U.S. patent application number 11/300848 was filed with the patent office on 2006-05-04 for nk1 antagonists.
Invention is credited to Gregory Reichard, Neng-Yang Shih, Cheng Wang, Steven Wang, Dong Xiao.
Application Number | 20060094720 11/300848 |
Document ID | / |
Family ID | 30115630 |
Filed Date | 2006-05-04 |
United States Patent
Application |
20060094720 |
Kind Code |
A1 |
Shih; Neng-Yang ; et
al. |
May 4, 2006 |
NK1 antagonists
Abstract
Disclosed are NK.sub.1 antagonists having the formula: ##STR1##
Also disclosed are methods for treating a number of physiological
disorders, symptoms or diseases, including emesis, depression,
anxiety and cough, using the compounds of formula (I).
Inventors: |
Shih; Neng-Yang; (Warren,
NJ) ; Wang; Steven; (Jersey City, NJ) ;
Reichard; Gregory; (Ann Arbor, MI) ; Xiao; Dong;
(Warren, NJ) ; Wang; Cheng; (Summit, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
30115630 |
Appl. No.: |
11/300848 |
Filed: |
December 15, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10612176 |
Jul 2, 2003 |
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11300848 |
Dec 15, 2005 |
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60393708 |
Jul 3, 2002 |
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Current U.S.
Class: |
514/235.2 ;
514/317; 514/326; 544/128; 546/207; 546/211; 546/223 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 29/02 20180101; C07D 401/04 20130101; A61P 13/02 20180101;
A61P 25/24 20180101; A61P 25/28 20180101; C07D 413/12 20130101;
C07D 413/04 20130101; A61P 25/36 20180101; A61P 25/22 20180101;
A61P 11/14 20180101; A61P 29/00 20180101; A61P 25/08 20180101; A61P
25/32 20180101; A61P 17/00 20180101; C07D 417/12 20130101; A61P
25/06 20180101; C07D 417/14 20130101; A61P 25/30 20180101; C07D
401/12 20130101; A61P 25/04 20180101; A61P 3/04 20180101; A61P 3/10
20180101; C07D 405/12 20130101; A61P 27/02 20180101; A61P 1/14
20180101; A61P 1/08 20180101; A61P 15/00 20180101; A61P 25/18
20180101; A61P 31/18 20180101; C07D 211/98 20130101; C07D 409/12
20130101; A61P 1/04 20180101; A61P 25/00 20180101; A61P 19/04
20180101; A61P 25/20 20180101; A61P 9/10 20180101; A61P 13/10
20180101 |
Class at
Publication: |
514/235.2 ;
514/317; 514/326; 544/128; 546/207; 546/211; 546/223 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/454 20060101 A61K031/454; A61K 31/453
20060101 A61K031/453; C07D 409/02 20060101 C07D409/02; C07D 413/02
20060101 C07D413/02 |
Claims
1. A compound having the formula (I): ##STR117## or a
pharmaceutically acceptable salt or solvate thereof, wherein
Ar.sup.1 and Ar.sup.2 are each independently selected from the
group consisting of (R.sup.19).sub.n7-heteroaryl- and ##STR118##
X.sup.1 is selected from the group consisting of --O--, --S--,
--SO--, --SO.sub.2--, --NR.sup.12--, --N(COR.sup.12)-- and
--N(SO.sub.2R.sup.15)--; R.sup.1, R.sup.3 and R.sup.5 are each
independently selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl; R.sup.2, R.sup.4 and R.sup.6 are each
independently selected from the group consisting of H,
--CONR.sup.13R.sup.14 and --(CH.sub.2).sub.n1-G; wherein G is
selected from the group consisting of H, --CF.sub.3, --CHF.sub.2,
--CH.sub.2F, --OH, --O--(C.sub.1-C.sub.6)alkyl, --SO.sub.2R.sup.13,
--O--(C.sub.3-C.sub.8 cycloalkyl), --NR.sup.13R.sup.14,
--SO.sub.2NR.sup.13R.sup.14, --NR.sup.13SO.sub.2R.sup.15,
--NR.sup.13COR.sup.12, --NR.sup.12(CONR.sup.13R.sup.14),
--CONR.sup.13R.sup.14, --COOR.sup.12 and C.sub.3-C.sub.8
cycloalkyl; or R.sup.1 and R.sup.2, taken together with the carbon
to which they are attached, form a C.sub.3-C.sub.6 cycloalkyl ring;
or R.sup.1 and R.sup.2, taken together with the carbon to which
they are attached, form a ##STR119## group, provided that X1 is
--O-- or --NR.sup.12 when said ##STR120## is formed; or R.sup.3 and
R.sup.4, taken together with the carbon to which they are attached,
form a ##STR121## group; or R.sup.5 and R.sup.6, taken together
with the carbon to which they are attached, form a ##STR122##
group; R.sup.7 and R.sup.11 are each independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, (R.sup.16).sub.n7-aryl-, (R.sup.19).sub.n7-heteroaryl-,
--COOR.sup.29, --CONR.sup.21R.sup.22,
--CON(R.sup.21)(CH.sub.2).sub.n-G.sup.1,
--S(O).sub.n5(CH.sub.2).sub.n-G.sup.1, --S(O).sub.n5R.sup.13,
--CO(CH.sub.2).sub.n-G.sup.1 and --(CH.sub.2).sub.n1-G.sup.1;
wherein n is 0-4, and G.sup.1 is selected from the group consisting
of H, --OH, (C.sub.1-C.sub.6)alkyl, --O--(C.sub.1-C.sub.6 alkyl),
--S(O).sub.n5R.sup.13, --O--(C.sub.3-C.sub.8 cycloalkyl),
--NR.sup.13R.sup.14, --SO.sub.2NR.sup.13R.sup.14,
--NR.sup.13SO.sub.2R.sup.15, --NR.sup.13COR.sup.12,
--NR.sup.12(CONR.sup.13R.sup.14), --OC(.dbd.O)R.sup.12,
--CONR.sup.13R.sup.14, --COOR.sup.12, C.sub.3-C.sub.8 cycloalkyl,
--CF.sub.3, (R.sup.16).sub.n7-aryl-O--, (R.sup.16).sub.n7-aryl-,
(R.sup.19).sub.n7-heteroaryl-, (R.sup.19).sub.n7-heterocycloalkyl-
and alkenyl, and provided that, when n is 0, then G.sup.1 is
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
alkenyl, --CONR.sup.13R.sup.14, --COOR.sup.12, C.sub.3-C.sub.8
cycloalkyl, --CF.sub.3, (R.sup.16).sub.n7-aryl-,
(R.sup.19).sub.n7-heteroaryl-, and
(R.sup.19).sub.n7-heterocycloalkyl-; and provided that, when
n.sub.1 is 1, then G.sup.1 is selected from the group consisting of
H, (C.sub.1-C.sub.6)alkyl, alkenyl, --S(O).sub.n5R.sup.13,
--SO.sub.2NR.sup.13R.sup.14, --CONR.sup.13R.sup.14, --COOR.sup.12,
C.sub.3-C.sub.8 cycloalkyl, --CF.sub.3, (R.sup.16).sub.n7-aryl-,
(R.sup.19).sub.n7-heteroaryl- wherein said heteroaryl ring is bound
by a ring carbon to the --(CH.sub.2).sub.n1-- group, and
(R.sup.19).sub.n7-heterocycloalkyl- wherein said heterocycloalkyl
ring is bound by a ring carbon to the --(CH.sub.2).sub.n1-- group;
or R.sup.7 and R.sup.11, taken together with the nitrogen to which
they are attached, form a 5-7 membered heterocycloalkyl ring of the
following formula: ##STR123## R.sup.7 and R.sup.11, taken together
with the nitrogen to which they are attached, form a 5-membered
ring having the formula (A) or (B): ##STR124## X is selected from
the group consisting of --NR.sup.20--, --N(CONR.sup.13R.sup.14)--,
--N(CO.sub.2R.sup.13)--, --N(SO.sub.2R.sup.15)--,
--N(COR.sup.12)--, --N(SO.sub.2NHR.sup.13)--, --O--, --S--, --SO--,
--SO.sub.2--, --CF.sub.2--, --CH.sub.2--, and --C(R.sup.12)F--;
R.sup.8, R.sup.9 and R.sup.10 are each independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, --OR.sup.12, halogen, --CN, --NO.sub.2, --CF.sub.3,
--CHF.sub.2, --CH.sub.2F, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--COOR.sup.12, --CONR.sup.21R.sup.22, --NR.sup.21COR.sup.12,
--NR.sup.21CO.sub.2R.sup.15, --NR.sup.21CONR.sup.21R.sup.22,
--NR.sup.21SO.sub.2R.sup.15, --NR.sup.21R.sup.22,
--SO.sub.2NR.sup.21R.sup.22, --S(O).sub.n5R.sup.15,
(R.sup.16).sub.n7-aryl- and (R.sup.19).sub.n7-heteroaryl-; R.sup.12
is selected from the group consisting of H, C.sub.1-C.sub.6 alkyl
and C.sub.3-C.sub.8 cycloalkyl; R.sup.13 and R.sup.14 are each
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.3 alkyl-O--CH.sub.3,
C.sub.3-C.sub.8 cycloalkyl,
(R.sup.19).sub.n7-aryl(CH.sub.2).sub.n6-- and
(R.sup.19).sub.n7-heteroaryl-(CH.sub.2).sub.n6--; or R.sup.13 and
R.sup.14, taken together with the nitrogen to which they are
attached, form a 4-7 membered ring containing from 0-3 additional
heteroatoms selected from the group consisting of --O--, --S-- and
--NR.sup.12--; R.sup.15 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl or --CF.sub.3; R.sup.16 is 1 to 3 substituents each
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen
and --CF.sub.3; R.sup.19 is 1 to 3 substituents each independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, --OH, halogen, --CN, --NO.sub.2,
--C(O)CF.sub.3, --CF.sub.3, --CHF.sub.2, --CH.sub.2F, --OCF.sub.3,
--OCHF.sub.2, --OCH.sub.2F, --O--(C.sub.1-C.sub.6 alkyl),
--O--(C.sub.3-C.sub.8 cycloalkyl),
--COOR.sup.12--CONR.sup.21R.sup.22, --NR.sup.21R.sup.22,
--NR.sup.21COR.sup.12, --NR.sup.21CO.sub.2R.sup.12,
--NR.sup.21CONR.sup.21R.sup.22, --NR.sup.21SO.sub.2R.sup.15 and
--S(O).sub.n5R.sup.15; R.sup.20 is H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, --(CH.sub.2).sub.n6-heterocycloalkyl,
(R.sup.19).sub.n7-aryl(CH.sub.2).sub.n6-- or
(R.sup.19).sub.n7-heteroaryl-(CH.sub.2).sub.n6--; R.sup.21 and
R.sup.22 are each independently selected from the group consisting
of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl and benzyl;
or R.sup.21 and R.sup.22, taken together with the nitrogen to which
they are attached, form a 4-7 membered heteroaryl ring containing
from 0-3 additional heteroatoms selected from the group consisting
of --O--, --S-- and --NR.sup.12--; R.sup.23 and R.sup.24 are each
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl and --CONR.sup.13R.sup.14; or R.sup.23 and
R.sup.24, taken together with the carbon atom to which they are
attached, form a ##STR125## group; R.sup.25, R.sup.26, R.sup.27 and
R.sup.28 are each independently selected from the group consisting
of H and C.sub.1-C.sub.6 alkyl; or R.sup.25 and R.sup.26, taken
together with the carbon atom to which they are attached, form a
##STR126## group; or R.sup.27 and R.sup.28, taken together with the
carbon atom to which they are attached, form a ##STR127## group;
R.sup.29 is selected from the group consisting of C.sub.1-C.sub.6
alkyl and C.sub.3-C.sub.8 cycloalkyl; n.sub.1 is 1-4; n.sub.2 and
n.sub.3 are each independently 0-3, provided that a sum of n.sub.2
and n.sub.3 is 0-4; n.sub.4 is 0-2; n.sub.5 is 0-2; n.sub.6 is 0-3;
and n.sub.7 is 0-3; and provided that, when n.sub.4 is 0, and
R.sup.25 and R.sup.26 are each H, then X is not --O--,
--NR.sup.20-- or --S--.
2. The compound of claim 1 wherein X.sup.1 is --O--.
3. The compound of claim 1 wherein Ar.sup.1 and Ar.sup.2 are each
independently ##STR128##
4. The compound of claim 3 wherein R.sup.8, R.sup.9 and R.sup.10
are each independently selected from the group consisting of H,
--CH.sub.3, halogen and --CF.sub.3.
5. The compound of claim 1 wherein X.sup.1 is --O--; and Ar.sup.1
and Ar.sup.2 are each independently ##STR129## wherein R.sup.8,
R.sup.9 and R.sup.10 are each independently selected from the group
consisting of H, --CH.sub.3, halogen and --CF.sub.3.
6. The compound of claim 1 wherein ##STR130## wherein, R.sup.8 is
selected from the group consisting of H and F, and R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of H, --CH.sub.3, F, Cl and --CF.sub.3.
7. The compound of claim 6 wherein X.sup.1 is --O--; and R.sup.3,
R.sup.4, R.sup.27 and R.sup.28 are each H.
8. The compound of claim 6 wherein R.sup.5 and R.sup.6 are H.
9. The compound of claim 7 wherein R.sup.7 and R.sup.11, taken
together with the nitrogen to which they are attached, form a 5-7
membered ring having the following formula: ##STR131##
10. The compound of claim 1 having the formula ##STR132## wherein
R.sup.7, R.sup.8 and R.sup.11 are selected from the group
consisting of: TABLE-US-00003 R.sup.8 R.sup.7 R.sup.11 H H H H H
##STR133## H H ##STR134## H H ##STR135## H H ##STR136## H H
##STR137## H H ##STR138## H H ##STR139## H H ##STR140## H H
##STR141## H H ##STR142## H H ##STR143## H H ##STR144## H H
##STR145## H H ##STR146## H H ##STR147## H H ##STR148## H H
##STR149## H H ##STR150## H H ##STR151## H H ##STR152## H H
##STR153## H H ##STR154## H H ##STR155## H H ##STR156## H H
##STR157## H H ##STR158## H H ##STR159## H ##STR160## ##STR161## H
##STR162## ##STR163## F H ##STR164## F H H F H ##STR165## F H
##STR166## F H ##STR167## F H ##STR168## F H ##STR169## F H
##STR170## F H ##STR171## H H ##STR172## H H ##STR173## F H
##STR174## F H ##STR175## H H ##STR176## H H ##STR177## H H
##STR178## H H ##STR179##
11. The compound of claim 1 having the formula: ##STR180## wherein
R.sup.1, R.sup.2, R.sup.7, R.sup.8 and R.sup.11 are selected from
the group consisting of: TABLE-US-00004 R.sup.8 R.sup.1 R.sup.2
--NR.sup.7R.sup.11 H H H ##STR181## H H H ##STR182## H H H
##STR183## H H H ##STR184## F H H ##STR185## F H H ##STR186## F H H
##STR187## H H H ##STR188## H H CH.sub.3 ##STR189## H H CH.sub.2OH
##STR190## H H H ##STR191## H H H ##STR192## H H H ##STR193## H H H
##STR194## H H H ##STR195## H H H ##STR196## H H H ##STR197##
12. The compound of claim 11 or the pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.1, R.sup.2, R.sup.7, R.sup.8
and R.sup.11 are selected from the group consisting of
TABLE-US-00005 R.sup.8 R.sup.1 R.sup.2 --NR.sup.7R.sup.11 H H H
##STR198## H H H ##STR199## H H CH.sub.3 ##STR200## H H CH.sub.2OH
##STR201## H H H ##STR202##
13. The compound of claim 12 having the formula: ##STR203##
14. The compound of claim 12 having the formula: ##STR204##
15. The compound of claim 12 having the formula: ##STR205##
16. The compound of claim 12 having the formula: ##STR206##
17. The compound of claim 12 having the formula: ##STR207##
18. A pharmaceutical composition comprising at least one compound
of claim 1, and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier, at least one serotonin reuptake inhibitor, and
at least one compound of claim 1.
20. A method for treating a physiological disorder, symptom or
disease in a patient in need of such treatment, comprising
administering to said patient an effective amount of at least one
compound of claim 1, wherein said physiological disorder, symptom
or disease is selected from the group consisting of: respiratory
diseases, inflammatory diseases, skin disorders, ophthalmological
disorders, central nervous system conditions, addictions, epilepsy,
nociception, psychosis, schizophrenia, Alzheimer's disease, AIDs
related dementia, Towne's disease, stress related disorders,
obsessive/compulsive disorders, eating disorders, sleep disorders,
mania, premenstrual syndrome, gastrointestinal disorders,
atherosclerosis, fibrosing disorders, obesity, Type II diabetes,
pain related disorders, bladder and genitourinary disorders, and
nausea.
21. A method for treating a physiological disorder, symptom or
disease in a patient in need of such treatment, comprising
administering to said patient an effective amount of at least one
compound of claim 1, wherein said physiological disorder, symptom
or disease is selected from the group consisting of: a respiratory
disease, depression, anxiety, phobia, bipolar disorder, alcohol
dependence, psychoactive substance abuse, nociception, psychosis,
schizophrenia, stress related disorder, obsessive/compulsive
disorder, bulemia, anorexia nervosa, binge eating, sleep disorder,
mania, premenstrual syndrome, gastrointestinal disorder, obesity,
headache, neuropathic pain, post-operative pain, chronic pain
syndrome, bladder disorder, genitourinary disorder, cough, emesis
and nausea.
22. A method for treating a physiological disorder, symptom or
disease in a patient in need of such treatment, comprising
administering to said patient an effective amount of at least one
compound of claim 1, and an effective amount of at least one active
ingredient selected from the group consisting of: other NK.sub.1
receptor antagonists, selective serotonin reuptake inhibitors,
dopamine receptor agonists, serotonin 5-HT.sub.3 receptor
antagonists, serotonin 5-HT.sub.2c receptor agonists, nociceptin
receptor agonists, glucocorticoids and inhibitors of multidrug
resistance protein 5, wherein said physiological disorder, symptom
or disease is selected from the group consisting of: a respiratory
disease, depression, anxiety, phobia, bipolar disorder, alcohol
dependence, psychoactive substance abuse, nociception, psychosis,
schizophrenia, stress related disorder, obsessive/compulsive
disorder, bulemia, anorexia nervosa, binge eating, sleep disorder,
mania, premenstrual syndrome, gastrointestinal disorder, obesity,
headache, neuropathic pain, post-operative pain, chronic pain
syndrome, bladder disorder, genitourinary disorder, cough, emesis
and nausea.
23. A method of treating emesis and/or nausea in a patient in need
of such treatment comprising administering to said patient an
effective amount of at least one compound having the formula (I) in
combination with an effective amount of at least one serotonin
5-HT.sub.3 receptor antagonist and/or at least one
glucocorticoid.
24. The method of claim 23 wherein said serotonin 5-HT.sub.3
receptor antagonist is ondansetron and said glucocorticoid is
dexamethasone.
25. The method of claim 21, wherein the physiological disorder,
symptom or disease is emesis, depression, anxiety or cough.
26. The method of claim 25 wherein the physiological disorder,
symptom or disease is depression or anxiety.
27. The method of claim 26, further comprising administering to the
patient an effective amount of at least one anti-depressant agent
and/or at least one anti-anxiety agent.
28. The method of claim 25 wherein depression is being treated and
said method further comprises administering to the patient an
effective amount of at least one selective serotonin reuptake
inhibitor.
29. A method for antagonizing an effect of a Substance P at a
neurokinin-1 receptor site or for blocking at least one
neurokinin-1 receptor, in a patient in need of such treatment,
comprising administering to said patient an effective amount of at
least one compound of claim 1.
30. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat an
NK.sub.1 receptor mediated disease, wherein one container comprises
a pharmaceutical composition comprising an effective amount of a
compound of claim 1 in a pharmaceutically acceptable carrier, and
wherein, a separate container comprises a pharmaceutical
composition comprising another therapeutic agent in a
pharmaceutically acceptable carrier, said therapeutic agent being
selected from the group consisting of: SSRIs, other types of
NK.sub.1 receptor antagonists, prostanoids, H.sub.1 receptor
antagonists, .alpha.-adrenergic receptor agonists, dopamine
receptor agonists, melanocortin receptor agonists, endothelin
receptor antagonists, endothelin converting enzyme inhibitors,
angiotensin II receptor antagonists, angiotensin converting enzyme
inhibitors, neutral metalloendopeptidase inhibitors, ET.sub.A
antagonists, renin inhibitors, serotonin 5-HT.sub.3 receptor
antagonists, serotonin 5-HT.sub.2c receptor agonists, nociceptin
receptor agonists, glucocorticoids, rho kinase inhibitors,
potassium channel modulators and inhibitors of multi-drug
resistance protein 5.
31. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat
depression and/or anxiety, wherein one container comprises a
pharmaceutical composition comprising an effective amount of a
compound of claim 1 in a pharmaceutically acceptable carrier, and
wherein, a separate container comprises a pharmaceutical
composition comprising an antidepressant agent in a
pharmaceutically acceptable carrier, and/or wherein a separate
container comprises a pharmaceutical composition comprising an
antianxiety agent in a pharmaceutically acceptable carrier.
32. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat an
NK.sub.1 receptor mediated disease, wherein one container comprises
a pharmaceutical composition comprising an effective amount of a
compound of claim 1 in a pharmaceutically acceptable carrier, and
wherein, a separate container comprises a pharmaceutical
composition comprising an SSRI in a pharmaceutically acceptable
carrier.
33. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat
depression and/or anxiety, wherein one container comprises a
pharmaceutical composition comprising an effective amount of a
compound of claim 1 in a pharmaceutically acceptable carrier, and
wherein, a separate container comprises a pharmaceutical
composition comprising an SSRI in a pharmaceutically acceptable
carrier.
34. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat emesis
and/or nausea, j wherein one container comprises a pharmaceutical
composition comprising an effective amount of a compound of claim 1
in a pharmaceutically acceptable carrier, and wherein, a separate
container comprises a pharmaceutical composition comprising a
serotonin 5-HT.sub.3 receptor antagonist in a pharmaceutically
acceptable carrier, and/or wherein a separate container comprises a
pharmaceutical composition comprising a glucocorticoid in a
pharmaceutically acceptable carrier.
35. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat emesis
and/or nausea, wherein one container comprises a pharmaceutical
composition comprising an effective amount of a compound of claim 1
in a pharmaceutically acceptable carrier, and wherein, a separate
container comprises ondansetron, and/or wherein a separate
container comprises dexamethasone.
Description
REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. application Ser.
No. 10/612,176, filed Jul. 2, 2003, and claims the benefit of U.S.
Provisional Application Ser. No. 60/393,708 filed Jul. 3, 2002.
BACKGROUND OF THE INVENTION
[0002] This invention relates to antagonists of the neuropeptide
neurokinin-1 (NK.sub.1 or NK-1) receptor, compositions containing
the antagonists, and methods of using the antagonists for the
treatment of various diseases and conditions, including emesis,
depression, anxiety and cough.
[0003] Tachykinins are peptide ligands for neurokinin receptors.
Neurokinin receptors, such as NK.sub.1, NK.sub.2 and NK.sub.3, are
involved in a variety of biological processes. They can be found in
a mammal's nervous and circulatory systems, as well as in
peripheral tissues. Consequently, the modulation of these types of
receptors have been studied to potentially treat or prevent various
mammalian disease states. For instance, NK.sub.1 receptors have
been reported to be involved in microvascular leakage and mucus
secretion. Representative types of neurokinin receptor antagonists
and the disorders that can be treated with them include, for
example, sleep, pain, migraine, emesis, nociception and
inflammation, see, for example, U.S. Pat. No. 6,329,401, U.S. Pat.
No. 5,760,018, U.S. Pat. No. 5,620,989, WO 95/19344, WO 94/13639,
and WO 94/10165.
[0004] It would be beneficial to provide a NK.sub.1 antagonist that
is potent, selective, and possesses beneficial therapeutic and
pharmacological properties, and good metabolic stability. It would
further be beneficial to provide a NK.sub.1 antagonist that is
effective for treating a variety of physiological disorders,
symptoms and diseases, while minimizing side effects. This
invention provides such NK.sub.1 antagonists.
SUMMARY OF THE INVENTION
[0005] This invention is directed to a compound of the formula (I):
##STR2## or a pharmaceutically acceptable salt or solvate thereof,
wherein
[0006] Ar.sup.1 and Ar.sup.2 are each independently selected from
the group consisting of (R.sup.19).sub.n7-heteroaryl- and
##STR3##
[0007] X.sup.1 is selected from the group consisting of --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.12--, --N(COR.sup.12)-- and
--N(SO.sub.2R.sup.15)--;
[0008] R.sup.1, R.sup.3 and R.sup.5 are each independently selected
from the group consisting of H and C.sub.1-C.sub.6 alkyl;
[0009] R.sup.2, R.sup.4 and R.sup.6 are each independently selected
from the group consisting of H, --CONR.sup.13R.sup.14 and
--(CH.sub.2).sub.n1-G; wherein G is selected from the group
consisting of H, --CF.sub.3, --CHF.sub.2, --CH.sub.2F, --OH,
--O--(C.sub.1-C.sub.6) alkyl, --SO.sub.2R.sup.13,
--O--(C.sub.3-C.sub.8 cycloalkyl), --NR.sup.13R.sup.14,
--SO.sub.2NR.sup.13R.sup.14, --NR.sup.13SO.sub.2R.sup.15,
--NR.sup.13COR.sup.12, --NR.sup.12(CONR.sup.13R.sup.14),
--CONR.sup.13R.sup.14, --COOR.sup.12 and C.sub.3-C.sub.8
cycloalkyl; or
[0010] R.sup.1 and R.sup.2, taken together with the carbon to which
they are attached, form a C.sub.3-C.sub.6 cycloalkyl ring; or
[0011] R.sup.1 and R.sup.2, taken together with the carbon to which
they are attached, form a ##STR4## group, provided that X1 is --O--
or --NR.sup.12 when said ##STR5## is formed; or
[0012] R.sup.3 and R.sup.4, taken together with the carbon to which
they are attached, form a ##STR6## group; or
[0013] R.sup.5 and R.sup.6, taken together with the carbon to which
they are attached, form a ##STR7## group;
[0014] R.sup.7 and R.sup.11 are each independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, (R.sup.6).sub.n7-aryl-, (R.sup.19).sub.n7-heteroaryl-,
--COOR.sup.29, --CONR.sup.21R.sup.22,
--CON(R.sup.21)(CH.sub.2).sub.n-G.sup.1,
--S(O).sub.n5(CH.sub.2).sub.n-G.sup.1, --S(O).sub.n5R.sup.13,
--CO(CH.sub.2).sub.n-G.sup.1 and --(CH.sub.2).sub.n1-G.sup.1;
wherein [0015] n is 0-4, and [0016] G.sup.1 is selected from the
group consisting of H, --OH, (C.sub.1-C.sub.6)alkyl,
--O--(C.sub.1-C.sub.6 alkyl), --S(O).sub.n5R.sup.13,
--O--(C.sub.3-C.sub.8 cycloalkyl), --NR.sup.13R.sup.14,
--SO.sub.2NR.sup.13R.sup.14, --NR.sup.13SO.sub.2R.sup.15,
--NR.sup.13COR.sup.12, --NR.sup.12(CONR.sup.13R.sup.14),
--OC(.dbd.O)R.sup.12, --CONR.sup.13R.sup.14, --COOR.sup.12,
C.sub.3-C.sub.8 cycloalkyl, --CF.sub.3, (R.sup.16).sub.n7-aryl-O--,
(R.sup.16).sub.n7-aryl-, (R.sup.19).sub.n7-heteroaryl-,
(R.sup.19).sub.n7-heterocycloalkyl- and alkenyl (e.g.,
--CH.dbd.CH.sub.2, and --CH.sub.2--CH.dbd.CH.sub.2), and [0017]
provided that, when n is 0, then G.sup.1 is selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl, alkenyl,
--CONR.sup.13R.sup.14, --COOR.sup.12, C.sub.3-C.sub.8 cycloalkyl,
--CF.sub.3, (R.sup.16).sub.n7-aryl-, (R.sup.19).sub.n7-heteroaryl-,
and (R.sup.19).sub.n7-heterocycloalkyl-; and [0018] provided that,
when n, is 1, then G.sup.1 is selected from the group consisting of
H, (C.sub.1-C.sub.6)alkyl, alkenyl,
--S(O).sub.n5R.sup.13--SO.sub.2NR.sup.13R.sup.14,
--CONR.sup.13R.sup.14, --COOR.sup.12, C.sub.3-C.sub.8 cycloalkyl,
--CF.sub.3, (R.sup.16).sub.n7-aryl-, (R.sup.19).sub.n7-heteroaryl-
wherein said heteroaryl ring is bound by a ring carbon to the
--(CH.sub.2).sub.n1-- group, and
(R.sup.19).sub.n7-heterocycloalkyl- wherein said heterocycloalkyl
ring is bound by a ring carbon to the --(CH.sub.2).sub.n1-- group;
or
[0019] R.sup.7 and R.sup.11, taken together with the nitrogen to
which they are attached, form a 5-7 membered heterocycloalkyl ring
of the following formula: ##STR8##
[0020] R.sup.7 and R.sup.11, taken together with the nitrogen to
which they are attached, form a 5-membered ring having the formula
(A) or (B): ##STR9##
[0021] X is selected from the group consisting of --NR.sup.20--,
--N(CONR.sup.13R.sup.14)--, --N(CO.sub.2R.sup.13)--,
--N(SO.sub.2R.sup.15)--, --N(COR.sup.12)--,
--N(SO.sub.2NHR.sup.13)--, --O--, --S--, --SO--, --SO.sub.2--,
--CF.sub.2--, --CH.sub.2--, and --C(R.sup.12)F--;
[0022] R.sup.8, R.sup.9 and R.sup.10 are each independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, --OR.sup.12, halogen, --CN, --NO.sub.2,
--CF.sub.3, --CHF.sub.2, --CH.sub.2F, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2F, --COOR.sup.12, --CONR.sup.21R.sup.22,
--NR.sup.21COR.sup.12, --NR.sup.21CO.sub.2R.sup.15,
--NR.sup.21CONR.sup.21R.sup.22, --NR.sup.21SO.sub.2R.sup.15,
--NR.sup.21R.sup.22, --SO.sub.2NR.sup.21R.sup.22,
--S(O).sub.n5R.sup.15, (R.sup.16).sub.n7-aryl- and
(R.sup.19).sub.n7-heteroaryl-;
[0023] R.sup.12 is selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.8 cycloalkyl;
[0024] R.sup.13 and R.sup.14 are each independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.3
alkyl-O--CH.sub.3, C.sub.3-C.sub.8 cycloalkyl,
(R.sup.19).sub.n7-aryl(CH.sub.2).sub.n6-- and
(R.sup.19).sub.n7-heteroaryl-(CH.sub.2).sub.n6--; or
[0025] R.sup.13 and R.sup.14, taken together with the nitrogen to
which they are attached, form a 4-7 membered ring containing from
0-3 additional heteroatoms selected from the group consisting of
--O--, --S-- and --NR.sup.12--;
[0026] R.sup.15 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl or --CF.sub.3;
[0027] R.sup.16 is 1 to 3 substituents each independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6 alkoxy, halogen and --CF.sub.3;
[0028] R.sup.19 is 1 to 3 substituents each independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, --OH, halogen, --CN, --NO.sub.2, --C(O)CF.sub.3,
--CF.sub.3, --CHF.sub.2, --CH.sub.2F, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2F, --O--(C.sub.1-C.sub.6 alkyl), --O--(C.sub.3-C.sub.8
cycloalkyl), --COOR.sup.12, --CONR.sup.21R.sup.22,
--NR.sup.21R.sup.22, --NR.sup.21COR.sup.12,
--NR.sup.21CO.sub.2R.sup.12, --NR.sup.21CONR.sup.21R.sup.22,
--NR.sup.21SO.sub.2R.sup.15 and --S(O).sub.n5R.sup.15;
[0029] R.sup.20 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, --(CH.sub.2).sub.n6-heterocycloalkyl,
(R.sup.19).sub.n7-aryl(CH.sub.2).sub.n6-- or
(R.sup.19).sub.n7-heteroaryl-(CH.sub.2).sub.n6--;
[0030] R.sup.21 and R.sup.22 are each independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl and benzyl; or
[0031] R.sup.21 and R.sup.22, taken together with the nitrogen to
which they are attached, form a 4-7 membered heteroaryl ring
containing from 0-3 additional heteroatoms selected from the group
consisting of --O--, --S-- and --NR.sup.12--;
[0032] R.sup.23 and R.sup.24 are each independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl and
--CONR.sup.13R.sup.14; or
[0033] R.sup.23 and R.sup.24, taken together with the carbon atom
to which they are attached, form a ##STR10## group;
[0034] R.sup.25, R.sup.26, R.sup.27 and R.sup.28 are each
independently selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl; or
[0035] R.sup.25 and R.sup.26, taken together with the carbon atom
to which they are attached, form a ##STR11## group; or
[0036] R.sup.27 and R.sup.28, taken together with the carbon atom
to which they are attached, form a ##STR12## group;
[0037] R.sup.29 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.8 cycloalkyl;
[0038] n.sub.1 is 1-4;
[0039] n.sub.2 and n.sub.3 are each independently 0-3, provided
that a sum of n.sub.2 and n.sub.3 is 0-4;
[0040] n.sub.4 is 0-2;
[0041] n.sub.5 is 0-2;
[0042] n.sub.6 is 0-3; and
[0043] n.sub.7 is 0-3; and
[0044] provided that, when n.sub.4 is 0, and R.sup.25 and R.sup.26
are each H, then X is not --O--, --NR.sup.20-- or --S--.
[0045] This invention is also directed to a pharmaceutical
composition comprising an effective amount of at least one (e.g.,
one) compound of formula (I) and a pharmaceutically acceptable
carrier.
[0046] This invention is also directed to a method for effecting an
NK.sub.1 receptor in a patient comprising administering to said
patient an effective amount of at least one (e.g., one) compound of
formula (I).
[0047] This invention is also directed to a method for treating an
NK.sub.1 receptor mediated disease (i.e., a disease associated with
an NK.sub.1 receptor, or a disease involving an NK.sub.1 receptor
in part of the disease process) in a patient in need of such
treatment comprising administering to said patient an effective
amount of at least one (e.g., one) compound of formula (I).
[0048] This invention is also directed to a method of treating a
disease (or disorder or condition) in a patient in need of such
treatment, wherein said disease is selected from the group
consisting of: (1) respiratory diseases (e.g., chronic lung
disease, bronchitis, pneumonia, asthma, allergy, cough and
bronchospasm), (2) inflammatory diseases (e.g., arthritis and
psoriasis), (3) skin disorders (e.g., atopic dermatitis and contact
dermatitis), (4) ophthalmalogical disorders (e.g., retinitis,
ocular hypertension and cataracts), (4) central nervous system
conditions, such as depressions (e.g., neurotic depression),
anxieties (e.g., general anxiety, social anxiety and panic anxiety
disorders), phobias (e.g., social phobia), and bipolar disorder,
(5) addictions (e.g., alcohol dependence and psychoactive substance
abuse), (6) epilepsy, (7) nociception, (8) psychosis, (9)
schizophrenia, (10) Alzheimer's disease, (11) AID's related
dementia, (12) Towne's disease, (13) stress related disorders
(e.g., post tramautic stress disorder), (14) obsessive/compulsive
disorders, (15) eating disorders (e.g., bulemia, anorexia nervosa
and binge eating), (16) sleep disorders, (17) mania, (18)
premenstrual syndrome, (19) gastrointestinal disorders (e.g.,
irritable bowel syndrome, Crohn's disease, colitis, and emesis),
(20) atherosclerosis, (21) fibrosing disorders (e.g., pulmonary
fibrosis), (22) obesity, (23) Type II diabetes, (24) pain related
disorders (e.g., headaches, such as migraines, neuropathic pain,
post-operative pain, and chronic pain syndromes), (25) bladder and
genitourinary disorders (e.g., interstitial cystitis and urinary
incontinence), (26) emesis (e.g., chemotherapy-induced (e.g.,
induced by cisplatin, doxorubicin, and taxane), radiation-induced,
motion sickness, ethanol-induced, and post operative nausea and
vomiting), and (27) nausea, comprising administering to said
patient an effective amount of at least one (e.g., one) compound of
formula (I).
[0049] This invention is also directed to a method of treating a
disease (or disorder or condition) in a patient in need of such
treatment, wherein said disease is selected from the group
consisting of: respiratory diseases (e.g., cough), depression,
anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive
substance abuse, nociception, psychosis, schizophrenia, stress
related disorders, obsessive/compulsive disorder, bulemia, anorexia
nervosa, binge eating, sleep disorders, mania, premenstrual
syndrome, gastrointestinal disorders, obesity, pain related
disorders (e.g., headaches, such as migraines, neuropathic pain,
post-operative pain, and chronic pain syndromes), bladder
disorders, genitourinary disorders, emesis and nausea, comprising
administering to said patient an effective amount of at least one
(e.g., one) compound of formula (I).
[0050] This invention is also directed to a method of treating a
disease wherein there is microvascular leakage and mucus secretion
in a patient in need of such treatment, comprising administering to
said patient an effective amount of at least one (e.g., one)
compound of formula (I).
[0051] This invention is also directed to a method of treating
asthma, emesis, nausea, depressions, anxieties, cough and pain
related disorders in a patient in need of such treatment comprising
administering to said patient an effective amount of at least one
(e.g., one) compound of formula (I).
[0052] This invention is also directed to a method of treating
emesis, depression, anxiety and cough in a patient in need of such
treatment comprising administering to said patient an effective
amount of at least one (e.g., one) compound of formula (I).
[0053] This invention is also directed to a method for antagonizing
an effect of a Substance P at a neurokinin-1 receptor site in a
patient in need of such treatment, comprising administering to said
patient at least one (e.g., one) compound of formula (I).
[0054] This invention is also directed to a method for the blockade
of neurokinin-1 receptors in a patient in need of such treatment,
comprising administering to said patient at least one (e.g., one)
compound of formula (I).
[0055] This invention is also directed to a method for treating
depression and/or anxiety in a patient in need of such treatment
comprising administering to said patient an effective amount of one
or more (e.g., one) compounds of formula (I) in combination with an
effective amount of one or more (e.g., one) anti-depressant agents
and/or one or more (e.g., one) anti-anxiety agents.
[0056] This invention is also directed to a method of treating an
NK.sub.1 receptor mediated disease in a patient in need of such
treatment comprising administering to said patient an effective
amount of one or more (e.g., one) compounds of formula (I) in
combination with an effective amount of one or more (e.g., one)
selective serotonin reuptake inhibitors ("SSRIs").
[0057] This invention is also directed to a method of treating
depression and/or anxiety in a patient in need of such treatment
comprising administering to said patient an effective amount of one
or more (e.g., one) compounds of formula (I) in combination with an
effective amount of one or more (e.g., one) selective serotonin
reuptake inhibitors.
[0058] This invention is also directed to a method of treating an
NK.sub.1 receptor mediated disease in a patient in need of such
treatment comprising administering to said patient an effective
amount of at least one (e.g., one) compound of formula (I) in
combination with at least one (e.g., one) therapeutic agent
selected from the group consisting of: other types of NK.sub.1
receptor antagonists (e.g., those that are disclosed in the
neurokinin receptor antagonist patents cited in the above
Background Section), prostanoids, H.sub.1 receptor antagonists,
.alpha.-adrenergic receptor agonists, dopamine receptor agonists,
melanocortin receptor agonists, endothelin receptor antagonists,
endothelin converting enzyme inhibitors, angiotensin II receptor
antagonists, angiotensin converting enzyme inhibitors, neutral
metalloendopeptidase inhibitors, ET.sub.A antagonists, renin
inhibitors, serotonin 5-HT.sub.3 receptor antagonists (e.g.,
ondansetron), serotonin 5-HT.sub.2c receptor agonists, nociceptin
receptor agonists, glucocorticoids (e.g., dexamethasone), rho
kinase inhibitors, potassium channel modulators and inhibitors of
multi-drug resistance protein 5.
[0059] This invention is also directed to a method for treating an
NK.sub.1 mediated disease in a patient in need of such treatment
comprising administering to said patient an effective amount of a
compound of formula (I) in combination at least one (e.g., one)
therapeutic agent selected from the group consisting of:
prostanoids, such as prostaglandin E.sub.1; .alpha.-adrenergic
agonists, such as phentolamine mesylate; dopamine receptor
agonists, such as apomorphine; angiotensin II antagonists, such as
losartan, irbesartan, valsartan and candesartan; ET.sub.A
antagonists, such as bosentan and ABT-627; serotonin 5-HT.sub.3
receptor antagonists, such as ondansetron; and glucocorticoids,
such as dexamethasone.
[0060] This invention is also directed to a method for treating an
NK.sub.1 mediated disease in a patient in need of such treatment
comprising administering to said patient an effective amount of at
least one (e.g., one) compound of formula (I) in combination with
and effective amount of at least one (e.g., one) therapeutic agent
selected from the group consisting of: other types of NK.sub.1
receptor antagonists, SSRIs, dopamine receptor agonists, serotonin
5-HT.sub.3 receptor antagonists, serotonin 5-HT.sub.2c receptor
agonists, nociceptin receptor agonists, glucocorticoids and
inhibitors of multi-drug resistance protein 5.
[0061] This invention is also directed to a method for treating
emesis, nausea and/or vomiting in a patient in need of such
treatment comprising administering to said patient an effective
amount of at least one (e.g., one) compound of formula (I) in
combination with and effective amount of at least one (e.g., one)
serotonin 5-HT.sub.3 receptor antagonist (e.g., ondansetron) and/or
at least one glucocorticoid (e.g., dexamethasone).
DETAILED DESCRIPTION OF THE INVENTION
[0062] Except where stated otherwise, the following definitions
apply throughout the specification and claims. Chemical names,
common names, and chemical structures may be used interchangeably
to describe the same structure. These definitions apply regardless
of whether a term is used by itself or in combination with other
terms, unless otherwise indicated. Hence, the definition of "alkyl"
applies to "alkyl" as well as the "alkyl" portions of
"hydroxyalkyl," "haloalkyl," "alkoxy," etc.
[0063] (Boc) is tert-butoxy carbonyl.
[0064] (Boc).sub.2O is di-tert-butyl dicarbonate.
[0065] CBS is (S)-methyloxazaborolidine, a Corey-Bakshi-Shibata
catalyst (described in E. S. Corey, R. K. Bakshi and S. Shibata, J.
Am. Chem. Soc., 109, 7925 (1987)).
[0066] CBZ is carbonylbenzyloxy (i.e.,
--C(O)OCH.sub.2C.sub.6H.sub.5).
[0067] CDI is carbonyldiimidazole.
[0068] DBU is 1,8-diazabicyclo[5.4.0]un dec-7-ene.
[0069] DCC is 1,3-dicyclohexylcarbodiimide.
[0070] DIBAL or DIBAL-H is diisobutylaluminum hydride.
[0071] DIEA is diisopropylethyl amine.
[0072] DMAP is dimethylaminopyridine.
[0073] DMSO is dimethylsulfoxide.
[0074] EDC is 1-(3-dimethylaminopropyl)-3-ethycarbodiimide HCl.
[0075] HOBT is hydroxybenzotriazole.
[0076] Ph represents phenyl.
[0077] TEMPO is a free radical of 2, 2, 6, 6-tetra
methyl-1-piperidinyloxy.
[0078] THF is tetrahydrofuran.
[0079] TLC is thin layer chromatography.
[0080] TMSCl is chlorotrimethylsilane.
[0081] "At least one", examples include 1-3, 1-2 or 1.
[0082] "Heteroatom" means a nitrogen, sulfur or oxygen atom.
Multiple heteroatoms in the same group may be the same or
different.
[0083] "One or more", examples include 1-3,1-2 or 1.
[0084] "Patient" includes mammals (e.g., humans) and
non-mammals.
[0085] "Alkyl" means a substituted or unsubstituted, straight or
branched saturated hydrocarbon chain having the designated number
of carbon atoms. Where the number of carbon atoms is not specified,
1 to 20 carbons are intended. Preferred alkyl groups contain 1 to
12 carbon atoms in the chain. More preferred alkyl groups contain 1
to 6 carbon atoms in the chain. Non-limiting examples of suitable
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl and
trifluoromethyl.
[0086] "Alkoxy" means an --O-alkyl group. Representative alkoxy
groups include methoxy, ethoxy and isopropoxy.
[0087] "Aryl" means a substituted or unsubstituted, aromatic, mono-
or bicyclic, carbocyclic ring system having from one to two
aromatic rings. The aryl moiety will generally comprise from 6 to
14 carbon atoms, preferably 6 to 10 carbon atoms, with all
available substitutable carbon atoms of the aryl moiety being
intended as possible points of attachment. Representative examples
include phenyl, tolyl, xylyl, cumenyl, naphthyl, indanyl, indenyl,
and the like. The carbocyclic ring can optionally be substituted
with from one to five, preferably one to three, moieties, such as
mono- through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy,
alkoxy, phenoxy, amino, monoalkylamino, dialkylamino, and the like,
said moieties being independently selected.
[0088] "Cycloalkyl" or "cycloalkane" means an unsubstituted or
substituted, saturated, stable, non-aromatic, carbocyclic ring,
having, preferably, from three to fifteen carbon atoms, more
preferably, from three to eight carbon atoms. The cycloalkyl ring
may be fused with one to three cycloalkyl, aromatic (e.g.,
benzofused), heterocyclic or heteroaromatic rings. The cycloalkyl
may be attached at any endocyclic carbon atom that results in a
stable structure. Preferred carbocyclic rings have from five to six
carbons. Examples of cycloalkyl rings include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[0089] "Hal" or "halo" or "halogen" or "halide means a chloro,
bromo, fluoro or iodo atom radical. Chlorides, bromides and
fluorides are preferred halides.
[0090] "Heteroaryl" means an aromatic mono- or multi-cyclic ring
system comprising about 5 to about 14 ring atoms, preferably about
5 to about 10 ring atoms, in which one or more of the ring atoms is
an atom other than carbon, for example, nitrogen, oxygen or sulfur,
i.e., the heteroaryl ring comprises one or more heteroatoms
independently selected from nitrogen, oxygen and sulfur. Preferred
heteroaryl rings comprise about 5 to about 6 ring atoms.
Optionally, a nitrogen atom of a heteroaryl ring can be oxidized to
the corresponding N-oxide. Representative heteroaryl
(heteroaromatic) groups include pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl,
thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl,
isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl,
isoxazolyl, 1,3,5-triazinyl and indolyl groups.
[0091] "Heterocycloalkyl" means an unsubstituted or substituted,
saturated, mono- or multi-cyclic ring system comprising from three
to fifteen members, and preferably, from three to ring atoms,
wherein from 1-3 of said ring atoms are heteroatoms selected from
the group consisting of --NR.sup.30--, --O-- and --S--, wherein
R.sup.30 is selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl and --COCF.sub.3,
said heterocycloalkyl ring being optionally substituted on the ring
carbons with from 1 to 3 the substituents selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
--OH, halogen, --CN, --NO.sub.2, --C(O)CF.sub.3, --CF.sub.3,
--CHF.sub.2, --CH.sub.2F, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--O--(C.sub.1-C.sub.6 alkyl), --O--(C.sub.3-C.sub.8 cycloalkyl),
--COOR.sup.12, --CONR.sup.21R.sup.22, --NR.sup.21R.sup.22,
--NR.sup.21COR.sup.12, --NR.sup.21CO.sub.2R.sup.12,
--NR.sup.21CONR.sup.21R.sup.22, --NR.sup.21SO.sub.2R.sup.15 and
--S(O).sub.n5R.sup.15;
[0092] "Hydroxyalkyl" means an alkyl group having at least one
hydroxy (e.g., one --OH) substituent. The alkyl group may also be
substituted with other groups. Representative hydroxyalkyl groups
include hydroxymethyl, hydroxyethyl and hydroxypropyl groups.
[0093] "Prodrug" represents compounds that are drug precursors
which, following administration to a patient, release the drug in
vivo via a chemical or physiological process (e.g., a prodrug on
being brought to a physiological pH or through an enzyme action is
converted to the desired drug form). A discussion of prodrugs is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, Vol. 14 of A.C.S. Symposium Series (1987), and in
Bioreversible Carriers in Drug Design, E. B. Roche, ed., American
Pharmaceutical Ass'n and Pergamon Press (1987), each of which is
incorporated herein by reference thereto.
[0094] "Effective amount" means an amount of a compound or
composition which is sufficient enough to significantly and
positively modify the symptoms and/or conditions to be treated
(e.g., provide a positive clinical response). The effective amount
of an active ingredient for use in a pharmaceutical composition
will vary with the particular condition being treated, the severity
of the condition, the duration of the treatment, the nature of
concurrent therapy, and the particular active ingredient(s) being
employed, and like factors within the knowledge and expertise of
the attending physician.
[0095] Unless stated to the contrary, a substitutent is bound to a
structure through the last named moiety of the substituent. For
example, an "arylalkyl" substituent is bound to a structure through
the "alkyl" moiety of the substituent.
[0096] When a substituent occurs more than once in a formula (e.g.,
(R.sup.16).sub.n7 wherein n7 is 2 or 3), each selection for each
occurrence is made independently of the other selections, unless
stated otherwise.
[0097] This invention is directed to compounds having the formula
(I), including any and all isomers, such as enantiomers,
stereoisomers, diastereomers, atropisomers, rotomers, and
tautomers, and prodrugs of the compounds having the formula (I),
and the isomers thereof, and their corresponding salts, solvates
(e.g., hydrates), esters, and the like.
[0098] The invention is also directed to pharmaceutical
compositions comprising one or more compounds of formula (I) and
one or more pharmaceutically acceptable excipients/carriers, or
salts, solvates, and esters thereof.
[0099] The compounds of formula (I) can be useful for treating a
variety of diseases, symptoms and physiological disorders, such as
emesis, depression, anxiety and cough. Thus, the invention is also
directed to methods of treating such types of diseases, symptoms
and disorders by administering to a patient in need of such
treatment an effective amount of a pharmaceutical composition
comprising at least one compound having the formula (I) and at
least one pharmaceutically acceptable excipient/carrier.
[0100] Compounds having the formula (I) can have at least one
asymmetrical carbon atom. All isomers, including stereoisomers,
diastereomers, atropisomers, enantiomers, tautomers and rotational
isomers, in pure form and mixtures, including racemic mixtures, are
contemplated as being part of the invention. Prodrugs, salts,
solvates, esters, etc., derived from the compounds having the
formula (I), or precursors thereof, are also within the scope of
the invention. The invention includes d- and l-isomers in pure form
and in admixture, including racemic mixtures. Isomers can be
prepared using conventional techniques, either by reacting
optically pure or optically enriched starting materials or by
separating isomers of a compound having the formula (I).
[0101] The inventive compounds can exist in unsolvated as well as
solvated forms, including hydrated forms. In general, the solvated
forms, with pharmaceutically-acceptable solvents, such as water,
ethanol, and the like, are equivalent to the unsolvated forms for
purposes of this invention.
[0102] The inventive compounds may form pharmaceutically-acceptable
salts with organic and inorganic acids. For example,
pyrido-nitrogen atoms may form salts with strong acids, while
compounds having basic substituents, such as amino groups, also
form salts with weaker acids. Examples of suitable acids for salt
formation are hydrochloric, sulfuric, phosphoric, acetic, citric,
malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,
methanesulfonic and other mineral and carboxylic acids well known
to those skilled in the art. The salts are prepared by contacting
the free base forms with a sufficient amount of the desired acid to
produce a salt in a conventional manner. The free base forms may be
regenerated by treating the salt with a suitable dilute aqueous
base solution, such as dilute aqueous sodium hydroxide, potassium
carbonate, ammonia or sodium bicarbonate. The free base forms may
differ somewhat from their respective salt forms in certain
physical properties, such as solubility in polar solvents, but the
salts are otherwise equivalent to their respective free base forms
for purposes of the invention. Acidic compounds of the invention
(e.g., those compounds which possess a carboxyl group or a phenolic
hydroxyl group) form pharmaceutically-acceptable salts with
inorganic and organic bases. Representative examples of such types
of salts are sodium, potassium, calcium, aluminum, gold and silver
salts. Also included are salts formed with
pharmaceutically-acceptable amines, such as ammonia, alkyl amines,
hydroxyalkylamines, N-methylglucamine, and the like. Many such
types of salts are known in the art, for example, those that are
described in WO 87/05297, which is incorporated in its entirety by
reference herein. Preferred cationic salts include alkali metal
salts (e.g., sodium and potassium) and alkaline earth metal salts
(e.g., magnesium and calcium). Preferred anionic salts include
halide (e.g., chloride), acetate and phosphate salts.
[0103] All such acid and base salts are intended to be
pharmaceutically acceptable salts within the scope of the
invention, and all acid and base salts are considered equivalent to
the free forms of the corresponding compounds for purposes of the
invention.
[0104] In a preferred embodiment of the compounds of formula (I):
[0105] X.sup.1 is --O--; and [0106] Ar.sup.1 and Ar.sup.2 are each
independently ##STR13## [0107] wherein R.sup.8, R.sup.9 and
R.sup.10 are as defined for formula (I).
[0108] In a more preferred embodiment of the compounds of formula
(1): [0109] X.sup.1 is --O--; and [0110] Ar.sup.1 and Ar.sup.2 are
each independently ##STR14## [0111] wherein R.sup.8, R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of H, --CH.sub.3, halogen and CF.sub.3; [0112] R.sup.1 is selected
from the group consisting of H and CH.sub.3; and [0113] R.sup.2 is
selected from the group consisting of H, CH.sub.3 and
CH.sub.2OH.
[0114] Preferably, for the compounds of formula (I), R.sup.4 is H,
or R.sup.3 and R.sup.4, taken together with the carbon to which
they are attached form the group ##STR15##
[0115] Preferably, for the compounds of formula (I), R.sup.7 and
R.sup.11, taken together with the nitrogen to which they are
attached, form a 5-7 membered heterocycloalkyl ring of the formula:
##STR16## wherein X, R.sup.5, R.sup.6, R.sup.23, R.sup.24,
R.sup.25, R.sup.26 and n.sub.4 are as defined for formula (I).
[0116] Preferably, for the compounds of formula (I), one or two of
R.sup.8, R.sup.9 and R.sup.10 are the same or different halogen
(for example, each halogen is independently selected from the group
consisting of F and Cl), and the remaining one or two of R.sup.8,
R.sup.9 and R.sup.10 are each H.
[0117] In another embodiment of the compounds of formula (I),
preferably: ##STR17## [0118] wherein R.sup.8 is selected from the
group consisting of H and F, and R.sup.9 and R.sup.10 are each
independently selected from the group consisting of H, --CH.sub.3,
F, Cl and --CF.sub.3.
[0119] In other embodiments of the compounds of formula (I): [0120]
X.sup.1 is, preferably, selected from the group consisting of --O--
and --NR.sup.12--, and more preferably, X.sup.1 is --O--, [0121] X
is, preferably, selected from the group consisting of
--NR.sup.20--, --O-- and --CH.sub.2--, [0122] when Ar.sup.1,
Ar.sup.2, R.sup.7 and/or R.sup.11 comprise a (R.sup.19).sub.n7
substituent, then preferably n.sub.7 is 1 to 3 and each R.sup.19
substituent is independently selected from the group consisting of
H and C.sub.1-C.sub.6 alkyl (e.g., --CH.sub.3); and/or [0123] when
X is --NR.sup.20--, then preferably R.sup.20 is selected from the
group consisting of H and C.sub.1-C.sub.6 alkyl (e.g.,
--CH.sub.3).
[0124] In another embodiment of the compounds of formula (I),
preferably: [0125] X.sup.1 is --O--; and [0126] R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.27 and R.sup.28 are each H.
[0127] In another embodiment of the compounds of formula (I), when
R.sup.7 is selected from the group consisting of H and alkyl, then
R.sup.11 is selected from the group consisting of C.sub.3-C.sub.8
cycloalkyl, (R.sup.16).sub.n7-aryl-, (R.sup.19).sub.n7-heteroaryl-,
--COOR.sup.29, --CONR.sup.21R.sup.22,
--CON(R.sup.21)(CH.sub.2).sub.n-G.sup.1,
--S(O).sub.n5(CH.sub.2).sub.n-G.sup.1, --S(O).sub.n5R.sup.13,
--CO(CH.sub.2).sub.n-G.sup.1 and --(CH.sub.2).sub.n1-G.sup.1.
[0128] In another embodiment of the compounds of formula (I),
R.sup.7 is selected from the group consisting of H and alkyl, and
R.sup.11 is selected from the group consisting of C.sub.3-C.sub.8
cycloalkyl, (R.sup.16).sub.n7-aryl-, (R.sup.19).sub.n7-heteroaryl-,
--COOR.sup.29, --CONR.sup.21R.sup.22,
--CON(R.sup.21)(CH.sub.2).sub.n-G.sup.1,
--S(O).sub.n5(CH.sub.2).sub.n-G.sup.1, --S(O).sub.n5R.sup.13,
--CO(CH.sub.2).sub.n-G.sup.1 and --(CH.sub.2).sub.n1-G.sup.1.
[0129] In another embodiment of the compounds of formula (I),
R.sup.7 is H, and R.sup.11 is selected from the group consisting of
--COOR.sup.29, --CONR.sup.21R.sup.22,
--CON(R.sup.21)(CH.sub.2).sub.n-G.sup.1,
--S(O).sub.n5(CH.sub.2).sub.n-G.sup.1, --S(O).sub.n5R.sup.13, and
--CO(CH.sub.2).sub.n-G.sup.1 wherein said R.sup.11.
[0130] Preferred compounds of formula (I) are the compounds of
Examples 48 to 64 (see Table 2 below).
[0131] More preferred compounds of the invention include Example
Nos. 49, 51, 56, 57 and 64.
[0132] The following processes can be used to prepare compounds of
the formula (I).
[0133] Compounds of formula (I) can be prepared from intermediate
compound (5).
Preparation of Intermediate Compound (5)--Methods 1 to 3
Method 1
[0134] Step 1 ##STR18##
[0135] A suitably substituted commercially available piperidine
acid (1) can be reduced to the alcohol using metal hydride reducing
agents, preferably, LiAlH.sub.4. The resulting reaction mixture can
be treated with a suitable protective group, such as (Boc).sub.2O,
to afford a protected piperidine alcohol (2). Step 2 ##STR19##
[0136] Alkylation of the alcohol (2) is performed by standard
conditions, wherein treatment of the alkoxide of (2) with an
appropriate halide provides the desired ether. Preferably, R.sup.1
and R.sup.2 are each H and the leaving group L is bromide or
triflate. Step 3 ##STR20##
[0137] Compound (4) can be deprotected using strong acids, such as
HCl (gas or aqueous solution), in neutral, non-reactive solvents,
such as ether or dioxane. The resulting piperidine can be treated
in biphasic water-methylene chloride mixture containing NaNO.sub.2
and HOAc to give crude nitroso intermediate. The crude nitroso
intermediate compound can be reduced with a strong reducing agent,
preferably, LiAlH.sub.4, to afford the aminopiperidine (5).
Method 2
Step 1
[0138] The Boc-protected piperidine (4) can also be made by the
following sequence of reactions. ##STR21## Treatment of the aryl
nitrile (6) with an appropriate base, such as NaH, followed by
addition of compound (7), provides the substituted piperidine (8).
Preferably, a strong base, such as NaH, in a polar aprotic solvent,
such as DMSO is used in this reaction. Step 2 ##STR22##
[0139] The piperidine nitrile (8) can be converted to the alcohol
compound (2) using standard reduction chemistry. The nitrile (8)
can be reduced to the corresponding aldehyde using DIBAL. The crude
aldehyde can be further reduced to the alcohol (2) using
NaBH.sub.4.
[0140] Alternatively, using techniques well known in the art, the
nitrile (8) can be converted to the corresponding acid by
hydrolysis with subsequent esterification and reduction to produce
alcohol (2).
[0141] Following a procedure similar to that in Steps 2 and 3 of
Method 1, the alcohol (2) can then be further reacted to produce
the aminopiperidine (5).
Method 3
[0142] Step 1 ##STR23##
[0143] The suitably substituted piperidine acid (1) can be
protected using (Boc).sub.2O and NaOH in biphasic conditions, such
as water-THF-CH.sub.2Cl.sub.2. The resulting N-protected acid can
then be coupled with a suitably substituted alcohol using
carbodiimide, such as DCC, and DMAP to produce compound (9).
Preferably, the coupling reaction can be run using 0.25M of
starting acid (1) in a 6:1 mixture of toluene and CH.sub.2Cl.sub.2.
Step 2 ##STR24##
[0144] The ester compound (9) can be reduced in two steps using the
above reaction. First, the ester (9) can be partially reduced to a
hemiacetal that can be trapped with an appropriate anhydride (such
as acetic anhydride), pyridine (Py) and dimethylaminopyridine, at a
low temperature, such as -78.degree. C. Second, the intermediate
acetyl acetal can be further treated with a Lewis acid and a
reducing agent (such as a combination of BF.sub.3 etherate and
triethylsilane), at a low temperature (e.g., -78.degree. C. to
0.degree. C.) to give the Boc protected piperidine (4). Following a
procedure similar to that of Step 3 in Method 1, Compound (4) can
be reacted to produce the aminopiperidine (5).
Preparation of Compounds of formula (I) from Compound (5)--Methods
4 to 6
Method 4
Step 1
[0145] A suitably substituted aminopiperidine (5) or its
corresponding HCl salt can be treated with the corresponding
activated carbonyl derivatives of the R.sup.11 groups in (10) (such
as the corresponding acid halides, acid anhydrides and
isocyanates), in the presence of a base, such as DIEA. ##STR25##
(wherein R.sup.11 is --CO(CH.sub.2).sub.n-G.sup.1,
--CON(R.sup.21)(CH.sub.2).sub.n-G.sup.1 or --CONR.sup.21R.sup.22).
Step 2
[0146] The acylated aminopiperidine (10) can be treated with a
strong base, such as NaH, and an alkylating agent, such as alkyl
bromide, or, preferably, alkyl iodide, to give compounds of formula
(I) having the formula (I.1). The reaction can be conducted in a
polar, aprotic solvent, such as DMF. ##STR26## Method 5
[0147] The aminopiperidine (5) can be treated with a suitably
substituted carboxylic acid to afford the aminoamide (10.1). The
reaction can be run in CH.sub.2Cl.sub.2 in the presence of a
coupling reagent, such as EDC and HOBt. ##STR27## (wherein R.sup.11
is --CO(CH.sub.2).sub.n-G.sup.1). Method 6 Step 1
[0148] A suitably substituted aminopiperidine (5) or its
corresponding HCl salt can be treated with a suitable sulfonyl
chloride (e.g., ClSO.sub.2(CH.sub.2).sub.n-G.sup.1) in the presence
of a base, (such as DIEA), to give the desired aminosulphonamides
(10.2). ##STR28## (wherein R.sup.11 is
--SO.sub.2(CH.sub.2).sub.n-G.sup.1). Step 2
[0149] In the case where n is 0 and G.sup.1 is --CH.dbd.CH.sub.2,
the vinyl sulfonamide (12) can be further treated with an amine to
form compound (13). ##STR29## Preparation of Compounds of the
Formula (I.2)--Methods 7 to 11
[0150] Compounds of formula (I) having the formula (I.2) ##STR30##
can be prepared in Methods 7 to 11. Compounds of formula (I.2)
represent compounds of formula (I) wherein R.sup.7 and R.sup.11
taken together with the nitrogen to which they are bound form the
heterocycloalkyl ring ##STR31## Method 7 Step 1
[0151] The aminopiperidine (5) is treated with a suitably
substituted acid chloride in the presence of a base, such as DIEA,
to give intermediate (14), which has a tethered leaving group (LG).
The LG can be a halide, mesylate, tosylate or triflate. Preferably,
the LG is iodide, chloride, bromide, mesylate, tosylate or
triflate. More preferably, the LG is an iodide group. The reaction
can be run in a suitable solvent, such as CH.sub.2Cl.sub.2.
##STR32## Step 2
[0152] The intermediate (14) can be treated with an appropriate
base, such as NaH, at ambient temperature to 80.degree. C. in an
appropriate solvent, such as THF, to provide compounds of formula
(I.2a). ##STR33## Method 8 Step 1
[0153] Alternatively, the aminopiperidine (5) can be treated with a
suitably substituted aldehyde or ketone with a tethered carbonyl
ester to effect a reductive amination procedure. The reducing
reagent can be NaBH.sub.4, NaBH.sub.3CN or, preferably,
NaBH(OAc).sub.3. The reaction can be run in CH.sub.2Cl.sub.2 or,
preferably, ClCH.sub.2CH.sub.2Cl. ##STR34## Step 2
[0154] The crude product of step 1 can be treated with a Lewis
acid, such as AlMe.sub.3, in a high boiling inert solvent, such as
toluene, at a temperature ranging from about 80-125.degree. C., to
effect the ring closure. ##STR35## Method 9
[0155] The aminopiperidine (5) can be treated with suitably
substituted alkyl, preferably, ethyl, esters tethered with a
leaving group (LG) at an elevated temperature using AlMe.sub.3 to
complete the ring closure. The LG can be a halide, preferably,
iodide, chloride or bromide, more preferably, an iodide group. The
reaction can be run in toluene at a temperature of from ambient to
125.degree. C., ##STR36## Method 10 Step 1
[0156] A suitably substituted aminoalcohol (16) can be treated with
p-nitrophenyl-chloroformate in the presence of a base, such as
NaHCO.sub.3, in THF-water biphasic conditions to afford the
protected aminoalcohol (17). ##STR37## Step 2
[0157] The product (17) from Step 2 can be oxidized to the
corresponding aldehyde using bleach and a catalytic amount of
TEMPO. The reaction can be run in NaHCO.sub.3/water biphasic
conditions in the presence of NaBr. ##STR38## Step 3
[0158] The product (18) from Step 2 is treated with aminopiperidine
(5) and a metal hydride, such as NaBH.sub.3CN, at ambient
temperature in an inert solvent, such as THF, followed by heating
until the reaction is complete. ##STR39## Method 11 Step 1
[0159] A suitably substituted compound from Method 5 bearing a
protected amino group, such as Cbz, benzyl or, preferably, Boc, is
deprotected using conventional methods. ##STR40## Step 2
[0160] Compound (20) from Step 1 can be treated with a suitably
substituted haloacetyl halide, and subsequent cyclization provides
the desired diketopiperazine. One skilled in the art will recognize
that alternative methods for the synthesis of diketopiperazines can
be employed to provide this class of compounds. ##STR41## Assay
[0161] The in vitro and in vivo NK.sub.1, NK.sub.2 and NK.sub.3
activities of the compounds having the formula (I) can be
determined by various procedures known in the art, such as a test
for their ability to inhibit the activity of the NK.sub.1 agonist
Substance P. The percent inhibition of neurokinin agonist activity
is the difference between the percent of maximum specific binding
("MSB") and 100%. The percent of MSB is defined by the following
equation, wherein "dpm" represents "disintegrations per minute": %
.times. .times. MSB = ( dpm .times. .times. of .times. .times.
unknown ) - ( dpm .times. .times. of .times. .times. nonspecific
.times. .times. binding ) ( dpm .times. .times. of .times. .times.
total .times. .times. binding ) - ( dpm .times. .times. of .times.
.times. nonspecific .times. .times. binding ) .times. 100. .times.
##EQU1## The concentration at which the compound produces 50%
inhibition of binding is then used to determine an inhibition
constant ("Ki") using the Chang-Prusoff equation. In vivo activity
may be measured by inhibition of an agonist-induced foot tapping in
a gerbil, as descibed in Science, 281, 1640-1695 (1998), which is
herein incorporated by reference thereto.
[0162] The final compounds of Examples 1 to 64 had a K.sub.i in the
range of about 100 nM to about 0.3 nM.
[0163] The final compounds of Examples 48 to 64 had a K.sub.i in
the range of about 11 nM to about 0.3 nM.
[0164] The final compounds of Examples 49, 51, 56, 57 and 64 had a
K.sub.i in the range of about 3 to about 0.3 nM.
[0165] The final compound of Example 56 had a K.sub.i of about 0.3
nM.
[0166] Compounds of formula (I) are effective antagonists of the
NK.sub.1 receptor, and have an effect on its endogenous agonist,
Substance P, at the NK.sub.1 receptor site, and therefore, can be
useful in treating conditions caused or aggravated by the activity
of said receptor.
[0167] Compounds of the formula (I) have a number of utilities. For
instance, the inventive compounds can be useful as antagonists of
neurokinin receptors, particularly, NK.sub.1 receptors in a mammal,
such as a human. As such, they may be useful in treating and
preventing one or more of a variety of mammalian (human and animal)
disease states (physiological disorders, symptoms and diseases) in
a patient in need of such treatment, wherein said disease states
are selected from the group consisting of: (1) respiratory diseases
(e.g., chronic lung disease, bronchitis, pneumonia, asthma,
allergy, cough and bronchospasm), (2) inflammatory diseases (e.g.,
arthritis and psoriasis), (3) skin disorders (e.g., atopic
dermatitis and contact dermatitis), (4) ophthalmological disorders
(e.g., retinitis, ocular hypertension and cataracts), (5) central
nervous system conditions, such as depressions (e.g., neurotic
depression), anxieties (e.g., general anxiety, social anxiety and
panic anxiety disorders), phobias (e.g., social phobia), and
bipolar disorder, (6) addictions (e.g., alcohol dependence and
psychoactive substance abuse), (7) epilepsy, (8) nociception, (9)
psychosis, (10) schizophrenia, (11) Alzheimer's disease, (12) AIDs
related dementia, (13) Towne's disease, (14) stress related
disorders (e.g., post tramautic stress disorder), (15)
obsessive/compulsive disorders, (16) eating disorders (e.g.,
bulemia, anorexia nervosa and binge eating), (17) sleep disorders,
(18) mania, (19) premenstrual syndrome, (20) gastrointestinal
disorders (e.g., irritable bowel syndrome, Crohn's disease,
colitis, and emesis), (21) atherosclerosis, (22) fibrosing
disorders (e.g., pulmonary fibrosis), (23) obesity, (24) Type II
diabetes, (25) pain related disorders (e.g., headaches, such as
migraines, neuropathic pain, post-operative pain, and chronic pain
syndromes), (26) bladder and genitourinary disorders (e.g.,
interstitial cystitis and urinary incontinence), and (27)
nausea.
[0168] Preferably, the inventive compounds can be useful in
treating and preventing one of the following mammalian (e.g.,
human) disease states in a patient in need of such treatment:
respiratory diseases (e.g., cough), depression, anxiety, phobia,
and bipolar disorder, alcohol dependence, psychoactive substance
abuse, nociception, psychosis, schizophrenia, stress related
disorders, obsessive/compulsive disorder, bulemia, anorexia nervosa
and binge eating, sleep disorders, mania, premenstrual syndrome,
gastrointestinal disorders, obesity, pain related disorders,
bladder disorders, genitourinary disorders, emesis and nausea. In
particular, the compounds having the formulas (I) are useful for
treating disease states related to microvascular leakage and mucus
secretion. Consequently, the compounds of the invention are
especially useful in the treatment and prevention of asthma,
emesis, nausea, depressions, anxieties, cough and pain related
disorders, more especially, emesis, depression, anxiety and
cough.
[0169] In another aspect, the invention relates to pharmaceutical
compositions comprising at least one compound (e.g., one to three
compounds, preferably, one compound) represented by the formula (I)
and at least one pharmaceutically-acceptable excipient or carrier.
The invention also relates to the use of such pharmaceutical
compositions in the treatment of mammalian (e.g., human) disease
states, such as those listed above.
[0170] In still another aspect of the invention, a method is
provided for antagonizing an effect of a Substance P at a
neurokinin-1 receptor site or for the blockade of one or more
neurokinin-1 receptors in a mammal (i.e., a patient, e.g., a human)
in need of such treatment, comprising administering to the mammal
an effective amount of at least one (e.g., one) compound having the
formula (I).
[0171] In another embodiment of the invention, an effective amount
of one or more of the inventive NK.sub.1 receptor antagonists may
be combined with an effective amount of one or more anti-depressant
agents and/or one or more anti-anxiety agents (e.g., gepirone
(e.g., gepirone hydrochloride), and nefazodone (e.g., nefazodone
hydrochloride, e.g., Serzone.RTM.) to treat depression and/or
anxiety. U.S. Pat. No. 6,117,855 (2000), the disclosure of which is
incorporated herein by reference thereto, discloses a method for
treating or preventing depression or anxiety with a combination
therapy of a specific NK.sub.1 receptor antagonist together with an
anti-depressant and/or anti-anxiety agent. Thus, anti-depressant
and/or anti-anxiety agents, such as those disclosed in U.S. Pat.
No. 6,117,855 (2000), can be combined with one or more (e.g., one)
compounds of the formula (I) to treat depression and/or anxiety
disease states in a mammal, preferably, a human.
[0172] In still another embodiment of the invention, an effective
amount of one or more (e.g., one) of the inventive NK.sub.1
receptor antagonists may be combined with an effective amount of
one or more (e.g., one) selective serotonin reuptake inhibitors
("SSRIs") to treat a variety of mammalian disease states, such as
those described above. SSRIs alter the synaptic availability of
serotonin through their inhibition of presynaptic reaccumulation of
neuronally released serotonin. U.S. Pat. No. 6,162,805 (2000), the
disclosure of which is incorporated herein by reference thereto,
discloses a method for treating obesity with a combination therapy
of a NK.sub.1 receptor antagonist and an SSRI. An inventive
compound(s) of the formula (I) can be combined together with an
SSRI(s) in a single pharmaceutical composition, or it can be
administered simultaneously, concurrently or sequentially with an
SSRI. This combination may be useful in the treatment and
prevention of obesity or another of the above-identified human and
animal disease states. In particular, an effective amount of at
least one (e.g., one) compound having the formula (I), alone or
together with an effective amount of at least one (e.g., one)
selective serotonin reuptake inhibitor, can be useful in the
treatment and prevention of depression, and/or anxiety.
[0173] Numerous chemical substances are known to alter the synaptic
availability of serotonin through their inhibition of presynaptic
reaccumulation of neuronally released serotonin. Representative
SSRIs include, without limitation, the following: fluoxetine (e.g.,
fluoxetine hydrochloride, e.g., Prozac.RTM.), fluvoxamine (e.g.,
fluvoxamine maleate, e.g. Luvox.RTM.), paroxetine (e.g., paroxetine
hydrochloride, e.g., Paxil.RTM.), sertraline (e.g., sertraline
hydrochloride, e.g., Zoloft.RTM.), citalopram (e.g., citalopram
hydrobromide, e.g., Celexa.TM.), duloxetine (e.g., duloxetine
hydrochloride), and venlafaxine (e.g., venlafaxine hydrochloride,
e.g., Effexor.RTM.). Further SSRIs include those disclosed in U.S.
Pat. No. 6,162,805 (2000). Other compounds can readily be evaluated
to determine their ability to selectively inhibit serotonin
reuptake. Thus, one aspect of the invention relates to a
pharmaceutical composition comprising at least one (e.g., one)
NK.sub.1 receptor antagonist having the formula (I), at least one
(e.g., one) SSRI, and at least one pharmaceutically-acceptable
excipient or carrier. Another aspect of the invention relates to a
method of treating the above identified mammalian (e.g., human)
disease states, the method comprising administering to a patient in
need of such treatment an effective amount of a pharmaceutical
composition comprising at least one (e.g., one) NK.sub.1 receptor
antagonist having the formula (I) in combination with at least one
(e.g., one) SSRI, such as one of those recited above, and at least
one pharmaceutically-acceptable excipient or carrier.
[0174] In a preferred aspect, the invention relates to a method of
treating depression and anxiety, the method comprising
administering to a patient in need of such treatment an effective
amount of at least one (e.g., one) NK.sub.1 receptor antagonist
having the formula (I) in combination with at least one (e.g., one)
SSRI, such as one of those described above. When an inventive
NK.sub.1 receptor antagonist is combined with an SSRI for
administration to a patient in need of such treatment, the two
active ingredients can be administered simultaneously,
consecutively (one after the other within a relatively short period
of time), or sequentially (first one and then the other over a
period of time). In general, when the two active ingredients are
administered consecutively or sequentially, the inventive NK.sub.1
receptor antagonist is, preferably, administered before the
administration of the SSRI.
[0175] It is another embodiment of the invention to treat a patient
suffering from multiple ailments with a combination therapy, said
therapy comprising administering to a patient (e.g., a mammal,
preferably a human) in need of such treatment at least one compound
of formula (I), and at least one other active ingredient (i.e.,
drug) used for treating one or more of the ailments being suffered
by said patient. The compounds of formula (I) and the other active
ingredients can be administered sequentially, concurrently and/or
simultaneously. The compounds of formula (I) and the other active
ingredients can be administered separately in any suitable dosage
form. Preferably, administration is accomplished using an oral
dosage forms or using a transdermal patches. The compounds of
formula (I) and the other active ingredients can be formulated
together and administered in one combined dosage form.
[0176] Thus, the compounds of the invention may be employed alone
or in combination with other active agents. Combination therapy
includes the administration of two or more active ingredients to a
patient in need of treatment. In addition to the above described
NK.sub.1 receptor antagonist/SSRI combination therapy, the
compounds having the formula (I) may be combined with one or more
other active agents, such as the following: other types of NK.sub.1
receptor antagonists (e.g., those that are disclosed in the
neurokinin receptor antagonist patents cited above in the
Background of the Invention section), prostanoids, H.sub.1 receptor
antagonists, .alpha.-adrenergic receptor agonists, dopamine
receptor agonists, melanocortin receptor agonists, endothelin
receptor antagonists, endothelin converting enzyme inhibitors,
angiotensin II receptor antagonists, angiotensin converting enzyme
inhibitors, neutral metalloendopeptidase inhibitors, ET.sub.A
antagonists, renin inhibitors, serotonin 5-HT.sub.3-receptor
antagonists (e.g., ondansetron (e.g., ondansetron hydrochloride,
e.g., Zolfran.RTM.), palonosetron and granisetron (e.g.,
granisetron hydrochloride, e.g., Kytril.RTM.)), serotonin
5-HT.sub.2, receptor agonists, nociceptin receptor agonists,
glucocorticoids (e.g., dexamethasone), rho kinase inhibitors,
potassium channel modulators and/or inhibitors of multi-drug
resistance protein 5.
[0177] Preferable therapeutic agents for combination therapy with
compounds of the invention are the following: prostanoids, such as
prostaglandin E.sub.1; .alpha.-adrenergic agonists, such as
phentolamine mesylate; dopamine receptor agonists, such as
apomorphine; angiotensin 11 antagonists, such as losartan,
irbesartan, valsartan and candesartan; ET.sub.A antagonists, such
as bosentan and ABT-627; serotonin 5-HT.sub.3 receptor antagonists,
such as ondansetron; and glucocorticoids, such as dexamethasone. In
preferred embodiments of the invention, the inventive compounds can
be combined with: other types of NK.sub.1 receptor antagonists,
SSRIs, dopamine receptor agonists, serotonin 5-HT.sub.3 receptor
antagonists, serotonin 5-HT.sub.2c receptor agonists, nociceptin
receptor agonists, glucocorticoids and/or inhibitors of multi-drug
resistance protein 5.
[0178] A preferred embodiment of the invention is directed to a
method of treating emesis and/or nausea in a patient in need of
such treatment using a combination therapy comprising administering
to said patient an effective amount of at least one (e.g., one)
compound having the formula (I) in combination with an effective
amount of at least one (e.g., one) serotonin 5-HT.sub.3 receptor
antagonist (e.g., ondansetron) and/or at least one (e.g., one)
glucocorticoid (e.g., dexamethasone). Preferably, the compound of
formula (I) is administered orally or by IV.
[0179] Another embodiment of this invention is directed to a method
for treating a physiological disorder, symptom or disease in a
patient in need of such treatment, comprising administering to said
patient an effective amount of at least one compound of formula 1,
and an effective amount of at least one active ingredient selected
from the group consisting of: other NK.sub.1 receptor antagonists,
selective serotonin reuptake inhibitors, dopamine receptor
agonists, serotonin 5-HT.sub.3 receptor antagonists, serotonin
5-HT.sub.2c receptor agonists, nociceptin receptor agonists,
glucocorticoids and inhibitors of multidrug resistance protein 5,
wherein said physiological disorder, symptom or disease is selected
from the group consisting of: a respiratory disease, depression,
anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive
substance abuse, nociception, psychosis, schizophrenia, stress
related disorder, obsessive/compulsive disorder, bulemia, anorexia
nervosa, binge-eating, sleep disorder, mania, premenstrual
syndrome, gastrointestinal disorder, obesity, headache, neuropathic
pain, post-operative pain, chronic pain syndrome, bladder disorder,
genitourinary disorder, cough, emesis and nausea.
[0180] Another aspect of the invention is to provide a kit
comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat an
NK.sub.1 receptor mediated disease, wherein one container comprises
a pharmaceutical composition comprising an effective amount of a
compound of formula (I) in a pharmaceutically acceptable carrier,
and wherein, a separate container comprises a pharmaceutical
composition comprising another therapeutic agent in a
pharmaceutically acceptable carrier, said therapeutic agent being
selected from the group consisting of: SSRIs, other types of
NK.sub.1 receptor antagonists, prostanoids, H.sub.1 receptor
antagonists, .alpha.-adrenergic receptor agonists, dopamine
receptor agonists, melanocortin receptor agonists, endothelin
receptor antagonists, endothelin converting enzyme inhibitors,
angiotensin II receptor antagonists, angiotensin converting enzyme
inhibitors, neutral metalloendopeptidase inhibitors, ET.sub.A
antagonists, renin inhibitors, serotonin 5-HT.sub.3 receptor
antagonists, serotonin 5-HT.sub.2c receptor agonists, nociceptin
receptor agonists, glucocorticoids, rho kinase inhibitors,
potassium channel modulators and inhibitors of multi-drug
resistance protein 5.
[0181] Another aspect of the invention is to provide a kit
comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat
depression and/or anxiety, wherein one container comprises a
pharmaceutical composition comprising an effective amount of a
compound of formula (I) in a pharmaceutically acceptable carrier,
and wherein, a separate container comprises a pharmaceutical
composition comprising an antidepressant agent in a
pharmaceutically acceptable carrier, and/or wherein a separate
container comprises a pharmaceutical composition comprising an
antianxiety agent in a pharmaceutically acceptable carrier.
[0182] Another aspect of the invention is to provide a kit
comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat an
NK.sub.1 receptor mediated disease, wherein one container comprises
a pharmaceutical composition comprising an effective amount of a
compound of formula (I) in a pharmaceutically acceptable carrier,
and wherein, a separate container comprises a pharmaceutical
composition comprising an SSRI in a pharmaceutically acceptable
carrier.
[0183] Another aspect of the invention is to provide a kit
comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat
depression and/or anxiety, wherein one container comprises a
pharmaceutical composition comprising an effective amount of a
compound of formula (I) in a pharmaceutically acceptable carrier,
and wherein, a separate container comprises a pharmaceutical
composition comprising an SSRI in a pharmaceutically acceptable
carrier.
[0184] Another aspect of the invention is to provide a kit
comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat emesis
and/or nausea, wherein one container comprises a pharmaceutical
composition comprising an effective amount of a compound of formula
(I) in a pharmaceutically acceptable carrier, and wherein, a
separate container comprises a pharmaceutical composition
comprising a serotonin 5-HT.sub.3 receptor antagonist in a
pharmaceutically acceptable carrier, and/or wherein a separate
container comprises a pharmaceutical composition comprising a
glucocorticoid in a pharmaceutically acceptable carrier.
[0185] Another aspect of the invention is to provide a kit
comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat emesis
and/or nausea, wherein one container comprises a pharmaceutical
composition comprising an effective amount of a compound of formula
(I) in a pharmaceutically acceptable carrier, and wherein, a
separate container comprises ondansetron, and/or wherein a separate
container comprises dexamethasone.
[0186] Another aspect of the invention is to provide a kit
comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat an
NK.sub.1 receptor mediated disease, wherein one container comprises
a pharmaceutical composition comprising an effective amount of a
compound of formula (I) in a pharmaceutically acceptable carrier,
and wherein, a separate container comprises a pharmaceutical
composition comprising a therapeutic agent in a pharmaceutically
acceptable carrier, said therapeutic agent being selected from the
group consisting of: other types of NK.sub.1 receptor antagonists,
SSRIs, dopamine receptor agonists, serotonin 5-HT.sub.3 receptor
antagonists, serotonin 5-HT.sub.2c receptor agonists, nociceptin
receptor agonists, glucocorticoids and inhibitors of multi-drug
resistance protein 5.
[0187] Pharmaceutical compositions may contain from about 0.1 to
about 99.9 weight percent, or from about 5 to about 95 weight
percent, or from about 20 to about 80 weight percent of active
ingredient (compound of the formula (I)). For preparing
pharmaceutical compositions from the compounds described by this
invention, inert, pharmaceutically acceptable carriers can be
either solid or liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, cachets and suppositories.
The powders and tablets may be comprised of from about 5 to about
95 percent active ingredient. Suitable solid carriers are known in
the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar
or lactose. Tablets, powders, cachets and capsules can be used as
solid dosage forms suitable for oral administration. Examples of
pharmaceutically acceptable carriers and methods of manufacture for
various compositions may be found in A. Gennaro (ed.), Remington:
The Science and Practice of Pharmacy, 20.sup.th Edition, (2000),
Lippincott Williams & Wilkins, Baltimore, Md.
[0188] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0189] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen. Also included are solid form
preparations which are intended to be converted, shortly before
use, to liquid form preparations for either oral or parenteral
administration. Such liquid forms include solutions, suspensions
and emulsions.
[0190] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0191] Preferably the compound is administered orally.
[0192] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparations subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0193] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.01 mg to about
4000 mg, preferably from about 0.02 mg to about 1000 mg, more
preferably from about 0.3 mg to about 500 mg, and most preferably
from about 0.04 mg to about 250 mg according to the particular
application.
[0194] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill in the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0195] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 0.02 mg/day to about 2000
mg/day, in two to four divided doses.
[0196] The pharmaceutical compositions of the invention may be
administered from about 1 to about 5 times per day, or
alternatively, as a continuous infusion. Such administration can be
used as a chronic or acute therapy. The quantity of NK.sub.1
receptor antagonist in combination with a selective serotonin
reuptake inhibitor ("SSRI") in a unit dose of preparation may be
from about 10 to about 300 mg of NK.sub.1 receptor antagonist
combined with from about 10 to about 100 mg of SSRI. In another
combination the quantity of NK.sub.1 receptor antagonist in
combination with a SSRI in a unit dose of preparation may be from
about 50 to about 300 mg of NK.sub.1 receptor antagonist combined
with from about 10 to about 100 mg of SSRI. In another combination
the quantity of NK.sub.1 receptor antagonist in combination with
SSRI in a unit dose of preparation may be from about 50 to about
300 mg of NK.sub.1 receptor antagonist combined with from about 20
to about 50 mg of SSRI.
[0197] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required. Upon improvement of a
patient's condition, a maintenance dose of a compound, composition
or combination of the invention may be administered, if necessary.
Subsequently, the dosage or frequency of administration, or both,
may be reduced, as a function of the symptoms, to a level at which
the improved condition is retained. When the symptoms have been
alleviated to the desired level, treatment should cease. Patients
may, however, require intermittent treatment on a long-term basis
upon any recurrence of disease symptoms.
[0198] Specific dosage and treatment regimens for any particular
patient may be varied and will depend upon a variety of factors,
including the activity of the specific compound employed, the age,
body weight, general health status, sex and diet of the patient,
the time of administration, the rate of excretion, the specific
drug combination, the severity and course of the symptoms being
treated, the patient's disposition to the condition being treated
and the judgment of the treating physician. Determination of the
proper dosage regimen for a particular situation is within the
skill of the art.
EXAMPLES
[0199] The following examples are intended to illustrate, but not
to limit, the scope of the invention.
Example Nos. 1-47
[0200] Compounds of the formula ##STR42##
[0201] wherein R.sup.7, R.sup.8 and R.sup.11 are described in Table
1 are prepared by the procedures described after Table 1.
TABLE-US-00001 TABLE 1 Example Nos. R.sup.8 R.sup.7 R.sup.11 LRMS
(m + H) 1 H H H 433.4 2 H H ##STR43## 475.5 3 H H ##STR44## 503.5 4
H H ##STR45## 529.4 5 H H ##STR46## 519.5 6 H H ##STR47## 533.5 7 H
H ##STR48## 505.5 8 H H ##STR49## 527.5 9 H H ##STR50## 528.5 10 H
H ##STR51## 544.5 11 H H ##STR52## 560.5 12 H H ##STR53## 535.6 13
H H ##STR54## 533.5 14 H H ##STR55## 491.4 15 H H ##STR56## 557.6
16 H H ##STR57## 532.5 17 H H ##STR58## 626.5 18 H H ##STR59##
559.5 19 H H ##STR60## 567.5 20 H H ##STR61## 511.4 21 H H
##STR62## 523.5 22 H H ##STR63## 573.5 23 H H ##STR64## 546.5 24 H
H ##STR65## 530.5 25 H H ##STR66## 518.5 26 H H ##STR67## 562.5 27
H H ##STR68## 516.5 28 H H ##STR69## 476.4 29 H ##STR70## ##STR71##
600.5 30 H ##STR72## ##STR73## 639.6 31 F H ##STR74## 551.5 32 F H
H 451.4 33 F H ##STR75## 547.4 34 F H ##STR76## 537.4 35 F H
##STR77## 551.5 36 F H ##STR78## 523.5 37 F H ##STR79## 545.4 38 F
H ##STR80## 546.6 39 F H ##STR81## 548.5 40 H H ##STR82## 504.4 41
H H ##STR83## 518.5 42 F H ##STR84## 522.4 43 F H ##STR85## 536.5
44 H H ##STR86## 490.4 45 H H ##STR87## 594.6 46 H H ##STR88##
554.6 47 H H ##STR89## 610.6
Example 1
[0202] Method 1 ##STR90## Step 1
[0203] At 0.degree. C., to a mixture of commercially available
4-phenyl-4-carboxy piperidine tosylate (20 g, 52.9 mmol) in 100 mL
of anhydrous THF, was added dropwise 106 mL of 1.0 M of LAH
solution in THF. After the addition, the resultant suspension was
refluxed for 90 min, and allowed to cool to room temperature, then
quenched by addition of 6.4 mL of 2 N NaOH aqueous solution and 8
mL of water. Another solution of 2.1 g of NaOH in 25 mL of water
was added, followed by addition of a solution of
di-tert-butyl-dicarbonate (11.56 g, 52.9 mmol, 1 equiv.) in 65 mL
of dichloromethane. The mixture was stirred at room temperature for
18 hours, then filtered through a sodium sulfate pad. The filtrate
was dried under vacuum, and then taken up with dichloromethane. The
organic solution was washed with 10% NaOH (100 mL), water (100 mL),
and brine (100 mL), then dried over anhydrous MgSO.sub.4, filtered
and concentrated to give an oil as the crude product, which upon
recrystallization in ethyl ether, provided the Boc-amino alcohol 23
as a white solid (10.5 gram, yield 69%). MS:292 (M+1).
Step 2
[0204] To a solution of the carbinol 23 (3.34 g, 11.5 mmol, 1
equiv.) and 3,5-bis(trifluoromethyl)benzyl bromide (2.1 mL, 11.5
mmol, 1 equiv.) in 20 mL of dry DMF, was added slowly 60% NaH
dispersion in mineral oil (0.59 g, 14.8 mmol, 1.29 equiv.). After
stirring at room temperature overnight, the reaction mixture was
poured into 500 mL of water, then extracted with 230 mL of EtOAc.
The organic layer was washed with water (3.times.230 mL) and brine,
and then dried over Na.sub.2SO.sub.4, filtered and concentrated.
Flash chromatography eluting with Hexane/EtOAc 95/5.fwdarw.90/10
gave 4.66 g of 24 (yield 78%).
Step 3
[0205] A solution of
1-tert-Butoxycarbonyl-4-phenyl-4[(3,5-bistrifluoromethyl)
benzyloxymethyl] piperidine 24 (0.965 g, 1.86 mmol, 1 equiv.) in 30
mL of dry diethyl ether was streamed with hydrogen chloride gas for
40 min. The resultant solution was stirred for another 2.5 hours at
room temperature. The solvent was removed to give a solid. The
crude product was taken up with dichloromethane and neutralized
with 1 N NaOH (about 10 mL). The aqueous layer was further
extracted with EtOAc. The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated to give 0.639
g product 25 as the free base.
Step 4
[0206] A solution of 25 (470 mg as in free form, 1.13 mmol, 1
equiv.) in 5 mL dry THF was treated with a solution of NaNO.sub.2
(160 mg, 2.25 mmol, 2 equiv.) in 5 mL of water. After cooling to
0.degree. C., the mixture was treated with 0.09 mL of acetic acid.
After stirring overnight, the mixture was neutralized with an
excess of Na.sub.2CO.sub.3. The mixture was filtered through a
sintered glass funnel, and concentrated. The aqueous layer was
extracted with EtOAc (2.times.50 mL). The organic layer was dried
over Na.sub.2SO.sub.4, and then concentrated to give 450 mg of the
product 26 (90%).
Step 5
[0207] A solution of nitroso compound 26 (20.18 g, 45.2 mmol, 1
equiv.) in 250 mL of dry Et.sub.2O was treated with 81 mL of 1.0 M
LAH in Et.sub.2O at -2.degree. C. for a period of 30 min. After TLC
showed the reaction was nearly complete, it was quenched by adding
100 mL of EtOAc, and then 60 mL of ice-cold water. The mixture was
filtered through a sintered glass funnel, and the residue was
washed with Et.sub.2O (3.times.100 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, and concentrated to give 14.5 g of
the product (yield 74%). It was found that the amino-piperidine is
more stable as its hydrogen chloride salt, which can be obtained by
treating the product in free base form with 1 equivalent of
hydrogen chloride solution in Et.sub.2O. Method 2 ##STR91## Step
1
[0208]
4-phenyl-4-[(3,5-bistrifluoromethyl)benzyloxymethyl]piperidine
(25)) (417 mg, 1 mmol) was dissolved in CH.sub.2Cl.sub.2 (2 mL),
and was added dropwise to the solution of
3-(4-cyanophenyl)-1-oxaziridine carboxylate (246 mg, 1 mmol) in
ether (3 mL). Stirred at 23.degree. C. for 30 min and concentrated
to give the crude product. Separated on flash chromatography using
hexane and EtOAc (1:9) to yield the product (411 mg, 77%).
Step 2
[0209] Treated the product of Step 1 with HCl in ether using a
procedure similar to Step 3 in Method 1 of Example 1 to afford the
desired product (about 100%).
Example 2
[0210] Dissolved the compound of Example 1 (120 mg, 0.28 mmol) in
CH.sub.2Cl.sub.2 (3 mL) and treat with acetyl chloride and
diisopropylethylamine at 0.degree. C. Stirred for an additional 30
min and concentrated to afford a crude product. Purified the
product on column chromatograph using 1:99 MeOH (with NH.sub.3) and
CH.sub.2Cl.sub.2 to give the compound of Example 2 (18 mg, 14%).
Alternatively, the compound of Example 1 was reacted with acetic
acid using standard EDC/HOBt coupling conditions to afford the
desired compound.
Examples 3-19
[0211] Employing a procedure similar to that described in Example
2, and using the corresponding acid chloride or carboxylic acid,
provided the appropriate amide. For Examples 10 and 11, using a
procedure similar to that described in Example 2 but using
chloroacetyl chloride in place of acetyl chloride gave the crude
.alpha.-chloroamide. Treated the .alpha.-chloroamide with
pyrrolidine or morpholine at room temperature for 24-48 h provided
Examples 10 and 11, respectively.
Examples 20-22
[0212] Using a procedure similar to that described in Example 2,
using the corresponding sulfonyl chloride afforded the appropriate
sulfonamide.
Examples 23-28
[0213] Using a procedure similar to that described in Example 2,
substituting the corresponding isocyanate gave the appropriate
urea.
Example 29
[0214] Dissolved the compound of Example 9 (310 mg, 0.59 mmol) in
anhydrous DMF (2 mL), added sodium hydride (31 mg, 0.77 mmol) at
0.degree. C. and stirred for 30 min. Treated the mixture with
bromomethylacetate (68 .mu.L, 0.71 mmol), and stirred for
additional 2 hours at 23.degree. C. Removed the solvent, quenched
with saturated NaHCO.sub.3 solution, and extracted with
CH.sub.2Cl.sub.2 (2.times.15 mL). The combined organic layer was
dried over MgSO.sub.4 and concentrated to yield a crude product.
Purified on column chromatography using MeOH (sat. with NH.sub.3)
and CH.sub.2Cl.sub.2 (1:99) to give the target compound.
Example 30
[0215] Using a procedure similar to the one described in Example
29, substituting bromomethylacetate with thiazolemethylbromide
afforded the target compound.
Example 31
[0216] ##STR92## Step 1
[0217] To a suspension of bis(2-chloroethyl)amine hydrochloride (55
g, 0.31 mol, 1.09 equiv.) and (BOC).sub.2O (62 g, 0.28 mmol, 1
equiv.) in 380 mL CH.sub.2Cl.sub.2, was added dropwise Et.sub.3N
(48 mL, 0.345 mol, 1.22 equiv.). After stirring at room temperature
for 3 hours, TLC (Hexane CH.sub.2Cl.sub.2=90/10) indicated the
reaction was complete. The suspension was filtered through a
sintered glass funnel. The filtrate was diluted with 300 mL
CH.sub.2Cl.sub.2, and then washed with 1 M NaOH (200 mL). The
aqueous layer was extracted with another 300 mL CH.sub.2Cl.sub.2.
The combined organic layer was washed with saturated NaHCO.sub.3
(100 mL) and brine (100 mL), then dried over Na.sub.2SO.sub.4,
filtered and concentrated to give a liquid as crude. The reaction
mixture was purified through a silica gel plug eluting with
(CH.sub.2Cl.sub.2/Hexane=3/2) to give 28 as a liquid (57.18 g,
yield 84%). MS: 188 (M-56+1).
Step 2
[0218] To a solution of 4-fluorophenylacetonitrile (2.7 g, 10 mmol,
1 equiv.) in 30 mL DMSO, was added 60% NaH dispersion in mineral
oil (0.88 g, 22 mmol, 2.2 equiv). After stirring at room
temperature for 1.5 hours, the BOC amino-dichloride 28 was added
and stirred for 2 hours. The reaction mixture was poured into 150 g
of ice. The mixture was extracted with CH.sub.2Cl.sub.2
(2.times.150 mL). The combined organic layer was washed with water
(500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to
give 4.5 g of a liquid as the crude. The crude material was
purified with flash chromatography column (EtOAc/Hexane=5/95) to
give 29 as a liquid (1.83 g, yield 60%). MS: 305 (M+1).
Step 3
[0219] At 0.degree. C., to a solution of 29 (1.69 g, 5.6 mmol, 1
equiv.) in 10 mL dry benzene, was added 12 mL of 1.0 M DIBAL (12
mmol, 2 equiv.) in hexane. After stirring at 0.degree. C. for 30
min, the solution was warmed to room temperature. When the TLC
(EtOAc/Hexane=1/4) indicated the reaction was complete, the
reaction was quenched with 90 mL of 5% H.sub.2SO.sub.4. The aqueous
layer was extracted with Et.sub.2O (2.times.100 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated to give 0.72 g of crude. The crude material was
purified by flash column to give 30 as a liquid. (454 mg, yield
26%).
Step 4
[0220] At 0.degree. C., a solution of aldehyde 30 (3.9 g, 12.8
mmol, 1 equiv.) in 10 mL EtOH was treated with NaBH.sub.4 (580 mg,
15.3 mmol, 1.2 equiv.). After stirring at 0.degree. C. for 30 min,
the reaction was complete. The solvent was evaporated and the crude
product was taken up with 10 mL saturated NaHCO.sub.3, and
extracted with CH.sub.2Cl.sub.2 (2.times.120 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated to give 31 as a solid (3.96 g, yield 100%).
Step 5
[0221] Using a procedure similar to the procedure described in
Example 1, step 2, substituting 31 for 23 gave the compound of
Example 31.
Example 32
[0222] Using a procedure similar to the one described in Example 1,
step 3, gave the indicated compound.
Examples 33-39
[0223] Using a procedure similar to examples 4-10, respectively,
substituting Example 32 for Example 1 gave the indicated
compounds.
Examples 40
[0224] Dissolved the compound of Example 5 in MeOH saturated with
NH.sub.3, and stirred at 23.degree. C. for 48 hours in a sealed
tube. Evaporated the solvent to yield the target compound.
Examples 41-43
[0225] Using a procedure similar to that described in Example 40,
substituting the compounds of Examples 6, 34, and 35 for the
compound of Example 5, gave the compounds of Examples 41, 42, and
43 respectively.
Example 44
Step 1
[0226] Used a procedure similar to the EDC coupling procedure
described in Example 2 using Boc-glycine as the corresponding
carboxylic acid.
Step 2
[0227] Treated the product from Step 1 using a procedure similar to
Example 1, step 3, gave the target compound.
Example 45
[0228] Dissolved compound 21 (15 mg, 0.03 mmol) in pyrrolidine (2
mL), and stirred at 23.degree. C. for 48 hours. Evaporated the
solvent to yield the target compound.
Examples 46-47
[0229] Using a procedure similar to the one described in Example 45
using methylamine and morpholine in place of pyrrolidine gave the
compounds of Examples 46 and 47 respectively.
Examples 48-64
[0230] Compounds of the formula ##STR93##
[0231] wherein R.sup.1, R.sup.2, R.sup.7, R.sup.8 and R.sup.11 are
described in Table 2 were prepared by the procedures described
after Table 2. TABLE-US-00002 TABLE 2 Example LRMS Nos. R.sup.8
R.sup.1 R.sup.2 --NR.sup.7R.sup.11 (m + H) 48 H H H ##STR94## 515.5
49 H H H ##STR95## 501.5 50 H H H ##STR96## 517.5 51 H H H
##STR97## 502.5 52 F H H ##STR98## 533.5 53 F H H ##STR99## 519.5
54 F H H ##STR100## 535.5 55 H H H ##STR101## 530.5 56 H H CH.sub.3
##STR102## 515.1 57 H H CH.sub.2OH ##STR103## 531.1 58 H H H
##STR104## 544.1 59 H H H ##STR105## 558.1 60 H H H ##STR106##
602.1 61 H H H ##STR107## 515.1 62 H H H ##STR108## 515.1 63 H H H
##STR109## 485.1 64 H H H ##STR110## 501.1
Example 48
Step 1
[0232] Using a procedure similar to the one described in Example 2
using 5-chlorovaleryl chloride in place of acetyl chloride gave the
crude .delta.-chloroamide.
Step 2
[0233] Dissolved the crude .delta.-chloroamide from Step 1 (572 mg,
1.03 mmol) in anhydrous THF (10 mL), added sodium hydride (49 mg,
0.77 mmol) at 0.degree. C. and stirred for 30 min. Heated at
60.degree. C. for 3 hours. Removed the solvent, and quenched with
saturated NaHCO.sub.3 solution, and extracted with CH.sub.2Cl.sub.2
(2.times.15 mL). The combined organic layer was dried over
MgSO.sub.4 and concentrateded to yield a crude product. Purified
with column chromatography using MeOH (sat. with NH.sub.3) and
CH.sub.2Cl.sub.2 (1:99) to afford the target compound.
Example 49
[0234] Used a procedure similar to the one described in Example 48,
substituting 4-chlorobutyrylchloride for 5-chlorovaleryl chloride
in Step 1. Proceeded as described in Example 48, step 2 to afford
the target compound.
Example 50
Step 1
[0235] 2-(2-chloroethoxy)ethanol was oxidized in the standard
fashion with Jones reagent to give the corresponding carboxylic
acid.
Step 2
[0236] Used a procedure similar to that described in Example 2,
using the product of Step 1 as the carboxylic acid in a standard
carbodiimide coupling.
Step 3
[0237] Using a procedure similar to Example 48, Step 2, provided
the target compound.
Example 51
Step 1
[0238] Added saturated NaHCO.sub.3 solution (2.78 g in 7 mL
H.sub.2O) to a solution of 2-amino ethanol (2 mL, 33.1 mmol) in THF
(20 mL), and stirred at 0.degree. C. for 40 min. Treated the
reaction mixture with p-nitrophenyl chloroformate (7.0 g, 34.8
mmol) and stirred vigorously at 0.degree. C. for additional 2
hours. Quenched with saturated NaHCO.sub.3 solution, extracted with
EtOAc (2.times.150 mL). The combined organic layer was dried over
MgSO.sub.4 and concentrated to yield a crude product. Purified on
column chromatography using hexane and EtOAc (1:1) to give the
product.
Step 2
[0239] To the product from Step 1 (900 mg, 4 mmol) in EtOAc (25 mL)
at 0.degree. C., was added saturated NaHCO.sub.3 solution (25 mL),
NaBr (445 mg, 4.4 mmol) and Tempo reagent (10 mg). Commercial
bleach was added dropwise to the mixture with vigorous stirring at
0.degree. C. over 20 min. Quenched with Na.sub.2S.sub.2O.sub.3 (2
g) in H.sub.2O (10 mL), and added NaHCO.sub.3 solution (20 mL).
Extracted with EtOAc (2.times.100 mL), the combined organic layer
was dried over MgSO.sub.4 and concentrated to yield a crude
product. Purified on column chromatography using hexane and EtOAc
(1:1) to give the product.
Step 3
[0240] Dissolved the product from Step 2 (100 mg, 0.45 mmol) and
Example 1 (202 mg, 0.45 mmol) in THF, and treated with NaBH.sub.3CN
(57 mg, 0.9 mmol) at 23.degree. C. Heated at 60.degree. C. for an
additional 18 hours, and quenched with saturated NaHCO.sub.3
solution. Extracted with EtOAc (2.times.150 mL). Dried the combined
organic layer over MgSO.sub.4 and concentrated to yield a crude
product. Purified on column chromatography using MeOH (sat. with
NH.sub.3) and CH.sub.2Cl.sub.2 (1:99) to give the target
compound.
Examples 52-54
[0241] Prepared the target compounds using a procedure similar to
those used to prepare the compounds of Examples 48-50 substituting
the compound of Example 32 for the compound of Example 1.
Example 55
Step 1
[0242] Dissolved Example 44 in CH.sub.2Cl.sub.2, and used a
procedure similar to that described for Example 2 using chloride
acetyl chloride in place of acetyl chloride to provide the
.beta.-amido-.delta.-chloro amide.
Step 2
[0243] Used a procedure similar to Example 48, Step 2, to provide
the target compound.
Example 56
[0244] Step 1 ##STR111##
[0245] A flame-dried 50 mL one-necked flask was charged with 5.10 g
(20.1 mmol, 1.0 eq) of S-diphenylprolinol (32) and 56 mL of
anhydrous toluene. The solution was heated up to
140.about.150.degree. C. 36 mL of dry toluene was azeotropically
distilled through a Dean-Stark trap with an air condenser. Another
36 mL of toluene was added and the azeotropic distillation was
repeated three times. After the third azeotropic distillation was
done, another 36 mL of anhydrous toluene was added. The solution
was allowed to cool to room temperature. Methylboroxin (1.90 mL,
13.5 mmol, 0.67 eq) was added via syringe over 5 min. A solid was
formed after completion of the addition. The reaction mixture was
stirred at room temperature for 30 min and 36 mL of toluene was
distilled off. Another 36 mL of dry toluene was added and distilled
off again. The distillation was repeated one more time, then 20 mL
of 1.0 M of CBS catalyst (33) solution in toluene was prepared. The
solution was used in CBS reduction directly.
Step 2
[0246] A 1 L oven-dried round-bottomed flask was charged with
102.14 g (0.4 mol, 1.0 eq) of
3',5'-Bis(trifluoromethyl)acetophenone and 780 mL of anhydrous
dichloromethane. The resultant solution was transferred into a dry
dropping funnel. An oven-dried 3 L round-bottomed flask was cooled
to -20.degree. C., and 20 mL of 1.0 M CBS catalyst (33) toluene
solution was added via syringe, followed by 40 mL of 10.0-10.3 M
borane-methylsulfide complex. The
3',5'-Bis(trifluoromethyl)-acetophenone solution was added dropwise
through the dropping funnel. The addition was carried out over 2
days. During the addition, the temperature was maintained at
-20.degree. C. with a cooling machine. Once the addition was
finished, the reaction was monitored by TLC (EtOAc/Hexane=1/4).
When the starting material was completely consumed, 250 mL of
methanol was added slowly. Hydrogen gas was emitted. The reaction
solution was then concentrated to give a solid. The solid was
dissolved in 500 mL of diethyl ether, then 45 mL of 2.0 M of
hydrochloric acid in diethyl ether was added slowly at -20.degree.
C. A precipitate was formed. The reaction mixture was warmed to
room temperature and stirred for 30.about.40 min. The mixture was
filtered through a funnel and the filtrate was concentrated to give
101.5 g of a solid of 34 (yield 98.7%). Chiral HPLC Chiral
OD(Chiralcel) column (Hexane/IPA=98/2) showed 94.6%. ##STR112##
Step 3
[0247] A mixture of amino-acid (20 g, 53.0 mmol, 1 equiv.) and
di-tert-butyl dicarbonate (23.13 g, 106.0 mmol, 2 equiv.) in
dichloromethane (250 mL), THF (250 mL) and water (100 mL) was
stirred vigorously while 80 mL of 1 N NaOH solution was added
dropwise over a period of 25 min. The resultant suspension was
stirred at room temperature overnight. The reaction mixture was
neutralized with 1 N HCl to pH5, then extracted with
CH.sub.2Cl.sub.2 (400 mL.times.2). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to a solid as crude,
which upon recrystallization in is Et.sub.2O, gave 9 g of 35 as a
solid (yield 56%) MS: 306.1 (M+1).
Step 4
[0248] At 0.degree. C., to the suspension of 35 (7.15 g, 23.3 mmol,
1.2 equiv.) in 60 mL of anhydrous toluene and 10 mL of dry
CH.sub.2Cl.sub.2, was slowly added DCC (5.76 g, 27.9 mmol, 1.4
equiv.). After stirring at 0.degree. C. and room temperature each
for 20 min, the thick solution was treated at 0.degree. C. with
methyl-bis(triflouromethyl)benzyl alcohol 34 (5 g, 19.4 mmol, 1
equiv.), and DMAP (2.37 g, 19.4 mmol, 1 equiv.). Stirring at room
temperature till TLC(Hexane/EtOAc 3/2) indicated the complete
consumption of 34. The reaction mixture was then concentrated and
purified with flash chromatography column
(Hexane.fwdarw.Hexane/EtOAc 90/10 gradient) to give 36 as a liquid
(yield 90%). MS: 546 (M+1).
Step 5
[0249] 10 mL of precooled 1.0 M DIBAL solution in hexane was added
slowly at -78.degree. C. via cannula to a solution of 36 (2.48 g,
4.55 mmol, 1 equiv.) in 25 mL of anhydrous CH.sub.2Cl.sub.2. After
stirring at -78.degree. C. until TLC (Hexane/EtOAc 3/2) showed
complete consumption of 36, were added 1.1 mL of dry pyridine, a
solution of DMAP (1.1 g, 9 mmol, 2 equiv.) in 9 mL of dry
CH.sub.2Cl.sub.2, and 2.58 mL of Ac.sub.2O. The reaction solution
was stirred at -78.degree. C. for 15 hours, then warmed to
-10.degree. C. and stirred for another 2 hours before it was
quenched by slowly adding saturated NH.sub.4Cl solution (35 mL) and
saturated sodium potassium tartrate solution (35 mL). The mixture
was stirred at room temperature for 30 min and extracted with
CH.sub.2Cl.sub.2 (3.times.125 mL). The combined organic layer was
washed with 1 M NaHSO.sub.4 (2.times.35 mL), saturated NaHCO.sub.3
(2.times.100 mL), and brine (100 mL), then dried over
Na.sub.2SO.sub.4, filtered and concentrated to give 2.71 g of a
liquid as crude. Further purification by flash chromatography
eluting with (Hexane.fwdarw.Hexane/EtOAc 97/3 gradient with 2%
Et.sub.3N) gave 37 as a liquid (1.55 g, yield 58%).
Step 6
[0250] A solution of acetoxy ether 37 (1.48 g, 2.51 mmol, 1 equiv.)
in 40 mL of dry CH.sub.2Cl.sub.2 was treated with triethylsilane
(2.67 mL, 16.7 mmol, 6.5 equiv.) and BF.sub.3 Et.sub.2O (0.57 mL,
4.50 mmol, 1.79 equiv.) at -78.degree. C. The solution was stirred
overnight while the temperature was raised to 0.degree. C. When TLC
(Hexane/EtOAc 90/10+2% Et.sub.3N) showed complete consumption of
37, the reaction was quenched with saturated NaHCO.sub.3 (40 mL).
The aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.150
mL). The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated to give a liquid. The crude was dissolved
in 20 mL of CH.sub.2Cl.sub.2, and treated with 6.28 mL of 4.0 N HCl
in 1,4-dioxane to give 826.4 mg of a solid as 38. MS: 432 (M+1).
##STR113## Step 7
[0251] The hydrochloride salt (38) was neutralized as described in
Example 1, Step 3. Use a procedure similar to Example 1, Step 4-5
to provide the aminopiperidine 39.
Step 8
[0252] A solution of amino-piperidine 39 (600 mg, 1.24 mmol, 1
equiv.) in 20 mL dry toluene was treated with 0.75 mL of 2.0 M
trimethylaluminum solution in toluene. After stirring at room
temperature for 30 min, the solution was heated to 125.degree. C.,
then treated with 0.18 mL of ethyl 4-bromobutyrate. The mixture was
heated to reflux for 3.5 hours (TLC (MeOH/CH.sub.2Cl.sub.2=5:95)),
whereupon it was quenched with 15 mL saturated sodium potassium
tartrate and diluted with 100 mL of EtOAc. The aqueous layer was
further extracted with EtOAc (2.times.50 mL). The combined organic
layer was washed with brine (100 mL), dried over NaSO4, filtered
and concentrated to give 750 mg crude. Purification on flash column
(CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH=95/5 gradient) gave
compound 56 as a liquid (442 mg, yield 69%).
Example 57
[0253] ##STR114## ##STR115## Step 1
[0254] A solution of 3,5-bis(triflouromethyl)phenylacetic acid in
MeOH was refluxed overnight with a catalytic amount of concentrated
H.sub.2SO.sub.4. The solvent was evaporated, taken up with
Et.sub.2O and washed with saturated NaHCO.sub.3. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated to give
the methyl 3,5-bis(triflouromethyl)phenylacetate as a liquid.
(yield 95%).
Step 2
[0255] A solution of methyl 3,5-bis(triflouromethyl)phenylacetate
(2.18 g, 7.62 mmol, 1 equiv.) in 12.5 mL dry CH.sub.3CN was treated
with 2,4,6-triisopropyl benzenesulfonyl azide (2.65 g, 8.56 mmol,
1.12 equiv.), and 1.26 mL of DBU at -9.degree. C. After stirring at
about -8 to -5.degree. C. for 1.5 hours, the solution was stirred
at room temperature for another 1 hour. The solution was
concentrated and purified on column (Hexane/EtOAc=97/3) to afford
the product 40 (2.27 g, yield 96%).
Step 3:
[0256] To a solution of 23 (Example 1, Step 1) (2.92 g, 10 mmol,
1.74 equiv.) and Rhodium (II) acetate (5 mg, 0.011 mmol, 0.2%
equiv.) in 5 mL of dry benzene, was added a solution of diazo-ester
40 (1.8 g, 5.77 mmol, 1 equiv.) in 2.6 mL dry benzene through
syringe pump at a rate of 0.09 mL/h. The addition was done over 29
hours. The reaction mixture was stirred for another 30 min until
TLC (Et.sub.2O/Hexane=25%) showed 40 was completely consumed. The
solvent was evaporated and purified on column
(Hexane/Et.sub.2O=3:1.fwdarw.3:2) to give the product 41 as a
liquid (1.64 g, yield 49%).
Step 4
[0257] The Boc protected piperidine was deprotected and neutralized
in a similar fashion to Example 1, Step 3 to provide the
corresponding piperidine.
Step 5
[0258] Used a procedure similar to Example 1, Steps 4-5, to provide
aminopiperidine 43.
Step 6:
[0259] Used a procedure similar to Example 49, to provide the
target compound.
Example 58
Step 1
[0260] A suspension of 1 hydrochloride (2.0 g) in 1,2
dichloroethane (15 mL) was treated with dimethyl-2-oxo-glutarate
(0.65 mL) and NaB(OAc).sub.3H (1.27 g). Gas evolution ensued
whereupon HOAc (0.75 mL) was added. The resultant solution was
stirred at 23.degree. C. for 1 h whereupon additional
NaB(OAc).sub.3H (2 g) was added. The mixture was stirred for 14 h,
then poured into sat. NaHCO.sub.3 (40 mL), and extracted with
CH.sub.2Cl.sub.2 (2.times.150 mL). The combined organic layers were
washed with brine (40 mL), dried (Na.sub.2SO.sub.4) and
concentrated to give the crude as an oil (2.51 g).
Step 2:
[0261] The crude material from Step 1 was dissolved in dry toluene
(100 mL), heated to 115.degree. C., and treated with Me.sub.3Al
(2.14 mL of 2 M in toluene). The resultant solution was stirred for
5 h whereupon additional Me.sub.3Al (2.14 mL of 2 M in toluene) was
added. The mixture was stirred further until TLC
(CH.sub.2Cl.sub.2/MeOH 95/5) indicated near complete reaction. The
mixture was diluted with EtOAc (200 mL), cooled to 0.degree. C.,
and quenched with sat sodium-potassium tartrate (100 mL). After
stirring at 0.degree. C. for 30 min, the layers were separated, and
the aqueous layer was extracted with EtOAc (200 mL). The combined
organic layers were washed with brine (100 mL), dried
(Na.sub.2SO.sub.4), and concentrated to give the crude.
Purification by silica gel chromatography
(hexane.fwdarw.hexane/EtOAc 1:1) provided 615 mg (26%) of the
lactam ester.
Step 3
[0262] Used a procedure similar to that used in Example 40,
substituting the lactam ester product of Step 2 above for 5 to give
58.
Examples 59-60
[0263] Used a procedure similar to that used in Example 58 but
substituted methylamine and MeOCH.sub.2CH.sub.2NH.sub.2 for ammonia
in Step 3 to afford 59 and 60 respectively.
Example 61
[0264] Used a procedure similar to that used in Example 58, Steps
1-2, using methyl levulinate in place of dimethyl-2-oxo-glutarate
to give the target compound.
Example 62
[0265] A solution of 1 hydrochloride (500 mg) in dry toluene (100
mL) was treated with succinic anhydride (133 mg) and TsOH (60 mg)
and heated to reflux with a Dean Stark trap for 96 h. The reaction
mixture was concentrated in vacuo and purified by silica gel
chromatography (hexane/EtOAc 2:1.fwdarw.hexane/EtOAc 1:1) to give
167 mg of the target compound.
Example 63
[0266] A solution of 1 hydrochloride (500 mg) and
1,2-diformylhydrazine (226 mg) in dry pyridine (10 mL) was dried by
azeotropic distillation under reduced pressure (2.times.10 mL
pyridine). Pyridine (5 mL) was added, followed by TMSCl (2 mL) and
NEt.sub.3. The resultant solution was stirred at 80.degree. C. for
2.5 d, whereupon it was concentrated in vacuo, dissolved in
CH.sub.2Cl.sub.2 (50 mL) and washed with sat NaHCO.sub.3 (15 mL).
The aqueous layer was extracted with CH.sub.2Cl.sub.2 (50 mL) and
the combined organic layers were washed with 2N HCl (15 mL)/brine
(5 mL), dried (Na.sub.2SO.sub.4), and concentrated to give the
crude. Purification by silica gel chromatography (hexane/EtOAc
1:1.fwdarw.EtOAc) provided 220 mg (43%) of the target compound.
Example 64
[0267] ##STR116## Step 1
[0268] To a 50 mL round bottom flask was added t-butyl carbazate
(0.155 g, 1.17 mmol, 1.1 equiv.) and THF (4 mL). To the resulting
colorless solution was added CDI (0.207 g, 1.28 mmol, 1.2 equiv.)
and a few 3 .ANG. molecular sieves, and the reaction mixture was
stirred at about 23.degree. C. for about 18 hours. Triethyl amine
(0.18 mL 28 mmol, 1.2 equiv.) was added to the reaction mixture
followed by addition of Example 1 (0.5 g, 1.02 mmol, 1 equiv.). The
reaction mixture turned into a white suspension. The reaction
mixture was stirred at about 23.degree. C. for about 0.5 hour. The
reaction mixture was purified using Biotage (CH.sub.2Cl.sub.2, then
2% MeOH/CH.sub.2Cl.sub.2) to give 0.23 g of compound 44.
Step 2
[0269] To a solution of compound 44 (0.1 g, 0.17 mmol, 1 equiv.) in
CH.sub.2Cl.sub.2 (10 mL) was added a solution of 4 M HCl in dioxane
(0.5 mL, 2 mmol, 11.78 equiv.). The reaction mixture was stirred at
about 23.degree. C. for about 3 hours. The solvent was then
evaporated. MeOH was added to the residue followed by a solution of
trimethyl orthoformate (0.5 mL) in MeOH (0.3 mL). The reaction
mixture was stirred at about 23.degree. C. for about 18 hours. The
reaction mixture was then concentrated and purified by column
chromatography (hexane, then 40% EtOAc/hexane) to afford the
product Example 64. LCMS (M+H).sup.+ 501.1.
[0270] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and variations thereof will be apparent
to those of ordinary skill in the art. All such alternatives,
modifications and variations are intended to fall within the spirit
and scope of the present invention.
* * * * *