014] One aspect of the invention provides a method of decreasing
in vivo concentrations of androgens to normal or sub-normal levels
in a patient suffering from a disease state which is exacerbated
by, or caused by excessive, inappropriate or unregulated androgen
production or secretion. Another aspect of the invention provides a
method of prophylactic androgen modulation.
[0015] Another aspect of the invention provides a method of
treating a symptom or disorder associated with a production and/or
secretion of androgen comprising administering to a patient in need
of such treatment a therapeutically effective amount of an
antagonist selected from the group consisting of: (a) antagonists
of neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and
neurokinin-3 (NK.sub.3) receptors, (b) antagonists of NK.sub.1 and
NK.sub.2 receptors, (c) antagonists of NK.sub.2 and NK.sub.3
receptors, (d) antagonists of NK.sub.1 and NK.sub.3 receptors, (e)
antagonists of NK.sub.1 receptors, and (f) antagonists of NK.sub.2
receptors.
[0016] Further provided is a method of treating a symptom or
disorder associated with a production and/or secretion of androgen,
comprising administering to a patient in need of such treatment a
therapeutically effective amount of a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and an antagonist
selected from the group consisting of: (a) antagonists of
neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and neurokinin-3
(NK.sub.3) receptors, (b) antagonists of NK.sub.1 and NK.sub.2
receptors, (c) antagonists of NK.sub.2 and NK.sub.3 receptors, (d)
antagonists of NK.sub.1 and NK.sub.3 receptors, (e) antagonists of
NK.sub.1 receptors, and (f) antagonists of NK.sub.2 receptors.
[0017] Another aspect of the invention is directed to a method of
treating a symptom or disorder associated with the production
and/or secretion of androgen comprising administering to a patient
in need of such treatment a therapeutically effective amount of a
pharmaceutical composition comprising the antagonist of formula 1
shown below and a pharmaceutically acceptable carrier.
[0018] The invention also provides a method of treating a symptom
or disorder associated with a production and/or secretion of
androgen comprising administering to a patient in need of such
treatment a therapeutically effective amount of a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and an
antagonist selected from the group of compounds consisting of:
1
[0019] The invention further provides a method of treating a
symptom or disorder associated with a production and/or secretion
of luteinizing hormone (LH), comprising administering to a patient
in need of such treatment a therapeutically effective amount of an
antagonist selected from the group consisting of: (a) antagonists
of neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and
neurokinin-3 (NK.sub.3) receptors, (b) antagonists of NK.sub.1 and
NK.sub.2 receptors, (c) antagonists of NK.sub.2 and NK.sub.3
receptors, (d) antagonists of NK.sub.1 and NK.sub.3 receptors, (e)
antagonists of NK.sub.1 receptors, and (f) antagonists of NK.sub.2
receptors.
[0020] The invention further provides a method of treating a
symptom or disorder selected from the following: benign prostatic
hyperplasia, metastatic carcinoma, testicular cancer, androgen
dependent acne, male pattern baldness, precocious puberty in boys,
hyperandrogenism, hirsutism, virilization, PCOS, HAIR-AN syndrome,
ovarian hyperthecosis, follicular maturation arrest, atresia,
anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility, and androgen-producing tumors, by modulating a
production and/or secretion of androgen and/or luteinizing hormone,
comprising administering to a patient in need of such treatment a
therapeutically effective amount of an antagonist selected from the
group consisting of: (a) antagonists of neurokinin-1 (NK.sub.1),
neurokinin-2 (NK.sub.2) and neurokinin-3 (NK.sub.3) receptors, (b)
antagonists of NK.sub.1 and NK.sub.2 receptors, (c) antagonists of
NK.sub.2 and NK.sub.3 receptors, (d) antagonists of NK.sub.1 and
NK.sub.3 receptors, (e) antagonists of NK.sub.1 receptors, and (f)
antagonists of NK.sub.2 receptors.
[0021] Also provided by the invention is a method of inhibiting a
production and/or secretion of an androgen in a mammal comprising
administering to the mammal an inhibitory amount of a compound
according to formula 1 or formula 2 shown below.
[0022] The invention further provides a method of inhibiting a
production and/or secretion of luteinizing hormone (LH) in a mammal
comprising administering to the mammal an inhibitory amount of a
compound according to formula 1 or formula 2 shown below.
[0023] Moreover, the invention provides a method of modulating a
level of an androgen in a mammal comprising administering to the
mammal an effective amount of a compound according to formula 1 or
formula 2 shown below.
[0024] Further provided is a method of modulating a level of
luteinizing hormone in a mammal comprising administering to the
mammal an effective amount of a compound according to formula 1 or
formula 2 shown below.
[0025] Representative (e.g., non-selective) antagonist compounds of
neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and neurokinin-3
(NK.sub.3) receptors which are useful in the methods of the
invention are described and set forth in commonly assigned U.S.
Pat. Nos. 5,696,267, 5,840,725 and 6,063,926, the entire contents
of which are incorporated herein by reference.
[0026] Compounds useful in the methods of the invention, which are
disclosed in U.S. Pat. No. 5,696,267 and in U.S. Pat. No.
5,840,725, are represented by the formula (1): 2
[0027] or a pharmaceutically acceptable salt thereof, wherein:
[0028] a is 0, 1, 2 or3;
[0029] R is H, C.sub.1-6 alkyl, --OH or C.sub.2-C.sub.6
hydroxyalkyl;
[0030] A is an optionally substituted oxime, optionally substituted
hydrazone or optionally substituted olefin;
[0031] X is a bond, --C(O)--, --O--, --NR.sup.6--, --S(O).sub.e--,
--N(R.sup.6)C(O)--, --C(O)N(R.sup.6)-- --OC(O)NR.sup.6--,
--OC(.dbd.S)NR.sup.6--, --N(R.sup.6)C(.dbd.S)O--,
--C(.dbd.NOR.sup.1)--, --S(O).sub.2N(R.sup.6)--,
--N(R.sup.6)S(O).sub.2--, --N(R.sup.6)C(O)O-- or --OC(O)--;
[0032] b, d and e are independently 0, 1 or 2;
[0033] T is H, phthalimidyl, aryl, heterocycloalkyl, heteroaryl,
cycloalkyl or bridged cycloalkyl;
[0034] Q is --SR.sup.6, --N(R.sup.6)(R.sup.7), --OR.sup.6, phenyl,
naphthyl or heteroaryl;
[0035] R.sup.6a, R.sup.7a, and R.sup.8a are each independently H,
C.sub.1-6 alkyl, C.sub.2-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6
alkoxy-C.sub.1-C.sub.6 alkyl, phenyl or benzyl;
[0036] R.sup.6 and R.sup.7 are each independently H, C.sub.1-6
alkyl, C.sub.2-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6
alkoxy-C.sub.1-C.sub.6 alkyl, phenyl or benzyl; or R.sup.6 and
R.sup.7, together with the nitrogen to which they are attached,
form a ring;
[0037] R.sup.9a is R.sup.6 or --OR.sup.6;
[0038] Z is morpholinyl, optionally N-substituted piperazinyl,
optionally substituted 3
[0039] or substituted 4
[0040] g is 0-3;
[0041] h is 1-4, provided the sum of h and g is 1-7;
[0042] wherein each aryl, heterocycloalkyl, heteroaryl, cycloalkyl
and bridged cycloalkyl groups are all optionally substituted.
[0043] In particular, compounds useful in the methods of the
invention, disclosed in U.S. Pat. No. 6,063,926, have the formula
2: 5
[0044] or a pharmaceutically acceptable salt thereof, wherein: T
is
[0045] 1) phenyl, substituted with two or three substituents
independently selected from the group consisting of:
[0046] a) chloro;
[0047] b) methyl, and
[0048] c) methoxy; or
[0049] 2) pyridyl, substituted with two or three substituents
independently selected from the group consisting of:
[0050] a) chloro, and
[0051] b) methyl;
[0052] R.sup.1 is H, methyl, ethyl, --CH.sub.2CN,
--CH.sub.2C(O)NH.sub.2, --(CH.sub.2).sub.3SO.sub.3H,
--CH.sub.2C(O)NHCH.sub.3, --CH.sub.2C(O)NHOH,
--CH.sub.2C(O)NHOCH.sub.3, --CH.sub.2C(O)NHCH.sub.2CN- ,
--CH.sub.2F, --CH.sub.2C(O)NHCH.sub.2SO.sub.3H, 6
[0053] R.sup.4 is methyl or ethyl; and
[0054] Z is 7
[0055] The invention further provides methods of treatment that
employ compounds having formula 1 or formula 2, including any and
all isomers, such as enantiomers, stereoisomers, diastereomers,
rotomers, tautomers, etc., and prodrugs of the compounds having
formula 1 or 2, and the isomers thereof, and their corresponding
salts, solvates (e.g., hydrates), esters, and the like. The
invention further encompasses methods of treatment that employ
pharmaceutically-acceptable compositions prepared from one or more
compounds according to formulae 1 and 2 and one or more
pharmaceutically-acceptable excipients/carriers, or salts,
solvates, esters, etc., thereof. The compounds having formulae 1
and 2 can be useful for treating androgen-dependent symptoms and
disorders, such as diseases. Accordingly, the invention includes
methods of treating a symptom or disorder associated with a
production and/or secretion of androgen by administering to a
patient in need of such treatment an effective amount of a
pharmaceutical composition comprising at least one compound having
formula 1 or formula 2 and at least one pharmaceutically-acceptable
excipient/carrier.
[0056] Preferably, the invention relates to the use of one or more
compounds of formula 1 or 2, or pharmaceutical salts thereof, in
pharmaceutical compositions for the treatment of BPH, metastatic
prostatic carcinoma, testicular cancer, androgen dependent acne,
male pattern baldness, precocious puberty in boys,
hyperandrogenism, hirsutism, virilization, PCOS, HAIR-AN syndrome,
ovarian hyperthecosis, follicular maturation arrest, atresia,
anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility, and androgen-producing tumors.
[0057] A further understanding of the invention will be had from
the following detailed description of the invention, including its
preferred embodiments.
DETAILED DESCRIPTION
Definitions and Usage of Terms
[0058] The following definitions and terms are used herein or are
otherwise known to a skilled artisan. Except where stated
otherwise, the following definitions apply throughout the
specification and claims. Chemical names, common names, and
chemical structures may be used interchangeably to describe the
same structure. These definitions apply regardless of whether a
term is used by itself or in combination with other terms, unless
otherwise indicated. Hence, the definition of "alkyl" applies to
"alkyl" as well as the "alkyl" portions of "hydroxyalkyl,"
"haloalkyl," "alkoxy," etc.
[0059] Unless otherwise known, stated or shown to be to the
contrary, the point of attachment for a multiple term substituent
(multiple terms that are combined to identify a single moiety) to a
subject structure is through the last named term of the multiple
term. For example, a cycloalkylalkyl substituent attaches to a
targeted through the latter "alkyl" portion of the substituent
(e.g., Structure-alkyl-cycloalkyl).
[0060] The identity of each variable appearing more than once in a
formula may be independently selected from the definition for that
variable, unless otherwise indicated.
[0061] Unless stated, shown or otherwise known to be the contrary,
all atoms illustrated in chemical formulas for covalent compounds
possess normal valencies. Thus, hydrogen atoms, double bonds,
triple bonds and ring structures need not be expressly depicted in
a general chemical formula.
[0062] Double bonds, where appropriate, may be represented by the
presence of parentheses around an atom in a chemical formula. For
example, a carbonyl functionality, --CO--, may also be represented
in a chemical formula by --C(O)-- or --C(.dbd.0)--. Similarly, a
double bond between a sulfur atom and an oxygen atom may be
represented in a chemical formula by --SO--, --S(O)-- or
--S(.dbd.O)--. One skilled in the art will be able to determine the
presence or absence of double (and triple bonds) in a
covalently-bonded molecule. For instance, it is readily recognized
that a carboxyl functionality may be represented by --COOH,
--C(O)OH, --C(.dbd.O)OH or --CO.sub.2H.
[0063] The term "substituted," as used herein, means the
replacement of one or more atoms or radicals, usually hydrogen
atoms, in a given structure with an atom or radical selected from a
specified group. In the situations where more than one atom or
radical may be replaced with a substituent selected from the same
specified group, the substituents may be, unless otherwise
specified, either the same or different at every position. Radicals
of specified groups, such as alkyl, cycloalkyl, heterocycloalkyl,
aryl and heteroaryl groups, independently of or together with one
another, may be substituents on any of the specified groups, unless
otherwise indicated. Unless noted otherwise, preferred substitution
groups for formula 1 herein are the same as those disclosed in U.S.
Pat. Nos. 5,840,725, 5,696,267; and preferred substitution groups
for formula 2 herein are the same as those disclosed in U.S. Pat.
No. 6,063,926.
[0064] The term "chemically-feasible" is usually applied to a ring
structure present in a compound and means that the ring structure
(e.g., a 4- to 7-membered ring, optionally substituted by . . . )
would be expected to be stable by a skilled artisan.
[0065] The term "heteroatom," as used herein, means a nitrogen,
sulfur, or oxygen atom. Multiple heteroatoms in the same group may
be the same or different.
[0066] The term "alkyl," as used herein, means an unsubstituted or
substituted, straight or branched, hydrocarbon chain (i.e.,
comprising carbon and hydrogen atoms bonded together), having,
preferably, from one to twenty-four carbon atoms, more preferably,
from one to twelve carbon atoms, and even more preferably, from one
to six carbon atoms.
[0067] The term "cycloalkyl" or "cycloalkane," as used herein,
means an unsubstituted or substituted, saturated, stable,
non-aromatic, chemically-feasible carbocyclic ring, having,
preferably, from three to fifteen carbon atoms, more preferably,
from three to eight carbon atoms. The cycloalkyl carbon ring
radical is saturated and may be fused, for example, benzofused,
with one to two cycloalkyl, aromatic, heterocyclic or
heteroaromatic rings. The cycloalkyl may be attached at any
endocyclic carbon atom that results in a stable structure.
Preferred carbocyclic rings have from five to six carbons. Examples
of cycloalkyl radicals include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[0068] The term "aryl," as used herein, means a substituted or
unsubstituted, aromatic, mono- or bicyclic, chemically-feasible
carbocyclic ring system having from one to two aromatic rings. The
aryl moiety will generally have from 6 to 14 carbon atoms with all
available substitutable carbon atoms of the aryl moiety being
intended as possible points of attachment. Representative examples
include phenyl, tolyl, xylyl, cumenyl, naphthyl,
tetrahydronaphthyl, indanyl, indenyl and the like. If desired, the
carbocyclic moiety can be substituted with from one to five,
preferably, one to three, moieties, such as mono- through
pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy,
phenoxy, amino, monoalkylamino, dialkylamino, and the like.
[0069] The term "heteroaryl," as used herein, means a mono- or
bicyclic, chemically-feasible ring system containing one or two
aromatic rings and at least one nitrogen, oxygen or sulfur atom in
the aromatic ring. Mono- and polycyclic (e.g., bicyclic) heteroaryl
groups can be unsubstituted or substituted with a plurality of
substituents, preferably, one to five substituents, more
preferably, one, two or three substituents (e.g., mono- through
pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy,
phenoxy, amino, monoalkylamino, dialkylamino, and the like).
Typically, a heteroaryl group represents a chemically-feasible
cyclic group of five or six atoms, or a chemically-feasible
bicyclic group of nine or ten atoms, at least one of which is
carbon, and having at least one oxygen, sulfur or nitrogen atom
interrupting a carbocyclic ring having a sufficient number of pi
(.pi.) electrons to provide aromatic character. Representative
heteroaryl (heteroaromatic) groups are pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl,
benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl,
pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl groups.
[0070] The term "heterocycloalkyl" as used herein, means an
unsubstituted or substituted, saturated, chemically-feasible cyclic
ring system having from three to fifteen members, preferably, from
three to eight members, and comprising carbon atoms and at least
one heteroatom as part of the ring.
[0071] The term "heterocyclic ring" or "heterocycle," as used
herein, means an unsubstituted or substituted, saturated,
unsaturated or aromatic, chemically-feasible ring, comprised of
carbon atoms and one or more heteroatoms in the ring. Heterocyclic
rings may be monocyclic or polycyclic. Monocyclic rings preferably
contain from three to eight atoms in the ring structure, most
preferably, five to seven atoms. Polycyclic ring systems consisting
of two rings preferably contain from six to sixteen atoms, most
preferably, ten to twelve atoms. Polycyclic ring systems consisting
of three rings contain, preferably, from thirteen to seventeen
atoms, most preferably, fourteen to fifteen atoms. Each
heterocyclic ring has at least one heteroatom. Unless otherwise
stated, the heteroatoms may each be independently selected from the
group consisting of the following: nitrogen, sulfur and oxygen
atoms.
[0072] The term "carbocyclic ring" or "carbocycle," as used herein,
means an unsubstituted or substituted, saturated, unsaturated or
aromatic (e.g., aryl), chemically-feasible hydrocarbon ring, unless
otherwise specifically identified. Carbocycles may be monocyclic or
polycyclic. Monocyclic rings, preferably, contain from three to
eight atoms, more preferably, five to seven atoms. Polycyclic rings
having two rings, preferably, contain from six to sixteen atoms,
more preferably, ten to twelve atoms, and those having three rings,
preferably, contain from thirteen to seventeen atoms, more
preferably, fourteen to fifteen atoms.
[0073] The term "alkoxy," as used herein, means an oxygen atom
bonded to a hydrocarbon chain, such as an alkyl group (--O-alkyl).
Representative alkoxy groups include methoxy, ethoxy and isopropoxy
groups.
[0074] The term "hydroxyalkyl," as used herein, means a substituted
hydrocarbon chain, preferably, an alkyl group, having at least one
hydroxy substituent (-alkyl-OH). Additional substituents to the
alkyl group may also be present. Representative hydroxyalkyl groups
include hydroxymethyl, hydroxyethyl and hydroxypropyl groups. The
term "halo," "halogen" or "halide," as used herein, means a chloro,
bromo, fluoro or iodo atom radical. Chlorides, bromides and
fluorides are preferred halides.
[0075] The term "sulfonyl," as used herein, represents a group
having the formula --S(O).sub.2--.
[0076] The term "prodrug," as used herein, represents compounds
that are drug precursors which, following administration to a
patient, release the drug in vivo via a chemical or physiological
process (e.g., a prodrug on being brought to a physiological pH or
through an enzyme action is converted to the desired drug form). A
discussion of prodrugs is provided in T. Higuchi and V. Stella,
Pro-drugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium
Series (1987), and in Bioreversible Carriers in Drug Design, E. B.
Roche, ed., American Pharmaceutical Ass'n and Pergamon Press
(1987), each of which is incorporated herein by reference in its
entirety.
[0077] The terms "compound having the formula 1", "compound having
the formula 2", and the like as used herein, represent a compound
having a chemical structure encompassed by formula 1 or formula 2,
and includes any and all isomers (e.g., enantiomers, stereoisomers,
diastereomers, rotomers, tautomers) and prodrugs of the compound.
These compounds can be neutral, acidic or alkaline, and further
include their corresponding pharmaceutically-acceptable salts,
solvates, esters, and the like.
[0078] The phrase "effective amount," as used herein, means an
amount of a compound or composition which is sufficient enough to
significantly and positively modify the symptoms and/or conditions
to be treated (e.g., provide a positive clinical response). The
effective amount of an active ingredient for use in a
pharmaceutical composition will vary with the particular condition
being treated, the severity of the condition, the duration of the
treatment, the nature of concurrent therapy, the particular active
ingredient(s) being employed, the particular
pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and
like factors within the knowledge and expertise of the attending
physician.
[0079] By the term "disorder", it is meant an abnormal physical or
mental condition. As used herein, "disorders" include, but are not
limited to, diseases.
[0080] By the term "symptom", it is meant subject evidence of
disease or something that indicates the presence of a bodily
disorder, such as, but not limited to, a disease.
[0081] The phrase "inhibitory amount", as used herein, means an
amount of a compound or composition which is sufficient to reduce
the level or activity of a biological agent to a value less as
compared to when the compound or composition is not present.
[0082] In a preferred embodiment of the compounds of the formula 1
or 2,
[0083] T is phenyl, substituted with two or three substituents
independently selected from the group consisting of:
[0084] a) chloro;
[0085] b) methyl, and
[0086] c) methoxy.
[0087] More preferably, T is phenyl, substituted with
[0088] a) two chloro substituents, or
[0089] b) two methyl substituents (preferably 3,5-dichloro or
3,5-dimethyl), or
[0090] c) two methoxy and one methyl substituent (i.e.,
3,5-methoxy4-methyl), with two chloro substituents being most
preferred.
[0091] Also preferred are compounds of the formulas 1 or 2 wherein
R.sup.1 is methyl, --CH.sub.2F, --CH.sub.2CN,
--(CH.sub.2).sub.3SO.sub.3H, 8
[0092] with methyl being more preferred.
[0093] R.sup.4 is preferably methyl.
[0094] Another group of preferred compounds are those wherein
[0095] Z is 9
[0096] being more preferred,
[0097] and 10
[0098] being most preferred.
[0099] In one aspect of the invention, compounds suitable for use
in the methods of the invention are non-selective NK receptor
antagonists. For example, useful non-selective NK antagonists are
disclosed in the following U.S. Pat. Nos.: 5,688,960, 5,696,267,
5,840,725, 5,945,428, 6,063,926, and 6,204,265, each of which is
incorporated herein in its entirety by reference.
[0100] The following compounds are preferred for use in accordance
with the method of the invention: 11
[0101] Compounds useful in the methods of the invention and methods
for their syntheses are described in the aforementioned U.S. Pat.
Nos. 5,696,267, 5,840,725 and 6,063,926, which are incorporated
herein in their entirety by reference.
[0102] Compounds suitable for the methods of the present invention
can have at least one asymmetric carbon atom and all isomers,
including diastereomers, enantiomers and rotational isomers, as
well as E and Z isomers of the oxime, hydrazone and olefin groups,
are contemplated. The compounds include d and I isomers, in both
pure form and in admixture, including racemic mixtures. Isomers can
be prepared using conventional techniques, either by reacting
optically pure or optically enriched starting materials or by
separating isomers of a compound. The Z-isomers of the compounds of
formulas 1 or 2 are preferred.
[0103] Those skilled in the art will appreciate that, for some
compounds useful for practice of the present invention, one isomer
will show greater pharmacological activity than other isomers.
[0104] Compounds for use in the methods of the invention have at
least one amino group which can form pharmaceutically acceptable
salts with organic and inorganic acids. Examples of suitable acids
for salt formation are hydrochloric, sulfuric, phosphoric, acetic,
citric, oxalic, malonic, salicylic, malic, fumaric, succinic,
ascorbic, maleic, tartaric, methanesulfonic and other mineral and
carboxylic acids well known to those in the art.
[0105] The salt is prepared by contacting the free base form with a
sufficient amount of the desired acid to produce a salt. The free
base form may be regenerated by treating the salt with a suitable
dilute aqueous base solution such as dilute aqueous sodium
bicarbonate.
[0106] Certain compounds suitable for use in the present invention
are acidic (e.g., those compounds which posses a carboxyl group).
These compounds form pharmaceutically acceptable salts with
inorganic and organic bases. Examples of such salts are the sodium,
potassium, calcium, aluminum, gold and silver salts. Also included
are salts formed with pharmaceutically acceptable amines such as
ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and
the like.
[0107] The compounds for use in the inventive methods can exist in
unsolvated as well as solvated forms, including hydrated forms. In
general, the solvated forms, with pharmaceutically-acceptable
solvents, such as water, ethanol, and the like, are equivalent to
the unsolvated forms for purposes of this invention.
[0108] Disorders or symptoms which may be treated with an
antagonist of one or more of the NK.sub.1, NK.sub.2, and NK.sub.3
receptors in accordance with this invention include, but are not
limited to, BPH, metastatic prostatic carcinoma, testicular cancer,
androgen dependent acne, male pattern baldness, precocious puberty
in boys, hyperandrogenism, hirsutism, virilization, PCOS, HAIR-AN
syndrome, ovarian hyperthecosis, follicular maturation arrest,
atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,
infertility, and androgen-producing tumors.
[0109] A pharmaceutical composition comprising the antagonist of
the NK.sub.1, NK.sub.2 and/or NK.sub.3 receptors for use in the
inventive methods may be prepared by admixture of a compound
exhibiting such activity, and preferably, one or more compounds
specifically described herein, with an appropriate carrier which
may contain a diluent, binder, filler, disintegrant, flavoring
agent, coloring agent, lubricant or preservative in conventional
manner. A pharmaceutical composition typically contains from about
0.1 to about 99.9 weight percent, preferably, from about 5 to about
95 weight percent, more preferably, from about 20 to about 80
weight percent, of active ingredient (i.e., non-selective
antagonist of the NK.sub.1, NK.sub.2, and/or NK.sub.3
receptors).
[0110] Preferably, the pharmaceutical composition is in unit dosage
form and in a form adapted for use in the medical or veterinarial
fields. For example, such preparations may be in a pack form
accompanied by written or printed instructions for use as an agent
in the treatment of the conditions.
[0111] The suitable dosage range for the compounds of the invention
depends on the compound to be employed and on the condition of the
patient. It will also depend, inter alia, upon the relation of
potency to absorbability and the frequency and route of
administration.
[0112] The quantity of active ingredient (i.e., non-selective
antagonist of the NK.sub.1, NK.sub.2 and/or NK.sub.3 receptors) in
a unit dose of preparation may be varied or adjusted from about
0.01 to about 4,000 mg, preferably, from about 0.02 to about 1,000
mg, more preferably, from about 0.3 to about 500 mg, and most
preferably, from about 0.04 to about 250 mg, according to the
particular application. A typical recommended daily dosage regimen
for oral administration can range from about 0.02 to about 2,000
mg/day, in two to four divided doses. For convenience, the total
daily dosage may be divided and administered in portions during the
day as required. Typically, pharmaceutical compositions of the
invention will be administered from about 1 to about 5 times per
day, or alternatively, as a continuous infusion. Such
administration can be used as a chronic or acute therapy. The
amount of active ingredient that may be combined with carrier
materials to produce a single dosage form will vary depending upon
the host treated and the particular mode of administration.
[0113] The pharmaceutical composition may be formulated for
administration by any route, and is preferably in unit dosage form
or in a form that a human patient may self-administer in a single
dosage. Advantageously, the composition is suitable for oral,
rectal, topical, parenteral, intravenous or intramuscular
administration. Preparations may be designed to give slow release
of the active ingredient.
[0114] Pharmaceutical compositions may, for example, be in the form
of tablets, capsules, sachets, vials, powders, granules, lozenges,
reconstitutable powders, or liquid preparations, for example
solutions or suspensions, or suppositories.
[0115] The pharmaceutical compositions, for example those suitable
for oral administration, may contain conventional excipients such
as binding agents, such as syrup, acacia, gelatin, sorbitol,
tragacanth, or polyvinylpyrrolidone; fillers, such as lactose,
sugar, maize-starch, calcium phosphate, sorbitol or glycine;
tabletting lubricants, such as, magnesium stearate; disintegrants,
such as starch, polyvinyl-pyrrolidone, sodium starch glycollate or
microcrystalline cellulose; or pharmaceutically acceptable setting
agents such as sodium lauryl sulphate.
[0116] Solid pharmaceutical compositions may be obtained by
conventional methods of blending, filling, tabletting or the like.
Repeated blending operations may be used to distribute the active
agent throughout those compositions employing large quantities of
fillers. When the medicament is in the form of a tablet, powder, or
lozenge, any carrier suitable for formulating solid pharmaceutical
compositions may be used, examples being magnesium stearate,
starch, glucose, lactose, sucrose, rice flour and chalk. Tablets
may be coated according to methods well known in normal
pharmaceutical practice, in particular with an enteric coating. The
medicament may also be in the form of an ingestible capsule, such
as of gelatin containing the compound, optionally with a carrier or
other excipients.
[0117] Pharmaceutical compositions for oral administration as
liquids may be in the form of, for example, emulsions, syrups, or
elixirs, or may be presented as a dry product for reconstitution
with water or other suitable vehicle before use. Such liquid
compositions may contain conventional additives such as suspending
agents, for example sorbitol, syrup, methyl cellulose, gelatin,
hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate
gel, hydrogenated edible fats; emulsifying agents, such as
lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous
vehicles which include edible oils, such as almond oil,
fractionated coconut oil, oily esters, such as esters of glycerine,
or propylene glycol, or ethyl alcohol, glycerine, water or normal
saline; preservatives, such as methyl or propyl ph-hydroxybenzoate
or sorbic acid; and if desired conventional flavoring or coloring
agents.
[0118] The compounds disclosed herein may also be administered by a
non-oral route. In accordance with routine pharmaceutical
procedure, the compositions may be formulated, for example for
rectal administration as a suppository. They may also be formulated
for presentation in an injectable form in an aqueous or non-aqueous
solution, suspension or emulsion in a pharmaceutically acceptable
liquid, e.g., sterile pyrogen-free water or a parenterally
acceptable oil or a mixture of liquids. The liquid may contain
bacteriostatic agents, anti-oxidants or other preservatives,
buffers or solutes to render the solution isotonic with the blood,
thickening agents, suspending agents or other pharmaceutically
acceptable additives. Such forms will be presented in unit dose
form such as ampoules or disposable injection devices or in multi-
dose forms such as a bottle from which the appropriate dose may be
withdrawn or a solid form or concentrate which can be used to
prepare an injectable formulation.
[0119] The compounds disclosed herein may also be administered by
inhalation, via intranasal or oral routes. Such administration can
be carried out with a spray formulation comprising a compound of
the invention and a suitable carrier, optionally suspended in, for
example, a hydrocarbon propellant.
[0120] Preferred spray formulations comprise micronized compound
particles in combination with a surfactant, solvent or a dispersing
agent to prevent the sedimentation of suspended particles.
Preferably, the compound particle size is from about 2 to 10
microns.
[0121] A further mode of administration of the compounds described
herein comprises transdermal delivery utilizing a skin-patch
formulation. A preferred formulation comprises a compound of the
invention dispersed in a pressure sensitive adhesive which adheres
to the skin, thereby permitting the compound to diffuse from the
adhesive through the skin for delivery to the patient. For a
constant rate of percutaneous absorption, pressure sensitive
adhesives known in the art such as natural rubber or silicone can
be used.
[0122] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
amounts until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired.
[0123] The amount and frequency of administration of the
therapeutic agents will be regulated according to the judgment of
the attending clinician (physician) considering such factors as
age, condition and size of the patient as well as severity of the
disease being treated.
[0124] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
[0125] A unit dose will generally contain from 20 to 1000 mg and
preferably will contain from 30 to 500 mg, in particular 50, 100,
150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may
be administered one or more times a day, and the total daily dose
for a 70 kg adult will normally be in the range of 100 to 3000 mg.
Alternatively the unit dose will contain from 2 to 20 mg of active
ingredient and be administered in multiples, if desired, to give
the preceding daily dose.
[0126] Neurokinin B has been shown to interact with the NK.sub.3
receptor; however similar to substance P and neurokinin A,
neurokinin B has overlapping specificity with other NK receptors.
Furthermore, there have been recent disclosures of the involvement
of neurokinin B, as well as possibly substance P and neurokinin A
in the hypothalamic-pituitary axis (Debeljuk, L. and Lasaga, M.
Peptides 1999, 20,285). As described above, the pituitary gland is
involved in the stimulation of production of androgens by the
gonads. Since any of these three neuropeptides is capable of
eliciting responses from all three neurokinin receptors, it is
likely that inhibition of two or more of the neurokinin receptors
may lead to a greater reduction in androgen production relative to
that obtained when only one of the NK receptors is inhibited.
[0127] Compounds having the formula 1 or 2 can be effective
antagonists of at least one receptor selected from the group
consisting of neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) and
neurokinin-3 (NK.sub.3) receptors. In one aspect of the invention,
NK.sub.1 selective antagonists are utilized in the methods of the
invention. In another aspect of the invention, NK.sub.2 selective
antagonists are utilized in the methods of the invention. In
preferred embodiments of the methods of the invention, the
compounds antagonize two or more of the NK.sub.1, NK.sub.2 and
NK.sub.3 receptors. In more preferred embodiments of the methods of
the invention, the compounds non-selectively antagonize all three
of the NK.sub.1, NK.sub.2 and NK.sub.3 receptors
[0128] The compounds of the inventive method can be used to affect
androgen production in a mammal (e.g., humans, dogs, cats, etc.).
They can be administered to cause a chemical castration in a mammal
(both male and female). Thus, male dogs can be neutered and female
cats can be spayed with the inventive method. The inventive method
can also be used to treat patients desiring prophylactic androgen
modulation.
[0129] The in vitro and in vivo NK.sub.1, NK.sub.2 and NK.sub.3
activities of the compounds having formula 1 or 2 can be determined
by various procedures known in the art, such as a test for their
ability to inhibit the activity of the NK.sub.1 agonist Substance
P, an isolated hamster trachea NK.sub.2 assay, measurement of
NK.sub.2 activity in vivo in guinea pigs, measurement of
bronchoconstriction due to NKA and neurokinin receptor binding
assay(s). Typical procedures are described in WO 96/34857.
Procedures for determining NK.sub.3 activity may be found in, for
example, Molecular Pharmacol, 48 (1995), p. 711-716.
[0130] The percent inhibition of neurokinin agonist activity is the
difference between the percent of maximum specific binding ("MSB")
and 100%. The percent of MSB is defined by the following equation,
wherein "dpm" represents "disintegrations per minute": 1 % MSB = (
dpm of unknown ) - ( dpm of nonspecific binding ) ( dpm of total
binding ) - ( dpm of nonspecific binding ) .times. 100
[0131] The concentration at which a compound having formula 1 or 2
produces 50% inhibition of binding is then used to determine an
inhibition constant ("Ki") using the Chang-Prusoff equation.
[0132] It will be recognized that the compounds having formula 1 or
2 can exhibit NK.sub.1, NK.sub.2 and NK.sub.3 receptor antagonist
activities of varying degrees. For instance, certain compounds can
exhibit strong NK.sub.1 antagonist activity, but weaker NK.sub.2
and NK.sub.3 antagonist activity, while other compounds may be
strong NK.sub.2 antagonists, but weaker NK.sub.1 and NK.sub.3
antagonists.
[0133] The compounds useful for practice of the invention exhibit
potent affinities for one or more of the NK.sub.1, NK.sub.2 and
NK.sub.3 receptors as measured by Ki values (in nM). The activities
(potencies) for these compounds are determined by measuring their
Ki values. The smaller the Ki value, the more active is a compound
for antagonizing a particular NK receptor. Suitable compounds for
use in the invention may exhibit a wide range of activities. The
average Ki values for the NK.sub.1, NK.sub.2 and NK.sub.3 receptors
of compounds for use with the inventive methods generally range
from >0 nM (e.g., 0.01 nM) to about 1000 nM, preferably, from
about 0.05 nM to about 500 nM, with values of from about 0.1 nM to
about 100 nM being more preferred.
Biological Data
[0134] The androgen-suppressing effect of compounds which are
antagonists of one or more of NK.sub.1, NK.sub.2, and NK.sub.3
receptors have been determined as follows:
[0135] The compounds in Table I below were evaluated:
1TABLE I COMPOUND A 12 COMPOUND B 13 COMPOUND C 14 COMPOUND D 15
COMPOUND E 16 COMPOUND F 17
Reproductive System Effects in Dogs
[0136] Compound A was administered as an aqueous solution in
sterile water by daily oral gavage to adult healthy beagle
dogs.
[0137] The dogs received 28 consecutive daily doses at dose levels
of 0, 15, 30 or 60 mg/kg. All dogs survived the treatment period.
Compound A-related organ weight and histopathologic changes were
observed in both males and females, in the testes, epididymides,
prostate gland, ovaries, and uterus. Organ weights of male and
female reproductive tract tissues were 33-86% lower than that of
concurrent controls, and occurred in all dose groups.
Microscopically, atrophy of seminiferous tubules (severe) in the
testes, epididymides (minimal to moderate) and prostate gland (mild
to moderate) was observed in all dose groups in males.
Aspermia/hypospermia in the epididymides was also observed in all
dose groups. In the epididymides, vacuolation (mild) of epithelium
was also present in the mid- and high-dose males. In females, the
ovaries and uteri from at least one dog in each dose group
receiving Compound A appeared immature. This was characterized in
the ovaries by a lack of antral follicles, and most follicles that
were present were small and contained only small numbers of
granulosa cells. Compared to control dogs, the uterine bodies and
horns had less myometrial tissue present. Uterine epithelium from
dogs receiving Compound A with immature uteri had very little
cytoplasm present. The changes in the female reproductive system
may be related to atrophy rather than immaturity.
[0138] To further characterize reproductive system effects, adult
male healthy beagle dogs were administered sterile water (placebo)
or Compound A orally by gavage for 1, 3 or 7 days (Day 0=first day
of dosing). Serum was collected from blood for determination of
serum concentrations of testosterone (T) and luteinizing hormone
(LH).
[0139] Pretest and postdose control (placebo) serum LH and T
concentrations typically had a pulsatile pattern with primarily
lower baseline values interrupted by spikes of varying height and
incidence. There were typically one to three spikes of LH and T
within the sampling period. In many dogs the LH spikes preceded the
T spikes by 20 to 40 minutes.
[0140] In dogs receiving Compound A, serum LH and T concentrations
were generally near the lower baseline values at the first time
point evaluated (1 hour after the first doses), and then typically
declined throughout the 4-hour evaluation. This trend toward
decreased LH and T concentrations from 60 to 300 minutes postdose
was statistically significant (p<0.0001). LH and T remained at
low concentrations for the remainder of the study. Compared to
concurrent controls, group mean serum LH and T concentrations were
significant lower at Day 0, 2 and 6 (p.ltoreq.0.0005 for LH,
p.ltoreq.0.0001 for T). The decline in LH to very low (mean values
of 1.5 to 3.8 ng/ml for Compound A versus 10.2 to 14.8 ng/ml for
Controls) concentration was more rapid than that seen with T. In
dogs receiving Compound A, serum LH and T concentrations at Day 2
were generally lower than those at Day 0. Serum LH concentrations
on Day 6 were similar to those on Day 2, while serum T
concentrations on Day 6 were generally lower than those on Day 2.
By Days 2 and 6, some LH and many T samples were below the limit of
detection despite using sensitive assays.
[0141] In addition to having overall low values of LH and T, dogs
receiving Compound A lacked the normal pulsatile patterns of LH and
T, although a few small pulses were occasionally observed.
[0142] Another study was conducted to evaluate the effects of lower
doses (0.1, 0.5, 2.5, 12.5 mg/kg) of Compound A administered to
male beagle dogs for 7 days. Histopathologic changes seen after
dosing with Compound A included degeneration and cellular debris in
the seminiferous tubules, interstitial cell vacuolation in the
testes, epithelial vacuolation, atrophy, apoptosis, hypospermia,
and interstitial edema of the epididymides. Epithelial apoptosis
and atrophy of the prostate gland was also observed. Decreases in
serum LH, T, DHEA (dehydroepiandrosterone), and androstenedione
were clearly observed at doses of 2.5 and 12.5 mg/kg.
Reversibility of the Effects On Hormones
[0143] The following investigative study was conducted to determine
whether the changes observed after 1 week of Compound A
administration were reversible after a 14-day postdose period. The
first day of dosing was Day 1.
[0144] There were eight dogs in Group 1, who received placebo
(sterile water) and twelve dogs in Group 2, who received Compound
A. Dogs were scheduled to be dosed for 7 days; however, one dog
died shortly after receiving the sixth dose of compound A. All
eight dogs in Group 1 had hormonal evaluations on Day 7; 4 of these
dogs were necropsied on Day 8. The remaining four dogs in Group 1
had hormonal evaluations on Day 21 (14 days postdose), and were
necropsied on Day 22. In Group 2, eleven dogs had hormonal
evaluations on Day 7, and five were necropsied on Day 8. The
remaining six dogs in Group 2 had hormonal evaluations on Day 21
(14 days postdose).and were necropsied on Day 22.
[0145] Serum LH (luteinizing hormone) and T (testosterone)
concentrations from pretest samples, and from control dogs from
Days 7 and 21, often had a pulsatile pattern with primarily lower
baseline values interrupted by spikes of varying height and
incidence (although in some dogs the patterns were more erratic).
There were typically one to three spikes of LH and T within the
sampling period. In many dogs the LH spikes preceded the T spikes
by 30 to 60 minutes. Androstenedione and DHEA concentrations tended
to rise and fall with those of T, although in some dogs there were
many values below the limit of quantitation.
[0146] In dogs receiving Compound A at Day 7, serum LH, T,
androstenedione, and DHEA concentrations were often very low. Group
mean values for LH, T, androstenedione, and DHEA were 14.7, 1.5,
0.37, and 0.88 ng/ml for dogs receiving sterile water, while dogs
receiving Compound A had group mean values of 2.4, 0.05, 0.01 and
0.03 ng/ml, respectively. Compared to concurrent controls, group
mean peak and peak mean serum LH, T, androstenedione, and DHEA
concentrations were significantly lower at Day 7 (p>0.001 for
LH, p.ltoreq.0.0043 for T, p.ltoreq.0.001 for androstenedione, and
p.ltoreq.0.0002 for DHEA). It should also be noted that on Day 7
almost all T, androstenedione, and DHEA samples were below the
limit of detection despite using sensitive assays.
[0147] At Day 21, serum LH, T, androstenedione, and DHEA group mean
and peak mean concentrations in dogs receiving Compound A were not
significantly different from those of concurrent controls,
indicating that the effects are reversible after a 14-day postdose
period.
[0148] In summary, Compound A administration caused serum LH, T,
androstenedione, and DHEA concentrations to decrease rapidly and
dramatically, beginning shortly after a single dose. Because LH
drives the release of androgens, including T, the changes in
androgen levels may be due, in part, to the alterations in the
level of LH. Moreover, it is also possible that a direct effect on
androgen synthesis and/or release may be contributory to the
changes observed.
Reduction of Serum Testosterone in Mice
[0149] The effects of Compounds A, B, C, D, E and F on serum
testosterone were tested in mice given intramuscular (i.m.)
luteinizing hormone releasing hormone (LHRH) to drive testicular
androgen biosynthesis.
[0150] Male nude mice (8 weeks old, 5 mice/group) were dosed orally
with 0, 5, 15, 45, 90, 150 or 300 mg/kg of Compound A in 20%
hydroxypropyl .beta.-cyclodextran (HP.beta.CD). After 1 hour,
animals were given an i.m. injection of LHRH (250 ng/kg in 50 .mu.l
Sterile Water) into the biceps femoris muscle to drive testosterone
production. After an additional hour, the animals were anesthetized
with ketamine/xylazine, bled by cardiac puncture, and serum
testosterone levels were determined by radioimmunoassay. Compound A
reduced serum testosterone in a dose-dependent manner with 62%
inhibition of serum testosterone at 15 mg/kg Compound A and a
maximum of 83% inhibition at 300 mg/kg.
[0151] The effects of 90 mg/kg of Compounds A, B, C, D, E and F on
LHRH-stimulated serum testosterone levels were compared in male
nude mice. All compounds showed a statistically significant
(p<0.01) reduction of serum testosterone except Compound D,
which reduced mean serum testosterone by 19% but failed to reach
statistical significance.
Inhibition of Growth of Androgen-dependent Tumors in Mice (Shionogi
Murine Carcinoma)
[0152] Following the observation of reduction of serum testosterone
in mice, the effects of Compound A on androgen-dependent tumor
growth were tested. Two tumor models were used to determine whether
Compound A could selectively inhibit growth of androgen-dependent
tumors. Shionogi mouse mammary carcinoma tumors were grown in nude
mice as an androgen-dependent model, and DU-145 human prostate
carcinoma tumors were grown in nude mice as an androgen-independent
model.
[0153] In the Shionogi experiment, male nu/nu mice (8-9 weeks old,
10 mice/group) were inoculated with Shionogi carcinoma cells and
tumors were grown to approximately 150 mm.sup.3 before initiation
of Compound A administration. Mice were treated twice daily, i.p.
with 20% HP.beta.CD vehicle control, 5 mg/kg Compound A or 15 mg/kg
Compound A. Tumor growth was inhibited over 15 days of Compound A
treatment relative to vehicle control animals. At the end of 15
days, mean tumor volumes were inhibited by 41% and 69% in the 5
mg/kg and 15 mg/kg groups, respectively. These data indicate that
Compound A can be used to treat or prevent growth of
androgen-dependent tumors.
[0154] In the DU-145 experiment, male nu/nu mice (9-10 weeks old,
10 mice/group) were inoculated with DU-145 prostate carcinoma cells
and tumors were grown to approximately 65 mm.sup.3 before
initiation of Compound A administration. Mice were treated twice
daily, i.p. with 20% HP.beta.CD vehicle control, 15 mg/kg, 45 mg/kg
or 90 mg/kg of Compound A. As expected, tumor growth was not
inhibited over 30 days in any of the Compound A groups. Castrated
mice run in parallel also showed no inhibition of DU-145 tumor
growth substantiating the androgen independence of this tumor
model. Taken together with the Shionogi carcinoma results, these
data indicate that Compound A is selective for androgen-dependent
diseases, and lacks nonspecific effects on androgen-independent
tumor growth.
* * * * *