U.S. patent application number 09/737036 was filed with the patent office on 2002-09-05 for selective neurokinin antagonists.
Invention is credited to Blythin, David J., Chen, Xiao, Paliwal, Sunil, Piwinski, John J., Reichard, Gregory A., Shih, Neng-Yang, Shue, Ho-Jane, Xiao, Dong.
Application Number | 20020123491 09/737036 |
Document ID | / |
Family ID | 26868142 |
Filed Date | 2002-09-05 |
United States Patent
Application |
20020123491 |
Kind Code |
A1 |
Shih, Neng-Yang ; et
al. |
September 5, 2002 |
SELECTIVE NEUROKININ ANTAGONISTS
Abstract
Compound represented by the structural formula 1 or a
pharmaceutically acceptable salt thereof, wherein Ar.sup.1 and
Ar.sup.2 are optionally substituted heteroaryl or optionally
substituted phenyl; X.sup.1 is --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.12--, --NCOR.sup.12-- or --NR.sup.12SO.sub.2R.sup.15; 2 is
selected from the group consisting of 3 X.sup.2is --O--, --S-- or
--NR.sup.5; Y is .dbd.O, .dbd.S or .dbd.NR.sup.11; Y.sup.1 is H,
C.sub.1-C.sub.6 alkyd, --NR.sup.17R.sup.15, --SCH.sub.3,
R.sup.19-aryl(CH.sub.2).sub.n6--,
R.sup.19-heteroaryl-(CH.sub.2).sub.n6--- ,
--(CH.sub.2).sub.n6-heterocycloalkyl,
-(C.sub.1-C.sub.3)alkyl-NH--C(O)O(- C.sub.1-C.sub.6)alkyl or
--NHC(O)R.sup.15; R.sup.5 is H or --(CH.sub.2).sub.n1-G, wherein
n.sub.1 is 0-5, G is 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.su- p.15,
--NR.sup.13COR.sup.12, --NR.sup.12(CONR.sup.13R.sup.14),
--CONR.sup.13R.sup.14, --COOR.sup.12, C.sub.3-C.sub.8 cycloalkyl,
R.sup.19-aryl, R.sup.19-heteroaryl, and provided when n.sub.1=0, G
is not H; R.sup.1, R.sup.2, R.sup.3 and R.sup.7 are H, alkyl,
cycloalkyl, --CHF.sub.2, --CH.sub.2F or --CF.sub.3; or R.sup.1 and
R.sup.2, together with the carbon to which they are attached, form
an alkylene ring; or R.sup.1 and R.sup.2 together are .dbd.O,
R.sup.6 is R.sup.7or --OH; and the remaining variables are as
defined in the specifiation, methods of treating diseases
susceptible to treatment with neurokinin antagonists with said
compounds, and pharmaceutical compositions comprising said
compounds are disclosed. Also disclosed are pharmaceutical
compositions comprising an effective amount of a compound of claim
1, at least one pharmaceutically acceptable carrier, and in
combination with an effective amount of a selective serotonin
reuptake inhibitor.
Inventors: |
Shih, Neng-Yang; (North
Caldwell, NJ) ; Shue, Ho-Jane; (Pine Brook, NJ)
; Reichard, Gregory A.; (Morris Plains, NJ) ;
Paliwal, Sunil; (Scotch Plains, NJ) ; Blythin, David
J.; (North Caldwell, NJ) ; Piwinski, John J.;
(Clinton Township, NJ) ; Xiao, Dong; (Scotch
Plains, NJ) ; Chen, Xiao; (Edison, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
26868142 |
Appl. No.: |
09/737036 |
Filed: |
December 14, 2000 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60172489 |
Dec 17, 1999 |
|
|
|
Current U.S.
Class: |
514/222.5 ;
514/227.2; 514/228.8; 514/269; 514/362; 514/386; 544/315; 544/54;
544/8; 548/127; 548/182; 548/229; 548/316.4 |
Current CPC
Class: |
C07D 239/10 20130101;
C07C 45/71 20130101; C07D 285/10 20130101; C07D 233/16 20130101;
C07D 233/78 20130101; C07D 413/06 20130101; C07C 217/48 20130101;
C07D 413/04 20130101; C07D 233/32 20130101; C07D 233/14 20130101;
C07D 233/42 20130101; C07D 233/48 20130101; C07C 45/71 20130101;
C07D 233/46 20130101; C07D 413/10 20130101; C07D 233/22 20130101;
C07C 47/575 20130101; C07D 211/58 20130101; C07D 233/30 20130101;
C07D 401/04 20130101; C07D 409/06 20130101; C07D 403/12 20130101;
C07D 401/12 20130101; C07F 9/6506 20130101 |
Class at
Publication: |
514/222.5 ;
514/269; 514/362; 514/386; 514/227.2; 514/228.8; 544/8; 544/54;
544/315; 548/127; 548/182; 548/229; 548/316.4 |
International
Class: |
A61K 031/549; A61K
031/54; A61K 031/535; A61K 031/513; A61K 031/433; A61K 031/415 |
Claims
We claim:
1. A compound represented by the structural formula 277or a
pharmaceutically acceptable salt thereof, wherein Ar.sup.1 and
Ar.sup.1 are independently selected from the group consisting of
R.sup.7-heteroaryl and 278X.sup.1 is --O--, --S--, --SO--,
--SO.sub.2-, --NR.sup.12--, --N(COR.sup.12)-- or
--N(SO.sub.2R.sup.15)--; R.sup.1, R.sup.2, R.sup.3 and R.sup.7 are
each independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, hydroxy(C.sub.1-C.sub.3)alk- yl,
C.sub.3-C.sub.8 cycloalkyl, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3; or R.sup.1 and R.sup.2, together with the carbon to
which they are attached, form a C.sub.3-C.sub.6 alkylene ring; or,
when X.sup.1 is --O--, --S-- or --NR.sup.12--, R.sup.1 and R.sup.2
together are .dbd.O; each R.sup.6 is independently selected from H,
C.sub.1-C.sub.6 alkyl, --OR.sup.13 or --SR.sup.12; n is 1-4, if n
is greater than 1, then R.sup.6 and R.sup.7 can be the same or
different on each carbon; 279is selected from the group consisting
of 280X.sup.2 is --O--, --S-- or --NR.sup.5--; Y is .dbd.O, .dbd.S
or=NR.sup.1; Y.sup.1 is H, C.sub.1-C.sub.6 alkyl, --NR.sup.17R
.sup.3, --SCH.sub.3, R.sup.19-aryl(CH.sub.2).sub.n6-,
R.sup.19-heteroaryl--(CH.sub.2).sub.n6--- ,
--(CH.sub.2).sub.n6-heterocycloalkyl,
-(C.sub.1-C.sub.3)alkyl--NH--C(O)O- (C.sub.1-C.sub.6)alkyl or
--NHC(O)R.sup.15; R.sup.1 is H or --(CH.sub.2).sub.n1-G, wherein n,
is 0-5, G is 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.3R.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, C.sub.3-C.sub.8 cycloalkyl, R.sup.19-aryl,
R.sup.19-heteroaryl, 281or when n, is 0, R.sup.5 can also be
--C(O)R.sup.13 or -C(S)R.sup.13; provided that G is not H when
n.sub.1=0; X is --NR.sup.20--, --N(CONR.sup.13R.sup.14)--,
--N(CO.sub.2Rl.sup.3)--, --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-- or --CR.sup.12F--;
R.sup.8, R.sup.9 and R.sup.10 are independently selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, --OR .sup.2, 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.2, --CONR.sup.21R.sup.22, --NR.sup.2 COR.sup.2,
--NR.sup.2CO.sub.2R.sup.5, --NR.sup.2 CONR.sup.2 R.sup.22 --NR
SO.sub.2R.sup.15, --NR.sup.21R.sup.22, --SO.sub.2NR.sup.2 R.sup.22,
--S(O).sub.n5R.sup.15, R.sup.16-aryl and R.sup.19-heteroaryl;
R.sup.11 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
--NO.sub.2, --CN, OH, -0R.sup.12, -O(CH.sub.2)R.sub.6R.sup.12,
--(C.sub.1-C.sub.3)alkyl--C(O)NHR .sup.2,
R.sup.19-aryl(CH.sub.2).sub.n6-- - or
R.sup.19-heteroaryl--(CH.sub.2).sub.n6--; R.sup.4 and R.sup.12 are
each independently 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 independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl,
R.sup.19-aryl(CH.sub.2).sub.n6- or
R.sup.9-heteroaryl--(CH.sub.2).sub.n6-- -, ; or R.sup.13 and
R.sup.14 together are C.sub.3-C.sub.6 alkylene and with the
nitrogen to which they are attached form a 4-7 membered ring, or
one of the carbon atoms in the alklyene chain formed by R.sup.13
and R.sup.14 is replaced by a heteroatom selected from the group
consisting of --O--, --S-- and --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 independently selected from the group consisting of H,
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.17 is H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, --COOR .sup.2, --CONR.sup.2
R.sup.22, --NR.sup.21R.sup.22, --NR.sup.21COR.sup.2 N R.sup.2
CO.sub.2R.sup.2, --NR.sup.2 CONR.sup.2NR.sup.22, --NR.sup.2t
SO.sub.2R.sup.15 or --S(O).sub.n5R.sup.15; R.sup.18 is H,
C.sub.1-C.sub.6 alkyl or --P(O)(OH).sub.2; R.sup.19 is 1 to 3
substituents independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, --OH, halogen,
--CN, --NO.sub.2, --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.2,
--CONR.sup.21R.sup.22, --NR.sup.21R.sup.22, --NR.sup.2 COR .sup.2,
--NR.sup.2 CO.sub.2R .sup.2, --NR.sup.2 CONR.sup.21R.sup.22
--NR.sup.2RSO.sub.2R.sup.15 and S(O)f5R15; R.sup.20 is H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl or
--(CH.sub.2).sub.n6-heterocycloalkyl R.sup.21 and R.sup.22 are
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 together are C.sub.3-C.sub.6 alkylene and
with the nitrogen to which they are attached form a 4-7 membered
ring, or one of the carbon atoms in the alklyene chain formed by
R.sup.21 and R.sup.22 is replaced by a heteroatom selected from the
group consisting of --O--, --S-- and --NR.sup.12--; R.sup.23,
R.sup.24, R.sup.25 and R.sup.26 are H, C.sub.1-C.sub.6 alkyl and
can be together as .dbd.O; when n.sub.5=0, and R.sup.25 and
R.sup.26.dbd.H, X is not O, N, S n.sub.3 and n.sub.4 are
independently 1-5, provided that the sum of n.sub.3 and n.sub.4 is
2-6; n.sub.5 is independently 0-2; n.sub.6 is independently 0-3;
and q and r are independently 1 or 2.
2. The compound of claim 1 wherein R.sup.1, R.sup.3, R.sup.4 and
R.sup.7 are each hydrogen.
3. The compound of claim 1 wherein R5 is H or OH.
4. The compound of claim 1 wherein X.sup.1 is --O-- or
--NR.sup.12--.
5. The compound of claim 1 wherein Ar.sup.1 and Ar.sup.2 are each
R.sup.8,R.sup.9,R.sup.10-phenyl.
6. The compound of claim 1 wherein 282is 283
7. The compound of claim 6 wherein n is 1 or 2.
8. The compound of claim 7 wherein X.sup.2 is --NR.sup.5-- and Y is
.dbd.O.
9. The compound of claim 1 wherein R.sup.1, R.sup.3, R.sup.4 and
R.sup.7 are each hydrogen; X.sup.1 is --O-- or --NR .sup.2--;
Ar.sup.1 and Ar.sup.2 are each R5,R.sup.9,R.sup.10-phenyl; n is 1
or2; x.sup.2 is --NR.sup.5--; and R.sup.6 is H or --OH, Y is
.dbd.O.
10. The compound of claim 1 selected from the group of compounds
represented by the formula 284wherein R.sup.8 is H or halogen;
R.sup.2 is H, --CH.sub.3 or --CH.sub.2OH ; R is H or --OH; and R9
is selected from the group consisting of hydrogen and groups of the
formula --(CH.sub.2).sub.n1-G.
11. The compound of claim 10 wherein X.sup.1 is --O--, --NH--,
--N(CH.sub.3)-- or --N(COCH.sub.3); Re is H or halogen; R.sup.2 is
H. --CH.sub.3 or --CH.sub.2OH; R.sup.1 is H or --OH; R.sup.9 is
--OCF.sub.3 or 5-(trifluoromethyl)-1H-tetrazol-1-yl; R.sup.12 is
--CH.sub.3 or cyclopropyl; and R.sup.5 is selected from slt the
group consisting of hydrogen and groups of the formula
--(CH.sub.2)).sub.1-G, wherein --(CH.sub.2).sub.n1-G is selected
from the group consisting of 285and --(CH.sub.2).sub.n1-G', wherein
n1 is 2-4 and G.sup.1 is H, --OH, --OCH.sub.3--, ethoxy,
isopropyloxy, -O-cyclopropyl, or --CONR.sup.13R.sup.14, wherein
R.sup.13 and R.sup.14 are independently selected from the group
consisting of H, --CH.sub.3, ethyl, isopropyl, or cyclopropyl.
12. A compound of any of examples 1 to 166.
13. The compound of claim 1 selected from the compounds of
Examples: 2, 17, 19, 31, 59, 261, 65, 67, 76, 77, 78, 79a, 79b, 92,
93, 99, 100, 103, 104, 110, 111, 113, 20 120, 121, 126, 127, 128,
129, 130, 135, 142, 165, 165a, 165b 166a, 66b or compound 118.
14. The compound of claim 1 wherein said compound is the compound
of Example 61.
15. The compound of claim 1 wherein said compound is the compound
of Example 93.
16. The compound of claim 1 wherein said compound is the compound
of Example 2.
17. The compound of claim 1 wherein said compound is the compound
of Example 92.
18. The compound of claim 1 wherein said compound is the compound
of Example 127.
19. The compound of claim 1 wherein said compound is the compound
of Example 126.
20. The compound of claim 1 wherein said compound is the compound
of Example 129.
21. The compound of claim 1 wherein said compound is the compound
of Example 128.
22. The compound of claim 1 wherein said compound is the compound
of Example 79b.
23. The compound of claim 1 wherein said compound is the compound
of Example 79a.
24. The compound of claim 1 wherein said compound is the compound
of Example 166a.
25. The compound of claim 1 wherein said compound is the compound
of Example 166b.
26. The compound of claim 1 wherein said compound is the compound
of Example 165a.
27. The compound of claim 1 wherein said compound is the compound
of Example 165b.
28. A pharmaceutical composition comprising an effective amount of
the compound of claim 1 and a pharmaceutically acceptable
carrier.
29. The pharmaceutical composition of claim 28 wherein the compound
is selected from the compounds of examples 2, 61, 79a, 79b, 92, 93,
126, 127, 128, 129, 165a, 165b, 166a and 166b.
30. A pharmaceutical composition comprising an effective amount of
a compound of claim 1, in combination with an effective amount of a
selective serotonin reuptake inhibitor and a pharmaceutically
acceptable carrier.
31. The pharmaceutical composition of claim 30 wherein the compound
is selected from the compounds of examples 2, 61, 79a, 79b, 92, 93,
126, 127, 128, 129, 165a, 165b, 166a and 166b.
32. A method of treating respiratory diseases; inflammatory
diseases; skin disorders; ophthalmalogical disorders; addictions;
stress related disorders; obsessive/compulsive disorders; eating
disorders; mania; premenstrual syndrome; central nervous system
conditions; gastrointestinal disorders; bladder disorders;
atherosclerosis; fibrosing disorders; obesity; Type II diabetes;
pain related disorders; and genitourinary disorders comprising
administering to a patient in need of such treatment an effective
amount of a compound of claim 1.
33. The method of claim 32 wherein the compound used is selected
from the compounds of examples 2, 61, 79a, 79b, 92, 93, 126, 127,
128, 129, 165a, 165b, 166a and 166b.
34. A method of treating emesis, depression, anxiety and cough
comprising administering to a patient in need of such treatment an
effective amount of a compound of claim 1.
35. The method of claim 34 wherein the compound used is selected
from the compounds of examples 2, 61, 79a, 79b, 92, 93, 126, 127,
128, 129, 165a, 165b, 166a and 166b.
36. A method of treating respiratory diseases; inflammatory
diseases; skin disorders; ophthalmalogical disorders; addictions;
stress related disorders; obsessive/compulsive disorders; eating
disorders; mania; premenstrual syndrome, central nervous system
conditions; gastrointestinal disorders; bladder disorders;
atherosclerosis; fibrosing disorders; obesity; Type II diabetes;
pain related disorders; and genitourinary disorders comprising
administering to a patient in need of such treatment an effective
amount of a compound of claim 1 in combination with an effective
amount of a selective serotonin receptor inhibitor.
37. The method of claim 36 wherein the compound used is selected
from the compounds of examples 2, 61, 79a, 79b, 92, 93, 126, 127,
128, 129, 165a, 165b, 166a and 166b.
38. A method of treating emesis, depression, anxiety and cough
comprising administering to a patient in need of such treatment an
effective amount of a compound of claim 1 with an effective amount
of a selective serotonin receptor inhibitor.
39. The method of claim 38 wherein the compound used is selected
from the compounds of examples 2, 61, 79a, 79b, 92, 93, 126, 127,
128, 129, 165a, 165b, 166a and 166b.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a genus of substituted
cyclic ureas and derivatives thereof useful as antagonists of
tachykinin receptors, in particular as antagonists of the
neuropeptides neurokinin-1 receptor (NK.sub.1).
[0002] Neurokinin receptors are found in the nervous system and the
circulatory system and peripheral tissues of mammals, and therefore
are involved in a variety of biological processes. Neurokinin
receptor antagonists are consequently expected to be useful in the
treatment or prevention of various mammalian disease states, for
example respiratory diseases such as chronic lung disease,
bronchitis, pneumonia, asthma, allergy, cough, bronchospasm;
inflammatory diseases such as arthritis and psoriasis; skin
disorders such as atopic dermatitis and contact dermatitis;
ophthalmological disorders such as retinitis, ocular hypertension
and cataracts; addictions such as alcohol dependence and
psychoactive substance abuse; stress related disorders such as post
tramautic stress disorder; obsessive/compulsive disorders; eating
disorders such as bulemia, anorexia nervosa and binge eating
disorders; mania; premenstrual syndrome; central nervous system
conditions such as anxiety, general anxiety disorder, panic
disorder, phobias, bipolar disorders, migraine, epilepsy,
nociception, emesis, depression, psychosis, schizophrenia,
Alzheimer's disease, AIDs related dementia and Towne's disease;
gastrointestinal disorders such as Crohn's disease and colitis;
nausea; bladder disorders; atherosclerosis; fibrosing disorders;
obesity; Type II diabetes; pain related disorders such as
neuropathic pain, post-operative pain, headache and chronic pain
syndromes; and genitourinary disorders such as interstitial
cystitis and urinary incontinence.
[0003] In particular, NK.sub.1 receptors have been reported to be
involved in microvascular leakage and mucus secretion, making
NK.sub.1 receptor antagonists especially useful in the treatment
and prevention of asthma, emesis, nausea, depression, anxiety,
cough, pain and migraine.
SUMMARY OF THE INVENTION
[0004] Compounds of the present invention are represented by the
formula I 4
[0005] or a pharmaceutically acceptable salt thereof, wherein
Ar.sup.1 and Ar.sup.2 are independently selected from the group
consisting of R.sup.17 heteroaryl and 5
[0006] X.sup.1 is --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.12--, --N(COR.sup.12)-- or --N(SO.sub.2R.sup.15)--;
[0007] R.sup.1, R.sup.2, R.sup.3 and R.sup.7 are each independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
hydroxy(C.sub.1-C.sub.3)alkyl, C.sub.3-C.sub.8 cycloalkyl,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3; or R.sup.1 and R.sup.2,
together with the carbon to which they are attached, form a
C.sub.3-C.sub.6 alkylene ring; or, when X.sup.1 is --O--, --S-- or
--NR.sup.12--, R.sup.1 and R.sup.2 together are .dbd.O;
[0008] each R.sup.6 is independently selected from H,
C.sub.1-C.sub.6 alkyl, -OR.sup.13 or --R.sup.12;
[0009] n is 1-4, if n is greater than 1, then R.sup.6 and R.sup.7
can be the same or different on each carbon; 6
[0010] is selected from the group consisting of 7
[0011] X.sup.2 is --O--, --S-- or --NR.sup.5--;
[0012] Y is .dbd.O, .dbd.S or .dbd.NR.sup.11;
[0013] Y.sup.1 is H, C.sub.1-C.sub.6 alkyl, --NR.sup.17R.sup.13,
--SCH.sub.3, R.sup.19-ary)(CH.sub.2).sub.n6--,
R.sup.19-heteroaryl-(CH.su- b.2).sub.16--,
--(CH.sub.2).sub.n6-heterocycloalkyl,
-(C.sub.1-C.sub.3)alkyl-NH--C(O)O(C.sub.1-C.sub.6)alkyl or
--NHC(O)R.sup.15;
[0014] R.sup.5 is H or --(CH.sub.2).sub.n1-G, wherein n.sub.1 is
0-5, G is 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.su- p.15, --NR.sup.13COR.sup.12,
--NR.sup.12(CONR.sup.13R.sup.14), --CONR.sup.13R.sup.14,
--COOR.sup.12, C.sub.3-C.sub.8 cycloalkyl, R.sup.19-aryl,
R.sup.19-heteroaryl, 8
[0015] or when n.sub.1 is 0, R.sup.5 can also be --C(O)R.sup.13 or
--C(S)R.sup.13; provided that G is not H when n1.dbd.O;
[0016] X is --NR.sup.20, --N(CONR.sup.13R.sup.14).sub.2,
--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-- or --CR.sup.12F--;
[0017] R.sup.8, R.sup.9 and R.sup.10 are independently selected
from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, --OR; , 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.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.su- p.22, --S(O).sub.n5R.sup.15, R.sup.16-aryl
and R.sup.19-heteroaryl;
[0018] R.sup.11 is --H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, --NO.sub.2, --CN, OH, --OR.sup.12,
--O(CH.sub.2).sub.n6R.sup.12,
--(C.sub.1-C.sub.3)alkyl-C(O)NHR.sup.12,
R.sup.19-aryl(CH.sub.2).sub.n6- or
R.sup.19-heteroaryl(CH.sub.2)n.sub.6-;
[0019] R.sup.4 and R.sup.11 are each independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl and
C.sub.3-C.sub.8 cycloalkyl;
[0020] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, R.sup.19-aryl(CH.sub.2).sub.n6- or
R.sup.19-heteroaryl(CH.sub.2).sub.n6-; or R.sup.13 and R.sup.14
together are C.sub.3-C.sub.6 alkylene and with the nitrogen to
which they are attached form a 4-7 membered ring, or one of the
carbon atoms in the alklyene chain formed by R.sup.13 and R.sup.14
is replaced by a heteroatom selected from the group consisting of
--O--, --S-- and --R.sup.15 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl or --CF.sub.3;
[0021] R.sup.16 is 1 to 3 substituents independently selected from
the group consisting of H, 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;
[0022] R.sup.17 is H, C.sub.1-C.sub.6 alkyl, 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.21CNOR.sup.21R.sup.22,
--NR.sup.21SO.sub.2R.sup.15 or --S(O).sub.n5R.sup.15;
[0023] R.sup.18 is H, C.sub.1-C.sub.6 alkyl or
--P(O)(OH).sub.2;
[0024] R.sup.19 is 1 to 3 substituents independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, --OH, halogen, --CN, --NO.sub.2, --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.2Rl.sup.2,
--NR.sup.21CONR.sup.2lR.sup.22, --NR.sup.21SO.sub.2R.sup.15 and
--S(O).sub.n5R.sup.15;
[0025] R.sup.20 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl or --(CH.sub.2).sub.n6-heterocycloalkyl
[0026] R.sup.21 and R.sup.22 are 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 together are
C.sub.3-C.sub.6 alkylene and with the nitrogen to which they are
attached form a 4-7 membered ring, or one of the carbon atoms in
the alklyene chain formed by R.sup.21 and R.sup.22 is replaced by a
heteroatom selected from the group consisting of --O--, --S-- and
--NR.sup.12--;
[0027] R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are H,
C.sub.1-C.sub.6 alkyl and can be together as .dbd.O; when
n.sub.5=0, and R.sup.25 and R.sup.26 =H, X is not O, N, S;
[0028] n.sub.3 and n.sub.4 are independently 1-5, provided that the
sum of n.sub.3 and n.sub.4 is 2-6;
[0029] n.sub.5 is independently 0-2;
[0030] n.sub.6 is independently 0-3; and
[0031] q and r are independently 1 or 2.
[0032] Preferred are compounds of formula I wherein R.sup.4 and
R.sup.7 are each H. Also preferred are compounds of formula I
wherein R.sup.1 and R.sup.3 are each H. Also preferred are
compounds of formula I wherein R.sup.1, R.sup.3, R.sup.4 and
R.sup.7 are each H. R.sup.6 is preferably H or --OH. Preferably,
X.sup.1 is --O-- or --NR .sup.2--. Ar.sup.1 and Ar2 are each
preferably R.sup.8, R.sup.9, R.sup.10-phenyl, wherein R.sup.8,
R.sup.9 and R.sup.10 are independently selected. Y is preferably
.dbd.O, and n is preferably 1 or 2. When Y is .dbd.O, x.sup.2 is
preferably --NR.sup.5--. More preferred are compounds of formula I
wherein Q is --X.sup.2--C(.dbd.Y)--NR.sup.4-- (i.e., the first
structure shown in the definition of Q), R.sup.1, R.sup.3, R.sup.4
and R.sup.7 are each H; R.sup.6 is H or --OH; X.sup.1 is --O-- or
--NR.sup.12--; Ar.sup.1 and Ar.sup.2 are each
R.sup.8,R.sup.9,R.sup.10-phenyl; Y is =0 and x.sup.2 is
--NR.sup.5-; n is 1 or 2; R.sup.5 is H or --(CH.sub.2).sub.n1-G, G
is not H when n.sub.1=0; R.sup.19-aryl or R.sup.19-heteroaryl. Most
preferred are compounds of formula I wherein R.sup.5 is H.
[0033] This invention also relates to the use of a compound of
formula I in the treatment of, for example, respiratory diseases
such as chronic lung disease, bronchitis, pneumonia, asthma,
allergy, cough, bronchospasm; inflammatory diseases such as
arthritis and psoriasis; skin disorders such as atopic dermatitis
and contact dermatitis; ophthalmalogical disorders such as
retinitis, ocular hypertension and cataracts; addictions such as
alcohol dependence and psychoactive substance abuse; stress related
disorders such as post tramautic stress disorder;
obsessive/compulsive disorders; eating disorders such as bulemia,
anorexia nervosa and binge eating disorders; mania; premenstrual
syndrome; central nervous system conditions such as anxiety,
general anxiety disorder, panic disorder, phobias, bipolar
disorders, migraine, epilepsy, nociception, emesis, depression,
psychosis, schizophrenia, Alzheimer's disease, AlDs related
dementia and Towne's disease; gastrointestinal disorders such as
Crohn's disease and colitis; nausea; bladder disorders;
atherosclerosis; fibrosing disorders; obesity; Type II diabetes;
pain related disorders such as neuropathic pain, post-operative
pain, headache and chronic pain syndromes; and genitourinary
disorders such as interstitial cystitis and urinary incontinence.
The treatment of mammals, both human and non-human, is
contemplated.
[0034] Further, the invention relates to a method for antagonizing
the effect of Substance P at its receptor site or for the blockade
of neurokinin-1 receptors in a mammal, comprising administering an
amount of a compound of formula I effective to antagonize the
effect of Substance P at its receptor site in a mammal in need of
such treatment.
[0035] In another aspect, the invention relates to a pharmaceutical
composition comprising a compound of formula I in a
pharmaceutically acceptable carrier. The invention also relates to
the use of said pharmaceutical composition in the treatment of the
mammalian disease states listed above.
[0036] The compounds of this invention can be combined with a
selective serotonin reuptake inhibitor (SSRI) (i.e., the compounds
of this invention can be combined with an SSRI in a pharmaceutical
composition, or the compounds of this invention can be administered
with an SSRI.
[0037] 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; fluoxetine, fluvoxamine,
paroxetine and sertaline, and pharmaceutically acceptable salts
thereof. Other compounds can readily be evaluated to determine
their ability to selectively inhibit serotonin reuptake.
[0038] In another aspect, the invention relates to a method of
treating the above diseases and disorders comprising administering
an effective amount of an NK1 antagonist of formula I in
combination with an SSRI described above.
[0039] In another aspect, the invention relates to a method of
treating the above diseases and disorders comprising administering
an effective amount of an NK1 antagonist of formula I in
combination with an SSRI selected from: fluoxetine, fluvoxamine,
paroxetine and sertaline, and pharmaceutically acceptable salts
thereof.
[0040] In another aspect, the invention relates to a method of
treating emesis, depression, anxiety, and cough comprising
administering an effective amount of an NK1 antagonist of formula I
in combination with an SSRI described above.
[0041] In the methods of this invention wherein a combination of an
NK1 antagonist of this invention (compound of formula 1) is
administered with an SSRI described above, the compound of formula
I and SSRI 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 antagonists are administered consecutively or
sequentially, the NK1 antagonist of this invention (compound of
formula I) is administered first.
[0042] Preferred are compounds of formula Ia and Ib 9
[0043] wherein R.sup.8 is H or halogen; R.sup.2 is H, --CH.sub.3 or
--CH.sub.2OH; R.sup.6 is H or --OH; and R.sup.5 is selected from
the group consisting of hydrogen and groups of the formula
--(CH.sub.2).sub.n1-G as follows, 10
[0044] --(CH.sub.2).sub.n1-R.sup.19-heteroaryl, 11 12
[0045] or --(CH.sub.2).sub.n1-G', wherein n, is 2-4 and G' is H,
--OH, --OCH.sub.3--, --OEt, --O(i-Pr), --O-- cyclopropyl, or
--CONR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are
independently selected from the group consisting of H, --CH.sub.3,
Et, i-Pr, or cyclopropyl (Et is ethyl and i-Pr is isopropyl).
[0046] Also preferred are compounds of the formula Ic and Id 13
[0047] wherein X' is --O--, --NH--, --N(CH.sub.3)-- or
--N(COCH.sub.3)--; R.sup.8 is H or halogen; R.sup.2 is H,
--CH.sub.3 or --CH.sub.2OH; R.sup.9 is --OCF.sub.3 or
5-(trifluoromethyl)-1H-tetrazol-1-yl; R.sup.6 is H or --OH;
R.sup.12 is --CH.sub.3 or cyclopropyl; and Rs is selected from the
group consisting of hydrogen and groups of the formula
--(CH.sub.2).sub.n1-G as shown above for structures la and Ib.
[0048] Preferred compounds of the invention are the compounds of
examples 2, 61, 79a, 79b, 92, 93, 126, 127, 128, 129, 165a, 165b,
166a and 166b.
DETAILED DESCRIPTION
[0049] As used herein, the term "alkyl" means straight or branched
alkyl chains. "Lower alkyl" refers to alkyl chains of 1-6 carbon
atoms and, similarly, lower alkoxy refers to alkoxy chains of 1-6
carbon atoms.
[0050] "Cycloalkyl" means cyclic alkyl groups having 3 to 8 carbon
atoms.
[0051] "Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl,
indanyl, anthracenyl or fluorenyl. R.sup.16-aryl and R.sup.19-aryl
refer to such groups wherein substitutable ring carbon atoms have
an R.sup.16 or an R.sup.19 substituent.
[0052] "Halogen" refers to fluoro, chloro, bromo or iodo atoms.
[0053] "Heteroaryl" refers to 5- to 10-membered single or
benzofused aromatic rings comprising 1 to 4 heteroatoms
independently selected from the group consisting of --O--, --S--,
--N.dbd. and --NH--, provided that the rings do not include
adjacent oxygen and/or sulfur atoms. Examples of single-ring
heteroaryl groups are furanyl, imidazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl,
pyrimidyl, pyrrolyi, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,
triazolyl and triazinyl. Examples of benzofused heteroaryl groups
are benzimidazolyl, benzofuranyl, benzo-thiophenyl, benzoxazolyl,
indolyl and quinolyl. N-oxides of nitrogen-containing heteroaryl
groups are also included. All positional isomers are contemplated,
e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl, and when R.sup.4 or
R.sup.5 is heteroaryl, it can be joined to the nitrogen atom of the
"-Q-" group either by a ring carbon or a ring nitrogen.
R.sup.19-heteroaryl refer to such groups wherein substitutable ring
carbon atoms have an R.sup.19 substituent. When R.sup.8, R.sup.9 or
R.sup.10 is heteroaryl, it is preferably tetrazolyl substituted by
H, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl, --CF.sub.3,
--SO.sub.2-(C.sub.1-C.sub.6 alkyl) or --OCF.sub.3.
[0054] "Heterocycloalkyl" refers to a 4- to 7-membered saturated
ring comprising 1 to 3 heteroatoms independently selected from the
group consisting of --O--, --S-- and --NR.sup.21--, wherein
R.sup.21 is H or C.sub.1-C.sub.6 alkyl, and wherein the remaining
ring members are carbon. Where a heterocyclic ring comprises more
than one heteroatom, no rings are formed where there are adjacent
oxygen atoms, adjacent sulfur atoms, or three consecutive
heteroatoms. Examples of heterocyclic rings are tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl,
thiomorpholinyl and piperazinyl.
[0055] In the above definitions, wherein variables R.sup.1 to
R.sup.26 are said to be independently selected from a group of
substituents, we mean that R.sup.1, R.sup.2, R.sup.3, etc., are
independently selected, but also that where an R.sup.8, for
example, occurs more than once in a molecule, those occurrences are
independently selected (e.g., if X.sup.1 is --NR.sup.12-- wherein
R.sup.12 is hydrogen, G can be --COOR.sup.12 wherein R.sup.12 is
methyl). Similarly, R.sup.8, R.sup.9 and R.sup.10 can be
independently selected from a group of substituents, and where more
than one R.sup.8, R.sup.9 or R.sup.10 is other than hydrogen, the
substituents are independently selected; those skilled in the art
will recognize that the size and nature of the substituent(s) will
affect the number of substituents which can be present.
[0056] The "Q" groups are always joined to the rest of the molecule
as shown, i.e., they are attached left-to-right, where --X.sup.2--
or --NR.sup.5-- is attached to the carbon to which R.sup.6 and
R.sup.7 are attached, and --NR.sup.4-- is always attached to the
carbon to which Ar.sup.1 is attached.
[0057] Compounds of formula I can have at least one asymmetrical
carbon atom and all isomers, including diastereomers, enantiomers
and rotational isomers are contemplated as being part of this
invention. The invention includes d and I isomers in both pure form
and in admixture, including racemic mixtures. Isomers can be
prepared using conventional techniques, either by reacting
optically pure or optically enriched starting materials or by
separating isomers of a compound of formula I.
[0058] Those skilled in the art will appreciate that for some
compounds of formula I, one isomer will show greater
pharmacological activity than other isomers.
[0059] Compounds of the invention which have an amino group can
form pharmaceutically acceptable salts with organic and inorganic
acids. Examples of suitable acids for salt formation are
hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic,
malonic, salicylic, malic, fumaric, tartaric, succinic, ascorbic,
maleic, methanesulfonic and other mineral and carboxylic acids well
known to those in the art. The salt is prepared by contacting the
free base form with a sufficient amount of the desired acid to
produce a salt. The free base form may be regenerated by treating
the salt with a suitable dilute aqueous base solution such as
dilute aqueous sodium bicarbonate. The free base form differs from
its respective salt form somewhat in certain physical properties,
such as solubility in polar solvents, but the salt is otherwise
equivalent to its respective free base forms for purposes of the
invention.
[0060] Certain compounds of the invention which are acidic (e.g.,
those compounds which possess a carboxyl group) form
pharmaceutically acceptable salts with inorganic and organic bases.
Examples of such salts are the sodium, potassium, calcium,
aluminum, gold and silver salts. Also included are salts formed
with pharmaceutically acceptable amines such as ammonia, alkyl
amines, hydroxyalkylamines, N-methylglucamine and the like.
[0061] Compounds of formula I can be prepared using methods known
to those skilled in the art. Typical procedures are described
below, although the skilled artisan will recognize that other
procedures may be applicable, and that the procedure may be
suitably modified to prepare other compounds within the scope of
formula I.
[0062] Method 1:
[0063] Compounds of formula I wherein X.sup.1 is --O-- or --S-- and
n is 1 can be prepared by the following method. 14
[0064] An alcohol (3), in which Ar.sup.1 and R.sup.3 are as defined
above is converted to the ketone (2), by reaction with an activated
derivative (1) of the alcohol (4), in which Ar.sup.2, R.sup.1 and
R.sup.2 are as defined above. 15
[0065] This reaction is most favorable when R.sup.1, R.sup.2 and
R.sup.3 are each H but, depending on the leaving group L, it may
work effectively if either R.sup.1, R.sup.2 or R.sup.3 is C1-C6
alkyl. A leaving group, L, of choice is CF.sub.3SO.sub.2-
(triflate) but others also suffice, such as Br or I. The base used
may vary but is preferably one of the hindered non-nucleophilic
kind, of which an example is 2,6-di-tert-butyl-4-methyl
pyridine.
[0066] The alkylating agent (3a) in which L is triflate may be
prepared from the alcohol-type starting material (4) using triflic
anhydride and the same hindered, non-nucleophilic base as is used
for the alkylation.
[0067] The ketone (2) may be used to prepare compounds in which n
is 1, X.sup.2 is --NR.sup.5-- and Y is .dbd.O (5). Reaction of (2)
with a metallic cyanide (e. g. KCN) and (NH.sub.4).sub.2CO.sub.3
results in the formation of the hydantoin, a process well known to
those skilled in the art of organic synthesis: 16
[0068] Selective reduction of the amide carbonyl and not the urea
carbonyl may be accomplished by using a mixture of lithium aluminum
hydride (LAH) and AlCl.sub.3 as a preferred method although other
methods are also available, such as the use of LAH in ether or THF
at or above room temperature, up to the boiling point of the
solution.
[0069] The reaction produces compounds of the invention in which
R.sup.4 and R.sup.5 are both H. Introduction of a substituent,
R.sup.5, may be performed relatively selectively although in some
cases a second substituent R.sup.4 (where R.sup.4.dbd.R.sup.5 in
this case) may be introduced at the same time. Such substitution
reaction at the nitrogen atoms of (5) may be accomplished using one
of many sets of conditions used for such transformations, for
example, use of an organic base, such as triethylamine or Hunig's
Base (di-isopropyl ethylamine) and the appropriate alkylating
agent, L-R.sup.5.
[0070] Reaction of the hydantoin (5) with p-methoxybenzyl chloride
in acetone in the presence of K.sub.2CO.sub.3 and a catalytic
quantity of tetra-n-butylammonium iodide produces the derivative
(5A) which can be readily reduced to a mixture of alcohols (5B) by
use of mild reducing conditions. Suitable reagents are LAH in THF
at 0-30.degree. C. for 1-6 hrs. 17
[0071] Subsequent removal of the PMB protecting group may be
carried out using Ce(NH.sub.4).sub.2 (NO.sub.3).sub.6 (CAN) in a
neutral solvent, preferably a CH.sub.3CN/water mixture. The mixture
of chiral alcohols can frequently be separated and purified by
chiral HPLC, preferably on one of the carbohydrate-based columns,
such as one of the Daicel Chiralcel.RTM. or Chiralpak.RTM. series
of columns.
[0072] Method 2:
[0073] Compounds of formula I wherein X.sup.1 is --O-- or --S-- and
Y is .dbd.O or .dbd.S can be prepared by the following method.
[0074] The ketone (2) may also be made by the following sequence of
reactions. The 15 alcohol (1) may be converted to its alkoxide
anion using a strong base, such as lithium bis(trimethyl
silyl)amide or the like, followed by reaction, in an inert solvent,
such as THF, with the N,O-dimethyl amide of the iodo-acid (7) to
produce (8) which is known as a "Weinreb amide". 18
[0075] Addition of an organometallic derivative of Ar.sup.1 (9)
results in formation of the ketone (2). Suitable organometallic
reagents include the Grignard (M is Mg) or lithium reagent.
Suitable media for this reaction include neutral, non-reactive
solvents such as ether or THF.
(8)+Ar.sup.1--M.fwdarw.(2) (9)
[0076] The ketone (2) may next be reacted with
trimethylsilylcyanide in the presence of a Lewis acid catalyst,
such as Znl.sub.2, and subsequently treated with saturated
NH.sub.3--CH.sub.3OH at ambient temperature to yield an
intermediate which may be reduced directly to diamine (10) using a
powerful hydride reducing agent such as LAH in a neutral solvent
such as THF. 19
[0077] Reaction of the diamine (10) with a reagent known to
introduce a carbonyl between two amines located in the correct
position leads to the cyclic ureas (5) which are compounds of the
invention. Examples of such reagents are COCl.sub.2, carbonyl
diimidazole and methyl or ethyl chloroformate. Subsequent
modification by introduction of R.sup.4 and R.sup.1 groups may be
performed as described in Method 1.
[0078] The reaction described above can also be used to prepare
compounds of the invention in which X.sup.1 is --S-- by employing
the thiol corresponding to the alcohol (4) shown above. In
addition, reagents known to introduce the --C(.dbd.S)-- function
between two appropriately placed nitrogen atoms (such as
thiocarbonyl diimidazole) may be used to prepare compounds in which
Y is .dbd.S.
[0079] A further use of compounds such as 10A is to introduce the
guanidine functions into compounds of the invention. Reacting (10A)
with CH.sub.3 I in a neutral solvent, such as CH.sub.3CN, THF, or a
mixture of the two, produces the S-methyl derivative (10B) which
may then be reacted with an amine, R.sup.11--NH.sub.2, to produce
guanidines (10C) or a tautomer. 20
[0080] The diamine (10) is also a useful intermediate for
preparation of products of the invention in which X.sup.2 is
--NR.sup.5--. The group R.sup.1 is introduced by use of an aldehyde
or ketone precursor of R.sup.1 by a process of reductive amination
(otherwise known as reductive alkylation of the amine (10)). A
proviso of this method is that the R.sup.5 group may not contain a
quaternary carbon atom next to the nitrogen atom. It also cannot be
H, nor certain other of the definitions of R.sup.5.sub.1 for
example, when G is --OH, --OF, --SO.sub.2R.sup.13 or
--NR.sup.13R.sup.14 etc., then n.sub.1 cannot be 0. To describe the
process, the starting material (10D) will be used. By reacting (10)
with (10D) in a neutral solvent, such as 1,2-dichloroethane, in the
presence of a suitable reducing agent (sodium
triacetoxy-borohydride is particularly suitable for this reaction),
and conventional work-up, a product (10E) is formed (R.sup.5 is
--(CH.sub.2).sub.n1-G in which n, is 0 and G is 21
[0081] in which n.sub.3=n.sub.4=2and X=0: 22
[0082] A variable amount of the isomeric structure (10F) (see
above) may also form in this reaction, depending upon the
reactants. It may be separated from (10E) by conventional
chromatographic methods and reacted, as above, to yield compounds
of the invention in which R.sup.4 is the introduced substituent
instead of R.sup.5.
[0083] Reactions with other precursors of the R.sup.5 group are
also possible, as will be evident to one skilled in the arts of
organic and medicinal chemistry. Ring closing of (10E) may be
carried out by direct cyclization to make many of the Q groups of
the invention in which an R.sup.5 group is present and where Y is
=0 or .dbd.S, or compounds wherein Y is =N--R.sup.5 can be made by
the sequence of reactions described earlier for the synthesis of
(10C).
[0084] A further use for the diamine (10) is in the preparation of
compounds of the invention in which Y.sup.1 is as defined above,
except that it is not --NH.sub.2, --NHCH, or --SCH.sub.3. The
diamine (10) may be heated with a carboxylic acid,
Y.sup.1--CO.sub.2H, in a high boiling, neutral solvent, such as
toluene to produce the amidines (10G) of the invention: 23
[0085] Method 3:
[0086] An alcohol (3) may be reacted with an O-substituted
hydroxylamine derivative, preferably methoxylamine to yield the
oxime derivative (11). Conversion of the oxime to the alkoxide may
be performed using a strong base, such as NaH, in a non-hydroxylic
solvent, such as THF. Reaction of this anion with the substituted
alkyl halide (12), in which Hal is preferably I or Br, produces the
oxime-ether (13). 24
[0087] Cleavage of the oxime-ether (13) under acidic conditions,
for instance, using 6N HCI at elevated temperature for 5 to 50
hours results in isolation of the ketone (2).
[0088] Further processing of (2) may be performed as described
above in Method 1.
[0089] Method 4:
[0090] Compounds of formula I wherein X.sup.1 is --O-- and n is 2-4
can be prepared by the following method (only R.sup.6 is shown in
the formulae, but both R.sup.6 and R.sup.7 can be present).
[0091] A diprotected aryl glycine ester, such as (14), in which
"Prot" is a protecting group, preferably benzyl, and "E" is an
ester group, preferably methyl or ethyl, may be converted to its
anion using a strong base, such as lithium diisopropylamide, in an
ether solvent, such as THF, at a temperature of about -78.degree.
C. Reaction of the anion with a halo-nitrile (15), in which "Hal"
is preferably 1, at temperatures between -78.degree. C. and
0.degree. C. results in the protected intermediate (16). 25
[0092] Reduction of the ester and nitrile simultaneously using a
powerful hydride reducing agent, such as LAH, in an inert solvent,
such as THF, at a temperature between about -78.degree. C. and
0.degree. C., produces aminoalcohol (17). 26
[0093] Removal of the protecting groups under standard conditions
(e.g. 20% Pd(OH).sub.2 on active carbon in methanol if "Prot" is
benzyl) yields the di-amine alcohol (18) which may be cyclized
using one of the reagents known to introduce a C.dbd.O, C.dbd.S or
--SO.sub.2-- group between two appropriately placed nitrogen atoms
(e.g. COCl.sub.2;
[0094] carbonyl diimidazole; thiocarbonyl diimidazole, etc.) to
yield (19). 27
[0095] wherein .dbd.Y is .dbd.O or .dbd.S; the thio-urea can be
prepared in a similar manner.
[0096] The alcohol (19) may be converted to a compound of the
invention (20), by reaction of the mono-anion prepared by using a
strong base, such as NaH, with a benzyl halide in the presence of
Ag.sub.2O. "Hal" is as defined above and the solvent is preferably
a polar, non-hydroxylic solvent such as DMF. 28
[0097] Subsequent modification by introduction of R.sup.4 and
R.sup.5 groups may be performed as described in Method 1.
[0098] Method 4a:
[0099] The intermediate (17), above, may also be converted to
compounds of the invention via its di-BOC protected derivative
(21).
[0100] Removal of the original protecting groups (if they are
benzyl groups or similar) by hydrogenolysis in the presence of
(BOC).sub.20 yields the di-BOC derivative (21). 29
[0101] Such intermediates may be converted to the ethers (22) by
reaction with an aryl halide (23), preferably a bromide or iodide.
Use of silver oxide (Ag.sub.2O) as a catalyst and base is
desirable. 30
[0102] Removal of the BOC protecting groups under standard
conditions (e.g. HCl/ether) produces the diamine which may be
cyclized to compounds of the invention using the same reagents as
described earlier in Method 2, e.g. COCl.sub.2, carbonyl
diimidazole, sulfonyl diimidazole, etc.
[0103] Method 5:
[0104] Compounds of the invention in which X.sup.1 is one of the
nitrogen-containing groups may be synthesized from the amino ketone
derivatives (10G), some of which may be commerically available
while others can be synthesized by well-known literature
techniques. Protection of the amino group in (10G), for instance as
its BOC derivative, allows the hydantoin-forming reaction to occur
to produce intermediates (10H) where "Prot" is the
previously-introduced protecting group, e.g. BOC: 31
[0105] Reduction of one of the carbonyl groups preferentially, as
described previously, using the LiALH.sub.4/AlCl.sub.3 mixed
reagents, followed by removal of the protecting group by an
appropriate method (e.g., CF.sub.3CO.sub.2H or HCl if it is BOC)
produces the amine (10I) 32
[0106] Reductive alkylation of the amine group with an aldehyde or
ketone (10J) under conditions described for this transformation
earlier (using sodium triacetoxyborohydride) or using one of the
many published procedures known to carry out this reaction (e.g.
sodium borohydride in an alcohol solvent) results in the amine
(10K) which may be further modified by reactions well known in the
art to produce other compounds of the invention, (10L) and (10M).
33
[0107] Reactive groups not involved in the above processes can be
protected during the reactions with conventional protecting groups
which can be removed by standard procedures after the reaction. The
following Table 1 shows some typical protecting groups:
1TABLE 1 Group to be Group to be Protected and Protected Protecting
Group --COOH --COOalkyl, --COObenzyl, --COOphenyl 34 35 36 37 38 39
40 41 42 --NH.sub.2 43 --OH --OCH.sub.3, --OCH.sub.2OCH.sub.3,
--OSi(CH.sub.3).sub.3, 44 or --OCH.sub.2phenyl
[0108] 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's Pharmaceutical Sciences, 18th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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.
[0113] Preferably the compound is administered orally.
[0114] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0115] The quantity of active compound in a unit dose of
preparation for treatment of respiratory diseases; inflammatory
diseases; skin disorders; ophthalmological disorders; addictions;
stress related disorders; obsessive/compulsive disorders; eating
disorders; mania; premenstrual syndrome; central nervous system
conditions; gastrointestinal disorders; bladder disorders;
atherosclerosis; fibrosing disorders; obesity; Type II diabetes;
pain related disorders; and genitourinary disorders; may be varied
or adjusted from about 1 mg to about 1500 mg, preferably from about
50 mg to about 500 mg, more preferably from about 20 mg to about
200 mg, according to the particular application.
[0116] 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.
[0117] 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 1 mg/day to about 1500 mg/day,
in two to four divided doses.
[0118] Following are examples of preparing compounds of formula 1.
As used herein, RT is room temperature, Me is methyl, Bu is butyl,
Br is bromo, Ac is acetyl, Et is ethyl, Ph is phenyl, THF is
tetrahydrofuran, EtOAc is ethyl acetate, Et.sub.2O is ether, LAH is
lithium aluminum hydride, CDI is 1,1-carbonyl diimidazole; HOBT is
hydroxybenzotriazole; DEC is 1,2-diethylaminoethyl chloride; TFA is
trifluoroacetic acid; Et.sub.3N is triethylamine, MTBE is t-butyl
methyl ether; DAST is diethylaminosulfur trifluoride.
EXAMPLE 1
[0119] 45
[0120] Method 1:
[0121] Step 1: 46
[0122] To a solution of 2-chloro-N-methylacetamide 98% (10.4 g, 74
mmol) in acetone (120 ml), Nal (12.2 g, 81.4 mmol) was added. The
flask was filled with N.sub.2 and covered with aluminum foil. After
stirring at RT for 30 h, the reaction mixture was filtered. The
filtrate was concentrated under vacuum to give a dark brown oil.
The crude product was directly used without further purification in
the next step.
[0123] Step 2: 47
[0124] To a cooled solution of 3,5-bis(trifluoromethyl)benzyl
alcohol (18.06 g, 74 mmol) in anhydrous THF (140 ml) at 0.degree.
C., solid KN(TMS).sub.2 (16.24 g, 81.4 mmol) was added slowly. The
reaction was kept at 0.degree. C. for 1 h. A solution of 2 in
anhydrous THF (60 ml) was then added dropwise into the cooled
solution. The reaction was allowed to gradually warm to RT over
night under a N.sub.2 atmosphere. After quenching with saturated
NH.sub.4Cl, the reaction was made slightly acidic with 1 N HCl and
extracted with EtOAc (200 ml.times.4). The combined organic layer
was washed with brine (200 ml.times.2), dried over MgSO.sub.4,
filtered and concentrated. The crude material was purified by flash
chromatography, eluting with 20% EtOAc in hexane to give 3 as an
oil (12.3 g, 35.6 mmol, 48% yield).
[0125] Step 3: 48
[0126] To a cooled solution of 3 (12.2 g, 35.34 mmol) in anhydrous
THF (150 ml) at -75.degree. C., phenyl lithium (22.58 ml, 40.64
mmol) was added dropwise. The reaction mixture was kept at low
temperature for 1.5 h, then the cold bath was removed and the
reaction was allowed to warm up to RT under N.sub.2 protection. The
reaction was cooled in an ice-water bath and quenched with
saturated NH.sub.4Cl solution (200 ml) using a dropping funnel
followed by neutralizing the aqueous solution to pH 7 with 1 N HCl.
After stirring for 15 min, the mixture was extracted with EtOAc
(200 ml.times.4). The EtOAc extracts were combined, washed with
brine (200 ml.times.2), dried over MgSO.sub.4, filtered and
concentrated to give a brown oil. The crude material was purified
by flash grade silica gel chromatography, eluting with 15% EtOAc in
hexane to give compound 4 (10.7 g, 28.44 mmol) with .about.80%
yield. FAB MS [M+1].sup.+263.1.
[0127] Step 4: 49
[0128] Trimethyl silyl cyanide (0.92 ml, 6.9 mmol) was added to a
flask containing a solution of 4 (2.0 g, 5.52 mmol) in
CH.sub.2Cl.sub.2 (11 ml), cooled with a water bath, followed by
addition of Znl.sub.2 (88 mg, 0.276 mmol). The reaction was
finished in 1 h. The insoluble Znl.sub.2 was filtered off and
rinsed with CH.sub.2CO.sub.2. Evaporation of the solvent yielded a
light yellow oil as crude product which was used in the next step.
50
[0129] The crude material 5 was treated with saturated
NH.sub.3--CH.sub.3OH (10 ml) and heated in an oil bath under
N.sub.2 at 45.degree. C. After 2 h of heating, solid was filtered
off and the filtrate was concentrated to give 5a.
[0130] To a suspension of LAH (0.84 g, 22 mmol) in anhydrous
Et.sub.2O (40 ml) at -78.degree. C., a suspension of 5a in
anhydrous Et.sub.2O (40 ml) was added through an addition funnel
under the protection of N.sub.2. The reaction mixture was stirred
at RT over night. After the reaction was complete, Et.sub.2O (250
ml) was added. The reaction was quenched with saturated
Na.sub.2SO.sub.4 solution and stirred for 2 h. The solid was
filtered off and the filtrate was dried over MgSO.sub.4, filtered
again and treated with 4M HCl in dioxane (3 ml). Evaporation of all
the volatile solvents gave the crude product, which was further
purified on Biotage cartiledge, eluting with 7.5%
NH.sub.40H--CH.sub.3OH (1:9) in 92.5% in CH.sub.2Cl.sub.2 to give 6
as an oil. FAB MS [M+1].sup.+393.1.
[0131] Step 5:
[0132] To a solution of 6 (0.155 g, 0.395 mmol) in anhydrous THF
(12 ml) was added 3 A molecular sieves (200 mg) and 1,1'-carbonyl
diimidazole (76.6 mg, 0.474 mmol). The mixture was stirred at RT
overnight under N.sub.2. Diluted with 200 ml EtOAc, the reaction
mixture was washed with brine (100 ml.times.2), dried over
MgSO.sub.4, filtered and concentrated. The crude material was
purified by flash chromatography, eluting with 5%
NH.sub.40H--CH.sub.3OH(1:9) in 95% CH.sub.2Cl.sub.2, to give the
title compound as a solid with a 97% yield. FAB MS
[M+1].sup.+419.1.
[0133] Method 2:
[0134] Step 1: 51
[0135] A mixture of 3,5-bis(trifluoromethyl)benzyl alcohol (39.9 g,
0.163 mol) and 2,6-di-t-butyl-4-methyl-pyridine (68.56g, 0.33 mol)
was placed in a 2 liter, 3-neck flask and vacuum dried overnight.
To this green mixture was added dry CH.sub.2Cl.sub.2 (600 ml)
(cooled with a water bath), followed by slow addition of
trifluoromethylmethane sulfonic anhydride (50 g, 0.177 mol) through
a dropping funnel under a N.sub.2 atmosphere. After stirring at RT
for 4 h, a solution of 2-hydroxy-acetophone (20.36 g, 0.149 mol) in
dry CH.sub.2Cl.sub.2 (120 ml) was added slowing through a dropping
funnel under N.sub.2. The reaction mixture was stirred at RT for 5
days, then solid was filtered off. The filtrate was washed with
brine (200 ml, 3x), dried (MgSO.sub.4), filtered and concentrated
to give a dark brown oil which was purified with flash grade silica
gel (1 Kg), eluting with 10% EtOAc/hexane. Compound 4 was obtained
as a solid (39.63 g, 0.11 mol, 74% yield).
[0136] Step 2: 52
[0137] A mixture containing compound 4 (39.5 g, 109 mmol), KCN
(10.64g, 163 mmol) and (NH.sub.4).sub.2CO.sub.3 (37.47 g, 380 mmol)
in 50% EtOH/H.sub.2O was heated in an oil bath at 60.degree. C.
under the N.sub.2 atmosphere for 22 h. After cooling, ice-water
(780 ml) was added and the mixture was stirred for 1 h. The white
solid was filtered and rinsed with water. The solid was
crystallized from hot dichloroethane. Pure compound 7 was obtained
as a white solid ( 39g, 90 mmol, 83%).
[0138] To a one-liter round bottom flask (cooled with an ice-water
bath) containing AlCl.sub.3 (24.6g, 186 mmol) was slowly added 1 M
LAH solution in Et.sub.2O (140 ml, 140 mmol) under an N.sub.2
atmosphere. After stirring at 0.degree. C. for 10 min, a solution
of compound 7 (20g, 46.2 mmol) in dry THF (170 ml) was added slowly
to the LAH-AlCl.sub.3 mixture. It was gradually warmed to RT and
stirred at RT for 3 days. After completion, the reaction mixture
was diluted with THF (200 ml) and excess LAH was decomposed with
saturated Na.sub.2SO.sub.4 and 3 N NaOH. The mixture was stirred
for 1 h at RT and solid was filtered off through a celite pad. The
filtrate was dried over MgSO.sub.4, filtered and concentrated to
give the title compound as a foam which was purified on flash
silica gel, eluting with 3.5% (1:9) NH.sub.4OH/CH.sub.3OH in 96.5%
CH.sub.2Cl.sub.2 to give pure title compound (16g, 40 mmol, 87%
yield) as a solid.
[0139] The racemic title compound was separated on a chiral column
by using either a ChiralPak AS (Hexane/IPA (80:20)) or a Chiralcel
OD (CH.sub.3CN) column to give enantiomer A and enantiomer B (mp
138-140.degree. C.). Enantiomer B: HRMS calculated for [M+1]:
C.sub.19H.sub.17F.sub.6N.sub.2O.sub.2 419.1194, Found: 419.1190; C,
H, N analysis: calculated C, 54.57; H, 3.71; N, 6.55; F 27.25
Found: C 54.55; H, 3.89; N, 6.59;F, 27.22; rotation in CH.sub.3OH
[(X].sup.20D=-67.0.degr- ee.
EXAMPLE 2
[0140] 53
[0141] Part A:
[0142] Step 1: 54
[0143] A suspension of 2-bromo-4'-fluoroacetophenone, 8, (30 g,
0.1368 mol) and HCOONa (59.2 g, 0.87 mol) in 85% EtOH (360 ml) was
heated to 80.degree. C. for 5 h. After cooling, it was stirred at
RT over night under N.sub.2. The reaction was stopped by
evaporating off the EtOH, and the residue was redissolved in brine
(500 ml) and extracted with EtOAc (200 ml.times.3). The combined
organic layers were dried (MgSO.sub.4), filtered and concentrated.
The purified product was obtained by triturating the crude material
with CH.sub.2Cl.sub.2, EtOAc and hexane to give 9 as a solid (18 g,
116 mmol, 85% yield).
[0144] Step 2: 55
[0145] To a suspension of 9 (5.0 g, 32.44 mmol) in absolute EtOH
(50 ml), 3A molecular sieves (0.8 g), CH.sub.3NH.sub.2.HCl (4.146
g, 48.67 mmol) and Et.sub.3N (6.77 ml, 48.67 mmol) were added. The
mixture was heated to 85.degree. C. under N.sub.2 for 2.5 h. The
mixture was cooled to RT, the solvent was evaporated under reduced
pressure, and the crude product was redissolved in EtOAc (350 ml).
This organic layer was washed with brine (150 ml.times.3), dried
(MgSO.sub.4), filtered and evaporated to dryness to give 10 as a
solid (13.5 g, 7.36 mmol) in 97% yield.
[0146] Step 3: 56
[0147] To a cooled solution of 10 (12.0 g, 65.5 mmol) in anhydrous
THF (60 ml) (cooled in an ice-water bath) was added 60% NaH in
mineral oil (3.14 g, 78.61 mmol). After stirring at RT for 15 min,
the yellow suspension was treated with a solution of
3,5-bis(trifluoromethyl)benzyl bromide (13.62 ml, 72.05 mmol) in
THF (13.62 ml). TLC indicated that the reaction was complete after
1.5 h at RT. Solvent was evaporated and the residue was redissolved
in EtOAc (200 ml). This solution was washed with brine (50
ml.times.2), dried (MgSO.sub.4), filtered and concentrated to give
11 as an oil (26.5 g, 64.77 mmol, 98% yield) FAB MS
[M+1].sup.+410.1.
[0148] Step 4: 57
[0149] To a solution of 11 (26 g, 63.55 mmol) in dioxane (116 ml)
was added 6N HCl (378 ml, 2.268 mol). The mixture was heated at
100.degree. C. for 2 days. After cooling to RT, the reaction
mixture was poured into ice-cold KOH solution (120 g, 2.142 mol in
240 ml H.sub.20). The products were extracted with CH.sub.2Cl.sub.2
(200 ml.times.3) from aqueous solution, dried (MgSO.sub.4) and
filtered. Solvents were evaporated to give a crude product as a
brown oil. The final product was further purified by flash
chromatography, eluting with 10% EtOAc in hexane to give 12 as a
solid (13.41 g, 35.27 mmol, 55.5% yield).
[0150] Part B:
[0151] Step 1: 58
[0152] To the mixture of 12 (3.23 g, 8.5 mmol) in 1:1 EtOH/H.sub.2O
(20 ml), KCN (0.83 g, 12.8 mmol) and (NH.sub.4).sub.2CO.sub.3 (2.86
g, 29.8 mmol) were added. The mixture was heated to 56.degree. C.
overnight, then cooled to RT. Iced water (60 ml) was added to the
complete go reaction. After 30 min, the solid was filtered off and
rinsed with CH.sub.2Cl.sub.2 to give 13 as a white powdery product
(3.12 g, 82%). FAB MS [M+1].sup.+451.1.
[0153] Step 2:
[0154] To a cooled 3-neck flask containing AlCl.sub.3 (1.4 g, 10.7
mmol) at 0.degree. C., 1 M LAH in Et.sub.2O (8 ml, 8 mmol) was
added dropwise via a syringe. A solution of 13 (1.2 g, 2.67 mmol)
in anhydrous THF (10 ml) was added slowly and the reaction mixture
was allowed to stir at RT overnight. After the reaction was
complete, THF (100 ml) was added and excess LAH was decomposed with
saturated Na.sub.2SO.sub.4 and 4N NaOH. After stirring for 1 h, the
organic layer was separated, dried (MgSO.sub.4), filtered and
concentrated. The crude material was purified by flash silica gel
eluting with 3.5% NH.sub.3--CH.sub.3OH (1:9)/96.5% CH.sub.2Cl.sub.2
to give the title compound as a white foam (0.95 g, 0.22 mmol, 82%
yield). FAB MS [M+1].sup.+437.1.
[0155] The racemic compound was separated with a Chiralcel OD
column, eluting with CH.sub.3CN to give enantiomers A and B. The
enantiomers A and B were reduced separately with LAH-AlCl.sub.3 to
give chiral compounds A and B. Pure chiral B was obtained by
crystallization from hot CH.sub.3CN and hexane. Enantiomer B: HRMS
calculated for [M+1]: C,,H.sub.1,F.sub.7N.sub.2O.sub.2437.1 103,
Found: 437.1 100; C, H, N analysis: calculated C, 52.30; H, 3.46;
N, 6.42; Found: C 52.38; H, 3.42; N, 6.31; rotation in CH.sub.3OH
[uC].sup.20D =-55.7, mp: 130-132.degree. C.
EXAMPLE 3
[0156] 59 60
[0157] To the cooled solution of
3,5-bis(trifluoromethyl)benzaldehyde 14 (15 g, 62 mmol) in
anhydrous Et.sub.2O (100 ml) at 0.degree. C., 3 M CH.sub.3MgBr (25
ml, 75 mmol) was added dropwise. The reaction was kept at 0.degree.
C. for another 2 h, then stirred at RT for 2 h. The reaction was
quenched by pouring into ice cold saturated NH.sub.4Cl. Routine
work-up gave 15 as an off-white solid product (15.4 g). 61
[0158] To the cooled solution of 15 (18.8 g, 72.9 mmol) in
anhydrous THF (100 ml) at 0.degree. C. was added solid
KN(TMS).sub.2 (17.4 g, 87 mmol) portionwise. After stirring at
0.degree. C for 1 h, the potassium salt solution of 15 was added
dropwise to a solution of 2 (17.5 g, 76.4 mmol) in anhydrous THF
(20 ml). The reaction was kept at 0.degree. C. overnight and
quenched with saturated NH.sub.4Cl (300 ml). The aqueous layer was
extracted with CH.sub.2Cl.sub.2 (300 ml.times.3). The combined
organic layer was washed with brine (300 ml), dried (MgSO.sub.4),
filtered and concentrated to a yellow oil (22 g). The crude product
was further purified on silica gel (1:4 EtOAc/hexane) to give 16 as
a pale yellow material (11 g, 31 mmol, 43% yield). 62
[0159] In a cooled flask (ice water bath) containing Mg turnings
(1.12 g, 46.2 mmol) in anhydrous Et.sub.2O (100 ml) was slowly
added 4-bromofluoro-benzene 17 (7.7 g, 44 mmol), followed by a
catalytic amount of 1,2-dibromoethane. After completion of the
addition, the reaction was heated at 80.degree. C. overnight under
a N.sub.2atmosphere. After cooling, a solution of 16 (7.9 g, 22
mmol) in anhydrous Et.sub.2O (40 ml) was added slowly to the
Grignard solution at RT. After reaction was complete, a saturated
NH.sub.4Cl solution was slowly added under a N.sub.2 atmosphere.
The product was extracted from aqueous solution with
CH.sub.2Cl.sub.2, combined, dried (Na.sub.2SO.sub.4), filtered and
evaporated to give 18 as an oil. The crude material was purified on
flash grade silica gel (400 g) eluting with 15% EtOAc/85% hexane to
give 18 (7 g, 1.78 mmol, 87% yield). FAB MS (M+1)+395.0. 63
[0160] Compound 19 was prepared by an analogous method to that of
Example 1 (step 4) using compound 18 in place of compound 4.
[0161] The title compound was prepared by a method analogous to
that described for Example 1 (step 5) using compound 19 in place of
compound 6. Two sets of diastereomers A and B were isolated by
flash silica chromatography at compound 19 stage and these were
cyclized separately to the title compounds with CDl reagent.
Diastereomer A of the title compound, FAB MS [M+1].sup.+451.1265,
calculated [M+1].sup.+451.1257; Diastereomer B of the title
compound, FAB MS [M+1].sup.+451.1261, calculated
[M+1].sup.+451.1257.
EXAMPLE 4
[0162] 64 65
[0163] The title compound was prepared by an analogous method to
that described for Examples 1 and 3 using a-methyl-3,5
-bis(trifluoromethyl)-b- enzyl alcohol in place of
3,5-bis(trifluoromethyl)benzyl alcohol. Two sets of diastereomers
were isolated by flash silica chromatography at compound 21 stage
and cyclized separately to the title compound with CDl reagent.
Diastereomer A of the title compound, FAB MS [M+1].sup.+433.1358,
calculated [M+l]+433.1351; diastereomer B of the title compound,
FAB MS [M+1].sup.+433.1358, calculated [M+1].sup.+433.1351.
EXAMPLE 5
[0164] 66
[0165] To a solution of compound 19 (0.22 g, 0.52 mmol) (prepared
from compound 18 in Example 3) in pyridine (2 ml), sulfamide (50
mg, 0.52 mmol) was added. The mixture was refluxed for 24 h. After
cooling, the reaction was diluted with EtOAc (200 ml), washed with
0.5 N HCl, brine, dried (MgSO4), filtered and concentrated to give
a gum which was further purified on silica gel (1:4 EtOAc/hexane)
to give the title compound as an off-white solid (40 mg, 16%
yield). FAB MS [M+1].sup.+487.3.
EXAMPLE 6
[0166] 67
[0167] A mixture of the product of Example 2 (0.42 g, 0.96 mmol),
toluene (5 ml), CH.sub.3ONa (0.13 g, 2.3 mmol) and
Bu.sub.4NHSO.sub.4 (3.3 mg, 0.01 mmol) was heated to 90.degree. C.
for 1 h. Methyl bromoacetate (0.35 g, 2.3 mmol) was added later.
After stirring at 80.degree. C. for 48 h, the reaction was cooled
to RT and product was extracted from the aqueous layer with
CH.sub.2Cl.sub.2 (50 ml, 3.times.), washed with brine, and the
organic layer was dried (MgSO.sub.4), filtered and concentrated to
give a cloudy gum (0.4 g) which was further chromatographed with 3%
NH.sub.3--CH.sub.3OH (1:9)/97% CH.sub.2Cl.sub.2 to give pure title
compound as a solid (35 mg, 0.07 mmol, 8% yield). Electrospray MS
[M+1].sup.+509.1.
EXAMPLE 7
[0168] 68 69
[0169] To the mixture of 22 (0.205 g, 0.5 mmol) (prepared
analogously to the procedures described for 6 in Example 1) in
dichloroethane (4 ml) were added tetrahydro-4H-pyranone (50 mg, 0.5
mmol) and sodium triacetoxy-borohydride (0.21 mg, 1 mmol). After
stirring overnight at RT, the reaction mixture was worked-up. The
crude product was further purified on silica gel, eluting with 3.5%
[1:9] NH.sub.3--CH.sub.3OH in 96.5% CH.sub.2Cl.sub.2. Compound 23
was obtained as an oil (0.21 g, 0.43 mmol, 84% yield). FAB MS
[M+1].sup.+495.45.
[0170] Step 2:
[0171] A mixture of 23 (0.15 g, 0.303 mmol) and CDl (120 mg, 0.74
mmol) in THF (5 ml) was stirred under a N.sub.2 atmosphere at RT
overnight. After work-up, a gummy material was obtained as a crude
product which was then purified by chromatography, eluting with 2%
NH.sub.3--CH.sub.3OH (1:9)/98% CH.sub.2Cl.sub.2 to give the title
compound as a white foam (0.11 g, 0.22 mmol, 73%). FAB MS
[M+1].sup.+521.2.
EXAMPLE 8
[0172] 70
[0173] The title compound 24 was prepared by an analogous method to
that described for compound 23 in Example 7 using
1-t-butoxylcarbonyl-4-piperi- done in place of
tetrahydro-4H-pyranone. FAB MS [M+1].sup.+594.1.
EXAMPLE 9
[0174] 71
[0175] The title compound was prepared from compound 24 by an
analogous method to that described for the title compound of
Example 7. FAB MS [M+1].sup.+620.2.
EXAMPLE 10
[0176] 72
[0177] A solution of the product of Example 9 (95 mg, 0.153 mmol)
in CH.sub.2Cl.sub.2 (1 ml) was treated with 4M HCl in dioxane (2
ml) for 2 h. The reaction was worked-up by evaporating solvents and
excess HCl. The title compound was obtained as an off-white
salt.
[0178] FAB MS [M+1].sup.+520.3.
EXAMPLE 11
[0179] 73 74
[0180] To a suspension of (R)-(-)-2-phenylglycine methyl ester
hydrochloride salt 25 (10 g, 49.6 mmol) in anhydrous THF (30 ml)
and anhydrous DMF (10 ml) at RT were added Et.sub.3N (22.13 ml,
158.9 mmol) and benzyl bromide (14.74 ml, 123.9 mmol). After 5 h of
heating, the reaction mixture was treated with another equivalent
of benzyl bromide (5.89 ml, 49.6 mmol) and Et.sub.3N (6.9 ml, 49.6
mmol). The solution was heated at 80.degree. C. under a N.sub.2
atmosphere overnight. Additional benzyl bromide (6.9 ml, 49.6 mmol)
was added next day and heating continued at 80.degree. C. overnight
to complete the reaction. After completion, the reaction mixture
was cooled to RT, and poured into a separatory funnel containing
NaHCO.sub.3 solution and EtOAc. The aqueous layer was extracted
with EtOAc (200 ml.times.3). The combined organic layer was washed
with brine (300 ml), dried over MgSO.sub.4, filtered and
concentrated. Crude product was purified by chromatography (3%
EtOAc in hexane) to give 26 as an oil (0.8.36 g, 22.62 mmol, 46% of
yield). Electrospray MS [M+1].sup.+346.1. 75
[0181] To a cooled solution of 26 (18 g, 52.11 mmol) in anhydrous
THF (125 ml) at -78.degree. C., a 2M LDA (32.6 ml, 65.2 mmol)
solution in THF/n-heptane was added slowly. The reaction mixture
was kept at this low temperature for another 2 h under a N.sub.2
atmosphere, then treated with 95% ICH.sub.2CN (4.97 ml, 65.2 mmol)
dropwise through a syringe. The reaction was stirred at -78.degree.
C. for 4 h and -20.degree. C. overnight. A mixture of chilled
saturated aqueous NH.sub.4Cl solution was added to quench the
reaction. The separated aqueous layer was extracted with EtOAc (200
ml.times.3). The combined organic layers were washed with brine
(300 ml), dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by flash chromatography (15% EtOAc in hexane)
to afford 27 as an oil (10.24 g, 51.2%). Electrospray MS
[M+1].sup.+385.1.
[0182] To a solution of 27 (6.0 g, 15.6 mmol) in anhydrous THF (100
ml) was added 1 M LAH in THF (100ml, 100 mmol) slowly at
-78.degree. C. under a N.sub.2 atmosphere. The reaction mixture was
let to stir from -78.degree. C. to RT overnight. After completion,
the reaction was diluted with THF (100 ml) and quenched (cooled in
an ice-bath) with a Na.sub.2SO.sub.4 saturated aqueous solution
slowly through a dropping funnel. The mixture was stirred at RT for
1 h, then filtered and concentrated. The crude product was
triturated with CH.sub.3OH and EtOAc and filtered. The solid (2.24
g) was the desired pure compound. The filtrate was further purified
by flash grade silica gel, eluting with 6% NH.sub.40H--CH.sub.3OH
(1:9)/94% CH.sub.2Cl.sub.2 to give compound 28 (1.3 g) as a solid
with a total yield of 64%. 76
[0183] To a solution of 28 (1.27 g, 3.523 mmol) in CH.sub.3QH (150
ml) was added t-BOC anhydride (1.8 g, 8.24 mmol) and 20%
Pd(OH).sub.2 on carbon (0.254 g). The mixture was hydrogenolyzed at
50 psi in a Parr Shaker overnight. After completion, excess
catalyst was filtered and rinsed with CH.sub.3OH. Solvent was
concentrated and gave the crude product 29, which was further
purified on flash grade of silica gel, eluting with 5%
NH.sub.3--CH.sub.3OH (1:9) in 95% CH.sub.2Cl.sub.2to give 29 as a
white solid (1.14 g, 2.99 mmol) with a 85% of yield. Electrospray
MS [M+1].sup.+381.1. 77
[0184] To a solution of 29 (2.4 g, 6.306 mmol) (from another batch)
in anhydrous DMF (20 ml) was added 4 A molecular sieves (1 g),
3,5-bis(trifluoromethyl)benzyl bromide (1.736 ml, 9.459 mmol) and
Ag.sub.2O (2.998 g, 12.61 mmol) under a N.sub.2 atmosphere. The
reaction was stirred at RT in the dark overnight. EtOAc (300 ml)
was added, and the mixture was washed with brine (100 ml.times.2),
dried over MgSO.sub.4, filtered and evaporated to give 30 as a
yellow oil. It was purified by chromatography, eluting with 0.75%
NH.sub.3--CH.sub.3OH (1:9)/99.5% CH.sub.2Cl.sub.2 to give 30 as a
solid (2.4 g, 3.95 mmol, 63% yield). Electrospray MS
[M+1].sup.+607.1. 78
[0185] To a solution of 30 (1.38 g, 2.27 mmol) in CH.sub.2Cl.sub.2
(8.5 ml) was added 2N HCl/Et.sub.2O (8.5 ml, 17 mmol). The solution
was stirred at RT overnight under a N.sub.2 atmosphere. After the
reaction was complete, all solvents were evaporated to give
compound 31 as a solid. Crude yield: 1.08 g, 99.6%.
[0186] Step 6:
[0187] To a suspension of 31 (1.07 g, 2.233 mmol) in anhydrous THF
(30 ml) was added 4 A molecular sieves (1.0 g), Et.sub.3N (0.653
ml, 4.69 mmol) and CDl (0.434 g, 2.679 mmol) at 0.degree. C. The
reaction mixture was stirred at ambient temperature overnight under
a N.sub.2 atmosphere. After completion, the reaction mixture was
evaporated and the residue was partitioned between EtOAc and water
(300 ml). The organic layer was combined and washed with brine (50
ml.times.3), dried over MgSO.sub.4, filtered and concentrated to
give a clear oil of the title compound. The crude product was
further purified on flash grade silica gel, eluting with 5%
NH.sub.4 0H-MeOH (1:9)/95 % CH.sub.2Cl.sub.2 to give the title
compound as a solid (0.46 g, 1.06 mmol) in a 48% of yield.
Electrospray MS [M+1].sup.+433.1.
EXAMPLE 12
[0188] 79 80
[0189] To a cooled solution of 31 (0.5 g, 1.044 mmol) in CH.sub.3OH
(14.65 ml) was added Et.sub.3N (0.29 ml, 2.088 mmol),
Na.sub.2SO.sub.4 (200 mg) and tetrahydro-4H-pyran-4-one (98 .mu.l,
1.044 mmol) at 0.degree. C. under N.sub.2 atmosphere. After 1 h,
NaBH.sub.3CN (103.5 mg, 1.566 mmol) and HOAc (125.6 .mu.l, 2.088
mmol) were added. The reaction was stirred at 0.degree. C. for 3 h
and 1 N NaOH was added until solution reached pH=1 0. The volatile
solvent was evaporated in vacuo. The residue was redissolved in
CH.sub.2Cl.sub.2 (300 ml) and washed with aqueous mixture of
saturated NaHCO.sub.3-NaCl--H.sub.20. The combined organic layer
was dried over MgSO.sub.4, filtered and evaporated to give 32 as an
oil. The crude product was passed through 50 g of flash grade
silica gel, eluting with 5% NH.sub.3--CH.sub.3OH (1:9) I 95%
CH.sub.2Cl.sub.2 to give 32 as an oil (0.28 g, 0.57 mmol, 55%).
Part of this material (100 mg) was redisolved in CH.sub.2Cl.sub.2
and two equivalents of HCl-ether solution was added. After stirring
for 10 min, solvents were evaporated to give HCl salt of compound
32 as a solid. Electrospray MS [M+1].sup.+491.1.
[0190] Step 2:
[0191] To a solution of 32 (180 mg, 0.367 mmol) in anhydrous THF
(7.0 ml) was added 4A molecular sieves (300 mg) and CDl (71.4 mg,
0.44 mmol). The reaction mixture was stirred at RT for over 50 h. A
small amount of NaHCO.sub.3 solution was added to quench the
reaction. The cloudy mixture was diluted with EtOAc (200 ml). The
organic layer was washed with brine (50 ml.times.3), dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified on 30 g of flash grade silica gel, eluting with 5%
NH.sub.3--CH.sub.3OH (1:9)/95% CH.sub.2CO.sub.2 to give the title
compound as a solid (0.118 g, 0.23 mmol, 63%). FAB MS
[M+1].sup.+517.1.
EXAMPLE 13
[0192] 81
[0193] To a cooled solution of the product of Example 11 (0.36 g,
0.832 mmol) in anhydrous DMF (2 ml) at 0.degree. C. was added 60%
NaH (40 mg, 0.998 mmol) in mineral oil. After stirring 30 min,
methylbromo acetate (88 1l, 0.915 mmol) was added. The reaction was
stirred at 0.degree. C. to RT overnight under a N.sub.2 atmosphere.
EtOAc (300 ml) was added and the mixture was washed with brine (100
ml.times.3), dried over MgSO.sub.4, filtered and concentrated to
give a crude material. It was separated on flash grade silica gel
(50 g), eluting with 5% NH.sub.3--CH.sub.3OH (1:9) in 95%
CH.sub.2Cl.sub.2 to give the title compound as a gummy oil (15 mg,
0.029 mmol, 3.5%). Electrospray MS [M+1].sup.+505.1.
EXAMPLE 14
[0194] 82
[0195] Compound 33 was prepared by an analogous method to that
described in Examples 8 and 9 using compound 31 as starting
material in place of compound 22. Electrospray MS
[M+1].sup.+616.1.
[0196] To a solution of 33 (328 mg, 0.533 mmol) in CH.sub.2Cl.sub.2
(2.66 ml) was added 2N HCl-Et.sub.2O (2.66 ml, 5.33 mmol). The
reaction mixture was stirred at RT for 18 h under a N.sub.2
atmosphere. Crude title compound was obtained by evaporating off
the solvents and used directly in the following step. FAB MS
[M+1].sup.+516.1.
EXAMPLE 15
[0197] 83
[0198] To a solution of the product of Example 14 (110 mg, 0.199
mmol) in anhydrous CH.sub.2Cl.sub.2 (2.2 ml) was added Et.sub.3N
(61 Hl, 0.438 mmol), followed by the addition of HOAc (12 tl, 0.2
mmol), HOBT (27 mg, 0.2 mmol) and DEC (46 mg, 0.24 mmol). The
reaction mixture was stirred at RT for 3 h under a N.sub.2
atmosphere. After completion, CH.sub.2Cl.sub.2 (200 ml) was added
and the reaction mixture was washed with brine (50 ml.times.2),
dried over MgSO.sub.4, filtered and evaporated to give the title
compound as a foam. The crude material was purified on flash grade
silica gel, eluting with 5% NH.sub.4OH/CH.sub.3OH (1:9)/95%
CH.sub.2Cl.sub.2to afford the title compound as a white solid (90
mg, 0.16 mmol, 81%). Electrospray MS [M+1].sup.+558.1.
EXAMPLE 16
[0199] 84
[0200] The title compound was prepared by an analogous method to
that described in Example 13 using 4-chloromethyl-3,
5-dimethyl-isoxazole in place of methylbromo acetate and 60% NaH in
mineral oil (1.5 equivalent). Electrospray MS [M+1].sup.+542.1.
EXAMPLE 17
[0201] 85 86
[0202] The title compound and compound 34 were prepared by a method
analogous to that described in Examples 12 using
1-methyl-4-piperidone in place of tetrahydro-4H-pyran-4-one.
Electrospray MS [M+l]+530.1.
EXAMPLE 18
[0203] 87 88
[0204] To a solution of 35 (14.8 g, 86.23 mmol) and Et.sub.3N (36
ml, 258.69 mmol) in CH.sub.2Cl.sub.2 (200 ml), (BOC).sub.2O (20.70
g, 94.85 mmol) was added at RT. Stirred for 18 h, the reaction was
stopped by diluting with CH.sub.2Cl.sub.2 (100 ml) and transferred
into a separatory funnel. The organic mixture was washed with water
(100 ml.times.2), dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give a light yellow solid 36 (20 g, 85 mmol, 99% ).
This crude product was used without purification in the following
step. 89
[0205] In a flask containing 36 (20.28 g, 86.195 mmol),
(NH.sub.4).sub.2CO.sub.3 (28.99 g, 301.68 mmol) and KCN (8.42 g,
129.29 mmol) was added a (1:1) mixture of EtOH and water (180 ml).
The mixture was heated to 56.degree. C. under N.sub.2 atmosphere
for 48 h. The reaction was cooled with an ice bath and then the
precipitate was filtered off. The residue was rinsed with water,
then hexane, and air dried to give 37 as a white solid (20 g). The
filtrate was diluted with EtOAc (500 ml ) and the organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The solid was triturated with Et.sub.2O then CH.sub.2Cl.sub.2, and
dried in air to give additional 37 (4.8 g) as a solid (total 24.8
g, 81.2 mmol, 94%). 90
[0206] To a 3-neck flask equipped with a N.sub.2 inlet was added
AlCl.sub.3 (10.48 g, 78.60 mmol). An ice-bath was placed under the
flask. A solution of 1 M LAH in Et.sub.2O (59 ml, 59 mmol) was
added dropwise to the cooled flask. After 10 min, a solution of
hydantoin 37 (6 g, 19.65 mmol) in anhydrous THF (100 ml) was added
to the reaction mixture slowly. The reaction was kept at 0.degree.
C. for additional 15 min then gradually warmed up to RT overnight.
In a cooling bath, the reaction was carefully quenched with water
(3 ml), followed by 15% NaOH (3 ml) and water (9 ml) under an
atmosphere of N.sub.2. Stirred for 15 min, the reaction mixture was
filtered and rinsed with EtOAc, the THF. The filtrate was
transferred to a separatory funnel containing water (50 ml). The
organic layer was separated, dried over Na.sub.2SO.sub.4, filtered,
and concentrated to give 38 as a white solid (4.5 g, 15.44 mmol,
79%). The crude product was used without further purification. FAB
MS [M+1].sup.+292.1. 91
[0207] To a solution of 38 (0.9 g, 3.09 mmol) in CH.sub.3OH (20
ml), a 4 N HCl (8 ml, 31 mmol) solution in dioxane was added. After
stirring at RT for 2 h, the reaction was stopped by evaporating off
the volatile solvents. CH.sub.3OH was added twice with subsequent
evaporation. A white foam (0.65 g, 2.85 mmol, 92% yield) was
obtained as crude product, which was used directly in the following
step. 92
[0208] To a solution of alcohol 40 (0.5 g, 2.43 mmol) in dioxane
(2.5 ml), water (0.15 ml) was added, followed by Cs.sub.2CO.sub.3
(3.96 g, 12.15 mmol) and CH.sub.3l (0.45 ml, 7.29 mmol). The
mixture was heated to 72.degree. C. in a sealed tube for 3 h. The
reaction mixture was then cooled to RT and concentrated. The
residue was flashed through silica gel, eluting with 40% EtOAc/
hexane. Compound 41 was obtained as an oil (0.52 g, 2.36 mmol, 97%
yield).
[0209] Step 6:
[0210] To a solution of 39 (0.28 g, 1.23 mmol) in (9:1) of
trifluoroethanol/Et.sub.3N (10 ml), aldehyde 41 (0.27 g, 1.23 mmol)
was added, followed by 3 A molecular sieves (1.5 g) and sodium
triacetoxyborohydride (0.91 g, 4.31 mmol). This turbid reaction was
made clear by adding dichloroethane (15 ml). After 18 h, the
reaction mixture was filtered and rinsed with EtOAc (200 ml) and
CH.sub.3OH (200 ml). The combined filtrate was concentrated. The
residue was redissolved in EtOAc (250 ml) and washed with saturated
NaHCO.sub.3 (100 ml). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude material was
purified on flash silica gel, eluting with EtOAc /Et.sub.3N (9:1)
to give the title compound as an oil (0.3 g, 0.76 mmol, 62% yield),
FAB MS [M+1].sup.+396.1. The compound was treated with one
equivalent of 1 N HCl-Et.sub.2O solution and isolated as a HCl
salt.
EXAMPLE 19
[0211] 93 94
[0212] To a solution of triphenyl phosphine (99.5 g, 379.43 mmol)
in CCl.sub.4 (51 ml), Et.sub.3N (16.98 ml, 121.80 mmol) and
trifluoro acetic acid, 42, (7.8 ml, 101.08 mmol) were added. After
stirring at 0.degree. C. for 10 min, a solution of p-anisidine 43
(15 g, 121.80 mmol) in CCl.sub.4 (51 ml) was added. The reaction
mixture was refluxed for 3 h. Cooled down to RT, the reaction
mixture was filtered and rinsed 10 with hexane until there was no
yellow color filtered off. The filtrate was concentrated and the
brown residue was distilled at 110.degree. C. to give the desired
product 44 (17 g, 71.55 mmol, 59% yield) as a yellow oil. 95
[0213] To a solution of compound 44 (7 g, 29.46 mmol) in AcOH (110
ml) was added NaN.sub.3 (6.13 g, 94.27 mmol). The reaction mixture
was heated at 70.degree. C. overnight.
[0214] After cooling to RT, the reaction mixture was filtered and
the filtrate was diluted with CH.sub.2Cl.sub.2 (200 ml) and washed
with saturated NaHCO.sub.3 (100 ml) solution, water (100 ml) and
dried over Na.sub.2SO.sub.4, filtered and concentrated. Compound 45
(7 g, 28.67 mmol, 98% yield) was obtained and used directly without
further purification. 96
[0215] To the flask containing compound 45 (15 g, 61.43 mmol) and
AcOH (100 ml) was added 48% aqueous HBr (100 ml). The reaction
mixture was heated to 100.degree. C. for 48 h. After cooling to RT,
the reaction mixture was concentrated to half of its volume on the
rotary evaporator and extracted with EtOAc (200 ml.times.2). The
combined organic layer was washed with water (150 ml.times.3),
dried over Na.sub.2SO.sub.4, filtered and concentrated to give 46
(8.0 g, 34.76 mmol, 57% yield) which was used without further
purification. 97
[0216] To the solution of phenol 46 (4 g, 17.39 mmol) in TFA (40
ml) was added hexamethylene tetramine (11.2 g, 79.89 mmol). The
reaction mixture was heated at 70.degree. C. under a N.sub.2
atmosphere for 48 h. Cooled to RT, the reaction mixture was poured
into 2 N H.sub.2SO.sub.4 (100 ml). This mixture was then extracted
with EtOAc (200 ml, 2.times.), dried over Na.sub.2SO.sub.4,
filtered and concentrated to give compound 47 (3.4 g, 13.17 mmol,
76% yield) as a crude product which was used in the next step
directly.
[0217] Compound 47 (3.4 g, 13.17 mmol) was dissolved in anhydrous
DMF (20 ml). To this solution was added K.sub.2CO.sub.3 (3.6 g,
26.34 mmol) and CH.sub.3I (1.7 ml, 26.34 mmol). The reaction
mixture was stirred at RT for 3 h and then poured into a separatory
funnel containing water (125 ml) and EtOAc (250 ml). The organic
layer was washed with water (100 ml.times.2), brine (100 ml) and
concentrated. The crude product was apurified by flash silica gel,
eluting with hexane/EtOAc (9:1) to give 48 as a white solid (3 g,
1.02 mmol, 84%)
[0218] Step 5:
[0219] To a solution of hydrochloride salt of 39 (0.25 g, 1.098
mmol), a (9:1) mixture of trifluoroethanol/Et.sub.3N (20 ml) and
aldehyde 48 (0.3 g, 1.098 mmol) was added followed by 3A molecular
sieves (1.5 g). The reaction mixture was stirred under N.sub.2
protection for 0.5 h before sodium triacetoxy borohydride (0.81 g,
3.83 mmol) was added. After 18 h of stirring, the reaction was
filtered and rinsed with a (1:1) mixture of CH.sub.3OH/EtOAc (200
ml). The filtrate was concentrated and purified with flash grade
silica gel, eluting with EtOAc/Et.sub.3N (9:1) to give the title
compound (0.3 g, 0.67 mmol, 61% yield) FAB MS [M+1].sup.+448.1. The
compound was treated with one equivalent of 1 N HCl-Et.sub.2O
solution and isolated as a HCl salt.
EXAMPLE 20
[0220] 98 99
[0221] To the solution of hydantoin compound 7 (0.1 g, 0.23 mmol)
(Example 1, method 2) in anhydrous DMF (1 ml), K.sub.2CO.sub.3 (45
mg, 0.322 mmol) was added. After stirring at RT for 25 min,
CH.sub.3I (29 pl, 0.46 mmol) was added. After stirring at RT
overnight, the reaction mixture was quenched by pouring into EtOAc
(100ml). The organic layer was washed with a saturated
K.sub.2CO.sub.3 (100 ml.times.2) solution, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatography (EtOAc/hexane 1:4) to give
compound 49 as a solid (67 mg, 0.17 mmol, 74% yield). FAB MS
[M+1].sup.+447.1.
[0222] Step 2:
[0223] To a 2-neck flask containing AlCl.sub.3 (0.37 g, 2.77 mmol),
1 M LAH(2.07 ml, 2.07 mmol) in Et.sub.2O was added slowly. Stirred
for a few minutes, a solution of hydantoin 49 (0.31 g, 0.69 mmol)
in anhydrous Et.sub.2O (5 ml) was added to the white suspension.
The reaction mixture was left at RT for 48 h and quenched by adding
water (1 ml), dropwise, followed by 15% NaOH (1 ml). The white
precipitate was filtered and rinsed with EtOAc. The filtrate was
washed with brine (50 ml), dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude product was purified by flash
chromatography (2% CH.sub.3OH in CH.sub.2Cl.sub.2) and the title
compound was isolated as a solid (0.22 g, 0.51 mmol, 74% yield).
FAB MS [M+1].sup.+433.1.
EXAMPLE 21
[0224] 100
[0225] To the mixture of the compound of Example 18 (0.05 g, 0.126
mmol) in CH.sub.2Cl.sub.2 (2 ml), Et.sub.3N (35 pl, 0.252 mmol) and
CH.sub.3COCl (18 ,l, 0.252 mmol) were added. The reaction mixture
was left at RT overnight and flashed through silica gel, eluting
with EtOAc/Et.sub.3N (9:1), to give the title compound as a foam
(35 mg, 0.075 mmol, 60% yield).
[0226] FAB MS [M+1].sup.+438.1.
EXAMPLE 22
[0227] 101 102
[0228] To the solution of 37 (2 g, 6.55 mmol) in anhydrous DMF (12
ml), K.sub.2CO.sub.3 (1.27 g, 9.19 mmol) was added. After stirring
at RT for 0.5 h, CH.sub.3I (0.82 ml, 13.17 mmol) was added. After
stirring at RT overnight, the reaction was diluted with EtOAc (150
ml) and washed with water (100 ml.times.2), dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give a white solid
as the crude 50. The crude material was further purified on the
flash grade silica gel, eluting with 20% EtOAc in hexane to give
pure 50 as a solid (1.88 g, 5.89 mmol, 90% yield).
[0229] To a cooled flask containing AlCl.sub.3 (3.14 g, 23.55 mmol)
at 0.degree. C., 1M solution of LAH in anhydrous THF (18 ml 18
mmol) was added slowly. The resulting white slurry was treated with
a solution of hydantoin 50 (1.88 g, 5.89 mmol) in anhydrous THF (40
ml). The reaction mixture was stirred at RT for 3 days. Water (2
ml) was added carefully to quench the remaining reactants, followed
by 15% NaOH (2 ml) and water (6 ml). The mixture was then poured
into a separatory funnel containing EtOAc (200 ml), and the organic
layer was washed with water (100 ml.times.2), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product 51
(1.28 g, 4.19 mmol, 72% yield) was used directly in the next step.
103
[0230] The mixture of BOC compound 51 (1.28 g, 4.19 mmol) in 4 M
HCl solution of dioxane (25 ml, 100 mmol) was stirred at RT for 18
h. After completion, all solvents were evaporated off and the
residue was dried by azotropical distillation with CH.sub.3OH
twice. The foamy crude product 52 (0.1 g, 0.487 mmol) was dissolved
in a solution of CF.sub.3CH.sub.2OH/Et.sub.3N 9:1 (10 ml). To this
clear solution, aldehyde 41 (0.107 g, 0.487 mmol) was added,
followed by 3A molecular sieves (0.7 g). After stirring at RT for
45 min, NaBH(OAc).sub.3 (0.36 g, 1.7 mmol) was added. The reaction
was stirred overnight at RT. After reaction was complete, the
mixture was filtered and washed with CH.sub.3OH and EtOAc.
Evaporation of all solvents gave the title compound as a crude
product which was further purified by silica gel chromatography
with EtOAc/hexane (1:1) as eluting solvents to give the title
compound (80 mg, 0.195 mmol, 40%) as an oil. FAB MS
[M+1].sup.+410.1.
[0231] The compound was treated with one equivalent of 1 N
HCl-Et.sub.2O solution and isolated as the HCl salt.
EXAMPLE 23
[0232] 104 105
[0233] A solution of the alcohol 53 (10 g, 81.2 mmol) in anhydrous
DMF (50 ml) was cooled to .sup.0.degree. C. and treated with 60%
NaH (3.6 g, 89.3 mmol) in mineral oil portionwise. The cooling bath
was removed after 30 min and the reaction was stirred at RT for 2
h. The reaction mixture was cooled again to 0.degree. C. and then
treated with bromide 54. After stirring for 4 h, the reaction was
quenched by pouring into EtOAc (250 ml). The organic mixture was
washed with water (200 ml, .times.4), brine (50 ml), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified on a Biotage 75S column, eluting with hexane/EtOAc (5:1)
to give 55 ( 22.2 g, 63.6 mmol, 78% yield). Electrospray MS
[M+1].sup.+350.1. 106
[0234] A solution of 55 (10 g, 28.6 mmol) in CH.sub.2Cl.sub.2 (50
ml) was treated with MCPBA (6.2 g, 28.6 mmol). After 2 h,
additional 2 g of MCPBA was added abd the mixture was stirred for 6
h. The mixture was poured into EtOAc (250 ml) and washed with
saturated aqueous Na.sub.2S.sub.2O.sub.3 (200 ml), saturated
aqueous NaHCO.sub.3 (200 ml), and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the N-oxide 56
as a lightly colored solid (10.18 g, 27.9 mmol, 97.5% yield).
Electrospray MS [M+l]+366.1. 107
[0235] A mixture of N-oxide 56 (6.0 g, 16.43 mmol) and
trifluoroacetic anhydride (17.3 g, 82. 2 mmol) in CH.sub.2Cl.sub.2
(75 ml) was heated under reflux for 4 h and then stirred at RT
overnight. The reaction mixture was concentrated in vacuo. The
residue was dissolved in THF (40 ml) and saturated aqueous
NaHCO.sub.3 was added until gas no longer evolved. EtOAc (200 ml)
and brine (200 ml) were added and the organic phase was separated.
The aqueous phase was extracted with EtOAc (150 ml, .times.2). The
combined organic layers were washed with brine (200 ml), dried over
Na.sub.2SO.sub.4, filtered and concentrated to give a crude orange
oil, which was further purified on the Biotage column, eluting with
hexane/EtOAc ( 4:1) to give 57 (4.11 g, 11.26 mmol, 68.5% yield).
Electrospray MS [M+1].sup.+366.9. 108
[0236] CH.sub.2Cl.sub.2 (100 ml) was added to a solution of alcohol
57 (4.11 g, 11.25 mmol) in warm DMSO (11 ml). The solution was
cooled to 0.degree. C. and P.sub.20.sub.5 (6.39 g, 22.5 mmol) was
then added portionwise over 30 min, followed by addition of
Et.sub.3N (6.3 ml, 45 mmol). The reaction mixture was stirred at RT
for 18 h, then quenched with saturated aqueous NaHCO.sub.3. The
aqueous layer was extracted with EtOAc (200 ml, .times.3). The
combined organic phases were washed with brine (200 ml), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
triturated with hexane to give a light tan powder as desired
product. The filtrate was further purified on the Biotage column,
eluting with hexane/EtOAc (4:1) to give 58 as tan solid (2.46 g,
6.74 mmol, 60.25%). Electrospray MS [M+1].sup.+364.1. 109
[0237] A suspension of ketone 58 (2.30 g, 6.30 mmol) in a mixture
of (1:1) water/EtOAc (30 ml) was treated with
(NH.sub.4).sub.2CO.sub.3 (2.12 g, 22.1 mmol) followed by KCN(0.62
g, 9.5 mmol). The solution was heated to 60.degree. C. and stirred
overnight. After cooling to RT, the reaction mixture was taken up
in EtOAc (100 ml) and washed with water (1 00ml.times.2). The
separated organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The crude product was purified on a
Biotage column, eluting with hexane/EtOAc (1:1) to give the desired
product 59 as a white solid ( 2.03 g, 4.69 mmol,. 74.5% yield).
Electrospray MS [M+1].sup.+434.1.
[0238] Step 6:
[0239] To a cooled flask containing AlCl.sub.3 (614 mg, 4.6 mmol)
at 0.degree. C., a 1M solution of LAH in Et.sub.2O (3.5 ml, 3.5
mmol) was added dropwise. 10 min later, a solution of hydantoin 59
(500 mg, 1.15 mmol) in anhydrous THF (10 ml) was added slowly.
After 25 min at 0.degree. C., the reaction was complete as
determined by TLC. Water (3 ml) was added slowly to the reaction
mixture, followed by 15% NaOH (3 ml) and water (9 ml). After
stirring at RT for 15 min, the emulsion was filtered and rinsed
with EtOAc and THF. The filtrate was washed with water (50 ml),
dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude
product was purified on the Biotage column, eluting with
EtOAc/Et.sub.3N (9:1) to give the title compound as a solid (0.229
g, 0.546 mmol, 47.5% yield). Electrospray MS [M+1].sup.+420.1.
EXAMPLE 24
[0240] 110
[0241] The title compound was prepared by a similar method to that
described in Example 23, Step 2, using the cyclic urea, 56, of
Example 23 in place of ether 55. Yield was 67.1%. Electrospray MS
[M+1].sup.+436.1.
EXAMPLE 25
[0242] 111 112
[0243] To the flask containing compound 13 (1.35 g, 3 mmol) in
acetone (45 ml), 4-(2-chloroethyl)morpholine hydrochloride salt,
60, (0.614 g, 3.3 mmol) was added, followed by KI (0.1 g, 0.6 mmol)
and K.sub.2CO.sub.3 (1.24 g, 9 mmol). The reaction mixture was
heated to reflux for 44 h. After cooling to RT, EtOAc (60 ml) was
added and the organic mixture was washed with water (20 ml), dried
over MgSO.sub.4, filtered and concentrated to give 61 as an oil.
The crude product was further purified on a silica gel column,
eluting with 20% EtOAc/CH.sub.2Cl.sub.2to give 61 (1.3 g, 2.3 mmol,
76% of yield).
[0244] Step 2:
[0245] To a cooled flask containing AlCl.sub.3 (0.35 g, 2.63 mmol)
at 0.degree. C. under a N.sub.2 atmosphere, 1 M solution of LAH in
Et.sub.2O (2.0 ml, 2.0 mmol) was added dropwise. Stirred for 5 min,
a solution of 61 (0.37 g, 0.66 mmol) in anhydrous THF (10 ml) was
added slowly. The reaction mixture was allowed to stir from
0.degree. C. to RT over the weekend and quenched with 20% NaOH (1
ml). The solids were filtered and rinsed well with CH.sub.2Cl.sub.2
after stirring for 15 min. The filtrate was concentrated and
purified on flash grade silica gel, eluting with 5% CH.sub.3OH in
CH.sub.2CO.sub.2 to give the title compound as a white foam (70 mg,
0.13 mmol, 20% of yield). High Resolution MS: [M+1]+measured
566.1899, calculated 566.1890.
EXAMPLE 26
[0246] 113
[0247] To a cooled flask containing AlCl.sub.3 (1.23 g, 9.24 mmol)
at 0.degree. C. under N.sub.2 atmosphere, 1 M solution of LAH in
Et.sub.2O (7.0 ml, 7.0 mmol) was added dropwise. Stirred for 5 min,
a solution of 61 (1.3 g, 2.3 mmol) in anhydrous THF (25 ml) was
added slowly. The reaction mixture was allowed to stir at 0.degree.
C. for 15 min then heated at 70.degree. C. for 64 h. The reaction
was quenched with 20% NaOH (2 ml) and stirred at RT for 15 min. The
solids were filtered and rinsed well with CH.sub.2Cl.sub.2. The
filtrate was concentrated and purified on flash grade silica gel,
eluting with 5% CH.sub.3OH in CH.sub.2Cl.sub.2 to give the title
compound as a gummy solid (0.46 g, 0.8 mmol, 36% yield). High
Resolution MS: [M+1]+measured 550.1948, calculated 550.1941.
EXAMPLE 27
[0248] 114
[0249] Compound 62 was prepared in a similar method as described in
Example 25 using 2-chlorethyl-1-piperidine in place of
4-(2-chloroethyl)-morpholine. A mixture of Ex. 27A and Ex. 27B was
separated by flash column chromatography, eluting with 2.about.5%
CH.sub.3OH in CH.sub.2Cl.sub.2 to afford Ex. 27A (33% yield) (FAB
MS [M+l]+564) and Ex. 27B (43% yield) FAB MS [M+1].sup.+549.
EXAMPLE 28
[0250] 115
[0251] The title compound was prepared by an analogous method to
that described in Example 16 using the compound of Example 1 in
place of the compound of Example 11 to give the title compound in a
22% yield.
[0252] FAB MS [M+1].sup.+546.3.
EXAMPLE 29
[0253] 116
[0254] The title compound was prepared by analogous methods as
described for Examples 1 and 2, except for the preparation of
ketone intermediate 66. Compound 66 was prepared by treatment of
compound 64 (24.1 g, 98.8 mmol) and 2, 6-di-t-butyl-4-methyl
pyridine (42 g, 206 mmol) in dry CH.sub.2Cl.sub.2 (400 ml) at
0.degree. C. with slow addition of trifluoromethyl-methane sulfonic
anhydride (30 g, 107 mmol) under a N.sub.2 atmosphere. After
stirring at RT for 1 h, a solution of compound 64 (14 g, 82.3 mmol)
in CH.sub.2Cl.sub.2 (200 ml) was added dropwise. After stirring at
RT for 6 days, the solid was filtered and filtrate was washed with
brine, dried (MgSO.sub.4), filtered and concentrated to give a
crude 66 as a brown oil. Compound 66 was obtained by purification
through a flash grade silica gel, eluting with 8% EtOAc/hexane to
give 66 as an oil (19.5 g, 50 mmol, 61% of yield). Compound 67 was
synthesized from compound 66 with a 60% of yield and title compound
was prepared from 67 by selective reduction with AlCl.sub.3-LAH in
a 52% yield. FAB MS [M+1].sup.+467.
EXAMPLE 30
[0255] 117
[0256] The title compound was prepared by a method analogous to
that described in Example 7 by using compound 22 and replacing
tetrahydro-4H-pyranone with 1-methyl-4-piperidone. HRMS [M+1].sup.+
calculated, 534.1992; found, 534.1987.
EXAMPLE 31
[0257] 118
[0258] To a solution of the product of Example 10 (0.2 g, 0.36
mmol) in dichloroethane (3 ml) and acetone (21mg, 0.36 mmole) at RT
was added Na(OAc).sub.3BH (0.15 g, 0.72 mmol). The mixture was
stirred at RT for two days under a N.sub.2 atmosphere. After
completion, to the reaction was added CH.sub.2Cl.sub.2 (50 ml) and
saturated NaHCO.sub.3 solution, followed by routine work-up to give
a crude product. Product was purified on flash grade silica gel,
eluting with 3% NH.sub.4QH--CH.sub.3OH (1 :9)/ 97% CH.sub.2Cl.sub.2
to afford pure title compound as a solid (0.12 g, 0.22 mmol) in a
62% of yield. FAB MS [M+1].sup.+562.4.
EXAMPLE 32
[0259] 119
[0260] The title compound was prepared by a method analogous to
that described in Example 25 for compound 61 in step 1, using
compound 7 in place of compound 13 and N, N-dimethyaminoethyl
chloride hydrochloride in place of 1-(2-chloro-ethyl)-morpholine
hydrochloride. The title compound was obtained as a solid in a 96%
yield. Electrospray MS [M+1].sup.+504.1.
EXAMPLE 33
[0261] 120
[0262] Reduction of the compound from Example 32 with
LAH-ALCl.sub.3 complex, analogous to the method described in
Example 26, gave the title compound in a 32% yield. Electrospray MS
[M+1].sup.+490.1.
EXAMPLE 34
[0263] 121
[0264] The title compound was prepared by an analogous method to
that described in Example 25, Step 1, using
1-(2-chloroethyl)pyrrolidine HCl salt in place of
1-(2-chloroethyl)-morpholine hydrochloride salt. The title compound
was obtained as a solid in a 77% yield. Electrospray MS
[M+1].sup.+548.1.
EXAMPLE 35
[0265] 122
[0266] Reduction of compound the product of Example 34 with
LAH-ALCl.sub.3 complex as described in Example 26, heating at
70.degree. C. for 1 day, gave the title compound in a 36% yield.
Electrospray MS [M+1].sup.+550.1
EXAMPLE 36
[0267] 123
[0268] Reduction of the product of Example 34 with LAH-ALCl.sub.3
complex at 70.degree. C. for 1 day, analogous to the method as
described in Example 26, gave the title compound in a 11% yield.
Electrospray MS [M+1].sup.+534.1.
EXAMPLE 37
[0269] 124
[0270] The title compound was prepared by an analogous method to
that described in Example 25, Step 1, using 2-dimethylamine ethyl
chloride hydrochloride salt in place of
1-(2-chloroethyl)-morpholine hydrochloride salt. The title compound
was obtained as a solid in a 83% of yield. Electrospray MS
[M+1].sup.+522.1.
EXAMPLE 38
[0271] 125
[0272] Reduction of the product of Example 37 with LAH-ALCl.sub.3
complex at 70.degree. C. for 1 day, analogous to the method
described in Example 26, gave the title compound in a 26% yield.
Electrospray MS [M+1].sup.+524.1
EXAMPLE 39
[0273] 126
[0274] Reduction of the product of Example 38 with LAH-ALCl.sub.3
complex at 70.degree. C. for 1 day, analogous to the method
described in Example 26, gave the title compound in a 15% yield.
Electrospray MS [M+1].sup.+508.1.
EXAMPLE 40
[0275] 127
[0276] The title compound was prepared by an analogous method to
that described in Example 25, Step 1, using
3-chloropropyl-morpholine in place of 1-(2-chloroethyl)-morpholine
hydrochloride. The title compound was obtained as a solid in a 57%
yield. FAB MS [M+1].sup.+578.1.
EXAMPLE 41
[0277] 128
[0278] Reduction of t he compound from Example 40 with LAH-ALC t3
complex, analogous to the meth od as described in Example 26, gave
the title compound in a 9% yield. Electrospray MS
[M+1].sup.+564.1.
EXAMPLE 42
[0279] 129
[0280] The titl e compound was prepared by an analogous method to
that described in Example 25, Step 1, using N.
N-dimethylaminopropyl chloride HCl in place of
1-(2-chloroethyl)-morpholine hydrochloride. The title compound was
obtained as a solid in a 69% yield. FAB MS [M+1].sup.+536.1.
EXAMPLE 43
[0281] 130
[0282] Reduction of the compound from Example 42 with
LAH-ALCl.sub.3 complex, analogoust tithe method as described in
Example 26, gave the title compound in a 1.5% yield. Electrospray
MS [M+l]+522.3.
EXAMPLE 44
[0283] 131
[0284] The title compound was prepared by an analogous method to
that described in Example 25, Step 1, using bromomethyl
cyclopropane replacing 1-(2-chloroethyl)-morpholine hydrochloride.
The title compound was obtained as a solid in a 94% of yield. FAB
MS [M+1].sup.+505.1.
EXAMPLE 45
[0285] 132
[0286] Reduction of the compound from Example 44 with
LAH-ALCl.sub.3 complex, analogous to the method as described in
Example 26, gave the title compound in a 57% yield. Electrospray MS
[M+1].sup.+491.1.
EXAMPLE 46
[0287] 133
[0288] The title compound was prepared by an analogous method to
that described in Example 25, Step 1, using compound 7 in place of
compound 13. The title compound was obtained as a solid in a 90%
yield. FAB MS [M+1].sup.+546.1.
EXAMPLE 47
[0289] 134
[0290] Reduction of the compound from Example 46 with
LAH-ALCl.sub.3 complex, analogous to the method as described in
Example 26, gave the title compound in a 67% yield. Electrospray MS
[M+1].sup.+532.1.
EXAMPLE 48
[0291] 135
[0292] The title compound was prepared by an analogous method to
that described in Example 25, Step 1, using compound 7 in place of
compound 13 and 1-(2-chloro-ethyl)-piperidine hydrochloride in
place of 1-(2-chloroethyl)-morpholine hydrochloride. The title
compound was obtained as a solid in a 90% yield. FAB MS
[M+1].sup.+544.3.
EXAMPLE 49
[0293] 136
[0294] Reduction of the compound from Example 48 with
LAH-ALCl.sub.3 complex, analogous to the method as described for
Example 26, gave the title compound in a 52% yield. Electrospray MS
[M+1].sup.+530.1.
EXAMPLE 50
[0295] 137
[0296] The title compound was prepared by an analogous method to
that described in Example 25, Step 1, using compound 7 in place of
compound 13 and 1-(2-chloroethyl)-pyrrolidine hydrochloride in
place of 1-(2-chloroethyl)-morpholine hydrochloride. The title
compound was obtained as a solid in a 76% yield. Electrospray MS
[M+1].sup.+530.1.
EXAMPLE 51
[0297] 138
[0298] Reduction of the compound from Example 50 with
LAH-ALCl.sub.3 complex, analogous to the method as described in
Example 26, gave the title compound in a 65% yield. Electrospray MS
[M+1].sup.+516.1.
EXAMPLE 52
[0299] 139
[0300] The title compound was prepared by a method analogous to
Example 42, using 7 in place of 13. Reduction of the resulting
hydantoin with LAH/AlCl.sub.3 complex, analogous to the method
described in Example 26, gave the title compound in 8% yield. FAB
MS [M+1] 504.1.
EXAMPLE 53
[0301] 140
[0302] The title compound was prepared by a method analogous to
that described in Example 7, using N-methylpiperidone in place of
tetrahydro-4H-pyranone. The title compound was obtained as a solid
in a 28% yield. FAB MS [M+1] 534.
EXAMPLE 54
[0303] 141
[0304] A solution of the product of Example 10 (0.3 g, 0.54 mmol)
in CH.sub.2Cl.sub.2 (3 ml), N, N-diisopropylethylamine (0.24 g, 1.9
mmol), and 1-(2-chloroethyl)pyrrolidine hydrochloride (92 mg, 0.54
mmol) was stirred under an atmosphere of N.sub.2 at RT for 14 days.
After work-up, a cloudy gum was obtained as a crude product which
was purified by chromatography, eluting with 4.5%
NH.sub.3--CH.sub.3OH (1:9)/95.5% CH.sub.2Cl.sub.2 to give the title
compound as an off-white solid (20 mg, 7% ). FAB MS [M+1]
617.1.
EXAMPLE 55
[0305] 142
[0306] The title compound was prepared by a method analogous to
Example 54, using 4-(2-chloroethyl)morpholine in place of
1-(2-chloroethyl)pyrrol- idine. The title compound was obtained as
a solid in a 35% yield. FAB MS [M+1] 633.3.
EXAMPLE 56
[0307] 143
[0308] A solution of the product of Example 10 (0.2 g, 0.36 mmol)
in 1,2-dichloroethane (3 ml), acetone (21 mg, 0.36 mmol), and
Na(OAc).sub.3BH (0.15 g, 0.72 mmol) was stirred under N.sub.2
atmosphere at RT for 2 days. After work-up, a solid was obtained as
a crude product which was then purified by chromatography, eluting
with 3% NH.sub.3--CH.sub.3OH (1:9)/97% CH.sub.2Cl.sub.2 to give the
title compound as a white solid (120 mg, 60%). FAB MS [M+1]
562.4.
EXAMPLE 57
[0309] 144
[0310] The title compound was prepared by a method analogous to
Example 10, using 6 in place of 22. The title compound was obtained
as a HCl salt, FAB MS [M+1] 502.1.
EXAMPLE 58
[0311] 145
[0312] A solution of the product of Example 57 (0.3 g, 0.56 mmol)
in CH.sub.2Cl.sub.2 (3 ml), N, 20 N-diisopropylethylamine (0.14 g,
1.12 mmol), and CH.sub.3I (71 mg, 0.5 mmol) was stirred under
N.sub.2 atmosphere at 0.degree. C. for 2 h. After work-up, a solid
was obtained as a crude product which was then purified by
chromatography, eluting with 3.5% NH.sub.3--CH.sub.3OH (1:9)/96.5%
CH.sub.2Cl.sub.2 to give the title compound as a white solid (90
mg, 36%). FAB MS [M+1] 516.1.
EXAMPLE 59
[0313] 146
[0314] The title compound was prepared by a method analogous to
Example 56, using the product of Example 57 in place of Example 10.
The title compound was obtained as a solid in a 52% yield. FAB MS
[M+1] 544.2.
EXAMPLE 60
[0315] 147
[0316] The title compound was prepared by a method analogous to
Example 15, using Example 57 in place of Example 14. The title
compound was obtained as a solid in a 80% yield. FAB MS [M+1]
544.1.
EXAMPLE 61
[0317] 148 149
[0318] To a cooled solution of (S)-N-tBoc-4-fluoro-phenyl glycine
in anhydrous CH.sub.2Cl.sub.2 at 0.degree. C., HOBT (3.66 g, 22.4
mmol), Et.sub.3N (3.12 ml, 22.4 mmol), DEC (4.29 g, 22.4 mmol) and
2M CH.sub.3NH.sub.2 in THF (10.23 ml, 20.46 mmol) were added. After
stirring at 0.degree. C. for 30 min, the reaction mixture was
gradually warmed up to RT under N.sub.2 protection over night.
Diluted with CH.sub.2Cl.sub.2 (300 ml), the reaction mixture was
washed with 10% citric acid (2.times.100 ml), saturated
NaHCO.sub.3--NaCl solution (2.times.100 ml), brine (1.times.100
ml). The combined organic layer was dried over MgSO.sub.4, filtered
and concentrated in vacuo to give crude 69 (4.88 g). 150
[0319] To a cooled solution of 69 (24.3 g, 86 mmol) in
CH.sub.2Cl.sub.2 (58.8 ml) and CH.sub.3OH (30 ml) at 0.degree. C.
was added 4M HCl-dioxane solution (200 ml, 800 mmol). The clear
solution was kept at 0.degree. C. for 2.5 hours. Solvent was
evaporated and the solid material was taken up with distilled water
(200 ml), neutralized with NaOH (3.4 g) in water (100 ml). Final pH
was adjusted to 9.5 with K.sub.2CO.sub.3. This aqueous solution was
extracted with CH.sub.2Cl.sub.2 (4.times.250 ml). The combined
organic layer was dried over MgSO.sub.4, filtered and concentrated
in vacuo to give a white solid which further turned into a pale
yellow solid 70. (14.9 g, 96%). 151
[0320] A mixture of compound 70 (14.84 g, 81.5 mmol), pentane (85
ml) and pivaldehyde (11.13 ml, 101.88 mmol) was heated to
65.degree. C. with a Dean-Stark trap for 2.5 hours under N.sub.2.
The reaction mixture was then concentrated and the crude oil was
taken up with CH.sub.3OH (22.5 ml), cooled down to 0.degree. C.,
and the crude product was treated with saturated HCl--CH.sub.3OH
(52.5 ml) through a dropping funnel over 20 min. and stirred at
ambient temperature over night. Volatile solvent was again
evaporated and the residue was suspended in a mixture of brine (100
ml) and 2% K.sub.2CO.sub.3 solution (150 ml). This basic solution
(pH=9.5) was extracted with CH.sub.2Cl.sub.2 (4.times.200 ml) and
the combined organic layer was dried over MgSO.sub.4, filtered and
concentrated in vacuo . The crude product (20 g) was purified on a
silica gel column, eluting with 25% EtOAc in hexane (4 l), 30%
EtOAc in hexane (4 l) to give compound 71 (11.67 g, 58%) as an
oil.
[0321] Step 4: 152
[0322] To a cooled solution of 71 (11.5 g, 46.08 mmol) in freshly
distilled degassed THF (62 ml) and anhydrous degassed toluene (192
ml) at -78.degree. C., 0.5M KHMDS (97 ml, 48.5 mmol) in toluene was
added slowly over 10 min through an addition funnel. The solution
was stirred at -78.degree. C. for 40 min before 72 (17 g, 49 mmol)
was added via a syringe. Kept stirring at this low temperature for
another 2.5 hours, the reaction was quenched with saturated
NH.sub.4Cl solution (350 ml). The separated aqueous layer was
extracted with CH.sub.2Cl.sub.2 (3.times.200 ml). The combined
organic layer was dried over MgSO.sub.4, filtered and concentrated.
The crude product was further purified by flash chromatography,
eluting with 15% EtOAc in hexane (6 I), 20% EtOAc in hexane (4 l).
73 was obtained as an oil (13.06 g, 56%). 153
[0323] A mixture of 73 (12.55 g, 24.2 mmol) and 6N HCl (132 ml) was
heated to 100.degree. C. under N.sub.2 for 4 h. After cooling to
RT, volatile solvent was evaporated. The gummy material was
redissolved in 2.5% K.sub.2CO.sub.3 solution (300 ml) and brine
(100 ml). The aqueous solution was extracted with CH.sub.2Cl.sub.2
(4.times.250 ml). The combined organic layer was dried over
MgSO.sub.4, filtered and concentrated in vacuo to give a gummy
material (10.9 g) which was purified on a silica gel column,
eluting with 20% EtOAc in hexane then 1.5% NH.sub.3--CH.sub.3OH in
CH.sub.2Cl.sub.2. 74 was obtained as an oil (8.45 g, 78%). 154
[0324] To a cooled solution of 74 (7.5 g, 16.6 mmol) in anhydrous
CH.sub.2Cl.sub.2 (85 ml) at 0.degree. C. was added ClSO.sub.2NCO
(1.45 ml, 16.6 mmol) using a syringe. After stirring for 20 min,
the reaction was finished and the solvent was evaporated. Taken up
with 1,4-dioxane (70 ml) and 4N HCl (70 ml), the reaction mixture
was then heated up to 95.degree. C. under N.sub.2 for 4.5 hours.
TLC showed completed reaction. Evaporation of volatile solvents
yielded crude gummy material, which was taken up with 2.5%
K.sub.2CO.sub.3 solution (300 ml) and CH.sub.2Cl.sub.2 (200 ml).
The aqueous solution was extracted with CH.sub.2Cl.sub.2
(4.times.200 ml). The combined organic layer was dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatography, eluting with 3.5% (1:9)
NH.sub.4QH--CH.sub.3OH in CH.sub.2CO.sub.2 to give 75 as a solid
(6.88 g, 90%).
[0325] Step 7:
[0326] To a cooled flask containing AlCl.sub.3 (4.3 g, 32.16 mmol)
was added LAH (24.12 ml, 24.12 mmol) at 0.degree. C. under N.sub.2.
After 15 min, a solution of 75 (3.73 g, 8.04 mmol) in anhydrous THF
(126 ml) was added through a syringe. The reaction mixture was
stirred at 0.degree. C. for 10 min before warming up to RT. After 4
h, the reaction was quenched with saturated Na.sub.2SO.sub.4
solution (10 ml) in an ice-bath. Diluted with THF (200 ml) and
stirred for 1 h at RT, the reaction was dried over MgSO.sub.4,
filtered and concentrated to give crude 76 (3.5 g), which was
purified by flash chromatography eluting with 1%
NH.sub.4OH/CH.sub.3OH (1:9) in CH.sub.2CO.sub.2. mp 136-137.degree.
C., FABMS [M+1].sup.+451.1; [.alpha.].sub.D20.degree.
C.-49.4.degree. C.
EXAMPLE 62
[0327] 155
[0328] The title compound was prepared by a method analogous to
step 7 of Example 61, using compound 74 in place of compound 75.
FAB MS [M+1].sup.+439.1.
EXAMPLE 63
[0329] 156
[0330] To a solution of Example 62 (180 mg, 0.41 mmol) in dioxane
(4 ml), sulfamide (48.5 mg, 0.51 mmol) was added. After heating to
110.degree. C. for 5 h, the reaction was concentrated. The residue
was purified by flash chromatography, eluting with 4%
NH.sub.4OH:CH.sub.3OH(1:9) in CH.sub.2Cl.sub.2. The title compound
was collected as off-white solid (35 mg, 17%). FAB MS
[M+1].sup.+518.1.
EXAMPLE 64
[0331] 157
[0332] To a cooled solution of NaH (27 mg, 0.67 mmol) in anhydrous
DMF (5 ml), was added compound 76 from Example 61 (0.25 g, 0.56
mmol) at 0.degree. C. After 15 min, the cold bath was removed. The
reaction was warmed to RT for 45 min before p-methoxy
benzyl-chloride (0.08 ml, 0.59 mmol) was added. The reaction was
then stirred at RT for another 2 h. Water was used to quench the
reaction and the aqueous solution was extracted with EtOAc. The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated. Crude material was purified through a silica gel
column, eluting with 2:1 hexane to EtOAc to give the title compound
as a solid (86.8 mg, 27%). FAB MS [M+1].sup.+571.1.
EXAMPLE 65
[0333] 158
[0334] The title compound was prepared by a method analogous to
Example 64, using bromo acetamide in place of p-methoxy benzyl
chloride. FAB MS [M+1].sup.+508.1.
EXAMPLE 66
[0335] 159
[0336] To a cooled solution of 76 (0.2 g, 0.44 mmol) in anhydrous
CH.sub.2Cl.sub.2 (4.2 ml) at 0.degree. C., diethylisopropylamine
(0.12 ml, 0.69 mmol) was added dropwise followed by
CH.sub.3SO.sub.2Cl (0.04 ml, 0.52 mmol). The reaction was warmed to
RT and stirred overnight. The volatile solvent was evaporated and
the crude product was purified on a silica gel column, eluting with
4% CH.sub.3OH (saturated with NH.sub.3) in CH.sub.2Cl.sub.2. FAB MS
[M+1].sup.+529.1.
EXAMPLE 67
[0337] 160
[0338] The title compound was prepared by methods analogous to
Example 1, method 1, step 5, using the compound of Example 62 in
place of 6. The title compound was obtained as a solid in a 51%
yield. Electrospray MS [M+l]+465.1.
EXAMPLE 68
[0339] 161
[0340] To a solution of compound of Example 67 (0.31 g, 0.64 mmol)
in anhydrous THF (12.8 ml) at RT, CH.sub.3I (0.09 ml, 1.28 mmol)
was added. The reaction mixture was stirred under N.sub.2 for 5 h.
Evaporation of the solvent gave a yellow foam, which was further
purified by flash chromatography eluting with 7.5% CH.sub.3OH
(saturated with NH.sub.3) in CH.sub.2Cl.sub.2. Electrospray MS
[M+1].sup.+504.
EXAMPLE 69
[0341] 162
[0342] The title compound was prepared by a method analogous to
Example 25, step 1, using 75 in place of 13 and 2-bromoethyl methyl
ether in place of 4-(2-chloroethyl)-morpholine hydrochloride salt.
The title compound was obtained in a 61% yield. Electrospray MS
[M+1].sup.+505.1.
EXAMPLE 70
[0343] 163
[0344] Reduction of the product of Example 69 with LAH-AlCl.sub.3
complex at RT overnight, analogous to the method described in
Example 26, gave the title compound 78 as a clear oil and compound
79 as a crystalline solid after separation of crude product using
3% CH.sub.3OH(NH.sub.3) in CH.sub.2Cl.sub.2. Electrospray MS:
compound 78, MS [M+1].sup.+491.1 and compound 79, MS
[M+1].sup.+507.4.
EXAMPLE 71
[0345] 164
[0346] The title compound was prepared by analogous methods to that
described in Examples 61, Step 7 and 62, using the phenyl analog in
place of 74 in Example 62. The title compound was obtained as an
oil. MS [M+1].sup.+407.1.
EXAMPLE 72
[0347] 165
[0348] The title compound was prepared in a method analogous to
Example 63, using Example 71 in place of the compound of Example
62. The title compound was obtained as an oil in 44% yield. NMR
(CDCl.sub.3) 1.45 (d, 3H), 2.38 (s, 3H), 3.87 (d, 1 H), 3.27 (d,
1H), 3.45 (d, 1 H), 3.55(d, 1H), 4.55 (q, 3H), and aromatic protons
(7.3-0.7.4, 7.58, 7.78).
EXAMPLE 73
[0349] 166 167
[0350] To a solution of compound 6 (1.85 g, 3.97 mmol) in dry THF
(30 ml) was added Et.sub.3N (0.6 ml, 4.3 mmol), 4 A molecular sieve
(3 g) and thiocarbonyl diimidazole (1.179 g, 5.95 mmol). The
mixture was stirred at 0.degree. C. under N.sub.2 for 20 h. After
completion, molecular sieve was filtered off and THF evaporated.
The residue was redissolved in EtOAc (300 ml), washed with 0.04 N
HCl (50 ml, 2X), dried (MgSO.sub.4), filtered and evaporated. Pure
80 was obtained as a solid (1.41 g, 3.25 mmol) in 82% yield by
flash silica chromatography (50 g), eluting with 5% (1:9)
[NH.sub.4OH/CH.sub.3OH]/95% CH.sub.2Cl.sub.2. 168
[0351] To a solution of 80 (0.75 g, 1.73 mmol) in CH.sub.3CN and
THF (6 ml) was added CH.sub.3I (0.13 ml, 2.1 mmol). The solution
was stirred at RT overnight under an atmosphere of N.sub.2. After
completion, solvent was evaporated and the product used in the next
step without further purification.
[0352] Step 3
[0353] 81 (150 mg, 0.334 mmol) was treated with 2 M
NH.sub.3--CH.sub.3OH solution (1 ml). The solution was stirred in a
vial with a sealed cap for 5 days. After completion, solvent was
evaporated and product was purified by flash silica gel (50 g),
eluting with 5% (1:9) NH.sub.4OH- CH.sub.3OH/95% CH.sub.2Cl.sub.2.
LCMS [M+1].sup.+418.1.
EXAMPLE 74
[0354] 169
[0355] The title compound was prepared in a method analogous to
Example 73, step 3, using 2M NH.sub.2CH.sub.3 in place of 2M
NH.sub.3. Product was purified on flash silica gel (50 g), eluting
with 5% (1:9) NH.sub.4OH- CH.sub.3OH/95% CH.sub.2Cl.sub.2. LCMS
[M+1].sup.+432.1.
EXAMPLE 75
[0356] 170
[0357] To a solution of 83 (0.4 g, 0.96 mmol) in anhydrous DMF (2
ml) was added 60% NaH (46.4 mg, 1.16 mmol) under N.sub.2. After 20
min, 2-bromoacetamide (163.3 mg, 1.16 mmol) was added. The reaction
was stopped by evaporating off the DMF after 20 h. The residue was
redissolved in EtOAc (200 ml) and washed with brine (2.times.50
ml). The separated organic layer was dried over MgSO.sub.4,
filtered and concentrated in vacuo. Crude material was purified by
flash silica chromatography, eluting with 4.5% (1:9)
NH.sub.4OH--CH.sub.3OH in 96.5% CH.sub.2Cl.sub.2 to give the title
compound 84 in a 25% yield. Electrospray MS [M+1].sup.+476.1.
EXAMPLE 76
[0358] 171
[0359] To a flask containing Example 71 (0.2 g, 0.48 mmol) and
molecular sieves (0.18 g) in anhydrous toluene (4.5 ml), glacial
acetic acid (0.3 ml, 5.24 mmol) was added. The reaction mixture was
heated to 100.degree. C. for 48 h. Cooled down to RT, the reaction
was worked up by pouring into a separatory funnel containing EtOAc
and saturated NaHCO.sub.3. The aqueous layer was extracted with
EtOAc (2.times.50 ml). The combined organic layer was washed with
brine (50 ml), dried over Na.sub.2SO.sub.4, filtered and
concentrated. The title compound 85 was obtained by purifying
through flash chromatography, eluting with 20% EtOAc in hexane.
Yield: 43%. Electrospray MS [M+1].sup.+445.1.
EXAMPLE 77
[0360] 172
[0361] The title compound was prepared in a method analogous to
Example 76, using propanoic acid in place of glacial acetic acid.
The title compound was obtained in a 25% yield. Electrospray MS
[M+1].sup.+459.1.
EXAMPLE 78
[0362] 173
[0363] The title compound was prepared by a method analogous to
Example 1, Method 1, Step 5, using Example 62 in place of 6.
Purification by flash silica chromatography, using 5% (1
:9)[NH.sub.4OH/CH.sub.3OH]/95% CH.sub.2Cl.sub.2 gave the title
compound as a solid with a yield of 51%. LCMS [M+1
].sup.+465.1.
EXAMPLE 79
[0364] 174 175
[0365] A solution of 74 (1.8 g, 4 mmol) in 1.4-dioxane (17 ml) and
4-methoxybenzyl-isocyanate (98 mg, 6 mmol) was stirred under
N.sub.2 at RT for 4 h. The mixture was mixed with 10% aqueous HCl
in dioxane (17 ml), then heated to 90.degree. C. for 5.5 h. After
work-up, a solid was obtained as a crude product which was then
purified by chromatography, eluting with 15% EtOAc/85% hexane to
give 86 as a white solid (1.8 g, 82%). FAB MS [M+1] 584. 176
[0366] A mixture of 86 (1.7 g, 2.91 mmol) in THF (10 ml) and
LiAlH.sub.4 (1M in ether, 3.3 ml, 3.2 mmol ) was stirred under
N.sub.2 at 0C for 30 min., then RT for 3 h. After work-up, a solid
was obtained as a crude product which was then purified by
chromatography, eluting with 2% NH.sub.3--CH.sub.3OH (1 :9)/98%
CH.sub.2Cl.sub.2 to give 87 as a white solid (1.54 g, 91%). FAB MS
[M+1] 587.4.
[0367] Step 3:
[0368] A mixture of 87 (1.48 g, 2.53 mmol) in CH.sub.3CN (33
ml)/H.sub.2O (10 ml) and Ce(NH.sub.4).sub.2(NO.sub.3).sub.6 (5.54
g, 10.1 mmol) was stirred under N.sub.2 at RT for 50 min. After
work-up, an oil was obtained as a crude product which was then
purified by chiral HPLC (Chiralpak.RTM. AD), to give the title
compounds, examples 79a and 79b,as a white solid (0.19 g, 16%). FAB
MS [M+1] 467.1.
EXAMPLE 80
[0369] 177
[0370] Example 80
[0371] 89 was prepared by a method analogous to Examples 61 and 62,
using s-(+)-2-phenylglycine methyl ester hydrochloride in place of
(s)-N-BOC-4-fluorophenyl-glycine in Example 61. A mixture of 89
(2.03 g, 5 mmol) in THF (6 ml) and
1,1'-thiocarbonyidiimidazole(1.34 g, 7.5 mmol) was stirred under
N.sub.2 at RT for 18 h. After work-up, a yellow paste was obtained
as a crude product which was then purified by chromatography,
eluting with 25% EtOAc/75% hexanes, to give the title compound 90
as a solid (1.35 g, 62%). FAB MS [M+1] 449.1.
EXAMPLE 81
[0372] 178
[0373] A solution of the product of Example 80 (1.2 g, 2.68 mmol)
in THF (10 ml) and CH.sub.3I (0.45 g, 3.2 mmol) was stirred under
N.sub.2 at RT for 5 h. After work-up, a solid was obtained as a
crude product which was then purified by trituation with ether to
give the title compound as a pale yellow salt (1. 5 g, 94%). FAB MS
[M+1] 463.1.
EXAMPLE 82
[0374] 179
[0375] A solution of the product of Example 81 (0.3 g, 0.51 mmol)
and 7 N NH.sub.3 (2 ml, 14 mmol) in CH.sub.3OH was stirred under
N.sub.2 at RT for 4 days. After work-up, a solid was obtained as a
crude product which was then purified by chromatography, eluting
with 9% NH.sub.3--CH.sub.3OH (1:9)/91% CH.sub.2CO.sub.2 to give the
title compound as a solid (0.19 g, 86%). FAB MS [M+1] 432.1.
EXAMPLE 83
[0376] 180
[0377] The title compound was prepared by a method analogous to
Example 82, using 2 M CH.sub.3NH.sub.2 in CH.sub.3OH in place of 7
M NH.sub.3 in CH.sub.3OH. The title compound was obtained as a
solid in a 95% yield. FAB MS [M+1] 446.1.
EXAMPLE 84
[0378] 181
[0379] The title compound was prepared by a method analogous to
Example 82, using 2 M ethylamine in CH.sub.3OH in place of 7 M
NH.sub.3 in CH.sub.3OH. The title compound was obtained as a solid
in a 17% yield. FAB MS [M+1] 460.1.
EXAMPLE 85
[0380] 182
[0381] A mixture of 22 (0.3 g, 0.73 mmol) and N,
N-dimethylformamide dimethyl acetal (87 mg, 0.73 mmol) was heated
to 60.degree. C. for 18 h. The reaction mixture was purified by
chromatography, eluting with 3.5% NH.sub.3--CH.sub.3OH (1:9)196.5%
CH.sub.2Cl.sub.2 to give the title compound as an off-white solid
(180 mg, 60%). FAB MS [M+1] 421.1.
EXAMPLE 86
[0382] 183
[0383] A mixture of 6 (0.4 g, 1 mmol) in toluene (3 ml) and acetic
acid (0.24 g, 4 mmol) was heated to reflux for 6 days. After
work-up, an oil was obtained as a crude product which was purified
by chromatography, eluting with 5% NH.sub.3--CH.sub.3OH (1:9)/95%
CH.sub.2Cl.sub.2 to give the title compound as a HCl salt (75 mg,
18%) after treating the pure compound with 1 eq. of 2 N
HCl-Et.sub.2O solution. FAB MS [M+1] 417.1.
EXAMPLE 87
[0384] 184
[0385] A mixture of 89 (0.4 g, 0.985 mmol) in toluene (3 ml) and
acetic acid (0.59 g, 9.85 mmol) was heated to 100.degree. C. for 40
h. After work-up, an oil was obtained as a crude product which was
purified by chromatography, eluting with 3.5% NH.sub.3--CH.sub.3OH
(1:9)/96.5% CH.sub.2Cl.sub.2 to give the title compound as a HCl
salt (0.32 g, 76%) after treating the pure compound with 1 eq. of 2
N HCl-Et.sub.2O solution. FAB MS [M+1] 431.1.
EXAMPLE 88
[0386] 185
[0387] The title compound was prepared by a method analogous to
Example 87, using propionic acid in place of acetic acid. The title
compound was obtained as a HCl salt in a 59% yield. FAB MS [M+1]
445.1.
EXAMPLE 89
[0388] 186
[0389] The title compound was prepared by a method analogous to
Example 87, using n-butyric acid in place of acetic acid. The title
compound was obtained as a HCl salt in a 88% yield. FAB MS [M+1]
459.1.
EXAMPLE 90
[0390] 187
[0391] The title compound was prepared by a method analogous to
Example 87, using N-t-BOC glycine in place of acetic acid. The
title compound was obtained as a HCl salt in a 63% yield. FAB MS
[M+1] 546.1.
EXAMPLE 91
[0392] 188
[0393] The title compound was prepared by a method analogous to
Example 76 using Example 62 in place of Example 71. Purification
the crude material by flash silica chromatography, using 5% (1
:9)[NH.sub.4OH/CH.sub.3OH]/95- % CH.sub.2Cl.sub.2 gave the title
compound as a solid with a yield of 75%. LCMS [M+1].sup.+463.1.
EXAMPLE 92
[0394] 189 190
[0395] A flame-dried flask was charged with compound 91 (50 g,
204.8 mmol, 1 equiv.) and paraformaldehyde (6.76 g, 225.3 mmol, 1.1
equiv.). The solid mixture was dissolved under N.sub.2 with a heat
gun until the solution was homogeneous, approximately 20 min. The
solution was allowed to cool to RT. HBr gas was bubbled into the
solution at a fast rate at RT. The reaction was continued for 2.5
h. The layers were separated, the upper layer was diluted with
hexane (150 ml) and any aqueous remnants were removed. The hexane
layer was dried over MgSO.sub.4 overnight, then filtered and
concentrated. Short path distillation (high vac, 75.degree. C.)
gave pure 92 (67.86 g, 98%) as a clear oil. .sup.1H NMR
(CDCl.sub.3) .delta. 4.85 (s, 2H), 5.79 (s, 2H), 7.84 (s, 2H), 7.87
(s, 1 H). 191
[0396] Compound 93 (100 g, 496 mmol, 1 equiv.) was added to
CH.sub.3NH.sub.2 (160 ml, 40% in H.sub.20, 4 equiv.) in a cool
water bath at 10-16.degree. C. over a period of 15 min. After
complete addition, the solution was warmed to RT and stirred for 1
h. The reaction was monitored by TLC in 98:2 EtOAc/CH.sub.3OH. Upon
completion, the reaction was quenched with brine (25% in H.sub.20,
500 ml). The solution was extracted with 1:1 THF/EtOAc (4.times.400
ml) and the combined organic phases were dried (Na.sub.2SO.sub.4)
and concentrated. The residue was dried on high vacuum to give 94
(79.47 g, 98%). Electrospray MS [M+l]+165.0. 192
[0397] A mixture of 94 (79.44 g, 483.8 mmol, 1 equiv.), pentane
(550 ml), and trimethylacetaldehyde (65.7 ml, 604.8 mmol, 1.25
equiv.) was heated to 65.degree. C. in a system equipped with a
condenser, Dean-Stark trap and N.sub.2 inlet. The mixture was
heated for 3 h and the suspension dissolved. The solution was
cooled to RT and stirred overnight (16 h). The solution was
concentrated, redissolved in CH.sub.3OH (140-150 ml), cooled in an
ice bath for 30 min, and then saturated HCl--CH.sub.3OH (300 ml)
was slowly added via a dropping funnel over 30 min. The solution
was stirred at 0.degree. C., then warmed to RT under N.sub.2
overnight and concentrated on high vac to yield a crude, yellow oil
(109.1 g). The oil was redissolved in CH.sub.2Cl.sub.2 (800 ml) and
washed with 25% K.sub.2CO.sub.3 (w/w, 400 ml). The aqueous portion
was washed again with CH.sub.2Cl.sub.2 (2.times.400 ml). The
combined organics were dried (Na.sub.2SO.sub.4) and concentrated to
give a yellow solid (98.7 g). The crude solid was recrystallized
out of hot MTBE (300 ml), then cooled to 0.degree. C. to give 95 as
a white solid (54.88 g, 49%). Mother liquor still contained product
which could be isolated by another recrystallization or by
chromatography. Electrospray MS [M+1].sup.+451.1 193
[0398] All reagents were deoxygenated under Ar prior to use. 95
(42.05 g, 181 mmol, 1 equiv.) was dissolved in dry THF from a still
(550 ml) while agitating with a mechanical stirrer. The solution
was cooled to approximately -70.degree. C. in dry ice/acetone and a
solution of 1.5 M LDATHF in cyclohexane (124.3 ml, 186.5 mmol, 1.03
equiv.) was added over 20 min. The resultant dark orange/brown
solution was allowed to stir at -78.degree. C. for 30 min. Bromide
92 (64.0 g, 190 mmol, 1.05 equiv.) was slowly added via syringe
over 20 min. The solution was stirred at -78.degree. C. and
monitored by TLC in 4:1 Hex/EtOAc. The reaction was complete after
2 h. The reaction was quenched with sat. aq. NH.sub.4Cl (300 ml) at
-78.degree. C. and then warmed to RT while stirring vigorously.
Phases were separated and the organic phase washed with H.sub.2O
(2.times.150 ml). The aqueous layer was washed with EtOAc (300 ml).
The combined organics were dried (Na.sub.2SO.sub.4) and
concentrated to give a crude, light yellow solid (32.63 g), which
was recrystallized out of hot pentane to give 96 (33.66 g). The
mother liquor was again concentrated to an orange solid and
recrystallized out of pentane (150 ml) to give an additional 10.50
g of product (Overall yield =44.16 g, 50%). The mother liquor (46.7
g, approximately 50% pure by NMR) still contained starting product
which could be isolated. Electrospray MS [M+1].sup.+489.1 194
[0399] To a solution of 96 (33.58 g, 68.76 mmol, 1 equiv.) in
CH.sub.3OH (300 ml), concentrated HCl (300 ml) was added dropwise
with stirring. The solution was heated to 95.degree. C. and stirred
vigorously, and was stirred and heated overnight. The reaction was
monitored by TLC. Upon completion, solvent was evaporated and the
residue was taken up in CH.sub.2Cl.sub.2 (750 ml). The solution was
treated with 25% aq. K.sub.2CO.sub.3 (approximately 350 ml) until
pH 12. The mixture was filtered and the layers separated. The
organic layer was washed with 25% aq. K.sub.2CO.sub.3 (500 ml).
Combined aqueous layers were extracted with CH.sub.2Cl.sub.2
(2.times.750 ml). Combined organic layers were dried
(Na.sub.2SO.sub.4), and concentrated to a yellow oil. .sup.1H NMR
shows pure 97 (29.20 g, 100%). .sup.1H NMR (CDCl.sub.3) .delta.
2.04 (s, 2H), 2.80 (d, J=4.8 Hz, 3H), 3.67 (d, J=8.8 Hz, 1H), 4.53
(d, J=8.8 Hz, 1H), 4.67 (d, J=12.5 Hz, 1H), 4.77 (d, J=12.5 Hz,
1H), 7.26-7.36 (m, 3H), 7.51 (d, J=8.1 Hz, 2H), 7.65 (d, J=4.4 Hz,1
H), 7.75 (s, 2H), 7.79 (s,1 H).
[0400] Step 6:
[0401] The title compound was prepared from 97 using procedures
similar to Example 61, steps 6 and 7.
EXAMPLE 93
[0402] 195 196
[0403] A flame-dried flask was charged with 98 (5.10 g, 20.1 mmol,
1.0 eq) and anhydrous toluene (56 ml). This cloudy 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. This azeotropical
distillation was repeated three times to ensure 98 was totally dry.
After the third azotropical distillation was done, another 36 ml of
anhydrous toluene was added. The solution was allowed to cool down
toRT. 99 (1.90 ml, 13.5 mmol, 0.67 eq) was syringed in within 5
min. White solid was formed at about 6 min after completion of the
addition. The reaction mixture was stirred at RT for 30 min, then
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, and 20 ml of 1.0 M of 100 (CBS catalyst
B-Me-4(S)solution in toluene) was prepared. The almost colorless
solution can be used in CBS reduction directly. 197
[0404] 101 (102.14 g, 0.4 mol, 1.0 eq) was dissolved in anhydrous
CH.sub.2CO.sub.2 (780 ml) and the resulting solution was
transferred into a dry dropping funnel. An oven-dried 3L flask was
cooled to -20.degree. C., and 20 ml of 102 toluene solution was
syringed in, followed by 40 ml of 10.0.about.10.3 M
borane-methylsulfide complex. Then the 101 solution was added
dropwise through the dropping funnel over 2 days. During the
addition, the temperature was maintained at -20.degree. C. Once the
addition was finished, the reaction was monitored by TLC in 4:1
hexane/EtOAc. When 101 was completely consumed, 250 ml of
CH.sub.3OH was added slowly. and hydrogen gas was emitted. The
reaction solution was then concentrated to give white solid. The
solid was dissolved in Et.sub.2O (500 ml), then 45 ml of 2.0 M of
HCl in Et.sub.2O was added slowly at -20.degree. C. White
precipitate was formed. The reaction mixture was warmed to RT and
stirred for 30.about.40 min. The mixture was filtered and the
filtrate concentrated to give 101.5 g of white solid 102 (yield
98.7%). Chiral HPLC Chiral OD(Chiralcel) column (Hexane/IPA=98/2)
showed 94.6% ee. 198
[0405] 103 was prepared in a method analogous to Example 92, Step 1
using 102 in place of 91. 199
[0406] Amino amide 104 (14.14 g, 32.55 mmol, 1 equiv.) (prepared in
a similar procedure to that described in Example 92, substituting
103 in place of 92 in step 4) was taken up in dry CH.sub.2Cl.sub.2
(120 ml). The solution was cooled to -78.degree. C. and
chlorosulfonyl isocyanate (2.84 ml, 32.55 mmol, 1 equiv.) was
added. The reaction was stirred at 0.degree. C. for 3 h and then
concentrated to a white solid. The solid was dissolved in
1,4-dioxane (120 ml) and 3 N aqueous HCl (120 ml), then stirred at
900C for 5 h, then at RT overnight. The solution was diluted with
H.sub.2O (250 ml) and extracted with EtOAc (3.times.400 ml). The
combined organics were dried (Na.sub.2SO.sub.4), and concentrated
to a crude, white foam (15.80 g). the foam was purified by plug
chromatography on a 600 ml fritted funnel, eluting with 2:1
Hex/EtOAc. The fractions 2-8 were collected and concentrated to
give pure 105 (10.26 g, 71%). FAB MS [M+1].sup.+447.1
[0407] Step 5:
[0408] AlCl.sub.3 (12.2 g, 91.4 mmol, 4 equiv.) was added to a
flask equipped with a N.sub.2 inlet. The flask was cooled to
0.degree. C. and a solution of 1 M LAH in ether (68.6 ml, 68.6
mmol, 3 equiv.) was slowly added. The resultant white slurry was
stirred at 0.degree. C. for 15 min. Next, a solution of hydantoin
105 (10.2 g, 22.85 mmol, 1 equiv.) in 150 ml dry THF was added via
canula. The solution was warmed to RT and stirred for 41 h. The
solution was again cooled to 0.degree. C. and H.sub.2O (20 ml) was
added, then 15% aq. NaOH (w/w, 20 ml) followed by H.sub.2O (60 ml).
The biphasic solution was stirred for 30 min. All emulsion formed
was dissolved with 1 N HCl (approximately 300-400 ml) and the
=layers were separated. The aqueous layer was extracted with EtOAc
(2.times.500 ml). The combined organics were washed with H.sub.2O
(200 ml), dried (Na.sub.2SO.sub.4), and concentrated to give the
crude (9.86 g). The crude material was initially purified by plug
chromatography on a 2L fritted funnel, eluting with 1:1 Hex/EtOAc,
followed by 98:2 EtOAc to give 8.0 g of material, which still
contained 3% of a less polar impurity. The solid was recrystallized
from hot MTBE (30 ml) to provide pure Example 93 (6.5 g, 79%). FAB
MS [M+1].sup.+433.1
EXAMPLE 94
[0409] 200 201
[0410] 104 (3.0 g, 6.63 mmol, 1 equiv.) (prepared analogously to
the procedure described in a Example 92) was dissolved in
CH.sub.2Cl.sub.2 (100 ml) and cooled to 0.degree. C. Et.sub.3N
(2.78 ml, 19.89 mmol, 3 equiv.) followed by triphosgene (787 mg,
2.65 mmol, 0.4 equiv.) was added and the solution was allowed to
stir and warm to RT. Reaction was complete after 2 h as determined
by TLC. The reaction was quenched with sat. aq. NaHCO.sub.3 (100
ml) and the layers were separated. The organic layer was washed
with brine (100 ml), dried (Na.sub.2SO.sub.4), and concentrated.
The crude product was purified by Biotage chromatography, eluting
with CH.sub.2Cl.sub.2 to give 2.024 g (64%) of 106. FAB MS
[M+1].sup.+479.1.
[0411] Step 2:
[0412] 106 (919 mg, 1.92 mmol, 1 equiv.) was dissolved in dry THF
(10 ml) and cooled to 00C. A 1 M solution of LAH in Et.sub.2O (1.92
ml, 1.92 mmol, 1 equiv.) was slowly added and the solution was
stirred at 0.degree. C. for 10 min. The reaction was warmed to RT
and completed after 2 h. The solution was cooled to 0.degree. C.
and water (3 ml) was slowly added, followed by 15% aq. NaOH (3 ml),
and then more water (10 ml). The emulsion was dissolved with 1 M
HCl and the layers were separated. The aqueous layer was extracted
with EtOAc (2.times.100 ml) and the organic layers were combined,
washed with water (50 ml), dried (Na.sub.2SO.sub.4), and
concentrated to give crude product (914 mg). Biotage
chromatography, eluting with 98:2 CH.sub.2Cl.sub.2/CH.sub.3OH(NH.-
sub.3) gave a 3:2 mixture of diastereomers (798 mg) (87%). Prep
HPLC on 50 mg of product using a chiralcel OD column, eluting with
85:15 Hex/IPA gave the title compound (tR=6.4 min), a white powder
(12.7 mg, 51%, 98% de). HRMS [M+1].sup.+481.1362.
EXAMPLE 95
[0413] 202
[0414] The title compound was prepared from 106 using the procedure
of Example 94. Prep HPLC on 50 mg of material on chiralcel OD
column, eluting with 85:15 Hex/IPA gave the title compound (tR=8.2
min) as a clear oil (17.5 mg, 70%, 78% de). HRMS
[M+1].sup.+481.1362
EXAMPLE 96
[0415] 203
[0416] A 2:3 diastereomeric mixture of Examples 94 and 95 (100 mg,
0.208 mmol, 1 equiv.) was dissolved in CH.sub.2Cl.sub.2 (2 ml) and
treated with NaSCH.sub.3 (29.2 mg, 0.416 mmol, 2 equiv.). The
suspension was treated with concentrated HCl (4-5 drops) and
stirred at RT. The reaction was complete after 30 min as determined
by TLC. The reaction mixture was diluted with CH.sub.2Cl.sub.2 (40
ml), washed with sat. aq. NaHCO.sub.3 (30 ml) and brine (30 ml),
dried (Na.sub.2SO.sub.4), and concentrated. The crude product was
purified by Biotage chromatography, eluting with 1:1 Hex/EtOAc to
give the title compound (92.1 mg, 87%) as a 1:1 mixture of
diastereomers. Electrospray MS [M+1].sup.+511.1
EXAMPLE 97
[0417] 204
[0418] A 2:3 diastereomeric mixture of Examples 94 and 95 (100 mg,
0.208 mmol, 1 equiv.) was dissolved in CH.sub.3OH (3 ml), cooled to
0.degree. C., and treated with concentrated HCl in CH.sub.3OH (14
drops). This was warmed to RT and stirred to completion (24 h). The
reaction mixture was diluted with CH.sub.2Cl.sub.2 (100 ml), washed
with sat. aq. NaHCO.sub.3 (30 ml) and then brine (30 ml), dried
(Na.sub.2SO.sub.4), and concentrated. The crude mixture was
purified by Biotage chromatography, eluting with 3:2 EtOAc/Hex (2%
NEt.sub.3) to give a product as a 3:2 mixture of diastereomers.
Isolation by prep HPLC on an chiralcel OD column, eluting with 95:5
Hex/IPA gave the title compound (tR=6.7 min) (29 mg, 28%). HRMS
[M+1].sup.+495.1419
EXAMPLE 98
[0419] 205 206
[0420] A solution of K2CO.sub.3 (31.0 g, 187.5 mmol, 3 equiv.),
K.sub.3Fe(CN).sub.6 (61.75 g, 187.5 mmol, 3 equiv.),
(DHQ).sub.2PHAL (2.44 g, 3.13 mmol, 0.05 equiv.), and
K.sub.2OsO.sub.4.2H.sub.2O (1.16 g, 3.13 mmol, 0.05 equiv.) in
.sup.tBuOH/H.sub.20 1:1 (750 ml) was stirred and cooled to
0.degree. C. The suspension was treated with 107 (11.25 ml, 62.5
mmol, 1 equiv.) and stirred at 0.degree. C. for 3.5 h. The reaction
mixture was treated with Na.sub.2SO.sub.3 (95 g, 750 mmol, 12
equiv.) and warmed to RT. The biphasic solution was separated and
the aqueous layer was extracted with EtOAc (500 ml). Combined
organic fractions were washed with brine (200 ml), dried
(Na.sub.2SO.sub.4), and concentrated to a yellow solid. The crude
product was recrystallized from minimum 1,2-dichloroethane to give
108 (14.12 g, 83%) as a white solid. .sup.1H NMR (CD.sub.3OD)
.delta. 3.67 (d, J=5.6 Hz, 2H), 4.85 (t, J=5.6 Hz,1 H), 7.85 (s, 1
H), 7.99 (s, 2H). 207
[0421] A mixture of 108 (4.0 g, 14.6 mmol, 1 equiv.) and dibutyltin
oxide (3.64 g, 14.6 mmol, 1 equiv.) in toluene (60 ml) was refluxed
for 2 h under a Dean Stark trap. The solution was concentrated to
obtain a white solid. To this solid, CsF (4.30 g, 28.32 mmol, 1.94
equiv.) was added and the mixture was dried in vacuo overnight.
Benzyl bromide (3.0 ml, 25.11 mmol, 1.72 equiv.) in dry DMF (60 ml)
was added and the reaction mixture was stirred vigorously for 6 h.
The solution was concentrated, taken up in EtOAc (200 ml) and the
solid filtered off. The organics were extracted with water
(4.times.100 ml), dried (Na.sub.2SO.sub.4), and concentrated. The
crude product was purified by Biotage chromatography eluting with
9:1 Hex/EtOAc.fwdarw.4:1 Hex/EtOAc to give 109 (4.15 g, 78%) as a
pale yellow oil. FAB MS [M+1].sup.+363.0. 208
[0422] NaH (834 mg, 20.85 mmol, 1.1 equiv.) was added to a stirred
solution of 109 (6.90 g, 18.95 mmol, 1 equiv.) in THF (20 ml) under
N.sub.2. The mixture was stirred for 1 h, then cooled to 0.degree.
C. MOMBr (2.63 g, 21.06 mmol, 1 equiv.) was added dropwise. The
solution was warmed to RT and stirred for 1 h. The white mixture
was filtered through a plug of celite and the filtrate was
concentrated to give 110 (7.90 g, >95%) as a pure, yellow oil.
.sup.1H NMR (CDCl.sub.3) .delta. 3.36 (s, 3H), 4.55 (s, 2H), 4.61
(d, 7.0 Hz, 1H), 4.75 (d, 6.6 Hz, 1 H), 4.92 (t, J=4.8 Hz, 1H),
7.21-7.31 (m, 5H), 7.82 (s, 1 H), 7.83 (s, 2H). 209
[0423] To an ice-cooled solution of 110 (5.85 g, 14.33 mmol, 3
equiv.) in CH.sub.2Cl.sub.2 (15 ml) was added a solution of 1 M
BBr.sub.3 in CH.sub.2Cl.sub.2 (1.64 ml, 1.64 mmol, 1 equiv.). The
solution was warmed to RT and stirred for 4 h. The reaction mixture
was concentrated to a crude brown oil 111 1(6.1 g, 93%) which was
used in the next step.
[0424] Step 5:
[0425] The title compound was prepared by a method analogous to
Example 92 using 111 in place of 92 for step 4.
EXAMPLE 99
[0426] 210
[0427] The product of Example 92 (0.25 g, 0.59 mmol, 1.0 equiv.)
was taken up in 4 ml dry DMF and cooled to 0.degree. C. in a ice
bath. NaH (60% dispersion in mineral oil) (0.0179 g, 0.59 mmol, 1.0
equiv.) was added to the reaction mixture, the solution was warmed
to RT and stirred for 45 min. CH.sub.3I (0.053 ml, 0.66 mmol, 1.1
equiv.) was added and reaction mixture was stirred at RT over
night. The reaction was monitored by TLC in 4/1 EtOAc/Hexane. The
reaction did not go to completion, hence was quenched with H.sub.2O
(3.times.1 5ml). The mixture was extracted with EtOAc (2.times.15
ml) dried (Na.sub.2SO.sub.4), concentrated and dried on high
vacuum. Purification using Biotage chromatography with 60/40
Hexane/EtOAc gave the title compound (0.127 g, 50%). MS
[M+1].sup.+433.1.
EXAMPLE 100
[0428] 211
[0429] The title compound was prepared using a procedure similar to
Example 99 using the product of Example 2B in place of Example 92.
MS [M+1].sup.+451.1.
EXAMPLE 101
[0430] 212
[0431] The title compound was prepared using a procedure similar to
Example 99 using ethyl iodide in place of CH.sub.3I to give the
title compound. MS [M+1].sup.+ of crude 447.1.
EXAMPLE 102
[0432] 213 214
[0433] 74 (6.0 g, 13.7 mmo, 1.0 eqv), Ba(OH)2 (20.8 g, 65.9 mmol,
4.8 equiv.) and H.sub.2O (50 ml) were combined in a high pressure
bomb equipped with a stirring bar. It was heated at 165.degree. C.
for 64 h, and then the temperature was increased to 180.degree. C.
The bomb was heated for another 3 days, then cooled, and the crude
product was treated with CH.sub.3OH (NH.sub.3) to transfer the
hardened crude to solution. The mass gradually dissolved using 10
(40-50 ml) portions with sonication each time. The resulting turbid
solution was filtered and concentrated. The crude was then
dissolved in ether, filtered and concentrated to give pale yellow
solid 112 (6.2 g, >95%). 215
[0434] A solution of LiBH.sub.4 (0.01 g, 0.46 mmol, 2.0 eqiv) was
treated with TMSCl (0.1 15 ml, 0.91 mmol, 4.0 eqiv). After 5 min,
112 (0.1 g, 0.227 mmol, 1.0 equiv.) was added as a powder and the
mixture was stirred for 18 h. It was monitored by TLC 70:10:20
(EtOAc: Et.sub.3N:CH.sub.3OH). Upon completion, the reaction was
quenched with 5 ml CH.sub.3OH and stirred for another 1 h.
Purification by Biotage in 97:3 CH.sub.2Cl.sub.2/CH.sub.3OH
(NH.sub.3) gave the product 113 (0.65 g, 67%).
[0435] Step 3:
[0436] A solution of 113 (0.63 g, 0.148 mmol, 1.0 equiv) in dry
CH.sub.2Cl.sub.2 (4ml) was treated with diisopropyl ethyl amine
(0.077 ml, 0.444 mmol, 3.0 equiv.) followed by triphosgene (0.0176
g, 0.059 mmol, 0.4 equiv.). The reaction mixture was stirred at RT
for 10 min. Monitoring by TLC 2/1 Hexane/EtOAc showed reaction
completion. The crude product was purified using Biotage
chromatography, eluting with 98/2 CH.sub.2Cl.sub.2/CH.sub.3OH to
give the title compound as a white foam (0.58 g, 86%). MS
[M+1].sup.+452.
EXAMPLE 103
[0437] 216 217
[0438] To a solution of 104 (0.225 g, 0.518 mmol) in
CH.sub.2Cl.sub.2 (3 ml) was added 2-methylthiophenylisocyanate and
the resulting solution was stirred for 12 h. The solvent was
removed and the residue treated with dioxane/25% HCl (4 ml, 2:1,
v/v) and heated at 900C overnight. After cooling to RT, the
solution was diluted with EtOAc and water and the layers separated.
The aqueous layer was extracted with EtOAc three times. The
combined organic layers were washed with half saturated NaHCO.sub.3
solution and brine, dried over MgSO.sub.4, filtered and
concentrated. Flash chromatography afforded 114 (0.265 g, 95%).
Electrospray MS [M+1].sup.+569.1
[0439] Step 2:
[0440] To solid AlCl.sub.3 (346.7 mg, 2.6 mmol) at 0.degree. C.
under N.sub.2 was added LiAlH.sub.4 (2.03 ml, 1M in Et.sub.2O, 2.03
mmol). The resulting suspension was stirred for 10 min, then a
solution of 114 (320 mg ) in THF (19 ml) was cannulated into the
hydride suspension dropwise. After 5 min, the solution was allowed
to warm to 23.degree. C. and stirred for 2 h. The reaction mixture
was cooled to 0.degree. C., quenched with 10 ml saturated sodium
potassium tartrate, stirred at 23.degree. C. for 2 h, then
patitioned between water and EtOAc. The organic layer was washed
with brine, dried over MgSO.sub.4, filtered and concentrated.
[0441] Step 3
[0442] A solution of the crude hydroxyurea from Step 2 in
CH.sub.2Cl.sub.2 (3 ml) was treated with triethylsilane (1.5 ml)
followed by addition of TFA (0.178 ml), stirred overnight, further
treated with TFA (0.998 ml) and stirred for 4 h. The mixture was
concentrated, then re-dissolved in CH.sub.2Cl.sub.2 and stirred
with solid K.sub.2CO.sub.3 for 2 h. The solution was filtered and
concentrated. Flash chromatography afforded the title urea.
Electrospray MS [M+1].sup.+555.1.
EXAMPLES 104-111
[0443] The following examples were prepared in a similar fashion to
Example 103 using the appropriate isocyanate:
2 218 Example R.sup.5 MS [M + 1].sup.+ 104 219 539.1 105 220 545.1
106 221 527.1 107 222 539.1 108 223 537.1 109 224 539.1 110 225
569.1 111 226 528.1
EXAMPLES 112-113
[0444] 227 228
[0445] 104 (1.26 g, 2.9 mmol) was dissolved in CH.sub.2Cl.sub.2 (58
ml) at 0.degree. C., followed by addition of Et.sub.3N (1.2 ml, 8.7
mmol). Triphosgene (0.35 g, 1.13 mmol) was added in one portion.
The solution was allowed to warm to 23.degree. C. and stirred for 2
h. The reaction was then diluted with EtOAc, washed with 5%
HCl(aq.), half saturated NaHCO.sub.3 solution and brine, then dried
over Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
to give 115 (1.31 g, 98%).
[0446] Step 2:
[0447] Using a procedure similar to Example 94, step 2, a mixture
of Examples 112 and 113 was prepared. Separation by silica gel
chromatography using gradient of hexane to EtOAc/NEt.sub.3
9:1:provided the title compounds.
EXAMPLES 114-115
[0448] The following examples were prepared in a similar fashion to
Example 103, steps 1-2, omitting step 3 and using the appropriate
isocycanate:
3 229 Example R.sup.5 MS [M + 1].sup.+ 114 230 555.1 115 231
561.1
EXAMPLES 116-117
[0449] The following examples were prepared in a similar fashion to
Example 96, using 116 to prepare Example 116 and Example 115 to
prepare Example 117 in place of hydroxyureas from Examples 94 and
95:
4 232 Example R.sup.5 MS [M + 1].sup.+ 116 Me 493.1 117 233
591.1
EXAMPLES 118-119
[0450] 234
[0451] To the alcohol mixture of Examples 112 and 1 13 was added
saturated dry HCl in CH.sub.3OH (5 ml, precooled to -20.degree.
C.). The solution was stirred at 23.degree. C. for 2 h, then poured
into 10% Na.sub.2CO.sub.3 (25 ml). The aqueous layer was extracted
with EtOAc (3.times.30 ml). The combined organic layer was washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. Flash chromatography afforded an
inseparable mixture of two methyl ethers. The mixture was then
separated on 10 HPLC using Chiralpak OD eluted with (95:5)
Hexane/iPA. Electrospray MS [M+1.sup.]+477.1
EXAMPLE 120
[0452] 235
[0453] To a solution of Example 103 (170 mg, 0.306 mmol) in
CH.sub.2Cl.sub.2 was added solid Oxone (1.14 g, 17.4 mmol), the
resulting suspension was stirred vigorously for 20 h, then quenched
with saturated NaHCO.sub.3 solution and extracted with EtOAc. The
organic layers were washed with brine, dried over Na.sub.2SO.sub.4
and concentrated. Flash chromatography afforded the title compound.
Electrospray MS [M+1].sup.+571.1
EXAMPLE 121
[0454] 236
[0455] To a solution of Example 120 in CH.sub.2Cl.sub.2 was added
m-CPBA and the resulting solution was stirred for 30 h, then
quenched with NaHCO.sub.3 solution and extracted with EtOAc. The
organic layers were washed with brine, dried over Na.sub.2SO.sub.4
and concentrated. Flash chromatography afforded the title compound.
Electrospray MS [M+1].sup.+587.1.
EXAMPLE 122
[0456] 237
[0457] To Example 92 (0.150 g, 0.36 mmol), CsF (0.109 g, 0.72 mmol)
in DMF (3.5 ml) at 0C and NaH 0.018 g (60% in mineral oil) was
added. After stirring for 10 min, 2,5-difluorobenzonitrile (0.0587
g, 0.0378 mmol) was added in small portions. The solution was
allowed to warm to 23.degree. C. and was stirred overnight. The
reaction was quenched with saturated NH.sub.4Cl solution, extracted
with EtOAc, and the combined organic layer was washed with water
and brine, dried over Na.sub.2SO.sub.4 and concentrated. Flash
chromatography afforded the title compound (0.051 g, 26%).
Electrospray MS [M+1].sup.+538.1.
EXAMPLE 123
[0458] 238
[0459] In a procedure similar to Example 122,
4-F-phenylmethylsulfone was used in place of
2,5-difluorobenzonitrile to obtain the title compound. Electrospray
MS [M+1].sup.+573.1.
EXAMPLE 124
[0460] 239
[0461] In a procedure similar to Example 122, 2-F-pyridine was used
in place of 2,5-difluorobenzonitrile and Example 1 was used in
place of Example 92 to obtain the title compound. Electrospray MS
[M+1].sup.+496.1
EXAMPLE 125
[0462] 240
[0463] In a procedure similar to Example 122, 2-F-pyridine was used
in place of 2,5-difluorobenzonitrile in step 1, followed by a
procedure similar to that used in Example 121 for the oxidation to
the N-oxide to obtain the title compound. Electrospray MS
[M+1].sup.+512.1.
EXAMPLES 126-127
[0464] 241 242
[0465] A mixture of hydantoin (prepared from 97 using procedures
similar to Example 61, step 6) (5.0 g, 11.6 mmol, 1 equiv.), and
p-methoxybenzylisocyanate (2.5 ml, 17.4 mmol, 1.5 equiv.) in dry
dioxane (20 ml) was stirred at RT for 3 h, then 3N aqueous HCl (20
ml) was added and the mixture stirred at 90.degree. C. for 14 h.
The mixture was poured into 250 ml EtOAc and washed with H.sub.2O
(2.times.125 ml). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give 6.5 g of the
crude racemic 116. 243
[0466] LiAlH.sub.4 (35 ml of 1 M solution in ether, 35 mmol, 3
equiv.) was added slowly to AlCl.sub.3 (6.3 g, 47.06 mmol, 4
equiv.) at 0.degree. C., and stirred for 10 min, then a solution of
116 (6.5 g, 11.76 mmol, 1 equiv.) in dry THF (70 ml) was carefully
added. After stirring at 23.degree. C. for 2.5 h, the mixture was
cooled to 0.degree. C., quenched slowly with 30 ml saturated
aqueous sodium potassium tartarate and stirred for 14 h at
23.degree. C. The mixture was diluted with water (100 ml), and
extracted with EtOAc (2.times.200 ml). The organic layers were
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
Purification using 400 ml silica and eluting with 2/1 hexane/EtOAc
provided 4.62 g of the product as white solid.
[0467] Step 3:
[0468] To a suspension of 117a/b (4.62 g, 8.33 mmol, 1 equiv.) in
CH.sub.3CN/water (150 ml, 2:1) at RT was added ceric ammonium
nitrate (18.27 g, 33.33 mmol, 4 equiv.). After stirring at
23.degree. C. for 1 h, the mixture was poured into 300 ml EtOAc/150
ml saturated aq. NaHCO.sub.3 and filtered through a frit. The
organic layer was isolated, the aqueous layer was washed with EtOAc
(1.times.300 ml) and the combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification
using the Biotage silica gel system, eluting with 1/1 hexane/EtOAc,
1 L, followed by 5% CH.sub.3OH/EtOAc, 1 L, provided 2.0 g of the
product as a mixture of two isomers. HPLC separation on chiralpak
AD column, eluting with (90/10) hexane/IPA mixture gave Example 127
FAB, (M.sup.+1)=435.0, and Example 126, FAB, (M.sup.+1)=435.0.
EXAMPLES 128-129
[0469] 244
[0470] Step 1:
[0471] A mixture of 105 (0.976 g, 2.19 mmol, 1 equiv.),
K.sub.2CO.sub.3 (0.453 g, 3.28 mmol, 1.5 equiv.) in dry DMF (10 ml)
was stirred at RT for 30 min. p-Methoxy-benzyl chloride (0.34 ml,
2.5 mmol, 1.15 equiv.) was added at once and the resulting mixture
was stirred at 23.degree. C. for 14 h. The mixture was then poured
into EtOAc (150 ml) and washed with H.sub.2O (3.times.100 ml) and
saturated aq. NaCl (100 ml). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give 1.27 g of the
crude product. It was used in the next step without further
purification.
[0472] Step 2:
[0473] The product of step 1 was converted to Examples 128 and 129
using procedures similar to Examples 126 and 127, steps 2-3, using
LAH in place of LAH/AlCl.sub.3 in step 2 to provide 0.14 g of the
products, obtained as mixture of two isomers. HPLC separation on
chiralpak AD column using (85/15) hexane/IPA mixture gave 80 mg
(29% yield) of Example 129, FAB, (M.sup.+1) 449.2 and 30 mg (11%
yield) of Example 128 FAB, (M+.sup.1) 449.2.
EXAMPLE 130
[0474] 245 246
[0475] To a solution of Example 93 (0.1 g, 0.23 mmol, 1.0 equiv.)
in dry DMF (0.5 ml) cooled to 0.degree. C., POCl.sub.3 (0.024 ml,
0.254 mmol, 1.1 equiv.) was added slowly. The mixture was warmed to
RT, stirred for 30 min, and poured into 5 g ice. The resultant
mixture was poured into water (100 ml) and extracted with EtOAc
(100 ml). The organic layer was separated, washed with saturated
aq. NaCl (1.times.100 ml), dried over anhydrous Na.sub.2SO.sub.4
and concentrated. Flash chromatography over 200 ml silica using (1)
4/1 hex/EtOAc, and (2) 1/1 hex/EtOAc gave 0.070 g (66% yield) of
118 as solid. MS (M.sup.+1) 461.1. 247
[0476] 118 (0.1 g, 0.22 mmol, 1.0 equiv.) and Lawesson's reagent
(0.044 g, 0.108 mmol, 0.5 equiv.) in toluene (1 ml) were heated at
80.degree. C. for 0.5 h. The solvent was evaporated and the residue
purified by Biotage chromatography using 15% EtOAc/hexane to obtain
119 as a yellow foam, 0.085 g (81% yield).
[0477] Step 3:
[0478] 119 (0.3 g, 0.626 mmol, 1.0 equiv.) was taken up in
CH.sub.2Cl.sub.2 (3 ml) at RT. DAST (0.17 ml, 1.25 mmol, 2.0
equiv.) was added slowly and the mixture was stirred at RT
overnight. The reaction was slowly quenched with saturated aq.
NaHCO.sub.3 (5 ml), the mixture was poured into saturated aq.
NaHCO3 (100 ml) and CH.sub.2Cl.sub.2 (100 ml) added. The organic
layer was separated, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by Biotage
chromatography using 4/1 hex/EtOAc to obtain the title compound,
0.080 g (27% yield). MS (M+.sup.1)=483.1.1.
EXAMPLE 131
[0479] 248
[0480] Using procedures similar to Example 130, substituting
Example 92 for Example 93, the title compound was prepared.
Electrospray MS [M+1].sup.+469.1
EXAMPLE 132
[0481] 249
[0482] Using procedures similar to those in Example 102, and
substituting 97 for 74 in step 1, the title compound was prepared.
Electrospray MS [M+1].sup.+434.1.
EXAMPLE 133
[0483] 250
[0484] Example 93 (0.633 g, 1.465 mmol, 1.0 equiv.), Lawesson's
reagent (0.81 g, 2.04 mmol, 1.37 equiv.) and toluene (12 ml) were
heated at 85.degree. C. for 1.5 h, then cooled to RT and
concentrated. The residue was purified by silica gel chromatography
using 15% EtOAc/hex, then 10% EtOAc/CH.sub.2Cl.sub.2 to give 0.61 g
(93% Yield) of the title compound. MS (M.sup.+1)=449.1.
EXAMPLE 134
[0485] 251
[0486] A procedure similar to that used in Example 133, using
Example 92 in place of Example 93, provided the title compound. MS
(M.sup.+1)=435.1
EXAMPLES 135-139
[0487] The compounds were prepared using procedures similar to
those used in Example 99, using Example 92 and the appropriate
alkyliodide . For Example 139, Example 76 was used as the starting
cyclic urea.
5 252 Example R.sup.5 R.sup.4 R.sup.8 MS [M + 1].sup.+ 135 Me H H
447.1. 136 Et H H 461.1. 137 H Et H 461.1. 138 iPr H H 475.1. 139
Et H F 479.1.
EXAMPLES 140-141
[0488] 253
[0489] The title compounds were prepared using procedures similar
to those in Example 94, using ethyl isocyanate in place of methyl
isocyanate. Purification via HPLC (Chiralpak AD column using 98/2
hex/isopropanol) provided Example 140 MS [M+1].sup.+477.1 and
Example 141 MS [M+1].sup.+477.1.
EXAMPLE 142
[0490] 254
[0491] Example 133 (0.61 g, 1.36 mmol, 1.0 equiv.) in THF (20 ml)
was treated with CH.sub.31 (0.10 ml, 1.63 mmol, 1.2 equiv.),
stirred for 14 h, then concentrated. The crude was dissolved in
CH.sub.3OH (20 ml), treated with NH.sub.2CN (0.37 g, 8.84 mmol, 6.7
equiv.) and heated to 60.degree. C. for 14 h. The mixture was
concentrated and purified by silica gel chromatography, using 1/1
EtOAc/hex to give the title compound, 0.1 g (17% yield) as a white
solid. MS (M.sup.+1)=457.1.
EXAMPLE 143
[0492] 255
[0493] To Example 92 (2.0 g, 4.78 mmol) in THF (15 ml) at 0.degree.
C. was added NaNO.sub.2 (0.39 g, 5.7 mmol) in H.sub.2O (7.5 ml),
then H.sub.2SO.sub.4 (conc.) (1 ml) was added slowly. The solution
was allowed to warm to 23.degree. C. and stirred for 1 h. It was
then diluted with water and extracted with EtOAc. The organic
layers were washed with NaHCO.sub.3 solution, brine, dried over
Na.sub.2SO.sub.4 and concentrated to give the title compound.
Electrospray MS [M+1].sup.+448.1.
EXAMPLE 144
[0494] 256
[0495] To Example 143 (0.95 g, 2.1 mmol) in Et.sub.2O (10 ml) at
0.degree. C. was added dropwise LiAIH.sub.4 (4.2 ml, 1 M in
Et.sub.2O). The solution was allowed to warm to 23.degree. C. and
stirred for 2 hr. It was quenched with saturated K,Na tartrate
solution and then partitioned between water and EtOAc. The aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to
give the title compound. Electrospray MS [M+1].sup.+434.1
EXAMPLE 145
[0496] 257
[0497] To Example 144 (0.3 g, 0.69 mmol) in acetic acid (3 ml) was
added 2,5-dimethoxy-3-tetrohydrofuran (3 ml) and the mixture was
heated at 70.degree. C. for 1.5 h. It was cooled to 23.degree. C.
and diluted with EtOAc. The organic layers were washed with
NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and concentrated. A
stream of N.sub.2 was introduced into the residue to remove excess
2,5-dimethoxy-3-tetra-hydrofuran. The crude product was purified by
silica gel chromatography to give the title compound. Electrospray
MS [M+1].sup.+484.1.
EXAMPLE 146
[0498] 258
[0499] Example 144 (0.65 g, 1.5 mmol) in pyridine (15 ml) was
concentrated under reduced pressure at 50.degree. C. using a water
bath. The procedure was repeated twice. The residue was treated
with 1,2-diformylhydrozine (0.34 g, 3.6 mmol), followed by the
addition of pyridine (7.5 ml), Et.sub.3N (1.5 ml) and TMSCl (3 ml).
The thick paste was heated at 80.degree. C. under N.sub.2 for 65 h,
then concentrated under reduced pressure to give a yellow residue.
The residue was partitioned between water and EtOAc. The aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to
give a crude product. Further purification using biotage followed
by a prep TLC afforded the title compound. Electrospray MS
[M+1].sup.+486.1.
EXAMPLE 147
[0500] 259
[0501] The title compound was prepared in a method analogous to
Example 73, using 89 in place of 6. The title compound was obtained
in 95% yield. Electrospray MS [M+1].sup.+432.1.
EXAMPLE 148
[0502] 260
[0503] To a cooled solution of Example 147 (0.3 g, 0.70 mmol), DEC
(0.14 g, 0.73 mmol), HOBT (0.1 g, 0.74 mmol) and NaSO.sub.4 (0.59
g) in anhydrous CH.sub.2Cl.sub.2 (4.5 ml), glacial acetic acid
(0.05 ml, 0.87 mmol) was added followed by Et.sub.3N (0.1 ml, 0.72
mmol). The reaction was allowed to react for 18 h at RT, then
quenched with brine. The aqueous solution was extracted with
CH.sub.2Cl.sub.2 (50 ml.times.3). The combined organic layer was
dried, filtered and concentrated. The pure title compound was
obtained through flash chromatography, eluting with 2% (1:9)
NH.sub.4OH--CH.sub.3OH in CH.sub.2Cl.sub.2 to give the final
product in 39% yield. Electrospray MS [M+1].sup.+474.1.
EXAMPLE 149
[0504] 261
[0505] To a cooled solution of Example 147 (0.2 g, 0.46 mmol) in
anhydrous CH.sub.2CO.sub.2 (5 ml) at 0.degree. C., trifluoroacetic
an hyd ride (0.09 ml, 0.64 mmol) neat was added followed by
Et.sub.3N (0.08 ml, 0.57 mmol). The reaction was allowed to react
for 18 h at RT. Volatile solvents were evaporated. The pure title
compound was obtained through flash chromatography, eluting with
50% EtOAc in hexane to give the final product in 33% yield.
Electrospray MS [M+1].sup.+528.1.
EXAMPLE 150
[0506] 262
[0507] A mixture of 89 (0.38 g, 0.93 mmol) and N,
N-dimethylformamide dimethyl acetal (0.11 ig, 0.93 mmol) was heated
to 60.degree. C. for 18 h. The reaction mixture was purified by
chromatography, eluting with 3.5% NH.sub.3--CH.sub.3OH (1:9)/96.5%
CH.sub.2Cl.sub.2 to give the title compound later as a HCl salt (
0.2 g, 50%). FAB MS [M+1] 417.
EXAMPLE 151
[0508] 263
[0509] Using a method analogous to Example 82, using morpholine in
place of 7 M NH.sub.3 in CH.sub.3OH, the title compound was
obtained as a solid in a 36% yield. FAB MS [M+1] 502.
EXAMPLE 152
[0510] 264
[0511] Using a method analogous to that Example 82, using
2-methoxyethyl-amine in place of 7 M NH.sub.3 in CH.sub.3OH, the
title compound was obtained as a solid in a 80% yield. FAB MS [M+1]
490.1.
EXAMPLE 153
[0512] 265
[0513] Using a method analogous to Example 82, using
4-(aminomethyl)pyridine in place of 7 M NH.sub.3 in CH.sub.3OH, the
title compound was obtained as a solid in a 26% yield. FAB MS [M+1]
523.4.
EXAMPLE 154
[0514] 266
[0515] Using a method analogous to Example 82, using glycinamide in
place of 7 M NH.sub.3 in CH.sub.3OH, the title compound was
obtained as a solid in a 14% yield. FAB MS [M+1] 489.2.
EXAMPLE 155
[0516] 267
[0517] A solution of Example 82 (0.2 g, 0.464 mmol) in
CH.sub.2Cl.sub.2 (2 ml) and isocyanate (53 mg, 0.93 mmol was
stirred under N.sub.2 at RT for 18 h. After work-up, a solid was
obtained as a crude product which was then purified by
chromatography, eluting with 2% NH.sub.3--CH.sub.3OH (1:9)/98%
CH.sub.2Cl.sub.2 to give the title compound as a solid ( 55 mg, 24
%). FAB MS [M+1] 489.3.
EXAMPLE 156
[0518] 268
[0519] Using a method analogous to Example 155, using ethane
sulfonyl chloride in place of isocyanate, the title compound was
obtained later as a HCl salt in a 25% yield. FAB MS [M+1]
524.3.
EXAMPLE 157
[0520] 269
[0521] Using a method analogous to Example 87, using 6 in place of
89 and TFA in place of acetic acid, the title compound was later
obtained as a HCl salt in a 34% yield. FAB MS [M+1] 471.
EXAMPLE 158
[0522] 270
[0523] Using a method analogous to Example 89, using 2-thiophene
acetic acid in place of acetic acid, the title compound was later
obtained as a HCl salt in a 24% yield. FAB MS [M+1] 512.9.
EXAMPLE 159
[0524] 271
[0525] Using a method analogous to Example 89, using phenyl acetic
acid in place of acetic acid, the title compound was later obtained
as a HCl salt in a 15% yield. FAB MS [M+1] 507.1.
EXAMPLE 160
[0526] 272
[0527] Step 1 A mixture of hydantoin 7 (9.2 g, 21.3 mmol, 1
equiv.), K.sub.2C0.sub.3 (8.8 g, 63.9 mmol, 3.0 equiv.) and
tetrabutylammonium iodide (0.79 g, 2.13 mmol, 0.1 equiv.) in 180 mL
acetone was stirred at room temperature for 30 minutes, treated
with p-methoxybenzyl chloride (3.25 mL, 23.9 mmol, 1.12 equiv.) at
reflux for 10 2 hours, then cooled to room temperature and filtered
through sintered glass funnel. The filtrate was concentrated to
give pale yellow solid, which was washed with small amount of
ice-cold Et.sub.2O (2 .times.5 mL) to give 11 g of the crude
racemic p-methoxybenzyl (pmb)-hydantoin 120. It was used in the
next step without further purification.
[0528] Step 2 A mixture of pmb-hydantoin 120 (6.0 g, 10.9 mmol, 1
equiv.), 4-(dimethylamino)pyridine (DMAP) (0.02 g, 0.16 mmol, 1.5%
equiv.) in 60 mL dry THF was stirred at room temperature for 1.5
hours. The solvent was evaporated under vacuum. The residue was
taken up in CH.sub.2Cl.sub.2 (150 mL) and washed with saturated
sodium bicarbonate (50 mL). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, then concentrated. The crude was
purified with Biotage (EtOAc/Hexane=10%) to give 5.5 g (77.7%
yield) of BOC-pmb-hydantoin 121 as white solid.
[0529] Step 3 A solution of BOC-pmb-hydantoin 121 (540 mg, 0.83
mmol, 1 equiv.) in 10 mL dry THF was treated with 3.0 M
methylmagnesium bromide Et.sub.2O solution (0.42 mL, 1.25 mmol, 1.5
equiv.) at 0 C. After addition, the reaction was warmed up to room
temperature gradually and stirred for another hour. THF was
evaporated under vacuum. The residue was taken up with 100 mL
CH.sub.2Cl.sub.2, then washed with 10 mL of saturated aq.
NaHCO.sub.3 solution. The resulting white solid was filtered off.
The filtrate was concentrated and purified by Biotage
(EtOAc/Hexane=20%) to give 290 mg(52.3% yield) of
Methyl-hydroxy-BOC-pmb-- urea 122 as white solid.
[0530] Step 4 A solution of methyl-hydroxy-BOC-pmb-urea 122(310 mg,
0.46 mmol, 1 equiv.) in 5 mL of dry CH.sub.2Cl.sub.2 was treated
with 1.16 mL of 4.0 M HCl in 1,4-dioxane at 0 C. The reaction was
allowed to warm up to room temperature and stirred overnight. The
crude product was taken up with Et.sub.2O, then washed with 3 mL of
saturated NaHCO.sub.3. The aqueous layer was further extracted with
ether. The combined organic layer was dried over Na.sub.2SO.sub.4,
then concentrated, and purified with Biotage (EtOAc/Hexane=15%) to
give 150 mg (56.5% yield) of Methyl-hydroxy-pmb-urea 123 as white
solid.
[0531] Step 5 A white suspension of Methyl-hydroxy-pmb-urea 123 (1
g, 1.76 mmol, 1 equiv.) in 22.5 mL of CH.sub.3CN and 6.75 mL of
water was treated with ceric ammonium nitrate (7.72 g, 14.0 mmol, 8
equiv.). Stirred at room temperature for 8 hours, then partitioned
between 300 mL of EtOAc and 100 mL of saturated aq. NaHCO.sub.3.
The yellow solid was filtered off and aqueous layer was further
extracted with 2.times.100 mL EtOAc. Combined organic layers were
dried over anhy. Na.sub.2SO.sub.4, filtered and concentrated.
Flashed over Biotage (EtOAc/Hexane/Et.sub.3N=1:1:2%) to give 703 mg
(93% yield) of 124 as white solid.
[0532] Step 6 A solution of 124 (312 mg, .93 mmol, 1 equiv.) in 8
mL EtOH was reacted with NaBH.sub.4 (600 mg, 15.9 mmol, 17 equiv.)
at room temperature for 2 days. The crude was partitioned between 2
.times.100 mL of CH.sub.2Cl.sub.2 and 100 mL saturated aq.
NaHCO.sub.3, then washed with 80 mL of Brine. The combined organic
layer was dried over anhy. Na.sub.2SO.sub.4, filtered, concentrated
to give 300 mg of liquid as crude. It was purified with Biotage
(EtOAc/Hexane=30%) to give two diastereomers (100mg and 70 mg
each), which were separated on HPLC with a ChiralCel OD column to
give the 4 stereoisomers of example 160. MS: (M+1)=433.
EXAMPLE 161
[0533] 273
[0534] Examples 161 a and 161b were synthesized using procedure
similar to example 160 starting from optical pure hydantoin 105.
MS: (M+1)=447.
EXAMPLES 162-164
[0535]
6 274 Example R.sup.1 R.sup.2 MS [M + 1].sup.+ 162 F CF.sub.3
382.1. 163 Cl Cl 364.1. 164 CF.sub.3 CF.sub.3 432.1
[0536] The title compounds were prepared using the acylation
procedure similar to those used in example 21 using amnie 39 and
the appropriate substituted benzoyl chloride to provide the title
benzamides.
EXAMPLE 165
[0537] 275
[0538] Step 1
[0539] A solution of Example 92 (224 mg, 0.536 mmol, 1 equiv.) in
THF (12 mL) at 0C was treated with 2.5 M n-BuLi (215 tL, 0.536
mmol, 1 equiv.). The resulting mixture was stirred cold for 5 min.
Tetrabutyl pyrophosphate (405 mg, 0.751 mmol, 1.4 equiv.) was added
to the reaction mixture as a solid in one portion. The cooling bath
was removed and the reaction was stirred at room temperature for 45
minutes at which point a white suspension formed. The reaction was
quenched with sat. aq. NaHCO.sub.3 (20 mL) and extracted with EtOAc
(2.times.30 mL). The solution was dried (Na.sub.2SO.sub.4),
filtered, and concentrated to give crude product (461 mg). This was
not purified and used crude in the next step.
[0540] Step 2
[0541] A solution of the product of step 1 (364 mg, 0.536 mmol, 1
equiv.) in MeOH (10 mL), a solution of N-Me-D-glucamine (206 mg,
1.072 mmol, 2 equiv.) in H.sub.2O (2 mL), and 10% Pd/C (29 mg) were
combined and the mixture was hydrogenated at 40 psi for 2 h. The
reaction mixture was filtered through a pad of Celite and rinsed
with MeOH (80 mL). The solution was concentrated under reduced
pressure and the crude product redissolved in MeOH (5 mL)_.
.sup.1PrOH (25 mL) was added to the solution and the resulting
mixture was aged at room temperature for 30 min to form a white
precipitate. The precipitate was filtered, washed with .sup.1PrOH
(15 mL) and EtOAc (15 mL), and dried. The solid was partitioned
between EtOAc (30 mL) and H.sub.2O (30 mL) and an emulsion formed.
The emulsion was transferred in 10-12 mL portions to centrifuge
tubes and centrifuged at 3000 rpm for 15 min. Decanted away the
organic layer. The aqueous layers were combined, filtered, and
lyophilized to provide example 165 (306 mg, 64% yield, 1:1 mixture
of regioisomers 165a and 165b).
EXAMPLE 166
[0542] 276
[0543] Using procedures similar to those in example 165 and
substituting Example 93 for Example 92, the title compounds were
prepared.
[0544] Compounds of formula I have been found to be antagonists of
the NK.sub.1 receptor and of the effect of Substance P at its
receptor site, and are therefore useful in treating conditions
caused or aggravated by the activity of said receptor.
[0545] The in vitro and in vivo activity of the compounds of
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 NK1
agonist Substance P. % 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" is disintegrations per minute: 1 % MSB = (
dpm of unknown ) - ( dpm of nonspecific binding ) ( dpm of total
binding ) - ( dpm of nonspecific binding ) .times. 100
[0546] The concentration at which the compound produces 50%
inhibition of binding is then used to determine the inhibition
constant (ki) using the Chang-Prusoff equation.
[0547] In addition, functional antagonism of calcium channel
activity is measured using FLIPR technology known to those skilled
in the art.
[0548] In vivo activity is measured by inhibition of
agonist-induced foot tapping in the gerbil, as descibed in Science,
(1998), 281, p. 1640-1695.
[0549] It will be recognized that compounds of formula I exhibit
NK.sub.1 antagonist activity to varying degrees, e.g., certain
compounds have strong NK.sub.1 antagonist activity, while others
are weaker NK.sub.1 antagonists.
[0550] Compounds of the present invention exhibit a range of
activity: Ki values range from about 0.1 to 1000 nM, with Ki values
of about 0.1 to 100 being preferred and Ki values of 0.1 to 25 nM
being more preferred. Most preferred are compounds having a
Ki.ltoreq.10 nM for the NK.sub.1 receptor.
[0551] 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's Pharmaceutical Sciences, 18th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0552] 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.
[0553] 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.
[0554] 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.
[0555] 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.
[0556] Preferably the compound is administered orally.
[0557] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0558] The quantity of NK.sub.1 receptor antagonists in combination
with selective serotonin reuptake inhibitors in a unit dose of
preparation may be varied or adjusted from about 10 mg to about 300
mg of NK.sub.1 receptor antagonists with about 10 mg to about 100
mg of SSRI. A further quantity of NK.sub.1 receptor antagonists in
combination with selective serotonin reuptake inhibitors in a unit
dose of preparation may be varied or adjusted from about 50 mg to
about 300 mg of NK.sub.1 receptor antagonists with about 10 mg to
about 100 mg of SSRI. An even further quantity of NK.sub.1 receptor
antagonists in combination with selective serotonin reuptake
inhibitors in a unit dose of preparation may be varied or adjusted
from about 50 mg to about 300 mg of NK.sub.1 receptor antagonists
with about 20 mg of SSRI, according to the particular
application.
[0559] 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.
[0560] 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 1 mg/day to about 300 mg/day,
preferably 1 mg/day to 75 mg/day, in two to four divided doses.
[0561] While the present 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.
* * * * *