U.S. patent application number 11/770586 was filed with the patent office on 2008-01-10 for androgen receptor modulators and method of treating disease using the same.
This patent application is currently assigned to Acadian Pharmaceuticals, Inc.. Invention is credited to Fabrizio Badalassi, Alma Fejzic, Rasmus Lewinsky, Birgitte Winther Lund, Roger Olsson, Jan Pawlas, Nathalie Schlienger, Mikkel Boas Thygesen.
Application Number | 20080009489 11/770586 |
Document ID | / |
Family ID | 35241157 |
Filed Date | 2008-01-10 |
United States Patent
Application |
20080009489 |
Kind Code |
A1 |
Schlienger; Nathalie ; et
al. |
January 10, 2008 |
ANDROGEN RECEPTOR MODULATORS AND METHOD OF TREATING DISEASE USING
THE SAME
Abstract
Disclosed herein are bicycloaryl compounds of Formula (I) that
selectively modulate nuclear receptors, preferably the androgen
receptor, or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, and methods of treating disease comprising
administering a compound of Formula (I) to a patient in need
thereof.
Inventors: |
Schlienger; Nathalie;
(Frederiksberg, DK) ; Pawlas; Jan; (Frederiksberg,
DK) ; Fejzic; Alma; (Frederiksberg, DK) ;
Olsson; Roger; (US) ; Lund; Birgitte Winther;
(Bagsvaerd, DK) ; Badalassi; Fabrizio; (Copenhagen
K, DK) ; Lewinsky; Rasmus; (Herlev, DK) ;
Thygesen; Mikkel Boas; (Copenhagen O, DK) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
94304-1050
US
|
Assignee: |
Acadian Pharmaceuticals,
Inc.
San Diego
CA
|
Family ID: |
35241157 |
Appl. No.: |
11/770586 |
Filed: |
June 28, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11130669 |
May 16, 2005 |
7268232 |
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11770586 |
Jun 28, 2007 |
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60571961 |
May 17, 2004 |
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Current U.S.
Class: |
514/231.5 ;
435/375; 514/299; 514/317; 514/427 |
Current CPC
Class: |
C07D 211/70 20130101;
C07D 451/02 20130101; C07D 451/06 20130101; A61P 3/04 20180101;
A61P 3/06 20180101; C07D 237/34 20130101; C07D 241/42 20130101;
C07D 491/10 20130101; C07F 9/6561 20130101; C07D 211/48 20130101;
C07D 211/60 20130101; C07D 215/48 20130101; C07D 221/22 20130101;
A61P 19/04 20180101; A61P 21/04 20180101; C07D 211/64 20130101;
C07D 215/40 20130101; C07D 295/096 20130101; A61P 5/24 20180101;
A61P 9/10 20180101; C07D 207/14 20130101; C07D 215/20 20130101;
C07D 217/22 20130101; A61P 31/18 20180101; C07D 211/42 20130101;
C07D 207/08 20130101; A61P 25/22 20180101; A61P 5/26 20180101; C07D
451/00 20130101; A61P 15/08 20180101; A61P 5/00 20180101; C07D
211/34 20130101; A61P 15/12 20180101; C07D 217/02 20130101; C07D
217/24 20130101; C07D 211/22 20130101; A61P 9/00 20180101; C07D
471/04 20130101; C07D 295/155 20130101; A61P 9/12 20180101; A61P
3/00 20180101; A61P 25/18 20180101; C07D 471/08 20130101; C07C
255/58 20130101; A61P 15/10 20180101; C07D 211/46 20130101; C07D
211/32 20130101; C07D 221/20 20130101; C07D 207/16 20130101; C07D
217/04 20130101; C07D 487/08 20130101; C07F 9/572 20130101; A61P
3/02 20180101; A61P 15/00 20180101; C07D 207/20 20130101; C07D
207/10 20130101; C07D 207/09 20130101; C07D 451/04 20130101; A61P
25/28 20180101; C07D 211/58 20130101; C07D 295/073 20130101; A61P
43/00 20180101; C07D 211/62 20130101; C07D 207/12 20130101; A61P
5/30 20180101; A61P 21/00 20180101; A61P 25/24 20180101; C07D
295/06 20130101; C07D 471/10 20130101; A61P 35/00 20180101; A61P
3/10 20180101; C07D 211/38 20130101; C07D 285/14 20130101 |
Class at
Publication: |
514/231.5 ;
435/375; 514/299; 514/317; 514/427 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61K 31/40 20060101 A61K031/40; A61K 31/445 20060101
A61K031/445; A61K 31/5375 20060101 A61K031/5375; A61P 15/00
20060101 A61P015/00; A61P 21/00 20060101 A61P021/00; A61P 35/00
20060101 A61P035/00; A61P 5/00 20060101 A61P005/00; C12N 5/00
20060101 C12N005/00 |
Claims
1-13. (canceled)
14. A method of activating an androgen receptor comprising
contacting said receptor with a compound of Formula (I): ##STR9##
wherein R.sub.1 and R.sub.2 are each independently selected from
the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl,
halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy,
aryl, heteroaryl, COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4,
NHSO.sub.2R.sub.4, OCOR.sub.4, COR.sub.4, SR.sub.4,
S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9; R.sub.3 is selected
from the group consisting of cyano, nitro, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4,
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5), COOR.sub.4; ring A is a 5- or 6-membered,
optionally aromatic, partially saturated or completely saturated
carbocycle or heterocycle, containing up to two heteroatoms,
selected from the group consisting of NR.sub.6R.sub.7, O, SO.sub.2)
S, C.dbd.O and C.dbd.S; ring B is an optionally substituted
monocyclic or bicyclic heterocycle, containing up to three
heteroatoms, selected from the group consisting of NR.sub.6R.sub.7,
O, S, C.dbd.O and C.dbd.S; Y.sub.1 and Y.sub.2 are CR.sub.6R.sub.7;
R.sub.4 and R.sub.5 are each independently selected from the group
consisting of hydrogen, cyano, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted
heterocyclylalkyl, optionally substituted arylalkyl, optionally
substituted aryl, optionally substituted heteroarylalkyl,
optionally substituted heteroaryl; R.sub.6 and R.sub.7 are each
independently selected from the group consisting of hydrogen, halo,
cyano, hydroxy, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted aryl,
optionally substituted heteroarylalkyl, optionally substituted
heteroaryl, OR.sub.4, NR.sub.4R.sub.5, SR.sub.4, COR.sub.4,
COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4,
CSOR.sub.4, CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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; R.sub.8 and R.sub.9 are each independently
selected from the group consisting of hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted heteroarylalkyl; and n is an integer from 1
to 3; or pharmaceutically acceptable salts, esters, amides,
prodrugs, or stereoisomers thereof.
15. A method of ameliorating symptoms of hypogonadism comprising
identifying a patient in need thereof and administering to said
patient a compound of Formula (I): ##STR10## wherein R.sub.1 and
R.sub.2 are each independently selected from the group consisting
of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano,
hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl,
COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4, NHSO.sub.2R.sub.4,
OCOR.sub.4, COR.sub.4, SR.sub.4, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9; R.sub.3 is selected from the group
consisting of cyano, nitro, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4,
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5).sub.2, COOR.sub.4; ring A is a 5- or
6-membered, optionally aromatic, partially saturated or completely
saturated carbocycle or heterocycle, containing up to two
heteroatoms, selected from the group consisting of NR.sub.6R.sub.7,
O, SO.sub.2, S, C.dbd.O and C.dbd.S; ring B is an optionally
substituted monocyclic or bicyclic heterocycle, containing up to
three heteroatoms, selected from the group consisting of
NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and C.dbd.S; Y.sub.1 and
Y.sub.2 are CR.sub.6R.sub.7; R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
cyano, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
cycloalkyl, optionally substituted heterocyclylalkyl, optionally
substituted arylalkyl, optionally substituted aryl, optionally
substituted heteroarylalkyl, optionally substituted heteroaryl;
R.sub.6 and R.sub.7 are each independently selected from the group
consisting of hydrogen, halo, cyano, hydroxy, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted
heteroarylalkyl; and n is an integer from 1 to 3; or
pharmaceutically acceptable salts, esters, amides, prodrugs, or
stereoisomers thereof.
16. A method of treating a disease or ameliorating the symptoms
thereof, comprising identifying a patient in need thereof and
administering to said patient a compound of Formula (I): ##STR11##
wherein R.sub.1 and R.sub.2 are each independently selected from
the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl,
halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy,
aryl, heteroaryl, COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4,
NHSO.sub.2R.sub.4, OCOR.sub.4, COR.sub.4, SR.sub.4,
S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9; R.sub.3 is selected
from the group consisting of cyano, nitro, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4,
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5).sub.2, COOR.sub.4; ring A is a 5- or
6-membered, optionally aromatic, partially saturated or completely
saturated carbocycle or heterocycle, containing up to two
heteroatoms, selected from the group consisting of NR.sub.6R.sub.7,
O, SO.sub.2, S, C.dbd.O and C.dbd.S; ring B is an optionally
substituted monocyclic or bicyclic heterocycle, containing up to
three heteroatoms, selected from the group consisting of
NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and C.dbd.S; Y.sub.1 and
Y.sub.2 are CR.sub.6R.sub.7; R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
cyano, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
cycloalkyl, optionally substituted heterocyclylalkyl, optionally
substituted arylalkyl, optionally substituted aryl, optionally
substituted heteroarylalkyl, optionally substituted heteroaryl;
R.sub.6 and R.sub.7 are each independently selected from the group
consisting of hydrogen, halo, cyano, hydroxy, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted
heteroarylalkyl; and n is an integer from 1 to 3; or
pharmaceutically acceptable salts, esters, amides, prodrugs, or
stereoisomers thereof; wherein said disease is selected from the
group consisting of lower than normal testosterone plasma levels,
infertility in males, spermatogenesis 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
including lack of well being, lack of vigor, anger, irritability,
sadness, tiredness, and 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.
17. A method of hormonal replacement therapy, comprising
identifying a patient in need thereof and administering to the
patient a compound of Formula (I): ##STR12## wherein R.sub.1 and
R.sub.2 are each independently selected from the group consisting
of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano,
hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl,
COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4, NHSO.sub.2R.sub.4,
OCOR.sub.4, COR.sub.4, SR.sub.4, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9; R.sub.3 is selected from the group
consisting of cyano, nitro, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4,
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5).sub.2, COOR.sub.4; ring A is a 5- or
6-membered, optionally aromatic, partially saturated or completely
saturated carbocycle or heterocycle, containing up to two
heteroatoms, selected from the group consisting of NR.sub.6R.sub.7,
O, SO.sub.2, S, C.dbd.O and C.dbd.S; ring B is an optionally
substituted monocyclic or bicyclic heterocycle, containing up to
three heteroatoms, selected from the group consisting of
NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and C.dbd.S; Y.sub.1 and
Y.sub.2 are CR.sub.6R.sub.7; R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
cyano, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
cycloalkyl, optionally substituted heterocyclylalkyl, optionally
substituted arylalkyl, optionally substituted aryl, optionally
substituted heteroarylalkyl, optionally substituted heteroaryl;
R.sub.6 and R.sub.7 are each independently selected from the group
consisting of hydrogen, halo, cyano, hydroxy, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted
heteroarylalkyl; and n is an integer from 1 to 3; or
pharmaceutically acceptable salts, esters, amides, prodrugs, or
stereoisomers thereof.
18. The method of claim 17, wherein need for hormonal replacement
therapy is caused by orchiectomy by surgical or chemical means.
19. A method of improving muscle strength in conditions including
muscular dystrophy, myotonic dystrophy, glucocorticoid-treated
asthma, comprising identifying a patient in need thereof and
administering to the patient a compound of Formula (I): ##STR13##
wherein R.sub.1 and R.sub.2 are each independently selected from
the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl,
halo, nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy,
aryl, heteroaryl, COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4,
NHSO.sub.2R.sub.4, OCOR.sub.4, COR.sub.4, SR.sub.4,
S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9; R.sub.3 is selected
from the group consisting of cyano, nitro, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4,
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5).sub.2, COOR.sub.4; ring A is a 5- or
6-membered, optionally aromatic, partially saturated or completely
saturated carbocycle or heterocycle, containing up to two
heteroatoms, selected from the group consisting of NR.sub.6R.sub.7,
O, SO.sub.2, S, C.dbd.O and C.dbd.S; ring B is an optionally
substituted monocyclic or bicyclic heterocycle, containing up to
three heteroatoms, selected from the group consisting of
NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and C.dbd.S; Y.sub.1 and
Y.sub.2 are CR.sub.6R.sub.7; R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
cyano, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
cycloalkyl, optionally substituted heterocyclylalkyl, optionally
substituted arylalkyl, optionally substituted aryl, optionally
substituted heteroarylalkyl, optionally substituted heteroaryl;
R.sub.6 and R.sub.7 are each independently selected from the group
consisting of hydrogen, halo, cyano, hydroxy, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted
heteroarylalkyl; and n is an integer from 1 to 3; or
pharmaceutically acceptable salts, esters, amides, prodrugs, or
stereoisomers thereof.
20. A method of preventing a condition selected from the group
consisting of 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, comprising administering to the
patient a compound of Formula (I): ##STR14## wherein R.sub.1 and
R.sub.2 are each independently selected from the group consisting
of hydrogen, lower alkyl, alkenyl, alkynyl, halo, nitro, cyano,
hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl, heteroaryl,
COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4, NHSO.sub.2R.sub.4,
OCOR.sub.4, COR.sub.4, SR.sub.4, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9; R.sub.3 is selected from the group
consisting of cyano, nitro, S(O).sub.nR.sub.8,
SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4, P(O)(OR.sub.4(OR.sub.5),
P(O)(OH)(NR.sub.4R.sub.5), PO(NR.sub.4R.sub.5).sub.2, COOR.sub.4;
ring A is a 5- or 6-membered, optionally aromatic, partially
saturated or completely saturated carbocycle or heterocycle,
containing up to two heteroatoms, selected from the group
consisting of NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and C.dbd.S;
ring B is an optionally substituted monocyclic or bicyclic
heterocycle, containing up to three heteroatoms, selected from the
group consisting of NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and
C.dbd.S; Y.sub.1 and Y.sub.2 are CR.sub.6R.sub.7; R.sub.4 and
R.sub.5 are each independently selected from the group consisting
of hydrogen, cyano, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted aryl,
optionally substituted heteroarylalkyl, optionally substituted
heteroaryl; R.sub.6 and R.sub.7 are each independently selected
from the group consisting of hydrogen, halo, cyano, hydroxy,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted cycloalkyl,
optionally substituted heterocyclylalkyl, optionally substituted
arylalkyl, optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted
heteroarylalkyl; and n is an integer from 1 to 3; or
pharmaceutically acceptable salts, esters, amides, prodrugs, or
stereoisomers thereof.
21. 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 the patient a compound
of Formula (I): ##STR15## wherein R.sub.1 and R.sub.2 are each
independently selected from the group consisting of hydrogen, lower
alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower
aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, NHSO.sub.2R.sub.4, OCOR.sub.4,
COR.sub.4, SR.sub.4, S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9;
R.sub.3 is selected from the group consisting of cyano, nitro,
S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4,
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5), COOR.sub.4; ring A is a 5- or 6-membered,
optionally aromatic, partially saturated or completely saturated
carbocycle or heterocycle, containing up to two heteroatoms,
selected from the group consisting of NR.sub.6R.sub.7, O, SO.sub.2,
S, C.dbd.O and C.dbd.S; ring B is an optionally substituted
monocyclic or bicyclic heterocycle, containing up to three
heteroatoms, selected from the group consisting of NR.sub.6R.sub.7,
O, SO.sub.2, S, C.dbd.O and C.dbd.S; Y.sub.1 and Y.sub.2 are
CR.sub.6R.sub.7; R.sub.4 and R.sub.5 are each independently
selected from the group consisting of hydrogen, cyano, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl; R.sub.6 and
R.sub.7 are each independently selected from the group consisting
of hydrogen, halo, cyano, hydroxy, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted
heterocyclylalkyl, optionally substituted arylalkyl, optionally
substituted aryl, optionally substituted heteroarylalkyl,
optionally substituted heteroaryl, OR.sub.4, NR.sub.4R.sub.5,
SR.sub.4, COR.sub.4, COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4,
OCOR.sub.4, CSR.sub.4, CSOR.sub.4, CSNR.sub.4R.sub.5, NHCSR.sub.4,
OCSR.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; R.sub.8 and R.sub.9 are each
independently selected from the group consisting of hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted cycloalkyl,
optionally substituted heterocyclylalkyl, optionally substituted
arylalkyl, optionally substituted heteroarylalkyl; and n is an
integer from 1 to 3; or pharmaceutically acceptable salts, esters,
amides, prodrugs, or stereoisomers thereof.
22. A method of delaying the progression of prostate cancer,
comprising administering to the patient a compound of Formula (I):
##STR16## wherein R.sub.1 and R.sub.2 are each independently
selected from the group consisting of hydrogen, lower alkyl,
alkenyl, alkynyl, halo, nitro, cyano, hydroxy, amino, lower
aminoalkyl, lower alkoxy, aryl, heteroaryl, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, NHSO.sub.2R.sub.4, OCOR.sub.4,
COR.sub.4, SR.sub.4, S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9;
R.sub.3 is selected from the group consisting of cyano, nitro,
S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9, OSO.sub.2R.sub.4,
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5).sub.2, COOR.sub.4; ring A is a 5- or
6-membered, optionally aromatic, partially saturated or completely
saturated carbocycle or heterocycle, containing up to two
heteroatoms, selected from the group consisting of NR.sub.6R.sub.7,
O, SO.sub.2, S, C.dbd.O and C.dbd.S; ring B is an optionally
substituted monocyclic or bicyclic heterocycle, containing up to
three heteroatoms, selected from the group consisting of
NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and C.dbd.S; Y.sub.1 and
Y.sub.2 are CR.sub.6R.sub.7; R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
cyano, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
cycloalkyl, optionally substituted heterocyclylalkyl, optionally
substituted arylalkyl, optionally substituted aryl, optionally
substituted heteroarylalkyl, optionally substituted heteroaryl;
R.sub.6 and R.sub.7 are each independently selected from the group
consisting of hydrogen, halo, cyano, hydroxy, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted cycloalkyl, optionally substituted heterocyclylalkyl,
optionally substituted arylalkyl, optionally substituted
heteroarylalkyl; and n is an integer from 1 to 3; or
pharmaceutically acceptable salts, esters, amides, prodrugs, or
stereoisomers thereof.
Description
RELATED APPLICATIONS
[0001] This application is a non-provisional of, and claims
priority to, the U.S. Provisional Patent Application Ser. No.
60/571,961, filed on May 17, 2005, by Schlienger et al., and
entitled "ANDROGEN RECEPTOR MODULATORS AND METHOD OF TREATING
DISEASE USING THE SAME," the disclosure of which is incorporated by
reference herein in its entirety, including any drawings.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates novel compounds and methods of
using the same for medicinal use and/or to modulate androgen
receptors.
[0004] 2. Description of the Related Art
[0005] 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) 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.
[0006] 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.
[0007] 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".
[0008] 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 bums. 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, and in the ophthalmologic arena, in
disorders such as dry eye. More recent studies have highlighted a
correlation between decreasing testosterone levels and increased
incidence of Alzheimer's disease.
[0009] 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; combined with the frequent
injections, 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.
[0010] Finally, the use of such steroid replacement therapy is
widely believed to yield increase in prostate size. This androgenic
property of testosterone and testosterone analogs constitute an
additional and significant risk for prostate cancer.
SUMMARY OF THE INVENTION
[0011] One aspect of the present invention provides compounds of
the general Formula (I) that selectively modulate nuclear
receptors, preferably the androgen receptor, ##STR1## or a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof,
wherein
[0012] R.sub.1 and R.sub.2 are each independently selected from the
group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo,
nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl,
heteroaryl, COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4,
NHSO.sub.2R.sub.4, OCOR.sub.4, COR.sub.4, SR.sub.4,
S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9;
[0013] R.sub.3 is selected from the group consisting of cyano,
nitro, S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9,
OSO.sub.2R.sub.4, P(O)(OR.sub.4)(OR.sub.5),
P(O)(OH)(NR.sub.4R.sub.5), PO(NR.sub.4R.sub.5).sub.2,
COOR.sub.4;
[0014] ring A is a 5- or 6-membered, optionally aromatic, partially
saturated or completely saturated carbocycle or heterocycle,
containing up to two heteroatoms or heterogroups selected from the
group consisting of NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and
C.dbd.S;
[0015] ring B is an optionally substituted monocyclic or bicyclic
heterocycle, containing up to three heteroatoms or heterogroups,
selected from the group consisting of NR.sub.6R.sub.7, O, SO.sub.2,
S, C.dbd.O and C.dbd.S;
[0016] Y.sub.1 and Y.sub.2 are CR.sub.6R.sub.7;
[0017] R.sub.4 and R.sub.5 are each independently selected from the
group consisting of hydrogen, cyano, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted
heterocyclylalkyl, optionally substituted arylalkyl, optionally
substituted aryl, optionally substituted heteroarylalkyl,
optionally substituted heteroaryl;
[0018] R.sub.6 and R.sub.7 are each independently selected from the
group consisting of hydrogen, halo, cyano, hydroxy, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
[0019] R.sub.8 and R.sub.9 are each independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted
heterocyclylalkyl, optionally substituted arylalkyl, optionally
substituted heteroarylalkyl; and
[0020] n is an integer from 1 to 3.
[0021] In another aspect, the present invention relates to the
administration of a compound of Formula (I) to a patient in order
to treat a condition in the patient. In various embodiments, the
condition treated includes 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 other
embodiments, a compound of Formula (I) may be administered to a
patient in order to prevent a condition in the patient. In various
embodiments, the condition prevented includes 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 shows the effect of daily subcutaneous administration
for two weeks of 3, 10 or 30 mg/kg 116BG33 or 0.1 mg/kg
testosterone propionate (TP) on wet weight of prostate.
[0023] FIG. 2 shows the effect of daily subcutaneous administration
for two weeks of 3, 10 or 30 mg/kg 116BG33 or 0.1 mg/kg
testosterone propionate (TP) on wet weight of seminal vesicle.
[0024] FIG. 3 shows that plasma levels of luteinizing hormone are
increased by about 4-5 fold upon castration.
[0025] FIG. 4 shows the effect of daily subcutaneous administration
of testosterone propionate (TP), at a dose of 1 mg/kg for a period
of two weeks on wet tissue weights of prostate as compared to
vehicle.
[0026] FIG. 5 shows the effect of daily subcutaneous administration
of testosterone propionate (TP), at a dose of 1 mg/kg for a period
of two weeks on wet tissue weights of seminal vesicle as compared
to vehicle.
[0027] FIG. 6 shows the effect of daily subcutaneous administration
of testosterone propionate (TP), at a dose of 1 mg/kg for a period
of two weeks on wet tissue weights of levator ani muscle as
compared to vehicle.
[0028] FIG. 7 shows that upon castration, plasma levels of
luteinizing hormone (LH) increased by approximately 3-4 fold.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0029] Because of the undesirable adverse effects of steroidal AR
ligands, the search for Selective Androgen Receptor Modulators or
SARMs has been initiated. This class of ligands demonstrate better
pharmacokinetic and specificity profiles than the current steroidal
therapies. In particular, non-steroidal SARMs display evident
therapeutic benefit but lack androgenic properties. These adverse
androgenic effects include manifestations such as prostate
enlargement, acne, hirsutism, virilization and masculinization.
Second generation SARMs contribute additional therapeutic benefits
by displaying positive anabolic properties and antagonistic
androgenic components. Another desirable feature of SARMs is
significant bioavailability. In some embodiments, the SARMs are
provided in a "once-a-day" dosing pill.
[0030] Thus, in a first aspect, the present invention provides
compounds of the Formula (I) that selectively modulate nuclear
receptors, preferably the androgen receptor, ##STR2## wherein
[0031] R.sub.1 and R.sub.2 are each independently selected from the
group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, halo,
nitro, cyano, hydroxy, amino, lower aminoalkyl, lower alkoxy, aryl,
heteroaryl, COOR.sub.4, CONR.sub.4R.sub.5, NHCOR.sub.4,
NHSO.sub.2R.sub.4, OCOR.sub.4, COR.sub.4, SR.sub.4,
S(O).sub.2R.sub.8, SO.sub.2NR.sub.8R.sub.9;
[0032] R.sub.3 is selected from the group consisting of cyano,
nitro, S(O).sub.nR.sub.8, SO.sub.2NR.sub.8R.sub.9,
OSO.sub.2R.sub.4, P(O)(OR.sub.4)(OR.sub.5),
P(O)(OH)(NR.sub.4R.sub.5), PO(NR.sub.4R.sub.5).sub.2,
COOR.sub.4;
[0033] ring A is a 5- or 6-membered, optionally aromatic, partially
saturated or completely saturated carbocycle or heterocycle,
containing up to two heteroatoms, selected from the group
consisting of NR.sub.6R.sub.7, O, SO.sub.2, S, C.dbd.O and
C.dbd.S;
[0034] ring B is an optionally substituted monocyclic or bicyclic
heterocycle, containing up to three heteroatoms or heterogroups,
selected from the group consisting of NR.sub.6R.sub.7, O, SO.sub.2,
S, C.dbd.O and C.dbd.S;
[0035] Y.sub.1 and Y.sub.2 are CR.sub.6R.sub.7;
[0036] R.sub.4 and R.sub.5 are each independently selected from the
group consisting of hydrogen, cyano, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted
heterocyclylalkyl, optionally substituted arylalkyl, optionally
substituted aryl, optionally substituted heteroarylalkyl,
optionally substituted heteroaryl;
[0037] R.sub.6 and R.sub.7 are each independently selected from the
group consisting of hydrogen, halo, cyano, hydroxy, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocyclylalkyl, optionally substituted arylalkyl,
optionally substituted aryl, optionally substituted
heteroarylalkyl, optionally substituted heteroaryl, OR.sub.4,
NR.sub.4R.sub.5, SR.sub.4, COR.sub.4, COOR.sub.4,
CONR.sub.4R.sub.5, NHCOR.sub.4, OCOR.sub.4, CSR.sub.4, CSOR.sub.4,
CSNR.sub.4R.sub.5, NHCSR.sub.4, OCSR.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;
[0038] R.sub.8 and R.sub.9 are each independently selected from the
group consisting of hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted
heterocyclylalkyl, optionally substituted arylalkyl, optionally
substituted heteroarylalkyl; and
[0039] n is an integer from 1 to 3.
[0040] In some embodiments, the compound of Formula (I) is not
4-piperidin-1-ylnaphthalene-1-carbonitrile. In other embodiments,
the compound of Formula (I) is not
4-piperidin-1-ylnaphthalene-1-carbonitrile. In yet other
embodiments, the compound of Formula (I) is not
4-piperidin-1-ylnaphthalene-1-carbonitrile
[0041] As used herein, a "heterogroup" refers to a group of two or
more atoms, at least one of which is not carbon or hydrogen. Thus,
a carbonyl group (C.dbd.O) or thiocarbonyl group (C.dbd.S), or a
substituted nitrogen atom (NRR') in a ring are examples of
heterogroups.
[0042] The compounds of the invention can be used alone, in
combination with other compounds in the invention, or in
combination with one or more other agents active in the therapeutic
areas described herein.
[0043] Some embodiments include prodrugs, stereoisomers and
pharmaceutically acceptable salts thereof. In one embodiment ring A
is an aromatic, heteroaromatic, or aliphatic ring. In some
embodiments, ring A is benzene, cyclohexyl or pyridine. In one
embodiment ring B is a bicyclic heterocycle. In one embodiment ring
B is tropane or an optionally substituted tropane. In one
embodiment R.sub.3 is cyano or nitro. In one embodiment ring B is
optionally substituted with one or more groups selected from the
group consisting of hydrogen, halogen, hydroxy, optionally
substituted alkoxy, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted aminoalkyl, and NHCOR.sub.4. In one embodiment ring B
is optionally substituted with one or more hydroxy groups. In one
embodiment R.sub.6 or R.sub.7 is hydroxy or alkyl. Some embodiments
include a prodrug ester, carbonate, carbamate, sulfate, amide,
phosphate or phosphoramidate derivative.
[0044] In one embodiment, ring B includes only bicyclic or
tricyclic non-aromatic heterocycles as described above. In one
embodiment, ring B does not include piperazine or
1,4-diazepine.
[0045] In some embodiments, prodrugs, metabolites, stereoisomers,
and pharmaceutically acceptable salts of the compounds of Formula
(I) are provided.
[0046] 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.
[0047] The term "prodrug 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 prodrug 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 prodrug ester groups can be found in, for example, T.
Higuchi and V. Stella, in "Prodrugs 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.
[0048] Metabolites of the compounds of Formula (I) include active
species that are produced upon introduction of the compounds into
the biological milieu.
[0049] Where the compounds of Formula (I) 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) 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.
[0050] 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.
[0051] 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.
[0052] In various embodiments, the compounds of Formula (I) can be
used alone, in combination with other compounds according to
Formula (I), or in combination with one or more other agents active
in the therapeutic areas described herein.
[0053] The term "halogen atom," as used herein, means any one of
the radio-stable atoms of column 7 of the Periodic Table of the
Elements, e.g., fluorine, chlorine, bromine, or iodine, with
fluorine and chlorine being preferred.
[0054] 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), heterocyclylalkyl, arylalkyl or
heteroarylalkyl, cycloalkylalkyl, (the rings bonded through the
alkyllinker) and heteroalicyclic (bonded through a ring carbon),
and where n is 0 or 1.
[0055] 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),
heterocyclylalkyl, arylalkyl or heteroarylalkyl, cycloalkylalkyl,
(the rings bonded through the alkyllinker) 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 molecule of
the present invention, thereby forming a prodrug.
[0056] 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, 3rd Ed., John Wiley & Sons, New York, N.Y.,
1999, which is incorporated herein in its entirety.
[0057] 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.
[0058] 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.
[0059] 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
cycloalkenyl, 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-carbamyl,
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.
[0060] 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.
[0061] 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.
[0062] An "alkyne" moiety refers to a group consisting of at least
two carbon atoms and at least one carbon-carbon triple bond.
[0063] 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).
[0064] 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.
[0065] An "O-carboxy" group refers to a RC(.dbd.O)O-- group, where
R is as defined herein.
[0066] A "C-carboxy" group refers to a --C(.dbd.O)OR groups where R
is as defined herein.
[0067] An "acetyl" group refers to a --C(.dbd.O)CH.sub.3,
group.
[0068] A "trihalomethanesulfonyl" group refers to a
X.sub.3CS(.dbd.O).sub.2-- group where X is a halogen.
[0069] A "cyano" group refers to a --CN group.
[0070] An "isocyanato" group refers to a --NCO group.
[0071] A "thiocyanato" group refers to a --CNS group.
[0072] An "isothiocyanato" group refers to a --NCS group.
[0073] A "sulfinyl" group refers to a --S(.dbd.O)--R group, with R
as defined herein.
[0074] A "S-sulfonamido" group refers to a --S(.dbd.O).sub.2NR,
group, with R as defined herein.
[0075] A "N-sulfonamido" group refers to a RS(.dbd.O).sub.2NH--
group with R as defined herein.
[0076] A "trihalomethanesulfonamido" group refers to a
X.sub.3CS(.dbd.O).sub.2NR-- group with X and R as defined
herein.
[0077] An "O-carbamyl" group refers to a --OC(.dbd.O)--NR,
group-with R as defined herein.
[0078] An "N-carbamyl" group refers to a ROC(.dbd.O)NH-- group,
with R as defined herein.
[0079] An "O-thiocarbamyl" group refers to a --OC(.dbd.S)--NR,
group with R as defined herein.
[0080] An "N-thiocarbamyl" group refers to an ROC(.dbd.S)NH--
group, with R as defined herein.
[0081] A "C-amido" group refers to a --C(.dbd.O)--NR.sub.2 group
with R as defined herein.
[0082] An "N-amido" group refers to a RC(.dbd.O)NH-- group, with R
as defined herein.
[0083] The term "perhaloalkyl" refers to an alkyl group where all
of the hydrogen atoms are replaced by halogen atoms.
[0084] 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.
[0085] 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.
[0086] 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, 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.
[0087] 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 said
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.
[0088] 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.
[0089] 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.
[0090] 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, and 1,3-oxathiolane.
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.
[0091] 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.
[0092] 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, phosphorous,
and oxygen.
[0093] 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.
[0094] 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 trifluoromethyl. 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.
[0095] 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.
[0096] In certain embodiments, the compound of Formula (I) is
selected from [0097] 1-(4-Nitronaphthalen-1-yl)pyrrolidine
(116BG33), [0098] 3,5-Dimethyl-4-(4-nitronaphthalen-1-yl)piperidine
(116BG35-5), [0099]
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxylic acid diethylamide
(136BG73-4), [0100]
2,6-Dimethyl-4-(4-nitronaphthalen-1-yl)morpholine (116BG35-23),
[0101] 1-(4-Nitronaphthalen-1-yl)-4-pyrrolidin-1-yl-piperidine
(116BG35-2), [0102] 1-(4-Nitronaphthalen-1-yl)piperidine
(116BG35-6), [0103] 4-Methyl-4-(4-nitronaphthalen-1-yl)piperidine
(116BG35-7), [0104]
1-(4-Nitronaphthalen-1-yl)piperidine-4-carboxylic acid ethyl ester.
(116BG35-1), [0105] 4-(4-Nitronaphthalen-1-yl)morpholine
(116BG35-10), [0106]
2,5-Dimethyl-4-(4-nitronaphthalen-1-yl)pyrrolidine (116BG35-24),
[0107] 4-(3-Hydroxymethylpiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-1), [0108]
4-[4-(2-Hydroxyethyl)piperidin-1-yl]naphthalene-1-carbonitrile
(136BG73-9), [0109] 4-Piperidin-1-ylnaphthalene-1-carbonitrile
(136BG73-10), [0110]
4-(4-Methylpiperidin-1-yl)naphthalene-1-carbonitrile (136BG73-11),
[0111] 4-(4-Hydroxypiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-12), [0112]
4-(4-Hydroxymethylpiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-13), [0113]
1-(4-Cyanonaphthalen-1-yl)piperidine-4-carboxylic acid amide
(136BG73-17), [0114]
N-[1-(4-Cyanonaphthalen-1-yl)pyrrolidin-3-yl]-N-methylacetamide
(136BG73-18), [0115]
4-(3-Dimethylaminopyrrolidin-1-yl)naphthalene-1-carbonitrile
(136BG73-19), [0116]
4-(3-Hydroxypiperidin-1-yl)naphthalene-1-carbonitrile (136BG73-25),
[0117] 4-(2,6-Dimethylmorpholin-4-yl)naphthalene-1-carbonitrile
(136BG73-26), [0118]
4-(3-Hydroxypyrrolidin-1-yl)naphthalene-1-carbonitrile (136BG85-2),
[0119]
4-((S)-2-Hydroxymethylpyrrolidin-1-yl)naphthalene-1-carbonitrile
(136BG85-3-3), [0120] 4-Pyrrolidin-1-ylnaphthalene-1-carbonitrile
(136BG65-3), [0121] 4-Pyrrolidin-1-ylnaphthalene-1-carboxylic acid
ethyl ester (154BG19), [0122]
4-Pyrrolidin-1-ylnaphthalene-1-carboxylic acid (154BG23), [0123]
4-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(154BG31), [0124]
4-(3-Oxo-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(156AF03-217), [0125]
4-(3-Propylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile,
hydrochloride (156AF01-222 & 156AF01-223), [0126]
4-(3-Dimethylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile-
, hydrochloride (156AF05-224), [0127]
4-[3-(3-Hydroxypropylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-car-
bonitrile, hydrochloride (156AF07-225), [0128]
4-[3-(2-Ethoxyethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbo-
nitrile, hydrochloride (156AF09-226 & 156AF09-227), [0129]
4-{3-[2-(1H-Imidazol-4-yl)ethylamino]-8-azabicyclo[3.2.1]oct-8-yl}naphtha-
lene-1-carbonitrile, dihydrochloride (156AF11-229), [0130]
4-(3-Cyclopropylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitr-
ile, hydrochloride (156AF11-230), [0131]
4-[3-(2-Dimethylaminoethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene--
1-carbonitrile, dihydrochloride (156AF11-231), [0132]
4-[3-(Cyclohexylmethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-ca-
rbonitrile, hydrochloride (156AF11-232), [0133]
4-{3-[(Furan-2-ylmethyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}naphthalene-1--
carbonitrile, hydrochloride (156AF11-233), [0134]
4-[3-(2-Morpholin-4-ylethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-
-1-carbonitrile, dihydrochloride (156AF11-234), [0135]
4-{3-[(Pyridin-2-ylmethyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}naphthalene--
1-carbonitrile, dihydrochloride (156AF11-235), [0136]
4-[3-(2-Isopropoxyethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-c-
arbonitrile, hydrochloride (156AF11-237), [0137]
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)naphthalene-1-carbonitrile
(156AF14-239), [0138]
4-(3-Hydroxyimino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(156AF17-240), [0139] 3-Chloropropionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(156AF31-245), [0140] Methoxyacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(88PS39), [0141] 3-Morpholin-4-ylpropionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF32-246), [0142]
3-(4-Ethylpiperazin-1-yl)propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF35-247), [0143] 3-Diethylaminopropionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (88PS37), [0144] Chloroacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(156AF36-248), [0145] Morpholin-4-ylacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF37-249), [0146] Imidazol-1-ylacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF40-251), [0147] (4-Ethylpiperazin-1-yl)acetic
acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
ester, dihydrochloride (156AF42-252), [0148] Diethylaminoacetic
acid endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
ester, hydrochloride (156AF43-253), [0149] Succinic acid mono
endo-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]ester
(156AF48-254), [0150] Trifluoroacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(156AF54-259), [0151]
4-(3,4-Dihydroxypyrrolidin-1-yl)naphthalene-1-carbonitrile
(156AF59-258), [0152]
4-(3-exo-Ethynyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naph-
thalene-1-carbonitrile (88PS41), [0153]
4-[3-(2-[1,3]Dioxan-2-ylethyl)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl]naph-
thalene-1-carbonitrile (156AF53-260), [0154]
4-(endo-3-Methoxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(88PS44), [0155]
(1S,4S)-5-(4-Cyanonaphthalen-1-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbo-
xylic acid tert-butyl ester (165RL03), [0156]
4-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)naphthalene-1-carbonitrile
hydrochloride (165RL09), [0157]
4-[(1S,4S)-5-(Methoxyacetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]naphthalene-
-1-carbonitrile (165RL10), [0158]
4-((1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl)naphthalene-1-carbon-
itrile (165RL11), [0159]
4-[(1S,4S)-5-(2-Hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]naphthalen-
e-1-carbonitrile (165RL12), [0160]
4-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)naphthalene-1-carbon-
itrile hydrochloride (165RL15), [0161]
4-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile,
hydrochloride (165RL21), [0162]
2-Chloro-N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetam-
ide, hydrochloride (165RL23), [0163]
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-(4-ethylpipe-
razin-1-yl)acetamide, dihydrochloride (165RL27), [0164]
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-diethylamino-
acetamide, hydrochloride (165RL28), [0165] 2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
N,N-diisopropylamidophosphate (165RL22), [0166]
Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
hydrogen N,N-diisopropylamidophosphate (165RL29), [0167]
1-(3,4-Dinitronaphthalen-1-yl)pyrrolidine, hydrochloride (159JP06),
[0168] 1-(4,5,7-Trinitronaphthalen-1-yl)pyrrolidine, hydrochloride
(159JP09), [0169]
2-Bromo-4-pyrrolidin-1-ylnaphthalene-1-carbonitrile, hydrochloride
(159JP07), [0170] 4-Pyrrolidin-1-ylnaphthalene-1,3-dicarbonitrile,
hydrochloride (159JP26), [0171]
1-(4,8-Dinitronaphthalen-1-yl)pyrrolidine, hydrochloride (159JP29),
[0172] 4-Pyrrolidin-1-ylnaphthalene-1-sulfonic acid (139 MBT58-C),
[0173] [4-(Pyrrolidin-1-yl)naphthalen-1-yl]phosphonic acid diethyl
ester (139 MBT64-B), [0174]
[4-(Pyrrolidin-1-yl)naphthalen-1-yl]phosphonic acid monoethyl ester
(139 MBT64-2C), [0175]
1-(4-Methanesulfonylnaphthalen-1-yl)pyrrolidine (139 MBT70-B),
[0176] [4-(Pyrrolidin-1-yl)naphthalen-1-yl]sulfonic acid amide (139
MBT76-C), [0177]
[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]urea (139
MBT94-C), [0178] Dimethylcarbamic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(139 MBT84-1E), [0179]
4-(4-Hydroxy-4-phenylpiperidin-1-yl)naphthalene-1-carbonitrile (196
MBT2-4), [0180] 4-Azepan-1-ylnaphthalene-1-carbonitrile (196
MBT2-6), [0181]
4-(2,5-Dimethyl-2,5-dihydropyrrol-1-yl)naphthalene-1-carbonitrile
(196 MBT2-7), [0182]
4-(3,6-Dihydro-2H-pyridin-1-yl)naphthalene-1-carbonitrile (196
MBT2-9), [0183]
4-(8-Oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido[1,2-a][1,5]di-
azocin-3-yl)naphthalene-1-carbonitrile (196MBT2-10), [0184]
4-Thiomorpholin-4-ylnaphthalene-1-carbonitrile (196 MBT2-11),
[0185]
4-(4-Benzyl-4-hydroxypiperidin-1-yl)naphthalene-1-carbonitrile (196
MBT2-16), [0186]
4-(4-Oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl)naphthalene-1-carbonitr-
ile (196 MBT2-17), [0187]
4-(4-Benzoylpiperidin-1-yl)naphthalene-1-carbonitrile (196
MBT2-19), [0188]
1-(4-Cyanonaphthalen-1-yl)4-phenylpiperidine-4-carbonitrile (196
MBT2-20), [0189]
4-((S)-4a-Hydroxyoctahydroisoquinolin-2-yl)naphthalene-1-carbonitrile
(196 MBT2-24), [0190]
4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)naphthalene-1-carbonitrile
(196 MBT2-26), [0191]
4-((R)-2-Phenylaminomethylpyrrolidin-1-yl)naphthalene-1-carbonitrile
(196 MBT2-2), [0192]
4-(9-Hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]non-3-yl)naphthalene--
1-carbonitrile (196 MBT2-13), [0193]
4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1--
carbonitrile (156AF70-267), [0194]
4-(3-endo-hydroxy-3-exo-propyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1--
carbonitrile (156AF96-284), [0195]
4-(endo-Spiro[8-azabicyclo[3.2.1]octane-3,2'-oxiran]-8-yl)naphthalene-1-c-
arbonitrile (183AF16-294), [0196]
4-[3-exo-(4-ethylpiperazin-1-ylmethyl)-3-endo-hydroxy-8-azabicyclo[3.2.1]-
oct-8-yl]naphthalene-1-carbonitrile (183AF18-295), [0197]
4-(3-endo-hydroxy-3-exo-hydroxymethyl-8-azabicyclo[3.2.1]oct-8-yl)naphtha-
lene-1-carbonitrile (183AF19-296), [0198]
4-(3-exo-Cyanomethyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthale-
ne-1-carbonitrile (183AF21-297), [0199]
4-(3-endo-Hydroxy-3-exo-{[2-(1H-imidazol-4yl)ethylamino]methyl}-8-azabicy-
clo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile (183AF23-298), [0200]
4-(3-endo-Hydroxy-3-exo-methoxymethyl-8-azabicyclo[3.2.1]oct-8-yl)naphtha-
lene-1-carbonitrile (183AF24-299), [0201]
7-Bromo-4-pyrrolidin-1-ylnaphthalene-1-carbonitrile, hydrochloride
and 6-bromo-4-pyrrolidin-1-ylnaphthalene-1-carbonitrile,
hydrochloride (159JP02-X3), [0202]
4-(8-Azaspiro[4.5]dec-8-yl)naphthalene-1-carbonitrile (159JP61AA),
[0203] 4-Nitrobenzoic acid
exo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(159JP66C), [0204]
4-(3-exo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP68F6), [0205]
4-(3-exo-Methoxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP72A), [0206]
(S)-1-(4-Cyanonaphthalen-1-yl)pyrrolidine-2-carboxylic acid methyl
ester (159JP74A), [0207]
4-(8-Azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile
(159JP80XX), [0208]
4-(8-Azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(173FBA64b), [0209] Acrylic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(159JP79), [0210] 3-Pyrrolidin-1-yl-propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
fumarate (159JP82F6), [0211] 3-Imidazol-1-yl-propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
fumarate (159JP83A), [0212] 3-Pyrazol-1-yl-propionic acid
endo-8-(4-cyano-naphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
fumarate (159JP85A), [0213]
4-(2-Methyl-3-oxo-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP84), [0214]
4-(2-Methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP87A), [0215]
4-(3-exo-Benzyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1--
carbonitrile (159JP92A), [0216]
8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylic
acid methyl ester (159JP95C), [0217]
8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]octane-2-carboxylic
acid methyl ester (159JP97A), [0218]
4-(2-Hydroxymethyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carboni-
trile (159JP98C), [0219]
(1R,2R,3S,5S)-3-Benzoyloxy-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]-
octane-2-carboxylic acid methyl ester (195JP02A), [0220]
(1R,2R,3S,5S)-4-(3-Hydroxy-2-hydroxymethyl-8-azabicyclo[3.2.1]oct-8-yl)na-
phthalene-1-carbonitrile (195JP05BX), [0221] 2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
N,N-diisopropylamidophosphite (165RL31), [0222] 2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
diisopropylamidophosphate (165RL37), [0223] 2-Cyanoethyl ethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
phosphate (165RL38), [0224] Ethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
hydrogen phosphate (165RL41), [0225] Bis(2-cyanoethyl)
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
phosphate (165RL42), [0226]
Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
dihydrogen phosphate (165RL43), [0227] 2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phenyl
phosphate (165RL44), [0228]
Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phenyl
hydrogen phosphate (165RL45), [0229]
N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide
(165RL51), [0230]
3-Chloro-N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]propan-
amide (165RL50), [0231]
N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-(4-ethylpipe-
razin-1-yl)propanamide, dihydrochloride (165RL52), [0232]
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-diethylamino-
propionamide, hydrochloride (165RL53), [0233]
N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-(1H-imidazol-
-1-yl)propanamide hydrochloride (165RL55), [0234]
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-(ethoxyethox-
y)acetamide (165RL57), [0235]
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxylic acid ethyl ester
(165RL60), [0236]
4-(2-Methylpiperidin-1-yl)naphthalene-1-carbonitrile (165RL62),
[0237] 1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxylic
acid (165RL63), [0238]
[1-(4-Cyanonaphthalen-1-yl)piperidin-3-ylmethyl]carbamic acid
tert-butyl ester (165RL65), [0239]
4-(3-Aminomethylpiperidin-1-yl)naphthalene-1-carbonitrile
(165RL66), [0240]
N-[1-(4-Cyanonaphthalen-1-yl)piperidin-3-ylmethyl]acetamide
(165RL70), [0241]
4-(3-Ethylaminomethylpiperidin-1-yl)naphthalene-1-carbonitrile
hydrochloride (165RL72sec), [0242]
4-(3-Diethylaminomethylpiperidin-1-yl)naphthalene-1-carbonitrile
hydrochloride (165RL72tert), [0243]
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carbonitrile (165RL73-3),
[0244] 1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxamide
(165RL73-5), [0245]
4-(3-Fluoropiperidin-1-yl)naphthalene-1-carbonitrile (165RL74),
[0246] trans-4-(4-Hydroxycyclohexylamino)naphthalene-1-carbonitrile
(165RL96),
[0247] Methanesulfonic acid
trans-4-(4-cyanonaphthalen-1-ylamino)cyclohexyl ester (165RL97),
[0248] 4-(7-Azabicyclo[2.2.1]hept-7-yl)naphthalene-1-carbonitrile
hydrochloride (198RL01), [0249]
N'-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methylbenze-
nesulfonylhydrazone (173FBA60a), [0250]
4-[2-(Hydroxymethyl)piperidin-1-yl]naphthalene-1-carbonitrile (173
FBA70e), [0251]
3-exo-[8-(4-Cyanonaphthalen-1-yl)-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-3-
-yl]-N,N-dimethylpropanamide (173FBA51bH), [0252]
2-exo-[8-(4-Cyanonaphthalen-1-yl)-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-3-
-yl]-N,N-dimethylethanesulfonamide (173FBA56b3), [0253]
4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1--
carbonitrile, hydrochloride (197FBA23a), [0254]
4-(3-Methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile
(197FBA24c), [0255] 4-Pyrrolidin-1-yl-phthalazine-1-carbonitrile,
hydrochloride (141JP56P2A), [0256]
7-Pyrrolidin-1-yl-benzo[1,2,5]thiadiazole-4-carbonitrile,
hydrochloride (141JP57P1), [0257]
1-Pyrrolidin-1-yl-isoquinoline-4-carbonitrile, hydrochloride
(141JP71F), [0258] 8-Pyrrolidin-1-yl-quinoxaline-5-carbonitrile,
hydrochloride (141JP76PY), [0259]
5-Pyrrolidin-1-yl-isoquinoline-8-carbonitrile, hydrochloride
(141JP79P1), [0260] 8-Pyrrolidin-1-yl-isoquinoline-5-carbonitrile,
hydrochloride (141JP79P2A), [0261]
5-Nitro-8-pyrrolidin-1-yl-quinoline, hydrochloride (144AF60-214B),
[0262] 1-(4-Nitro-5,6,7,8-tetrahydronaphthalen-1-yl)pyrrolidine
(173FBA22a), [0263] 8-Nitro-5-pyrrolidin-1-yl-isoquinoline
(173FBA26b), [0264]
8-Nitro-5-pyrrolidin-1-yl-1,2,3,4-tetrahydroisoquinoline
(173FBA29b3), [0265]
5-Nitro-8-pyrrolidin-1-yl-1,2,3,4-tetrahydroquinoline (173FBA33b),
[0266]
1-(8-Nitro-5-pyrrolidin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone
(173FBA35b), [0267] 5-Pyrrolidin-1-yl-quinoline-8-carbonitrile
(88PS18), [0268] 3-piperazin-1-ylpropionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
dihydrochloride. (88PS64), [0269]
3-[Bis(2-hydroxyethyl)amino]propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
fumarate (88PS65), [0270]
3-(3-Dimethylaminopyrrolidin-1-yl)propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
difumarate (88PS67), [0271] 3-(4-Methylpiperazin-1-yl)propionic
acid endo-8-(4-cyanonaphthalen-1-yl)-8-aza-bicyclo[3.2.1]oct-3-yl
ester, difumarate (88PS69), and [0272]
4-(3-Diethylaminomethyl-3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-
-1-carbonitrile, hydrochloride, (183AF03-288). Methods of
Preparation
[0273] The compounds of Formula (I) can 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 of Formula (I), it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This can 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 can 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.
[0274] In one embodiment, the compounds disclosed herein can be
prepared starting from halo-substituted aromatic rings such as C
(Scheme1) by base catalyzed aromatic nucleophilic substitution of a
halogen with the appropriate amine D to get compounds of the
general Formula (I). The process can be carried out in a suitable
solvent, e.g. an aprotic solvent such as toluene, acetonitrile,
benzene, dioxane, THF, DMSO or DMF with a suitable base such as
pyridine, DBU or potassium carbonate and using an excess of the
secondary amine (which also can act as the base). The reaction can
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. ##STR3## R.sub.1,
R.sub.2, R.sub.3, R.sub.6, R.sub.7 in Scheme 1 are defined as in
Formula (I), above, or are suitable precursors thereof, and X
represents a halide.
[0275] In another embodiment, the compounds of Formula (I)
disclosed herein 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
bicyclic (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 can 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.
[0276] In yet another embodiment, the compounds of Formula (I)
disclosed herein can be prepared from the appropriately substituted
aniline-based derivatives using an appropriate bifunctional
alkyl-linker as shown in Scheme 2. The leaving groups L.sub.1 and
L.sub.2 are 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
120.degree. C. ##STR4## R.sub.1, R.sub.2, R.sub.3, R.sub.6, R.sub.7
in Scheme 2 are, defined in are defined as in Formula (I), above,
or are suitable precursors thereof, and L.sub.1 and L.sub.2
represent a suitable leaving group.
[0277] The appropriate starting materials are commercially
available or can be prepared according to methodology disclosed in
the literature. Substituents R.sub.1, R.sub.2 and R.sub.3 and any
R.sub.6 and R.sub.7 can each be individually introduced at any
appropriate stage of the preparation of the compounds, following
procedures known in the literature (e.g. W. Adcock et al., J. Am.
Chem. Soc., 1967, 89, 386-390; G. Schiemann et al., Ann., 1931,
487, 270-287; Dewar et al., J. Am. Chem. Soc., 1962, 84, 3541-3546;
S. Sekiguchi et al., J. Org. Chem., 1979, 44, 3921-3925, all of
which are incorporated by reference herein in their entirety).
[0278] Compounds of the invention in which R.sub.3 is nitro can be
prepared by classical nitration methods described in the
literature, using HNO.sub.3/H.sub.2SO.sub.4 or other methods known
to those skilled in the art.
[0279] Compounds of the invention in which R.sub.1, R.sub.2 or
R.sub.3 are halogen, can 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 diazotization according to the
Sandmeyer methodology using sodium nitrite in acetic acid or
trifluoroacetic acid, and then reacted with an acid, 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).
[0280] Compounds of the invention in which R.sub.1, R.sub.2 or
R.sub.3 are cyano, CONR.sub.4R.sub.5, COOR.sub.4 can 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 references are incorporated herein by
reference in its entirety. The nitriles can 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 can be
further derivatized to amides by classical acylation reactions or
coupling agents methodology described in the art.
[0281] Compounds of the invention in which R.sub.1, R.sub.2 or
R.sub.3 are S(O)R.sub.8, S(O).sub.2R.sub.8, S(O)(OR.sub.8),
S(O).sub.2(OR.sub.8), or SO.sub.2NR.sub.8R.sub.9 can be prepared
using the following methods: Sulfonates can 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. Sulfonic acid esters and sulfonamides are conveniently
prepared from sulfonyl chlorides by reaction alcohols and amines.
Sulfones can be prepared by Friedel-Crafts type reaction of
aromatic compounds with sulfonyl halides, by reaction of alkyl
halides or sulfonates with aryl sulfinic acid salts, by addition of
Grignard reagents to sulfonyl chlorides or by oxidation of aryl
sulfides. Sulfoxides may be prepared by oxidation of aryl
sulfides.
[0282] Compounds of the invention in which R.sub.3 are
P(O)(OR.sub.4)(OR.sub.5), P(O)(OH)(NR.sub.4R.sub.5),
PO(NR.sub.4R.sub.5).sub.2 can be prepared using the following
methods: Phosphonates can be prepared by addition of
dialkylchlorophosphates to aryl metal complexes, e.g. aryl lithium
or aryl Grignard reagents, followed by hydrolysis of one or both of
the ester groups. Alternatively, phosphonates can be prepared by
addition of PCl.sub.3 to a diazonium salt in the presence of
cuprous chloride, followed by hydrolysis. In a similar fashion,
using the appropriate halide derivatives, phosphonoamidates
or--diamidates can be prepared.
[0283] Compounds of the invention in which R.sub.1, R.sub.2 or
R.sub.3 are alkoxy, OCOR.sub.4 can be typically prepared by
Williamson ether synthesis from the corresponding hydroxyaryl
derivatives for the alkoxy derivatives or by acylation using
methods described below.
[0284] Compounds of the invention in which R.sub.1, R.sub.2 or
R.sub.3 are COR.sub.4 can 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 can 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 (GooBen 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 its
entirety).
[0285] Compounds of the invention in which R.sub.1, R.sub.2 or
R.sub.3 are amino, lower aminoalkyl, NHCOR.sub.4, NHSO.sub.2R.sub.4
can be obtained from an aniline-based precursor, which is
commercially available or can 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
amination (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 its 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 its
entirety). Additionally, compounds of this type can 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. 1, 2000, 17, 2901-2902; Nigam & Weedon, J.
Chem. Soc., 1957, 2000, all of which are hereby incorporated herein
by reference in its 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 its entirety)
or sulfonylation. Alternatively, compounds bearing amide
substituents can 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 (Buchwald et al, J.
Am. Chem. Soc., 2002, 124, 7421-7428, which is hereby incorporated
herein by reference in its entirety) amidation chemistries.
[0286] Compounds of the invention in which R.sub.1 or R.sub.2 is SR
can 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 can be
prepared by alkylation of corresponding aryl-thiol 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 its entirety).
Alternatively, alkylarylsulfanyls can 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).
[0287] 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).
[0288] In general, an amine or alcohol functionality can be further
derivatized and 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. 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 can 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. ##STR5## wherein R and Aryl
are defined in agreement with Formula (I), Z, is OH, NH.sub.2, NHR*
or SH, Z.sub.2 is O, NH, NR* or S, Z.sub.3 is O or S, and X
represents a halide and R* is an alkyl or substituted alkyl.
[0289] Alternatively, an amine or alcohol functionality can 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.
[0290] Furthermore, ketones, exemplified in Scheme 4 by tropanone
derivative G, can be modified by reductive amination using any
primary or secondary amine HNRR*, Alternatively the same
methodology can 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.3pyridine,
H.sub.2/Pd--C or any related reagent can be used, including
solid-supported reagents. The reaction is typically carried out at
room temperature, but less reactive carbonyl compounds can require
higher temperatures and/or the pre-formation of the corresponding
imine under water removal before addition of the reducing agent.
##STR6## wherein R.sub.4, R.sub.5 and Aryl are defined in agreement
with Formula (I)
[0291] Furthermore, ketones, exemplified in Scheme 5 by tropanone
derivative G, can 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), 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 can improve the reaction yields.
[0292] Alternatively, ketones exemplified by tropanone G (Scheme 5)
can 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 can
then be converted into the corresponding epoxide by treatment with
oxidation reagents such as hydroperoxide or MCPBA. Epoxides such as
derivative L can 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-M6, where R.sub.4, R.sub.5,
R.sub.6, and Aryl are defined in agreement with Formula (I).
Certain reactions can be facilitated by the addition of a Lewis
acid catalyst such as ytterbium triflate or boron trifluoride
etherate. Furthermore, the epoxide can 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 can be used, including solid-supported
reagents. The reactions can typically be carried out at
temperatures of 0-100.degree. C. in solvents such as THF,
diethylether, or diglyme. ##STR7##
[0293] Furthermore, the introduction of substituents on ring A or
on the phenyl moiety can occur at any stage of the synthetic
pathway, and thus ring A can 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). The
amine function may require transient protecting groups (PG) such as
Boc, CBz, benzyl, p-methoxybenzyl. ##STR8##
[0294] Where the processes for the preparation of the compounds
according to the invention give rise to mixtures of stereoisomers,
such isomers can be separated by conventional techniques such as
preparative chiral chromatography. The compounds can be prepared in
racemic form or individual enantiomers can be prepared by
stereoselective synthesis or by resolution. The compounds can 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-l-tartaric acid, followed by
fractional crystallization and regeneration of the free base. The
compounds can 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
[0295] In some embodiments, compounds of Formula (I), as disclosed
and described herein, are capable of modulating the activity of an
androgen receptor.
[0296] 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. In some
embodiments, 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.
[0297] 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.
[0298] 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.
[0299] In some embodiments, a compound of Formula (I) may be an
agonist of an androgen receptor, while in other embodiments, the
compound may be an antagonist of an androgen receptor. In yet other
embodiments, 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 yet other circumstances, the
compound may be a tissue-specific modulator, while in other
circumstances, the compound may be a gene-specific modulator.
[0300] In one embodiment, an androgen receptor is activated by
contacting it with a compound of Formula (I). 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
certain embodiments, 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 some embodiments, the patient
is a human.
[0301] Another aspect of the present invention is directed to a
method of activating an androgen receptor comprising contacting the
receptor with a compound of Formula (I).
[0302] Another aspect of the present invention is directed to a
method of treating hypogonadism comprising identifying a patient
inflicted with hypogonadism and administering to the patient a
compound of Formula (I).
[0303] Another aspect of the present invention is directed to a
method of treating a patient with lower than normal testosterone
plasma levels comprising identifying a patient having less than
normal testosterone plasma and administering to the patient a
compound of Formula (I).
[0304] Another aspect of the present invention is directed to a
method of treating infertility in males comprising identifying a
male patient inflicted with infertility and administering to the
patient a compound of Formula (I).
[0305] Another aspect of the present invention is directed to a
method of modulating spermatogenesis in males by administering to a
male patient a compound of Formula (I).
[0306] Another aspect of the present invention is directed to a
method of treating erectile dysfunction in males comprising
identifying a male patient inflicted with erectile dysfunction and
administering to the patient a compound of Formula (I).
[0307] Another aspect of the present invention is directed to a
method of treating andropause in males comprising identifying a
male patient in a state of andropause and administering to the
patient a compound of Formula (I).
[0308] Another aspect of the present invention is directed to a
method of treating endometriosis in females comprising identifying
a female patient inflicted with endometriosis and administering to
the patient a compound of Formula (I).
[0309] Another aspect of the present invention is directed to a
method of treating dyspareunia in females comprising identifying a
female patient suffering from dyspareunia and administering to the
patient a compound of Formula (I).
[0310] Another aspect of the present invention is directed to a
method of treating vaginismus in females comprising identifying a
female patient suffering from vaginismus and administering to the
patient a compound of Formula (I).
[0311] Another aspect of the present invention is directed to a
method of treating sexual arousal disorders in females comprising
identifying a female patient inflicted with sexual arousal disorder
and administering to the patient a compound of Formula (I).
[0312] Another aspect of the present invention is directed to a
method of treating sexual orgasmic disorders in females comprising
identifying a female patient inflicted with sexual orgasmic
disorder and administering to the patient a compound of Formula
(I).
[0313] Another aspect of the present invention is directed to a
method of treating disorders of libido in males comprising
identifying a male patient inflicted with a disorder of libido and
administering to the patient a compound of Formula (I).
[0314] Another aspect of the present invention is directed to a
method of hormonal replacement therapy comprising identifying a
patient in need of hormonal replacement therapy and administering
to the patient a compound of Formula (I). In one embodiment, the
need for hormonal replacement therapy is caused by orchiectomy by
surgical or chemical means.
[0315] Another aspect of the present invention is directed to a
method of treating cachexia, HIV wasting, and critical illnesses in
which muscle wasting is apparent comprising identifying a patient
inflicted with muscle wasting and administering to the patient a
compound of Formula (I).
[0316] Another aspect of the present invention is directed to a
method of improving muscle strength in conditions including
muscular dystrophy, myotonic dystrophy, glucocorticoid-treated
asthma comprising identifying a patient in need of muscle strength
improvement and administering to the patient a compound of Formula
(I).
[0317] Another aspect of the present invention is directed to a
method of treating a condition selected from the group consisting
of sarcopenia; frailty; short stature; dwarfism; bone density loss;
mood disorders including lack of well being, lack of vigor, anger,
irritability, sadness, tiredness, and 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, comprising
identifying a patient inflicted with at least one of these
conditions and administering to the patient a compound of Formula
(I).
[0318] Another aspect of the present invention is directed to a
method of preventing a condition selected from the group consisting
of 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, comprising identifying a patient susceptible to at least
one of these conditions and administering to the patient a compound
of Formula (I).
[0319] Another aspect of the present invention is directed to a
method of improving a health-related quality of life parameters
selected from the group consisting of survival, impairment,
functional status, health perception, and opportunities, comprising
identifying a patient desiring an improvement in at least one of
said parameters and administering to the patient a compound of
Formula (I).
[0320] Still another aspect of the present invention is directed to
a method of delaying the progression of prostate cancer comprising
identifying a patient inflicted with prostate cancer and
administering to the patient a compound of Formula (I).
[0321] In some embodiments, a compound of Formula (I) is
particularly 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 these conditions. In
various embodiments, the condition treated in the male includes
infertility, erectile dysfunction, andropause, and disorders of
libido. In some embodiments, a compound of Formula (I) may be
administered to a male patient in order to modulate spermatogenesis
in the male patient.
[0322] In other embodiments, a compound of Formula (I) is
particularly 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 these conditions. In
various embodiments, the condition treated in the female includes
endometriosis, dyspareunia, vaginismus, sexual arousal disorder,
and sexual orgasmic disorder.
[0323] In one embodiment, a compound of Formula (I) may be
administered to a patient in order to effect hormone
replacement.
[0324] In one embodiment, a compound of Formula (I) may be
administered to a patient in order to improve muscle strength. For
example, the compound may be administered to a patient in need of
improvement in muscle strength due to muscular dystrophy, mytonic
dystrophy, or glucocorticoid-treated asthma.
[0325] In one embodiment, a compound of Formula (I) 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.
[0326] In one embodiment, a compound of Formula (I) may be
administered to a male patient suffering from prostate cancer in
order to delay the progression of the prostate cancer.
Pharmaceutical Compositions
[0327] In another aspect, the present disclosure 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. In various embodiments, 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.
[0328] 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.
[0329] 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.
[0330] 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.
[0331] The term "physiologically acceptable" defines a carrier or
diluent that does not abrogate the biological activity and
properties of the compound.
[0332] 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.
[0333] 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.
[0334] 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.
[0335] 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.
[0336] 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.
[0337] 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.
[0338] For transmucosal administration, penetrants appropriate to
the barrier to be permeated may be used in the formulation.
[0339] 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.
[0340] 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.
[0341] 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.
[0342] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0343] 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.
[0344] 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.,
Opthalmologica, 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 intraauricular delivery include
suspensions and ointments for topical application in the ear.
Common solvents for such aural formulations include glycerin and
water.
[0345] 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.
[0346] 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.
[0347] 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.
[0348] 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.
[0349] 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.
[0350] 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
[0351] The compounds or pharmaceutical compositions 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.
[0352] 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.
[0353] 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.
[0354] 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.
[0355] 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.
[0356] 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.
[0357] 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.
[0358] 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.
[0359] 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%.
[0360] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0361] 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.
[0362] 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.
[0363] 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
Chemical Synthesis
[0364] General procedures. .sup.1H NMR spectra were recorded at 400
MHz on a Varian Mercury-VX400 MHz spectrometer or 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.
Coupling constants, J, are reported in Hertz. Unless otherwise
stated, the NMR spectra of the compounds are described for their
free amine form. Acidic ion-exchange solid phase extraction (SPE)
cartridges were MEGA BE-SCX from Varian. Materials and solvents
were of the highest grade available from commercial sources and
were used without further purification.
HPLC/LCMS Methods.
Analytical LCMS Method I
[0365] 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.
Analytical LCMS Method II
[0366] 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.
Analytical LC/MS Method III
[0367] 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.
[0368] 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.
Preparative HPLC Purification Procedure.
[0369] Preparative purification was performed on a Waters auto
purification system (600 pumps, 2700 sample manager, 996 PDA
detector, ZMD mass spectrometer). The columns used were YMC C18
J'sphere ODS H80. Buffer A was 0.15% TFA in water, buffer B was
0.15% TFA in acetonitrile/water 95/5. The columns were operated at
17 mL/min. Following an initial hold of 2.5 min at 30% buffer B,
compounds were separated using a gradient of 30-100% buffer B in
8.5 min.
[0370] Preparation of Hydrochloride Salts. Typically, the Compounds
were dissolved in dichloromethane, treated with an excess of 1 M
HCl in diethylether and precipitated from n-heptane. The solvents
were removed in vacuo and after drying, the hydrochloride salts
were obtained as solids.
Method A
3,5-Dimethyl-4-(4-nitronaphthalen-1-yl)piperidine (116BG35-5)
[0371] A Pyrex tube was charged with 1-chloro-4-nitronaphthalene
(52 mg, 0.25 mmol) and 3,5-dimethylpiperidine (133 .mu.L, 1.0 mmol)
followed by acetonitrile (2 mL). The tube was capped and the
reaction tube was exposed to microwave irradiation (180.degree. C.,
5 min). The reaction mixture was filtered and the solid washed with
cold ethanol. If needed the compound was purified according to
Purification method C. Yield: 58 mg (82%).
[0372] Major isomer: LCMS m/z 285 [M+H].sup.+. HPLC t.sub.R=16.9
min (method III). .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta.
8.58-8.55 (m, 1H), 8.16 (d, J=8.4, 1H), 8.07 (m, 1H), 7.59-7.54 (m,
1H), 7.49-7.44 (m, 1H), 6.89 (d, J=8.4, 1H), 3.35-3.31 (m, 2H),
2.24 (t, J=11.6, 2H), 2.0-1.85 (m, 2H), 1.85-1.79 (m, 1H), 0.85 (d,
J=6.6, 6H), 0.68 (q, J=11.6, 1H).
[0373] Minor isomer: LCMS m/z 285 [M+H].sup.+. HPLC t.sub.R=16.8
min (method III). .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta.
8.58-8.55 (m, 1H), 8.19-8.18 (m, 1H), 8.07 (m, 1H), 7.59-7.54 (m,
1H), 7.49-7.44 (m, 1H), 6.90 (d, J=8.4, 1H), 3.10-3.03 (m, 2H),
2.75-2.63 (m, 2H), 2.18 (m, 2H), 1.43 (t, J=5.7, 2H), 1.03 (d,
J=6.6, 1H).
Method B
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxylic acid diethylamide
(136BG73-4)
[0374] A solution of 1-cyano-4-fluoronaphthalene in pyridine (0.6
M, 1 mL) was transferred to a Pyrex tube and
N,N-diethylnipecotamide (447 mg, 2.4 mmol) was added. The tube was
capped and the reaction tube was exposed to microwave irradiation
(220.degree. C., 10 min). The reaction mixture was concentrated and
purified according to Purification Method A.
[0375] LCMS m/z 336 [M+H].sup.+. HPLC t.sub.R=9.0 min (method I).
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 8.15 (d, J=8.2, 1H), 8.00
(d, J=8.2, 1H), 7.77 (d, J=7.8, 1H), 7.60-7.52 (m, 2H), 7.05 (d,
J=7.8, 1H), 3.60-3.36 (m, 4H), 3.36-3.21 (m, 1H), 3.21-3.10 (m,
1H), 3.03-2.92 (m, 1H), 2.78-2.65 (m, 1H), 2.08-1.83 (m, 4H),
1.78-1.60 (m, 1H), 1.30-1.16 (m, 3H), 1.07 (t, J=7.04, 3H).
.sup.13C-NMR (CD.sub.3OD, 100 MHz) 173.9, 155.1, 133.7, 133.6,
128.4, 128.1, 126.6, 125.1, 124.5, 118.1, 114.1, 103.6, 56.1, 53.7,
42.3, 40.4, 39.9, 27.8, 25.0, 14.2, 12.2.
Purification Method A
[0376] The concentrated crude material was taken up in ethyl
acetate and extracted with 2 M HCl. The organic phase was then
dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo.
Purification Method B
[0377] The concentrated crude material was taken up in ethyl
acetate and extracted with 2 M HCl. The organic phase was then
dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo and
purified by preparative HPLC. (40% A; 80% B, NH.sub.4OAc)
Purification Method C
[0378] The concentrated crude material was purified by preparative
HPLC.
2,6-Dimethyl-4-(4-nitronaphthalen-1-yl)morpholine (116BG35-23)
[0379] Prepared according to Method A. Major isomer: LCMS m/z 287
[M+H].sup.+. HPLC t.sub.R=11.1 min (method I). Minor isomer: LCMS
m/z 287 [M+H].sup.+. HPLC t.sub.R=10.7 min (method I).
1-(4-Nitronaphthalen-1-yl)-4-pyrrolidin-1-yl-piperidine
(116BG35-2)
[0380] Prepared according to Method A. LCMS m/z 326 [M+H].sup.+.
HPLC t.sub.R=1.7 min (method III). Yield: 51%.
1-(4-Nitronaphthalen-1-yl)piperidine (116BG35-6)
[0381] Prepared according to Method A. LCMS m/z 257 [M+H].sup.+.
HPLC t.sub.R=13.5 min (method III). Yield: 79%.
4-Methyl-4-(4-nitronaphthalen-1-yl)piperidine (116BG35-7)
[0382] Prepared according to Method A. LCMS m/z 271 [M+H].sup.+.
HPLC t.sub.R=14.8 min (method I). Yield: 66%.
1-(4-Nitronaphthalen-1-yl)piperidine-4-carboxylic acid ethyl ester.
(116BG35-1)
[0383] Prepared according to Method A. Purified according to
Purification Method C. LCMS, m/z 329 [M+H].sup.+. HPLC t.sub.R=12.1
min (method III). Yield: 16%.
4-(4-Nitronaphthalen-1-yl)morpholine (116BG35-10)
[0384] Prepared according to Method A. Purified according to
Purification method C. LCMS m/z 259 [M+H].sup.+. HPLC t.sub.R=8.0
min (method III). Yield: 8%.
2,5-Dimethyl-4-(4-nitronaphthalen-1-yl)pyrrolidine (116BG35-24)
[0385] Prepared according to Method A. Purified according to
Purification method C. LCMS m/z 271 [M+H].sup.+. HPLC t.sub.R=10.4
min (method III). Yield: 7%.
4-(3-Hydroxymethylpiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-1)
[0386] Prepared according to Method B. Purified according to
Purification method A. LCMS m/z 267 [M+H].sup.+. HPLC t.sub.R=7.9
min (method I).
4-[4-(2-Hydroxyethyl)piperidin-1-yl]naphthalene-1-carbonitrile
(136BG73-9)
[0387] Prepared according to Method B. Purified according to
Purification method A. LCMS m/z 281 [M+H].sup.+. HPLC t.sub.R=8.3
min (method III).
4-Piperidin-1-ylnaphthalene-1-carbonitrile (136BG73-10)
[0388] Prepared according to Method B. Purified according to
Purification method B. LCMS m/z 237 [M+H].sup.+. HPLC t.sub.R=10.5
min (method I).
4-(4-Methylpiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-11)
[0389] Prepared according to Method B. Purified according to
Purification method C. LCMS m/z 251 [M+H].sup.+. HPLC t.sub.R=15.9
min (method III).
4-(4-Hydroxypiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-12)
[0390] Prepared according to Method B. Purified according to
Purification method C. LCMS m/z 253 [M+H].sup.+. HPLC t.sub.R=9.3
min (method III).
4-(4-Hydroxymethylpiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-13)
[0391] Prepared according to Method B. Purified according to
Purification method B. LCMS m/z 267 [M+H].sup.+. HPLC t.sub.R=7.6
min (method I).
1-(4-Cyanonaphthalen-1-yl)piperidine-4-carboxylic acid amide
(136BG73-17)
[0392] Prepared according to Method B. Purified according to
Purification method C. LCMS m/z 280 [M+H].sup.+. HPLC t.sub.R=8.4
min (method III).
N-[1-(4-Cyanonaphthalen-1-yl)pyrrolidin-3-yl]-N-methylacetamide
(136BG73-18)
[0393] Prepared according to Method B. Purified according to
Purification method C. LCMS m/z 294 [M+H].sup.+. HPLC t.sub.R=9.5
min (method III).
4-(3-Dimethylaminopyrrolidin-1-yl)naphthalene-1-carbonitrile
(136BG73-19)
[0394] Prepared according to Method B. Purified according to
Purification method C. LCMS m/z 266 [M+H].sup.+. HPLC t.sub.R=3.8
min (method I). .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 8.26-8.22
(m, 1H), 8.02-7.99 (m, 1H), 7.70 (d, J=8.4, 1H), 7.61-7.56 (m, 1H),
7.49-7.45 (m, 1H), 6.75 (d, J=8.2, 1H), 3.72-3.65 (m, 1H),
3.58-3.47 (m, 3H), 2.93-2.82 (m, 1H), 2.33 (s, 6H), 2.28-2.20 (m,
1H), 1.94-1.83 (m, 1H). .sup.13C-NMR (CD.sub.3OD, 100 MHz) .delta.
151.7, 134.6, 133.7, 128.0, 125.9, 125.5, 124.8, 124.8, 119.1,
108.4, 98.4, 65.4, 56.6, 51.6, 43.2, 29.8.
4-(3-Hydroxypiperidin-1-yl)naphthalene-1-carbonitrile
(136BG73-25)
[0395] Prepared according to Method B. Purified according to
Purification method C. LCMS m/z 253 [M+H].sup.+. HPLC t.sub.R=7.2
min (method I).
4-(2,6-Dimethylmorpholin-4-yl)naphthalene-1-carbonitrile
(136BG73-26)
[0396] Prepared according to Method B. Purified according to
Purification method C. LCMS m/z 267 [M+H].sup.+. HPLC t.sub.R=9.3
min (method III).
4-(3-Hydroxypyrrolidin-1-yl)naphthalene-1-carbonitrile
(136BG85-2)
[0397] 1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was
transferred to a Pyrex tube and 3-pyrrolidinol (162 .mu.L, 2.0
mmol) was added followed by toluene (0.5 mL). The tube was capped
and the reaction tube was exposed to microwave irradiation
(180.degree. C., 5 min). The reaction mixture was concentrated and
purified by re-crystallization with EtOH. Yield: 51 mg (43%).
[0398] LCMS m/z 239 [M+H].sup.+. HPLC t.sub.R=6.0 min (method I).
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 8.36-8.33 (m, 1H),
7.97-7.95 (m, 1H), 7.83 (d, J=8.4, 1H), 7.70-7.65 (m, 1H),
7.53-7.48 (m, 1H), 6.74 (d, J=8.4, 1H), 5.05 (d, J=3.2, 1H), 4.10
(s, 1H), 3.93-3.89 (m, 1H), 3.85-3.78 (m, 1H), 3.55-3.49 (m, 1H),
2.10-2.02 (m, 1H), 2.02-1.90 (m, 1H). .sup.13C-NMR (CD.sub.3OD, 100
MHz) .delta. 152.4, 135.1, 135.0, 129.3, 127.3, 125.4, 125.4,
125.1, 120.4, 108.3, 96.5, 70.1, 62.0, 51.0, 34.5.
4-((S)-2-Hydroxymethylpyrrolidin-1-yl)naphthalene-1-carbonitrile
(136BG85-3-3)
[0399] 1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was
transferred to a Pyrex tube and L-prolinol (197 .mu.L, 2.0 mmol)
was added followed by toluene (0.5 mL). The tube was capped and the
reaction tube was exposed to microwave irradiation (180.degree. C.,
5 min). The reaction mixture was concentrated and purified by flash
chromatography on silica gel (eluent: 0-3% methanol in
dichloromethane). Yield: 23 mg (18%).
[0400] LCMS m/z 253 [M+H].sup.+. HPLC t.sub.R=7.3 min (method I).
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 8.30 (d, J=8.6, 1H),
8.08-8.05 (m, 1H), 7.80 (d, J=8.2, 1H), 7.67-7.63 (m, 1H),
7.56-7.51 (m, 1H), 7.07 (d, J=8.2, 1H), 4.21-4.15 (m, 1H),
4.10-4.00 (m, 1H), 3.68-3.64 (m, 1H), 3.55-3.50 (m, 1H), 3.36-3.30
(m, 1H), 2.40-2.29 (m, 1H), 2.10-1.98 (m, 2H), 1.90-1.71 (m, 1H).
.sup.13C-NMR (CD.sub.3OD, 100 MHz) .delta. 153.5, 135.7, 134.6,
129.3, 128.6, 127.4, 126.1, 125.9, 120.1, 111.5, 100.4, 63.8, 62.4,
57.6, 30.2, 26.1.
4-Pyrrolidin-1-ylnaphthalene-1-carbonitrile (136BG65-3)
[0401] 1-Cyano-4-fluoronaphthalene (2.0 g, 11.7 mmol) was
transferred to a 25 mL flask and pyrrolidine (4.0 mL) was added.
The reaction mixture was stirred for 15 min where after the product
precipitated out. The reaction mixture was concentrated in vacuo.
The solid was then re-crystallized with MeOH and the crystals
washed with EtOH. Yield: 1.6 g (62%).
[0402] LCMS m/z 223 [M+H].sup.+. HPLC t.sub.R=9.7 min (method I).
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 8.38-8.35 (m, 1H),
8.05-8.02 (m, 1H), 7.75 (d, J=8.2, 1H), 7.64-7.60 (m, 1H),
7.51-7.45 (m, 1H), 6.80 (d, J=8.2, 1H), 3.65-3.61 (m, 4H),
2.07-2.03 (m, 4H). .sup.13C-NMR (CD.sub.3OD, 100 MHz) .delta.
152.6, 135.2, 134.1, 128.2, 126.6, 125.8, 125.0, 124.6, 119.6,
108.0, 97.4, 53.0, 25.9.
4-Pyrrolidin-1-ylnaphthalene-1-carboxylic acid ethyl ester
(154BG19)
[0403] 4-Fluoro-1-naphthoic acid (190 mg, 1.0 mmol) was transferred
to a Pyrex tube and ethanol (0.6 mL) was added followed by conc.
sulphuric acid (0.1 mL). The tube was capped and the reaction tube
was exposed two times to microwave irradiation (2.times.120.degree.
C., 5 min). The reaction mixture was transferred to a separation
funnel with ethyl acetate and washed with 2 M NaOH. The aqueous
phase was acidified with 2 M HCl and extracted with ethyl acetate.
The organic phases were collected, dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield 4-fluoronaphthalene-1-carboxylic
acid ethyl ester (154BG85-11, 156 mg, 72%).
[0404] .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 8.89-8.85 (m, 1H),
8.06 (dd, J=5.7, 8.2, 1H), 7.59-7.54 (m, 1H), 7.53-7.48 (m, 1H),
7.09 (dd, J=8.2, 10.2, 1H), 4.36 (q, J=6.8, 2H), 1.38 (t, J=6.8,
3H).
[0405] 154BG85-11 (156 mg, 0.7 mmol) was transferred to a Pyrex
tube and pyrrolidine (1 mL) was added. The tube was capped and the
reaction tube was exposed to microwave irradiation (100.degree. C.,
3 min). The microwave exposure was repeated for 5 min at
130.degree. C. The pyrrolidine was evaporated and the reaction
mixture was transferred to a separation funnel with ethyl acetate
and washed with 2 M NaOH. The aqueous phase was acidified with 2 M
HCl and extracted with ethyl acetate. The organic phases were
collected, dried over Na.sub.2SO.sub.4, filtered and concentrated
to yield 135 mg (70%) of the title compound.
[0406] LCMS m/z 270 [M+H].sup.+. HPLC t.sub.R=7.3 min (method I).
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 9.11-9.09 (m, 1H),
8.25-8.22 (m, 1H), 8.17 (d, J=8.4, 1H), 7.58-7.54 (m, 1H),
7.44-7.40 (m, 1H), 6.81 (d, J=8.4, 1H), 4.43 (q, J=7.0, 2H),
3.57-3.53 (m, 4H), 2.05-2.01 (m, 4H), 1.44 (t, J=7.0, 3H).
.sup.13C-NMR (CDCl.sub.3, 100 MHz) .delta. 167.8, 134.1, 132.1,
127.5, 126.7, 126.3, 125.5, 123.9, 108.3, 60.5, 53.2, 25.7,
14.7.
4-Pyrrolidin-1-ylnaphthalene-1-carboxylic acid (154BG23)
[0407] 154BG19 (30 mg, 0.11 mmol) was transferred to a Pyrex tube
and LiOH.times.H.sub.2O (14 mg, 0.33 mmol) was added, followed by
H.sub.2O (0.18 mL) and THF (0.37 mL). The tube was capped and the
reaction tube was exposed to microwave irradiation (160.degree. C.,
5 min). The reaction mixture was transferred to a separation funnel
with ethyl acetate and washed with 2 M NaOH. The aqueous phase was
acidified with 2 M HCl and extracted with ethyl acetate. The
organic phases were collected, dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield 18 mg (68%) of the title
compound.
[0408] LCMS m/z 240 [M-H].sup.-. LCMS m/z 242 [M+H].sup.+. HPLC
t.sub.R=3.2 min (method I). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz)
.delta. 9.09-9.07 (m, 1H), 8.26-8.23 (m, 1H), 8.09 (d, J=8.4, 1H),
7.73-7.68 (m, 1H), 7.66-7.62 (m, 1H), 6.83 (d, J=8.4, 1H),
3.53-3.49 (m, 4H), 1.99-1.95 (m, 4H). .sup.13C-NMR (DMSO-d.sub.6,
100 MHz) .delta. 169.1, 152.4, 134.3, 132.8, 127.7, 126.4, 126.4,
126.1, 124.1, 108.3, 53.1, 25.8.
4-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(154BG31)
[0409] 1-Cyano-4-fluoronapthalene (104 mg, 0.6 mmol), nortropanol
(305 mg, 2.4 mmol) and pyridine (93 .mu.L, 0.6 mmol) were
transferred to a Pyrex tube. The tube was capped and the reaction
tube was exposed to microwave irradiation (220.degree. C., 5 min).
The mixture was transferred to a separation funnel with ethyl
acetate and with 2 M HCl and the organic phases were then washed
with brine. The organic layer was collected, dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield 157 mg (92%)
of the title compound.
[0410] LCMS m/z 279 [M+H].sup.+. HPLC t.sub.R=6.8 min (method I).
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 8.21-8.16 (m, 2H), 7.75
(d, J=8.0, 1H), 7.66-7.62 (m, 1H), 7.56-7.52 (m, 1H), 6.90 (d,
J=8.0, 1H), 4.32 (t, J=5.1, 1H), 4.14-4.11 (m, 2H), 2.51-2.45 (m,
2H), 2.34-2.28 (m, 2H), 2.02-1.96 (m, 4H). .sup.13C-NMR
(CDCl.sub.3, 100 MHz) .delta. 153.1, 134.5, 133.7, 128.4, 127.9,
126.0, 125.9, 125.4, 119.1, 111.0, 102.0, 65.2, 60.1, 40.7,
27.4.
[0411] Alternatively, 154BG31 was prepared by the following
procedure: 1-Cyano-4-fluoronaphthalene (20.0 g, 117 mmol) was
dissolved in pyridine (100 mL). A solution of nortropine (59.4 g,
467 mmol) in pyridine (100 mL) was added, and the reaction mixture
was heated to reflux for 20 hours. The resulting black solution was
concentrated, and water (800 mL) was added. The pH was adjusted to
I by addition of 2 M HCl. The product was extracted into
dichloromethane (2.times.800 mL), and the combined organic phases
were washed with 0.5 M NaOH (400 mL), dried over sodium sulfate,
filtered and evaporated. The crude product was dissolved in hot
ethyl acetate (200 mL), and crystallization occurred upon cooling
to rt. Crystallization was continued at 5.degree. C. for 20 hours.
Filtration afforded a first crop of the title compound (21.2 g, 65%
yield) as a white solid. The mother liquors contained more product
(as shown by LC-MS), but re-crystallization of the mother liquors
was not pursued further.
4-(3-Oxo-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(156AF03-217).
[0412] A solution of oxalyl chloride (440 .mu.L, 5.11 mmol) in
anhydrous dichloromethane (3 mL) was added dropwise to a cold
solution of dry dimethylsulfoxide (726 .mu.L, 10.22 mmol) in
dichloromethane (5 mL) at -60.degree. C. under argon atmosphere. A
solution of 154BG31 (647 mg, 2.32 mmol) in dry dichloromethane (7
mL) was added dropwise to the cold reaction mixture. The mixture
was allowed to warm up to -40.degree. C. over 50 min. Afterwards
the mixture was cooled to -60.degree. C. and triethylamine (1.90
mL, 13.92 mmol) was added dropwise. The mixture was allowed to warm
up to rt slowly and stirring was continued overnight at rt. The
mixture was partitioned between dichloromethane and water. The
organic layer was dried over sodium sulfate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with a mixture of ethyl acetate and
n-heptane (50:50), afforded the desired compound (0.55 g, 86%).
[0413] R.sub.f=0.51 (Ethyl acetate/n-Heptane 50:50). LCMS m/z 277
[M+H].sup.+. HPLC t.sub.R=10.9 (method III). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.27-8.21 (m, 2H, Ar--H), 7.79 (d,
1H, J=8.0, Ar--H), 7.68 (m, 1H, Ar--H), 7.61 (m, 1H, Ar--H), 6.93
(d, 1H, J=8.0, Ar--H), 4.39 (m, 2H, Tr-H), 3.03 (m, 2H, Tr-H), 2.53
(m, 2H, Tr-H), 2.20 (m, 2H, Tr-H), 1.85 (m, 2H, Tr-H).
4-(3-Propylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile,
hydrochloride (156AF01-222 & 156AF01-223)
[0414] n-Propylamine (54 .mu.L, 0.65 mmol) and acetic acid (50
.mu.L, 0.87 .mu.mol) were added to a solution of 156AF03-217 (64
mg, 0.23 mmol) in THF (1 mL). After 1 h stirring at rt a solution
of sodium cyanoborohydride (33 mg, 0.52 mmol) in methanol (2 mL)
was added. The reaction mixture was stirred in a sealed flask for
20 min at 110.degree. C. The solvent was removed by evaporation and
the residue partitioned between dichloromethane and water. The
organic layer was evaporated to dryness and the residue was
purified by passage over an acidic ion-exchange cartridge.
Separation of the diastereomers (endo/exo 41:59) was performed by
column chromatography on silica gel eluting with a stepwise
gradient of 5-10% methanol in dichloromethane. The two
diastereomers were converted to the corresponding hydrochloride
salt as described above.
[0415] Endo-diastereomer 156AF01-222: R.sub.f=0.34
(MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 320 [M+H].sup.+. HPLC
t.sub.R=2.8 min (method II). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.21 (d, 1H, J=8.0, Ar--H), 8.15 (d, 1H, J=8.0, Ar--H),
7.72 (d, 1H, J=8.0, Ar--H), 7.62 (m, 1H, Ar--H), 7.53 (m, 1H,
Ar--H), 6.86 (d, 1H, J=8.0, Ar--H), 4.09 (m, 2H, Tr-H), 3.13 (m,
1H, Tr-H), 2.61 (t, 2H, J=7.2, NCH.sub.2CH.sub.2CH.sub.3),
2.45-2.38 (m, 2H, Tr-H), 2.18 (m, 2H, Tr-H), 1.98-1.92 (m, 2H,
Tr-H), 1.78 (m, 2H, Tr-H), 1.52 (h, 2H, J=7.2,
NCH.sub.2CH.sub.2CH.sub.3), 0.96 (t, 3H, J=7.2,
NCH.sub.2CH.sub.2CH.sub.3).
[0416] Exo-diastereomer 156AF01-223: R.sub.f=0.19
(MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 320 [M+H].sup.+. HPLC
t.sub.R=4.1 min (method II). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.21 (d, 1H, J=8.0, Ar--H), 8.15 (d, 1H, J=8.0, Ar--H),
7.72 (d, 1H, J=8.0, Ar--H), 7.62 (m, 1H, Ar--H), 7.53 (m, 1H,
Ar--H), 6.86 (d, 1H, J=8.0, Ar--H), 4.17 (m, 2H, Tr-H), 3.04 (m,
1H, Tr-H), 2.64 (t, 2H, J=7.2, NCH.sub.2CH.sub.2CH.sub.3),
2.11-2.00 (m, 4H, Tr-H), 1.85-1.75 (m, 4H, Tr-H), 1.54 (h, 2H,
J=7.2, NCH.sub.2CH.sub.2CH.sub.3), 0.96 (t, 3H, J=7.2,
NCH.sub.2CH.sub.2CH.sub.3).
4-(3-Dimethylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile,
hydrochloride (156AF05-224)
[0417] Dimethylamine (200 .mu.L, 0.40 mmol) and acetic acid (50
.mu.L, 0.87 .mu.mol) were added to a solution of 156AF03-217 (56
mg, 0.20 mmol) in a mixture of THF and methanol (1:1, 2 mL). The
mixture was stirred in a sealed flask for 10 min under microwave
irradiation at 110.degree. C. A solution of sodium cyanoborohydride
in methanol (300 .mu.L) was added to the reaction mixture at rt.
The mixture was stirred in a sealed flask for 18 min under
microwave irradiation at 110.degree. C. The solvent was removed and
the residue partitioned between dichloromethane and water. The
organic layer was evaporated to dryness. Purification of the
residue by silica gel column chromatography, eluting with stepwise
gradient of 5-10% methanol in dichloromethane, afforded the desired
product as a diastereomeric mixture-ratio 80:20 (27 mg, 44%). The
product was converted to the corresponding hydrochloride salt as
described above.
[0418] R.sub.f=0.18 (MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 306
[M+H].sup.+. HPLC t.sub.R=2.5 min (method II).
4-[3-(3-Hydroxypropylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carb-
onitrile, hydrochloride (156AF07-225)
[0419] The product was synthesized from 3-amino-1-propanol (31 mg,
0.41 mmol) and 156AF03-217 (57 mg, 0.21 mmol) using the same method
as for the preparation of 156AF05-224. The product was isolated as
a diastereomeric mixture (11 mg, 16%). The product was converted to
the corresponding hydrochloride salt as described above.
[0420] R.sub.f=0.22 (MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 336
[M+H].sup.+. HPLC t.sub.R=2.6 min (method II).
4-[3-(2-Ethoxyethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-carbon-
itrile, hydrochloride (156AF09-226 & 156AF09-227)
[0421] The title compound was synthesized from 2-ethoxyethylamine
(35 mg, 0.40 mmol) and 156AF03-217 (54 mg, 0.19 mmol) using the
same method as for the preparation of 156AF05-224. Separation of
the diastereomers (endo/exo 41:59) was performed by column
chromatography on silica gel eluting with a stepwise gradient of
5-10% methanol in dichloromethane. The products were converted to
the corresponding hydrochloride salt as described above.
[0422] Endo-diasteromer 156AF09-226: R.sub.f=0.46
(MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 350 [M+H].sup.+. HPLC
t.sub.R=4.9 min (method II). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.21 (d, 1H, J=8.0, Ar--H), 8.16 (d, 1H, J=8.0, Ar--H),
7.72 (d, 1H, J=8.0, Ar--H), 7.63 (m, 1H, Ar--H), 7.54 (m, 1H,
Ar--H), 6.87 (d, 1H, J=8.0, Ar--H), 4.10 (m, 2H, Tr-H), 3.59-3.49
(m, 4H, CH.sub.2O), 3.16 (m, 1H, Tr-H), 2.83 (m, 2H, NCH.sub.2),
2.46-2.40 (m, 2H, Tr-H), 2.22-2.15 (m, 2H, Tr-H), 1.96 (m, 2H,
Tr-H), 1.82 (m, 2H, Tr-H), 1.24 (t, 3H, J=7.2,
OCH.sub.2CH.sub.3).
[0423] Exo-diasteromer 156AF09-227: R.sub.f 0.25
(MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 350 [M+H].sup.+. HPLC
t.sub.R=5.9 min (method II). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.16 (d, 1H, J=8.0, Ar--H), 8.08 (d, 1H, J=8.0, Ar--H),
7.65 (d, 1H, J=8.0, Ar--H), 7.55 (m, 1H, Ar--H), 7.45 (m, 1H,
Ar--H), 6.80 (d, 1H, J=8.0, Ar--H), 4.11 (m, 2H, Tr-H), 3.56-3.44
(m, 4H, CH.sub.2O), 3.10 (m, 1H, Tr-H), 2.84 (m, 2H, NCH.sub.2),
2.09-1.69 (m, 8H, Tr-H), 1.15 (t, 3H, J=7.2,
OCH.sub.2CH.sub.3).
4-{3-[2-(1H-Imidazol-4-yl)ethylamino]-8-azabicyclo[3.2.1]oct-8-yl}naphthal-
ene-1-carbonitrile, dihydrochloride (156AF11-229)
[0424] A solution of histamine (16 mg, 0.14 mmol) in methanol (1
mL) was added dropwise to a solution of 156AF03-217 (20 mg, 72.4
.mu.mmol) in THF (0.5 mL) followed by addition of acetic acid (25
.mu.L, 0.43 mmol). After 2 hours stirring at rt a solution of
sodium cyanoborohydride (10 mg, 0.16 mmol) in methanol (0.10 mL)
was added. The reaction mixture was shaken overnight at 48.degree.
C. The solvent was removed and the residue was partitioned between
dichloromethane and 1 M aqueous sodium hydroxide. The organic layer
was evaporated to dryness to give the desired product as a
diastereomeric mixture, ratio 60:40. The product was converted to
the corresponding hydrochloride salt as described above.
[0425] LCMS m/z 372 [M+H].sup.+. HPLC t.sub.R=3.1 & 3.9 min
(method I).
4-(3-Cyclopropylamino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitri-
le, hydrochloride (156AF11-230)
[0426] The title compound (diastereomers, ratio 28:72) was
synthesized from cyclopropylamine (8.3 mg, 0.14 mmol) and
156AF03-217 (20 mg, 72.4 .mu.mol) using the same method as for the
preparation of 156AF11-229. The product was converted to the
corresponding hydrochloride salt as described above.
[0427] LCMS m/z 318 [M+H].sup.+. HPLC t.sub.R=6.4 & 8.9 min
(method I).
4-[3-(7-Dimethylaminoethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-
-carbonitrile, dihydrochloride (156AF11-231)
[0428] The title compound (diastereomers, ratio 45:55) was
synthesized from N,N-dimethylethylene diamine (13 mg, 0.15 mmol)
and 156AF03-217 (20 mg, 72.4 .mu.mol) using the same method as for
the preparation of 156AF11-229. The product was converted to the
corresponding hydrochloride salt as described above.
[0429] LCMS m/z 349 [M+H].sup.+. HPLC t.sub.R=4.7 & 6.0 min
(method I).
4-[3-(Cyclohexylmethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-car-
bonitrile, hydrochloride (156AF11-232)
[0430] The title compound (diastereomers, ratio 47:53) was
synthesized from aminomethylcyclohexane (16 mg, 0.15 mmol) and
156AF03-217 (20 mg, 72.4 .mu.mol) using the same method as for the
preparation of 156AF11-229. The product was converted to the
corresponding hydrochloride salt as described above.
[0431] LCMS m/z 374 [M+H].sup.+. HPLC t.sub.R=7.7 & 9.1 min
(method I).
4-{3-[(Furan-2-ylmethyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}naphthalene-1-c-
arbonitrile, hydrochloride (156AF11-233)
[0432] The title compound (diastereomers, ratio 65:35) was
synthesized from furfurylamine (14 mg, 0.15 mmol) and 156AF03-217
(20 mg, 72.4 .mu.mol) using the same method as for the preparation
of 156AF11-229. The product was converted to the corresponding
hydrochloride salt as described above.
[0433] LCMS m/z 358 [M+H]. HPLC t.sub.R=7.5 & 9.8 min (method
I).
4-[3-(2-Morpholin-4-ylethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene--
1-carbonitrile, dihydrochloride (156AF11-234)
[0434] The title compound (diastereomers, ratio 38:62) was
synthesized from 4-(2-aminoethyl)morpholine (19 mg, 0.15 mmol) and
156AF03-217 (20 mg, 72.4 .mu.mol) using the same method as for the
preparation of 156AF11-229. The product was converted to the
corresponding hydrochloride salt as described above.
[0435] LCMS m/z 391 [M+H].sup.+. HPLC t.sub.R=4.2 & 5.5 min
(method I).
4-{3-[(Pyridin-2-ylmethyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}naphthalene-1-
-carbonitrile, dihydrochloride (156AF11-235)
[0436] The title compound (diastereomers, ratio 49:51) was
synthesized from 2-(aminomethyl)pyridine (16 mg, 0.15 mmol) and
156AF03-217 (20 mg, 72.4 .mu.mol) using the same method as for the
preparation of 156AF11-229. The product was converted to the
corresponding hydrochloride salt as described above.
[0437] LCMS m/z 369 [M+H].sup.+. HPLC t.sub.R=6.7 & 8.6 min
(method I).
4-[3-(2-Isopropoxyethylamino)-8-azabicyclo[3.2.1]oct-8-yl]naphthalene-1-ca-
rbonitrile, hydrochloride (156AF11-237)
[0438] The title compound (diastereomers, ratio 42:58) was
synthesized from 2-aminoethyl isopropyl ether (15 mg, 0.15 mmol)
and 156AF03-217 (20 mg, 72.4 .mu.mol) using the same method as for
the preparation of 156AF11-229. The product was converted to the
corresponding hydrochloride salt as described above.
[0439] LCMS m/z 364 [M+H].sup.+. HPLC t.sub.R=6.7 & 7.7 min
(method I).
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)naphthalene-1-carbonitrile
(156AF14-239)
[0440] 1,4-dioxa-8-azaspiro[4.5]decane (332 mg, 2.32 mmol) was
added to a solution of 1-cyano-1-fluoronaphthalene (120 mg, 0.70
mmol) in anhydrous THF (1 mL). After 48 hours stirring at rt the
mixture was partitioned between ethyl acetate and water. The
organic layer was dried over sodium sulfate, filtered and
evaporated to dryness. The residue was washed with a mixture of
ethyl acetate and n-heptane (50:50). Purification by silica gel
column chromatography, eluting with 5% methanol in dichloromethane
afforded the desired compound (126 mg, 43%). The compound was
converted to the corresponding hydrochloride salt as described
above.
[0441] R.sub.f 0.45 (ethyl acetate/n-heptane 50:50). LCMS m/z 295
[M+H].sup.+. HPLC t.sub.R=12.3 min (method I). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.21-8.15 (m, 2H, Ar--H), 7.82 (d,
1H, J=8.0, Ar--H), 7.65 (m, 1H, Ar--H), 7.58 (m, 1H, Ar--H), 7.04
(d, 1H, J=8.0, Ar--H), 4.03 (m, 4H, dioxolane-H), 3.27 (m, 4H,
pip-H), 2.01 (m, 4H, pip-H).
4-(3-Hydroxyimino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(156AF17-240)
[0442] A solution of sodium acetate in water (1 mL) was added to a
solution of 156AF03-217 (61 mg, 0.22 mmol) and hydroxylamine
hydrochloride (31 mg, 0.44 mmol) in THF (2 mL). The reaction
mixture was stirred in a sealed flask for 2.times.10 min under
microwave irradiation at 120.degree. C. The resulting yellow
organic layer was separated and evaporated to dryness. The desired
product was crystallized from a mixture of ethyl acetate and
n-heptane (50:50).
[0443] R.sub.f=0.25 (Ethyl acetate/n-Heptane 50:50). LCMS m/z 292
[M+H].sup.+. HPLC t.sub.R=10.2 min (method III). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.26-8.19 (m, 2H, Ar--H), 7.76 (d,
1H, J=8.0, Ar--H), 7.67 (m, 1H, Ar--H), 7.59 (m, 1H, Ar--H), 6.93
(d, 1H, J=8.0, Ar--H), 4.32-4.23 (m, 2H, Tr-H), 3.32 (m, 1H, Tr-H),
2.94 (m, 1H, Tr-H), 2.62-2.49 (m, 2H, Tr-H), 2.13-2.03 (m, 2H,
Tr-H), 1.86-1.69 (m, 2H, Tr-H).
3-Chloropropionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(156AF31-245)
[0444] A solution of 3-chloropropionyl chloride (370 .mu.L, 3.84
mmol) in dry dichloromethane (2 mL) was added dropwise to a cold
solution of 154BG31 (712 mg, 2.56 mmol) and triethylamine (714
.mu.L, 5.12 mmol) in dry dichloromethane (8 mL) at -30.degree. C.
under argon atmosphere. The mixture was allowed to warm up to rt.
After 4 hours stirring at rt the solvent was removed and the
residue was partitioned between ethyl acetate and water. The
organic layer was dried over sodium sulfate, filtered and
evaporated to dryness (801 mg, 85%). The compound was used without
further purification.
[0445] R.sub.f=0.58 (Ethyl acetate/n-Heptane 50:50). LCMS m/z 369
[M+H].sup.+. HPLC t.sub.R=13.6 min (method III).
Methoxyacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(88PS39)
[0446] The compound was synthesized from methoxyacetyl chloride (50
.mu.L, 0.54 mmol) and 154BG31 (100 mg, 0.36 mmol) using the same
method as for preparation of 156AF31-245. The reaction time was
extended to 20 hours. Purification by silica gel column
chromatography, eluting with a stepwise gradient of 50-80% ethyl
acetate in n-heptane, afforded the desired compound.
[0447] LCMS m/z 351 [M+H].sup.+. HPLC t.sub.R=12.2 min (method
III). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.19 (m, 2H,
Ar--H), 7.76 (d, 1H, J=8.0, Ar--H), 7.66 (m, 1H, Ar--H), 7.57 (m,
1H, Ar--H), 6.91 (d, 1H, J=8.0, Ar--H), 5.39 (m, 1H, Tr-H),
4.18-4.07 (m, 4H, Tr-H, COCH.sub.2O), 3.51 (s, 3H, OCH.sub.3),
2.61-2.51 (m, 2H, Tr-H), 2.18-2.01 (m, 6H, Tr-H).
3-Morpholin-4-ylpropionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF32-246)
[0448] Sodium iodide (129 mg, 0.86 mmol) was added to a solution of
156AF31-245 (318 mg, 0.86 mmol) in dichloromethane. Morpholine (500
.mu.L, 5.73 mmol) was added dropwise to the mixture at rt. Stirring
was continued overnight at rt. The mixture was suspended on silica
gel and purified by silica gel column chromatography eluting with
5% methanol in dichloromethane. The product (236 mg, 65%) was
converted to the corresponding hydrochloride salt as described
above.
[0449] R.sub.f=0.26 (MeOH/CH.sub.2Cl.sub.2 5:95). LCMS m/z 420
[M+H].sup.+. HPLC t.sub.R=4.1 min (method 11). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.16 (m, 2H, Ar--H), 7.73 (d, 1H,
J=8.0, Ar--H), 7.63 (m, 1H, Ar--H), 7.54 (m, 1H, Ar--H), 6.88 (d,
1H, J=8.0, Ar--H), 5.27 (m, 1H, Tr-H), 4.11 (m, 2H, Tr-H),
3.70-3.60 (m, 7H, morpholine-H, COCH.sub.2CH.sub.2N), 3.46 (m, 1H,
COCH.sub.2CH.sub.2N), 2.72 (m, 2H, Tr-H), 2.55-2.48 (m, 6H, Tr-H,
morpholine-H), 2.18-1.98 (m, 6H, Tr-H).
3-(4-Ethylpiperazin-1-yl)propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF35-247).
[0450] The desired compound was prepared from 156AF31-245 (480 mg,
1.30 mmol) and 1-ethylpiperazine (742 mg, 6.50 mmol) using the same
method as for the preparation of 156AF32-246. The product (584 mg,
100%) was converted to the corresponding hydrochloride salt as
described above.
[0451] R.sub.f=0.36 (MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 447
[M+H].sup.+. HPLC t.sub.R=3.3 min (method II). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.16 (m, 2H, Ar--H), 7.73 (d, 1H,
J=8.0, Ar--H), 7.63 (m, 1H, Ar--H), 7.54 (m, 1H, Ar--H), 6.88 (d,
1H, J=8.0, Ar--H), 5.27 (m, 1H, Tr-H), 4.11 (m, 2H, Tr-H), 2.74 (m,
2H, COCH.sub.2CH.sub.2N), 2.55-2.40 (m, 12H, CH.sub.2Et,
COCH.sub.2CH.sub.2N, piperazine-H), 2.18-1.98 (m, 6H, Tr-H), 1.10
(t, 3H, J=7.2, CH.sub.3Et).
3-Diethylaminopropionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (88PS37).
[0452] The desired compound was prepared from 156AF31-245 (272 mg,
0.74 mmol) and diethylamine (270 mg, 3.67 mmol) using the same
method as for the preparation of 156AF32-246. The product (139 mg,
46%) was converted to the corresponding hydrochloride salt as
described above.
[0453] LCMS m/z 406 [M+H].sup.+. HPLC t.sub.R=3.2 min (method II).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.19 (m, 2H, Ar--H), 7.76
(d, 1H, J=8.0, Ar--H), 7.66 (m, 1H, Ar--H), 7.56 (m, 1H, Ar--H),
6.91 (d, 1H, J=8.0, Ar--H), 5.29 (m, 1H, Tr-H), 4.13 (m, 2H, Tr-H),
2.93 (m, 2H, COCH.sub.2CH.sub.2N), 2.68-2.48 (m, 6H, CH.sub.2Et,
Tr-H), 2.16-2.00 (m, 6H, Tr-H), 1.11 (t, 6H, J=7.2,
CH.sub.3Et).
Chloroacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(156AF36-248)
[0454] The compound was synthesized form 154BG31 (235 mg, 0.84
mmol) and chloroacetyl chloride (100 .mu.L, 1.26 mmol) using the
same method as for the preparation of 156AF31-245. The reaction
time was extended to 20 hours. Purification by silica gel column
chromatography, eluting with a mixture of ethyl acetate and
n-heptane (50:50), afforded the desired compound (189 mg, 64%).
[0455] R.sub.f=0.59 (Ethyl acetate/n-Heptane 50:50). LCMS m/z 355
[M+H].sup.+. HPLC t.sub.R=5.1 min (method II). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.17 (m, 2H, Ar--H), 7.74 (d, 1H,
J=8.0, Ar--H), 7.64 (m, 1H, Ar--H), 7.55 (m, 1H, Ar--H), 6.90 (d,
1H, J=8.0, Ar--H), 5.35 (m, 1H, Tr-H), 4.13 (m, 4H, Tr-H,
COCH.sub.2Cl), 2.60-2.51 (m, 2H, Tr-H), 2.18 (m, 2H, Tr-H), 2.05
(m, 4H, Tr-H).
Morpholin-4-ylacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF37-249)
[0456] The desired compound was synthesized from 156AF36-248 (175
mg, 0.49 mmol) and morpholine (430 .mu.L, 4.93 mmol) using the same
method as for the preparation of 156AF32-246. The product (175 mg,
88%) was converted to the corresponding hydrochloride salt as
described above.
[0457] R.sub.f=0.24 (MeOH/CH.sub.2Cl.sub.2 4:96). LCMS m/z 406
[M+H].sup.+. HPLC t.sub.R=4.2 min (method II). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.16 (m, 2H, Ar--H), 7.73 (d, 1H,
J=8.0, Ar--H), 7.63 (m, 1H, Ar--H), 7.54 (m, 1H, Ar--H), 6.88 (d,
1H, J=8.0, Ar--H), 5.32 (m, 1H, Tr-H), 4.12 (m, 2H, Tr-H), 3.78 (m,
4H, morpholine-H), 3.25 (s, 2H, COCH.sub.2N), 2.65 (m, 4H,
morpholine-H), 2.55-2.49 (m, 2H, Tr-H), 2.15-1.99 (m, 6H,
Tr-H).
Imidazol-1-ylacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF40-251)
[0458] The desired compound was synthesized from 156AF36-248 (177
mg, 0.50 mmol) and imidazole (170 mg, 2.49 mmol) using the same
method as for preparation of 156AF32-246. The reaction time was
extended to 3 days. The product (153 mg, 81%) was converted to the
corresponding hydrochloride salt as described above.
[0459] R.sub.f=0.42 (MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 387
[M+H].sup.+. HPLC t.sub.R=3.6 min (method II). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.16 (d, 1H, J=8.0, Ar--H), 8.11 (d,
1H, J=8.0, Ar--H), 7.73 (d, 1H, J=8.0, Ar--H), 7.63 (m, 1H, Ar--H),
7.54 (m, 2H, Ar--H, imidazole-H), 7.12 (m, 1H, imidazole-H), 6.98
(m, 1H, imidazole-H), 6.85 (d, 1H, J=8.0, Ar--H), 5.35 (m, 1H,
Tr-H), 4.06 (m, 2H, Tr-H), 3.48 (s, 2H, COCH.sub.2N), 2.55-2.49 (m,
2H, Tr-H), 1.96 (m, 4H, Tr-H), 1.79 (m, 2H, Tr-H).
(4-Ethylpiperazin-1-yl)acetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
dihydrochloride (156AF42-252)
[0460] The desired compound was synthesized from 156AF36-248 (222
mg, 0.63 mmol) and ethyl piperazine (357 mg, 3.13 mmol) using the
same method as for the preparation of 156AF32-246. The product (181
mg, 67%) was converted to the corresponding hydrochloride salt as
described above.
[0461] R.sub.f=0.15 (MeOH/CH.sub.2Cl.sub.2 7:93). LCMS m/z 433
[M+H].sup.+. HPLC t.sub.R=6.4 min (method II). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.16 (m, 2H, Ar--H), 7.73 (d, 1H,
J=8.0, Ar--H), 7.63 (m, 1H, Ar--H), 7.54 (m, 1H, Ar--H), 6.88 (d,
1H, J=8.0, Ar--H), 5.30 (m, 1H, Tr-H), 4.11 (m, 2H, Tr-H), 3.22 (s,
2H, COCH.sub.2N), 2.71-2.40 (m, 12H, piperazine-H, Tr-H,
CH.sub.2Et), 2.16-1.98 (m, 6H, Tr-H), 1.08 (t, 3H, J=7.2,
CH.sub.3Et).
Diethylaminoacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
hydrochloride (156AF43-253)
[0462] The desired compound was synthesized from 156AF36-248 (151
mg, 0.43 mmol) and diethylamine (155 mg, 2.12 mmol) using the same
method as for the preparation of 156AF32-246. The product (136 mg,
81%) was converted to the corresponding hydrochloride salt as
described above.
[0463] R.sub.f=0.47 (MeOH/CH.sub.2Cl.sub.2 7:93). LCMS m/z 392
[M+H].sup.+. HPLC t.sub.R=7.9 min (method II). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.16 (m, 2H, Ar--H), 7.73 (d, 1H,
J=8.0, Ar--H), 7.63 (m, 1H, Ar--H), 7.54 (m, 1H, Ar--H), 6.88 (d,
1H, J=8.0, Ar--H), 5.30 (m, 1H, Tr-H), 4.11 (m, 2H, Tr-H), 3.33 (s,
2H, COCH.sub.2N), 2.69 (q, 4H, J=7.2, CH.sub.2Et), 2.54-2.48 (m,
2H, Tr-H), 2.15 (m, 2H, Tr-H), 2.02 (m, 4H, Tr-H), 1.08 (t, 6H,
J=7.2, CH.sub.3Et).
Succinic acid mono
endo-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]ester
(156AF48-254)
[0464] Succinic anhydride (368 mg, 3.68 mmol) was added to a
solution of 154BG31 (129 mg, 0.46 mmol) and triethylamine (160
.mu.L, 1.15 mmol) in ethyl acetate (10 mL) at rt. The mixture was
stirred at 50.degree. C. for a week. Purification of the reaction
mixture by silica gel column chromatography, eluting with a mixture
of ethyl acetate and n-heptane (55:45) afforded the desired product
(69 mg, 40%).
[0465] R.sub.f=0.17 (Ethyl acetate). LCMS m/z 379 [M+H].sup.+. HPLC
t.sub.R=2.6 min (method II). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 8.10 (m, 2H, Ar--H), 7.68 (d, 1H, J=8.0, Ar--H), 7.57 (m,
1H, Ar--H), 7.48 (m, 1H, Ar--H), 6.83 (d, 1H, J=8.0, Ar--H), 5.20
(m, 1H, Tr-H), 4.05 (m, 2H, Tr-H), 2.70-2.56 (m, 4H,
COCH.sub.2CH.sub.2COOH), 2.48-2.40 (m, 2H, Tr-H), 2.12-2.00 (m, 6H,
Tr-H).
Trifluoroacetic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(156AF54-259)
[0466] Trifluoroacetic anhydride (198 .mu.L, 1.40 mmol) was added
to a solution of 154BG31 (77 mg, 0.28 mmol) in ethyl acetate at rt.
The mixture was stirred overnight at 60.degree. C. The mixture was
partitioned between ethyl acetate and water. The organic layer was
dried over sodium sulfate, filtered and evaporated to dryness.
Purification of the residue by silica gel column chromatography,
eluting with a mixture of ethyl acetate and n-heptane (55:45)
afforded the desired product (20 mg, 19%).
[0467] R.sub.f=0.71 (Ethyl acetate/n-heptane 55:45). LCMS m/z 375
[M+H].sup.+. HPLC t.sub.R=5.8 min (method II). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.17 (m, 2H, Ar--H), 7.79 (d, 1H,
J=8.0, Ar--H), 7.71 (m, 1H, Ar--H), 7.59 (m, 1H, Ar--H), 6.93 (d,
1H, J=8.0, Ar--H), 5.49 (m, 1H, Tr-H), 4.18 (m, 2H, Tr-H),
2.68-2.60 (m, 2H, Tr-H), 2.27-2.03 (m, 6H, Tr-H).
4-(3,4-Dihydroxypyrrolidin-1-yl)naphthalene-1-carbonitrile
(156AF59-258)
[0468] 1-Boc-3,4-pyrrolidindiol (178 mg, 0.88 mmol) was stirred in
a 2 M solution of hydrochloride acid in diethyl ether (3 mL). After
2 hours stirring at rt hydrochloride form of 3,4-pyrrolidindiol was
isolated from the mixture by filtration. The product was dissolved
in methanol and left on standing overnight with PS-trisamine resin
(3.38 mmol/g, 0.5 g). The resin was removed by filtration and the
solution was concentrated in vacuo affording 3,4-pyrrolidindiol as
colourless oil. This material was dissolved in DMF (3 mL) and
1-cyano-4-fluoronaphthalene (66 mg, 0.39 mmol) was added to the
solution. After 48 hour stirring at rt the reaction mixture was
partitioned between ethyl acetate and water. The organic layer was
washed with brine, dried over sodium sulfate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with a stepwise gradient of 5-10%
methanol in dichloromethane, afforded the desired compound (14 mg,
14%).
[0469] R.sub.f0.38 (MeOH/CH.sub.2Cl.sub.2 10:90). LCMS m/z 255
[M+H].sup.+. HPLC t.sub.R=2.13 min (method III). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.21-8.12 (m, 2H, Ar--H), 7.69 (d,
1H, J=8.0, Ar--H), 7.60 (m, 1H, Ar--H), 7.49 (m, 1H, Ar--H), 6.68
(d, 1H, J=8.0, Ar--H), 4.50-4.41 (m, 2H, pyrrolidine-H), 3.94-3.80
(m, 2H, pyrrolidine-H), 3.72-3.51 (m, 2H, pyrrolidine-H), 2.88
(broad s, 2H, OH).
4-(3-exo-Ethynyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1--
carbonitrile (88PS41)
[0470] Ethynyl magnesium bromide reagent (0.5 M solution in
anhydrous THF, 877 .mu.L, 0.44 mmol) was added dropwise to a cold
solution of 156AF03-217 (100 mg, 0.36 mmol) in anhydrous THF (2 mL)
at 0.degree. C. The mixture was allowed to warm up to rt. After 20
h stirring at rt the reaction was quenched with water. The mixture
was partitioned between water and ethyl acetate. The organic layer
was dried over sodium sulfate, filtered and evaporated to dryness.
Purification of the residue by silica gel column chromatography,
eluting with a stepwise gradient of 40-100% ethyl acetate in
n-heptane, afforded the desired compound (6.4 mg, 6%).
[0471] LCMS m/z 303 [M+H].sup.+. HPLC t.sub.R=11.5 min (method
III). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.13-8.08 (m, 2H,
Ar--H), 7.68 (d, 1H, J=8.0, Ar--H), 7.58 (m, 1H, Ar--H), 7.48 (m,
1H, Ar--H), 6.83 (d, 1H, J=8.0, Ar--H), 4.11-4.03 (m, 2H, Tr-H),
2.67-2-57 (m, 2H, Tr-H), 2.48 (s, 1H, CC--H), 2.26-2.13 (m, 4H,
Tr-H), 1.92-1.78 (m, 3H, Tr-H, OH).
4-[3-(2-[1,3]Dioxan-2-ylethyl)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl]napht-
halene-1-carbonitrile (156AF53-260)
[0472] 1,3-Dioxane-2-ylethyl magnesium bromide reagent (0.5 M
solution in anhydrous THF: 860 .mu.L, 0.43 mmol) was added dropwise
to a solution of 156AF03-217 (80 mg, 0.29 mmol) in anhydrous THF (2
mL) at rt. After 48 h stirring at rt the reaction was quenched with
saturated ammonium chloride. The mixture was partitioned between
ammonium chloride and ethyl acetate. The organic layer was dried
over sodium sulfate, filtered and evaporated to dryness.
Purification of the residue by silica gel column chromatography,
eluting with a stepwise gradient of 40-100% ethyl acetate in
n-heptane, afforded the desired compound as a diastereomeric
mixture, ratio 85:15 (37 mg, 45%).
[0473] LCMS m/z 393 [M+H].sup.+. HPLC t.sub.R=4.3 & 4.8 min
(method II). Major diastereomer: .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 8.10-8.05 (m, 2H, Ar--H), 7.66 (d, 1H, J=8.0, Ar--H), 7.56
(m, 1H, Ar--H), 7.45 (m, 1H, Ar--H), 6.82 (d, 1H, J=8.0, Ar--H),
4.54 (m, 1H, dioxane-H), 4.11-4.02 (m, 4H, Tr-H, dioxane-H),
3.78-3.67 (m, 2H, dioxane-H), 2.29-156 (m, 1H, Tr-H,
CH.sub.2CH.sub.2COH, dioxane-H), 1.34-1.24 (m, 1H, dioxane-H).
4-(endo-3-Methoxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(88PS44)
[0474] Sodium hydride (50% suspension in an mineral oil, 10 mg,
0.21 mmol) was added to solution of 154BG31 (50 mg, 0.18 mmol) at
rt. After 15 minutes stirring at rt methyl iodide (22 .mu.L, 0.36
mmol) was added to the mixture and stirring was continued overnight
at 60.degree. C. The mixture was allowed to cool down to rt and
partitioned between ethyl acetate and water. The organic layer was
dried over sodium sulfate, filtered and evaporated to dryness.
Purification by silica gel column chromatography, eluting with a
mixture of ethyl acetate and n-heptane (50:50), afforded the
desired compound (4.4 mg, 8%).
[0475] LCMS m/z 293 [M+H].sup.+. HPLC t.sub.R=5.6 min (method
II).
(1S,4S)-5-(4-Cyanonaphthalen-1-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbox-
ylic acid tert-butyl ester (165RL03)
[0476] 1-Cyano-4-fluoronaphthalene (50 mg, 0.29 mmol) and
t-butyl(1S,4S)-(--)-2,5-diazobicyclo-[2.2.1]heptane-2-carboxylate
(86 mg, 0.44 mmol) was dissolved in pyridine (1 mL). DBU (18 .mu.L,
0.12 mmol) was added and the mixture was shaken in a vial at
60.degree. C. for 40 hours. After cooling to rt hydrochloric acid
(1 M, 10 mL) was added and the mixture was extracted with
dichloromethane (3.times.5 mL). The combined organic layers was
washed with sodium hydrogen carbonate, dried over sodium sulfate
and evaporated to dryness. The solid was purified by column
chromatography on silica gel using ethyl acetate/n-heptane (1:1)
giving a white solid (42 mg, 41%).
[0477] R.sub.f=0.40 (EtOAc/n-heptane 1:1). LCMS m/z 350
[M+H].sup.+. HPLC t.sub.R=12.4 min (method III). .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 8.09 (d, 1H, J=7.9 Hz, Ar--H), 8.01
(d, 1H, J=7.9 Hz, Ar--H), 7.65 (d, 1H, J=7.9 Hz, Ar--H), 7.54 (m,
1H, Ar--H), 7.39 (m, 1H, Ar--H), 6.65 (d, 1H, J=7.9 Hz, Ar--H),
4.60-4.48 (m, 2H, pip-H); 3.92-3.39 (m, 4H, pip-H), 2.01-1.82 (m,
2H, pip-H), 1.36 (s, 9H, CH.sub.3 t-butyl).
4-((1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl)naphthalene-1-carbonitrile
hydrochloride (165RL09)
[0478] 165RL03 (207 mg, 0.59 mmol) was dissolved in dichloromethane
(2 mL). Trifluoroacetic acid (2 mL) was added and the mixture was
shaken in a vial at rt for 3 hours. TLC showed no more starting
material. Hydrochloric acid (1 M, 5 mL) was added and the mixture
was washed with ethyl acetate (2.times.10 mL). The aqueous layer
was made alkaline with sodium hydroxide (2 M) and extracted with
ethyl acetate (3.times.20 mL). The combined organic layers were
dried over sodium sulfate and evaporated to dryness to give an
off-white solid (146 mg, 99%). The product was converted to the
corresponding hydrochloride salt as described above.
[0479] LCMS m/z 250 [M+H].sup.+. HPLC t.sub.R=1.2 min (method II).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.13 (m, 2H, Ar--H), 7.72
(d, 1H, J=8.3, Ar--H), 7.60 (m, 1H, Ar--H), 7.45 (m, 1H, Ar--H),
6.70 (d, 1H, J=8.3, Ar--H), 4.48 (s, 1H, pip-H), 4.04 (dd, 1H,
J=2.3, 9.4, pip-H), 3.86 (s, 1H, pip-H), 3.45-3.37 (m, 2H, pip-H),
3.17 (dd, 1H, J=2.1, 10.2, pip-H), 2.06-1.89 (m, 2H, pip-H), 2.01
(br, 1H, NH).
4-[(1S,4S)-5-(Methoxyacetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]naphthalene--
1-carbonitrile (165RL10)
[0480] 165RL09 (16.5 mg, 0.066 mmol) was dissolved in
dichloromethane (1 mL). N,N-Diisopropylethylamine (DIPEA) (9.4 mg,
0.073 mmol) was added followed by methoxyacetyl chloride (7.9 mg,
0.073 mmol). The mixture was shaken in a vial at rt for 18 hours.
Water (3 mL) was added and the layers were separated. The aqueous
layer was extracted with ethyl acetate (2.times.5 mL) and the
combined organic layers were evaporated. The compound was further
purified by column chromatography on silica gel using ethyl
acetate/methanol (1:1) to give the title compound (21 mg, 97%).
[0481] R.sub.f=0.66 (EtOAc/MeOH 1:1). LCMS m/z 322 [M+H].sup.+.
HPLC t.sub.R=2.5 min (method II). .sup.1H-NMR (CD.sub.3OD, 300 MHz,
rotamers 0.5:0.5) d 8.17 (d, 1H, J=8.4, Ar--H), 8.03 (dd, 1H, J=0.8
and 8.4, Ar--H), 7.76 (m, 1H, Ar--H), 7.63 (m, 1H, Ar--H), 7.51 (m,
1H, Ar--H), 6.90 (d, 1H, J=8.3, Ar--H), 4.96-4.66 (m, 2H, pip-H),
4.15 and 4.01 (2s, 2H, COCH.sub.2O), 4.14-4.04 (m, 1H, pip-H),
3.91-3.80 (m, 1H, pip-H), 3.71-3.48 (m, 2H, pip-H), 3.38 and 3.36
(2s, 2H, OCH.sub.3), 2.23-1.97 (m, 2H, pip-H)
4-((1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl)naphthalene-1-carboni-
trile (165RL11)
[0482] 165RL09 (16.3 mg, 0.065 mmol) was dissolved in
dichloromethane (1 mL). DIPEA (9.3 mg, 0.072 mmol) was added
followed by acetyl chloride (5.6 mg, 0.072 mmol). This was shaken
in a vial at rt for 18 hours. Water (3 mL) was added and the layers
were separated. The aqueous layer was extracted with ethyl acetate
(2.times.5 mL) the combined organic layers were evaporated. The
compound was further purified by column chromatography on silica
gel using ethyl acetate/methanol (9/1). Yield: 10.0 mg (53%)
[0483] R.sub.f=0.23 (EtOAc/MeOH 9:1). LCMS m/z 292 [M+H].sup.+.
HPLC t.sub.R=2.5 min (method I). .sup.1H-NMR (CDCl.sub.3, 300 MHz,
rotamers 0.5:0.5) d 8.17 (d, 1H, J=8.3, Ar--H), 8.06 (t, 1H, J=8.0,
Ar--H), 7.73 (m, 1H, Ar--H), 7.63 (m, 1H, Ar--H), 7.48 (m, 1H,
Ar--H), 6.75 (m, 1H, Ar--H), 5.04-4.53 (m, 2H, pip-H), 4.06-3.81
(m, 2H, pip-H), 3.65-3.53 (m, 2H, pip-H), 2.21-1.96 (m, 2H, pip-H),
2.12 and 1.98 (2s, 3H, CH.sub.3).
4-[(1S,4S)-5-(2-Hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]naphthalene-
-1-carbonitrile (165RL12)
[0484] 165RL09 (16.2 mg, 0.065 mmol) was dissolved in THF (1 mL).
Sodium carbonate (9.3 mg, 0.130 mmol) was added followed by
2-iodoethanol (5.6 mg, 0.072 mmol). The mixture shaken in a vial at
50.degree. C. for 18 hours. Water (3 mL) was added and the layers
were separated. The aqueous layer was extracted with ethyl acetate
(2.times.5 mL) and the combined organic layers were evaporated. The
compound was purified by column chromatography on silica gel using
triethylamine/methanol (1:24) followed by preparative HPLC, giving
5.0 mg (26%) of pure compound.
[0485] R.sub.f=0.30 (Et.sub.3N/MeOH 1:24). LCMS m/z 292
[M+H].sup.+. HPLC t.sub.R=1.5 min (method II). .sup.1H-NMR
(CD.sub.3OD, 300 MHz) .delta. 8.23 (d, 1H, J=8.5, Ar--H), 8.06 (dd,
1H, J=0.8 and 8.4, Ar--H), 7.78 (d, 1H, J=8.3 Hz, Ar--H), 7.65 (m,
1H, Ar--H), 7.52 (m, 1H, Ar--H), 6.88 (d, 1H, J=8.3, Ar--H), 4.52
(s, 1H, pip-H), 3.89-3.72 (m, 3H, pip-H), 3.67 (t, 2H, J=5.8,
CH.sub.2), 3.25-2.14 (m, 2H, pip-H), 2.84 (m, 2H, CH.sub.2), 1.29
(m, 2H, pip-H).
4-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)naphthalene-1-carboni-
trile hydrochloride (165RL15)
[0486] 165RL09 (26.4 mg, 0.106 mmol) was dissolved in methanol (5
mL) and formaldehyde (37% in water, 16 .mu.L, 0.21 mmol) was added.
The mixture was acidified by adding acetic acid (10 .mu.L). After 5
min of shaking, sodium cyanoborohydride (46.6 mg, 0.741 mmol) was
added and the mixture was allowed to react for 2 hours. The mixture
was hydrolyzed by adding 5 drops of sodium hydroxide (2M) followed
by water (10 mL) and the mixture extracted with dichloromethane
(3.times.10 mL). The combined organic layers were dried over sodium
sulfate, filtered and evaporated to dryness. The product (23 mg,
83%) needed no further purification and was converted to the
corresponding hydrochloride salt as described above.
[0487] LCMS m/z 263 [M+H].sup.+. HPLC t.sub.R=1.5 min (method I).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.13 (m, 2H, Ar--H), 7.70
(d, 1H, J=8.3, Ar--H), 7.59 (m, 1H, Ar--H), 7.44 (m, 1H, Ar--H),
6.66 (d, 1H, J=8.3, Ar--H), 4.36 (s, 1H, pip-H), 3.80-3.67 (m, 2H,
pip-H), 3.51 (s, 1H, pip-H), 3.06-2.79 (m, 2H, pip-H), 2.41 (s, 3H,
NCH.sub.3), 2.05-1.92 (m, 2H, pip-H).
4-(3-Amino-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile,
hydrochloride (165RL21)
[0488] 156AF03-217 (252 mg, 0.912 mmol) was dissolved in methanol
(25 mL). Ammonium acetate (702 mg, 9.12 mmol) and sodium
cyanoborohydride (57.3 mg, 0.912 mmol) were added together with
some molecular sieves (3 .ANG.). This mixture was allowed to react
at rt for 60 hours. Hydrochloric acid (2 M) was added until pH<2
and the mixture was washed with ethyl acetate (2.times.25 mL). The
aqueous layer was made alkaline with sodium hydroxide and extracted
with ethyl acetate (3.times.30 mL). The combined organic layers
were evaporated to dryness and purified by ion-exchange (SCX) to
give 90 mg (36%) of the title compound.
[0489] LCMS m/z 278 [M+H].sup.+. HPLC t.sub.R=2.1 min (method II).
.sup.1H-NMR (CD.sub.3OD, 300 MHz, diastereomers endo:exo 3:2) d
8.17 (m, 2H, Ar--H), 7.71 (d, 1H, J=8.1, Ar--H), 7.61 (m, 1H,
Ar--H), 7.52 (m, 1H, Ar--H), 6.86 (d, 1H, J=8.1, Ar--H), 4.10 (br,
2H, NH.sub.2), 3.53 (m, 0.6H, endo-CH), 3.24 (m, 0.4H, exo-CH),
2.53-2.44 (m, 1H, Tr-H), 2.21 (m, 1H, Tr-H), 2.10-1.62 (m, 8H,
Tr-H).
2-Chloro-N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetami-
de, hydrochloride (165RL23)
[0490] DMF (1.5 mL) was cooled to -30.degree. C. and chloroacetyl
chloride (20 .mu.L, 0.251 mmol) was added. To this mixture a
solution of 165RL21 (63 mg, 0.225 mmol) and DIPEA (44 .mu.L, 0.249
mmol) in DMF (3.5 mL) was added over a period of 5 min. After
stirring for 1 hour, the mixture was allowed to react at rt
overnight. Water (15 mL) was then added and the mixture extracted
with ethyl acetate (2.times.15 mL). The combined organic layers
were evaporated and purified using column chromatography on silica
gel eluting with n-heptane/ethyl acetate (1:4). The product (36 mg,
45%) was converted to the corresponding hydrochloride salt as
described above.
[0491] R.sub.f=0.42 (EtOAc/n-heptane 4:1). LCMS m/z 432
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz, diastereomers
endo:exo 3:2) d 8.18 (m, 2H, Ar--H), 7.73 (d, 1H, J=8.0, Ar--H),
7.64 (m, 1H, Ar--H), 7.55 (m, 1H, Ar--H), 7.17 (d, 0.6H, J=7.3,
CONH), 6.87 (m, 1H, Ar--H), 6.53 (d, 0.4H, J=8.2, CONH), 4.39 (m,
1H, Tr-H), 4.17 (m, 1H, Tr-H), 4.09 (s, 1.2H, CH.sub.2--Cl), 4.07
(s, 0.6H, CH.sub.2--Cl), 2.66-2.58 (m, 1H, Tr-H), 2.17-1.18 (m, 7H,
Tr-H).
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-(4-ethylpiper-
azin-1-yl)acetamide, dihydrochloride (165RL27)
[0492] 165RL23 (18 mg, 0.051 mmol), 1-ethylpiperazine (13 .mu.L,
0.10 mmol) and potassium carbonate (14.1 mg, 0.10 mmol) were added
to acetonitrile (2 mL). The mixture was shaken in a vial at
50.degree. C. for 3 hours and then at rt for 3 days. The mixture
was filtered, evaporated and purified by column chromatography on
silica gel using methanol/ethyl acetate (9:1) as eluent. The pure
product was evaporated and dissolved in dichloromethane (1 mL). The
product was converted to the corresponding dihydrochloride salt (21
mg, 83%) as described above.
[0493] R.sub.f=0.21 (EtOAc/MeOH 1:9). LCMS m/z 432 [M+H].sup.+.
HPLC t.sub.R=2.8 and 3.0 min (method II). .sup.1H-NMR (CDCl.sub.3,
300 MHz, diastereomers endo:exo 3:2) d 8.19 (m, 2H, Ar--H), 7.94
(d, 0.6H, J=8.2, CONH), 7.73 (m, 1H, Ar--H), 7.65 (m, 1H, Ar--H),
7.56 (m, 1H, Ar--H), 7.08 (d, 0.4H, J=8.7, CONH), 6.88 (m, 1H, AR),
4.39 (m, 1H, Tr-H), 4.17 (m, 2H, Tr-H), 3.03 (s, 1.2H, COCH.sub.2),
3.02 (s, 0.8H, COCH.sub.2), 2.68-2.39 (m, 11H), 2.19-1.82 (m, 7H),
1.08 (m, 3H, CH.sub.3).
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-diethylaminoa-
cetamide, hydrochloride (165RL28)
[0494] Synthesized according to the same procedure as 165RL27.
[0495] R.sub.f=0.28 (EtOAc/MeOH 9:1). LCMS m/z 391 [M+H].sup.+.
HPLC t.sub.R=4.2 and 4.6 min (method II). .sup.1H-NMR (CDCl.sub.3,
300 MHz, diastereomers endo:exo 3:2) d 8.19 (m, 2H, Ar--H), 8.13
(br, 0.6H, CONH), 7.74 (m, 1H, Ar--H), 7.65 (m, 1H, Ar--H), 7.56
(m, 1H, Ar--H), 7.40 (br, 0.4H, CONH), 6.88 (m, 1H, AR), 4.37 (m,
1H, Tr-H), 4.17 (m, 2H, Tr-H), 3.06 (s, 2H, COCH.sub.2), 2.64-2.56
(m, 5H), 2.16-1.87 (m, 7H, Tr-H), 1.07 (m, 6H, CH.sub.3).
2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
N,N-diisopropylamidophosphate (165RL22)
[0496] 2-cyanoethyl tetraisopropylphosphoroamidite (98.5 mg, 0.327
mmol) was dissolved in dichloromethane (10 mL) and added under
argon to 154BG31 (45.5 mg, 0.163 mmol), followed by the addition of
1H-tetrazole (3% in acetonitrile, 1.5 mL, 0.49 mmol). The mixture
was stirred at rt for 75 min. After cooling to 0.degree. C.,
m-chloroperbenzoic acid (110 mg, 0.490 mmol) was added and the
stirring was continued for another 40 min at 0.degree. C. The
reaction mixture was washed with a 10% aqueous sodium thiosulfate
solution (15 mL) followed by sat. sodium hydrogen carbonate
solution (15 mL). The organic layer was dried over sodium sulfate
and evaporated. The compound was further purified by column
chromatography on silica gel using n-heptane/ethyl (1:4) as eluent,
followed by preparative HPLC purification, giving the title
compound (11.3 mg).
[0497] R.sub.f=0.21 (n-heptane/ethyl acetate 1:4). LCMS m/z 495
[M+H].sup.+. HPLC t.sub.R=5.6 min (method II).
Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
hydrogen N,N-diisopropylamidophosphate (165RL29)
[0498] 165RL22 (11.3 mg, 0.023 mmol) was dissolved in acetonitrile
(2 mL) and 2 M sodium hydroxide (2 mL) was added. After 2 hours of
stirring at rt TLC showed full conversion. The mixture was made
acidic with 4 M hydrochloric acid and extracted with
dichloromethane (3.times.5 mL). The combined organic layers were
dried over sodium sulfate, filtered and evaporated to give 9.6 mg
(95%) of pure product.
[0499] LCMS m/z 442 [M+H].sup.+. HPLC t.sub.R=3.2 min (method II).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.33 (br, 1H, P--OH),
8.16 (m, 2H, Ar--H), 7.74 (d, 1H, J=8.1, Ar--H), 7.63 (m, 1H,
Ar--H), 7.57 (m, 1H, Ar--H), 6.88 (d, 1H, J=8.1, Ar--H), 4.76 (m,
1H, Tr-H), 4.12 (m, 2H, Tr-H), 3.63-3.47 (m, 2H,
N--CH--(CH.sub.3).sub.2), 2.46 (m, 2H), 2.32-2.22 (m, 4H),
2.03-1.96 (m, 2H), 1.26 (d, 12H, J=6.8, CH--(CH.sub.3).sub.2).
1-(3,4-Dinitronaphthalen-1-yl)pyrrolidine, hydrochloride
(159JP06)
[0500] Pyrrolidine (2.0 mL) was added to 2,4-dinitro-1-naphthyl
trifluoromethanesulfonate (219 mg, 0.57 mmol, Yang and Denny, J.
Org. Chem., 2002, 67, 8958-8961) which resulted in an immediate,
highly exothermic reaction. Volatiles were removed in vacuo and
preparative TLC (dichloromethane, 10.times. eluted) afforded 2.8 mg
(2.0%) of 159JP06 as a yellow solid. The product was converted to
the corresponding hydrochloride salt as described above.
[0501] R.sub.f=0.52 (CH.sub.2Cl.sub.2). LCMS m/z 288 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 9.09 (s, 1H), 8.79 (m,
1H), 8.17 (m, 1H), 7.74 (m, 1H), 7.52 (m, 1H), 3.74 (m, 4H), 2.15
(m, 4H). HPLC t.sub.R=11.3 min (method III).
1-(4,5,7-Trinitronaphthalen-1-yl)pyrrolidine, hydrochloride
(159JP09)
[0502] Pyrrolidine (2.5 mL) was added to
1-chloro-4,5,7-trinitronaphthalene (100 mg, 0.33 mmol, Bassilios et
al, Recueil, 1962, 81, 209-214) which resulted in an immediate,
highly exothermic reaction. Volatiles were removed in vacuo and
purification as in 159JP06 afforded 23 mg (22%) of 159JP09 as a red
solid. The product was converted to the corresponding hydrochloride
salt as described above.
[0503] R.sub.f=0.60 (CH.sub.2Cl.sub.2). LCMS not ionizable.
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 9.09 (d, 1H, J=2.4), 8.81
(d, 1H, J=2.4), 8.32 (d, 1H, J=9.3), 7.21 (d, 1H, J=9.3), 3.85 (m,
4H), 2.19 (m, 4H). HPLC t.sub.R=11.3 min (method III).
2-Bromo-4-pyrrolidin-1-ylnaphthalene-1-carbonitrile, hydrochloride
(159JP07)
[0504] 4-Pyrrolidin-1-ylnaphthalene-1-carbonitrile (136BG65-3, 320
mg, 1.44 mmol) was added to bromine (2 mL) and the resulting
solution was stirred at rt overnight. Quenching the reaction with 4
M NaOH (50 mL), extraction with dichloromethane (3.times.50 mL),
drying over Na.sub.2SO.sub.4, filtration and evaporation to dryness
gave the crude product. Purification as in 159JP06 (dichloromethane
as eluent) followed by recrystallisation (ethyl acetate/n-heptane)
afforded 3.5 mg (0.8%) of 159JP07 as an off-white solid. The
product was converted to the corresponding hydrochloride salt as
described above.
[0505] R.sub.f=0.64 (CH.sub.2Cl.sub.2). LCMS m/z 302 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 8.23 (m, 1H), 8.12 (m,
1H), 7.59 (m, 1H), 7.43 (m, 1H), 6.85 (s, 1H), 3.62 (m, 4H), 2.05
(m, 4H). HPLC t.sub.R=5.2 min (method II).
1-(2,4-Dibromonaphthalen-1-yl)pyrrolidine (159JP19)
[0506] 2,4-Dibromo-1-naphthylamine (3.77 g, 12.5 mmol, Consden
& Kenyon, J. Chem. Soc., 1935, 1591-1596), 1,4-dibromobutane
(2.70 g, 12.5 mmol), N,N-diisopropylethylamine (3.88 g, 30 mmol)
and toluene (15 mL) were heated at 120.degree. C. for 3 days. The
reaction was then cooled to rt, filtered, evaporated to dryness and
purified by vacuum flash chromatography (dichloromethane/n-heptane
1:5) to provide 159JP19 (2.50 g, 56%) as a yellowish thick oil
which solidified on standing to give an off white solid.
[0507] R.sub.f=0.83 (CH.sub.2Cl.sub.2). LCMS m/z 354 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.22-8.03 (m, 2H), 7.85
(s, 1H), 7.62-7.40 (m, 2H), 3.55-3.20 (m, 4H), 2.25-1.96 (m, 4H).
HPLC t.sub.R=5.4 min (method II).
4-Pyrrolidin-1-ylnaphthalene-1,3-dicarbonitrile, hydrochloride
(159JP26)
[0508] Adapting a protocol by Alterman and Hallberg (J. Org. Chem.,
2000, 65, 7984-7989), 159JP19 (249 mg, 0.70 mmol), Zn(CN).sub.2 (42
mg, 0.35 mmol) and Pd(PPh.sub.3).sub.4 (24 mg, 21 .mu.mol), were
weighed into a dried heavy-walled Pyrex tube under Ar atmosphere.
DMF (3 mL) was added, the reaction vessel was sealed and the
resulting mixture was exposed to microwave irradiation (60 W) for 7
min. The reaction was cooled to rt, partitioned between ethyl
acetate and water, the organic layer dried over Na.sub.2SO.sub.4,
filtered and evaporated to dryness. Purification as in 159JP06
using dichloromethane/n-heptane (3:1) as eluent provided 15 mg (9%)
of 159JP26 as an off-white solid. The product was converted to the
corresponding hydrochloride salt as described above.
[0509] R.sub.f=0.59 (CH.sub.2Cl.sub.2). LCMS m/z 248 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.18-8.02 (m, 2H), 7.73
(s, 1H), 7.68-7.60 (m, 1H), 7.50-7.42 (m, 1H), 3.98-3.88 (m, 4H),
2.09-1.98 (m, 4H). HPLC t.sub.R=4.4 min (method II).
1-(4,8-Dinitronaphthalen-1-yl)pyrrolidine, hydrochloride
(159JP29)
[0510] Pyrrolidine (5.0 mL) was added to
1-chloro-4,8-dinitronaphthalene (50 mg, 0.20 mmol, Bassilios et al,
Recueil, 1962, 81, 209-214) which resulted in an immediate, highly
exothermic reaction. The reaction was further agitated for 5 min
while heating using a heatgun. Volatiles were removed in vacuo and
purification as in 159JP06 (dichloromethane/n-heptane 4:1, 5.times.
eluted) afforded 12 mg (21%) of 159JP29 as an orange solid. The
product was converted to the corresponding hydrochloride salt as
described above.
[0511] R.sub.f=0.58 (CH.sub.2Cl.sub.2). LCMS m/z 288 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.05 (dd, 1H, J=8.9,
1.0), 8.40 (d, 1H, J=9.2), 7.95 (dd, 1H, J=7.5, 1.0), 7.59 (t, 1H,
J=8.8), 6.78 (d, 1H, J=9.2), 3.30 (m, 4H), 1.95 (m, 4H). HPLC
t.sub.R=4.8 min (method II).
4-Pyrrolidin-1-ylnaphthalene-1-sulfonic acid (139 MBT58-C)
[0512] 1-Naphtylamine-4-sulfonic acid (200 mg, 0.90 mmol),
1,4-dibromobutane (193 mg, 0.90 mmol), N,N-diisopropylethylamine
(383 .mu.L, 2.24 mmol) and DMF (10 mL) were heated at 120.degree.
C. for 24 hours. The mixture was then cooled to rt and evaporated
to dryness. The resulting oil was purified by preparative TLC,
eluting with 8% methanol in dichloromethane, followed by cationic
ion-exchange to provide 139 MBT58-C (15 mg, 6%) as a green
solid.
[0513] R.sub.f=0.05 (CH.sub.2Cl.sub.2/methanol 9:1). LCMS m/z 277
[M+H].sup.+. HPLC t.sub.R=1.2 min (method II). .sup.1H-NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.96-8.88 (m, 1H), 8.24-8.15 (m,
1H), 7.98-7.89 (m, 1H), 7.67-7.52 (m, 2H), 7.42-7.30 (m, 1H),
3.76-3.45 (m, 4H), 2.18-2.00 (m, 4H).
[4-(Pyrrolidin-1-yl)naphthalen-1-yl]phosphonic acid diethyl ester
(139 MBT64-B)
[0514] A solution of 1-bromo-4-fluoronaphthalene (500 mg, 2.22
mmol) in tetrahydrofuran (5 mL) was added dropwise to stirred
solution of t-BuLi (1.4 M in pentane, 3.17 mL, 4.44 mmol) in
tetrahydrofuran (5 mL) at -78.degree. C. The reaction mixture was
stirred for 1 hour at -78.degree. C., after which diethyl
chlorophosphate (0.96 mL, 6.66 mmol) was added dropwise. The
reaction mixture was left to warn to rt and concentrated. The
residue was suspended in 2 M NaOH (50 mL) and extracted with
dichloromethane (2.times.50 mL). The combined organic phases were
dried over sodium sulfate, filtered and evaporated to give crude
(4-fluoronaphthalen-1-yl)phosphonic acid diethyl ester (139
MBT60-8C, 512 mg, 60% pure by NMR) as a yellow oil. 139 MBT60-8C
(200 mg, 0.425 mmol) was dissolved in pyrrolidine (0.5 mL) and
stirred 2 hours at rt. The reaction mixture was concentrated and
re-dissolved in dichloromethane (20 mL). The organic phase was
washed with 2 M NaOH (20 mL) and dried over sodium sulfate,
filtered and evaporated. The residue was purified by preparative
TLC (0-5% methanol in dichloromethane) to give the title compound
(89 mg, 30%) as a white solid.
[0515] LCMS m/z 334 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
8.47-8.42 (m, 1H), 8.28-8.24 (m, 1H), 8.17-8.07 (m, 1H), 8.08-7.52
(m, 1H), 7.47-7.40 (m, 1H), 6.86-6.80 (m, 1H), 4.26-4.12 (m, 2H),
4.12-3.97 (m, 2H), 3.60-3.53 (m, 4H), 2.08-2.02 (m, 4H), 1.35-1.27
(m, 6H).
[4-(Pyrrolidin-1-yl)naphthalen-1-yl]phosphonic acid monoethyl ester
(139 MBT64-2C)
[0516] (4-Pyrrolidin-1-ylnaphthalen-1-yl)phosphonic acid diethyl
ester 139 MBT64-B (40 mg, 0.11 mmol) was dissolved in pyrrolidine
(0.5 mL) and the mixture was heated to 80.degree. C. for 20 hours.
The mixture was concentrated and the crude product was purified by
preparative TLC (0-10% methanol in dichloromethane) to give the
title compound (20 mg, 55%) as a white solid.
[0517] LCMS m/z 306 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
10.6-10.3 (bs, 1H), 8.35-8.29 (m, 1H), 8.05-8.00 (m, 1H), 7.95-7.82
(m, 1H), 7.53-7.40 (m, 2H), 7.19-7.12 (m, 1H), 4.01-3.82 (m, 6H),
2.34-2.22 (m, 4H), 1.25-1.15 (m, 3H).
1-(4-Methanesulfonylnaphthalen-1-yl)pyrrolidine (139 MBT70-B)
[0518] A solution of 1-bromo-4-fluoronaphthalene (500 mg, 2.22
mmol) in tetrahydrofuran (1.5 mL) was added dropwise to stirred
solution of t-BuLi (1.4 M in pentane, 3.17 mL, 4.44 mmol) in
tetrahydrofuran (10 mL) at -78.degree. C. The reaction mixture was
stirred for 20 minutes at -78.degree. C., after which the
temperature was raised to -40.degree. C., and sulfur dioxide was
bubbled through the mixture for 5 minutes. The resulting clear
solution was left to warm to rt and concentrated. Dry ether (20 mL)
was added and the resulting white solid was collected by filtration
to give the crude sulfinate salt (139 MBT66-A, 280 mg) as a white
solid. 139 MBT66-A (100 mg) was suspended in DMF (3 mL), and
potassium carbonate (192 mg, 1.39 mmol) was added followed by
methyl iodide (0.09 mL, 1.39 mmol). The reaction mixture was
stirred at rt for 20 hours, then concentrated and re-dissolved in
dichloromethane (20 mL). The organic phase was washed with 2 M NaOH
(20 mL) and dried over sodium sulfate, filtered and evaporated to
give crude 1-fluoro-4-methanesulfonylnaphthalene (139 MBT66-B, 89
mg, 86% yield). 139 MBT66-B (89 mg, 0.397 mmol) was dissolved in
pyrrolidine (0.5 mL) and stirred for 20 hours at rt. The reaction
mixture was concentrated and the residue was re-dissolved in
dichloromethane (20 mL). The organic phase was washed with 2 M NaOH
(20 mL) and dried over sodium sulfate, filtered and evaporated. The
residue was purified by preparative TLC (0-5% methanol in
dichloromethane) to give the title compound (34 mg, 31% yield) as
white solid.
[0519] LCMS m/z 276 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
8.69-8.63 (m, 1H), 8.34-8.28 (m, 1H), 8.18-8.13 (m, 1H), 7.68-7.60
(m, 1H), 7.51-7.44 (m, 1H), 6.80-6.74 (m, 1H), 3.66-3.59 (m, 4H),
3.18 (s, 3H), 2.10-2.03 (m, 4H).
[4-(Pyrrolidin-1-yl)naphthalen-1-yl]sulfonic acid amide (139
MBT76-C)
[0520] The sulfinate salt 139 MBT66-A (100 mg, 0.46 mmol) was
dissolved in tetrahydrofuran (3 mL). Sulfuryl chloride (62 mg, 0.46
mmol) was added at 0.degree. C. and the mixture was left to warm to
rt. The mixture was again cooled to 0.degree. C., and 25% aqueous
ammonia (1 mL) was added. The mixture was left to warm to rt. Water
(50 mL) was added, and the product was extracted with
dichloromethane (2.times.50 mL). The combined organic phases were
dried over sodium sulfate, filtered and evaporated to give crude
[4-fluoronaphthalen-1-yl]sulfonic acid amide (139 MBT68-B, 60 mg).
139 MBT68-B (60 mg, 0.27 mmol) was dissolved in pyrrolidine (0.5
mL) and stirred for 20 hours at rt. The reaction mixture was
concentrated and the residue was re-dissolved in dichloromethane
(40 mL). The organic phase was washed with 2 M NaOH (40 mL) and
dried over sodium sulfate, filtered and evaporated. The residue was
purified by preparative TLC (0-5% methanol in dichloromethane) to
give the title compound (8 mg, 6% yield from 139 MBT66-A) as white
solid.
[0521] LCMS m/z 277 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
8.58-8.53 (m, 1H), 8.31-8.26 (m, 1H), 8.16-8.11 (m, 1H), 7.65-7.58
(m, 1H), 7.50-7.42 (m, 1H), 6.75-6.70 (m, 1H), 3.61-3.54 (m, 4H),
2.07-2.01 (m, 4H).
[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]urea (139
MBT94-C).
[0522] The amine 165RL21 (40 mg, 0.144 mmol) was dissolved in
tetrahydrofuran (1 mL) and cooled to 0.degree. C. Trichloroacetyl
isocyanate (0.019 mL) was added and the solution was left to warm
to rt and stirring was continued for 30 minutes. The mixture was
concentrated and the residue was dissolved in methanol (1 mL). 2 M
NaOH (1 mL) was added, and the mixture was heated to 70.degree. C.
for 1 hour. Then, water (20 mL) was added and methanol was removed
by evaporation in vacuo. The aqueous phase was extracted with
dichloromethane (2.times.20 mL), and the combined organic phases
were dried over sodium sulfate, filtered and evaporated. The
residue was purified by preparative TLC (0-5% methanol in
dichloromethane) to give the title compound (24 mg, 52% yield) as a
white solid.
[0523] LCMS m/z 321 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, exo/endo:
0.5:0.5) .delta. 8.20-8.15 (m, 2H), 7.76-7.72 (m, 1H), 7.67-7.61
(m, 1H), 7.58-7.51 (m, 1H), 6.90-6.84 (m, 1H), 4.86-4.82 (m, 0.5H),
4.37-4.11 (m, 5.5H), 2.66-2.58 (m, 1H), 2.20-1.80 (m, 8H).
Dimethylcarbamic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(139 MBT84-1E)
[0524] The alcohol 154BG31 (150 mg, 0.54 mmol) was dissolved in
toluene (1 mL). Triethylamine (0.150 mL, 1.08 mmol) was added
followed by dimethylcarbamoyl chloride (0.074 mL, 0.81 mol). The
reaction mixture was stirred at 90.degree. C. for 3 days, and then
concentrated. The crude product was purified by preparative TLC
(0-5% methanol in dichloromethane) to give the title compound (32
mg, 17% yield) as a white solid.
[0525] LCMS m/z 350 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3) .delta.
8.21-8.15 (m, 2H), 7.77-7.73 (m, 1H), 7.68-7.61 (m, 1H), 7.59-7.52
(m, 1H), 6.92-6.88 (m, 1H), 5.20-5.15 (m, 1H), 4.16-4.10 (m, 2H),
2.97 (s, 6H), 2.57-2.46 (m, 2H), 2.20-2.00 (m, 6H).
4-(4-Hydroxy-4-phenylpiperidin-1-yl)naphthalene-1-carbonitrile (196
MBT2-4)
[0526] 1-Cyano-4-fluoronaphthalene (20 mg, 0.117-mol) was dissolved
in pyridine (1 mL). 4-Hydroxy-4-phenylpiperidine (83 mg, 0.467
mmol) was added and the reaction mixture was shaken at 110.degree.
C. for 3 days in a sealed vial. The reaction mixture was
concentrated and re-suspended in 2 M HCl (1 mL). The product
mixture was extracted with ethyl acetate (2.times.10 mL), and the
combined organic phases were concentrated. The residue was purified
by preparative reversed phase HPLC to give the title compound (14
mg, 36% yield) as a white solid.
[0527] LCMS m/z 329 [M+H].sup.+.
4-Azepan-1-ylnaphthalene-1-carbonitrile (196 MBT2-6)
[0528] The title compound (7 mg, 24% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and hexamethyleneimine (46 mg, 0.468 mmol).
[0529] LCMS m/z 251 [M+H].sup.+.
4-(2,5-Dimethyl-2,5-dihydropyrrol-1-yl)naphthalene-1-carbonitrile
(196 MBT2-7)
[0530] The title compound (1 mg, 3% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and 2,5-dimethyl-2,5-dihydro-1H-pyrrole (45 mg, 0.468
mmol).
[0531] LCMS m/z 249 [M+H].sup.+.
4-(3,6-Dihydro-2H-pyridin-1-yl)naphthalene-1-carbonitrile (196
MBT2-9)
[0532] The title compound (7 mg, 26% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and 1,2,3,6-tetrahydropyridine (39 mg, 0.468 mmol).
[0533] LCMS m/z 235 [M+H].sup.+.
4-(8-Oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido[1,2-a][1,5]diazocin-3--
yl)naphthalene-1-carbonitrile (196 MBT2-10)
[0534] The title compound (3 mg, 8% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and
8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido[1,2-a][1,5]diazocine
(89 mg, 0.468 mmol).
[0535] LCMS m/z 342 [M+H].sup.+.
4-Thiomorpholin-4-ylnaphthalene-1-carbonitrile (196 MBT2-11)
[0536] The title compound (6 mg, 20% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and thiomorpholine (48 mg, 0.468 mmol).
[0537] LCMS m/z 255 [M+H].sup.+.
4-(4-Benzyl-4-hydroxypiperidin-1-yl)naphthalene-1-carbonitrile (196
MBT2-16)
[0538] The title compound (12 mg, 30% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and 4-benzyl-4-hydroxypiperidine (89 mg, 0.468
mmol).
[0539] LCMS m/z 343 [M+H].sup.+.
4-(4-Oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl)naphthalene-1-carbonitri-
le (196 MBT2-17)
[0540] The title compound (7 mg, 16% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and 1-phenyl-1,3,8-triazaspiro-[4,5]decan-4-one (108
mg, 0.468 mmol).
[0541] LCMS m/z 383 [M+H].sup.+.
4-(4-Benzoylpiperidin-1-yl)naphthalene-1-carbonitrile (196
MBT2-19)
[0542] The title compound (3 mg, 8% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and 4-benzoylpiperidine (89 mg, 0.468 mmol).
[0543] LCMS m/z 341 [M+H].sup.+.
1-(4-Cyanonaphthalen-1-yl)4-phenylpiperidine-4-carbonitrile (196
MBT2-20)
[0544] The title compound (1 mg, 3% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and 4-cyano-4-phenylpiperidine (87 mg, 0.468 mmol).
[0545] LCMS m/z 338 [M+H].sup.+.
4-((S)-4a-Hydroxyoctahydroisoquinolin-2-yl)naphthalene-1-carbonitrile
(196 MBT2-24)
[0546] The title compound (8 mg, 22% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and (S)-4a-hydroxyoctahydroisoquinoline (73 mg, 0.468
mmol).
[0547] LCMS m/z 307 [M+H].sup.+.
4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)naphthalene-1-carbonitrile
(196 MBT2-26)
[0548] The title compound (7 mg, 19% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and 6-methoxy-3,4-dihydro-1H-isoquinoline (76 mg, 0.468
mmol).
[0549] LCMS m/z 315 [M+H].sup.+.
4-((R)-2-Phenylaminomethylpyrrolidin-1-yl)naphthalene-1-carbonitrile
(196 MBT2-2)
[0550] The title compound (7 mg, 18% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and (R)-(-)-2-phenylaminomethylpyrrolidine (82 mg,
0.468 mmol).
[0551] LCMS m/z 328 [M+H].sup.+.
4-(9-Hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]non-3-yl)naphthalene-1-
-carbonitrile (196 MBT2-13)
[0552] The title compound (3 mg, 8% yield) was prepared as
described for 196 MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg,
0.117 mmol) and
9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane (86 mg,
0.468 mmol).
[0553] LCMS m/z 336 [M+H].sup.+.
4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-c-
arbonitrile (156AF70-267)
[0554] A solution of methyl magnesium bromide in diethyl ether (3
M, 3.7 mL, 11.09 mmol) was diluted with anhydrous THF (5 mL).
Lithium bromide (1.93 g, 22.1 mmol) was slowly added to the
solution at rt, followed by addition of a solution of
Boc-nortropinone (500 mg, 2.21 mmol) in anhydrous THF (5 mL). The
reaction mixture was stirred at 50.degree. C. for 2 hours and
stirring was continued overnight at rt. The reaction was quenched
with water and the mixture partitioned between ethyl acetate and
water. The organic layer was dried over sodium sulfate, filtered
and evaporated to dryness. Purification of the residue by silica
gel column chromatography, eluting with a mixture of ethyl acetate
and n-heptane (50:50), afforded
3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid
tert-butyl ester (168 mg, 31%). The obtained product was dissolved
in 2 M HCl in diethyl ether (5 mL). After 4 hours stirring at rt
the mixture was left on standing overnight. The formed participate,
3-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride, was isolated
by filtration and dissolved in a mixture of dichloromethane and
methanol (90:10). PS-Trisamine was added to the solution and it was
left standing overnight. The resin was removed by filtration and
washed with dichloromethane. The filtrate was evaporated to dryness
affording pure 3-methyl-8-azabicyclo[3.2.1]octan-3-ol.
1-Cyano-4-fluoronaphthalene (37.1 mg, 0.22 mmol) was added to a
solution of 3-methyl-8-azabicyclo[3.2.1]octan-3-ol (91 mg, 0.64
mmol) in DMF (1 mL), followed by addition of pyridine (1 mL). The
reaction mixture was stirred overnight at 100.degree. C., cooled
down to rt and partitioned between ethyl acetate and water. The
organic layer was dried over sodium sulfate, filtered and
evaporated to dryness. Purification of the residue by silica gel
column chromatography, eluting with a mixture of ethyl acetate and
n-heptane (50:50), and by reverse phase preparative HPLC afforded
the title compound (58 mg, 90%).
[0555] R.sub.f=0.31 (Ethyl acetate/n-Heptane 50:50). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.26-8.15 (m, 2H, Ar--H), 7.78 (d,
1H, J=8.0, Ar--H), 7.71-7.51 (m, 2H, Ar--H), 6.91 (d, 1H, J=8.0,
Ar--H), 4.21-4.10 (m, 2H, Tr-H), 2.39-2.28 (m, 4H, Tr-H), 2.02-1.89
(m, 4H, Tr-H), 1.39 (m, 3H, CH.sub.3). LCMS m/z 293 [M+H].sup.+.
HPLC t.sub.R=4.1 (method A).
[0556] Alternatively, the title compound was obtained using the
following procedure: To a solution of 197FBA20a (2.375 g, 13.42
mmol) in DMSO (35 mL) was added 1-cyano-4-fluonaphthalene (1.767 g,
10.32 mmol) and potassium carbonate (4.636 g, 33.54 mmol) and the
reaction was allowed to stir at 100.degree. C. for 18 h. The
mixture was cooled, diluted with ethyl acetate (200 mL) and washed
with water (3.times.35 mL). The organic phase was dried over sodium
sulfate, filtered and evaporated to give a crude product which was
purified by filtration over silica gel. Elution with a stepwise
gradient of 30-50% ethyl acetate in heptane afforded the title
compound as a white solid (2.539 g, 84%).
[0557] LCMS m/z 293 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.19 (d, J=8.5, 2H), 7.76 (d, J=8.1, 1H), 7.70-7.60 (m,
1H), 7.60-7.50 (m, 1H), 6.92 (d, J=8.1, 1H), 4.27-4.08 (m, 2H),
2.43-2.26 (m, 4H), 2.06-1.86 (m, 4H), 1.37 (s, 3H). .sup.13C-NMR
(CDCl.sub.3, 75 MHz) 153.0, 134.6, 133.8, 128.5, 128.0, 126.2,
126.1, 125.6, 119.3, 111.2, 102.2, 69.9, 60.6, 46.2, 34.7,
26.9.
[0558] Alternatively, the title compound was obtained using the
following procedure: To a suspension of lithium chloride (26 mg,
0.621 mmol) and sodium borohydride (23 mg, 0.621 mmol) in diglyme
(0.5 mL) was added a solution of 183AF16-294 (120 mg, 0.414 mmol)
in diglyme (0.5 mL), and the reaction mixture was stirred at
90.degree. C. After 13 h the mixture was diluted with diethylether
and washed with water. The organic phase was dried over sodium
sulfate, filtered and evaporated. The crude product (98 mg, 76%)
was purified by recrystallization from ethyl acetate or by
filtration over silica gel as described above to give pure title
compound.
4-(3-endo-Hydroxy-3-exo-propyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-c-
arbonitrile (156AF96-284)
[0559] The title compound was prepared from
3-propyl-8-azabicyclo[3.2.1]octan-3-ol and
1-cyano-4-fluoronaphthalene using the same method as for
preparation of 156AF70-267.
[0560] R.sub.f=0.43 (ethyl acetate/n-heptane 50:50). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.20 (m, 2H, --Ar--H), 7.77 (d, 1H,
J=8.0, Ar--H), 7.70-7.51 (m, 2H, Ar--H), 6.91 (d, 1H, J=8.0,
Ar--H), 4.21-4.10 (m, 2H, Tr-H), 2.39-2.22 (m, 4H, Tr-H), 2.01-1.84
(m, 4H, Tr-H), 1.63-1.40 (m, 4H, CH.sub.2Pr), 1.00 (m, 3H,
CH.sub.3Pr). LCMS m/z 321 [M+H].sup.+. HPLC t.sub.R=5.1 min (method
A).
4-(endo-Spiro[8-azabicyclo[3.2.1]octane-3,2'-oxiran]-8-yl)naphthalene-1-ca-
rbonitrile (183AF16-294)
[0561] Trimethylsulfoxonium iodide (359 mg, 1.63 mmol) was added to
a suspension of sodium hydride (55%, 71 mg, 1.63 mmol) in dry DMSO
(1.5 mL) at rt under argon atmosphere. After 1 hour stirring at rt,
a solution of
4-(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(156AF03-217) in DMSO (2.0 mL) was added to the reaction mixture at
rt. Stirring was continued overnight at rt. The reaction mixture
was partitioned between ethyl acetate and water. The organic layer
was washed with 4% (w/v) aqueous magnesium sulfate, dried over
sodium sulfate, filtered and evaporated to dryness. Purification of
the residue by silica gel column chromatography, eluting with a
stepwise gradient of 30 to 45% of ethyl acetate in n-heptane,
afforded the title compound (194 mg, 61%).
[0562] R.sub.f=0.26 (Ethyl acetate/n-Heptane 45:55). LCMS m/z 291
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.24 (d,
J=8.4, 1H), 8.20 (d, J=8.3, 1H), 7.77 (d, J=8.0, 1H), 7.71-7.62 (m,
1H), 7.61-7.52 (m, 1H), 6.94 (d, J=8.0, 1H), 4.33-4.16 (m, 2H),
2.85-2.71 (m, 2H), 2.58 (s, 2H), 2.36-2.17 (m, 2H), 2.15-1.97 (m,
2H), 1.55-1.41 (m, 2H). .sup.13C-NMR (CDCl.sub.3, 75 MHz) 152.9,
134.6, 133.8, 128.6, 128.1, 126.5, 126.1, 125.5, 119.2, 111.6,
102.7, 61.0, 55.1, 48.7, 40.9, 27.3.
4-[3-exo-(4-ethylpiperazin-1-ylmethyl)-3-endo-hydroxy-8-azabicyclo[3.2.1]o-
ct-8-yl]naphthalene-1-carbonitrile (183AF18-295)
[0563] N-Ethyl piperazine (2.0 mL, 15.8 mmol) was added to a
solution of 183AF16-294 (74 mg, 0.25 mmol) in methanol (0.5 mL) at
rt. The reaction mixture was shaken overnight at 70.degree. C.,
allowed to cool down to rt and partitioned between ethyl acetate
and water. The organic layer was washed with brine, dried over
sodium sulfate, filtered and evaporated to dryness. Purification of
the residue by silica gel column chromatography, eluting with 10%
methanol in dichloromethane, afforded the title compound (85 mg,
84%).
[0564] R.sub.f=0.22 (MeOH/CH.sub.2Cl.sub.2 15:85). LCMS m/z 405
[M+H].sup.+. HPLC t.sub.R=2.6 min (method A). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.22-8.11 (m, 2H), 7.76 (d, 1H,
J=8.0), 7.69-7.50 (m, 2H), 6.90 (d, 1H, J=8.0), 4.21-4.10 (m, 2H),
2.84-2.30 (m, 14H), 2.19-2.09 (m, 2H), 2.01-1.84 (m, 4H), 1.18-1.08
(m, 3H).
4-(3-endo-hydroxy-3-exo-hydroxymethyl-8-azabicyclo[3.2.1]oct-8-yl)naphthal-
ene-1-carbonitrile (183AF19-296)
[0565] Aqueous sulfuric acid (0.2 M, 2.5 mL) was added dropwise to
a solution of 183AF16-294 (60 mg, 0.21 mmol) in THF (2.5 mL) at rt.
After 3 hours stirring at rt the reaction mixture was neutralized
with saturated sodium bicarbonate. THF was removed and the residue
passed over an acidic ion-exchange SPE cartridge. The obtained
product was purified by silica gel column chromatography using
ethyl acetate as eluent. Yield: 20 mg, 31%.
[0566] R.sub.f=0.13 (MeOH/CH.sub.2Cl.sub.2 05:95). LCMS m/z 309
[M+H].sup.+. HPLC t.sub.R=2.5 min (method A). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.31 (d, 1H, J=8.0, Ar--H), 8.21 (d,
1H, J=8.0, Ar--H), 7.79 (d, 1H, J=8.0, Ar--H), 7.73-7.60 (m, 2H,
Ar--H), 6.94 (d, 1H, J=8.0, Ar--H), 4.31-4.20 (m, 2H, Tr-H), 3.61
(s, 2H, CH.sub.2OH), 2.59-2.48 (m, 2H, Tr-H), 2.20-1.69 (m, 6H,
Tr-H).
4-(3-exo-Cyanomethyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalen-
e-1-carbonitrile (183AF21-297)
[0567] Potassium cyanide (45 mg, 0.69 mmol) and lithium perchlorate
(12 mg, 0.11 mmol) were added to a solution of 183AF16-294 (29 mg,
0.10 mmol) in acetonitrile (2 mL) at rt. The reaction mixture was
stirred at 70.degree. C. for 3 days. The reaction mixture was
allowed to cool to rt and partitioned between ethyl acetate and
water. The organic layer was dried over sodium sulfate, filtered
and evaporated to dryness. Purification of the residue by silica
gel column chromatography, eluting with a mixture of ethyl acetate
and n-heptane (45:55), afforded the title compound (13 mg,
41%).
[0568] R.sub.f=0.11 (ethyl acetate/n-heptane 45:55). LCMS m/z 318
[M+H].sup.+. HPLC t.sub.R=3.6 min (method A). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.21 (d, 1H, J=8.0, Ar--H), 8.14 (d,
1H, J=8.0, Ar--H), 7.78 (d, 1H, J=8.0, Ar--H), 7.70-7.55 (m, 2H,
Ar--H), 6.92 (d, 1H, J=8.0, Ar--H), 4.28-4.16 (m, 2H, Tr-H), 2.62
(s, 2H, CH.sub.2CN), 2.48-2.01 (m, 8H, Tr-H).
4-(3-endo-Hydroxy-3-exo-{[2-(1H-imidazol-4yl)ethylamino]methyl}-8-azabicyc-
lo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile (183AF23-298).
[0569] A solution of histamine (192 mg, 1.72 mmol) in methanol (1
mL) was added to a solution of 183AF16-294 (50 mg, 0.17 mmol) in
THF (1 mL). After 20 hours stirring at 60.degree. C., the reaction
mixture was allowed to cool to rt and partitioned between ethyl
acetate and water. The organic layer was dried over sodium sulfate,
filtered and evaporated to dryness. Purification of the residue by
silica gel column chromatography, eluting with a stepwise gradient
of 15-50% methanol in dichloromethane, afforded the title compound
(32 mg, 47%).
[0570] R.sub.f=0.11 (MeOH/CH.sub.2Cl.sub.2 50:50). LCMS m/z 402
[M+H].sup.+. HPLC t.sub.R=1.9 min (method A).
4-(3-endo-Hydroxy-3-exo-methoxymethyl-8-azabicyclo[3.2.1]oct-8-yl)naphthal-
ene-1-carbonitrile (183AF24-299)
[0571] A solution of concentrated sulfuric acid (14 .mu.L) in
methanol (1 mL) was added dropwise to solution of 183AF16-294 (53
mg, 0.18 mmol) in THF (1 mL) at rt. After 1 hour stirring at rt,
the reaction mixture was neutralized with saturated sodium
bicarbonate and concentrated in vacuo. The residue was partitioned
between ethyl acetate and water. The organic layer was washed with
brine, dried over sodium sulfate, filtered and evaporated to
dryness. Purification of the residue by silica gel column
chromatography, eluting with a stepwise gradient of 45-80% ethyl
acetate in n-heptane, afforded the title compound (17 mg, 29%).
[0572] R.sub.f=0.28 (ethyl acetate/n-heptane 80:20). LCMS m/z 323
[M+H].sup.+. HPLC t.sub.R=3.2 min (method A). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 8.18 (d, 1H, J=8.0, Ar--H), 8.12 (d,
1H, J=8.0, Ar--H), 7.67 (d, 1H, J=8.0, Ar--H), 7.61-7.53 (m, 2H,
Ar--H), 6.81 (d, 1H, J=8.0, Ar--H), 4.21-4.10 (m, 2H, Tr-H), 3.62
(s, 2H, CH.sub.2OCH.sub.3), 3.20 (s, 3H, CH.sub.2OCH.sub.3),
2.36-2.23 (m, 2H, Tr-H), 2.03-1.96 (m, 4H, Tr-H), 1.71-1.63 (m, 2H,
Tr-H).
7-Bromo-4-pyrrolidin-1-ylnaphthalene-1-carbonitrile, hydrochloride
and 6-bromo-4-pyrrolidin-1-ylnaphthalene-1-carbonitrile,
hydrochloride (159JP02-X3)
[0573] 1-Cyano-4-fluoronaphthalene (360 mg, 2.1 mmol) and bromine
(1.5 mL) were heated to 60.degree. C. for 1 h in a sealed vial.
After cooling to rt, the reaction mixture was quenched with 4 M
NaOH (50 mL), extracted with dichloromethane (3.times.50 mL), dried
over sodium sulfate, filtered and concentrated in vacuo. The
residue was passed through a pad of silica
(n-heptane/dichloromethane 1:1), and the collected fractions
concentrated in vacuo. Pyrrolidine (1.5 mL) was added to the
off-white residue thus obtained (90 mg) and the resulting mixture
was heated under microwave irradiation at 100.degree. C. for 10 min
and the reaction mixture concentrated in vacuo. Purification by
preparative TLC (n-heptane/dichloromethane, 1:1, 5.times. eluted)
afforded the title compounds (8.0 mg, 1.1%) as an off-white solid.
The product was converted to the corresponding hydrochloride salt
as described above.
[0574] R.sub.f=0.71 (CH.sub.2Cl.sub.2). LCMS m/z 302 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz, 3:1 mixture of two regioisomers)
.delta. 8.42 (d, 0.75H, J=3.2), 8.29 (d, 0.25H, J=3.2), 8.10 (d,
0.25H, J=10.0), 8.01 (d, 0.75H, J=10.0), 7.72 (d, 0.75H, J=10.0),
7.69 (d, 0.25H, J=10.0), 7.65 (dd, 0.75H, J=10.5, 2.0), 7.48 (dd,
0.25H, J=10.5, 2.0), 6.72 (d, 0.75H, J=8.8), 6.67 (d, 0.25H,
J=8.8), 3.61 (m, 4H), 2.04 (m, 4H). HPLC t.sub.R=5.5 min (method
III).
4-(8-Azaspiro[4.5]dec-8-yl)naphthalene-1-carbonitrile
(159JP61AA)
[0575] 4-Amino-1-naphthalenecarbonitrile (168.20 mg),
3,3-tetramethylene-1,5-dibromopentane (284 mg, 1.0 mmol, Klitgaard,
N. et al., Acta Chem. Scand. 1970, 24, 33-42),
N,N-diisopropylethylamine (323 mg, 2.5 mmol) and toluene (15 mL)
were heated to 120.degree. C. for 16 h. The crude product was
poured in water (100 mL), extracted with ethyl acetate (3.times.100
mL), the combined organic layers dried over sodium sulfate,
filtered and concentrated in vacuo. Purification by preparative TLC
(dichloromethane, 3.times. eluted) afforded the title compound (14
mg, 5.0%) as an off-white solid.
[0576] R.sub.f=0.57 (CH.sub.2Cl.sub.2). LCMS m/z 291 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.11 (d, 2H, J=11.0),
7.72 (d, 1H, J=11.0), 7.61-7.43 (m, 2H), 6.92 (d, 1H, J=11.0), 3.05
(m, 4H), 1.75-1.22 (m, 12H). HPLC t.sub.R=7.0 min (method III).
4-Nitrobenzoic acid
exo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(159JP66C)
[0577] Diisopropylazodicarboxylate (1.62 g, 8.0 mmol) was added
over 10 min to a solution of 154BG31 (556.7 mg, 2.0 mmol),
triphenylphosphine (2.098 g, 8.0 mmol) and 4-nitrobenzoic acid
(1.34 g, 8.0 mmol) in THF (15 mL) under argon atmosphere at
0.degree. C. The reaction was stirred overnight at rt, then
additional 3 h at 40.degree. C. before partitioning the mixture
between diethylether (150 mL) and sat. aq. NaHCO.sub.3 (150 mL).
The aqueous phase was extracted with additional diethylether (100
mL), n-heptane (300 mL) was added to the combined ether extracts
and the resulting solution was passed through a pad of silica. The
title compound crystallized upon standing as long yellow needles
which were collected by filtration and then dried in vacuo to
afford the desired product (425 mg, 50%).
[0578] R.sub.f=0.42 (CH.sub.2Cl.sub.2). LCMS m/z 428 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.35-8.25 (m, 6H), 7.78
(d, 1H, J=7.5), 7.70-7.55 (m, 2H), 6.82 (d, 1H, J=7.5), 5.53 (m,
1H), 4.12 (br s, 2H), 2.41-1.88 (m, 8H). HPLC t.sub.R=6.0 min
(method III).
4-(3-exo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP68F6)
[0579] 159JP66C (280 mg, 0.65 mmol), 2 M LiOH (30 mL) and
tetrahydrofuran (30 mL) were stirred overnight at rt, extracted
with dichloromethane (3.times.100 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
vacuum flash chromatography, eluting with a gradient of 0-50% ethyl
acetate in n-heptane, to give the title compound (162 mg, 89%) as
an off-white solid.
[0580] R.sub.f=0.21 (ethyl acetate/n-heptane 1:1). LCMS m/z 279
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.28-8.16
(m, 2H), 7.77 (d, 1H, J=8.1), 7.71-7.53 (m, 2H), 6.82 (d, 1H,
J=8.1), 4.21 (m, 3H), 2.22-1.79 (m, 6H), 1.38-0.89 (m, 2H). HPLC
t.sub.R=3.2 min (method III).
4-(3-exo-Methoxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP72A)
[0581] 159JP68F6 (34 mg, 0.12 mmol), sodium hydride (50%, 9 mg,
0.18 mmol) and iodomethane (35 mg, 0.24 mmol) were shaken in
tetrahydrofuran (5 mL) under argon atmosphere at 50.degree. C. for
24 h. The crude product was quenched by methanol (10 mL),
concentrated in vacuo. Purification by preparative TLC (ethyl
acetate/n-heptane 1:4, 3.times. eluted) afforded the title compound
(26 mg, 73%) as an off-white solid.
[0582] R.sub.f=0.34 (ethyl acetate/n-heptane 1:1). LCMS m/z 293
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.28-8.09
(m, 2H), 7.66 (d, 1H, J=8.8), 7.61-7.42 (m, 2H), 6.82 (d, 1H,
J=8.8), 4.12 (m, 2H), 3.63 (m, 1H), 3.32 (s, 3H), 2.17-1.64 (m,
8H). HPLC t.sub.R=4.6 min (method III).
(S)-1-(4-Cyanonaphthalen-1-yl)pyrrolidine-2-carboxylic acid methyl
ester (159JP74A)
[0583] 1-Cyano-4-fluoronaphthalene (109 mg, 0.64 mmol) and
L-proline methyl ester (380 mg, 2.95 mmol) were heated to
60.degree. C. for 2 days in a sealed vial. The crude product was
concentrated in vacuo and purified by preparative TLC (ethyl
acetate/n-heptane 1:3, 3.times. eluted) to afford the title
compound (2.9 mg, 1.7%) as an off-white solid.
[0584] R.sub.f=0.42 (ethyl acetate/n-heptane 1:1). LCMS m/z 281
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.18-8.08
(m, 2H), 7.68 (d, 1H, J=8.2), 7.60-7.41 (m, 2H), 6.78 (d, 1H,
J=8.2), 4.58 (t, 1H, J=5.8), 4.05 (m, 1H), 3.55 (s, 3H), 3.22 (m,
1H), 2.42-1.88 (m, 4H). HPLC t.sub.R=4.0 min (method III).
4-(8-Azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile
(159JP80XX).
[0585] Oxalyl chloride (6.84 mL, 79.4 mmol) in dichloromethane (300
mL) was added under argon to dimethylsulfoxide (11.28 mL) in
dichloromethane (100 mL) at -60.degree. C. To the resulting
solution, 154BG31 (10.02 g, 36 mmol) in dichloromethane (100 mL)
was added at a rate so that temperature did not exceed 60.degree.
C. The reaction was then kept at -50.degree. C. for 1 h before
cooling to -60.degree. C., adding triethylamine (29.53 mL, 216.3
mmol) slowly and allowing the reaction to warm to rt overnight. The
volatiles were removed in vacuo, the residue extracted with ethyl
acetate (3.times.300 mL), the combined ethyl acetate layers washed
with water (500 mL), and the organic phases were dried over sodium
sulfate, filtered and concentrated in vacuo. Crystallization from
ethyl acetate gave an off-white solid which was filtered off, the
mother liquor was concentrated in vacuo and preparative TLC (ethyl
acetate/n-heptane, 1:4, 5.times. eluted) afforded the title
compound (3.6 mg, 0.04%) as an off-white solid.
[0586] R.sub.f=0.57 (dichloromethane). LCMS m/z 261 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.15 (d, 1H, J=7.0),
7.70-7.42 (m, 4H), 6.92 (d, 1H, J=7.0), 6.05 (m, 1H), 5.52 (m, 1H),
4.43 (m, 1H), 4.02 (m, 1H), 2.40-1.90 (m, 6H). HPLC t.sub.R=5.4 min
(method III).
4-(8-Azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(173FBA64b).
[0587] To a solution of 173FBA60a (400 mg, 0.9 mmol) in
DMF/sulfolane 1:1 (5 mL) and cyclohexane (5 mL) was added sodium
cyanoborohydride (226 mg, 3.6 mmol) and p-toluenesulfonic acid
monohydrate (45 mg), and the reaction was stirred at 110.degree. C.
for 7 h. The reaction was then diluted with water and extracted
three times with cyclohexane. The cyclohexane solution was washed
twice with water, dried over sodium sulfate, filtered and
evaporated to give a crude product, which was purified by silica
gel column chromatography using heptane/ethyl acetate (8:2) as the
eluent, to give 173FBA64b as a white solid (94 mg, 40%).
[0588] LCMS m/z 263 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.28 (d, J=8.3, 1H), 8.18 (d, J=8.9, 11H), 7.75 (d, J=8.1,
11H), 7.71-7.61 (m, 1H), 7.61-7.51 (m, 1H), 6.90 (d, J=8.1, 1H),
4.28-4.02 (m, 2H), 2.28-1.92 (m, 4H), 1.92-1.58 (m, 6H).
.sup.13C-NMR (CDCl.sub.3, 75 MHz) 153.6, 134.7, 133.9, 128.5,
128.0, 126.1, 126.0, 125.9, 119.4, 111.0, 101.9, 61.6, 32.6, 27.5,
17.5.
[0589] Alternatively, the title compound was also obtained using
the following procedure: 8-Azabicyclo[3,2,1]octane (20 mg, 0.18
mmol), 1-cyano-4-fluoronaphthalene (46 mg, 0.27 mmol) and pyridine
(0.5 mL) were heated overnight at 100.degree. C., concentrated in
vacuo and the residue purified by preparative TLC (dichloromethane,
3.times. eluted) to afford the title compound (1.8 mg, 4.0%) as a
yellow oil.
Acrylic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester
(159JP79)
[0590] 154BG31 (2.0 g, 7.2 mmol) and triethylamine (1.45 g, 14.4
mmol) in dichloromethane (40 mL) were cooled to -20.degree. C. and
3-chloropropionyl chloride (1.37 g, 10.8 mmol) in dichloromethane
(5 mL) was added over 15 min and the reaction was allowed to warm
to rt overnight. Partitioning of the reaction mixture between ethyl
acetate (3.times.300 mL) and water (300 mL), drying of the combined
organic phases over Na.sub.2SO.sub.4, filtration and removing of
volatiles in vacuo afforded the title compound (920 mg, 40%) as a
yellow solid.
[0591] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.20 (d, 2H,
J=9.4), 7.81 (d, 1H, 9.4), 7.72-7.55 (m, 2H), 6.92 (d, 1H, J=9.4),
6.45 (m, 1H,), 6.18 (m, 1H), 5.81 (m, 1H), 5.38 (m, 1H), 4.18 (br
s, 2H), 2.62-2.07 (m, 8H).
3-Pyrrolidin-1-yl-propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
fumarate (159JP82F6).
[0592] 159JP79 (65 mg, 0.2 mmol) and pyrrolidine (2 mL) were heated
to 100.degree. C. overnight. Volatiles were concentrated in vacuo
and the residue purified by vacuum flash chromatography, eluting
with a gradient of 0-100% methanol in dichloromethane, to give of
title compound (24 mg, 30%) as a white solid. The product was
converted to the corresponding fumarate salt as described
above.
[0593] R.sub.f=0.42 (dichloromethane/MeOH, 10:1). LCMS m/z 404
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.12 (d, 2H,
J=8.8), 7.65 (d, 1H, J=8.1), 7.60-7.47 (m, 2H), 6.81 (d, 1H,
J=8.1), 5.20 (t, 1H, J=5.2), 4.05 (br s, 2H), 3.38 (m, 1H), 2.80
(m, 1H), 2.65-2.40 (m, 8H), 2.20-1.82 (m, 9H). HPLC t.sub.R=3.2 min
(method III).
3-imidazol-1-yl-propionic acid
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
fumarate (159JP83A).
[0594] 159JP79 (70 mg, 0.22 mmol), imidazole (200 mg, 2.94 mmol)
and 1-methyl-2-pyrrolidinone (0.5 mL) were placed in a sealed Pyrex
vial and heated under microwave irradiation at 180.degree. C. for
15 min. The reaction mixture was partitioned between ethyl acetate
(2.times.100 mL) and water, the combined organic phases dried over
Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo. The
residue was purified by preparative TLC (MeOH/dichloromethane 1:4,
5.times. eluted) to afford the title compound (48 mg, 55%) as a
thick oil. The product was converted to the corresponding fumarate
salt as described above.
[0595] R.sub.f=0.32 (dichloromethane/MeOH 10:1). LCMS m/z 401
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.18 (t, 2H,
J=8.4), 7.67 (d, 1H, J=8.0), 7.60-7.42 (m, 2H), 7.02-6.88 (m, 2H),
6.79 (d, 1H, J=8.0), 5.22 (t, 1H, J=5.2), 4.22 (t, 2H, J=6.4), 4.00
(br s, 2H), 3.31 (t, 1H, J=7.0), 2.78-2.70 (m, 3H), 2.45-2.38 (m,
2H), 2.29 (t, 1H, J=8.0), 1.95-1.80 (m, 3H). HPLC t.sub.R=3.8 min
(method III).
3-Pyrazol-1-yl-propionic acid
endo-8-(4-cyano-naphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl ester,
fumarate (159JP85A).
[0596] This reaction was carried out as in 159JP83, starting with
159JP79 (184 mg, 0.57 mmol) and using pyrazole instead of imidazole
to afford the title compound (88 mg, 39%) as a colorless oil. The
product was converted to the corresponding fumarate salt as
described above.
[0597] R.sub.f=0.41 (dichloromethane/MeOH, 10:1). LCMS m/z 401
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.20 (m,
2H), 7.72 (d, 1H, J=8.1), 7.69-7.45 (m, 4H), 6.88 (d, 1H, J=8.0),
6.21 (t, 1H, J=2.1), 5.31 (t, 1H, J=5.0), 4.49 (t, 2H, J=6.6), 4.09
(br s, 2H), 2.95 (t, 1H, J=6.6), 2.48 (m, 2H), 2.11-1.90 (m, 6H).
HPLC t.sub.R=4.6 min (method III).
4-(2-Methyl-3-oxo-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP84).
[0598] To 156AF03-217 (552 mg, 2 mmol) in THF (20 mL) under argon
atmosphere at -78.degree. C. was added dropwise lithium
bis(trimethylsilyl)amide (2.6 mL, 2.6 mmol, 1 M in THF). After 30
min at -78.degree. C., iodomethane (2.0 mL) was added over 1 min
and the reaction was allowed to warm to rt overnight. Partitioning
of the reaction mixture between ethyl acetate (2.times.500 mL) and
water (500 mL), drying of the combined organic phases over
Na.sub.2SO.sub.4, filtration, removing of volatiles in vacuo and
purification by preparative TLC (ethyl acetate/n-heptane 1:4,
5.times. eluted) afforded the title compound (115 mg, 20%) as a
thick oil.
[0599] R.sub.f=0.55 (ethyl acetate/n-heptane 1:1). LCMS m/z 291
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.25-8.10
(m, 2H), 7.71 (d, 1H, J=8.0), 7.65-7.50 (m, 2H), 6.92 (d, 1H, J=8),
4.32 (m, 1H), 4.12 (m, 1H), 2.98 (m, 2H), 2.43 & 2.37 (2d, 1H,
J=2.2), 2.11-1.65 (m, 4H), 1.05 (d, 3H, J=6.8). HPLC t.sub.R=4.3
min (method III).
4-(2-Methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile
(159JP87A).
[0600] 159JP84 (115 mg, 0.40 mmol) and p-toluenesulfonhydrazide (90
mg, 0.48 mmol) in absolute ethanol (1.0 mL) were refluxed overnight
and the resulting white precipitate was filtered off, dried in
vacuo and added to a vial containing sodium cyanoborohydride (101
mg, 1.60 mmol), N,N-dimethylformamide (2.0 mL), sulfolane (2.0 mL),
p-toluenesulfonic acid (25 mg) and cyclohexane (2.0 mL). The
resulting solution was heated at 110.degree. C. for 2 days, poured
into water (200 mL), extracted with ethyl acetate (2.times.200 mL),
dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo and
purified by preparative TLC (ethyl acetate/n-heptane 1:5, 5.times.
eluted) to afford the title compound (25.3 mg, 22%) as thick
oil.
[0601] R.sub.f=0.70 (ethyl acetate/n-heptane, 1:1). LCMS m/z 277
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.16 (d, 1H,
J=8.0), 8.09 (d, 1H, J=8.2), 7.67 (d, 1H, J=8.0), 7.62-7.45 (m,
2H), 6.82 (d, 1H, J=8.1), 4.02 (m, 1H), 3.88 (m, 1H), 2.12 (m, 1H),
2.05-1.92 (m, 2H), 1.89-1.60 (m, 5H), 1.21 (m, 1H), 0.83 (d, 1H,
J=6.8). HPLC t.sub.R=6.2 min (method III).
4-(3-exo-Benzyl-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-c-
arbonitrile (159JP92A)
[0602] To 183AF16-294 (188 mg, 0.65 mmol) in THF (10 mL) under
argon atmosphere at -78.degree. C. was dropwise added phenyllithium
(0.56 mL, 0.85 mmol, 1.5 M in hexanes) and the reaction was allowed
to warm to rt overnight. The reaction was quenched with sat. aq.
NH.sub.4Cl (100 mL), extracted with dichloromethane (3.times.200
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. Purification by preparative TLC (ethyl acetate/n-heptane
1:4, 4.times. eluted) afforded the title compound (132 mg, 56%) as
a yellow solid.
[0603] R.sub.f=0.48 (ethyl acetate/n-heptane 1:1). LCMS m/z 369
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.32 (d, 1H,
J=8.6), 7.81 (m, 3H), 7.52-7.28 (m, 6H), 6.97 (d, 1H, J=7.8), 4.21
(m, 2H) 2.81 (m, 2H), 2.64 (br s, 2H), 2.30-2.11 (m, 4H), 1.52 (d,
2H, J=9.7). HPLC t.sub.R=4.4 min (method III).
8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylic
acid methyl ester (159JP95C)
[0604] 8-Azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester
(225 mg, 1.35 mmol, Davies H. M. L. et al., J. Org. Chem. 1991, 56,
5696-5700), 1-cyano-4-fluoronaphthalene (230 mg, 1.35 mmol) and
pyridine (1.0 mL) were heated to 110.degree. C. for 2 days and
concentrated in vacuo. The residue was purified by preparative TLC
(ethyl acetate/n-heptane 1:4, 5.times. eluted) to afford the title
compound (25 mg, 6%) as a colorless oil.
[0605] R.sub.f=0.49 (ethyl acetate/n-heptane, 1:1). LCMS m/z 319
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) 8.13-8.05 (m, 2H),
7.66 (d, 1H, J=8.0), 7.61-7.48 (m, 2H), 6.78 (d, 1H, J=8.0), 4.58
(d, 1H, J=5.8), 4.43 (t, 1H, J=6.0), 3.78 (s, 3H), 2.39 (m, 2H),
2.22 (m, 1H), 2.05-1.91 (m, 2H), 1.72 (m, 1H), 1.51 (m, 1H). HPLC
t.sub.R=4.8 min (method III).
8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]octane-2-carboxylic
acid methyl ester (159JP97A)
[0606] 159JP95C (12 mg, 0.038 mmol) and palladium (10 mg, 10 wt. %
on activated carbon) in methanol (10 mL) were stirred for 3 days at
rt under hydrogen atmosphere (balloon). The suspension was filtered
through a pad of Celite, concentrated in vacuo and purification by
preparative TLC (ethyl acetate/n-heptane, 1:4, 2.times. eluted)
afforded the title compound (5.0 mg, 42%) as a colorless oil.
[0607] R.sub.f=0.57 (ethyl acetate/n-heptane 1:1). LCMS m/z 321
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.12 (m,
2H), 7.69 (d, 1H, J=8.0), 7.62-7.45 (m, 2H), 6.88 (d, 1H, J=8.1),
4.32 (m, 1H), 4.05 (m, 1H), 3.67 (s, 3H), 3.09 (m, 1H), 2.11-1.65
(m, 7H). HPLC t.sub.R=5.2 min (method III).
4-(2-Hydroxymethyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonit-
rile (159JP98C)
[0608] To lithium aluminum hydride (1.3 mg, 0.034 mmol) in
diethylether (1.0 mL) under argon atmosphere at 0.degree. C. was
added dropwise 159JP95C (7.2 mg, 0.023 mmol) in diethylether (1.0
mL). After stirring at 0.degree. C. for 0.5 h, the reaction mixture
was quenched with 2 M aq. NaOH (10 mL), acidified to pH 5 by adding
2 M hydrochloric acid, extracted with ethyl acetate (2.times.100
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. Purification by preparative TLC (ethyl acetate/n-heptane
1:3, 3.times. eluted) afforded the title compound (2.8 mg, 43%) as
a thick oil.
[0609] R.sub.f=0.38 (ethyl acetate/n-heptane, 1:1). LCMS m/z 291
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.11 (m,
2H), 7.64 (d, 1H, J=7.9), 7.60-7.44 (m, 2H), 6.93 (d, 1H, J=8.0),
5.22 (br s, 1H), 4.21 (m, 1H), 4.10 (br s, 2H), 4.04 (d, 1H,
J=6.2), 3.21 (s, 1H), 2.20-1.78 (m, 5H). HPLC t.sub.R=3.8 min
(method III).
(1R,2R,3S,5S)-3-Benzoyloxy-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]o-
ctane-2-carboxylic acid methyl ester (195JP02A)
[0610] Adapting a protocol by Wolfe and Buchwald (Tetrahedron
Lett., 1997, 37, 6359-6362), 1-bromo-4-cyanonaphthalene (124 mg,
0.53 mmol, Cakmak O. et al., Collect. Czech. Chem. Commun. 2000,
65, 1791-1804), norcocaine (185 mg, 0.64 mmol), Pd.sub.2(dba).sub.3
(23.8 mg, 0.026 mmol), rac-BINAP (24.7 mg, 0.040 mmol) and caesium
carbonate (242 mg, 0.74 mmol) were placed in an argon flushed vial,
toluene (1.0 mL) was added and the resulting mixture was stirred
under argon atmosphere at 110.degree. C. overnight. The crude was
then concentrated in vacuo and purification by preparative TLC
(ethyl acetate/n-heptane 1:4, 4.times. eluted) afforded the title
compound (68 mg, 29%) as an oil.
[0611] R.sub.f=0.21 (ethyl acetate/n-heptane 1:1). LCMS m/z 441
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.32 (d, 1H,
J=8.2), 8.19 (d, 1H, J=7.7), 8.11 (m, 2H), 7.77 (d, 1H, J=7.9),
7.72-7.45 (m, 5H), 6.91 (d, 1H, J=8.0), 5.58 (m, 1H), 4.64 (d, 1H,
J=6.8), 4.20 (br s, 1H), 3.61 (s, 3H), 3.39 (m, 1H), 3.15 (dt, 1H,
J=11.8, 2.0), 2.42 (m, 1H), 2.24-1.89 (m, 4H). HPLC t.sub.R=5.5 min
(method III).
(1R,2R,3S,5S)-4-(3-Hydroxy-2-hydroxymethyl-8-azabicyclo[3.2.1]oct-8-yl)nap-
hthalene-1-carbonitrile (195JP05BX)
[0612] 195JP02A (10 mg, 0.023 mmol) in dry diethylether (1.0 mL)
was added to lithium aluminum hydride (1.8 mg, 0.046 mmol) in dry
diethylether (5.0 mL) at 0.degree. C. under argon atmosphere. After
10 min at 0.degree. C., the reaction was quenched with 2 M NaOH
(5.0 mL), pH was adjusted to pH 7 by addition of 2 M HCl, extracted
with dichloromethane (3.times.100 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. Purification by preparative TLC
(dichloromethane/MeOH 10:1, 3.times. eluted) afforded the title
compound (3.4 mg, 48%) as a thick oil.
[0613] R.sub.f=0.31 (dichloromethane/MeOH 10:1). LCMS m/z 309
[M+H].sup.+. H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.12 (m, 2H), 7.69
(d, 1H, J=8.0), 7.65-7.48 (m, 2H), 6.83 (d, 1H, J=8.0), 4.32 (m,
1H), 4.25 (m, 1H), 4.13 (d, 1H, J=6.4), 3.98 (br s, 1H), 3.87 (dd,
1H, J=11.4, 3.9), 2.45-2.07 (m, 5H), 1.90-1.69 (m, 2H). HPLC
t.sub.R=2.5 min (method III).
2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
N,N-diisopropylamidophosphite (165RL31)
[0614] 88PS33 (34.0 mg, 0.122 mmol) was co-evaporated three times
with toluene (5 mL) evaporated to dryness and dissolved in
dichloromethane (2 mL) under argon atmosphere. 2-Cyanoethyl
tetraisopropylphosphoroamidite (55.2 mg, 0.183 mmol) was dissolved
in dichloromethane (2 mL) and added to the solution.
N,N-Diisopropylamine (34 .mu.L, 0.24 mmol) was added and the
mixture cooled to 0.degree. C. 1H-Tetrazole (3% in acetonitrile,
550 .mu.L, 0.24 mmol) was added and the cooling was removed. The
reaction mixture was stirred at rt for 2.5 hours and diluted with
ethyl acetate (10 mL). The solution was washed with sat. sodium
hydrogen carbonate solution (10 mL) followed by the addition of 2
drops of triethylamine to make sure the mixture was kept alkaline.
The solution was dried over Na.sub.2SO.sub.4, filtered and
evaporated to dryness. The residue was purified by column
chromatography on silica gel eluting with a mixture of
n-heptane/ethyl acetate/triethylamine (59/39/2), to give the title
compound (24.9 mg, 46%) as a clear oil.
[0615] R.sub.f=0.61 (n-heptane/ethyl acetate/TEA 59:39:2).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.16 (m, 2H, Ar--H), 7.74
(d, 1H, J=8.1, Ar--H), 7.63 (m, 1H, Ar--H), 7.57 (m, 1H, Ar--H),
6.88 (d, 1H, J=8.1, Ar--H), 4.34 (m, 1H, Tr-H), 4.12 (m, 2H, Tr-H),
3.94-3.55 (m, 4H), 2.65 (t, 2H, J=6.2, CH.sub.2), 2.48-1.93 (m,
8H), 1.21 (dd, 12H, J=6.8 and 4.4, CH--(CH.sub.3).sub.2).
2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
diisopropylamidophosphate (165RL37)
[0616] 165RL31 (59 mg, 0.12 mmol) was dissolved in dichloromethane
(5 mL), the solution cooled to -25.degree. C. and tert-butyl
hydroperoxide (70% in water, 88 .mu.L, 0.62 mmol) was added. The
reaction mixture was allowed to stir for 5 min, then the cooling
bath was removed. After 1 hour stirring the mixture was diluted
with dichloromethane (15 mL), washed with saturated sodium hydrogen
carbonate (10 mL), dried over sodium sulfate, filtered and
evaporated. The crude product was purified by column chromatography
on silica gel eluting with ethyl acetate, to give the desired
product (41.6 mg, 68%).
[0617] R.sub.f=0.64 (ethyl acetate). LCMS m/z 495 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.16 (m, 2H), 7.74 (d,
1H, J=8.1), 7.64 (m, 1H), 7.54 (m, 1H), 6.88 (d, 1H, J=8.1), 4.83
(m, 1H,), 4.26-4.00 (m, 4H), 3.59-3.35 (m, 2H), 2.90-2.64 (m, 2H),
2.56-2.40 (m, 2H), 2.33-2.12 (m, 4H), 2.02 (m, 2H), 1.27 (dd, 12H,
J=6.8 and 4.4).
2-Cyanoethyl ethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
phosphate (165RL38)
[0618] 165RL31 (101 mg, 0.211 mmol) was co-evaporated three times
with toluene (5 mL), evaporated to dryness and dissolved in
dichloromethane (5 mL) under argon atmosphere. Abs. ethanol (11
.mu.L. 0.19 mmol) was added, the reaction mixture cooled to
-45.degree. C. and 1H-tetrazole (3% in acetonitrile, 1.7 mL, 0.77
mmol) added. After 5 min the mixture was warmed to rt and stirred
for 1 hour. It was then cooled to -25.degree. C. and
tert-butylhydroperoxide (70% in water, 0.14 mL, 0.96 mmol) was
added. After 5 min the mixture was brought to rt and stirring was
continued for another 1 hour. The mixture was diluted with
dichloromethane (15 mL), washed with sodium hydrogen carbonate (10
mL), dried over sodium sulfate, filtered and evaporated. The crude
product was purified by column chromatography on silica gel using
methanol/ethyl acetate (1:9) followed by prep. HPLC. This gave 34.8
mg (38%) pure product.
[0619] R.sub.f=0.48 (MeOH/ethyl acetate 1:9). LCMS m/z 440
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.16 (m,
2H), 7.74 (d, 1H, J=8.1), 7.64 (m, 1H), 7.54 (m, 1H), 6.88 (d, 1H,
J=8.1), 4.94 (m, 1H,), 4.35-4.16 (m, 4H), 4.12 (m, 2H), 2.79 (t,
2H, J=6.0), 2.56-2.44 (m, 2H), 2.28-2.14 (m, 4H), 2.07-1.93 (m,
2H), 1.39 (t, 3H, J=7.0).
Ethyl endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
hydrogen phosphate (165RL41)
[0620] 165RL38 (34.8 mg, 0.103 mmol) and DBU (18.5 .mu.L, 0.123
mmol) in THF (2 mL) was stirred at rt for 5 hours. The reaction
mixture was diluted with dichloromethane (10 mL) and washed with
water (10 mL). The pH of the water layer was adjusted to 3-4 with
diluted hydrochloric acid and was extracted with ethyl acetate
(5.times.10 mL). The combined organic layers were dried and
evaporated. The product was further purified by preparative HPLC,
giving the title compound (20 mg, 50%) as a white solid.
[0621] LCMS m/z 387 [M+H].sup.+. .sup.1H-NMR (CD.sub.3OD, 300 MHz)
.delta. 8.23 (d, 1H, J=8.2), 8.05 (d, 1H, J=8.8), 7.79 (d, 1H,
J=8.1), 7.66 (m, 1H), 7.57 (m, 1H), 7.03 (d, 1H, J=8.1), 4.63 (m,
1H), 4.12 (m, 2H), 3.69 (m, 2H), 2.48-2.34 (m, 4H), 2.25 (m, 1H),
2.20 (m, 1H), 2.02-1.90 (m, 2H), 1.28 (t, 3H, J=7.0).
Bis(2-cyanoethyl)endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3--
yl phosphate (165RL42)
[0622] 165RL31 (92 mg, 0.19 mmol) was co-evaporated three times
with toluene (5 mL), evaporated to dryness and dissolved in
dichloromethane (5 mL) under argon atmosphere.
3-Hydroxypropionnitrile (12 .mu.L, 0.18 mmol) was added, the
reaction mixture was cooled to -45.degree. C. and 1H-tetrazole (3%
in acetonitrile, 2.1 mL, 0.70 mmol) was added. After 5 min the
mixture was brought to rt, stirred for 1 hour, cooled to
-25.degree. C. and tert-butylhydroperoxide (70% in water, 0.13 mL,
0.88 mmol) was added. After 5 min the mixture was brought to rt and
stirring was continued for another 1 hour. The mixture was diluted
with dichloromethane (15 mL), washed with sodium hydrogen carbonate
(10 mL), dried over sodium sulfate, filtered and evaporated. The
crude product was purified by preparative HPLC, giving the title
compound (44.3 mg, 50%).
[0623] LCMS m/z 465 [M+H].sup.+.
Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl
dihydrogen phosphate (165RL43)
[0624] 165RL42 (44 mg, 0.095 mmol) was dissolved in THF (2 mL).
Sodium hydroxide (0.5 M, 2 mL) was added and the reaction mixture
was stirred for 3 hours at rt. The mixture was evaporated to
dryness, the residue purified by preparative HPLC under buffer free
conditions, giving the desired compound (16.2 mg, 48%).
[0625] LCMS m/z 359 [M+H].sup.+. .sup.1H-NMR (CD.sub.3OD, 300 MHz)
.delta. 8.26 (d, 1H, J=8.2), 8.05 (d, 1H, J=8.8), 7.79 (d, 1H,
J=8.1), 7.66 (m, 1H), 7.57 (m, 1H), 7.04 (d, 1H, J=8.1), 4.61 (m,
1H), 4.12 (m, 2H), 2.58-2.48 (m, 2H), 2.43-2.25 (m, 4H), 1.98-1.86
(m, 2H).
2-Cyanoethyl
endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phenyl
phosphate (165RL44)
[0626] 165RL31 (94 mg, 0.20 mmol) was co-evaporated three times
with toluene (4 mL), evaporated to dryness and dissolved in
dichloromethane (5 mL) under argon atmosphere. A solution of phenol
(17 mg. 0.18 mmol) in toluene (1 mL) was added, the reaction
mixture cooled to -45.degree. C. and 1H-tetrazole (3% in
acetonitrile, 2.1 mL, 0.70 mmol) was added. After 5 min the mixture
was warmed to rt and stirred for 1 hour. It was then cooled to
-25.degree. C. and tert-butylhydroperoxide (70% in water, 0.13 mL,
0.89 mmol) was added. After 5 min the mixture was brought to rt and
stirring was continued for another 1 hour. The mixture was diluted
with dichloromethane (15 mL), washed with sat. sodium hydrogen
carbonate (10 mL), dried over sodium sulfate, filtered and
evaporated. The crude product was purified by column chromatography
on silica gel using n-heptane/ethyl acetate (1:9), giving the
desired product (55.1 mg, 57%).
[0627] R.sub.f=0.41 (n-heptane/ethyl acetate 1:9). LCMS m/z 488
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.19 (m,
2H), 7.74 (d, 1H, J=8.1), 7.64 (m, 1H), 7.54 (m, 1H), 7.39 (m, 2H),
7.28 (m, 3H) 6.88 (d, 1H, J=8.1), 5.07 (m, 1H), 4.47-4.29 (m, 2H),
4.12 (m, 2H), 2.88-2.69 (m, 2H), 2.61-2.44 (m, 2H), 2.32-1.92 (m,
6H).
Endo-8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl phenyl
hydrogen phosphate (165RL45)
[0628] 165RL44 (55.1 mg, 0.11 mmol) and DBU (20 .mu.L, 0.13 mmol)
were stirred in THF (2 mL) at 50.degree. C. for 3 hours. The
reaction mixture was diluted with ethyl acetate (10 mL) and washed
with sat. sodium hydrogen carbonate (5 mL). The organic layer was
dried over sodium sulfate, filtered, evaporated and the residue
purified by preparative HPLC to give the title compound (47 mg,
98%).
[0629] LCMS m/z 435 [M+H].sup.+. .sup.1H-NMR (CD.sub.3OD, 300 MHz)
.delta. 8.19 (d, 1H, J=8.3), 8.03 (d, 1H, J=8.2), 7.75 (d, 1H,
J=8.1), 7.63 (m, 1H), 7.54 (m, 1H), 7.33-7.25 (m, 4H), 7.04 (m,
1H), 6.97 (d, 1H, J=8.1), 4.74 (m, 1H), 4.06 (m, 2H), 2.46-2.30 (m,
4H), 2.18-2.13 (m, 2H), 1.93-1.86 (m, 2H).
N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide
(165RL51).
[0630] To a -30.degree. C. solution of acetyl chloride (15 .mu.L,
0.21 mmol) in DMF (1.5 mL) was added dropwise a solution of 165RL21
(54 mg, 0.20 mmol) and DIPEA (37 .mu.L, 0.21 mmol) in DMF (3.5 mL).
After 1 hour of stirring the reaction mixture was brought to rt and
allowed to react overnight. Water (20 mL) was then added and the
mixture extracted with ethyl acetate (3.times.20 mL). The combined
organic layers were dried over sodium sulfate, filtered and
evaporated. The crude product was purified by column chromatography
on silica gel using ethyl acetate/MeOH (9:1) to give the desired
compound (35 mg, 56%).
[0631] R.sub.f=0.32 (ethyl acetate/MeOH 9:1). LCMS m/z 320
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz, diastereomers
endo:exo 3:2) .delta. 8.19 (m, 2H, Ar--H), 7.72 (d, 1H, J=8.0,
Ar--H), 7.63 (m, 1H, Ar--H), 7.54 (m, 1H, Ar--H), 6.86 (m, 1H,
Ar--H), 5.95 (m, 0.6H, CONH), 5.53 (m, 0.4H, CONH), 4.47-4.30 (m,
1H, Tr-H), 4.15 (m, 2H, Tr-H), 2.66-2.53 (m, 1H, Tr-H), 2.20-1.79
(m, 7H, Tr-H), 2.02 and 2.00 (2s, 3H, COCH.sub.3).
3-Chloro-N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]propana-
mide (165RL50)
[0632] This compound was synthesized in the same way as 165RL23
using 165RL21 (320 mg, 1.15 mmol), 3-chloropropionyl chloride (120
.mu.L, 1.27 mmol), DIPEA (220 .mu.L, 1.27 mmol) and DMF (10 mL).
The crude product was purified by column chromatography using ethyl
acetate/MeOH (95:5) to give the title compound (318 mg, 75
[0633] R.sub.f=0.54 (ethyl acetate/MeOH 95:5). LCMS m/z 368
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz, diastereomers
endo:exo 3:2) .delta. 8.17 (m, 2H, Ar--H), 7.73 (d, 1H, J=8.0,
Ar--H), 7.65 (m, 1H, Ar--H), 7.56 (m, 1H, Ar--H), 6.87 (m, 1H,
Ar--H), 6.09 (m, 0.6H, CONH), 5.57 (m, 0.4H, CONH), 4.52-4.34 (m,
1H, Tr-H), 4.17 (m, 2H, Tr-H), 3.86-3.83 (m, 2H), 2.64 (m, 2H),
2.65-2.58 (m, 1H, Tr-H), 2.22-1.85 (m, 7H, Tr-H).
N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-(4-ethylpiper-
azin-1-yl)propanamide, dihydrochloride (165RL52)
[0634] 165RL50 (65 mg, 0.18 mmol), 1-ethylpiperazine (45 .mu.L,
0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol) were stirred
in acetonitrile (6 mL) at 50.degree. C. for 2 days. The reaction
mixture was diluted with ethyl acetate (15 mL) and washed with
water (2.times.10 mL). The organic solution was dried over sodium
sulfate, filtered and evaporated. The product was purified by
column chromatography using ethyl acetate/MeOH (9:1) to give the
title compound (37 mg, 46%) pure product.
[0635] R.sub.f=0.13 (ethyl acetate/MeOH 9:1). LCMS m/z 446
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz, diastereomers
endo:exo 3:2) .delta. 8.78 (m, 0.6H), 8.57 (m, 0.4H), 8.17 (m, 2H),
7.72 (d, 1H, J=8.0), 7.64 (m, 1H), 7.54 (m, 1H), 6.88 (m, 1H,),
4.52-4.34 (m, 1H), 4.15 (m, 2H), 2.78-2.32 (m, 14H), 2.20-1.75 (m,
8H), 1.08 and 1.07 (2t, 3H, J=7.2).
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-diethylaminop-
ropionamide, hydrochloride (165RL53)
[0636] The title compound (16 mg, 19%) was synthesized in the same
way as 165RL52 using 165RL50 (80 mg, 0.21 mmol), diethylamine (45
.mu.L, 0.44 mmol), potassium carbonate (60 mg, 0.44 mmol) and
acetonitrile (6 mL).
[0637] R.sub.f=0.15 (ethyl acetate/MeOH 9:1). LCMS m/z 405
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz, diastereomers
endo:exo 3:2) .delta. 9.07 (m, 0.6H), 8.76 (m, 0.4H), 8.17 (m, 2H),
7.72 (d, 1H, J=8.0), 7.64 (m, 1H), 7.54 (m, 1H), 6.88 (m, 1H),
4.52-4.34 (m, 1H), 4.15 (m, 2H), 2.92-2.48 (m, 7H), 2.46-2.33 (m,
2H), 1.98-1.76 (m, 7H), 1.08 and 1.06 (2t, 6H, J=7.2).
N-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-3-(1H-imidazol--
1-yl)propanamide hydrochloride (165RL55)
[0638] 165RL50 (61 mg, 0.17 mmol), imidazole (53 mg, 0.83 mmol),
sodium iodide (10 mg, 0.07 mmol) and dichloromethane (6 mL) were
shaken in a vial at 80.degree. C. for 2 days. The reaction mixture
was diluted with ethyl acetate (15 mL) and washed with water
(2.times.10 mL). The organic solution was dried over sodium
sulfate, filtered and evaporated. The residue was purified by
column chromatography using a stepwise gradient of 10-100% methanol
in ethyl acetate to give the title compound (32 mg, 47%).
[0639] R.sub.f=0.08 (ethyl acetate/MeOH 9:1). LCMS m/z 400
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz, diastereomers
endo:exo 3:2) .delta. 8.12 (m, 2H), 7.72 (d, 1H, J=8.0), 7.63 (m,
1H), 7.53 (m, 1H), 7.45 (s, 1H), 7.02 (s, 1H), 6.94 (s, 1H), 6.82
(m, 1H), 6.34 (m, 0.6H), 6.24 (m, 0.4H), 4.41-4.22 (m, 3H), 4.08
(m, 2H), 2.68-2.48 (m, 3H), 2.11-1.69 (m, 7H).
(2-Ethoxyethoxy)acetic acid (165RL54)
[0640] 2-Ethoxyethanol (0.88 mL, 11 mmol) and sodium hydride (60%
in oil, 1.08 g, 27 mmol) were stirred in DMF (20 mL) for 5 min.
Iodoacetic acid (2.02 g, 10.9 mmol) was dissolved in DMF (20 mL)
and added dropwise to the suspension. The thick orange suspension
was stirred at rt for 3 hours. The reaction was quenched by slowly
adding water (10 mL), followed by hydrochloric acid (4 M, 5 mL).
The reaction mixture was extracted with dichloromethane (3.times.50
mL) and the combined organic layers dried over sodium sulfate,
filtered and evaporated yielding a clear oil. The residue was
purified by distillation under reduced pressure to give the product
(1.1 g, 68%) as an oil.
[0641] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 10.61 (br, 1H),
4.16 (s, 2H), 3.74 (m, 2H), 3.56 (m, 4H), 1.21 (t, 3H, J=7.0).
N-[8-(4-Cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2-(ethoxyethoxy-
)acetamide (165RL57)
[0642] 165RL54 (19 mg, 0.13 mmol),
O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluorophosphate
(HBTU, 49 mg, 0.13 mmol), 1-hydroxybenzotriazole (18 mg, 0.13 mmol)
and triethylamine (37 .mu.L, 0.26 mmol) were dissolved in DMF (4
mL). 165RL21 (36 mg, 0.13 mmol)) was added and the mixture was
shaken at rt for 30 min. The solvent was removed in vacuo and the
product was purified by flash chromatography on silica gel using
ethyl acetate/methanol (9:1) as eluent, giving the desired compound
(38.1 mg, 72%).
[0643] R.sub.f=0.46 (ethyl acetate/MeOH 9:1). LCMS m/z 408
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz, diastereomers
endo:exo 3:2) .delta. 8.17 (m, 2H), 7.72 (d, 1H, J=8.0), 7.63 (m,
1H), 7.54 (m, 1H), 7.29 (m, 0.6H), 7.05 (m, 0.4H), 6.88 (m, 1H),
4.52-4.33 (m, 1H), 4.16 (m, 2H), 4.00 and 4.01 (2s, 2H), 3.76-3.51
(m, 6H), 2.63-2.52 (m, 1H), 2.18-1.85 (m, 7H), 1.26 and 1.20 (2t,
3H, J=7.0).
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxylic acid ethyl ester
(165RL60)
[0644] 1-Cyano-4-fluoronaphthalene (1.0 g, 5.84 mmol) and ethyl
nipecotate (3.63 mL, 23.4 mmol) were dissolved in pyridine (5 mL)
and stirred at 115.degree. C. for 20 hours. After cooling to rt
ethyl acetate (50 mL) was added and the solution washed with HCl
(0.4 M, 2.times.30 mL). The combined aqueous layers were extracted
with ethyl acetate (30 mL). The combined organic layers were washed
with sat. sodium hydrogen carbonate (30 mL), brine (30 mL), dried
and evaporated. The crude product was purified by silica gel column
chromatography eluted with a stepwise gradient of 0-70% ethyl
acetate in n-heptane to give the title compound (1.23 g, 68%) as a
yellowish oil
[0645] LCMS m/z 309 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.20 (m, 2H), 7.83 (d, 1H, J=7.9), 7.63 (m, 2H), 7.06 (d,
1H, J=7.9), 4.18 (q, 2H, J=7.1), 3.59 (m, 1H), 3.38 (m, 1H), 3.07
(m, 1H), 2.89 (m, 2H), 2.17 (m, 1H), 2.02 (m, 2H), 1.71 (m, 1H),
1.25 (t, 3H, J=7.1).
4-(2-Methylpiperidin-1-yl)naphthalene-1-carbonitrile (165RL62)
[0646] 1-Cyano-4-fluoronaphthalene (100 mg, 0.58 mmol),
2-methylpiperidine (0.28 mL, 2.3 mmol) and DBU (0.01 mL, 59
.mu.mol) were dissolved in pyridine (2 mL) and stirred at
60.degree. C. for 3 days. The temperature was raised to 110.degree.
C. and the stirring was continued for 10 days. The reaction was
worked up in the same way as for 198RL60. The crude compound was
purified by preparative TLC followed by preparative HPLC to give
the title compound (27.4 mg, 19%) as a colourless oil, which was
stored under argon atmosphere.
[0647] LCMS m/z 251 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.33 (d, 1H, J=8.2), 8.19 (d, 1H, J=8.2), 7.84 (d, 1H,
J=7.8), 7.59 (m, 2H), 7.10 (d, 1H, J=7.8), 3.53 (m, 1H), 3.28 (m,
1H), 2.75 (m, 1H), 2.01 (m, 1H), 1.88-1.53 (m, 5H), 0.92 (d, 3H,
J=6.3).
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxylic acid
(165RL63)
[0648] 198RL60 (862 mg, 2.80 mmol) was dissolved in THF (5.6 mL)
and sodium hydroxide (1 M, 5.6 mL). The reaction mixture was not
homogenous and ethanol (1 mL) was added to get a clear solution
which was stirred at rt overnight. The solution was made acidic by
addition of 4 M HCl, followed by extraction with ethyl acetate
(3.times.50 mL). The combined organic layers were dried over sodium
sulfate, filtered and evaporated to give the title compound (746
mg, 95%) as a pure white solid.
[0649] LCMS m/z 281 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.18 (m, 2H), 7.83 (d, 1H, J=7.9), 7.63 (m, 2H), 7.08 (d,
1H, J=7.9), 3.60 (m, 1H), 3.36 (m, 1H), 3.12 (m, 1H), 3.03-2.83 (m,
2H), 2.19 (m, 1H), 2.13 (m, 2H), 1.70 (m, 1H).
[1-(4-Cyanonaphthalen-1-yl)piperidin-3-ylmethyl]carbamic acid
tert-butyl ester (165RL65)
[0650] 1-Cyano-4-fluoronaphthalene (273 mg, 1.60 mmol), tert-butyl
(piperidin-3-ylmethyl)carbamate (411 mg, 1.92 mmol) and DBU (25
.mu.l, 0.16 mmol) were dissolved in pyridine (4 mL) and stirred at
60.degree. C. for 4 days. The reaction was worked up in the same
way as for 198RL60 followed by purification using silica gel column
chromatography eluted with a stepwise gradient of 0-70% ethyl
acetate in n-heptane, giving the desired compound (416 mg, 71%) as
a white solid.
[0651] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.18 (m, 2H,
Ar--H), 7.81 (d, 1H, J=7.9, Ar--H), 7.61 (m, 2H, Ar--H), 7.00 (d,
1H, J=7.9, Ar--H), 4.62 (m, 1H), 3.45 (m, 2H), 3.14 (m, 2H), 2.81
(m, 1H), 2.59 (m, 1H), 2.14 (m, 1H), 1.93 (m, 3H), 1.42 (s, 9H),
1.24 (m, 1H).
4-(3-Aminomethylpiperidin-1-yl)naphthalene-1-carbonitrile
(165RL66)
[0652] 165RL65 (416 mg, 1.14 .mu.mol) was dissolved in
dichloromethane (20 mL) followed by the addition of TFA (5 mL). The
mixture was stirred at rt for 3 h and the solvents removed in
vacuo. Sodium hydroxide (0.2 M, 10 mL) was added and the mixture
extracted with ethyl acetate (3.times.10 mL). The combined organic
layers were dried over sodium sulfate, filtered and evaporated to
give the title compound (292 mg, 97%) as a yellow oil.
[0653] LCMS m/z 266 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.15 (m, 2H), 7.79 (d, 1H, J=7.9), 7.59 (m, 2H), 7.00 (d,
1H, J=7.9), 3.51 (m, 1H), 3.40 (m, 1H), 2.85-2.61 (m, 3H), 2.53 (m,
1H), 2.03-1.74 (m, 6H), 1.18 (m, 1H).
N-[1-(4-Cyanonaphthalen-1-yl)piperidin-3-ylmethyl]acetamide
(165RL70)
[0654] To a solution of 165RL66 (40 mg, 151 .mu.mol) and
triethylamine (23 .mu.L, 17 .mu.mol) in dichloromethane (1 mL) was
added acetyl chloride (12 .mu.L, 17 .mu.mol). The mixture was
stirred at rt overnight, diluted with ethyl acetate (10 mL) and
washed with HCl (0.5 M, 10 mL). The aqueous phase was re-extracted
with ethyl acetate (2.times.20 mL). The combined organic layers
were washed with sat. sodium hydrogen carbonate (10 mL) and brine
(10 mL), dried over sodium sulfate, filtered and evaporated. The
remaining solid was purified by silica gel column chromatography
eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane
to give the title compound (26 mg, 56%) as a solid.
[0655] R.sub.f=0.65 (ethyl acetate/MeOH 9:1). LCMS m/z 308
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.15 (m,
2H), 7.76 (d, 1H, J=7.9), 7.58 (m, 2H), 7.00 (d, 1H, J=7.9), 5.74
(m, 1H), 3.42 (m, 2H), 3.27 (m, 2H), 2.78 (m, 1H), 2.59 (m, 1H),
2.14 (m, 1H), 2.01-1.86 (m, 3H), 1.97 (s, 3H), 1.25 (m, 1H).
4-(3-Ethylaminomethylpiperidin-1-yl)naphthalene-1-carbonitrile
hydrochloride (165RL72sec) and
4-(3-Diethylaminomethylpiperidin-1-yl)naphthalene-1-carbonitrile
hydrochloride (165RL72tert)
[0656] 165RL66 (106 mg, 0.40 mmol) was dissolved in methanol (20
mL). The pH was adjusted to .about.5 by addition of acetic acid
(.about.0.5 mL). Acetaldehyde (45 .mu.L, 0.80 mmol) was added and
the reaction mixture was stirred for 5 min before the addition of
sodium cyanoborohydride (175 mg, 2.80 mmol). The mixture was
stirred at rt for 3 hours, sodium hydroxide (2 M, 1 mL) was added
followed by water (10 mL) and stirring maintained for 5 min. Sodium
hydroxide (1 M, 25 mL) was added and the mixture extracted with
ethyl acetate (3.times.40 mL). The combined organic layers were
dried over sodium sulfate, filtered and evaporated to give a solid.
Purification by silica gel column chromatography eluted with a
stepwise gradient of 0-60% of methanol in ethyl acetate (1:9) in
n-heptane and pooling of the appropriate fractions gave the
monoethylated compound 165RL72sec and the diethylated compound
165RL72tert. Both products were further purified by preparative.
HPLC, giving 22.3 mg (19%) of 165RL72sec and 9.8 mg (8%) of
165RL72tert.
[0657] 165RL72sec: LCMS m/z 294 [M+H].sup.+. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 8.17 (m, 2H), 7.50 (d, 1H, J=7.9),
7.59 (m, 2H), 7.01 (d, 1H, J=7.9), 3.52 (m, 1H), 3.41 (m, 1H), 2.81
(m, 1H), 2.75-2.51 (m, 4H), 2.13 (m, 1H), 2.06-1.70 (m, 5H), 1.25
(m, 1H), 1.11 (t, 3H, J=7.1).
[0658] 165RL72tert: LCMS m/z 322 [M+H].sup.+. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 8.17 (m, 2H), 7.80 (d, 1H, J=7.9),
7.64 (m, 1H), 7.56 (m, 1H), 7.11 (d, 1H, J=7.9), 3.63 (m, 1H), 3.42
(m, 1H), 2.81 (m, 1H), 2.64-2.42 (m, 5H), 2.33 (m, 2H), 2.13 (m,
1H), 1.90 (m, 3H), 1.18 (m, 1H), 1.00 (t, 6H, J=7.1).
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carbonitrile (165RL73-3) and
1-(4-Cyanonaphthalen-1-yl)piperidine-3-carboxamide (165RL73-5)
[0659] 165RL63 (314 mg, 1.12 mmol), DMF (3 drops) and
dichloromethane (4 mL) was put in a flask under argon atmosphere
and the solution cooled to 0.degree. C. in an ice bath. Oxalyl
chloride (147 .mu.L, 1.68 mmol) was slowly added. The ice bath was
removed and the mixture was stirred for 4 hours. Solvents and the
excess of oxalyl chloride was then removed in vacuo. The remaining
acid chloride was taken up in dichloromethane (10 mL) under argon
atmosphere. Ammonium hydroxide solution (28% in water) (0.16 mL,
2.24 mmol) was slowly added and the mixture was stirred at rt over
night. The reaction mixture was diluted with ethyl acetate (50 mL)
and washed with sodium hydroxide (1 M, 30 mL). The organic layer
was dried over sodium sulfate, filtered and evaporated. The solid
was purified by silica gel column chromatography eluted with a
stepwise gradient of 0-80% ethyl acetate in n-heptane to give the
nitrile 165RL73-3 (9.5 mg, 3%) and the amide 165RL73-5 (66 mg,
21%).
[0660] 165RL73-3: LCMS m/z 262 [M+H].sup.+. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 8.30 (m, 1H), 8.21 (m, 1H), 7.84 (d,
1H, J=7.9), 7.66 (m, 2H), 7.05 (d, 1H, J=7.9, Ar--H), 3.48-3.06 (m,
5H), 2.26-1.88 (m, 4H).
[0661] 165RL73-5: LCMS m/z 280 [M+H].sup.+. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 8.19 (m, 1H), 8.11 (m, 1H), 7.82 (d,
1H, J=7.9), 7.61 (m, 2H), 7.06 (d, 1H, J=7.9), 6.10 and 5.86 (2s,
2H, CO--NH.sub.2), 3.53 (1H, m), 3.28 (m, 1H), 3.15 (m, 1H), 2.96
(m, 1H), 2.80 (m, 1H), 2.14-1.82 (m, 4H).
4-(3-Fluoropiperidin-1-yl)naphthalene-1-carbonitrile (165RL74)
[0662] 3-Fluoropiperidine hydrochloride (106 mg, 0.76 mol) was
dissolved in sodium hydroxide (1 M, 10 mL) and extracted with
dichloromethane (4.times.10 mL), the combined extracts were dried
over sodium sulfate, filtered and evaporated. Pyridine (2 mL) was
added, followed by 1-cyano-4-fluoronaphthalene (108 mg, 0.63 mmol)
and the vial was shaken at 110.degree. C. overnight. GC-MS and TLC
showed only very little conversion. DBU (10 mL) was added and the
shaking was continued for 2 weeks at 110.degree. C., after which
GC-MS showed 50% conversion. The reaction was worked up in the same
way as 165RL60 and purified by silica gel column chromatography
eluted with a stepwise gradient of 0-60% ethyl acetate in n-heptane
to give the title compound (29.3 mg, 12%) as a solid.
[0663] LCMS m/z 255 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.22 (m, 2H), 7.83 (d, 1H, J=7.9), 7.63 (m, 2H), 7.03 (d,
1H, J=7.9), 4.92 (dm, 1H, J.sub.H-F=48), 3.45-3.04 (m, 4H),
2.23-1.79 (m, 4H).
trans-4-(4-Hydroxycyclohexylamino)naphthalene-1-carbonitrile
(165RL96)
[0664] 1-Cyano-4-fluoronaphthalene (1.00 g, 5.84 mmol),
trans-4-amino cyclohexanol hydrochloride (1.33 g, 8.76 mmol) and
potassium carbonate (4.0 g, 29 mmol) were stirred in DMSO (20 mL)
at 120.degree. C. overnight. The reaction mixture was then diluted
with dichloromethane (100 mL) and washed with water (3.times.50
mL). The solution was dried over sodium sulfate, filtered and
evaporated. The residue was purified by silica gel column
chromatography eluted with a stepwise gradient of 0-70% ethyl
acetate in n-heptane, giving the title compound (1.187 g, 92%) as a
colorless solid.
[0665] R.sub.f=0.74 (ethyl acetate). LCMS m/z 267 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.16 (m, 1H), 7.75 (m,
2H), 7.64 (m, 1H), 7.52 (m, 1H), 6.58 (m, 1H), 3.76 (m, 1H), 3.54
(m, 1H), 2.27 (m, 2H), 2.10 (m, 2H), 1.70-1.30 (m, 5H), 2.26 (m,
1H).
Methanesulfonic acid
trans-4-(4-cyanonaphthalen-1-ylamino)cyclohexyl ester (165RL97)
[0666] 165RL96 (300 mg, 1.13 mmol) and triethylamine (188 .mu.L,
1.35 mmol) was dissolved in dichloromethane (10 mL). The solution
was cooled to 0.degree. C. and methanesulfonylchloride (105 .mu.L,
1.35 mmol) was added. After 10 min the ice bath was removed and the
mixture allowed to react at rt overnight. The reaction mixture was
diluted with dichloromethane (20 mL), washed with water (20 mL)
followed by sat. NaHCO.sub.3 (20 mL). The organic layer was dried
over sodium sulfate, filtered and evaporated to give the mesylated
product (353 mg) which was used without further purification.
4-(7-Azabicyclo[2.2.1]hept-7-yl)naphthalene-1-carbonitrile
hydrochloride (198RL01)
[0667] 165RL97 (129 mg, 374 .mu.mol) was stirred in DMF/toluene
(1:1, 20 mL) at -40.degree. C. and potassium tert-butoxide (42 mg,
374 .mu.mol) was added. The stirring was continued for 30 min
before the reaction mixture was brought to rt. After 2 hours, more
potassium tert-butoxide (20 mg, 0.18 mol) was added and the
reaction was stirred overnight. The mixture was diluted with
dichloromethane (50 mL) and washed with water (3.times.30 mL). The
organic layer was dried over sodium sulfate, filtered and
evaporated and the residue purified by column chromatography on
silica gel using dichloromethane as eluent, yielding the desired
compound (67.8 mg, 73%).
[0668] R.sub.f=0.75 (dichloromethane). LCMS m/z 249 [M+H].sup.+.
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.19 (m, 2H, Ar--H), 7.72
(d, 1H, J=8.0, Ar--H), 7.63 (m, 1H, Ar--H), 7.53 (m, 1H, Ar--H),
6.88 (d, 1H, J=8.0, Ar--H), 4.31 (m, 2H), 1.98 (m, 4H), 1.54 (m,
4H).
N'-[8-(4-cyanonaphthalen-1-yl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methylbenzen-
esulfonylhydrazone (173FBA60a)
[0669] To a mixture of ketone 156AF03-217 (500 mg, 1.811 mmol) in
abs. ethanol (6 mL) was added p-toluenesulfonylhydrazine (405 mg,
2.173 mmol) and the reaction was stirred and refluxed for 1 h. The
mixture was then cooled and the precipitated white solid filtered
and washed with abs. ethanol to give 173FBA60a (738 mg, 92%).
[0670] LCMS m/z 445 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.25-8.15 (m, 2H), 7.88 (d, J=8.3, 2H), 7.77 (d, J=8.0,
1H), 7.73-7.63 (m, 1H), 7.63-7.53 (m, 1H), 7.35 (d, J=8.0, 2H),
6.91 (d, J=8.0, 1H), 4.32-4.19 (m, 2H), 3.01-2.88 (m, 1H),
2.82-2.69 (m, 1H), 2.69-2.49 (m, 2H), 2.46 (s, 3H), 2.11-1.96 (m,
2H), 1.79-1.66 (m, 1H), 1.62-1.48 (m, 1H).
4-[2-(Hydroxymethyl)piperidin-1-yl]naphthalene-1-carbonitrile, tri
(173FBA70e)
[0671] A solution of 1-cyano-4-fluoronaphthalene (200 mg, 1.168
mmol) in pyridine (0.5 mL) was transferred to a Pyrex tube and
2-piperidinemethanol (538 mg, 4.67 mmol) was added. The tube was
capped and exposed to microwave irradiation (200.degree. C., 60
min). The reaction mixture was diluted with ethyl acetate, washed
with 0.4 N HCl and saturated aqueous NaHCO.sub.3. The organic phase
was dried and evaporated to give a crude product which was purified
by preparative TLC (65:35 n-heptane/ethyl acetate), followed by
further purification by preparative HPLC to give 173FBA70e (15 mg,
5%).
[0672] LCMS m/z 267 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.30 (d, J=8.1, 1H), 8.20 (d, J=7.8, 1H), 7.83 (d, J=7.8,
1H), 7.72-7.53 (m, 2H), 7.22 (d, J=8.0, 1H), 3.67-3.48 (m, 3H),
3.41-3.26 (m, 1H), 3.00-2.82 (m, 1H), 2.10-1.55 (m, 6H).
3-exo-[8-(4-Cyanonaphthalen-1-yl)-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-3--
yl]-N,N-dimethylpropanamide (173FBA51bH)
[0673] To a solution of N,N-diisopropylamine (69.6 mg, 0.688 mmol)
in dry THF (0.5 mL) at 0.degree. C. was added dropwise n-butyl
lithium (1.6 M in n-hexane, 0.688 mmol, 0.43 mL) and the mixture
allowed to stir for 10 min. Then a solution of
N,N-dimethylacetamide in dry THF (0.5 mL) was added (30 mg, 0.344
mmol) and the mixture stirred at rt. After 10 min a solution of
epoxide 183AF16-294 (50 mg, 0.172 mmol) in dry THF (0.5 mL) was
added at rt and the solution stirred at reflux for 4 h. The
reaction was quenched by sat. aqueous NH.sub.4Cl and water and
extracted with diethylether. The organic phase was dried over
sodium sulfate, filtered and evaporated to give a crude product
which was purified by preparative TLC using dichloromethane/acetone
8:2 as eluent and a second one using ethyl acetate/heptane/MeOH
8:1.5:0.5 as eluent to give 173FBA51bH as a white solid (4.0 mg,
6%).
[0674] LCMS m/z 378 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.18 (d, J=8.8, 2H), 7.76 (d, J=8.1, 1H), 7.69-7.60 (m,
1H), 7.60-7.48 (m, 1H), 6.92 (d, J=8.1, 1H), 4.22-4.10 (m, 2H),
3.08 (s, 3H), 3.00 (s, 3H), 2.55 (t, J=6.3, 2H), 2.42-2.32 (m, 2H),
2.23-2.15 (m, 2H), 2.07-1.85 (m, 6H).
2-exo-[8-(4-Cyanonaphthalen-1-yl)-3-endo-hydroxy-8-azabicyclo[3.2.1]oct-3--
yl]-N,N-dimethylethanesulfonamide (173FBA56b3)
[0675] To a solution of N,N-diisopropylamine (64.3 mg, 0.636 mmol)
in dry THF (0.5 mL) at 0.degree. C. was added dropwise n-butyl
lithium (1.6 M in hexane, 0.636 mmol, 0.4 mL) and the mixture
allowed to stir for 10 min. A solution of
N,N-dimethylmethanesulfonamide (39 mg, 0.318 mmol) in dry THF (0.5
mL) was added and the mixture stirred at rt. After 10 min a
solution of epoxide 183AF16-294 (46 mg, 0.159 mmol) in dry THF (0.5
mL) was added at rt and the solution stirred for 3 h. The reaction
mixture was then quenched by sat. aqueous NH.sub.4Cl and water and
extracted with diethylether. The organic phase was dried over
sodium sulfate, filtered and evaporated to give a crude product,
which was purified by preparative TLC using a 1:1 ethyl
acetate/heptane mixture as eluent. to give pure 173FBA56b3 as a
white solid (6.2 mg, 9%).
[0676] LCMS m/z 414 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.25-8.17 (m, 1H), 8.16-8.08 (m, 1H), 7.52-7.40 (m, 2H),
7.33 (d, J=7.8, 1H), 6.85 (d, J=7.8, 1H), 4.12-3.96 (m, 2H), 2.77
(s, 6H), 2.76-2.63 (m, 2H), 2.49 (s, 2H), 2.20-2.10 (m, 2H),
2.06-1.94 (m, 2H), 1.55-1.42 (m, 2H), 1.42-1.32 (m, 2H).
3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester (197FBA17d)
[0677] To a suspension of NaH (55-65% dispersion in mineral oil,
1.45 g, 33.3 mmol) in DMSO (20 mL) was slowly added
trimethylsulfoxonium iodide (7.33 g, 33.3 mmol) and the reaction
mixture was allowed to stir during 1 h. A solution of Boc-tropinone
(5.0 g, 22.2 mmol) was added and the mixture was stirred at rt
during 20 h. Partitioning of the mixture between ethyl acetate and
water, drying of the organic layer over sodium sulfate, filtration
and evaporation 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. To a solution of 197FBA10a (5.3 g,
22.2 mmol) in dry THF (10 mL), cooled with a water bath, was added
Super-Hydride.RTM. (1.0 M THF solution, 29.0 mmol, 29.0 mL) and the
reaction mixture was allowed to stir at rt. 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 over sodium sulfate, filtered 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%).
[0678] .sup.1H-NMR (CDCl.sub.3, 300 MHz) 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).
Endo-3-exo-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride
(197FBA20a).
[0679] To solution of 197FBA17d (3.81 g, 15.8 mmol) in diethylether
(40 mL) was added a solution of HCl in dioxane (4 M, 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 in vacuo to give 197FBA20a as a white solid (2.17 g,
77%).
[0680] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.87 (br s, 2H),
2.27 (d, J=7.3, 2H), 2.00 (dd, J=14.9, 3.2, 2H), 1.87-1.83 (m, 2H),
1.74 (d, J=14.6, 2H), 1.07 (s, 3H).
4-(3-Endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-c-
arbonitrile, hydrochloride (197FBA23a)
[0681] To a solution of 156AF70-267 (35 mg, 0.120 mmol) in
dichloromethane (0.5 mL) was added a solution of HCl in dioxane (4
M, 0.15 mL), the mixture stirred during 30 min and then evaporated
to give the title compound (38 mg, 100%) as a white solid.
[0682] LCMS m/z 293 [M+H].sup.+. .sup.1H-NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.18 (d, J=8.0, 1H), 8.00 (d, J=8.3, 1H), 7.90 (d,
J=8.1, 1H), 7.76-7.68 (m, 1H), 7.68-7.58 (m, 1H), 7.05 (d, J=8.2,
1H), 4.18-4.03 (m, 2H), 2.34-2.19 (m, 2H), 2.17-2.04 (m, 2H),
1.91-1.72 (m, 4H), 1.18 (s, 3H). .sup.13C-NMR (DMSO-d.sub.6, 75
MHz) 153.0, 134.3, 133.8, 128.9, 127.1, 126.4, 125.9, 125.0, 119.0,
111.4, 100.0, 67.7, 60.2, 45.3, 34.2, 26.4.
4-(3-Methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)naphthalene-1-carbonitrile
(197FBA24c)
[0683] To a solution of 156AF70-267 (43 mg, 0.147 mmol) in
dichloromethane (0.5 mL) was added aq. sulfuric acid (2 M, 0.15
mL), the reaction mixture stirred during 30 min. The solvent was
removed to give a solid, which was washed several times with
heptane and dichloromethane and dried. The crude was taken up in
sat. aqueous NaHCO.sub.3 and the water phase extracted twice with
ethyl acetate. The combined organic phases were dried over sodium
sulfate, filtered and evaporated to give a crude product which was
purified by silica gel column chromatography using heptane/ethyl
acetate (8:2) as the eluent, to give 197FBA24c (11 mg, 37%).
[0684] LCMS m/z 275 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 300 MHz)
.delta. 8.14-8.05 (m, 2H), 7.65 (d, J=8.0, 1H), 7.58-7.51 (m, 1H),
7.49-7.40 (m, 1H), 6.91 (d, J=8.0, 1H), 5.80-5.70 (m, 1H),
4.43-4.33 (m, 1H), 3.97 (t, J=5.2, 1H), 2.39-2.14 (m, 2H),
2.11-1.87 (m, 2H), 1.78-156 (m, 2H), 1.53 (s, 3H). .sup.13C-NMR
(CDCl.sub.3, 75 MHz) 162.7, 150.7, 134.4, 133.7, 131.9, 128.4,
127.6, 126.1, 125.5, 125.1, 119.4, 113.6, 102.2, 59.2, 58.5, 39.8,
34.7, 29.9, 22.7.
In Vitro Determination of Receptor Activity
[0685] Receptor Selection and Amplification (R-SAT) Assays. 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, 1998) 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. 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 colorimetric reaction was measured in a
spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data
were analyzed using the computer program XLFit (IDBSm).
[0686] Androgen Receptor Agonist Activity TABLE-US-00001 TABLE 1
compound % Efficacy pEC50 196MBT2-7 85 8.1 116BG35-24 94 8.1
136BG73-10 66 8.1 136BG85-2 41 7.1 156AF70-267 88 8.7 156AF11-229
44 6.8 156AF32-246 57 7.4
Determination of In Vivo Activity of Test Compounds as Androgen
Receptor Agonists. 116BG33 Results
[0687] Androgen Receptor agonist 116BG33 was administered s.c.
daily for two weeks to castrated male Sprague Dawley rats (n=3).
The effects of 116BG33 (3, 10, 30 mg/kg) were compared to
testosterone propionate (0.1 and 1 mg/kg; positive control) and
vehicle (10% Tween80; negative control). Blood and wet weights of
prostate gland and seminal vesicle were measured after sacrifice
that occurred 24 hours after the last dose. Blood was collected in
heparin collection tubes after sacrifice that occurred 24 hours
after the last dose. Blood was centrifuged and plasma collected and
plasma samples frozen.
[0688] Rat luteinizing hormone (LH) plasma levels were 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.
Results
[0689] Daily s.c. administration for two weeks of 3, 10 or 30 mg/kg
116BG33 or 0.1 mg/kg testosterone propionate (TP) did not have any
effect on wet weight of prostate (FIG. 1) or seminal vesicle (FIG.
2) after sacrifice compared to vehicle. In contrast, daily s.c.
administration for two weeks of 1 mg/kg testosterone propionate
(TP) resulted in a significant increase in wet weight of prostate
(FIG. 1) and seminal vesicle (FIG. 2) compared to vehicle. These
results suggest that 116BG33 will not exhibit the potential side
effect of increased seminal vesicle and prostate size that is
common after treatment with testosterone.
[0690] As shown in FIG. 3, upon castration, plasma levels of
luteinizing hormone are increased by about 4-5 fold. Chronic
exogeneous administration (14 days) of an AR agonist such as the
testosterone propionate analog results in a dose dependent reversal
of the LH levels to levels similar to naive (non-castrated
animals). Sub-cutaneous administration of 116BG33, a potent and
selective AR agonist, similarly reduces LH levels to physiological
norms. Complete reversal is evident at 30 mg/kg.
154BG31 Results
[0691] 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. 4), seminal
vesicle (FIG. 5), and levator ani muscle (FIG. 6) wet tissue
weights as compared to vehicle treatment. In contrast, daily s.c.
administration of 3 mg/kg 154BG31 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 154BG31 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 154BG31 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.
7) Chronic administration of TP (1 mg/kg, s.c. for 14 days), an AR
agonist, restored LH levels to those obtained in naive rats
(non-castrated animals). Daily administration of 154BG31 (various
doses, s.c. for 14 days), a potent and selective AR agonist,
produced a dose-dependent suppression of plasma LH levels, such
that a complete reversal was evident at 10 mg/kg.
* * * * *