U.S. patent application number 12/495514 was filed with the patent office on 2009-10-29 for aminophenyl derivatives as selective androgen receptor modulators.
Invention is credited to Fabrizio Badalassi, Rasmus Lewinsky, Birgitte Winther Lund, Roger Olsson, Jan Pawlas, NATHALIE SCHLIENGER, Mikkel Boas Thygesen.
Application Number | 20090270449 12/495514 |
Document ID | / |
Family ID | 36591321 |
Filed Date | 2009-10-29 |
United States Patent
Application |
20090270449 |
Kind Code |
A1 |
SCHLIENGER; NATHALIE ; et
al. |
October 29, 2009 |
AMINOPHENYL DERIVATIVES AS SELECTIVE ANDROGEN RECEPTOR
MODULATORS
Abstract
Disclosed herein is a novel class of aminophenyl compounds
having the structure: ##STR00001## wherein R.sub.1 is cyano or
nitro and ring A is a bi- or tricyclic bridged heterocycle and to
their use as modulators of androgen receptor for the treatment or
prevention of conditions relating thereto.
Inventors: |
SCHLIENGER; NATHALIE;
(Frederiksberg, DK) ; Thygesen; Mikkel Boas;
(Copenhagen O, DK) ; Pawlas; Jan; (Frederiksberg,
DK) ; Badalassi; Fabrizio; (Copenhagen K, DK)
; Lewinsky; Rasmus; (Herlev, DK) ; Lund; Birgitte
Winther; (Bagsvaerd, DK) ; Olsson; Roger;
(Bunkeflostrand, SE) |
Correspondence
Address: |
DUANE MORRIS LLP - San Diego
101 WEST BROADWAY, SUITE 900
SAN DIEGO
CA
92101-8285
US
|
Family ID: |
36591321 |
Appl. No.: |
12/495514 |
Filed: |
June 30, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11329267 |
Jan 9, 2006 |
7585877 |
|
|
12495514 |
|
|
|
|
60642841 |
Jan 10, 2005 |
|
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Current U.S.
Class: |
514/304 ;
546/124 |
Current CPC
Class: |
A61P 5/24 20180101; A61P
15/08 20180101; A61P 19/10 20180101; A61P 25/24 20180101; A61P 3/06
20180101; A61P 9/00 20180101; C07D 451/02 20130101; A61P 3/04
20180101; A61P 9/12 20180101; A61P 21/00 20180101; A61P 25/18
20180101; A61P 27/02 20180101; A61P 35/00 20180101; A61P 15/00
20180101; A61P 3/10 20180101; A61P 9/10 20180101; C07D 451/06
20130101; A61P 5/28 20180101; A61P 7/06 20180101; A61P 25/28
20180101; A61P 5/26 20180101; A61P 15/10 20180101 |
Class at
Publication: |
514/304 ;
546/124 |
International
Class: |
A61K 31/46 20060101
A61K031/46; C07D 451/02 20060101 C07D451/02 |
Claims
1. A compound selected from the group consisting of:
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile; a prodrug ester thereof, a stereoisomer thereof,
a pharmaceutically acceptable salt thereof, and/or a combination
thereof.
2. The compound of claim 1 wherein the pharmaceutically acceptable
salt is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-
-methylbenzonitrile hydrochloride and/or an enantiomer thereof.
3. The compound of claim 1 wherein the pharmaceutically acceptable
salt is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-
-methylbenzonitrile mesylate and/or an enantiomer thereof.
4. The compound of claim 1 wherein the stereoisomer is an
enantiomer.
5. A pharmaceutical composition comprising a therapeutically
effective amount of a compound selected from the group consisting
of:
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile; a prodrug ester thereof, a stereoisomer thereof,
a pharmaceutically acceptable salt thereof, and/or a combination
thereof.
6. The pharmaceutical composition of claim 5 further comprising a
pharmaceutically acceptable carrier, a diluent, an excipient, or a
combination thereof.
7. The pharmaceutical composition of claim 5 wherein the
pharmaceutically acceptable salt is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile hydrochloride and/or an enantiomer thereof.
8. The pharmaceutical composition of claim 5 wherein the
pharmaceutically acceptable salt is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile mesylate and/or an enantiomer thereof.
9. The pharmaceutical composition of claim 5 wherein the
stereoisomer is an enantiomer.
10. A compound selected from the group consisting of:
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile;
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile hydrochloride; and
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile mesylate.
11. A pharmaceutical composition comprising a therapeutically
effective amount of a compound selected from the group consisting
of:
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile;
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile hydrochloride; and
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile mesylate.
12. The pharmaceutical composition of claim 5 wherein the
pharmaceutically acceptable salt is an enantiomer of
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile hydrochloride.
13. The pharmaceutical composition of claim 5 wherein the
pharmaceutically acceptable salt is an enantiomer of
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile mesylate.
14. The compound of claim 10 wherein the compound is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile.
15. The compound of claim 10 wherein the compound is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile hydrochloride.
16. The compound of claim 10 wherein the compound is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile mesylate.
17. The pharmaceutical composition of claim 11 wherein the compound
is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile.
18. The pharmaceutical composition of claim 11 wherein the compound
is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile hydrochloride.
19. The pharmaceutical composition of claim 11 wherein the compound
is
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile mesylate.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/642,841, filed on Jan. 10, 2005; and is a
continuation of, and claims the benefit of, U.S. application Ser.
No. 11/329,267, filed on Jan. 9, 2006 and U.S. application Ser. No.
11/348,929, filed on Feb. 6, 2006; the contents of each of which is
incorporated herein by reference in its entirety.
FIELD
[0002] The present invention relates to the fields of chemistry and
medicine. More particularly, the present invention relates to novel
compounds and methods of using those compounds for medicinal use
and/or to modulate androgen receptors.
BACKGROUND
[0003] The discussion that follows is intended solely as background
information to assist in the understanding of this invention;
nothing in this section is intended to be, nor is it to be
construed as, prior art to the invention.
[0004] The androgen receptor (AR) belongs to the family of nuclear
hormone receptors. Nuclear hormone receptors define a superfamily
of ligand activated transcription factors. Members of this family
are characterized by a number of modular domains: a zinc finger DNA
binding domain (DBD), which triggers the interaction of the
receptor with specific response elements at the DNA site, a ligand
binding domain (LBD) adjacent to the DBD, and two transcriptional
activation domains AF-1 and AF-2, which are ligand-independent and
ligand-dependent, respectively. Upon ligand binding to the
receptor, a conformational change occurs within the LBD bringing
the AF-2 domain in closer proximity and allowing for the
recruitment of co-activators. Co-activators create a physical
interaction between the nuclear hormone receptor and components of
the transcriptional machinery, establishing transcriptional
modulation of target genes.
[0005] The steroid sex hormones testosterone and the more potent
dihydroxy testosterone (DHT) represent the AR endogenous ligands.
Through activation of the receptor, these "male sex hormones"
modulate a number of physiological processes most notably primary
and secondary male characteristics.
[0006] Clinical situations in which levels of plasma testosterone
are decreased, also known as hypogonadism, have been extensively
studied. For instance, children suffering from such a condition
exhibit a total absence of pubertal development. Delay in puberty
leads to psychological problems, secondary to short stature and/or
delay in the acquisition of secondary sexual characteristics and
the reduction of bone mass. Moreover, several epidemiological
studies have confirmed that plasma testosterone levels gradually
decrease with aging. On average a quarter of men in their sixties
display clinical hypogonadism. This condition is even more
prevalent among male octogenarians where 50-80% of men in this age
group clinically qualify for hypogonadism. Decreased testosterone
plasma levels are also seen in aging women. Age-related
hypogonadism is associated with an obvious impairment in the
quality of life from physical manifestations (muscle, bone density
loss) to psychological problems (mood disorders, cognition,
decreased libido). This condition is referred to as "male
menopause" or "andropause".
[0007] Current therapies rely on the use of testosterone and
testosterone analogs. They are the treatment of choice in delayed
male puberty, male fertility as well as endometriosis. Because of
the strong anabolic effects of this class of steroid hormones, they
have been therapeutically approved for restoring skeletal muscle
mass in patients suffering from burns. A number of placebo
controlled clinical studies have reported a therapeutic benefit to
androgen agonism in aging men. In particular, reports have emerged
demonstrating the benefit of testosterone replacement therapy in
improving a number of aspects of age related hypogonadism such as
bone density, anabolism, libido, mood disorders (lack of vigor,
well being) and cognition. In the opthalmologic arena, dry eye is
also amenable to treatment with testosterone or testosterone
analogs. More recent studies have highlighted a correlation between
decreasing testosterone levels and increased incidence of
Alzheimer's disease.
[0008] Since oral preparations of testosterone and testosterone
analogs are ineffective due to enhanced first-pass metabolism and
hepatotoxicity, intramuscular injectable forms of long-acting
esters have constituted the basis of testosterone replacement
therapy. However, the large fluctuations of serum testosterone
levels induced by these preparations cause unsatisfactory shifts of
mood and sexual function in some men; because of the frequent
injections required, this delivery mode is thus far from being
ideal. In contrast, transdermal testosterone patches display more
favorable pharmacokinetic properties and have proven to be an
effective mode of delivery. Nevertheless, testosterone patch
systems (especially scrotal patches) are hampered by the high rate
of skin irritations. Recently, testosterone gels have gained
approval. Gels are applied once daily on the skin in quantities
large enough to deliver sufficient amounts of testosterone to
restore normal hormonal values and correct the signs and symptoms
of hypogonadism. However while being very effective, this mode of
application raises matters of adequate and consistent delivery.
[0009] Steroidal AR ligands, however, are plagued by undesirable
adverse side effects, for instance prostate enlargement, acne,
hirsutism, virilization and masculinisation. Furthermore, the
androgenic property of testosterone and its analogs are thought to
constitute a enhanced risk of prostate cancer. Thus, a search has
been initiated for non-steroidal compounds that can modulate the
activity of AR ligands; such compounds are referred to as Selective
Androgen Receptor Modulators or SARMs. It is expected that this
class of compounds will in general demonstrate better
pharmacokinetic and specificity profiles than current steroidal
therapies. In particular, non-steroidal SARMs are expected to lack
androgenic properties. Second generation SARMs are expected
contribute additional therapeutic benefits by displaying positive
anabolic properties and antagonistic androgenic components. Another
desirable feature of SARMs is expected to be their significant
bioavailability.
SUMMARY
[0010] An embodiment of this invention is a compound represented by
formula (I) or formula (II):
##STR00002##
and prodrugs, stereoisomers, and pharmaceutical acceptable salts
thereof wherein:
[0011] Z.sub.1; Z.sub.2, Z.sub.3 and Z.sub.4 are each independently
selected from the group consisting of hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclyl, halogen, cyano, hydroxy, optionally
substituted aminoalkyl, optionally substituted alkoxy, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocyclylalkyl, optionally substituted
heteroarylalkyl, C(O)OR.sub.4, C(O)NR.sub.4R.sub.5, NHC(O)R.sub.4,
NHSO.sub.2R.sub.4, OC(O)R.sub.4, C.dbd.NOR.sub.4, CF.sub.3,
COR.sub.4, S.sub.4, S(O).sub.nR.sub.8, and SO.sub.2NR.sub.8R.sub.9;
provided that at least one of Z.sub.1; Z.sub.2, Z.sub.3 or Z.sub.4
is not hydrogen;
[0012] R.sub.1 is selected from the group consisting of cyano and
nitro;
[0013] ring A, which comprises atoms Y.sub.1 and Y.sub.2, is an
optionally substituted bicyclic or tricyclic non-aromatic
heterocycle containing up to three heteroatoms selected from the
group consisting of N, O, S, S.dbd.O, SO.sub.2, C.dbd.O, and
C.dbd.S, wherein neither Y.sub.1 nor Y.sub.2 is C.dbd.O or
C.dbd.S;
[0014] R.sub.4 and R.sub.5 are each independently selected from the
group consisting of hydrogen, cyano, alkyl or substituted alkyl,
alkenyl or substituted alkenyl, alkynyl or substituted alkynyl,
cycloalkyl or substituted cycloalkyl, heterocyclylalkyl or
substituted heterocyclylalkyl, arylalkyl or substituted arylalkyl,
aryl or substituted aryl, heteroarylalkyl or substituted
heteroarylalkyl, and heteroaryl or substituted heteroaryl;
[0015] R.sub.6 and R.sub.7 are each independently selected from the
group consisting of hydrogen, halo, cyano, hydroxy, alkyl or
substituted alkyl, alkenyl or substituted alkenyl, alkynyl or
substituted alkynyl, cycloalkyl or substituted cycloalkyl,
heterocyclylalkyl or substituted heterocyclylalkyl, arylalkyl or
substituted arylalkyl, aryl or substituted aryl, heteroarylalkyl or
substituted heteroarylalkyl, heteroaryl or substituted heteroaryl,
OR.sub.4, NR.sub.4R.sub.5, SR.sub.4, C(O)R.sub.4, C(O)OR.sub.4,
C(O)NR.sub.4R.sub.5, NHC(O)R.sub.4, NR.sub.4C(O)R.sub.5,
OC(O)R.sub.4, C(S)R.sub.4, C(S)OR.sub.4, C(S)NR.sub.4R.sub.5,
NHC(S)R.sub.4, OC(S)R.sub.4, S(O).sub.nR.sub.4,
SO.sub.2NR.sub.4R.sub.5, OSO.sub.2R.sub.4, NHSO.sub.2R.sub.4, and
alkyl substituted with OR.sub.4, NR.sub.4R.sub.5, SR.sub.4,
C(O)R.sub.4, C(O)OR.sub.4, C(O)NR.sub.4R.sub.5, NHC(O)R.sub.4,
NR.sub.4C(O)R.sub.5, OC(O)R.sub.4, C(S)R.sub.4, C(S)OR.sub.4,
C(S)NR.sub.4R.sub.5, NHC(S)R.sub.4, OC(S)R.sub.4,
S(O).sub.nR.sub.4, SO.sub.2NR.sub.4R.sub.5, OSO.sub.2R.sub.4, or
NHSO.sub.2R.sub.4;
[0016] R.sub.8 and R.sub.9 are each independently selected from the
group consisting of hydrogen, alkyl or substituted alkyl, alkenyl
or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl
or substituted cycloalkyl, heterocyclylalkyl or substituted
heterocyclylalkyl, arylalkyl or substituted arylalkyl, and
heteroarylalkyl or substituted heteroarylalkyl; and
[0017] n is an integer from 1 to 3.
[0018] In an embodiment of this invention, the compound of formula
I or formula II is not selected from the group consisting of:
##STR00003##
[0019] In an embodiment of this invention, ring A is a bicyclic
heterocycle.
[0020] In an embodiment of this invention, the bicyclic heterocycle
is a bridged bicyclic heterocycle.
[0021] In an embodiment of this invention:
Z.sub.1 and Z.sub.2 are independently selected from the group
consisting of hydrogen, unsubstituted --(C.sub.1-C.sub.4)alkyl,
--(C.sub.1-C.sub.4)alkylOH, --(C.sub.1-C.sub.4)alkyl(halo), halo,
cyano, --OR.sub.4, --OC(O)R.sub.4, --CF.sub.3, --CHO and
--CH.dbd.NOR.sub.4; R.sub.6 and R.sub.7 are independently selected
from the group consisting of hydrogen, unsubstituted
--(C.sub.1-C.sub.4)alkyl, --(C.sub.1-C.sub.4)alkylOH,
--(C.sub.1-C.sub.4)alkyl(halo), halo, cyano, --OR.sub.4,
--OC(O)R.sub.4 and --CF.sub.3; and, the bridged bicyclic
heterocycle comprises one nitrogen atom, wherein R.sub.4 is
selected from the group consisting of hydrogen, unsubstituted
(C.sub.1-C.sub.4)alkyl, unsubstituted (C.sub.3-C.sub.6)cycloalkyl
and unsubstituted aryl.
[0022] In an embodiment of this invention ring A has the
structure:
##STR00004##
[0023] In an embodiment of this invention ring A has the
structure:
##STR00005##
[0024] In an embodiment of this invention, R.sub.6 is hydroxy.
[0025] In an embodiment of this invention, R.sub.7 is
--(C.sub.1-C.sub.4)alkyl.
[0026] In an embodiment of this invention, R.sub.7 is bonded to the
same carbon atom to which R.sub.6 is bonded.
[0027] In an embodiment of this invention, ring A is tropane or an
optionally substituted tropane. In an embodiment of this invention,
ring A is optionally substituted with one or more substituents
selected from the group consisting of hydrogen, halogen, hydroxy,
alkoxy or substituted alkoxy, alkyl or substituted alkyl, alkenyl
or substituted alkenyl, alkynyl or substituted alkynyl, aminoalkyl
or substituted aminoalkyl, OC(O)R.sub.4, and NHC(O)R.sub.4. In an
embodiment of this invention, R.sub.1 is cyano. In an embodiment of
this invention, at least one of R.sub.6 or R.sub.7 on ring A is
hydroxy or alkyl. In an embodiment of this invention, Z.sub.1 is
alkyl, halogen, haloalkyl or hydroxyalkyl. In an embodiment of this
invention, Z.sub.2 is alkyl, halogen, haloalkyl or hydroxyalkyl. In
an embodiment of this invention, Z.sub.1 is methyl or ethyl and
Z.sub.2 is halogen. In an embodiment of this invention, Z.sub.1 is
methyl or ethyl and Z.sub.2 is chloro. In an embodiment of this
invention, Z.sub.1 is methyl and Z.sub.2 is chloro.
[0028] In an embodiment of this invention, the compound of formula
(I) or formula (II) is selected from the group consisting of:
[0029]
endo-8-(3-chloro-2-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;
[0030]
2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methyl-
benzonitrile; [0031]
2-Bromo-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-5-methylbenzonitri-
le; [0032]
6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitro-
benzoic acid; [0033]
2-(Trifluoromethyl)-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)benzo-
nitrile [0034]
3-Bromo-2-chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitri-
le; [0035]
endo-8-(2,3-Dimethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3--
ol; [0036]
2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-iodob-
enzonitrile; [0037]
endo-8-[2-(hydroxymethyl)-3-methyl-4-nitrophenyl]-8-azabicyclo[3.2.1]octa-
n-3-ol; [0038]
4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-trifluoromethylbenzonitr-
ile; [0039]
endo-8-(2-Chloro-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;
[0040]
2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitroben-
zaldehyde; [0041]
endo-8-(3-Chloro-2-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan--
3-ol; [0042]
2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitrobenzaldehy-
de oxime; [0043]
endo-8-(2-Chloro-3-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan--
3-ol; [0044]
endo-8-(5-Chloro-2-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;
[0045]
2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitril-
e; [0046]
6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrob-
enzoic acid; [0047]
endo-8-(2-Hydroxymethyl-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan--
3-ol; [0048]
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile; [0049]
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile hydrochloride; and [0050]
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile mesylate.
[0051] An embodiment of this invention is a prodrug ester,
carbonate, carbamate, sulfate, phosphate or phosphoramidate of a
compound or formula (I) or formula (II).
[0052] An embodiment disclosed herein includes a pharmaceutical
composition comprising a compound of formula (I) or formula (II)
and a pharmaceutically acceptable excipient.
[0053] An embodiment disclosed herein includes a method of treating
a condition selected from the group consisting of hypogonadism,
lower than normal testosterone plasma levels, infertility in males,
erectile dysfunction in males, andropause in males, endometriosis
in females, dyspareunia in females, vaginismus in females, sexual
arousal disorders in females, sexual orgasmic disorders in females,
disorders of libido in males, cachexia, HIV wasting, critical
illnesses in which muscle wasting is apparent, sarcopenia, frailty,
short stature, dwarfism, bone density loss, mood disorders,
depression, impaired cognitive functions, neurodegenerative
disorders, xerophthalmia, metabolic disorders, cardiovascular
disorders, obesity, anemia, prostate cancer, and schizophrenia,
comprising administering to a patient exhibiting one or more
symptoms of the condition a compound of a compound of this
invention or a prodrug, stereoisomer, or pharmaceutically
acceptable salt thereof.
[0054] In an embodiment of this invention, the mood disorder is
selected from the group consisting of lack of well being, lack of
vigor, anger, irritability, sadness, tiredness, and nervousness. In
an embodiment of this invention, the neurodegenerative disorder is
selected from the group consisting of Alzheimer's disease, Mild
cognition impairment (MCI), Lewis body dementia, and frontal
temporal dementia. In an embodiment of this invention, the
metabolic disorder is selected from the group consisting of
dyslipidemia, atherosclerosis, and non-insulin dependent diabetes
(NIDDM). In an embodiment of this invention, the cardiovascular
disorder is selected from the group consisting of hypertension,
coronary artery disease, and myocardial perfusion.
[0055] An embodiment of this invention is a method of modulating
spermatogenesis in males, comprising: administering to a male
subject a compound of this invention or a prodrug, a stereoisomer
or a pharmaceutically acceptable salt thereof.
[0056] An embodiment disclosed herein is a method of hormonal
replacement therapy, comprising administering to a subject in need
of hormonal replacement therapy a compound of this invention or a
prodrug, a stereoisomer or a pharmaceutically acceptable salt
thereof.
[0057] An embodiment of this invention, need for hormonal
replacement therapy is caused by orchiectomy by surgical or
chemical means.
[0058] An embodiment disclosed herein includes a method of
improving muscle strength comprising administering to a subject in
need thereof a compound of this invention or a prodrug, a
stereoisomer or a pharmaceutically acceptable salt thereof.
[0059] In an embodiment of this invention, need for improvement in
muscular strength is caused by muscular dystrophy, myotonic
dystrophy, or glucocorticoid-treated asthma.
[0060] An embodiment disclosed herein includes a method of
preventing a condition selected from the group consisting of bone
density loss, xerophthalmia, metabolic disorders, cardiovascular
disorders, obesity, and prostate cancer, comprising administering
to a subject a compound of this invention or a prodrug, a
stereoisomer or a pharmaceutically acceptable salt thereof.
[0061] In an embodiment of this invention, the metabolic disorder
is selected from the group consisting of dyslipidemia,
atherosclerosis, and non-insulin dependent diabetes (NIDDM). In one
embodiment, the cardiovascular disorder is selected from the group
consisting of hypertension, coronary artery disease, and myocardial
perfusion.
[0062] An embodiment disclosed herein includes a method of
improving a health-related quality of life parameter selected from
the group consisting of survival, impairment, functional status,
health perception, and opportunities, comprising administering to a
subject a compound of this invention or a prodrug, a stereoisomer
or a pharmaceutically acceptable salt thereof.
[0063] An embodiment disclosed herein includes a method of delaying
the progression of prostate cancer, comprising administering to a
patient in need thereof a compound of this invention or a prodrug,
a stereoisomer, or a pharmaceutically acceptable salt thereof.
[0064] An embodiment disclosed herein includes a method of
modulating an androgen receptor comprising contacting the receptor
with a compound of this invention or a prodrug, a stereoisomer or a
pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] FIG. 1 depicts bar graphs comparing wet tissue weights of
prostate tissues upon daily subcutaneous (s.c.) administration to
rats of 1 or 3 mg/kg of testosterone propionate (TP) with various
doses of compound 198RL26 (p.o.) for a period of two weeks.
[0066] FIG. 2 depicts bar graphs comparing wet tissue weights of
seminal vesicle tissues upon daily s.c. administration to rats of 1
or 3 mg/kg of testosterone propionate (TP) with various doses of
compound 198RL26 (p.o.) for a period of two weeks.
[0067] FIG. 3 depicts bar graphs comparing wet tissue weights of
levator ani muscle tissues upon daily s.c. administration to rats
of 1 or 3 mg/kg of testosterone propionate (TP) with various doses
of compound 198RL26 (p.o.) for a period of two weeks.
[0068] FIG. 4 depicts bar graphs of plasma levels of luteinizing
hormone (LH) in rats upon castration after daily (s.c.)
administration to rats of 1 or 3 mg/kg of testosterone propionate
(TP) with various doses of compound 198RL26 (p.o.) for a period of
two weeks.
DISCUSSION
[0069] As noted above, in an embodiment of this invention,
prodrugs, metabolites, stereoisomers, and pharmaceutically
acceptable salts of the compounds of this invention are
provided.
[0070] A "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in Design
of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby
incorporated herein by reference in its entirety. A non-limiting
example of a prodrug for use herein includes those that promote the
solubility of alcohols such as by the procedures described in
Mahfous, N. H. et al, J. Pharm. Pharmacol, 53, 841-848 (2001) and
Bundgaard, H. et al., J. Med. Chem., 32, 2503-2507 (1989), both of
which are incorporated herein by reference in their entirety.
[0071] The term "pro-drug ester" refers to derivatives of the
compounds disclosed herein formed by the addition of any of several
ester-forming groups that are hydrolyzed under physiological
conditions. Examples of pro-drug ester groups include
pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and
methoxymethyl, as well as other such groups known in the art,
including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Other
examples of pro-drug ester groups can be found in, for example, T.
Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems",
Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975);
and "Bioreversible Carriers in Drug Design: Theory and
Application", edited by E. B. Roche, Pergamon Press: New York,
14-21 (1987) (providing examples of esters useful as prodrugs for
compounds containing carboxyl groups). Each of the above-mentioned
references is herein incorporated by reference in their
entirety.
[0072] Metabolites of the compounds of this invention include
active species that are produced upon introduction of the compounds
into the biological milieu.
[0073] Where the compounds of formula (I) or formula (II) have at
least one chiral center, they may exist as a racemate or as
enantiomers. It should be noted that all such isomers and mixtures
thereof are included in the scope of the present invention.
Furthermore, some of the crystalline forms for the compounds of
formula (I) or formula (II) may exist as polymorphs. Such
polymorphs are included in one embodiment of the present invention.
In addition, some of the compounds of the present invention may
form solvates with water (i.e., hydrates) or common organic
solvents. Such solvates are included in one embodiment of the
present invention.
[0074] The term "pharmaceutically acceptable salt" refers to a salt
of a compound that does not cause significant irritation to an
organism to which it is administered and does not abrogate the
biological activity and properties of the compound. In some
embodiments, the salt is an acid addition salt of the compound.
Pharmaceutical salts can be obtained by reacting a compound with
inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or
hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and
the like. Pharmaceutical salts can also be obtained by reacting a
compound with an organic acid such as aliphatic or aromatic
carboxylic or sulfonic acids, for example acetic, succinic, lactic,
malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,
ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic
acid. Pharmaceutical salts can also be obtained by reacting a
compound with a base to form a salt such as an ammonium salt, an
alkali metal salt, such as a sodium or a potassium salt, an
alkaline earth metal salt, such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
C.sub.1-C.sub.7 alkylamine, cyclohexylamine, triethanolamine,
ethylenediamine, and salts with amino acids such as arginine,
lysine, and the like.
[0075] If the manufacture of pharmaceutical formulations involves
intimate mixing of the pharmaceutical excipients and the active
ingredient in its salt form, then it may be desirable to use
pharmaceutical excipients which are non-basic, that is, either
acidic or neutral excipients.
[0076] In an embodiment of this invention, the compounds of this
invention can be used alone, in combination with other compounds
hereof or in combination with one or more other agents active in
the therapeutic areas described herein.
[0077] The term "halogen atom," refers to fluorine, chlorine,
bromine, or iodine, with fluorine and chlorine being presently
preferred.
[0078] The term "ester" refers to a chemical moiety with formula
--(R).sub.n--COOR', where R and R' are independently selected from
the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded
through a ring carbon) and heteroalicyclic (bonded through a ring
carbon), and where n is 0 or 1.
[0079] An "amide" is a chemical moiety with formula
--(R).sub.n--C(O)NHR' or --(R).sub.n--NHC(O)R', where R and R' are
independently selected from the group consisting of alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
heteroalicyclic (bonded through a ring carbon), and where n is 0 or
1. An amide may be an amino acid or a peptide molecule attached to
a compound of this invention, thereby forming a prodrug.
[0080] Any amine, hydroxy, or carboxyl side chain on the compounds
of the present invention can be esterified or amidified. The
procedures and specific groups to be used to achieve this end are
known to those of skill in the art and can readily be found in
reference sources such as Greene and Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York,
N.Y., 1999, which is incorporated herein in its entirety.
[0081] The term "aromatic" refers to an aromatic group which has at
least one ring having a conjugated pi electron system and includes
both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups
(e.g., pyridine). The term includes monocyclic or fused-ring
polycyclic (i.e., rings which share adjacent pairs of carbon atoms)
groups. The term "carbocyclic" refers to a compound which contains
one or more covalently closed ring structures, and that the atoms
forming the backbone of the ring are all carbon atoms. The term
thus distinguishes carbocyclic from heterocyclic rings in which the
ring backbone contains at least one atom which is different from
carbon. The term "heteroaromatic" refers to an aromatic group which
contains at least one heterocyclic ring.
[0082] The term "alkyl," as used herein, means any unbranched or
branched, substituted or unsubstituted, saturated hydrocarbon. The
alkyl moiety, may be branched, straight chain, or cyclic. The alkyl
group may have 1 to 20 carbon atoms (whenever it appears herein, a
numerical range such as "1 to 20" refers to each integer in the
given range; e.g., "1 to 20 carbon atoms" means that the alkyl
group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,
etc., up to and including 20 carbon atoms, although the present
definition also covers the occurrence of the term "alkyl" where no
numerical range is designated). The alkyl group may also be a
medium size alkyl having 1 to 10 carbon atoms. The alkyl group
could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl
group may be designated as "C.sub.1-C.sub.4 alkyl" or similar
designations. By way of example only, "C.sub.1-C.sub.4 alkyl"
indicates that there are one to four carbon atoms in the alkyl
chain, i.e., the alkyl chain is selected from the group consisting
of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, and t-butyl.
[0083] The alkyl group may be substituted or unsubstituted. When
substituted, the substituent group(s) is(are) one or more group(s)
individually and independently selected from substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cylcloalkenyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroaryloxy, heterocyclyl, heterocyclooxy, heteroalicyclyl,
hydroxy, substituted or unsubstituted alkoxy, substituted or
unsubstituted aryloxy, acyl, thiol, substituted or unsubstituted
thioalkoxy, alkylthio, arylthio, cyano, halo, carbonyl,
thiocarbonyl, acylalkyl, acylamino, acyloxy, aminoacyl,
aminoacyloxy, oxyacylamino, keto, thioketo, O-carbamyl,
N-carbarnyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,
S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,
thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl,
and substituted or unsubstituted amino, including mono- and
di-substituted amino groups, and the protected derivatives thereof,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Typical alkyl groups include, but are in no
way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Wherever a substituent is described as being "optionally
substituted" that substitutent may be substituted with one of the
above substituents.
[0084] In the present context, the term "cycloalkyl" is intended to
cover three-, four-, five-, six-, seven-, and eight- or more
membered rings comprising carbon atoms only. A cycloalkyl can
optionally contain one or more unsaturated bonds situated in such a
way, however, that an aromatic pi-electron system does not arise.
Some examples of "cycloalkyl" are the carbocycles cyclopropane,
cyclobutane, cyclopentane, cyclopentene, cyclopentadiene,
cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene,
cycloheptane, or cycloheptene.
[0085] An "alkenyl" moiety refers to a group consisting of at least
two carbon atoms and at least one carbon-carbon double bond. An
alkenyl may be unbranched or branched, substituted or
unsubstituted, unsaturated hydrocarbon including polyunsaturated
hydrocarbons. In some embodiments, the alkenyl is a C.sub.1-C.sub.6
unbranched, mono-unsaturated or di-unsaturated, unsubstituted
hydrocarbons. The term "cycloalkenyl" refers to any non-aromatic
hydrocarbon ring, preferably having five to twelve atoms comprising
the ring.
[0086] An "alkyne" moiety refers to a group consisting of at least
two carbon atoms and at least one carbon-carbon triple bond.
[0087] The substituent "R" appearing by itself and without a number
designation refers to a substituent selected from the group
consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a
ring carbon) and heteroalicyclyl (bonded through a ring
carbon).
[0088] The term "alkoxy" refers to any unbranched, or branched,
substituted or unsubstituted, saturated or unsaturated ether, with
C.sub.1-C.sub.6 unbranched, saturated, unsubstituted ethers being
preferred, with methoxy being preferred, and also with dimethyl,
diethyl, methyl-isobutyl, and methyl-tert-butyl ethers also being
preferred. The term "cycloalkoxy" refers to any non-aromatic
hydrocarbon ring, preferably having five to twelve atoms comprising
the ring.
[0089] An "O-carboxy" group refers to a RC(.dbd.O)O-- group, where
R is as defined herein.
[0090] A "C-carboxy" group refers to a --C(.dbd.O)OR groups where R
is as defined herein.
[0091] An "acetyl" group refers to a --C(.dbd.O)CH.sub.3,
group.
[0092] A "trihalomethanesulfonyl" group refers to a
X.sub.3CS(.dbd.O)2-- group where X is a halogen.
[0093] A "cyano" group refers to a --CN group.
[0094] An "isocyanato" group refers to a --NCO group.
[0095] A "thiocyanato" group refers to a --CNS group.
[0096] An "isothiocyanato" group refers to a --NCS group.
[0097] A "sulfinyl" group refers to a --S(.dbd.O)--R group, with R
as defined herein.
[0098] A "S-sulfonamido" group refers to a --S(.dbd.O)2NR, group,
with R as defined herein.
[0099] A "N-sulfonamido" group refers to a RS(.dbd.O).sub.2NH--
group with R as defined herein.
[0100] A "trihalomethanesulfonamido" group refers to a
X.sub.3CS(.dbd.O).sub.2NR-- group with X and R as defined
herein.
[0101] An "O-carbamyl" group refers to a --OC(.dbd.O)--NR,
group-with R as defined herein.
[0102] An "N-carbamyl" group refers to a ROC(.dbd.O)NH-- group,
with R as defined herein.
[0103] An "O-thiocarbamyl" group refers to a --OC(.dbd.S)--NR,
group with R as defined herein.
[0104] An "N-thiocarbamyl" group refers to an ROC(.dbd.S)NH--
group, with R as defined herein.
[0105] A "C-amido" group refers to a --C(.dbd.O)--NR.sub.2 group
with R as defined herein.
[0106] An "N-amido" group refers to a RC(.dbd.O)NH-- group, with R
as defined herein.
[0107] The term "perhaloalkyl" refers to an alkyl group where all
of the hydrogen atoms are replaced by halogen atoms.
[0108] The term "acylalkyl" refers to a RC(.dbd.O)R'-- group, with
R as defined herein, and R' being a diradical alkylene group.
Examples of acylalkyl, without limitation, may include
CH.sub.3C(.dbd.O)CH.sub.2--, CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3CH.sub.2C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2CH.sub.2--, and the like.
[0109] The term "aminoalkyl" refers to a substituent selected from
the group consisting of --RNR'R'', --RNHR', and --RNH.sub.2, with
R, R', and R'' independently being as R is defined herein.
[0110] Unless otherwise indicated, when a substituent is deemed to
be "optionally substituted," it is meant that the substituent is a
group that may be substituted with one or more group(s)
individually and independently selected from morpholinoalkanoate,
cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroalicyclic,
hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano,
halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,
N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,
isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino,
including mono- and di-substituted amino groups, and the protected
derivatives thereof. The protecting groups that may form the
protective derivatives of the above substituents are known to those
of skill in the art and may be found in references such as Greene
and Wuts, above.
[0111] The term "heterocyclyl" is intended to mean three-, four-,
five-, six-, seven-, and eight- or more membered rings wherein
carbon atoms together with from 1 to 3 heteroatoms constitute the
ring. A heterocyclyl can optionally contain one or more unsaturated
bonds situated in such a way, however, that an aromatic pi-electron
system does not arise. The heteroatoms are independently selected
from oxygen, sulfur, and nitrogen.
[0112] A heterocyclyl can further contain one or more carbonyl or
thiocarbonyl functionalities, so as to make the definition include
oxo-systems and thio-systems such as lactams, lactones, cyclic
imides, cyclic thioimides, cyclic carbamates, and the like.
[0113] Heterocyclyl rings can optionally be fused ring systems
containing two or more rings wherein at least one atom is shared
between two or more rings to form bicyclic or tricyclic structures.
In some embodiments, such fused ring systems are formed by a
bridging moiety between two atoms of a heterocyclyl.
[0114] Heterocyclyl rings can optionally also be fused to aryl
rings, such that the definition includes bicyclic structures.
Typically such fused heterocyclyl groups share one bond with an
optionally substituted benzene ring. Examples of benzo-fused
heterocyclyl groups include, but are not limited to,
benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene
ring structures.
[0115] Some examples of "heterocyclyls" include, but are not
limited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,
piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,
piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,
imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole,
1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
oxazolidinone, thiazoline, thiazolidine, 1,3-oxathiolane, and an
azabicyclo system such as azabicyclo[3.2.1]octyl (tropane). Binding
to the heterocycle can be at the position of a heteroatom or via a
carbon atom of the heterocycle, or, for benzo-fused derivatives,
via a carbon of the benzenoid ring.
[0116] In the present context the term "aryl" is intended to mean a
carbocyclic aromatic ring or ring system. Moreover, the term "aryl"
includes fused ring systems wherein at least two aryl rings, or at
least one aryl and at least one C.sub.3-8-cycloalkyl share at least
one chemical bond. Some examples of "aryl" rings include optionally
substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl,
tetralinyl, fluorenyl, indenyl, and indanyl. The term "aryl"
relates to aromatic, including, for example, benzenoid groups,
connected via one of the ring-forming carbon atoms, and optionally
carrying one or more substituents selected from heterocyclyl,
heteroaryl, halo, hydroxy, amino, cyano, nitro, alkylamido, acyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl,
C.sub.1-6 aminoalkyl, C.sub.1-6 alkylamino, alkylsulfenyl,
alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. The
aryl group can be substituted at the para and/or meta positions. In
other embodiments, the aryl group can be substituted at the ortho
position. Representative examples of aryl groups include, but are
not limited to, phenyl, 3-halophenyl, 4-halophenyl,
3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl,
3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
4-trifluoromethoxyphenyl 3-cyanophenyl, 4-cyanophenyl,
dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl,
trifluoromethylphenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl,
4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and
4-(2-oxopyrrolidin-1-yl)phenyl.
[0117] In the present context, the term "heteroaryl" is intended to
mean a heterocyclic aromatic group where one or more carbon atoms
in an aromatic ring have been replaced with one or more heteroatoms
selected from the group comprising nitrogen, sulfur, and
oxygen.
[0118] Furthermore, in the present context, the term "heteroaryl"
comprises fused ring systems wherein at least one aryl ring and at
least one heteroaryl ring, at least two heteroaryl rings, at least
one heteroaryl ring and at least one heterocyclyl ring, or at least
one heteroaryl ring and at least one cycloalkyl ring share at least
one chemical bond.
[0119] The term "heteroaryl" is understood to relate to aromatic,
C.sub.3-8 cyclic groups further containing one oxygen or sulfur
atom or up to four nitrogen atoms, or a combination of one oxygen
or sulfur atom with up to two nitrogen atoms, and their substituted
as well as benzo- and pyrido-fused derivatives, for example,
connected via one of the ring-forming carbon atoms. Heteroaryl
groups can carry one or more substituents, selected from halo,
hydroxy, amino, cyano, nitro, alkylamido, acyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-aminoalkyl,
C.sub.1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl,
sulfamoyl, or trifiuoromethyl. In some embodiments, heteroaryl
groups can be five- and six-membered aromatic heterocyclic systems
carrying 0, 1, or 2 substituents, which can be the same as or
different from one another, selected from the list above.
Representative examples of heteroaryl groups include, but are not
limited to, unsubstituted and mono- or di-substituted derivatives
of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,
indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole,
benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole,
indazole, tetrazole, quionoline, isoquinoline, pyridazine,
pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole,
1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole,
pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine,
cinnoline, phthalazine, quinazoline, and quinoxaline. In some
embodiments, the substituents are halo, hydroxy, cyano,
O--C.sub.1-6-alkyl, C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, and
amino-C.sub.1-6-alkyl.
[0120] The terms "purified," "substantially purified," and
"isolated" as used herein refer to the compounds of the invention
being free of other, dissimilar compounds with which the compounds
of the invention are normally associated in their natural state, so
that the compounds of the invention comprise at least 0.5%, 1%, 5%,
10%, or 20%, and most preferably at least 50% or 75% of the mass,
by weight, of a given sample.
Synthesis
[0121] The compounds of this invention may be synthesized by
methods described below, or by modification of these methods. Ways
of modifying the methodology include, among others, temperature,
solvent, reagents etc., and will be obvious to those skilled in the
art. In general, during any of the processes for preparation of the
compounds it may be necessary and/or desirable to protect sensitive
or reactive groups on any of the molecules concerned. This may be
achieved by means of conventional protecting groups, such as those
described in Protective Groups in Organic Chemistry (ed. J. F. W.
McOmie, Plenum Press, 1973); and Greene & Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991, which are
both hereby incorporated herein by reference in their entirety. The
protecting groups may be removed at a convenient subsequent stage
using methods known from the art. Synthetic chemistry
transformations useful in synthesizing applicable compounds are
known in the art and include e.g. those described in R. Larock,
Comprehensive Organic Transformations, VCH Publishers, 1989, or L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons, 1995, which are both hereby incorporated herein by
reference in their entirety.
[0122] The compounds of formula (I) and formula (II) can be
prepared starting from halo-substituted aromatic rings such as C
and C' (Scheme 1) by base catalyzed aromatic nucleophilic
substitution of a halogen with the appropriate amine D to get
compounds of the general formula I, where R.sub.1, Z.sub.1,
Z.sub.2, Z.sub.3, Z.sub.4, R.sub.6, R.sub.7, Y.sub.1, Y.sub.2 are
defined as above for formulas (I) and (II), or are suitable
precursors thereof, and X represents a halide. The process may be
carried out in a suitable solvent, e.g. an aprotic solvent such as
toluene, acetonitrile, benzene, dioxane, DMSO, THF or DMF with a
suitable base such as pyridine, DBU, and using an excess of the
secondary amine (which also can act as the base). The reaction may
occur at a temperature between +20.degree. C. and +150.degree. C.
Alternatively, the reaction can be carried out under microwave
irradiation at temperatures up to 300.degree. C.
##STR00006##
[0123] Alternatively, compounds according to formula (I) or formula
(II) can be prepared by introducing the amine D through
metal-catalysed (e.g. palladium or nickel) nucleophilic
substitution on an appropriately substituted halo- or pseudohalo
aryl (e.g. Br, I-, Cl-, triflate-, nonaflate-, tosylate-substituted
aryl derivatives) (Hartwig, Angew. Chem. Int. Ed., 1998, 37,
2046-2067; Yang & Buchwald, J. Organometallic Chem., 1999, 576,
125-146; Hartwig in Modern Amination Methods; Ricci, Ed.;
Wiley-VCH: Weinheim, Germany, 2000) or Cu-catalyzed (Buchwald et
al, Org. Lett., 2002, 4, 581-584; Kwong & Buchwald, Org. Lett.,
2003, 5, 793-796). Metal-catalyzed amination reaction may also be
performed under microwave irradation (T. Wang et al., Org. Lett.,
2003, 5, 897-900); all of which are hereby incorporated herein by
reference in their entirety.
[0124] Alternatively, compounds according to formula (I) or formula
(II) may be prepared from the appropriately substituted
aniline-based derivatives using an appropriate bifunctional
alkylating agent as shown in Scheme 2, where R.sub.1, Z.sub.1,
Z.sub.2, Z.sub.3, Z.sub.4, R.sub.6, R.sub.7, Y.sub.1, Y.sub.2 are
defined as above for formulas (I) and (II), or are suitable
precursors thereof, and L.sub.1 and L.sub.2 represent a suitable
leaving group. Non-limiting examples of leaving groups L.sub.1 and
L.sub.2 are a halogen atom, e.g., chlorine, bromine or iodine, or a
sulfonate, e.g., tosylate or mesylate, or another leaving group
favoring the reaction. The reaction is conveniently carried out by
stirring the reagent under basic conditions in an inert solvent,
e.g., diisopropylethylamine in acetonitrile, or K.sub.2CO.sub.3 in
N,N-dimethylformamide. The reaction is typically carried out at
temperatures between room temperature and 120.degree. C.
##STR00007##
[0125] The appropriate starting materials may be commercially
available or may be prepared according to methodology disclosed in
the literature. Substituents R.sub.1, Z.sub.1, Z.sub.2, Z.sub.3,
Z.sub.4 and any R.sub.6 and R.sub.7 may each be individually
introduced at any appropriate stage of the preparation of the
compounds, following procedures known in the literature.
[0126] Compounds according to formula (I) or formula (II) in which
R.sub.1 is nitro may be prepared by classical nitration methods
well described in the literature, using HNO.sub.3/H.sub.2SO.sub.4
or other methods known to those skilled in the art.
[0127] Compounds according to formula (I) or formula (II) in which
Z.sub.1, Z.sub.2, Z.sub.3 or Z.sub.4 are halogen, may be prepared
by classical halogenation methods described in the literature,
using Br.sub.2 or other methods known to those skilled in the art.
Alternatively, an appropriately substituted aniline-based precursor
can be converted into a halo-derivative via a diazotisation
according to the Sandmeyer methodology using sodium nitrite in
acetic acid or trifluoroacetic acid, and then reacted with e.g.
with hexafluorophosphoric acid and decomposition of the resulting
salt to obtain the fluoro derivative (W. Adcock et al., J. Am.
Chem. Soc., 1967, 89, 386-390, which is hereby incorporated herein
by reference in its entirety).
[0128] Compounds according to formula (I) or formula (II) in which
R.sub.1, Z.sub.1, Z.sub.2, Z.sub.3 or Z.sub.4 are cyano,
CONR.sub.4R.sub.5, or COOR.sub.4 may be obtained by Pd catalyzed
cyanation from corresponding iodides, bromides (Alterman &
Hallberg, J. Org. Chem., 2000, 65, 7984-7989) and chlorides
(Sundermeier et al, Angew. Chem. Int. ed., 2003, 42, 1661-1664) as
well as by Ni mediated cyanation of aryl bromides and chlorides
(Arvela & Leadbeater, J. Org. Chem., 2003, 68, 9122-9125);
where all these reference are hereby incorporated herein by
reference in their entirety. The nitriles may also be obtained by
reaction of a halo-derivative or a Sandmeyer diazo-intermediate
with cuprous cyanide. The aryl nitriles thus obtained can be either
converted to the corresponding tetrazoles by microwave-induced
cycloaddition chemistry (Alterman & Hallberg, J. Org. Chem.,
2000, 65, 7984-7989, which is hereby incorporated herein by
reference in its entirety) or hydrolyzed to corresponding
carboxylic acids. In addition, compounds bearing carboxylic acid
residues can be accessed from corresponding aryl iodides, bromides
and triflates by Pd catalyzed hydroxycarbonylation chemistry
(Cacchi et al, Org. Lett, 2003, 5, 4269-4293; which is hereby
incorporated herein by reference in its entirety). Compounds
bearing aryl amide residues can be accessed from corresponding aryl
bromides by Pd catalyzed aminocarbonylation chemistry (Wan et al,
J. Org. Chem., 2002, 67, 6232-6235; which is hereby incorporated
herein by reference in its entirety). The carboxylic acids may be
further derivatized to amides by classical acylation reactions or
coupling agents methodology well described in the art.
[0129] Compounds according to formula (I) or formula (II) in which
Z.sub.1, Z.sub.2, Z.sub.3 or Z.sub.4, are S(O).sub.nR.sub.8 or
SO.sub.2NR.sub.8R.sub.9 may be prepared by direct aryl sulfonation
by use of concentrated sulfuric acid, SO.sub.3 or chlorosulphonic
acid or by hydrolysis of a sulfonyl chloride. The sulfonyl chloride
can be obtained by addition of SO.sub.2 to a diazonium salt in the
presence of cupric chloride. Alternatively, sulfonyl chlorides can
be prepared by addition of SO.sub.2 (forming a sulfinic acid salt)
to aryl metal complexes, e.g. aryl lithium or aryl Grignard
reagents, followed by reaction with sulfuryl chloride. Sulfonate
esters can be obtained by reaction of the sulfonyl chlorides with
alcohols. Sulfonic acid esters and sulfonamides are conveniently
prepared from sulfonyl chlorides. Sulfones can be prepared
Friedel-Craft type reaction of aromatic compounds with sulfonyl
halides, by reaction of alkyl halides or sulfonates with aryl
sulfinate salts, by addition of Grignard reagents to sulfonyl
chlorides or by oxidation of thiophenols.
[0130] Compounds according to formula (I) or formula (II) in which
Z.sub.1, Z.sub.2, Z.sub.3 or Z.sub.4 are alkoxy or OCOR.sub.4 may
be typically prepared by Williamson ether synthesis from the
corresponding hydroxyaryl derivatives or by acylation using methods
described below.
[0131] Compounds according to formula (I) or formula (II) in which
Z.sub.1, Z.sub.2, Z.sub.3 or Z.sub.4 are COR.sub.4 may be prepared
from corresponding aryl iodides by Pd catalyzed acylation chemistry
(Cacchi et al, Org. Lett, 2003, 5, 289-293, which is hereby
incorporated herein by reference in its entirety). Alternatively,
they may be obtained from the corresponding aryls by Friedel-Crafts
chemistry (Read, J. Am. Chem. Soc., 1922, 44, 1746-1755, which is
hereby incorporated herein by reference in its entirety), or by
addition of aryl-Grignard reagents to nitriles (Whitmore et al, J.
Am. Chem. Soc., 1947, 69, 235-237, which is hereby incorporated
herein by reference in its entirety) or to acyl chlorides (Whitmore
& Lester, J. Am. Chem. Soc., 1942, 64, 1247, which is hereby
incorporated herein by reference in its entirety), or by either
Pd-catalyzed (Goo.beta.en and Ghosh, Angew. Chem. Int. Ed. Engl,
2001, 40, 3458-3460) or Rh-catalyzed acylation of arylboronic acids
(Frost & Wadsworth, Chem. Commun., 2001, 22, 2316-2317; both of
which are hereby incorporated herein by reference in their
entirety).
[0132] Compounds according to formula (I) or formula (II) in which
Z.sub.1, Z.sub.2, Z.sub.3 or Z.sub.4 are lower aminoalkyl,
NHCOR.sub.4, or NHSO.sub.2R.sub.4 may be obtained from an
aniline-based precursor, which may be commercially available or may
be obtained by reduction from a nitro-derivative prepared as
described above, using e.g. Raney nickel and hydrazine or Pd or Pt
catalysts and hydrogen. Alternatively, an aminoalkyl group can be
introduced following the same methods as described above (Scheme 1)
or by reductive animation (Emerson & Walters, J. Am. Chem. Soc,
1938, 60, 2023; Milovic et al, Synthesis, 1991, 11, 1043-1045, both
of which are hereby incorporated herein by reference in their
entirety), or by dehydrative alkylation (Rice & Kohn, J. Am.
Chem. Soc, 1955, 77, 4052; Brown & Reid, J. Am. Chem. Soc,
1924, 46, 1838, both of which are hereby incorporated herein by
reference in their entirety). Additionally, compounds of this type
may also be synthesized from corresponding boronic acids by
Cu-catalyzed coupling (Antilla & Buchwald, Org. Lett., 2001, 3,
2077-2079, which is hereby incorporated herein by reference in its
entirety). The amino group can be further derivatized by
alkylation, acylation (Wolf, Liebigs Ann. Chem., 1952, 576, 35;
Yasukara et al, J. Chem. Soc. Perkin Trans. I, 2000, 17, 2901-2902;
Nigam & Weedon, J. Chem. Soc, 1957, 2000; all of which are
hereby incorporated herein by reference in their entirety),
formylation (Hirst & Cohen, J. Chem. Soc, 1895, 67, 830; Olah
& Kuhn, Chem. Ber. 1956, 89, 2211; Guthrie et al, Can. J.
Chem., 1993, 71, 2109-2122; all of which are hereby incorporated
herein by reference in their entirety) or sulfonylation.
Alternatively, compounds bearing amide substituents may be obtained
from suitable halo or pseudohalo precursor either by Pd catalyzed
(Yin & Buchwald, J. Am. Chem. Soc, 2002, 124, 6043-6048, which
is hereby incorporated herein by reference in its entirety) or by
Cu catalyzed amidation chemistries (Buchwald et al, J. Am. Chem.
Soc, 2002, 124, 7421-7428, which is hereby incorporated herein by
reference in its entirety).
[0133] Compounds according to formula (I) or formula (II) in which
Z.sub.1, Z.sub.2, Z.sub.3 or Z.sub.4 are SR.sub.4 may be obtained
from a suitable halo- or pseudohalo precursor by Pd catalyzed (Li,
J. Org. Chem., 2002, 67, 3643-3650, which is hereby incorporated
herein by reference in its entirety), or Cu catalyzed
thioetherification chemistry (Kwong & Buchwald, Org. Lett.,
2002, 4, 3517-3520, which is hereby incorporated herein by
reference in its entirety). Alternatively, these compounds may be
prepared by alkylation of corresponding arylthio precursors (Vogel,
J. Chem. Soc, 1948, 1809; Landini & Rocca, Synthesis, 1974,
565-566; Bun-Hoi et al, J. Org. Chem., 1951, 16, 988; all of which
are hereby incorporated herein by reference in their entirety).
Alternatively, alkylarylsulfanyls may be obtained by irradiation of
benzenethiols and alkenes (Screttas and Micha-Screttas, J. Org.
Chem., 1978, 43, 1064-1071, which is hereby incorporated herein by
reference in its entirety).
[0134] Furthermore, starting from aryl bromides and iodides,
employing alkyl lithium and alkyl Grignard reagents, halogen-metal
exchange chemistry can be utilized to introduce a broad range of
electrophiles such as alkyls, --Si(R).sub.3, --CHO, --COOH, --CN,
--SO.sub.2N(R).sub.2, --SR, --B(OR).sub.2, --Sn(R).sub.3, --ZnX
(X.dbd.Br, Cl).
[0135] In general, an amine or alcohol functionality may be further
derivatized, for example acylated using any carboxylic acid halide
e.g., chloride, or carboxylic anhydride to give amides, as
exemplified in Scheme 3 by amine or alcohol K, where R-.sub.5 and
Aryl are defined in agreement with formula (I) or formula (II),
Z.sub.1 is OH, NH.sub.2, NHR.sub.4, or SH; Z.sub.2 is O, NH,
NR.sub.4, or S; Z.sub.3 is O or S; X represents a halide, and
R.sub.4 is defined in agreement with formula (I) or formula (II).
The reaction is typically carried out using an excess of the
acylating agent and a suitable base, e.g., triethylamine or
diisopropylethylamine in an inert solvent, e.g., dichloromethane,
at a temperature between 0.degree. C. and room temperature and
under dry conditions. As an alternative to the carboxylic acid
halides and carboxylic acid anhydrides, the amine/alcohol may be
acylated using a carboxylic acid and a suitable coupling reagent
e.g. PyBroP, DCC or EDCI. The reaction is typically carried out
using an excess of the acylating agent and the coupling reagent in
an inert solvent, e.g., dichloromethane, at a temperature between
0.degree. C. and 100.degree. C. under dry conditions.
##STR00008##
[0136] Alternatively, an amine or alcohol functionality may be
alkylated using an appropriate alkylating agents, such as
T-L.sub.1. Leaving group L.sub.1 is suitably a halogen atom, e.g.,
chlorine, bromine or iodine, or a sulfonate, e.g., tosylate or
mesylate, or another leaving group favoring the reaction. The
reaction is conveniently carried out by stirring the reagent under
basic conditions in an inert solvent, e.g., diisopropylethylamine
in acetonitrile, or K.sub.2CO.sub.3 in N,N-dimethylformamide. The
reaction is typically carried out at temperatures between room
temperature and 80.degree. C.
[0137] Furthermore, ketones, exemplified in Scheme 4 by tropanone
derivative G, may be modified by reductive amination using any
primary or secondary amine HNR.sub.4R.sub.5, where R.sub.4 R.sub.5
and Aryl are defined in agreement with formula (I) or formula
(II).
[0138] Alternatively the same methodology may be used to modify
primary or secondary amines, exemplified by amine J (Scheme 4). The
reaction is conveniently carried out by stirring the reactants in
an inert solvent such as methanol or ethanol. As a reducing agent,
solid-supported borohydride, NaBH.sub.4, NaCNBH.sub.3,
BH.sub.3-pyridine, H.sub.2/Pd--C or any related reagent may be
used, including solid-supported reagents. The reaction is typically
carried out at room temperature, but less reactive carbonyl
compounds may require higher temperatures and/or the pre-formation
of the corresponding imine under water removal before addition of
the reducing agent.
##STR00009##
[0139] Furthermore, ketones, exemplified in Scheme 5 by tropanone
derivative G, may be reacted with a variety of organometallic
reagents, such as Grignard or lithium reagents, where R.sub.6 and
Aryl are defined in agreement with formula (I) or formula (II), to
give derivatives such as K. The Grignard reaction is typically
carried out in a solvent such as THF, and in some cases the
addition of anhydrous cerium trichloride may improve the reaction
yields.
[0140] Alternatively, ketones exemplified by tropanone G (Scheme 5)
may be converted to epoxides L upon reaction with a sulfur ylide
such as dimethylsulfoxonium methylide and dimethylsulfonium
methylide, generated from trimethylsulfoxonium iodide or
trimethylsulfonium iodide by addition of a base such as sodium
hydride, in an inert solvent such as dimethylsulfoxide at a
temperature of 0-40.degree. C. Alternatively, ketone G can be
converted into an olefin by a Wittig or Wadsworth-Horner-Emmons
reaction, or by Tebbe olefination. The alkenes thus obtained may
then be converted into the corresponding epoxide by treatment with
oxidation reagents such as hydroperoxide or MCPBA. Epoxides such as
derivative L may be further derivatized by reactions with a wide
variety of nucleophiles, such as cyanide, alkoxides, amines,
organometallic reagents, or carbanions derived from amide or
sulfonamide derivatives upon treatment with base, to give tertiary
alcohols exemplified by derivatives M1-M5, where R.sub.4, R.sub.5,
R.sub.6, Nu and Aryl are defined in agreement with formula (I) or
formula (II). Certain reactions can be facilitated by the addition
of a Lewis acid catalyst such as Ytterbium triflate or boron
trifluoride etherate. Furthermore, the epoxide may be reduced to
the tertiary alcohol using a reducing agent such as LiAlH.sub.4,
NaBH.sub.4/LiCl, Superhydride, borane, catalytic hydrogenation or
any related reagent may be used, including solid-supported
reagents. The reactions may typically be carried out at
temperatures of 0-100.degree. C. in solvents such as THF,
diethylether, or diglyme.
##STR00010##
[0141] Furthermore, the introduction of substituents on ring A or
on the phenyl moiety may occur at any stage of the synthetic
pathway, and thus ring A may be prepared first and its amine
function reacted with a suitable phenyl precursor in a later step
of the synthesis as shown in Scheme 6, in which the tropane
derivative P exemplifies ring A as defined in formula (I) or
formula (II). The amine function may require transient protecting
groups (PG) such as Boc, CBz, benzyl, p-methoxybenzyl.
##STR00011##
[0142] Where the processes for the preparation of the compounds of
formula (I) or formula (II) give rise to mixtures of stereoisomers,
such isomers may be separated by conventional techniques such as
preparative chiral chromatography. The compounds may be prepared in
racemic form or individual enantiomers may be prepared by
stereoselective synthesis or by resolution. The compounds may be
resolved into their component enantiomers by standard techniques,
such as the formation of diastereomeric pairs by salt formation
with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric
acid and/or (+)-di-p-toluoyl-1-tartaric acid, followed by
fractional crystallization and regeneration of the free base. The
compounds may also be resolved using a chiral auxiliary by
formation of diastereomeric derivatives such as esters, amides or
ketals followed by chromatographic separation and removal of the
chiral auxiliary.
Methods of Use
[0143] In an embodiment of this invention, compounds of this
invention are capable of modulating the activity of an androgen
receptor.
[0144] The term "modulate" refers to the ability of a compound
disclosed herein to alter the function of an androgen receptor. A
modulator may activate the activity of an androgen receptor, may
activate or inhibit the activity of an androgen receptor depending
on the concentration of the compound exposed to the androgen
receptor, or may inhibit the activity of an androgen receptor. The
term "modulate" also refers to altering the function of an androgen
receptor by increasing or decreasing the probability that a complex
forms between an androgen receptor and a natural binding partner. A
modulator may increase the probability that such a complex forms
between the androgen receptor and the natural binding partner, may
increase or decrease the probability that a complex forms between
the androgen receptor and the natural binding partner depending on
the concentration of the compound exposed to the androgen receptor,
and or may decrease the probability that a complex forms between
the androgen receptor and the natural binding partner. Modulation
of the androgen receptor may be assessed using Receptor Selection
and Amplification Technology (R-SAT) as described in U.S. Pat. No.
5,707,798, the disclosure of which is incorporated herein by
reference in its entirety.
[0145] The term "activate" refers to increasing the cellular
function of an androgen receptor. The term "inhibit" refers to
decreasing the cellular function of an androgen receptor. The
androgen receptor function may be the interaction with a natural
binding partner or catalytic activity.
[0146] The term "contacting" as used herein refers to bringing a
compound disclosed herein and a target androgen receptor together
in such a manner that the compound can affect the activity of the
androgen receptor, either directly; i.e., by interacting with the
androgen receptor itself, or indirectly; i.e., by interacting with
another molecule on which the activity of the androgen receptor is
dependent. Such "contacting" can be accomplished in a test tube, a
petri dish or the like. In a test tube, contacting may involve only
a compound and a androgen receptor of interest or it may involve
whole cells. Cells may also be maintained or grown in cell culture
dishes and contacted with a compound in that environment. In this
context, the ability of a particular compound to affect an androgen
receptor related disorder; i.e., the IC.sub.50 of the compound can
be determined before use of the compounds in vivo with more complex
living organisms is attempted. For cells outside the organism,
multiple methods exist, and are well-known to those skilled in the
art, to get the androgen receptors in contact with the compounds
including, but not limited to, direct cell microinjection and
numerous transmembrane carrier techniques. The term "contacting"
can also refer to bringing a compound disclosed herein to contact
with a target androgen receptor in vivo. Thus, if a compound
disclosed herein, or a prodrug thereof, is administered to an
organism and the compound is brought together with an androgen
receptor within the organism, such contacting is within the scope
of the present disclosure.
[0147] In an embodiment hereof, a compound of this invention may be
an agonist of an androgen receptor, while in other embodiments, the
compound may be an antagonist of an androgen receptor. In an
embodiment hereof, the compound may be a partial agonist of an
androgen receptor. A compound that is a partial agonists may in
some cases be a partial activator of a receptor, while in other
cases may be a partial repressor of a receptor. In an embodiment of
this invention, the compound may be a tissue-specific modulator,
while in other circumstances, the compound may be a gene-specific
modulator.
[0148] In an embodiment of this invention, an androgen receptor is
activated by contacting it with a compound of formula (I) or
formula (II). The contacting of the androgen receptor may be in
vivo or in vitro. When the receptor is contacted in vivo, the
contacting may be accomplished by administering the compound to the
living subject containing the receptor. In some embodiments, the
living subject is a patient. In an embodiment of this invention,
the patient may be a mammal. The mammal may be selected from the
group consisting of mice, rats, rabbits, guinea pigs, dogs, cats,
sheep, goats, cows, primates, such as monkeys, chimpanzees, and
apes, and humans. In an embodiment of this invention, the patient
is a human.
[0149] In an embodiment hereof, a compound of this invention may be
administered to a patient in order to treat a condition in the
patient. Such conditions include, without limitation, hypogonadism,
lower than normal testosterone plasma levels, infertility, sexual
arousal disorder, sexual orgasmic disorders, disorders of libido,
muscle wasting due to cachexia, HIV wasting, or critical illnesses,
sarcopenia, frailty, short stature, dwarfism, bone density loss,
mood disorders including lack of well being, lack of vigor, anger,
irritability, sadness, tiredness, nervousness, depression, impaired
cognitive functions including verbal fluency and spatial memory,
neurodegenerative disorders, including Alzheimer's disease, Mild
cognition impairment (MCI), Lewis body dementia, and frontal
temporal dementia, xerophthalmia, metabolic disorders, including
dyslipidemia, atherosclerosis, and non-insulin dependent diabetes
(NIDDM), cardiovascular disorders including but not limited to
hypertension, coronary artery disease, and myocardial perfusion,
obesity, anemia, prostate cancer, and schizophrenia. In an
embodiment hereof, a compound of this invention may be administered
to a patient in order to prevent a condition in the patient. The
condition prevented includes, without limitation, bone density
loss; xerophthalmia; metabolic disorders, including dyslipidemia,
atherosclerosis, and non-insulin dependent diabetes (NIDDM);
cardiovascular disorders including hypertension, coronary artery
disease, and myocardial perfusion; obesity; and prostate
cancer.
[0150] In an embodiment hereof, a compound of this invention is
effective in treating certain conditions in male patients. Thus,
the compound may be administered to the male patient in order to
treat one or more of the conditions. The condition treated in the
male includes, without limitation, infertility, erectile
dysfunction, andropause, and disorders of libido. In an embodiments
hereof, a compound of this invention may be administered to a male
patient in order to modulate spermatogenesis in the male
patient.
[0151] In an embodiment hereof, a compound of this invention is
effective in treating certain conditions in female patients. Thus,
the compound may be administered to the female patient in order to
treat one or more of the conditions. The condition treated in the
female includes, without limitation, endometriosis, dyspareunia,
vaginismus, sexual arousal disorder, and sexual orgasmic
disorder.
[0152] In an embodiment hereof, a compound of this invention may be
administered to a patient in order to effect hormone
replacement.
[0153] In an embodiment hereof, a compound of this invention may be
administered to a patient in order to improve muscle strength. For
example, the compound may be administered in need of improvement in
muscle strength due to muscular dystrophy, mytonic dystrophy, or
glucocorticoid-treated asthma.
[0154] In an embodiment hereof, a compound of this invention may be
administered to a patient in order to improve a health-related
quality of life parameter such as survival, impairment, functional
status, health perception, and opportunities.
[0155] In an embodiment hereof, a compound of this invention may be
administered to a male patient suffering from prostate cancer in
order to delay the progression of the prostate cancer.
Pharmaceutical Compositions
[0156] An embodiment of this invention relates to a pharmaceutical
composition comprising a physiologically acceptable surface active
agents, carriers, diluents, excipients, smoothing agents,
suspension agents, film forming substances, and coating assistants,
or a combination thereof, and a compound disclosed herein.
Acceptable carriers or diluents for therapeutic use are well known
in the pharmaceutical art, and are described, for example, in
Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co.,
Easton, Pa. (1990), which is incorporated herein by reference in
its entirety. Preservatives, stabilizers, dyes, sweeteners,
fragrances, flavoring agents, and the like may be provided in the
pharmaceutical composition. For example, sodium benzoate, ascorbic
acid and esters of p-hydroxybenzoic acid may be added as
preservatives. In addition, antioxidants and suspending agents may
be used. Alcohols, esters, sulfated aliphatic alcohols, and the
like may be used as surface active agents; sucrose, glucose,
lactose, starch, crystallized cellulose, mannitol, light anhydrous
silicate, magnesium aluminate, magnesium methasilicate aluminate,
synthetic aluminum silicate, calcium carbonate, sodium acid
carbonate, calcium hydrogen phosphate, calcium carboxymethyl
cellulose, and the like may be used as excipients; magnesium
stearate, talc, hardened oil and the like may be used as smoothing
agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be
used as suspension agents or lubricants; cellulose acetate
phthalate as a derivative of a carbohydrate such as cellulose or
sugar, or methylacetate-methacrylate copolymer as a derivative of
polyvinyl may be used as suspension agents; and plasticizers such
as ester phthalates and the like may be used as suspension
agents.
[0157] The term "pharmaceutical composition" refers to a mixture of
a compound disclosed herein with other chemical components, such as
diluents or carriers. The pharmaceutical composition facilitates
administration of the compound to an organism. Multiple techniques
of administering a compound exist in the art including, but not
limited to, oral, injection, aerosol, parenteral, and topical
administration. Pharmaceutical compositions can also be obtained by
reacting compounds with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid and the like.
[0158] The term "carrier" defines a chemical compound that
facilitates the incorporation of a compound into cells or tissues.
For example dimethyl sulfoxide (DMSO) is a commonly utilized
carrier as it facilitates the uptake of many organic compounds into
the cells or tissues of an organism.
[0159] The term "diluent" defines chemical compounds diluted in
water that will dissolve the compound of interest as well as
stabilize the biologically active form of the compound. Salts
dissolved in buffered solutions are utilized as diluents in the
art. One commonly used buffered solution is phosphate buffered
saline because it mimics the salt conditions of human blood. Since
buffer salts can control the pH of a solution at low
concentrations, a buffered diluent rarely modifies the biological
activity of a compound.
[0160] The term "physiologically acceptable" defines a carrier or
diluent that does not abrogate the biological activity and
properties of the compound.
[0161] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical
compositions where they are mixed with other active ingredients, as
in combination therapy, or suitable carriers or excipient(s).
Techniques for formulation and administration of the compounds of
the instant application may be found in "Remington's Pharmaceutical
Sciences," Mack Publishing Co., Easton, Pa., 18th edition,
1990.
[0162] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, topical, or intestinal administration;
parenteral delivery, including intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intranasal, or
intraocular injections. The compounds can also be administered in
sustained or controlled release dosage forms, including depot
injections, osmotic pumps, pills, transdermal (including
electrotransport) patches, and the like, for prolonged and/or
timed, pulsed administration at a predetermined rate.
[0163] The pharmaceutical compositions of the present invention may
be manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tabletting
processes.
[0164] Pharmaceutical compositions for use in accordance with the
present invention thus may be formulated in conventional manner
using one or more physiologically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen. Any of the well-known techniques, carriers,
and excipients may be used as suitable and as understood in the
art; e.g., in Remington's Pharmaceutical Sciences, above.
[0165] Injectables can be prepared in conventional forms, either as
liquid solutions or suspensions, solid forms suitable for solution
or suspension in liquid prior to injection, or as emulsions.
Suitable excipients are, for example, water, saline, dextrose,
mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine
hydrochloride, and the like. In addition, if desired, the
injectable pharmaceutical compositions may contain minor amounts of
nontoxic auxiliary substances, such as wetting agents, pH buffering
agents, and the like. Physiologically compatible buffers include,
but are not limited to, Hanks's solution, Ringer's solution, or
physiological saline buffer. If desired, absorption enhancing
preparations (for example, liposomes), may be utilized.
[0166] For transmucosal administration, penetrants appropriate to
the barrier to be permeated may be used in the formulation.
[0167] Pharmaceutical formulations for parenteral administration,
e.g., by bolus injection or continuous infusion, include aqueous
solutions of the active compounds in water-soluble form.
Additionally, suspensions of the active compounds may be prepared
as appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils such as sesame oil, or
other organic oils such as soybean, grapefruit or almond oils, or
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
or liposomes. Aqueous injection suspensions may contain substances
which increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. Optionally, the
suspension may also contain suitable stabilizers or agents that
increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions. Formulations for
injection may be presented in unit dosage form, e.g., in ampoules
or in multi-dose containers, with an added preservative. The
compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulatory
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0168] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by
combining the active compounds with solid excipient, optionally
grinding a resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. Dragee cores are provided with
suitable coatings. For this purpose, concentrated sugar solutions
may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments may be added to the
tablets or dragee coatings for identification or to characterize
different combinations of active compound doses. For this purpose,
concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be added to the tablets or dragee coatings for
identification or to characterize different combinations of active
compound doses.
[0169] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0170] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0171] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of, e.g., gelatin for use in an inhaler or insufflator
may be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0172] Further disclosed herein are various pharmaceutical
compositions well known in the pharmaceutical art for uses that
include intraocular, intranasal, and intraauricular delivery.
Suitable penetrants for these uses are generally known in the art.
Pharmaceutical compositions for intraocular delivery include
aqueous ophthalmic solutions of the active compounds in
water-soluble form, such as eyedrops, or in gellan gum (Shedden et
al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al.,
Opthalmologic 210(2):101-3 (1996)); ophthalmic ointments;
ophthalmic suspensions, such as microparticulates, drug-containing
small polymeric particles that are suspended in a liquid carrier
medium (Joshi, A., J. Ocul. Pharmacol, 10(1):29-45 (1994)),
lipid-soluble formulations (Alm et al., Prog. Clin. Biol Res.,
312:447-58 (1989)), and microspheres (Mordenti, Toxicol. Sci.,
52(1):101-6 (1999)); and ocular inserts. All of the above-mentioned
references, are incorporated herein by reference in their
entireties. Such suitable pharmaceutical formulations are most
often and preferably formulated to be sterile, isotonic and
buffered for stability and comfort. Pharmaceutical compositions for
intranasal delivery may also include drops and sprays often
prepared to simulate in many respects nasal secretions to ensure
maintenance of normal ciliary action. As disclosed in Remington's
Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.
(1990), which is incorporated herein by reference in its entirety,
and well-known to those skilled in the art, suitable formulations
are most often and preferably isotonic, slightly buffered to
maintain a pH of 5.5 to 6.5, and most often and preferably include
antimicrobial preservatives and appropriate drug stabilizers.
Pharmaceutical formulations for intra-auricular delivery include
suspensions and ointments for topical application in the ear.
Common solvents for such aural formulations include glycerin and
water.
[0173] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0174] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0175] For hydrophobic compounds, a suitable pharmaceutical carrier
may be a cosolvent system comprising benzyl alcohol, a nonpolar
surfactant, a water-miscible organic polymer, and an aqueous phase.
A common cosolvent system used is the VPD co-solvent system, which
is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant Polysorbate 80.TM., and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. Naturally, the proportions
of a co-solvent system may be varied considerably without
destroying its solubility and toxicity characteristics.
Furthermore, the identity of the co-solvent components may be
varied: for example, other low-toxicity nonpolar surfactants may be
used instead of POLYSORBATE 80.TM.; the fraction size of
polyethylene glycol may be varied; other biocompatible polymers may
replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other
sugars or polysaccharides may substitute for dextrose.
[0176] Alternatively, other delivery systems for hydrophobic
pharmaceutical compounds may be employed. Liposomes and emulsions
are well known examples of delivery vehicles or carriers for
hydrophobic drugs. Certain organic solvents such as
dimethylsulfoxide also may be employed, although usually at the
cost of greater toxicity. Additionally, the compounds may be
delivered using a sustained-release system, such as semipermeable
matrices of solid hydrophobic polymers containing the therapeutic
agent. Various sustained-release materials have been established
and are well known by those skilled in the art. Sustained-release
capsules may, depending on their chemical nature, release the
compounds for a few weeks up to over 100 days. Depending on the
chemical nature and the biological stability of the therapeutic
reagent, additional strategies for protein stabilization may be
employed.
[0177] Agents intended to be administered intracellularly may be
administered using techniques well known to those of ordinary skill
in the art. For example, such agents may be encapsulated into
liposomes. All molecules present in an aqueous solution at the time
of liposome formation are incorporated into the aqueous interior.
The liposomal contents are both protected from the external
micro-environment and, because liposomes fuse with cell membranes,
are efficiently delivered into the cell cytoplasm. The liposome may
be coated with a tissue-specific antibody. The liposomes will be
targeted to and taken up selectively by the desired organ.
Alternatively, small hydrophobic organic molecules may be directly
administered intracellularly.
[0178] Additional therapeutic or diagnostic agents may be
incorporated into the pharmaceutical compositions. Alternatively or
additionally, pharmaceutical compositions may be combined with
other compositions that contain other therapeutic or diagnostic
agents.
Methods of Administration
[0179] The compounds or pharmaceutical compositions of this
invention may be administered to the patient by any suitable means.
Non-limiting examples of methods of administration include, among
others, (a) administration though oral pathways, which
administration includes administration in capsule, tablet, granule,
spray, syrup, or other such forms; (b) administration through
non-oral pathways such as rectal, vaginal, intraurethral,
intraocular, intranasal, or intraauricular, which administration
includes administration as an aqueous suspension, an oily
preparation or the like or as a drip, spray, suppository, salve,
ointment or the like; (c) administration via injection,
subcutaneously, intraperitoneally, intravenously, intramuscularly,
intradermally, intraorbitally, intracapsularly, intraspinally,
intrasternally, or the like, including infusion pump delivery; (d)
administration locally such as by injection directly in the renal
or cardiac area, e.g., by depot implantation; as well as (e)
administration topically; as deemed appropriate by those of skill
in the art for bringing the compound of the invention into contact
with living tissue.
[0180] Pharmaceutical compositions suitable for administration
include compositions where the active ingredients are contained in
an amount effective to achieve its intended purpose. The
therapeutically effective amount of the compounds disclosed herein
required as a dose will depend on the route of administration, the
type of animal, including human, being treated, and the physical
characteristics of the specific animal under consideration. The
dose can be tailored to achieve a desired effect, but will depend
on such factors as weight, diet, concurrent medication and other
factors which those skilled in the medical arts will recognize.
More specifically, a therapeutically effective amount means an
amount of compound effective to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being
treated. Determination of a therapeutically effective amount is
well within the capability of those skilled in the art, especially
in light of the detailed disclosure provided herein.
[0181] As will be readily apparent to one skilled in the art, the
useful in vivo dosage to be administered and the particular mode of
administration will vary depending upon the age, weight and
mammalian species treated, the particular compounds employed, and
the specific use for which these compounds are employed. The
determination of effective dosage levels, that is the dosage levels
necessary to achieve the desired result, can be accomplished by one
skilled in the art using routine pharmacological methods.
Typically, human clinical applications of products are commenced at
lower dosage levels, with dosage level being increased until the
desired effect is achieved. Alternatively, acceptable in vitro
studies can be used to establish useful doses and routes of
administration of the compositions identified by the present
methods using established pharmacological methods.
[0182] In non-human animal studies, applications of potential
products are commenced at higher dosage levels, with dosage being
decreased until the desired effect is no longer achieved or adverse
side effects disappear. The dosage may range broadly, depending
upon the desired affects and the therapeutic indication. Typically,
dosages may be between about 10 microgram/kg and 100 mg/kg body
weight, preferably between about 100 microgram/kg and 10 mg/kg body
weight. Alternatively dosages may be based and calculated upon the
surface area of the patient, as understood by those of skill in the
art.
[0183] The exact formulation, route of administration and dosage
for the pharmaceutical compositions of the present invention can be
chosen by the individual physician in view of the patient's
condition. (See e.g., Fingl et al. 1975, in "The Pharmacological
Basis of Therapeutics", which is hereby incorporated herein by
reference in its entirety, with particular reference to Ch. 1, p.
1). Typically, the dose range of the composition administered to
the patient can be from about 0.5 to 1000 mg/kg of the patient's
body weight. The dosage may be a single one or a series of two or
more given in the course of one or more days, as is needed by the
patient. In instances where human dosages for compounds have been
established for at least some condition, the present invention will
use those same dosages, or dosages that are between about 0.1% and
500%, more preferably between about 25% and 250% of the established
human dosage. Where no human dosage is established, as will be the
case for newly-discovered pharmaceutical compounds, a suitable
human dosage can be inferred from ED.sub.50 or ID.sub.50 values, or
other appropriate values derived from in vitro or in vivo studies,
as qualified by toxicity studies and efficacy studies in
animals.
[0184] It should be noted that the attending physician would know
how to and when to terminate, interrupt, or adjust administration
due to toxicity or organ dysfunctions. Conversely, the attending
physician would also know to adjust treatment to higher levels if
the clinical response were not adequate (precluding toxicity). The
magnitude of an administrated dose in the management of the
disorder of interest will vary with the severity of the condition
to be treated and to the route of administration. The severity of
the condition may, for example, be evaluated, in part, by standard
prognostic evaluation methods. Further, the dose and perhaps dose
frequency, will also vary according to the age, body weight, and
response of the individual patient. A program comparable to that
discussed above may be used in veterinary medicine.
[0185] Although the exact dosage will be determined on a
drug-by-drug basis, in most cases, some generalizations regarding
the dosage can be made. The daily dosage regimen for an adult human
patient may be, for example, an oral dose of between 0.1 mg and
2000 mg of each active ingredient, preferably between 1 mg and 500
mg, e.g. 5 to 200 mg. In other embodiments, an intravenous,
subcutaneous, or intramuscular dose of each active ingredient of
between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg,
e.g. 1 to 40 mg is used. In cases of administration of a
pharmaceutically acceptable salt, dosages may be calculated as the
free base. In some embodiments, the composition is administered 1
to 4 times per day. Alternatively the compositions of the invention
may be administered by continuous intravenous infusion, preferably
at a dose of each active ingredient up to 1000 mg per day. As will
be understood by those of skill in the art, in certain situations
it may be necessary to administer the compounds disclosed herein in
amounts that exceed, or even far exceed, the above-stated,
preferred dosage range in order to effectively and aggressively
treat particularly aggressive diseases or infections. In some
embodiments, the compounds will be administered for a period of
continuous therapy, for example for a week or more, or for months
or years.
[0186] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety which are sufficient to
maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will
depend on individual characteristics and route of administration.
However, HPLC assays or bioassays can be used to determine plasma
concentrations.
[0187] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, preferably
between 30-90% and most preferably between 50-90%.
[0188] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0189] The amount of composition administered will, of course, be
dependent on the subject being treated, on the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician.
[0190] Compounds disclosed herein can be evaluated for efficacy and
toxicity using known methods. For example, the toxicology of a
particular compound, or of a subset of the compounds, sharing
certain chemical moieties, may be established by determining in
vitro toxicity towards a cell line, such as a mammalian, and
preferably human, cell line. The results of such studies are often
predictive of toxicity in animals, such as mammals, or more
specifically, humans. Alternatively, the toxicity of particular
compounds in an animal model, such as mice, rats, rabbits, or
monkeys, may be determined using known methods. The efficacy of a
particular compound may be established using several recognized
methods, such as in vitro methods, animal models, or human clinical
trials. Non-limiting examples of appropriate in vitro animal models
include castrated male rats or aged male orchidectomized rats. When
selecting a model to determine efficacy, the skilled artisan can be
guided by the state of the art to choose an appropriate model,
dose, and route of administration, and regime. Of course, human
clinical trials can also be used to determine the efficacy of a
compound in humans.
[0191] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions comprising a
compound of the invention formulated in a compatible pharmaceutical
carrier may also be prepared, placed in an appropriate container,
and labeled for treatment of an indicated condition.
EXAMPLES
General Procedures
[0192] NMR Methods. Unless otherwise stated, .sup.1H NMR spectra
were recorded on a Bruker Ultrashield 300 MHz and chemical shifts
are given in .delta.-values [ppm] referenced to the residual
solvent peak chloroform (CDCl.sub.3) at 7.26 and methanol
(CD.sub.3OD) at 3.31 ppm. .sup.1H NMR spectra were recorded at 400
MHz on a Varian Mercury-VX400 MHz spectrometer. Coupling constants,
J, are reported in Hertz. The NMR spectra of the compounds are
described for their free amine form. Materials and solvents were of
the highest grade available from commercial sources and were used
without further purification.
[0193] LC/MS Method I. The analysis was performed on a combined
prep/analytical Waters/Micromass system consisting of a ZMD single
quadropole mass spectrometer equipped with electrospray ionization
interface. The HPLC system consisted of a Waters 600 gradient pump
with on-line degassing, a 2700 sample manager and a 996 PDA
detector. Separation was performed on an X-Terra MS C18, 5 .mu.m
4.6.times.50 mm column. Buffer A: 10 mM ammonium acetate in water,
buffer B: 10 mM ammonium acetate in acetonitrile/water 95/5. A
gradient was run from 30% B to 100% B in 7 min, hold at 100% B for
1 min and re-equilibrated for 5.5 min. The system was operated at 1
ml/min.
[0194] LC/MS Method II. The analysis was performed on a
Waters/Micromass LC/MS system consisting of a ZQ single quadropole
mass spectrometer equipped with electro-spray ionization interface.
The HPLC was a Waters 2795 Alliance HT system with a 996 PDA
detector. Separation was performed on an X-Terra MS C18, 3.5 .mu.m
4.6.times.30 mm column. Buffer A: 10 mM ammonium acetate in water,
buffer B: 10 mM ammonium acetate in acetonitrile/water 95/5. A
gradient was run from 30% B to 100% B in 5.5 min, stay at 100% B
for 0.5 min, re-equilibrate for 2.5 min. System was operated at 1
mL/min.
[0195] LC/MS Method III. The analysis was performed on a combined
prep/analytical Waters/Micromass system consisting of a ZMD single
quadropole mass spectrometer equipped with electro-spray ionization
interface. The HPLC system consisted of a Waters 600 gradient pump
with on-line degassing, a 2700 sample manager and a 996 PDA
detector.
[0196] Separation was performed on an YMC C18 J'sphere ODS H80, 5
.mu.m 4.6.times.100 mm column. Buffer A: 0.15% TFA in water, buffer
B: 0.15% TFA in acetonitrile/water 95/5. A gradient was run from
30% B to 100% B in 10 min, stay at 100% B for 2 min, re-equilibrate
for 5 min. System was operated at 1 ml/min.
[0197] Preparation of Hydrochloride Salts. Typically, the Compounds
were dissolved in dichloromethane, treated with an excess of 1M HCl
in diethylether and precipitated from n-heptane. The solvents were
removed in vacuo and after drying, the hydrochloride salts were
obtained as solids.
Example 1
endo-8-(3-chloro-2-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol
(173FBA73bL)
[0198] To a solution of 198RL41 (0.050 g, 0.264 mmol) in pyridine
(0.5 mL) was added nortropine (0.134 g, 1.056 mmol) and the
reaction mixture was allowed to stir at 90.degree. C. during 17 h.
The mixture was diluted with ethyl acetate and the organic phase
washed with 0.4 N HCl and sat. aq. NaHCO.sub.3; evaporation of the
dried (Na.sub.2SO.sub.4) organic phase gave a crude product (0.055
g) which was purified by preparative TLC (n-heptane/ethyl acetate
7:3). Extraction of the lower R.sub.f band afforded 173FBA73bL
(0.026 g).
[0199] LC/MS m/z 297 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 7.62 (d, 1H, J=9.0), 6.72 (d, 1H, J=9.0), 4.14 (t, 1H,
J=4.9), 3.76 (br s, 2H), 2.35 (s, 3H), 2.25-2.13 (m, 4H), 1.94-1.79
(m, 4H). .sup.13C-NMR (CDCl.sub.3, 75 MHz) 155.6, 142.1, 130.7,
129.4, 124.5, 114.5, 65.1, 59.1, 40.5, 27.9, 18.3.
Example 2
3-Bromo-2-chloro-6-fluorotoluene (165RL91)
[0200] 2-chloro-6-fluorotoluene (5.00 g, 34.6 mmol) and iron (0.1
g, 0.17 mmol) was stirred in a 100 mL flask. Bromine (6.08 g, 38.1
mmol) was added slowly in 3 portions with 1 min between each
addition. The reaction was stirred for additional 15 min. Then
dichloromethane (50 ml) was added, the reaction mixture transferred
to a separation funnel and washed with a sodium thiosulphate
solution (10%, 30 mL) until it had turned colorless. The layers
were separated and the organic layer was washed with sat. sodium
hydrogen carbonate (30 mL), dried and evaporated to give the title
compound as a colorless oil (7.57 g, 98%) containing 15%
3-bromo-5-chloro-2-fluorotoluene (calc. by .sup.1H-NMR). The
compound was used in the next step without further
purification.
[0201] GC/MS m/z 222 [M+H].sup.+. `H-NMR (CDCl.sub.3, 300 MHz)
.delta. 7.53 (dd, 1H, J=5.5, 8.6, Ar--H), 7.07 (t, 1H, J=8.6,
Ar--H), 2.35 (d, 3H, J=2.3, CH.sub.3).
Example 3
2-Chloro-4-fluoro-3-methylbenzonitrile (165RL87a)
[0202] 3-Bromo-2-chloro-6-fluorotoluene 165RL91 (173 mg, 0.78
mmol), zinc cyanide (91 mg, 0.78 mmol) and
tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 .mu.mol) was
charged in a vial, DMF (1 mL) added, and the mixture irradiated for
150 sec at 200.degree. C. in a microwave oven. Diethyl ether (30
ml) was added and the reaction mixture washed with magnesium
sulphate (4% solution, 3.times.20 mL) followed by brine (20 mL).
The organic layer was dried and evaporated. The product was further
purified by column chromatography on silica gel using
n-heptane/ethyl acetate (9:1) giving a white solid (55 mg,
42%).
[0203] GC/MS m/z 169 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 7.43 (dd, 1H, J=5.6, 8.8, Ar--H), 6.87 (t, 1H, J=8.8,
Ar--H), 2.36 (d, 3H, J=2.4, CH.sub.3).
Example 4
2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbenzonit-
rile, hydrochloride (165RL90)
[0204] 2-Chloro-4-fluoro-3-methylbenzonitrile (165RL87a, 55 mg,
0.32 mmol) and nortropine (165 mg, 1.29 mmol) was dissolved in
pyridine (2 mL) and the mixture irradiated at 220.degree. C. for 2
hours in a microwave oven. Dichloromethane (50 mL) was added and
the mixture washed with hydrochloric acid (0.4 M, 2.times.30 mL)
followed by sat. sodium hydrogen carbonate (20 mL). The organic
layer was dried over sodium sulfate, filtered and evaporated. The
product was further purified by column chromatography using
dichloromethane to give the title compound (16.2 mg, 18%).
[0205] R.sub.f=0.45 (CH.sub.2Cl.sub.2). LC/MS m/z 277 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.37 (d, 1H, J=8.6,
Ar--H), 6.78 (d, 1H, J=8.6, Ar--H), 4.20 (m, 1H, Tr-H), 3.80 (m,
2H, Tr-H), 2.37 (s, 3H, Ar--CH.sub.3), 2.32-2.22 (m, 4H, Tr-H),
1.98-1.81 (m, 4H, Tr-H).
Example 5
2-(trifluoromethyl)-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)benzon-
itrile (196 MBT4-B)
[0206] Nortropine (269 mg, 2.12 mmol) and
4-fluoro-2-(trifluoromethyl)benzonitrile (100 mg, 0.529 mmol) were
dissolved in pyridine (2 mL). The mixture was heated to 100.degree.
C. in a sealed flask for 6 hours and then concentrated. The residue
was dissolved in 2 M HCl (20 mL) and extracted with dichloromethane
(2.times.20 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and evaporated, and the resulting oil
was purified by preparative TLC (eluting with dichloromethane) to
afford 133 mg (85%) of the title compound as a colorless solid.
[0207] LC/MS m/z 297 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
7.65-6.75 (m, 3H), 4.35-4.28 (m, 2H), 4.12-4.05 (m, 1H), 2.48-2.39
(m, 2H), 2.17-2.04 (m, 4H), 1.82-1.73 (m, 2H), 1.60-1.52 (m,
1H).
Example 6
3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester (197FBA17d)
[0208] Trimethylsulfoxonium iodide (7.33 g, 33.3 mmol) was slowly
added to a suspension of NaH (55-65% dispersion in mineral oil,
1.45 g, 33.3 mmol) in DMSO (20 mL) and the reaction mixture was
stirred for 1 h. A solution of Boc-tropinone (5.0 g, 22.2 mmol) was
added and the mixture was stirred at r.t. for 20 h. Aqueous work-up
(EtOAc/H.sub.20) and evaporation of the dried (MgSO.sub.4) organic
phase gave the crude epoxide
spiro[8-azabicyclo[3.2.1]octane-3,2'-oxirane]-8-carboxylic acid
tert-butyl ester (197FBA10a), which was used in the next step
without further purification.
[0209] Super-Hydride.RTM. (1.0 M THF solution, 29.0 mmol, 29.0 mL)
was added to a solution of 197FBA10a (5.3 g, 22.2 mmol) in dry THF
(10 mL), cooled with a water bath, and the reaction mixture was
stirred at r.t. After 1 h the mixture was cooled again (ice bath),
slowly quenched with water (10 mL), the aqueous phase was saturated
with K.sub.2CO.sub.3, and the reaction mixture was extracted with
diethylether. The organic phase was dried and evaporated to give a
crude product which was taken up in ethyl acetate (200 mL) and
filtered through a silica pad to give 197FBA17d as a colorless oil
(4.11 g, 77%).
[0210] GC-MS m/z 241. .sup.1H-NMR (CDCl.sub.3) 4.19 (m, 2H),
2.18-2.12 (m, 2H), 1.95-1.89 (m, 4H), 1.66 (d, J=14.3, 2H), 1.46
(s, 9H), 1.17 (s, 3H).
Example 7
endo-3-exo-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride
(197FBA20a)
[0211] 4 M HCl solution in dioxane (40 mL) was added to solution of
197FBA17d (3.81 g, 15.8 mmol) in diethylether (40 mL). The reaction
mixture was stirred during 2 h, then evaporated to give a white
solid, which was filtered, washed with heptane (70 mL), and dried
to give 197FBA20a as a white solid (2.17 g, 77%).
[0212] .sup.1H-NMR (DMSO-d.sub.6 .delta. 3.87 (br s, 2H), 2.27 (d,
J=7.3, 2H), 2.00 (dd, J=14.9 and 3.2, 2H), 1.87-1.83 (m, 2H), 1.74
(d, J=14.6, 2H), 1.07 (s, 3H).
Example 8
2-Chloro-4-fluoro-3-methylbenzonitrile (198RL18)
[0213] 3-Bromo-2-chloro-6-fiuorotoluene (7.0 g, 31 mmol), zinc
cyanide (3.7 g, 31 mmol) and
tetrakis(triphenylphosphine)palladium(0) (1.81 g, 1.56 mmol) was
added to a flask under argon atmosphere. Dry DMF (35 mL) was added
and the reaction mixture was stirred under argon at 120.degree. C.
The reaction was monitored by GC-MS and full conversion was
observed after 2 hours. The mixture was diluted with
dichloromethane (300 mL), washed with water (100 mL) and 4%
magnesium sulfate solution (100 mL), dried over magnesium sulphate,
filtered, and evaporated to give a clear oil. The product was
further purified by column chromatography on silica gel using
n-heptane/ethyl acetate (9:1) giving a white solid (3.79 g,
71%).
[0214] .sup.1H-NMR (CDCl.sub.3) .delta. 7.43 (dd, 1H, J=5.6, 8.8,
Ar--H), 6.87 (t, 1H, J=8.8, Ar--H), 2.36 (d, 3H, J=2.4,
CH.sub.3).
Example 9
Trifluoromethanesulfonic acid 2,3-dimethyl-4-nitrophenyl ester
(195JP07)
[0215] Trifluoromethanesulfonic anhydride (1.57 mL, 8.77 mmol) was
added to 2,3-dimethyl-4-nitrophenol (1.12 g, 6.70 mmol) and
triethylamine (2.5 mL, 17.9 mmol) in dichloromethane (40 mL) at
0.degree. C. under Ar atmosphere and the resulting mixture was
allowed to stir overnight at r.t. 2M HCl (50 mL) was then added and
the solution was extracted with dichloromethane (3.times.100 mL).
The organic extracts were combined, washed with saturated aqueous
NaHCO.sub.3 (100 mL), diluted with n-heptane (200 mL), and passed
through a pad of silica gel to give 1.96 g (98%) of 195JP07 as a
yellow oil.
[0216] GC/MS m/z 299 [M].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 7.72 (d, 1H, J=9.0), 7.28 (d, 1H, J=9.0), 2.48 (s, 3H),
2.41 (s, 3H).
Example 10
endo-8-(2,3-Dimethyl-4-nitro-phenyl)-8-azabicyclo[3.2.1]octan-3-ol
(195JP08)
[0217] 195JP07 (793 mg, 2.65 mmol), nortropine (1.01 g, 7.96 mmol),
and pyridine (2.5 mL) were heated to 110.degree. C. for 16 h. The
crude material was then cooled to r.t., poured into water (200 mL),
and extracted with ethyl acetate (3.times.100 mL). The combined
organic extracts were dried (Na.sub.2SO.sub.4), concentrated in
vacuo, and the residue purified by preparative TLC
(EtOAc/n-heptane, 1:8 as eluent) to give 49.7 mg (6.8%) of 195JP08
as a yellow solid.
[0218] R.sub.f=0.38 (EtOAc/n-heptane 1:1). LC/MS m/z 277
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.70 (d, 1H,
J=9.0), 6.79 (d, 1H, J=9.0), 4.25 (t, 1H, J=4.5), 3.79 (br s, 2H),
2.47 (s, 3H), 2.49-2.25 (m, 4H) 2.32 (s, 3H), 1.98-1.85 (m,
4H).
Example 11
2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-iodobenzonitrile
(195JP18)
[0219] Adapting a protocol by Uchiyama et al (J. Am. Chem. Soc,
2002, 124, 8514-8515), which reference is incorporated herein by
reference in its entirety, 2-chloro-4-fluorobenzonitrile (311 mg,
2.0 mmol) in dry THF (1.0 mL) was added dropwise to lithium
di-t-butyl(2,2,6,6-tetramethylpiperidino)zinncate (4.0 mmol in 10
mL THF, Uchiyama et al J. Am. Chem. Soc, 1999, 121, 3539-3540,
which is incorporated herein by reference in its entirety) at
0.degree. C. and stirred at 0.degree. C. for 3.5 h. Iodine (5.08 g,
20.0 mmol) was then added and the reaction was stirred at r.t.
overnight. Na.sub.2S.sub.2O.sub.3 (1.0 M, 50 mL) and saturated
aqueous NH.sub.4Cl (100 mL) were added, followed by extraction with
dichloromethane (3.times.100 mL), drying of the combined organic
layers over Na.sub.2SO.sub.4, filtering, and removal of the
solvents in vacuo. The residue was passed through a pad of silica
gel eluting with EtOAc/n-heptane (1:40), affording 112 mg (0.40
mmol) of 2-chloro-4-fluoro-3-iodobenzonitrile. This material was
combined with nortropine (114 mg, 0.90 mmol), K.sub.2CO.sub.3 (186
mg, 0.134 mol) and DMSO (2.0 mL), and stirred at 130.degree. C. for
1.5 h. The crude mixture thus obtained was diluted with n-heptane
(10 mL), passed through a pad of silica gel using EtOAc/n-heptane
(1:2), concentrated and purified by preparative TLC
(EtOAC/n-heptane, 1:1) to give 1.5 mg (1.7%) of 195JP18 as an
off-white solid.
[0220] R.sub.f=0.21 (EtOAc/n-heptane 1:1). LC/MS m/z 389
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta. 7.42 (d, 1H, J=8.6),
6.70 (d, 1H, J=8.6), 4.16 (br s, 1H), 3.95 (br s, 2H), 2.50-2.22
(m, 4H) 1.93-1.78 (m, 4H).
Example 12
3-Bromo-2-chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitril-
e (195JP22)
[0221] This reaction was carried out identically as in Example 11,
using bromine instead of iodine as the electrophile, to afford 4.0
mg (0.5%) of 195JP22 as an off-white solid.
[0222] R.sub.f=0.34 (EtOAc/n-heptane, 1:1). LC/MS m/z 342
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) 8 7.39 (d, 1H, J=8.6), 6.74
(d, 1H, J=8.6), 4.15 (t, 1H, J=5.0), 4.02 (br s, 2H), 2.38-2.20 (m,
4H), 1.92-1.79 (m, 4H).
Example 13
2-Bromo-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-5-methyl-benzonitri-
le (195JP26)
[0223] This reaction was carried out identically as in Example 12,
using 4-fluoro-3-methylbenzonitrile instead of
2-chloro-4-fluorobenzonitrile as the substrate, to afford 17.6 mg
(1.4%) of 195JP26 as an off-white solid.
[0224] R.sub.f=0.28 (EtOAc/n-heptane 1:1). LC/MS m/z 322
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta. 7.29 (s, 1H), 6.92
(s, 1H), 4.12 (t, 1H, J=5.0), 3.82 (br s, 2H), 2.30-2.13 (m, 4H),
2.19 (s, 3H), 1.92-1.72 (m, 4H).
Example 14
endo-8-(2-Chloro-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol
(196MBT14-B)
[0225] To a suspension of 2,3-dichlorotoluene (500 mg, 3.11 mmol)
in concentrated sulfuric acid (2.5 mL) was added dropwise a
solution of potassium nitrate (314 mg, 3.11 mmol) in concentrated
sulfuric acid (2.5 mL) at room temperature. The resulting
suspension was stirred 1 hour at room temperature and then poured
into ice/water (100 mL) under stirring. The resulting aqueous phase
was basified to pH 10 by addition of 25% aqueous ammonia and
subsequently extracted with dichloromethane (2.times.100 mL). The
combined organic phases were dried over sodium sulphate, filtered
and evaporated. The crude product was purified by preparative TLC
(0-100% ethyl acetate in heptane) to give a 4:1 mixture of 6- and
5-nitrated product (232 mg). 80 mg of this mixture was dissolved in
pyridine (1 mL). Nortropine (198 mg, 1.553 mmol) was added and the
mixture was heated to 110.degree. C. in a sealed flask for 20 hours
and then concentrated. The residue was dissolved in 2 M HCl (20 mL)
and extracted with dichloromethane (2.times.20 mL). The combined
organic phases were dried over Na.sub.2SO.sub.4, filtered and
evaporated, and the resulting oil was purified by preparative TLC
(eluting with dichloromethane) to afford the title compound (35 mg,
14% from 2,3-dichlorotoluene) as a yellow solid.
[0226] LC/MS m/z 297 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
7.76 (d, J=10.5, 1H), 6.80 (d, J=10.5, 1H), 4.24-4.16 (m, 1H),
4.14-4.05 (m, 2H), 2.59 (s, 3H), 2.40-2.25 (m, 4H), 1.97-1.81 (m,
4H), 1.55 (s, 1H).
Example 15
2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitro-benzaldehy-
de (196 MBT3O)
[0227] Potassium nitrate (638 mg, 6.31 mmol) was dissolved in
concentrated sulfuric acid (4.5 mL) and added dropwise to a stirred
solution of 2-chloro-6-fluorobenzaldehyde (1.0 g, 6.31 mmol) at
room temperature. The mixture was stirred 1 hour at room
temperature and then poured into icewater (100 mL) under stirring.
The resulting aqueous phase was basified to pH 10 by addition of
25% aqueous ammonia and subsequently extracted with dichloromethane
(2.times.100 mL). The combined organic phases were dried over
sodium sulphate, filtered and evaporated to give
2-chloro-6-fluoro-3-nitrobenzaldehyde (196MBT28-A, 1.16 g, 91%).
Regioselectivity was confirmed by .sup.13C-NMR.
[0228] Nortropine (62 mg, 0.491 mmol) and 196MBT28-A (100 mg, 0.491
mmol) were dissolved in pyridine (2 mL) and the mixture shaken in a
sealed flask for 2 hours and then concentrated. The residue was
dissolved dichloromethane (40 mL) and the organic phase was washed
with 2 M HCl (40 mL) followed by 2 M NaOH (40 mL) and finally dried
over Na.sub.2SO.sub.4, filtered and evaporated. The resulting oil
was purified by preparative TLC (0-5% methanol in dichloromethane)
to afford 40 mg (26%) of the title compound as a yellow solid.
[0229] LC/MS m/z 311 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
10.26 (s, 1H), 7.93 (d, J=9.5, 1H), 6.84 (d, J=9.5, 1H), 4.21-4.16
(m, 1H), 4.10-4.01 (m, 2H), 2.40-2.18 (m, 4H), 2.13-1.98 (m, 2H),
1.90-1.82 (m, 2H), 1.47 (s, 1H).
Example 16
endo-8-(3-Chloro-2-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]-octan--
3-ol (196MBT32)
[0230] 196MBT30 (20 mg, 0.064 mmol) was dissolved in methanol (1
mL). Sodium borohydride (3 mg, 0.064 mmol) was added and the
mixture was stirred 30 min at room temperature. Saturated aqueous
ammonium chloride (1 mL) was added and extracted with
dichloromethane (2.times.10 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated to give 18 mg
(90%) of the title compound as a yellow solid.
[0231] LC/MS m/z 313 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
7.80 (d, J=9.0, 1H), 6.82 (d, J=9.0, 1H), 4.86 (d, J=6.5, 2H),
4.24-4.18 (m, 1H), 4.16-4.05 (m, 2H), 3.00 (t, J=6.5, 1H),
2.36-2.22 (m, 4H), 2:00-1.86 (m, 4H), 1.36 (s, 1H).
Example 17
2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitro-benzaldehy-
de oxime (196MBT40)
[0232] 196MBT30 (132 mg, 0.426 mmol) was dissolved in
tetrahydrofuran (2 mL). Sodium carbonate (45 mg, 0.426 mmol) was
added followed by water (0.5 mL) and hydroxylamine hydrochloride
(30 mg, 0.426 mmol). The mixture was stirred 1 hour at room
temperature and then concentrated. Dichloromethane (50 mL) was
added and the organic phase was washed with 2 M HCl (50 mL)
followed by 2 M NaOH (50 mL) and finally dried over
Na.sub.2SO.sub.4, filtered and evaporated. The resulting residue
was purified by preparative TLC (0-5% methanol in dichloromethane)
to afford 45 mg (32%) of the title compound as a yellow solid.
[0233] LC/MS m/z 326 [M+H].sup.+. .sup.1H-NMR (MeOD) .delta. 8.15
(s, 1H), 7.90-6.90 (m, 2H), 4.25-4.00 (m, 3H), 2.35-1.80 (m,
8H).
Example 18
endo-8-(2-Chloro-3-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]-octan--
3-ol (196MBT48)
[0234] Potassium nitrate (578 mg, 5.71 mmol) was dissolved in
concentrated sulfuric acid (4.5 mL) and added dropwise to a stirred
solution of 2,3-dichlorobenzaldehyde (1.0 g, 5.71 mmol) at room
temperature. The mixture was left without stirring for 10 days at
room temperature. Material that had crystallized out of the
reaction mixture was collected by filtration to afford
2,3-dichloro-6-nitrobenzaldehyde (196MBT36, 433 mg, 34%) as yellow
needles. Regioselectivity was confirmed by the Bayer-Drewson indigo
synthesis.
[0235] 96MBT36 (100 mg, 0.455 mmol) was dissolved in methanol (2
mL). Sodium borohydride (17 mg, 0.455 mmol) was added and the
mixture was stirred for 30 minutes at room temperature. Saturated
aqueous ammonium chloride (1 mL) was added and extracted with
dichloromethane (2.times.10 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated to give
2,3-dichloro-6-nitrobenzyl alcohol (196MBT46-A, 92 mg, 91%) as a
yellow solid.
[0236] 196MBT46-A (92 mg, 0.418 mmol) and nortropine (53 mg, 0.418
mmol) were dissolved in pyridine (2 mL). The mixture was heated to
110.degree. C. in a sealed flask for 3 days and then concentrated.
The red residue was dissolved in 2 M HCl (20 mL) and extracted with
dichloromethane (2.times.20 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated, and the
resulting oil was purified by preparative TLC (0-5% methanol in
dichloromethane) to afford 1.0 mg (1%) of the title compound as a
yellow solid.
[0237] LC/MS m/z 313 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
7.90-6.85 (m, 2H), 5.00-4.97 (m, 2H), 4.26-4.15 (m, 3H), 3.00-2.92
(m, 1H), 2.40-2.30 (m, 4H), 2.00-1.83 (m, 4H), 1.27 (s, 1H).
Example 19
endo-8-(5-Chloro-2-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol
(196MBT6-1)
[0238] Nortropine (269 mg, 2.12 mmol) and
4-chloro-2-fluoro-5-nitrotoluene (100 mg, 0.527 mmol) were
dissolved in pyridine (2 mL). The mixture was heated to 110.degree.
C. in a sealed flask for 20 hours and then concentrated. The
residue was dissolved in 2 M HCl (20 mL) and extracted with
dichloromethane (2.times.20 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated, and the
resulting oil was purified by preparative TLC (eluting with
dichloromethane) to afford 14 mg (9%) of the title compound as a
colorless solid.
[0239] LC/MS m/z 297 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
7.86 (s, 1H), 6.75 (s, IH), 4.17-4.10 (m, 1H), 3.97-3.88 (m, 2H),
2.30-2.10 (m, 7H), 1.96-1.74 (m, 4H), 1.40-1.32 (m, 1H).
Example 20
2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile
(196MBT8-B)
[0240] Nortropine (269 mg, 2.12 mmol) and
2-chloro-4-fluorobenzonitrile (100 mg, 0.643 mmol) were dissolved
in pyridine (2 mL). The mixture was heated to 110.degree. C. in a
sealed flask for 20 hours and then concentrated. The residue was
dissolved in 2 M HCl (20 mL) and extracted with dichloromethane
(2.times.20 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and evaporated, and the resulting oil
was purified by preparative TLC (eluting with dichloromethane) to
afford 107 mg (63%) of the title compound as a colorless solid.
[0241] LC/MS m/z 263 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
7.46-6.51 (m, 3H), 4.29-4.16 (m, 2H), 4.16-4.00 (m, 1H), 2.45-2.27
(m, 2H), 2.18-1.96 (m, 4H), 1.79-1.65 (m, 2H), 1.56 (s, 1H).
Example 21
6-Chloro-2-methyl-3-nitrobenzoic acid (198RL35)
[0242] 2-Chloro-6-methylbenzoic acid (99 mg, 0.58 mmol) was
dissolved in conc. hydrochloric acid (1 mL) and cooled in an ice
bath. To this solution potassium nitrate in conc. hydrochloric acid
(1 mL) was added drop wise. The reaction mixture was stirred for 5
min, then the ice bath was removed and stirring was continued for
another 2 hours. The reaction mixture was poured onto ice (25 g)
and extracted with ethyl acetate (3.times.25 mL). The combined
organic layers were dried over sodium sulphate, filtered and
concentrated in vacuo to give a mixture of the desired 3-nitro
(70%) and the 5-nitro (30%) derivatives (118.6 mg, 95%). No effort
was made to separate the two isomers, and the mixture was used in
the next step.
[0243] .sup.1H-NMR (CDCl.sub.3) .delta. 10.53 (br, 1H, CO.sub.2H),
7.91 (d, 0.7H, J=8.8, Ar--H), 7.85 (d, 0.3H, J=8.4, Ar--H), 7.44
(d, 0.7H, J=8.8, Ar--H), 7.31 (d, 0.3H, J=8.4, Ar--H), 2.59 (s,
2.1H, Ar--CH.sub.3), 2.59 (s, 0.9H, Ar--CH.sub.3).
Example 22
6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenzoic
acid (198RL39)
[0244] 6-Chloro-2-methyl-3-nitrobenzoic acid (198RL35, containing
30% of the 5-nitro isomer, 227 mg, 1.05 mmol) and nortropine (536
mg, 4.21 mmol) were dissolved in pyridine (5 mL) and shaken in a
vial at 90.degree. C. for 5 days. The reaction mixture was diluted
with ethyl acetate (20 mL) and extracted with sodium hydroxide
solution (2 M, 3.times.20 mL). The pH of the combined alkaline
layers were regulated to approximately 5 with hydrochloric acid
solution (6 M) and extracted with ethyl acetate (3.times.30 mL).
The combined organic layers were dried over sodium sulfate and
concentrated in vacuo. The crude product was purified by
preparative HPLC to give a yellow solid (154 mg, 48%).
[0245] LC/MS m/z 307 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
9.90 (br, 1H, CO.sub.2H), 7.90 (d, 1H, J=9.2, Ar--H), 6.87 (d, 1H,
J=9.2, Ar--H), 4.20 (m, 3H, Tr-H), 2.52 (s, 3H, Ar--CH.sub.3),
2.40-2.27 (m, 4H, Tr-H), 2.12-2.04 (m, 4H, Tr-H), 1.90 (m, 1H,
Tr-OH).
Example 23
endo-8-(2-Hydroxymethyl-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]-octan--
3-ol (198RL48-3)
[0246]
6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenz-
oic acid (198RL39, 64 mg, 0.21 mmol) was dissolved in THF (1 mL).
This was stirred at 0.degree. C. while borane-THF complex (1 M,
0.35 mL, 0.35 mmol) was added dropwise. After complete addition the
mixture was allowed to warm to r.t. and stirring was continued
overnight after which LC-MS analysis showed approximately 50%
conversion. The reaction was worked up (water/ethyl acetate). The
crude product was purified twice by preparative TLC, using ethyl
acetate as the mobile phase, to afford the title compound (2.1 mg,
3%).
[0247] R.sub.f=0.57 (ethyl acetate). LCMS m/z 292 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.75 (d, 1H, J=9.1, Ar--H), 6.85
(d, 1H, J=9.1, Ar--H), 4.89 (s, 2H, Ar--CH.sub.2OH), 4.21 (m, 1H,
Tr-H), 3.95 (m, 2H, Tr-H), 2.57 (s, 3H, Ar--CH.sub.3), 2.43-2.25
(m, 4H, Tr-H), 2.14-2.01 (m, 4H, Tr-H).
Example 24
2-Chloro-4-fluoro-3-methyl-1-nitrobenzene (198RL41)
[0248] 1-Chloro-3-fluoro-2-methylbenzene (1.00 mL, 8.24 mmol) was
dissolved in sulfuric acid (18 M, 10 mL) and cooled in an ice bath.
Potassium nitrate (0.87 g, 8.65 mmol) dissolved in sulfuric acid
(18 M, 10 mL) was added dropwise to the cold solution. The reaction
mixture was stirred for 5 min, then the ice bath was removed and
stirring was continued for another 2 h. The reaction mixture was
poured onto ice (25 g) stirred for 5 min and extracted with ethyl
acetate (3.times.25 mL). The combined organic layers were dried
over sodium sulfate, filtered and evaporated to give a clear yellow
oil (1.34 g, purity 85%). The product was used without further
purification in the next reaction step.
[0249] .sup.1H-NMR (CDCl.sub.3) .delta. 7.11 (m, 1H, Ar--H), 7.10
(m, 1H, J=8.3, Ar--H), 2.40 (m, 3H, Ar--CH.sub.3).
Example 25
4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-trifluordmethylbenzo-nitr-
ile (196MBT10-B)
[0250] Nortropine (269 mg, 2.12 mmol) and
4-fluoro-3-(trifluoromethyl)benzonitrile (100 mg, 0.529 mmol) were
dissolved in pyridine (2 mL). The mixture was heated to 110.degree.
C. in a sealed flask for 20 hours and then concentrated. The
residue was dissolved in 2 M HCl (20 mL) and extracted with
dichloromethane (2.times.20 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated, and the
resulting oil was purified by preparative TLC (eluting with
dichloromethane) to afford 55 mg (35%) of the title compound as a
colorless solid.
[0251] LCMS m/z 297 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
7.80-6.85 (m, 3H), 4.15-4.00 (m, 3H), 2.33-2.10 (m, 4H), 2.00-1.84
(m, 2H), 1.82-1.70 (m, 2H), 1.39 (s, 1H).
Example 26
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-met-
hylbenzonitrile (198RL93)
[0252] 2-Chloro-4-fluoro-3-methylbenzonitrile (198RL18, 2.48 g,
14.6 mmol), endo-3-exo-methyl-8-azabicyclo[3.2.1]octan-3-ol
hydrochloride (197FBA20a, 3.37 g, 19.0 mmol), and potassium
carbonate (6.67 g, 48.2 mmol) were dissolved in dimethyl sulphoxide
(40 mL), and the mixture stirred under argon at 80.degree. C. for
18 hours. The reaction mixture was poured into water (200 mL) and
stirred for 30 min. The off-white solid was filtered off and
recrystallised twice from toluene, giving a white powder (1.53 g).
The mother liquor was evaporated and the residue recrystallised to
yield a second batch of compound (210 mg), giving an overall yield
of 40%.
[0253] Mp=145-147.degree. C. R.sub.f=0.68 (ethyl
acetate/dichloromethane 1:1) LC/MS m/z 291 [M+H].sup.+. .sup.1H-NMR
(CDCl.sub.3) .delta. 7.39 (d, 1H, J=8.6, Ar--H), 6.84 (d, 1H,
J=8.6, Ar--H), 3.82 (m, 2H, Tr-H), 2.36 (s, 3H, Ar--CH.sub.3),
2.32-2.22 (m, 2H, Tr-H), 2.17-1.98 (m, 2H, Tr-H), 1.92-1.77 (m, 4H,
Tr-H), 1.26 (s, 3H, Tr-CH.sub.3).
Example 27
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-met-
hylbenzonitrile hydrochloride (198RL26)
[0254] The hydrochloride salt was prepared by dissolving
2-chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile (198RL93) in diethyl ether and adding HC (1.1 eq,
4 M solution in 1,4-dioxane). The mixture was allowed to stir for
15 min and the precipitated salt was filtered off as a fine white
powder.
[0255] Mp=160.degree. C. (decomposition).
Example 28
2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-met-
hylbenzonitrile mesylate (198RL93-MS)
[0256] The mesylate salt was prepared by dissolving
2-chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-me-
thylbenzonitrile (198RL93) in diethyl ether and adding
methylsulfonate (1.1 eq). The mixture was allowed to stir for 15
min and the precipitated salt was filtered off as a fine white
powder.
[0257] Mp=164.degree. C. (decomposition).
Example 29
In Vitro Determination of Receptor Activity
[0258] The functional receptor assay, Receptor Selection and
Amplification Technology (R-SAT.TM.), was used with minor
modifications from the procedure described previously (Brann, M.
R., U.S. Pat. No. 5,707,798, which is hereby incorporated herein by
reference in its entirety) to screen compounds for efficacy at the
Androgen AR receptor. Briefly, NIH3T3 cells were grown in roller
bottles to 70-80% confluence. Cells were then transfected for 12-16
h with plasmid DNAs using Polyfect (Qiagen Inc.) as per the
manufacturer's protocol. R-SAT assays were typically performed by
transfecting 30 ug/bottle of receptor and 50 ug/bottle of
.beta.-galactosidase plasmid DNA. All receptor and helper
constructs used were in mammalian expression vectors. Helpers are
defined as signaling molecules that modulate both ligand-dependent
and/or ligand-independent function of the AR receptor, typically
co-activators.
[0259] NIH3T3 cells were transfected for 12-16 h, then trypsinized
and frozen in DMSO. Frozen cells were later thawed, plated at
10,000-40,000 cells per well of a 96 well plate containing drug.
Cells were then grown in a humidified atmosphere with 5% ambient
CO.sub.2 for five days. Media was then removed from the plates and
marker gene activity was measured by the addition of the
.beta.-galactosidase substrate o-nitrophenyl
.beta.-D-galactopyranoside (ONPG, in PBS with 5% NP-40). The
resulting calorimetric reaction was measured in a
spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data
were analyzed using the computer program XLFit (IDBSm).
[0260] Results for selected compounds are presented in Table 1.
TABLE-US-00001 TABLE 1 compound % Efficacy pEC50 173FBA73bL 80 8.5
198RL26 79 8.8 165RL90 81 8.7
Example 30
In Vivo Activity of Androgen Receptor Agonists
[0261] Test compounds of formula I are administered p.o. daily for
two weeks to castrated male Sprague Dawley rats (n=3). The effects
of the test compounds (1, 3, 10, 30 mg/kg) are compared to
testosterone propionate (1 and 3 mg/kg s.c; positive control) and
vehicle (10% Tween80; negative control). Blood and wet weights of
prostate gland and seminal vesicle are measured after sacrifice
that occurs 24 hours after the last dose. Blood is collected in
heparin collection tubes after sacrifice that occurred 24 hours
after the last dose. Blood is centrifuged and plasma collected and
plasma samples frozen.
[0262] Rat luteinizing hormone (LH) plasma levels are determined
using an enzyme linked immunoabsorbent assay (ELISA) from Amersham
as per manufacturer's instructions. The solid phase assay is based
on the competition between unlabeled rLH and a fixed quantity of
biotin labelled rLH for a limited amount of rLH specific antibody.
A conjugate streptavidin/peroxidase allows for signal amplification
and detection in presence of the substrate.
[0263] Results for 198RL26
[0264] Daily subcutaneous (s.c.) administration of testosterone
propionate (TP), at a dose of 1 mg/kg for a period of two weeks,
produced significant increases in prostate (FIG. 1), seminal
vesicle (FIG. 2), and levator ani muscle (FIG. 3) wet tissue
weights as compared to vehicle treatment. In contrast, daily s.c.
administration of 3 mg/kg 198RL26 for a period of two weeks did not
appear to significantly alter wet tissue weights. Daily
administration of higher doses (3 and 10 mg/kg) of 198RL26 appeared
to significantly increase wet tissue weights, however, not to the
extent of TP. These data suggest, as compared TP, the potential for
negative side effects (i.e, increased seminal vesicle and prostate
size) with 198RL26 may not be evident until doses of at least
100.times. of TP are reached. Upon castration, plasma levels of
luteinizing hormone (LH) increased by approximately 3-4 fold. (FIG.
4) Chronic administration of TP (1 mg/kg, s.c. for 14 days)
restored LH levels to those obtained in naive rats (non-castrated
animals). Daily administration of 198RL26 (various doses, p.o. for
14 days) produced a dose-dependent suppression of plasma LH levels,
such that a complete reversal was evident at 10 mg/kg.
[0265] Although the invention has been described with reference to
embodiments and examples, it should be understood that numerous and
various modifications can be made without departing from the scope
and spirit of the invention.
* * * * *