U.S. patent application number 11/159877 was filed with the patent office on 2005-12-01 for 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Case, Brenda, Garland, Danny J., Hayes, Michael J., Huang, Horng-Chih, Huang, Wei, Jones, Darin E., Long, Scott, Moormann, Alan E., Neumann, William L., Parlow, John J., Rueppel, Melvin L., Scholten, Jeffrey A., Snyder, Jeffery S., South, Michael S., Toth, Mihaly V., Trujillo, John, Webber, Ronald K..
Application Number | 20050267123 11/159877 |
Document ID | / |
Family ID | 27559729 |
Filed Date | 2005-12-01 |
United States Patent
Application |
20050267123 |
Kind Code |
A1 |
South, Michael S. ; et
al. |
December 1, 2005 |
6-Membered heterocyclic compounds useful for selective inhibition
of the coagulation cascade
Abstract
The present invention relates to compounds, and prodrugs
thereof, compositions and methods useful for preventing and
treating thrombotic conditions in mammals. The compounds of the
present invention, and prodrugs thereof, selectively inhibit
certain proteases of the coagulation cascade.
Inventors: |
South, Michael S.; (St.
Louis, MO) ; Webber, Ronald K.; (St. Charles, MO)
; Huang, Horng-Chih; (Chesterfield, MO) ; Toth,
Mihaly V.; (St. Louis, MO) ; Moormann, Alan E.;
(Weldon Springs, MO) ; Snyder, Jeffery S.;
(Manchester, MO) ; Scholten, Jeffrey A.;
(Chesterfield, MO) ; Garland, Danny J.; (Ballwin,
MO) ; Rueppel, Melvin L.; (St. Louis, MO) ;
Neumann, William L.; (St. Louis, MO) ; Long,
Scott; (Ballwin, MO) ; Huang, Wei; (Wildwood,
MO) ; Trujillo, John; (St. Peters, MO) ;
Parlow, John J.; (Arnold, MO) ; Jones, Darin E.;
(Ballwin, MO) ; Case, Brenda; (St. Louis, MO)
; Hayes, Michael J.; (St. Louis, MO) |
Correspondence
Address: |
SENNIGER POWERS LEAVITT AND ROEDEL
ONE METROPOLITAN SQUARE
16TH FLOOR
ST LOUIS
MO
63102
US
|
Assignee: |
Pharmacia Corporation
St. Louis
MO
|
Family ID: |
27559729 |
Appl. No.: |
11/159877 |
Filed: |
June 23, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11159877 |
Jun 23, 2005 |
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10263637 |
Oct 3, 2002 |
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60326721 |
Oct 3, 2001 |
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60338623 |
Oct 24, 2001 |
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60332857 |
Nov 6, 2001 |
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60350052 |
Nov 7, 2001 |
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60332107 |
Nov 21, 2001 |
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60331891 |
Nov 21, 2001 |
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Current U.S.
Class: |
514/252.14 ;
514/269; 544/295; 544/316 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
231/38 20130101; C07D 239/10 20130101; C07D 211/56 20130101; C07D
413/12 20130101; C07D 241/20 20130101; C07D 253/075 20130101; C07D
207/32 20130101; C07C 257/18 20130101; C07D 237/04 20130101; A61P
7/02 20180101; C07D 401/12 20130101; C07D 211/98 20130101; C07D
403/10 20130101; C07D 333/36 20130101; C07D 277/42 20130101; C07C
2601/04 20170501; C07D 231/48 20130101; C07D 307/22 20130101; C07C
2601/10 20170501; C07D 213/74 20130101; A61P 43/00 20180101; C07D
239/22 20130101; C07D 249/14 20130101; C07D 263/48 20130101; C07D
471/04 20130101; C07D 241/04 20130101; C07D 253/06 20130101; C07D
265/02 20130101 |
Class at
Publication: |
514/252.14 ;
514/269; 544/295; 544/316 |
International
Class: |
A61K 031/513; C07D
043/02 |
Claims
1. A compound having the structure: 47wherein X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each ring atoms defining
a 6-membered heterocyclic ring; X.sub.1, X.sub.3, and X.sub.4 are
independently carbon or nitrogen; X.sub.2, X.sub.5, and X.sub.6 are
independently carbon, nitrogen, oxygen or sulfur where X.sub.5 and
X.sub.6 are optionally substituted with a halogen; provided no more
than 4 of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6
are sp.sup.2 hybridized; L.sub.1, L.sub.3 and L.sub.4 are linkages
through which Z.sub.1, Z.sub.3, and Z.sub.4, respectively, are
covalently bonded to different ring atoms of the 6-membered
heterocyclic ring defined by X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, and X.sub.6, wherein Z.sub.1 is covalently bonded to
X.sub.1, Z.sub.3 is covalently bonded to X.sub.3, and Z.sub.4 is
covalently bonded to X.sub.4, each of L.sub.1, L.sub.3 and L.sub.4
independently being a covalent bond or comprising one or more atoms
through which Z.sub.1, Z.sub.3, and Z.sub.4 are covalently bonded
to X.sub.1, X.sub.3 and X.sub.4, respectively; Z.sub.1 is
hydrocarbyl or substituted hydrocarbyl; Z.sub.2 is hydrogen, an
electron pair, or a hydrogen bond acceptor covalently or datively
bonded to X.sub.2; Z.sub.3 comprises a 5- or 6-membered
heterocyclic or aromatic ring substituted with an amidine or a
derivatized amidine group, the ring atoms of the 5- or 6-membered
heterocyclic or aromatic ring of Z.sub.3 being carbon, sulfur,
nitrogen, or oxygen, wherein the 5- or 6-membered ring is
optionally substituted at any position with halogen, hydroxy,
haloalkyl, alkyl, carboxy, alkoxycarbonyl, or hydrocarbyloxy; and
Z.sub.4 comprises a 5- or 6-membered heterocyclic or carbocyclic
ring, the ring atoms of the 5- or 6-membered heterocyclic or
carbocyclic ring of Z.sub.4 being carbon, nitrogen, oxygen, or
sulfur.
2. The compound of claim 1 wherein Z.sub.2 is a hydrogen bond
acceptor covalently or datively bonded to X.sub.2; Z.sub.3
comprises a 5- or 6-membered heterocyclic or aromatic ring
substituted with an amidine or derivatized amidine group, the ring
atoms of the 5- or 6-membered heterocyclic or aromatic ring of
Z.sub.3 being carbon, sulfur, nitrogen, or oxygen, wherein the 5-
or 6-membered ring is optionally substituted at any position with
halogen, hydroxy, haloalkyl, or alkyl; and X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, X.sub.6, L.sub.1, L.sub.3, L.sub.4,
Z.sub.1, and Z.sub.4 are as defined in claim 1.
3. The compound of claim 1 wherein X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, and X.sub.6 are independently selected from
carbon and nitrogen provided at least one of X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, and X.sub.6 is nitrogen.
4. The compound of claims 1 or 2 wherein X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, X.sub.6, and Z.sub.2 are selected to provide a
heterocyclic ring selected from the group consisting of
piperidinone, dihydropyrimidinone, tetrahydropyrimidinone,
dehydropiperidinedione, dihydropyridazinone, dihydroisoxazinone,
tetrahydrotriazinedione, tetrahydrotriazinone, piperidine, and
piperazine.
5. The compound of claims 1 or 2 wherein L.sub.1 is covalently
bonded directly to X.sub.6 to form a fused ring.
6. The compound of claims 1 or 2 wherein L.sub.1 is X.sub.9NH,
wherein X.sub.9 is covalently bonded to Z.sub.1, and X.sub.9 is a
bond or (CH.sub.2).sub.m, wherein m is 1 to 5.
7. The compound of claim 6 wherein X.sub.9 is a bond.
8. The compound of claims 1 or 2 wherein L.sub.3 is selected from
the group consisting of a glycine derivative, an alanine
derivative, an amino derivative, and a sulfonyl derivative.
9. The compound of claim 8 wherein L.sub.3 is
CH.sub.2CONHCH.sub.2.
10. The compound of claim 1 wherein L.sub.4 is selected from the
group consisting of a bond, methylene, ethylene, or an optionally
substituted heteroatom selected from nitrogen, oxygen, sulfur and
phosphorus.
11. The compound of claim 10 wherein L.sub.4 is a bond.
12. The compound of claim 1 wherein Z.sub.1 is selected from the
group consisting of cyclopropyl, isopropyl, methyl, ethyl,
cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally
substituted at any substitutable position with fluorine, hydroxy,
carboxy or alkoxycarbonyl.
13. The compound of claims 1 or 2 wherein the 5- or 6-membered
heterocyclic or aromatic ring comprising Z.sub.3 is substituted
with a derivatized amidine which, upon hydrolysis, oxidation,
reduction or elimination yields an amidine group.
14. The compound of claim 1 wherein Z.sub.3 comprises a substituted
phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl
ring being substituted with an amidine or a derivatized amidine
group, and optionally further substituted at any substitutable
position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or
hydrocarbyloxy;
15. The compound of claim 14 wherein Z.sub.3 is 48wherein R.sub.304
and R.sub.306 are independently selected from the group consisting
of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and
alkoxycarbonyl; and R.sub.305 and R.sub.307 are independently
selected from the group consisting of hydrogen, fluorine, methoxy,
hydroxy and carboxy.
16. The compound of claim 2 wherein the 5- or 6-membered
heterocyclic or aromatic ring comprising Z.sub.3 is optionally
substituted at any position with fluorine, methyl or hydroxy.
17. The compound of claim 1 wherein Z.sub.4 comprises a 5- or
6-membered heterocyclic or carbocyclic ring, the ring atoms of
Z.sub.4 being Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.44 and Z.sub.45
when Z.sub.4 is a 5-membered ring and Z.sub.40, Z.sub.41, Z.sub.42,
Z.sub.43, Z.sub.44 and Z.sub.45 when Z.sub.4 is a 6-membered ring,
Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.43, Z.sub.44 and Z.sub.45,
being carbon, nitrogen, oxygen or sulfur, Z.sub.40 being the ring
atom through which Z.sub.4 is attached to the heterocyclic core
ring, Z.sub.41 and Z.sub.45 each being in an alpha position
relative to Z.sub.40, Z.sub.42 and Z.sub.44 each being in a beta
position relative to Z.sub.40, Z.sub.43 being in the gamma position
relative to Z.sub.40 when Z.sub.4 is a 6-membered ring, Z.sub.4
having a substituent R.sub.42 covalently attached to Z.sub.42, and
a second substituent bonded to one of Z.sub.41, Z.sub.43, Z.sub.44,
or Z.sub.45, the substituent being R.sub.41 when bonded to
Z.sub.41, the substituent being R.sub.43 when bonded to Z.sub.43,
the substituent being R.sub.44 when bonded to Z.sub.44, and the
substituent being R.sub.45 when bonded to Z.sub.45; R.sub.42 is
amino; and R.sub.41, R.sub.43, R.sub.44 and R.sub.45 are
independently hydrogen, hydrocarbyl, substituted hydrocarbyl,
heterocyclo, halogen, or a substituted or unsubstituted heteroatom
selected from nitrogen, oxygen, sulfur and phosphorus, provided at
least one of R.sub.41, R.sub.43, R.sub.44 or R.sub.45 is other than
hydrogen.
18. The compound of claim 17 wherein R.sub.44 is selected from the
group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy,
nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted
hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio,
hydrocarbylsulfonyl, and substituted hydrocarbylsulfonyl.
19. The compound of claim 1 wherein the compound has the structure:
49wherein X.sub.9 is a bond or (CH.sub.2).sub.m wherein m is 1 or
2; and X.sub.1, X.sub.2, X.sub.3 X.sub.4, X.sub.5, X.sub.6,
Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 are as defined in claim
1.
20. The compound of claim 19 wherein X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, and X.sub.6 are independently selected from
carbon and nitrogen, and at least one of X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, and X.sub.6 is nitrogen.
21. The compound of claims 1 or 19 wherein X.sub.2 is carbon and
Z.sub.2 is hydrogen, fluorine, oxygen, or sulfur.
22. The compound of claims 1 or 19 wherein X.sub.2 is nitrogen,
oxygen or sulfur and Z.sub.2 is hydrogen, an electron pair, or a
hydrogen bond acceptor.
23. The compound of claims 1 or 19 wherein X.sub.2 is nitrogen and
Z.sub.2 is hydrogen, oxygen, amino, or acyl.
24. The compound of claims 1 or 19 wherein X.sub.3 is nitrogen.
25. The compound of claims 1 or 19 wherein X.sub.2 is carbon and
X.sub.3 is nitrogen.
26. The compound of claim 19 wherein X.sub.9 is a bond.
27. The compound of claim 26 wherein Z.sub.1 is C.sub.1-C.sub.5
alkyl optionally substituted at any substitutable position with
fluorine, hydroxy, carboxy or alkoxycarbonyl.
28. The compound of claim 19 wherein Z.sub.1 is selected from the
group consisting of cyclopropyl, isopropyl, methyl, ethyl,
cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally
substituted at any substitutable position with fluorine, hydroxy,
carboxy or alkoxycarbonyl.
29. The compound of claim 19 wherein the 5- or 6-membered
heterocyclic or aromatic ring comprising Z.sub.3 is substituted
with a derivatized amidine which, upon hydrolysis, oxidation,
reduction or elimination, or any combination thereof, yields an
amidine group.
30. The compound of 19 wherein Z.sub.3 is phenyl substituted with a
derivatized amidine which, upon hydrolysis, oxidation, reduction or
elimination, or any combination thereof, under physiological
conditions yields an amidine group.
31. The compound of claim 19 wherein Z.sub.3 comprises a
substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl
or furanyl ring being substituted with an amidine or a derivatized
amidine group, and optionally further substituted at any
substitutable position with fluorine, hydroxy, carboxy,
alkoxycarbonyl, or hydrocarbyloxy
32. The compound of claim 31 wherein Z.sub.3 is 50wherein R.sub.304
and R.sub.306 are independently selected from the group consisting
of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and
alkoxycarbonyl; and R.sub.305 and R.sub.307 are independently
selected from the group consisting of hydrogen, fluorine, methoxy,
hydroxy and carboxy.
33. The compound of claims 1 or 19 wherein Z.sub.4 is a
substituted, 6-membered, carbocyclic aromatic ring.
34. The compound of claim 19 wherein Z.sub.4 is 51wherein: R.sub.42
is amino; R.sub.44 is hydrocarbyl, substituted hydrocarbyl, halogen
or an optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur; and R.sub.41, R43 and
R.sub.45 are independently hydrogen, hydrocarbyl, substituted
hydrocarbyl, halogen or an optionally substituted heteroatom
selected from the group consisting of oxygen, nitrogen, and
sulfur.
35. The compound of claim 34 wherein R.sub.41, R.sub.43 and
R.sub.45 are independently hydrogen, halogen, alkoxy, or alkyl,
optionally substituted with halogen or alkoxy and R.sub.42 and
R.sub.44 are as defined in claim 34.
36. The compound of claim 34 wherein R.sub.44 is selected from the
group consisting of hydrocarbyl, substituted hydrocarbyl,
acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy,
haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and
sulfonamidyl, optionally substituted with fluorine.
37. The compound of claim 36 wherein R.sub.44 is selected from the
group consisting of hydroxy, carboxy, carboxamido, alkoxy,
alkylsulfonyl, sulfonamido, or alkoxycarbonyl.
38. The compound of claim 37 wherein R.sub.44 is sec-butylamide,
carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isopropylamide or hydroxy.
39. The compound of claim 34 wherein R.sub.44 is selected from the
group consisting of hydrocarbyl, substituted hydrocarbyl,
acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl,
haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl,
and carboxamidoalkylaryl.
40. The compound of claim 39 wherein each of R.sub.41, R.sub.43 and
R.sub.45 is hydrogen.
41. The compound of claim 36 wherein Z.sub.41, Z.sub.43 or Z.sub.45
is substituted with fluorine or chlorine.
42. The compound of claim 19 wherein Z.sub.4 is 52wherein R.sub.42
is amino; R.sub.43 is hydrocarbyl, substituted hydrocarbyl, halogen
or an optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur; and R.sub.41, R.sub.44
and R.sub.45 are independently hydrogen, halogen or alkoxy.
43. The compound of claim 19 wherein Z.sub.4 is 53wherein R.sub.42
is amino; R.sub.45 is hydrocarbyl, substituted hydrocarbyl, halogen
or an optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur; and R.sub.41, R.sub.43
and R.sub.44 are independently hydrogen, halogen or alkoxy.
44. The compound of claim 19 wherein Z.sub.4 is 54wherein R.sub.42
is amino; R.sub.41 is hydrocarbyl, substituted hydrocarbyl, halogen
or an optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur; and R.sub.43, R.sub.44
and R.sub.45 are independently hydrogen, halogen or alkoxy.
45. The compound of claim 19 wherein Z.sub.4 has the following
structure: 55wherein Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.44, and
Z.sub.45 are independently selected from the group consisting of
carbon, nitrogen, oxygen and sulfur; R.sub.42 is amino; R.sub.44 is
hydrocarbyl, substituted hydrocarbyl, halogen or an optionally
substituted heteroatom selected from the group consisting of
oxygen, nitrogen, and sulfur; and R.sub.41 and R.sub.45 are
independently hydrogen, hydrocarbyl, substituted hydrocarbyl,
halogen or an optionally substituted heteroatom selected from the
group consisting of oxygen, nitrogen, and sulfur.
46. The compound of claim 45 wherein R.sub.41 and R.sub.45 are
independently hydrogen, halogen, alkoxy, or alkyl, optionally
substituted with halogen or alkoxy and R.sub.42 and R.sub.44 are as
defined in claim 45.
47. The compound of claim 45 wherein R.sub.44 is selected from the
group consisting of hydroxy, carboxy, carboxamido, alkoxy,
alkylsulfonyl, sulfonamido, or alkoxycarbonyl.
48. The compound of claim 47 wherein R.sub.44 is sec-butylamide,
carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isopropylamide or hydroxy.
49. The compound of claims 1 or 19 wherein X.sub.9 is a bond,
Z.sub.1 is selected from the group consisting of cyclopropyl,
isopropyl, cyclobutyl, isobutyl, sec-butyl, methyl, ethyl, and
phenyl, and Z.sub.3 is phenyl substituted with an amidine
group.
50. The compound of claims 1 or 19 wherein X.sub.9 is a bond,
Z.sub.4 is a substituted, 6-membered, carbocyclic aromatic ring,
Z.sub.3 is phenyl substituted with a derivatized amidine which,
upon hydrolysis, oxidation, reduction or elimination under
physiological conditions yields an amidine group, and Z.sub.1 is
selected from the group consisting of cyclopropyl, isopropyl,
methyl, ethyl, cyclobutyl, isobutyl, sec-butyl, and phenyl.
51. The compound of claims 1 or 19 wherein X.sub.9 is a bond,
Z.sub.1 is selected from the group consisting of optionally
substituted C.sub.1-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl and
phenyl, Z.sub.3 is phenyl substituted with a derivatized amidine
which, upon hydrolysis, oxidation, reduction or elimination under
physiological conditions yields an amidine group, and Z.sub.4 is
56wherein R.sub.42 is amino; R.sub.44 is selected from the group
consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an
optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur; and R.sub.41, R.sub.43
and R.sub.45 are independently selected from the group consisting
of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen and an
optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur.
52. The compound of claim 51 wherein R.sub.44 is selected from the
group consisting of hydroxy, alkylsulfonyl, haloalkyl, haloalkoxy,
haloalkylthio, carboxamidoalkyl, and carboxamidoalkylaryl.
53. The compound of claim 51 wherein each of R.sub.41, R.sub.43 and
R.sub.45 is hydrogen.
54. The compound of claim 51 wherein R.sub.44 is selected from the
group consisting of hydrocarbyl, substituted hydrocarbyl,
acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy,
haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and
sulfonamidyl, optionally substituted with fluorine; and each of
Z.sub.41, Z.sub.43 and Z.sub.45 is optionally substituted with
fluorine or chlorine.
55. The compound of claim 54 wherein R.sub.44 is sec-butylamide,
carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isopropylamide or hydroxy.
56. The compound of any of claims 1 or 19 wherein the 6-membered
heterocyclic ring defined by X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, and Z.sub.2 is selected from the group consisting
of piperidinone, dihydropyrimidinone, tetrahydropyrimidinone,
tetrahydrotriazinone, piperidine, and piperazine.
57. The compound of claim 1 having the structure: 57wherein
X.sub.1, X.sub.4, X.sub.5 and X.sub.6 are independently carbon or
nitrogen; Z.sub.1 is selected from the group consisting of
cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl,
tert-butyl, sec-butyl, and phenyl optionally substituted with
fluorine, hydroxy, carboxy, or alkoxycarbonyl; R.sub.440 is
C.sub.1-C.sub.6 alkyl, aryl, aralkyl, carboxy, or carboxyalkyl,
wherein said alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is
optionally further substituted by fluorine; and R.sub.310 and
R.sub.311 are independently selected from the group consisting of
hydrogen, fluorine, hydroxy, alkoxy, and carboxy.
58. The compound of claim 1 having the structure: 58wherein
X.sub.1, X.sub.4, X.sub.5 and X.sub.6 are independently carbon or
nitrogen; Z.sub.1 is selected from the group consisting of
cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl,
tert-butyl, sec-butyl, and phenyl optionally substituted with
fluorine, hydroxy, carboxy, or alkoxycarbonyl; R.sub.440 is
C.sub.1-C.sub.6 alkyl, aryl, aralkyl, carboxy, or carboxyalkyl,
wherein said alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is
optionally further substituted by fluorine; and R.sub.310 and
R.sub.311 are independently selected from the group consisting of
hydrogen, fluorine, hydroxy, alkoxy, and carboxy.
59. A compound having the structure: 59wherein X.sub.1, X.sub.2,
X.sub.5, and X.sub.6 are members of a heterocyclic ring; X.sub.1,
X.sub.2 and X.sub.3 are independently carbon or nitrogen; X.sub.5
and X.sub.6 are independently selected from the group consisting of
nitrogen, oxygen, sulfur, carbon, C(F) and C(Br); provided no more
than 4 of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6
are sp.sup.2 hybridized; T.sub.3is selected from the group
consisting of hydroxy, alkoxy, substituted alkoxy, and substituted
amino; T.sub.4 is selected from the group consisting of --Cl, --Br,
--I, --S(CH.sub.3), and --OSO.sub.2(CF.sub.3); Z.sub.1 is
hydrocarbyl, or substituted hydrocarbyl; and Z.sub.2 is a hydrogen
bond acceptor covalently or datively bonded to X.sub.2.
60. A compound having the structure: 60wherein X.sub.1, X.sub.2,
X.sub.5, and X.sub.6 are members of a heterocyclic ring; X.sub.1,
X.sub.2 and X.sub.3 are independently carbon or nitrogen; X.sub.5
and X.sub.6 are independently selected from the group consisting of
nitrogen, oxygen, sulfur, carbon, C(F) and C (Br); provided no more
than 4 of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6
are sp.sup.2 hybridized; Z.sub.4 comprises hydrocarbyl, substituted
hydrocarbyl or a 5 or 6 membered heterocyclic or carbocyclic ring,
the ring atoms of the 5 or 6 membered heterocyclic or carboxylic
ring of Z.sub.4 being carbon, nitrogen, oxygen, or sulfur; Z.sub.1
is hydrocarbyl, or substituted hydrocarbyl; and Z.sub.2 is a
hydrogen bond acceptor covalently or datively bonded to
X.sub.2.
61. The compound of claim 1 having the structure: 61wherein
Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, L.sub.3, X.sub.1, X.sub.2,
X.sub.3, X.sub.4, and X.sub.5 are as defined in claim 1; X.sub.6 is
carbon or nitrogen; X.sub.7 and X.sub.8 are independently carbon,
nitrogen, oxygen or sulfur; R.sub.70 and R.sub.80 are independently
selected from the group consisting of hydrogen, halogen, amino,
hydrocarbyl, substituted hydrocarbyl, phenyl optionally substituted
by hydroxy, amino, C.sub.1-C.sub.8 alkyl, or halogen provided that
R.sub.70 is not present when X.sub.7 is a bond and R.sub.80 is not
present when X.sub.8 is a bond; or R.sub.70 and R.sub.80, along
with the ring atoms to which each is attached, form a 5- or
6-membered saturated ring; and n is 0 to 2.
62. The compound of claim 61 having the structure: 62wherein
X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7,
X.sub.8, Z.sub.1, Z.sub.3, Z.sub.4, R.sub.70, R.sub.80 and n are as
defined in claim 61.
63. The compound of claim 62 wherein X.sub.7 and X.sub.8 are
carbon.
64. The compound of claim 62 wherein Z.sub.4 is 63wherein: R.sub.42
is amino; R.sub.44 is hydrocarbyl, substituted hydrocarbyl, halogen
or an optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur; and R.sub.41, R.sub.43
and R.sub.45 are independently hydrogen, hydrocarbyl, substituted
hydrocarbyl, halogen or an optionally substituted heteroatom
selected from the group consisting of oxygen, nitrogen, and
sulfur.
65. The compound of claim 62 wherein Z.sub.1 is methyl, ethyl,
isopropyl, cyclopropyl, sec-butyl, tert-butyl, and cyclobutyl
optionally substituted at any substitutable position with fluorine,
hydroxy, carboxy or alkoxycarbonyl.
66. The compound of claim 62 wherein Z.sub.3 is 64wherein R.sub.304
and R.sub.306 are independently selected from the group consisting
of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy, and
alkoxycarbonyl; and R.sub.305 and R.sub.307 are independently
selected from the group consisting of hydrogen, fluorine, methoxy,
hydroxy, and carboxy.
67. A compound having the structure: 65wherein Z.sub.1 is selected
from the group consisting of an optionally substituted C.sub.2 to
C.sub.8 alkyl, optionally substituted C.sub.3 to C.sub.6 cycloalkyl
and optionally substituted phenyl; Z.sub.3 comprises a 5- or
6-membered heterocyclic or aromatic ring substituted with an
amidine or a derivatized amidine group which, upon hydrolysis,
oxidation, reduction or elimination yields an amidine group, the
ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of
Z.sub.3 being carbon, sulfur, nitrogen, or oxygen; Z.sub.4
comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the
ring atoms of Z.sub.4 being Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.44
and Z.sub.45 when Z.sub.4 is a 5-membered ring and Z.sub.40,
Z.sub.41, Z.sub.42, Z.sub.43, Z.sub.44 and Z.sub.45 when Z.sub.4 is
a 6-membered ring, Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.43, Z.sub.44
and Z.sub.45, being carbon, nitrogen, oxygen or sulfur, Z.sub.40
being the ring atom through which Z.sub.4 is attached to the
heterocyclic core ring, Z.sub.41 and Z.sub.45each being in an alpha
position relative to Z.sub.40, Z.sub.42 and Z.sub.44 each being in
a beta position relative to Z.sub.40, Z.sub.43 being in the gamma
position relative to Z.sub.40 when Z.sub.4 is a 6-membered ring,
Z.sub.4 having a substituent R.sub.42 covalently attached to
Z.sub.42, and a second substituent bonded to one of Z.sub.41,
Z.sub.43, Z.sub.44, or Z.sub.45, the substituent being R41 when
bonded to Z.sub.41, the substituent being R.sub.43 when bonded to
Z.sub.43, the substituent being R.sub.44 when bonded to Z.sub.44,
and the substituent being R.sub.45 when bonded to Z.sub.45;
R.sub.42 is amino; and R.sub.41, R.sub.43, R.sub.44 and R.sub.45
are independently hydrogen, hydrocarbyl, substituted hydrocarbyl,
heterocyclo, halogen, or a substituted or unsubstituted heteroatom
selected from nitrogen, oxygen, sulfur and phosphorus, provided at
least one of R.sub.41, R.sub.43, R.sub.44 or R.sub.45 is other than
hydrogen.
68. The compound of claim 67 wherein Z.sub.1 is selected from the
group consisting of cyclopropyl, isopropyl, methyl, ethyl,
cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionally
substituted at any substitutable position with fluorine, hydroxy,
carboxy or alkoxycarbonyl.
69. The compound of claim 68 wherein Z.sub.1 is cyclopropyl or
isopropyl optionally substituted at any substitutable position with
fluorine, hydroxy, carboxy or alkoxycarbonyl.
70. The compound of claim 67 wherein Z.sub.3 comprises a
substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl
or furanyl ring being substituted with an amidine or a derivatized
amidine group, and optionally further substituted at any
substitutable position with fluorine, hydroxy, carboxy,
alkoxycarbonyl, or hydrocarbyloxy.
71. The compound of claim 70 wherein Z.sub.3 is 66wherein R.sub.304
and R.sub.306 are independently selected from the group consisting
of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and
alkoxycarbonyl; and R.sub.305 and R.sub.307 are independently
selected from the group consisting of hydrogen, fluorine, methoxy,
hydroxy and carboxy.
72. The compound of claim 70 wherein the 5- or 6-membered
heterocyclic or aromatic ring comprising Z.sub.3 is substituted
with a derivatized amidine which, upon hydrolysis, oxidation,
reduction or elimination, or any combination thereof, yields an
amidine group.
73. The compound of claim 67 wherein Z.sub.4 has the following
structure: 67wherein R.sub.42 is amino; R.sub.44 is hydrocarbyl,
substituted hydrocarbyl, halogen or an optionally substituted
heteroatom selected from the group consisting of oxygen, nitrogen,
and sulfur; and R.sub.41, R.sub.43 and R.sub.45 are independently
hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen or an
optionally substituted heteroatom selected from the group
consisting of oxygen, nitrogen, and sulfur.
74. The compound of claim 73 wherein R.sub.41, R.sub.43 and
R.sub.45 are independently hydrogen, halogen, alkoxy, or alkyl,
optionally substituted with halogen or alkoxy and R.sub.42 and
R.sub.44 are as defined in claim 73.
75. The compound of claim 73 wherein R.sub.44 is selected from the
group consisting of hydroxy, carboxy, carboxamido, alkoxy,
alkylsulfonyl, sulfonamido, or alkoxycarbonyl.
76. The compound of claim 75 wherein R.sub.44 is sec-butylamide,
carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isopropylamide or hydroxy.
77. The compound of claim 67 wherein Z.sub.4 has the following
structure: 68wherein Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.44, and
Z.sub.45 are independently selected from the group consisting of
carbon, nitrogen, oxygen and sulfur; R.sub.42 is amino; R.sub.44 is
hydrocarbyl, substituted hydrocarbyl, halogen or an optionally
substituted heteroatom selected from the group consisting of
oxygen, nitrogen, and sulfur; and R.sub.41 and R.sub.45 are
independently hydrogen, hydrocarbyl, substituted hydrocarbyl,
halogen or an optionally substituted heteroatom selected from the
group consisting of oxygen, nitrogen, and sulfur.
78. The compound of claim 77 wherein R.sub.41 and R.sub.45 are
independently hydrogen, halogen, alkoxy, or alkyl, optionally
substituted with halogen or alkoxy and R.sub.42 and R.sub.44 are as
defined in claim 77.
79. The compound of claim 77 wherein R.sub.44 is selected from the
group consisting of hydroxy, carboxy, carboxamido, alkoxy,
alkylsulfonyl, sulfonamido, or alkoxycarbonyl.
80. The compound of claim 79 wherein R.sub.44 is sec-butylamide,
carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isopropylamide or hydroxy.
81. A composition for substantially inhibiting thrombotic
conditions in blood comprising a compound of claims 1 or 19 and a
pharmaceutically acceptable carrier.
82. A method for substantially inhibiting thrombotic conditions in
blood comprising adding to blood a therapeutically effective amount
of the composition of claim 81.
83. A method for substantially inhibiting formation of blood
platelet aggregates in blood comprising adding to blood a
therapeutically effective amount of the composition of claim
81.
84. A method for substantially inhibiting thrombus formation in
blood comprising adding to blood a therapeutically effective amount
of the composition of claim 81.
85. A method for treating or preventing venuous thromboembolism and
pulmonary embolism in a mammal comprising administering to the
mammal a therapeutically effective amount of the composition of
claim 81.
86. A method for treating or preventing deep vein thrombosis in a
mammal comprising administering to the mammal a therapeutically
effective amount of the composition of claim 81.
87. A method for treating or preventing cardiogenic thromboembolism
in a mammal comprising administering to the mammal a
therapeutically effective amount of the composition of claim
81.
88. A method for treating or preventing thromboembolic stroke in
mammals comprising administering to the mammal a therapeutically
effective amount of the composition of claim 81.
89. A method for treating or preventing thrombosis associated with
cancer and cancer chemotherapy in mammals comprising administering
to the mammal a therapeutically effective amount of the composition
of claim 81.
90. A method for treating or preventing unstable angina in mammals
comprising administering to the mammal a therapeutically effective
amount of the composition of claim 81.
91. A method for substantially inhibiting thrombus formation in
blood comprising adding to blood a therapeutically effective amount
of the composition of claim 81 with a therapeutically effective
amount of fibrinogen receptor antagonist.
92. The method of any of claims 85-91 wherein the mammal is a
human.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from Provisional
Application Ser. Nos. 60/326,721 filed Oct. 3, 2001, 60/338,623
filed Oct. 24, 2001, 60/332,857 filed Nov. 6, 2001, 60/350,052
filed on Nov. 7, 2001, and 60/332,107 and 60/331,891 both filed on
Nov. 21, 2001, which are all hereby incorporated by reference in
their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds, compositions and
methods for preventing and treating thrombotic conditions such as
coronary artery and cerebrovascular disease. More particularly, the
invention relates to compounds, and prodrugs thereof, that
selectively inhibit serine proteases of the coagulation
cascade.
BACKGROUND OF THE INVENTION
[0003] Hemorrhage, intravascular thrombosis, and embolism are
common clinical manifestations of many diseases (see R. I. Handin
in Harrison's Principles of Internal Medicine (J. D. Wilson, et al.
eds., 12th ed. 1991) New York, McGraw-Hill Book Co., pp. 348-351).
The normal hemostatic system limits blood loss by precisely
regulated interactions between components of the vessel wall,
circulating blood platelets, and plasma proteins. Unregulated
activation of the hemostatic system, however, may cause thrombosis,
which can reduce blood flow to critical organs like the brain and
myocardium.
[0004] Physiological systems control the fluidity of blood in
mammals (see P. W. Majerus, et al. in Goodman & Gilman's The
Pharmacological Basis of Therapeutics (J. G. Hardman & L. E.
Limbird, eds., 9th ed. 1996) New York, McGraw-Hill Book Co., pp.
1341-1343). Blood must remain fluid within the vascular systems and
yet quickly be able to undergo hemostasis. Hemostasis, or clotting,
begins when platelets first adhere to macromolecules in
subendothelian regions of injured and/or damaged blood vessels.
These platelets aggregate to form the primary hemostatic plug and
stimulate local activation of plasma coagulation factors leading to
generation of a fibrin clot-that reinforces the aggregated
platelets. Plasma coagulation factors, also referred to as protease
zymogens, include factors II, V, VII, VIII, IX, X, XI, and XII.
These coagulation factors or protease zymogens are activated by
serine proteases leading to coagulation in a so called "coagulation
cascade" or chain reaction.
[0005] Coagulation or clotting occurs in two ways through different
pathways. An intrinsic or contact pathway leads from XII to XIIa to
XIa to IXa and to the conversion of X to Xa. Factor Xa in
combination with factor Va converts prothrombin (II) to thrombin
(IIa) leading to conversion of fibrinogen to fibrin. Polymerization
of fibrin leads to a fibrin clot. An extrinsic pathway is initiated
by the conversion of coagulation factor VII to VIIa by factor Xa.
Factor VIIa, a plasma protease, is exposed to, and combines with
its essential cofactor tissue factor (TF) which resides
constitutively beneath the endothelium. The resulting factor
VIIa/TF complex proteolytically activates its substrates, factors
IX and X, triggering a cascade of reactions that leads to the
generation of thrombin and a fibrin clot as described above.
[0006] While clotting as a result of an injury to a blood vessel is
a critical physiological process for mammals, clotting can also
lead to disease states. A pathological process called thrombosis
results when platelet aggregation and/or a fibrin clot blocks
(i.e., occludes) a blood vessel. Arterial thrombosis may result in
ischemic necrosis of the tissue supplied by the artery. When the
thrombosis occurs in a coronary artery, a myocardial infarction or
heart attack can result. A thrombosis occurring in a vein may cause
tissues drained by the vein to become edematous and inflamed.
Thrombosis of a deep vein may be complicated by a pulmonary
embolism. Preventing or treating clots in a blood vessel may be
therapeutically useful by inhibiting formation of blood platelet
aggregates, inhibiting formation of fibrin, inhibiting thrombus
formation, inhibiting embolus formation, and for treating or
preventing unstable angina, refractory angina, myocardial
infarction, transient ischemic attacks, atrial fibrillation,
thrombotic stroke, embolic stroke, deep vein thrombosis,
disseminated intravascular coagulation, ocular build up of fibrin,
and reocclusion or restenosis of recanalized vessels.
[0007] In order to treat such conditions, researchers have sought
to discover chemical compounds that efficaciously and selectively
control the clotting process. In addition, such compounds may
provide a better understanding of the pathways involved in the
coagulation process.
[0008] Thus far, many of the compounds that have been discovered
possess a polar or basic functional group which is integrally
responsible for the desired biological activity. Frequently, this
polar functional group is a nitrogen atom of, for example, a
guanidine, alkyl-amidine or aryl-amidine group. Because these
functionalities are highly basic, they remain protonated at
physiologically relevant pH's. The ionic nature of such protonated
species hinders their permeability across lipophilic membranes,
which can reduce bioavailability when the pharmaceutical agent is
administered orally.
[0009] In order to circumvent such a problem, it is often
advantageous to perform a derivatization or chemical modification
of the polar functionality such that the pharmaceutical agent
becomes neutrally charged and more lipophilic, thereby facilitating
absorption of the drug. However, for the derivatization to be
useful, the derivatization must be bioconvertable at the target
site or sites of desired pharmacological activity and cleaved under
normal physiological conditions to yield the biologically active
drug. The term "prodrug" has been used to denote such a chemically
modified intermediate.
SUMMARY OF THE INVENTION
[0010] Among the various aspects of the present invention,
therefore, is the provision of compounds useful for selective
inhibition of certain enzymes that act upon the coagulation cascade
thereby preventing and treating thrombotic conditions in
mammals.
[0011] Another aspect of the present invention is the provision of
prodrug compounds useful for selective inhibition of certain
enzymes that act upon the coagulation cascade thereby preventing
and treating thrombotic conditions in mammals. In general, these
prodrug compounds undergo hydrolysis, oxidation, reduction or
elimination at a derivatized amidine group to yield the active
compound.
[0012] Briefly, therefore, the present invention is directed to a
compound, per se, to the prodrug of the compound, to pharmaceutical
compositions comprising the compound or prodrug and a
pharmaceutically acceptable carrier, and to methods of use. The
compound corresponds to formula (1): 1
[0013] wherein:
[0014] X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are
each ring atoms defining a 6-membered heterocyclic ring;
[0015] X.sub.1, X.sub.3, and X.sub.4 are independently carbon or
nitrogen;
[0016] X.sub.2, X.sub.5, and X.sub.6 are independently carbon,
nitrogen, oxygen or sulfur, where X.sub.5 and X.sub.6 are
optionally substituted with a halogen, provided no more than 4 of
X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are
sp.sup.2 hybridized;
[0017] L.sub.1, L.sub.3 and L.sub.4 are linkages through which
Z.sub.1, Z.sub.3, and Z.sub.4, respectively, are covalently bonded
to different ring atoms of the 6-membered heterocyclic ring defined
by X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6,
wherein Z.sub.1 is covalently bonded to X.sub.1, Z.sub.3 is
covalently bonded to X.sub.3, and Z.sub.4 is covalently bonded to
X.sub.4, each of L.sub.1, L.sub.3 and L.sub.4 independently being a
covalent bond or comprising one or more atoms through which
Z.sub.1, Z.sub.3, and Z.sub.4 are covalently bonded to X.sub.1,
X.sub.3 and X.sub.4, respectively;
[0018] Z.sub.1 is hydrocarbyl or substituted hydrocarbyl;
[0019] Z.sub.2 is hydrogen, an electron pair, or a hydrogen bond
acceptor covalently or datively bonded to X.sub.2;
[0020] Z.sub.3 comprises a 5- or 6-membered heterocyclic or
aromatic ring substituted with an amidine or a derivatized amidine
group, the ring atoms of the 5- or 6-membered heterocyclic or
aromatic ring of Z.sub.3 being carbon, sulfur, nitrogen, or oxygen
wherein the 5- or 6-membered ring is optionally substituted at any
position with halogen, hydroxy, haloalkyl, alkyl, carboxy,
alkoxycarbonyl, or hydrocarbyloxy; and
[0021] Z.sub.4 comprises a 5- or 6-membered heterocyclic or
carbocyclic ring, the ring atoms of the 5- or 6-membered
heterocyclic or carbocyclic ring of Z.sub.4 being carbon, nitrogen,
oxygen, or sulfur.
[0022] Other aspects and features of this invention will be in part
apparent and in part pointed out hereafter.
[0023] Abbreviations and Definitions
[0024] The term "elimination" as used herein is generally meant to
encompass any one or more of the following reactions: (1) a
reaction that results in a compound fragmenting into two or more
compounds; and (2) a reaction that results in one or more groups
being removed from a compound without being replaced by other
groups.
[0025] The term "oxidation" as used herein is generally meant to
encompass any one or more of the following reactions: (1) a
reaction that results in an increase in the oxidation number of an
atom in a compound, whether the atom is uncharged or charged and
whether free or covalently bound; (2) a reaction that results in
the loss of hydrogen from a compound; (3) a reaction that results
in the loss or removal of one or more electrons from a compound,
with or without concomitant loss or removal of a proton or protons;
(4) the action or process of reacting a compound with oxygen; and
(5) a reaction that results in the addition of one or more oxygen
atoms to a compound.
[0026] The term "reduction" as used herein is generally meant to
encompass any one or more of the following reactions: (1) any
reaction which results in a decrease in the oxidation number of an
atom in a compound; and (2) any reaction that results in oxygen
being withdrawn from, hydrogen being added to, or an electron being
added to (with or without the addition of a proton) a compound.
[0027] The term "hydrolysis" as used herein is generally meant to
encompass any one or more of the following reactions: (1) any
reaction which results in the addition of a nucleophile to a
compound to form a new bond with concurrent loss of a group from
the compound; (2) any reaction which results in the addition of
water to a compound; and (3) any reaction that results in the
rupture of one or more chemical bonds by reaction with, and
involving the addition of, the elements of water.
[0028] The term "physiological conditions" are those conditions
characteristic to an organism's (to a human beings) healthy or
normal functioning.
[0029] The terms "hydrocarbon" and "hydrocarbyl" as used herein
describe organic compounds or radicals consisting exclusively of
the elements carbon and hydrogen. These moieties include alkyl,
alkenyl, alkynyl, and aryl moieties. These moieties also include
alkyl, alkenyl, alkynyl, and aryl moieties substituted with other
aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl
and alkynaryl. Unless otherwise indicated, these moieties
preferably comprise 1 to 20 carbon atoms.
[0030] The "substituted hydrocarbyl" moieties described herein are
hydrocarbyl moieties which are substituted with at least one atom
other than carbon, including moieties in which a carbon chain atom
is substituted with a heteroatom such as nitrogen, oxygen, silicon,
phosphorus, boron, sulfur, or a halogen atom. Exemplary substituted
hydrocarbyl moieties include, heterocyclo, alkoxyalkyl,
alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, hydroxyalkyl,
protected hydroxyalkyl, keto, acyl, nitroalkyl, aminoalkyl, cyano,
alkylalkylthio, arylalkylthio, ketals, acetals, amides, acids,
esters and the like.
[0031] The term "heteroatom" shall mean atoms other than carbon and
hydrogen.
[0032] Unless otherwise indicated, the alkyl groups described
herein are preferably lower alkyl containing from one to eight
carbon atoms in the principal chain and up to 20 carbon atoms. They
may be straight or branched chain or cyclic and include methyl,
ethyl, propyl, isopropyl, cyclopropyl, butyl, hexyl and the
like.
[0033] Unless otherwise indicated, the alkenyl groups described
herein are preferably lower alkenyl containing from two to eight
carbon atoms in the principal chain and up to 20 carbon atoms. They
may be straight or branched chain or cyclic and include ethenyl,
propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the
like.
[0034] Unless otherwise indicated, the alkynyl groups described
herein are preferably lower alkynyl containing from two to eight
carbon atoms in the principal chain and up to 20 carbon atoms. They
may be straight or branched chain and include ethynyl, propynyl,
butynyl, isobutynyl, hexynyl, and the like.
[0035] The terms "aryl" or "ar" as used herein alone or as part of
another group denote optionally substituted homocyclic aromatic
groups, preferably monocyclic or bicyclic groups containing from 6
to 12 carbons in the ring portion, such as phenyl, biphenyl,
naphthyl, substituted phenyl, substituted biphenyl or substituted
naphthyl. Phenyl and substituted phenyl are the more preferred
aryl.
[0036] The terms "halogen" or "halo" as used herein alone or as
part of another group refer to chlorine, bromine, fluorine, and
iodine.
[0037] The terms "heterocyclo" or "heterocyclic" as used herein
alone or as part of another group denote optionally substituted,
fully saturated or unsaturated, monocyclic or bicyclic, aromatic or
nonaromatic groups having at least one heteroatom in at least one
ring, and preferably 5 or 6 atoms in each ring. The heterocyclo
group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms,
and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the
remainder of the molecule through a carbon or heteroatom. Exemplary
heterocyclos include heteroaromatics such as furanyl, thienyl,
pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl
and the like. Exemplary substituents include one or more of the
following groups: hydrocarbyl, substituted hydrocarbyl, keto,
hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy,
alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol,
ketals, acetals, esters and ethers.
[0038] The term "heteroaromatic" as used herein alone or as part of
another group denote optionally substituted aromatic groups having
at least one heteroatom in at least one ring, and preferably 5 or 6
atoms in each ring. The heteroaromatic group preferably has 1 or 2
oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in
the ring, and may be bonded to the remainder of the molecule
through a carbon or heteroatom. Exemplary heteroaromatics include
furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl,
or isoquinolinyl and the like. Exemplary substituents include one
or more of the following groups: hydrocarbyl, substituted
hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy,
alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro,
cyano, thiol, ketals, acetals, esters and ethers.
[0039] The term "acetamidyl" as used herein describes a chemical
moiety represented by the formula NR.sub.1C(O)R.sub.2.
[0040] The term "carboxamido" as used herein, describes a chemical
moiety represented by the formula C(O)NR.sub.1R.sub.2.
[0041] The term "alkoxycarbonyl" as used herein describes a
chemical moiety represented by the formula C(O)OR.
[0042] The term "sulfonamido" as used herein describes a chemical
moiety represented by the formula SO.sub.2NR.sub.1R.sub.2.
[0043] The term "alkylsulfonyl" as used herein describes a chemical
moiety represented by the formula SO.sub.2R.
[0044] The term "sulfonamidyl" as used herein describes a chemical
moiety represented by the formula NRSO.sub.2R.
[0045] As described herein for the terms "acetamidyl",
"carboxamido", "alkocycarbonyl", "sulfonamido", "alkylsulfonyl",
and "sulfonamidyl", R, R.sub.1 and R.sub.2 are independently
hydrogen, alkyl, aryl, and arylakyl, optionally substituted with
halogen, hydroxy or alkoxy.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0046] In one embodiment of the present invention, the compounds
correspond to formula (1): 2
[0047] wherein:
[0048] X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are
each ring atoms defining a 6-membered heterocyclic ring;
[0049] X.sub.1, X.sub.3, and X.sub.4 are independently carbon or
nitrogen;
[0050] X.sub.2, X.sub.5, and X.sub.6 are independently carbon,
nitrogen, oxygen or sulfur where X.sub.5 and X.sub.6 are optionally
substituted with a halogen, provided no more than 4 of X.sub.1,
X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are sp.sup.2
hybridized;
[0051] L.sub.1, L.sub.3 and L.sub.4 are linkages through which
Z.sub.1, Z.sub.3, and Z.sub.4, respectively, are covalently bonded
to different ring atoms of the 6-membered heterocyclic ring defined
by X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5 and X.sub.6, wherein
Z.sub.1 is covalently bonded to X.sub.1, Z.sub.3 is covalently
bonded to X.sub.3, and Z.sub.4 is covalently bonded to X.sub.4,
each of L.sub.1, L.sub.3 and L.sub.4 independently being a covalent
bond or comprising one or more atoms through which Z.sub.1,
Z.sub.3, and Z.sub.4 are covalently bonded to X.sub.1, X.sub.3 and
X.sub.4, respectively;
[0052] Z.sub.1 is hydrocarbyl or substituted hydrocarbyl;
[0053] Z.sub.2 is hydrogen, an electron pair, or a hydrogen bond
acceptor covalently or datively bonded to X.sub.2;
[0054] Z.sub.3 comprises a 5- or 6-membered heterocyclic or
aromatic ring substituted with an amidine or a derivatized amidine
group, the ring atoms of the 5- or 6-membered heterocyclic or
aromatic ring of Z.sub.3 being carbon, sulfur, nitrogen, or oxygen
wherein the 5- or 6-membered ring is optionally substituted at any
position with halogen, hydroxy, haloalkyl, alkyl, carboxy,
alkoxycarbonyl, or hydrocarbyloxy; and
[0055] Z.sub.4 comprises a 5- or 6-membered heterocyclic or
carbocyclic ring, the ring atoms of the 5- or 6-membered
heterocyclic or carbocyclic ring of Z.sub.4 being carbon, nitrogen,
oxygen, or sulfur.
[0056] One aspect of the invention encompasses compounds
corresponding to formula (1) wherein X.sub.1, X.sub.3, and X.sub.4
are independently carbon or nitrogen and X.sub.2, X.sub.5, and
X.sub.6 are independently carbon, nitrogen, oxygen or sulfur.
Typically, in this embodiment, no more than 4 of X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are sp.sup.2 hybridized. It
one alternative of this embodiment, X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, and X.sub.6 are independently carbon or nitrogen,
provided at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, and X.sub.6 is nitrogen. In another alternative of this
embodiment, X.sub.3 is nitrogen, X.sub.2 is carbon, and Z.sub.2 is
hydrogen, fluorine, oxygen, or sulfur. In yet another alternative
of this embodiment, X.sub.2 is nitrogen, oxygen or sulfur and
Z.sub.2 is hydrogen, an electron pair, or a hydrogen bond acceptor.
In yet another alternative of this embodiment, X.sub.2 is nitrogen
and Z.sub.2 is hydrogen, oxygen, amino, or acyl. In still another
alternative of this embodiment, X.sub.2 is carbon and X.sub.3 is
nitrogen. Still another alternative of this embodiment embraces
compounds where at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, and X.sub.6 is carbon and the carbon is sp.sup.3
hybridized. For each of the alternatives of this embodiment,
X.sub.5 may be optionally substituted with a halogen. A preferred
halogen is chlorine. A more preferred halogen is fluorine.
[0057] In another aspect of compounds corresponding to formula (1),
X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and Z.sub.2
are as defined for compounds having formula (1) above and are
selected to form the following 6-membered heterocyclic rings:
piperidinone, dihydropyrimidinone, tetrahydropyrimidinone,
dehydropiperidinedione, dihydropyridazinone, dihydroisoxazinone,
tetrahydrotriazinedione, tetrahydrotriazinone, piperidine, and
piperazine. In one alternative of this embodiment, X.sub.1,
X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and Z.sub.2 are
selected to form a heterocyclic ring selected from
tetrahydrotriazinone, piperidinone, dihydropyrimidinone,
tetrahydropyrimidinone, piperidine, and piperazine. In another
alternative of this embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, and Z.sub.2 are selected to form a heterocyclic
ring selected from tetrahydrotriazinone, piperidinone,
dihydropyrimidinone, and tetrahydropyrimidinone. In a preferred
alternative of this embodiment, the heterocyclic ring defined by
X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and Z.sub.2
is tetrahydrotriazinone.
[0058] In one embodiment of compounds having formula (1), L.sub.1,
is X.sub.9NH wherein X.sub.9 is covalently bonded to Z.sub.1 and
X.sub.9 is a bond or (CH.sub.2).sub.m wherein m is 1 to 5. In one
alternative of this embodiment (i.e., when L.sub.1 is X.sub.9NH), m
is 1 to 2. In another alternative of this embodiment, L.sub.1 is
X.sub.9NH wherein X.sub.9 is covalently bonded to Z.sub.1 and is a
bond. In yet another alternative of this embodiment, L.sub.1 is a
methylene or ethylene group. In another alternative of this
embodiment, L.sub.1 optionally contains a bond to X.sub.6 to form a
fused ring with the heterocyclic ring.
[0059] In one embodiment of compounds corresponding to formula (1),
L.sub.3 is selected from the group consisting of a glycine
derivative, an alanine derivative, an amino derivative, and a
sulfonyl derivative. In one alternative of this embodiment, L.sub.3
is a glycine derivative. In another alternative of this embodiment,
L.sub.3 is CH.sub.2CONHCH.sub.2 where Z.sub.3 is bonded to the
methylene bonded to the amine group.
[0060] In one embodiment of compounds corresponding to formula (1),
L.sub.4 is selected from the group consisting of a bond, methylene,
ethylene, or an optionally substituted heteroatom selected from
nitrogen, oxygen, sulfur and phosphorus. In one alternative of this
embodiment, L.sub.4 is (CH.sub.2).sub.m wherein m is 0 to 2. In a
preferred alternative of this embodiment, L.sub.4 is a bond.
[0061] In one embodiment of compounds corresponding to formula (1),
Z.sub.1 is hydrocarbyl or substituted hydrocarbyl. In one
alternative of this embodiment (i.e., when Z.sub.1 is hydrocarbyl
or substituted hydrocarbyl), Z.sub.1 is optionally substituted
C.sub.2 to C.sub.8 alkyl, optionally substituted C.sub.3 to C.sub.6
cycloalkyl and optionally substituted phenyl. In another
alternative of this embodiment, Z.sub.1 is selected from the group
consisting of optionally substituted cyclopropyl, isopropyl,
cyclobutyl, isobutyl, sec-butyl, methyl, ethyl, and phenyl. In
another alternative of this embodiment, Z.sub.1 is C.sub.1-C.sub.8
alkyl, C.sub.2-C.sub.8 alkenyl, or C.sub.2-C.sub.8 alkynyl, the
alkyl, alkenyl, or alkynyl being optionally substituted with
fluorine, hydroxy, carboxy, or alkoxycarbonyl. In yet another
alternative of this embodiment, Z.sub.1 is selected from the group
consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl,
isobutyl, tert-butyl, sec-butyl, and phenyl optionally substituted
at any substitutable position with fluorine, hydroxy, carboxy or
alkoxycarbonyl. In yet another alternative of this embodiment,
Z.sub.1 is propyl, isopropyl, cyclopropyl, tert-butyl and
cyclobutyl. In another alternative of this embodiment, Z.sub.1 is
cyclopropyl or isopropyl optionally substituted at any
substitutable position with fluorine, hydroxy, carboxy or
alkoxycarbonyl. In still another alternative of this embodiment,
Z.sub.1 is phenyl optionally substituted with fluorine, hydroxy,
carboxy, or alkoxycarbonyl. In yet another alternative of this
embodiment, Z.sub.1 is trifluoroethyl or carboxymethyl.
[0062] In one embodiment of compounds corresponding to formula (1),
Z.sub.2 is a hydrogen bond acceptor. Generally, hydrogen bond
acceptors are heteroatoms that have a lone pair of electrons
available for hydrogen bonding. When taken with the carbon to which
Z.sub.2 is attached, suitable hydrogen bond acceptors are selected
from the group consisting of C(O), C(S), C(Cl), C(Br), C(F), C(OH),
COCH.sub.3, COR, C(SH), CSR, and CNR.sub.1R.sub.2 wherein R,
R.sub.1 and R.sub.2 are independently hydrogen, alkyl, aryl, and
arylakyl, optionally substituted with halogen, hydroxy or
alkoxy.
[0063] In one embodiment of compounds corresponding to formula (1),
Z.sub.3 is a 5- or 6-membered heterocyclic or aromatic ring
substituted with an amidine or a derivatized amidine group and may
be optionally substituted at any substitutable position with
halogen, hydroxy, haloalkyl, alkyl, carboxy, alkoxycarbonyl, or
hydrocarbyloxy, or any combination thereof. A preferred halogen is
fluorine. In one alternative of this embodiment, directed toward
the prodrugs of the compounds of formula (1), the 5- or 6-membered
heterocyclic or aromatic ring comprising Z.sub.3 is substituted
with a derivatized amidine which, upon hydrolysis, oxidation,
reduction or elimination, or any combination thereof, yields an
amidine group. In another alternative of this embodiment, Z.sub.3
is a 6-membered carbocyclic aromatic ring substituted with either
an amidine group, or for embodiments directed toward the prodrug,
with a derivatized amidine. In yet another embodiment, Z.sub.3
comprises a substituted phenyl, thienyl, or furanyl ring, the
phenyl, thienyl or furanyl ring being substituted with an amidine
or a derivatized amidine group, and optionally further substituted
at any substitutable position with fluorine, hydroxy, carboxy,
alkoxycarbonyl, or hydrocarbyloxy. For embodiments directed toward
the prodrug, the amidine group is derivatized according to any of
the embodiments described more thoroughly below. In yet another
alternative of this embodiment, Z.sub.3 corresponds to formula (a):
3
[0064] wherein
[0065] R.sub.304 and R.sub.306 are independently selected from the
group consisting of hydrogen, fluorine, hydroxy, carboxy,
hydrocarbyloxy and alkoxycarbonyl; and
[0066] R.sub.305 and R.sub.307 are independently selected from the
group consisting of hydrogen, fluorine, methoxy, hydroxy and
carboxy.
[0067] In one alternative of compounds wherein Z.sub.3 corresponds
to formula (a), Z.sub.3 is selected from the group consisting of
benzamidine-4-yl, 3-hydroxybenzamidine-4-yl,
3,5-dihydroxybenzamidine-4-y- l,
2,5,6-trifluoro-3-hydroxybenzamidine-4-yl,
2-hydroxybenzamidine-4-yl and
3,5,6-trifluoro-2-hydroxybenzamidine-4-yl.
[0068] In one embodiment of compounds corresponding to formula (1),
Z.sub.4 comprises a 5- or 6-membered heterocyclic or carbocyclic
ring, the ring atoms of the 5- or 6-membered heterocyclic or
carbocyclic ring of Z.sub.4 being carbon, nitrogen, oxygen, or
sulfur. In one alternative of this embodiment, Z.sub.4 comprises a
5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms
of Z.sub.4 being Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.44 and
Z.sub.45 when Z.sub.4 is a 5-membered ring and Z.sub.40, Z.sub.41,
Z.sub.42, Z.sub.43, Z.sub.44 and Z.sub.45 when Z.sub.4 is a
6-membered ring, Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.43, Z.sub.44
and Z.sub.45, being carbon, nitrogen, oxygen or sulfur, Z.sub.40
being the ring atom through which Z.sub.4 is attached to the
heterocyclic core ring, Z.sub.41 and Z.sub.45 each being in an
alpha position relative to Z.sub.40, Z.sub.42 and Z.sub.44 each
being in a beta position relative to Z.sub.40, Z.sub.43 being in
the gamma position relative to Z.sub.40 when Z.sub.4 is a
6-membered ring, Z.sub.4 having a substituent R.sub.42 covalently
attached to Z.sub.42, and a second substituent bonded to one of
Z.sub.41, Z.sub.43, Z.sub.44, or Z.sub.45, the substituent being
R.sub.41 when bonded to Z.sub.41, the substituent being R.sub.43
when bonded to Z.sub.43, the substituent being R.sub.44 when bonded
to Z.sub.44, and the substituent being R.sub.45 when bonded to
Z.sub.45; R.sub.42 is amino; and R.sub.41, R.sub.43, R.sub.44 and
R.sub.45 are independently hydrogen, hydrocarbyl, substituted
hydrocarbyl, heterocyclo, halogen, or a substituted or
unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and
phosphorus, provided at least one of R.sub.41, R.sub.43, R.sub.44
or R.sub.45 is other than hydrogen. In another alternative of this
embodiment, Z.sub.4 is a substituted, 6-membered, carbocyclic
aromatic ring. In another alternative of this embodiment, Z.sub.4
corresponds to formula (b): 4
[0069] wherein
[0070] R.sub.42 is amino;
[0071] R.sub.44 is hydrocarbyl, substituted hydrocarbyl,
heterocyclo, halogen or a substituted or unsubstituted heteroatom
selected from nitrogen, oxygen, sulfur and phosphorus; and
R.sub.41, R.sub.43 and R.sub.45 are independently hydrogen,
hydrocarbyl, substituted hydrocarbyl, halogen or an optionally
substituted heteroatom selected from the group consisting of
oxygen, nitrogen, and sulfur.
[0072] In one embodiment of compounds wherein Z.sub.4 corresponds
to formula (b), R.sub.44 is hydrocarbyl, substituted hydrocarbyl,
heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy,
nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted
hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio,
hydrocarbylsulfonyl, or substituted hydrocarbylsulfonyl. In one
alternative of this embodiment, wherein Z.sub.4 corresponds to
formula (b), R.sub.44 is hydroxy, alkylsulfonyl, haloalkyl,
carboxamidoalkyl, or carboxamidoalkylaryl. In another alternative
of this embodiment, wherein Z.sub.4 corresponds to formula (b),
R.sub.44 is selected from the group consisting of hydrocarbyl,
substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino,
alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy,
sulfonamido, carboxamido and sulfonamidyl, optionally substituted
with fluorine. In still another alternative of this embodiment,
R.sub.44 is selected from the group consisting of hydroxy, carboxy,
carboxamido, alkoxy, alkylsulfonyl, sulfonamido, and
alkoxycarbonyl. In a preferred alternative of this embodiment,
R.sub.44 is sec-butylamide, carboxy, ethoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy. In
yet another alternative of this embodiment, each of R.sub.41,
R.sub.43 and R.sub.45 is hydrogen. In still yet another alternative
of this embodiment, Z.sub.41, Z.sub.43 or Z.sub.45 is substituted
with fluorine or chlorine. In another embodiment of this invention,
R.sub.44 is hydroxy, alkylsulfonyl, haloalkyl, carboxamidoalkyl, or
carboxamidoalkylaryl.
[0073] In one alternative of compounds wherein Z.sub.4 corresponds
to formula (b), R.sub.42 is amino; R.sub.43 is hydrocarbyl,
substituted hydrocarbyl, halogen or an optionally substituted
heteroatom selected from the group consisting of oxygen, nitrogen,
and sulfur; and R.sub.41, R.sub.44 and R.sub.45 are independently
hydrogen, halogen or alkoxy.
[0074] In another alternative of compounds wherein Z.sub.4
corresponds to formula (b), R.sub.42 is amino; R.sub.45is
hydrocarbyl, substituted hydrocarbyl, halogen or an optionally
substituted heteroatom selected from the group consisting of
oxygen, nitrogen, and sulfur; and R.sub.41, R.sub.43 and R.sub.44
are independently hydrogen, halogen or alkoxy.
[0075] In yet another alternative of compounds wherein Z.sub.4
corresponds to formula (b), R.sub.42 is amino; R.sub.41 is
hydrocarbyl, substituted hydrocarbyl, halogen or an optionally
substituted heteroatom selected from the group consisting of
oxygen, nitrogen, and sulfur; and R.sub.43, R.sub.44 and R.sub.45
are independently hydrogen, halogen or alkoxy.
[0076] In an alternative embodiment of compounds of formula (1),
Z.sub.4 corresponds to formula (c): 5
[0077] wherein
[0078] Z.sub.40, Z.sub.41, Z.sub.42, Z.sub.44, and Z.sub.45 are
independently carbon, nitrogen, oxygen or sulfur, and R.sub.41,
R.sub.42, R.sub.44, and R.sub.45 are as defined in connection with
the 6-membered carbocylic aromatic ring.
[0079] In another aspect of the invention, the compounds of formula
(1) may be represented by formula (2): 6
[0080] wherein X.sub.1, X.sub.2, X.sub.3 X.sub.4, X.sub.5, X.sub.6,
Z.sub.1, Z.sub.2, Z.sub.3, and Z.sub.4 are as described for
compounds having structural formula (1) and X.sub.9 is a direct
bond or (CH.sub.2).sub.m wherein m is 1 or 2. In one alternative of
this embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6, and Z.sub.2 are selected to provide a piperidinone,
dihydropyrimidinone, tetrahydropyrimidinone,
dehydropiperidinedione, dihydropyridazinone, dihydroisoxazinone,
tetrahydrotriazinedione, tetrahydrotriazinone, piperidine, and
piperazine heterocyclic ring and Z.sub.1, Z.sub.2, Z.sub.3, and
Z.sub.4 are as described for formula (1) and X.sub.9 is a bond. In
another alternative of this embodiment, X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, X.sub.6 and Z.sub.2 are selected to provide a
heterocyclic ring selected from tetrahydrotriazinone, piperidinone,
dihydropyrimidinone, tetrahydropyrimidinone, piperidine, and
piperazine. In yet another alternative of this embodiment, X.sub.1,
X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6 and Z.sub.2 are
selected to provide a heterocyclic ring selected from
tetrahydrotriazinone, piperidinone, dihydropyrimidinone, and
tetrahydropyrimidinone. In a preferred alternative of this
embodiment, the heterocyclic ring defined by X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, X.sub.6 and Z.sub.2 is
tetrahydrotriazinone.
[0081] In a preferred embodiment of compounds corresponding to
formula (2), X.sub.9 is a bond; Z.sub.1 is selected from the group
consisting of cyclopropyl, methyl, ethyl, isobutyl, tert-butyl, and
sec-butyl optionally substituted at any substitutable position with
fluorine, hydroxy, carboxy, or alkoxycarbonyl; Z.sub.3 corresponds
to formula (a) and is optionally substituted at any substitutable
position with fluorine, hydroxy, carboxy, or hydrocarbyloxy;
Z.sub.4 corresponds to formula (b) wherein R.sub.42 is amino and
R.sub.44 is selected from the group consisting of hydrocarbyl,
substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino,
alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy,
sulfonamido, carboxamido and sulfonamidyl, optionally substituted
with fluorine; and X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6 and Z.sub.2 are as defined above for compounds having
formula (1).
[0082] In a preferred embodiment, compounds corresponding to
formula (2) may be represented by formula (2-a): 7
[0083] wherein
[0084] X.sub.1, X.sub.4, X.sub.5 and X.sub.6 are independently
carbon or nitrogen;
[0085] Z.sub.1 is selected from the group consisting of
cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl,
tert-butyl, sec-butyl, and phenyl optionally substituted with
fluorine, hydroxy, carboxy, or alkoxycarbonyl;
[0086] R.sub.440 is C.sub.1-C.sub.6 alkyl, aryl, aralkyl, carboxy,
or carboxyalkyl, wherein said alkyl, aryl, aralkyl, carboxy, or
carboxyalkyl is optionally further substituted by fluorine; and
[0087] R.sub.310 and R.sub.311 are independently selected from the
group consisting of hydrogen, fluorine, hydroxy, alkoxy, and
carboxy.
[0088] In another preferred embodiment, compounds corresponding to
formula (2) may be represented by formula (2-b): 8
[0089] wherein
[0090] X.sub.1, X.sub.4, X.sub.5 and X.sub.6 are independently
carbon or nitrogen;
[0091] Z.sub.1 is selected from the group consisting of
cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl,
tert-butyl, sec-butyl, and phenyl optionally substituted with
fluorine, hydroxy, carboxy, or alkoxycarbonyl;
[0092] R.sub.440 is C.sub.1-C.sub.6 alkyl, aryl, aralkyl, carboxy,
or carboxyalkyl, wherein said alkyl, aryl, aralkyl, carboxy, or
carboxyalkyl is optionally further substituted by fluorine; and
[0093] R.sub.310 and R.sub.311 are independently selected from the
group consisting of hydrogen, fluorine, hydroxy, alkoxy, and
carboxy.
[0094] In a preferred alternative of compounds corresponding to
formula (2), the compounds possess a tetrahydrotriazinone
heterocyclic ring having formula (2-c): 9
[0095] wherein:
[0096] Z.sub.1, Z.sub.2, and Z.sub.3 are as defined for compounds
having either of formula (1) and formula (2) above.
[0097] In one alternative of this embodiment (i.e., compounds
having a tetrahydrotriazinone heterocyclic ring core), Z.sub.1 is
optionally substituted C.sub.2 to C.sub.8 alkyl, optionally
substituted C.sub.3 to C.sub.6 cycloalkyl and optionally
substituted phenyl. Preferred Z.sub.1 substituents are optionally
substituted cyclopropyl, isopropyl, cyclobutyl, methyl, ethyl and
phenyl. In another alternative of this embodiment, Z.sub.4 is a
substituted, 6-membered, heterocyclic or carbocyclic aromatic
ring.
[0098] Another aspect of the invention embraces compounds which
correspond to formula (1) having the following fused ring formula
(3): 10
[0099] wherein
[0100] Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, L.sub.3, X.sub.1,
X.sub.2, X.sub.3, X.sub.4, and X.sub.5 are as defined for compounds
having formula (1) or (2) above;
[0101] X.sub.6 is carbon or nitrogen;
[0102] X.sub.7 and X.sub.8 are independently carbon, nitrogen,
oxygen or sulfur;
[0103] R.sub.70 and R.sub.80 are independently selected from the
group consisting of hydrogen, halogen, amino, hydrocarbyl,
substituted hydrocarbyl, aryl, wherein aryl is phenyl optionally
substituted by hydroxy, amino, C.sub.1-C.sub.8 alkyl, or halogen
provided that R.sub.70 is not present when X.sub.7 is a bond and
R.sub.80 is not present when X.sub.8 is a bond; or R.sub.70 and
R.sub.80, along with the ring atoms to which each is attached, form
a 5- or 6-membered saturated ring; and
[0104] n is 0 to 2.
[0105] In a preferred embodiment of compounds of formula (3),
L.sub.3 is CH.sub.2CONHCH.sub.2. In one alternative of this
embodiment, (i.e., when L.sub.3 is CH.sub.2CONHCH.sub.2), X.sub.7
and X.sub.8 are carbon. In another alternative of this embodiment,
Z.sub.3 corresponds to formula (a) and Z.sub.4 corresponds to
formula (b).
[0106] In another aspect of this invention, compounds corresponding
to any of formulas (1), (2), or (3) possess a hydroxy or carboxy
substituent at any one of Z.sub.1, Z.sub.2 or Z.sub.3.
[0107] In another aspect of this invention for compounds
corresponding to any of formulas (1), (2), or (3), Z.sub.3 is
--R.sub.300C(.dbd.NR.sub.301- )NR.sub.302R.sub.303, wherein
R.sub.300 is a 6-membered carbocyclic aromatic ring, R.sub.301,
R.sub.302, R.sub.303 are independently selected from the group
consisting of hydrogen, halogen, optionally substituted
hydrocarbyl, and an optionally substituted heteroatom selected from
the group consisting of oxygen, nitrogen, phosphorus and sulfur,
provided at least one of R.sub.301, R.sub.302, R.sub.303 is other
than hydrogen. In yet another alternative of this embodiment,
Z.sub.3 is --R.sub.300C(.dbd.NR.sub.301)NR.sub.302R.sub.303,
wherein R.sub.300 is a 6-membered carbocyclic aromatic ring, and at
least two of R.sub.301, R.sub.302, R.sub.303 are ring atoms of a
heterocyclic ring. In an alternative of this embodiment, Z.sub.3 is
--R.sub.300C(.dbd.NR.sub.301)N- R.sub.302R.sub.303, wherein
R.sub.300 is a 6-membered carbocyclic aromatic ring, and at least
one of R.sub.301, R.sub.302, R.sub.303 are ring atoms of a
heterocyclic ring fused to R.sub.300.
[0108] In yet another aspect of this invention for compounds
corresponding to any of formulas (1), (2), or (3), Z.sub.3 is a
benzamidine derivatized with one or more groups selected from
carbonyl, thiocarbonyl, imino, enamino, phosphorus, and sulfur,
where the benzamidine derivative hydrolyzes under physiological
conditions to form benzamidine. In a further embodiment, Z.sub.3 is
a benzamidine derivatized with one or more groups selected from
optionally substituted hydrocarbyl, provided that the carbon atom
directly bonded to the amidine is sp.sup.3 hybridized and aryl,
where the benzamidine derivative is oxidized under physiological
conditions to form benzamidine. In yet another embodiment, Z.sub.3
is a benzamidine derivatized with one or more heteroatoms selected
from oxygen, nitrogen in its most reduced state, and sulfur in its
most reduced state, where the benzamidine derivative is reduced
under physiological conditions to form benzamidine. In still
another embodiment, Z.sub.3 is a benzamidine derivatized with one
or more substituents selected from a hydrocarbyl substituted at the
beta carbon with carbonyl, sulfonyl, sulfinyl, cyano, nitro and an
alkyl, aryl, or heterocyclic group substituted with oxygen,
nitrogen, or sulfur at the carbon directly bonded to the amidine
group, where the benzamidine derivative undergoes elimination at
physiological conditions to form benzamidine.
[0109] In a further embodiment for compounds corresponding to any
of formulas (1), (2), or (3), Z.sub.3 corresponds to formula (d):
11
[0110] wherein:
[0111] R.sub.301, R.sub.302, and R.sub.303 are independently
selected from the group consisting of:
[0112] (i) hydrogen, --C(.dbd.O)R.sub.a, --C(.dbd.O)OR.sub.a,
--S(.dbd.O)OR.sub.a, --S(.dbd.O)SR.sub.a,
--S(.dbd.O).sub.2OR.sub.a, --S(.dbd.O).sub.2SR.sub.a and alkenyl,
wherein R.sub.a is selected from the group consisting of
hydrocarbyl, substituted hydrocarbyl, and heterocylo, provided,
however, that the carbon atom of R.sub.301, R.sub.302, and
R.sub.303 directly bonded to the amidine is sp.sup.2 hybridized
when R.sub.301, R.sub.302, and R.sub.303 is alkenyl,
[0113] (ii) hydrogen, optionally substituted hydrocarbyl and aryl,
provided, however, the carbon atom of R.sub.301, R.sub.302, and
R.sub.303 directly bonded to the amidine is sp.sup.3 hybridized
when R.sub.301, R.sub.302, and R.sub.303 is optionally substituted
hydrocarbyl,
[0114] (iii) hydrogen, --OR.sub.b, --SR.sub.b, --NR.sub.b, or
--N(R.sub.b).sub.2, wherein each R.sub.b is independently
optionally substituted hydrocarbyl, and heterocylo, and
[0115] (iv) hydrogen, substituted hydrocarbyl wherein the carbon
bonded to the amidine group is substituted with --OR.sub.c,
--SR.sub.c, --NR.sub.c, or --N(R.sub.c).sub.2, wherein each R.sub.c
is independently --C(O)R.sub.d, --C(O)NR.sub.d, --C(O)OR.sub.d,
--C(O)N(R.sub.d).sub.2 and each R.sub.d is independently
hydrocarbyl, substituted hydrocarbyl or heterocyclo, and
substituted alkyl with the carbon atom beta to the point of
attachment to the amidine group being an unsaturated electron
withdrawing group, provided, however, at least one of R.sub.301,
R.sub.302, and R.sub.303 is other than hydrogen;
[0116] R.sub.304 is selected from the group consisting of halogen,
hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio;
[0117] R.sub.305 is selected from the group consisting of oxygen,
sulfur, halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and
alkylthio;
[0118] R.sub.306 is selected from the group consisting of halogen,
hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio;
and
[0119] R.sub.307 is selected from the group consisting of oxygen,
sulfur, halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and
alkylthio.
[0120] In one embodiment, the benzamidine derivative is hydrolyzed
under physiological conditions to form benzamidine when Z.sub.3 is
a benzamidine derivative having formula (d) and R.sub.301,
R.sub.302, and R.sub.303 are independently selected from hydrogen,
--C(.dbd.O)R.sub.a, --C(.dbd.O)OR.sub.a, --S(.dbd.O)OR.sub.a,
--S(.dbd.O)SR.sub.a, --S(.dbd.O).sub.2OR.sub.a,
--S(.dbd.O).sub.2SR.sub.a and alkenyl, wherein R.sub.a is selected
from the group consisting of hydrocarbyl, substituted hydrocarbyl,
and heterocylo, provided, however, that the carbon atom of
R.sub.301, R.sub.302, and R.sub.303 directly bonded to the amidine
is sp.sup.2 hybridized when R.sub.301, R.sub.302, and R.sub.303 is
alkenyl.
[0121] In a further embodiment, the benzamidine derivative is
oxidized under physiological conditions to form benzamidine when
Z.sub.3 is a benzamidine derivative having formula (d) and
R.sub.301, R.sub.302, and R.sub.303 are independently selected from
hydrogen, optionally substituted hydrocarbyl and aryl, provided,
however, the carbon atom of R.sub.301, R.sub.302, and R.sub.303
directly bonded to the amidine is sp3 hybridized when R.sub.301,
R.sub.302, and R.sub.303 is optionally substituted hydrocarbyl.
[0122] In still another embodiment, the benzamidine derivative is
reduced under physiological conditions to form benzamidine when
Z.sub.3 is a benzamidine derivative having formula (d) and
R.sub.301, R.sub.302, and R.sub.303 are independently selected from
hydrogen, --OR.sub.b, --SR.sub.b, --NR.sub.b, or
--N(R.sub.b).sub.2, wherein each R.sub.b is independently
optionally substituted hydrocarbyl, and heterocylo.
[0123] In an alternative embodiment, the benzamidine derivative
undergoes elimination at physiological conditions to form
benzamidine when Z.sub.3 is a benzamidine derivative having formula
(d) and R.sub.301, R.sub.302, and R.sub.303 are independently
selected from hydrogen, substituted hydrocarbyl wherein the carbon
bonded to the amidine group is substituted with --OR.sub.c,
--SR.sub.c, --NR.sub.c, or --N(R.sub.c).sub.2, wherein each R.sub.c
is independently --C(O)R.sub.d, --C(O)NR.sub.d, --C(O)OR.sub.d,
--C(O)N(R.sub.d).sub.2 and each R.sub.d is independently
hydrocarbyl, substituted hydrocarbyl or heterocyclo, and
substituted alkyl with the carbon atom beta to the point of
attachment to the amidine group being an unsaturated electron
withdrawing group.
[0124] Another aspect of the invention embraces intermediate
compounds having either of two formulae. Compounds corresponding to
one of the formulae may be represented by formula (4): 12
[0125] wherein
[0126] X.sub.1, X.sub.2, X.sub.5, and X.sub.6 are members of a
heterocyclic ring;
[0127] X.sub.1, X.sub.2 and X.sub.3 are independently carbon or
nitrogen;
[0128] X.sub.5 and X.sub.6 are independently selected from the
group consisting of nitrogen, oxygen, sulfur, carbon, C(F) and
C(Br);
[0129] provided no more than 4 of X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, and X.sub.6 are sp.sup.2 hybridized;
[0130] Z.sub.1 is hydrocarbyl, or substituted hydrocarbyl;
[0131] Z.sub.2 is a hydrogen bond acceptor covalently or datively
bonded to X.sub.2;
[0132] T.sub.3 is selected from the group consisting of hydroxy,
alkoxy, substituted alkoxy, and substituted amino; and
[0133] T.sub.4 is selected from the group consisting of --Cl, --Br,
--I, --S(CH.sub.3), and --OSO.sub.2(CF.sub.3).
[0134] Intermediate compounds represented by the other formula
correspond to formula (5): 13
[0135] wherein
[0136] X.sub.1, X.sub.2, X.sub.5, and X.sub.6 are members of a
heterocyclic ring;
[0137] X.sub.1, X.sub.2 and X.sub.3 are independently carbon or
nitrogen;
[0138] X.sub.5 and X.sub.6 are independently selected from the
group consisting of nitrogen, oxygen, sulfur, carbon, C(F) and
C(Br);
[0139] provided no more than 4 of X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, and X.sub.6 are sp2 hybridized;
[0140] Z.sub.1 is hydrocarbyl, or substituted hydrocarbyl;
[0141] Z.sub.2 is a hydrogen bond acceptor covalently or datively
bonded to X.sub.2; and
[0142] Z.sub.4 comprises hydrocarbyl, substituted hydrocarbyl or a
5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms
of the 5 or 6 membered heterocyclic or carboxylic ring of Z.sub.4
being carbon, nitrogen, oxygen, or sulfur.
[0143] Among the preferred embodiments, therefore, are compounds
corresponding to any one of formulas (1), (2), or (3) wherein
X.sub.9 is a direct bond, Z.sub.4 is a substituted, 6-membered,
carbocyclic aromatic ring, Z.sub.3 is benzene substituted with an
amidine or a derivatized amidine group which, upon hydrolysis,
oxidation, reduction or elimination under physiological conditions
yields an amidine group, and Z.sub.1 is selected from the group
consisting of cyclopropyl, isopropyl, methyl, cyclobutyl,
trifluoroethyl, carboxymethyl and phenyl. In an alternative of this
embodiment, Z.sub.4 is phenyl substituted with two substituents,
R.sub.42 and R.sub.44 wherein R.sub.42 and R.sub.44 are as
described for any of formulas (1), (2), or (3).
[0144] Following the processes described in the Schemes, Examples
or elsewhere herein, compounds corresponding to each of formulae A,
B, C, and D and having any of the combinations of substituents
identified in Table 1 may be prepared. 14 15
[0145] wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and
X.sub.6 are selected to provide the following heterocyclic rings:
piperidinone, dihydropyrimidinone, tetrahydropyrimidinone,
dehydropiperidinedione, dihydropyridazinone, dihydroisoxazinone,
tetrahydrotriazinedione, tetrahydrotriazinone, piperidine, and
piperazine and, for structure (C), one of Z.sub.41 and Z.sub.45 is
sulfur while the other is carbon and, for structure (D), one of
Z.sub.41 and Z.sub.45 is nitrogen while the other is carbon. As
employed herein, unless otherwise indicated, "core" refers to the
6-membered ring to which Z.sub.1, Z.sub.3 and Z.sub.4, through
their respective linkages, are attached.
1 TABLE 1 Core Z.sub.1 R.sub.44 Piperidinone substituted hydroxy
alkyl Piperidinone substituted isobutylsulfonyl alkyl Piperidinone
substituted trifluoromethyl alkyl Piperidinone substituted
carboxamidobenzyl alkyl Piperidinone substituted
carboxamidobutyl-2- alkyl yl Piperidinone substituted isobutyramido
alkyl Piperidinone substituted isobutoxy alkyl Piperidinone
substituted carboethoxy alkyl Piperidinone substituted carboxyl
alkyl Piperidinone substituted amino alkyl Dihydropyrimidinone
substituted hydroxy alkyl Dihydropyrimidinone substituted
isobutylsulfonyl alkyl Dihydropyrimidinone substituted
trifluoromethyl alkyl Dihydropyrimidinone substituted
carboxamidobenzyl alkyl Dihydropyrimidinone substituted
carboxamidobutyl-2- alkyl yl Dihydropyrimidinone substituted
isobutyramido alkyl Dihydropyrimidinone substituted isobutoxy alkyl
Dihydropyrimidinone substituted carboethoxy alkyl
Dihydropyrimidinone substituted carboxyl alkyl Dihydropyrimidinone
substituted amino alkyl Tetrahydropyrimidinone substituted hydroxy
alkyl Tetrahydropyrimidinone substituted isobutylsulfonyl alkyl
Tetrahydropyrimidinone substituted trifluoromethyl alkyl
Tetrahydropyrimidinone substituted carboxamidobenzyl alkyl
Tetrahydropyrimidinone substituted carboxamidobutyl-2- alkyl yl
Tetrahydropyrimidinone substituted isobutyramido alkyl
Tetrahydropyrimidinone substituted isobutoxy alkyl
Tetrahydropyrimidinone substituted carboethoxy alkyl
Tetrahydropyrimidinone substituted carboxyl alkyl
Tetrahydropyrimidinone substituted amino alkyl
Dehydropiperidinedione substituted hydroxy alkyl
Dehydropiperidinedione substituted isobutylsulfonyl alkyl
Dehydropiperidinedione substituted trifluoromethyl alkyl
Dehydropiperidinedione substituted carboxamidobenzyl alkyl
Dehydropiperidinedione substituted carboxamidobutyl-2- alkyl yl
Dehydropiperidinedione substituted isobutyramido alkyl
Dehydropiperidinedione substituted isobutoxy alkyl
Dehydropiperidinedione substituted carboethoxy alkyl
Dehydropiperidinedione substituted carboxyl alkyl
Dehydropiperidinedione substituted amino alkyl Dihydropyridazinone
substituted hydroxy alkyl Dihydropyridazinone substituted
isobutylsulfonyl alkyl Dihydropyridazinone substituted
trifluoromethyl alkyl Dihydropyridazinone substituted
carboxamidobenzyl alkyl Dihydropyridazinone substituted
carboxamidobutyl-2- alkyl yl Dihydropyridazinone substituted
isobutyramido alkyl Dihydropyridazinone substituted isobutoxy alkyl
Dihydropyridazinone substituted carboethoxy alkyl
Dihydropyridazinone substituted carboxyl alkyl Dihydropyridazinone
substituted amino alkyl Dihydroisoxazinone substituted hydroxy
alkyl Dihydroisoxazinone substituted isobutylsulfonyl alkyl
Dihydroisoxazinone substituted trifluoromethyl alkyl
Dihydroisoxazinone substituted carboxamidobenzyl alkyl
Dihydroisoxazinone substituted carboxamidobutyl-2- alkyl yl
Dihydroisoxazinone substituted isobutyramido alkyl
Dihydroisoxazinone substituted isobutoxy alkyl Dihydroisoxazinone
substituted carboethoxy alkyl Dihydroisoxazinone substituted
carboxyl alkyl Dihydroisoxazinone substituted amino alkyl
Tetrahydrotriazinedione substituted hydroxy alkyl
Tetrahydrotriazinedione substituted isobutylsulfonyl alkyl
Tetrahydrotriazinedione substituted trifluoromethyl alkyl
Tetrahydrotriazinedione substituted carboxamidobenzyl alkyl
Tetrahydrotriazinedione substituted carboxamidobutyl-2- alkyl yl
Tetrahydrotriazinedione substituted isobutyramido alkyl
Tetrahydrotriazinedione substituted isobutoxy alkyl
Tetrahydrotriazinedione substituted carboethoxy alkyl
Tetrahydrotriazinedione substituted carboxyl alkyl
Tetrahydrotriazinedione substituted amino alkyl
Tetrahydrotriazinone substituted hydroxy alkyl Tetrahydrotriazinone
substituted isobutylsulfonyl alkyl Tetrahydrotriazinone substituted
trifluoromethyl alkyl Tetrahydrotriazinone substituted
carboxamidobenzyl alkyl Tetrahydrotriazinone substituted
carboxamidobutyl-2- alkyl yl Tetrahydrotriazinone substituted
isobutyramido alkyl Tetrahydrotriazinone substituted isobutoxy
alkyl Tetrahydrotriazinone substituted carboethoxy alkyl
Tetrahydrotriazinone substituted carboxyl alkyl
Tetrahydrotriazinone substituted amino alkyl Piperidine substituted
hydroxy alkyl Piperidine substituted isobutylsulfonyl alkyl
Piperidine substituted trifluoromethyl alkyl Piperidine substituted
carboxamidobenzyl alkyl Piperidine substituted carboxamidobutyl-2-
alkyl yl Piperidine substituted isobutyramido alkyl Piperidine
substituted isobutoxy alkyl Piperidine substituted carboethoxy
alkyl Piperidine substituted carboxyl alkyl Piperidine substituted
amino alkyl Piperazine substituted hydroxy alkyl Piperazine
substituted isobutylsulfonyl alkyl Piperazine substituted
trifluoromethyl alkyl Piperazine substituted carboxamidobenzyl
alkyl Piperazine substituted carboxamidobutyl-2- alkyl yl
Piperazine substituted isobutyramido alkyl Piperazine substituted
isobutoxy alkyl Piperazine substituted carboethoxy alkyl Piperazine
substituted carboxyl alkyl Piperazine substituted amino alkyl
Piperidinone alkyl hydroxy Piperidinone alkyl isobutylsulfonyl
Piperidinone alkyl trifluoromethyl Piperidinone alkyl
carboxamidobenzyl Piperidinone alkyl carboxamidobutyl-2- yl
Piperidinone alkyl isobutyramido Piperidinone alkyl isobutoxy
Piperidinone alkyl carboethoxy Piperidinone alkyl carboxyl
Piperidinone alkyl amino Dihydropyrimidinone alkyl hydroxy
Dihydropyrimidinone alkyl isobutylsulfonyl Dihydropyrimidinone
alkyl trifluoromethyl Dihydropyrimidinone alkyl carboxamidobenzyl
Dihydropyrimidinone alkyl carboxamidobutyl-2- yl
Dihydropyrimidinone alkyl isobutyramido Dihydropyrimidinone alkyl
isobutoxy Dihydropyrimidinone alkyl carboethoxy Dihydropyrimidinone
alkyl carboxyl Dihydropyrimidinone alkyl amino
Tetrahydropyrimidinone alkyl hydroxy Tetrahydropyrimidinone alkyl
isobutylsulfonyl Tetrahydropyrimidinone alkyl trifluoromethyl
Tetrahydropyrimidinone alkyl carboxamidobenzyl
Tetrahydropyrimidinone alkyl carboxamidobutyl-2- yl
Tetrahydropyrimidinone alkyl isobutyramido Tetrahydropyrimidinone
alkyl isobutoxy Tetrahydropyrimidinone alkyl carboethoxy
Tetrahydropyrimidinone alkyl carboxyl Tetrahydropyrimidinone alkyl
amino Dehydropiperidinedione alkyl hydroxy Dehydropiperidinedione
alkyl isobutylsulfonyl Dehydropiperidinedione alkyl trifluoromethyl
Dehydropiperidinedione alkyl carboxamidobenzyl
Dehydropiperidinedione alkyl carboxamidobutyl-2- yl
Dehydropiperidinedione alkyl isobutyramido Dehydropiperidinedione
alkyl isobutoxy Dehydropiperidinedione alkyl carboethoxy
Dehydropiperidinedione alkyl carboxyl Dehydropiperidinedione alkyl
amino Dihydropyridazinone alkyl hydroxy Dihydropyridazinone alkyl
isobutylsulfonyl Dihydropyridazinone alkyl trifluoromethyl
Dihydropyridazinone alkyl carboxamidobenzyl Dihydropyridazinone
alkyl carboxamidobutyl-2- yl Dihydropyridazinone alkyl
isobutyramido Dihydropyridazinone alkyl isobutoxy
Dihydropyridazinone alkyl carboethoxy Dihydropyridazinone alkyl
carboxyl Dihydropyridazinone alkyl amino Dihydroisoxazinone alkyl
hydroxy Dihydroisoxazinone alkyl isobutylsulfonyl
Dihydroisoxazinone alkyl trifluoromethyl Dihydroisoxazinone alkyl
carboxamidobenzyl Dihydroisoxazinone alkyl carboxamidobutyl-2- yl
Dihydroisoxazinone alkyl isobutyramido Dihydroisoxazinone alkyl
isobutoxy Dihydroisoxazinone alkyl carboethoxy Dihydroisoxazinone
alkyl carboxyl Dihydroisoxazinone alkyl amino
Tetrahydrotriazinedione alkyl hydroxy Tetrahydrotriazinedione alkyl
isobutylsulfonyl Tetrahydrotriazinedione alkyl trifluoromethyl
Tetrahydrotriazinedione alkyl carboxamidobenzyl
Tetrahydrotriazinedione alkyl carboxamidobutyl-2- yl
Tetrahydrotriazinedione alkyl isobutyramido Tetrahydrotriazinedione
alkyl isobutoxy Tetrahydrotriazinedione alkyl carboethoxy
Tetrahydrotriazinedione alkyl carboxyl Tetrahydrotriazinedione
alkyl amino Tetrahydrotriazinone alkyl hydroxy Tetrahydrotriazinone
alkyl isobutylsulfonyl Tetrahydrotriazinone alkyl trifluoromethyl
Tetrahydrotriazinone alkyl carboxamidobenzyl Tetrahydrotriazinone
alkyl carboxamidobutyl-2- yl Tetrahydrotriazinone alkyl
isobutyramido Tetrahydrotriazinone alkyl isobutoxy
Tetrahydrotriazinone alkyl carboethoxy Tetrahydrotriazinone alkyl
carboxyl Tetrahydrotriazinone alkyl amino Piperidine alkyl hydroxy
Piperidine alkyl isobutylsulfonyl Piperidine alkyl trifluoromethyl
Piperidine alkyl carboxamidobenzyl Piperidine alkyl
carboxamidobutyl-2- yl Piperidine alkyl isobutyramido Piperidine
alkyl isobutoxy Piperidine alkyl carboethoxy Piperidine alkyl
carboxyl Piperidine alkyl amino Piperazine alkyl hydroxy Piperazine
alkyl isobutylsulfonyl Piperazine alkyl trifluoromethyl Piperazine
alkyl carboxamidobenzyl Piperazine alkyl carboxamidobutyl-2- yl
Piperazine alkyl isobutyramido Piperazine alkyl isobutoxy
Piperazine alkyl carboethoxy Piperazine alkyl carboxyl Piperazine
alkyl amino Piperidinone substituted hydroxy phenyl Piperidinone
substituted isobutylsulfonyl phenyl Piperidinone substituted
trifluoromethyl phenyl Piperidinone substituted carboxamidobenzyl
phenyl Piperidinone substituted carboxamidobutyl-2- phenyl yl
Piperidinone substituted isobutyramido phenyl Piperidinone
substituted isobutoxy phenyl Piperidinone substituted carboethoxy
phenyl Piperidinone substituted carboxyl phenyl Piperidinone
substituted amino phenyl Dihydropyrimidinone substituted hydroxy
phenyl Dihydropyrimidinone substituted isobutylsulfonyl phenyl
Dihydropyrimidinone substituted trifluoromethyl phenyl
Dihydropyrimidinone substituted carboxamidobenzyl phenyl
Dihydropyrimidinone substituted carboxamidobutyl-2- phenyl yl
Dihydropyrimidinone substituted isobutyramido phenyl
Dihydropyrimidinone substituted isobutoxy phenyl
Dihydropyrimidinone substituted carboethoxy phenyl
Dihydropyrimidinone substituted carboxyl phenyl Dihydropyrimidinone
substituted amino phenyl Tetrahydropyrimidinone substituted hydroxy
phenyl Tetrahydropyrimidinone substituted isobutylsulfonyl phenyl
Tetrahydropyrimidinone substituted trifluoromethyl phenyl
Tetrahydropyrimidinone substituted carboxamidobenzyl phenyl
Tetrahydropyrimidinone substituted carboxamidobutyl-2- phenyl yl
Tetrahydropyrimidinone substituted isobutyramido phenyl
Tetrahydropyrimidinone substituted isobutoxy phenyl
Tetrahydropyrimidinone substituted carboethoxy phenyl
Tetrahydropyrimidinone substituted carboxyl phenyl
Tetrahydropyrimidinone substituted amino phenyl
Dehydropiperidinedione substituted hydroxy phenyl
Dehydropiperidinedione substituted isobutylsulfonyl phenyl
Dehydropiperidinedione substituted trifluoromethyl phenyl
Dehydropiperidinedione substituted carboxamidobenzyl phenyl
Dehydropiperidinedione substituted carboxamidobutyl-2- phenyl yl
Dehydropiperidinedione substituted isobutyramido phenyl
Dehydropiperidinedione substituted isobutoxy phenyl
Dehydropiperidinedione substituted carboethoxy phenyl
Dehydropiperidinedione substituted carboxyl phenyl
Dehydropiperidinedione substituted amino phenyl Dihydropyridazinone
substituted hydroxy phenyl Dihydropyridazinone substituted
isobutylsulfonyl phenyl Dihydropyridazinone substituted
trifluoromethyl phenyl Dihydropyridazinone substituted
carboxamidobenzyl phenyl Dihydropyridazinone substituted
carboxamidobutyl-2- phenyl yl Dihydropyridazinone substituted
isobutyramido phenyl Dihydropyridazinone substituted isobutoxy
phenyl Dihydropyridazinone substituted carboethoxy phenyl
Dihydropyridazinone substituted carboxyl phenyl Dihydropyridazinone
substituted amino phenyl Dihydroisoxazinone substituted hydroxy
phenyl Dihydroisoxazinone substituted isobutylsulfonyl phenyl
Dihydroisoxazinone substituted trifluoromethyl phenyl
Dihydroisoxazinone substituted carboxamidobenzyl phenyl
Dihydroisoxazinone substituted carboxamidobutyl-2- phenyl yl
Dihydroisoxazinone substituted isobutyramido phenyl
Dihydroisoxazinone substituted isobutoxy phenyl Dihydroisoxazinone
substituted carboethoxy phenyl Dihydroisoxazinone substituted
carboxyl phenyl Dihydroisoxazinone substituted amino phenyl
Tetrahydrotriazinedione substituted hydroxy phenyl
Tetrahydrotriazinedione substituted isobutylsulfonyl phenyl
Tetrahydrotriazinedione substituted trifluoromethyl phenyl
Tetrahydrotriazinedione substituted carboxamidobenzyl phenyl
Tetrahydrotriazinedione substituted carboxamidobutyl-2- phenyl yl
Tetrahydrotriazinedione substituted isobutyramido phenyl
Tetrahydrotriazinedione substituted isobutoxy phenyl
Tetrahydrotriazinedione substituted carboethoxy phenyl
Tetrahydrotriazinedione substituted carboxyl phenyl
Tetrahydrotriazinedione substituted amino phenyl
Tetrahydrotriazinone substituted hydroxy phenyl
Tetrahydrotriazinone substituted isobutylsulfonyl phenyl
Tetrahydrotriazinone substituted trifluoromethyl phenyl
Tetrahydrotriazinone substituted carboxamidobenzyl phenyl
Tetrahydrotriazinone substituted carboxamidobutyl-2- phenyl yl
Tetrahydrotriazinone substituted isobutyramido phenyl
Tetrahydrotriazinone substituted isobutoxy phenyl
Tetrahydrotriazinone substituted carboethoxy phenyl
Tetrahydrotriazinone substituted carboxyl phenyl
Tetrahydrotriazinone substituted amino phenyl Piperidine
substituted hydroxy phenyl Piperidine substituted isobutylsulfonyl
phenyl Piperidine substituted trifluoromethyl phenyl Piperidine
substituted carboxamidobenzyl phenyl Piperidine substituted
carboxamidobutyl-2- phenyl yl Piperidine substituted isobutyramido
phenyl Piperidine substituted isobutoxy
phenyl Piperidine substituted carboethoxy phenyl Piperidine
substituted carboxyl phenyl Piperidine substituted amino phenyl
Piperazine substituted hydroxy phenyl Piperazine substituted
isobutylsulfonyl phenyl Piperazine substituted trifluoromethyl
phenyl Piperazine substituted carboxamidobenzyl phenyl Piperazine
substituted carboxamidobutyl-2- phenyl yl Piperazine substituted
isobutyramido phenyl Piperazine substituted isobutoxy phenyl
Piperazine substituted carboethoxy phenyl Piperazine substituted
carboxyl phenyl Piperazine substituted amino phenyl Piperidinone
phenyl hydroxy Piperidinone phenyl isobutylsulfonyl Piperidinone
phenyl trifluoromethyl Piperidinone phenyl carboxamidobenzyl
Piperidinone phenyl carboxamidobutyl-2- yl Piperidinone phenyl
isobutyramido Piperidinone phenyl isobutoxy Piperidinone phenyl
carboethoxy Piperidinone phenyl carboxyl Piperidinone phenyl amino
Dihydropyrimidinone phenyl hydroxy Dihydropyrimidinone phenyl
isobutylsulfonyl Dihydropyrimidinone phenyl trifluoromethyl
Dihydropyrimidinone phenyl carboxamidobenzyl Dihydropyrimidinone
phenyl carboxamidobutyl-2- yl Dihydropyrimidinone phenyl
isobutyramido Dihydropyrimidinone phenyl isobutoxy
Dihydropyrimidinone phenyl carboethoxy Dihydropyrimidinone phenyl
carboxyl Dihydropyrimidinone phenyl amino Tetrahydropyrimidinone
phenyl hydroxy Tetrahydropyrimidinone phenyl isobutylsulfonyl
Tetrahydropyrimidinone phenyl trifluoromethyl
Tetrahydropyrimidinone phenyl carboxamidobenzyl
Tetrahydropyrimidinone phenyl carboxamidobutyl-2- yl
Tetrahydropyrimidinone phenyl isobutyramido Tetrahydropyrimidinone
phenyl isobutoxy Tetrahydropyrimidinone phenyl carboethoxy
Tetrahydropyrimidinone phenyl carboxyl Tetrahydropyrimidinone
phenyl amino Dehydropiperidinedione phenyl hydroxy
Dehydropiperidinedione phenyl isobutylsulfonyl
Dehydropiperidinedione phenyl trifluoromethyl
Dehydropiperidinedione phenyl carboxamidobenzyl
Dehydropiperidinedione phenyl carboxamidobutyl-2- yl
Dehydropiperidinedione phenyl isobutyramido Dehydropiperidinedione
phenyl isobutoxy Dehydropiperidinedione phenyl carboethoxy
Dehydropiperidinedione phenyl carboxyl Dehydropiperidinedione
phenyl amino Dihydropyridazinone phenyl hydroxy Dihydropyridazinone
phenyl isobutylsulfonyl Dihydropyridazinone phenyl trifluoromethyl
Dihydropyridazinone phenyl carboxamidobenzyl Dihydropyridazinone
phenyl carboxamidobutyl-2- yl Dihydropyridazinone phenyl
isobutyramido Dihydropyridazinone phenyl isobutoxy
Dihydropyridazinone phenyl carboethoxy Dihydropyridazinone phenyl
carboxyl Dihydropyridazinone phenyl amino Dihydroisoxazinone phenyl
hydroxy Dihydroisoxazinone phenyl isobutylsulfonyl
Dihydroisoxazinone phenyl trifluoromethyl Dihydroisoxazinone phenyl
carboxamidobenzyl Dihydroisoxazinone phenyl carboxamidobutyl-2- yl
Dihydroisoxazinone phenyl isobutyramido Dihydroisoxazinone phenyl
isobutoxy Dihydroisoxazinone phenyl carboethoxy Dihydroisoxazinone
phenyl carboxyl Dihydroisoxazinone phenyl amino
Tetrahydrotriazinedione phenyl hydroxy Tetrahydrotriazinedione
phenyl isobutylsulfonyl Tetrahydrotriazinedione phenyl
trifluoromethyl Tetrahydrotriazinedione phenyl carboxamidobenzyl
Tetrahydrotriazinedione phenyl carboxamidobutyl-2- yl
Tetrahydrotriazinedione phenyl isobutyramido
Tetrahydrotriazinedione phenyl isobutoxy Tetrahydrotriazinedione
phenyl carboethoxy Tetrahydrotriazinedione phenyl carboxyl
Tetrahydrotriazinedione phenyl amino Tetrahydrotriazinone phenyl
hydroxy Tetrahydrotriazinone phenyl isobutylsulfonyl
Tetrahydrotriazinone phenyl trifluoromethyl Tetrahydrotriazinone
phenyl carboxamidobenzyl Tetrahydrotriazinone phenyl
carboxamidobutyl-2- yl Tetrahydrotriazinone phenyl isobutyramido
Tetrahydrotriazinone phenyl isobutoxy Tetrahydrotriazinone phenyl
carboethoxy Tetrahydrotriazinone phenyl carboxyl
Tetrahydrotriazinone phenyl amino Piperidine phenyl hydroxy
Piperidine phenyl isobutylsulfonyl Piperidine phenyl
trifluoromethyl Piperidine phenyl carboxamidobenzyl Piperidine
phenyl carboxamidobutyl-2- yl Piperidine phenyl isobutyramido
Piperidine phenyl isobutoxy Piperidine phenyl carboethoxy
Piperidine phenyl carboxyl Piperidine phenyl amino Piperazine
phenyl hydroxy Piperazine phenyl isobutylsulfonyl Piperazine phenyl
trifluoromethyl Piperazine phenyl carboxamidobenzyl Piperazine
phenyl carboxamidobutyl-2- yl Piperazine phenyl isobutyramido
Piperazine phenyl isobutoxy Piperazine phenyl carboethoxy
Piperazine phenyl carboxyl Piperazine phenyl amino Piperidinone
cycloalkyl hydroxy Piperidinone cycloalkyl isobutylsulfonyl
Piperidinone cycloalkyl trifluoromethyl Piperidinone cycloalkyl
carboxamidobenzyl Piperidinone cycloalkyl carboxamidobutyl-2- yl
Piperidinone cycloalkyl isobutyramido Piperidinone cycloalkyl
isobutoxy Piperidinone cycloalkyl carboethoxy Piperidinone
cycloalkyl carboxyl Piperidinone cycloalkyl amino
Dihydropyrimidinone cycloalkyl hydroxy Dihydropyrimidinone
cycloalkyl isobutylsulfonyl Dihydropyrimidinone cycloalkyl
trifluoromethyl Dihydropyrimidinone cycloalkyl carboxamidobenzyl
Dihydropyrimidinone cycloalkyl carboxamidobutyl-2- yl
Dihydropyrimidinone cycloalkyl isobutyramido Dihydropyrimidinone
cycloalkyl isobutoxy Dihydropyrimidinone cycloalkyl carboethoxy
Dihydropyrimidinone cycloalkyl carboxyl Dihydropyrimidinone
cycloalkyl amino Tetrahydropyrimidinone cycloalkyl hydroxy
Tetrahydropyrimidinone cycloalkyl isobutylsulfonyl
Tetrahydropyrimidinone cycloalkyl trifluoromethyl
Tetrahydropyrimidinone cycloalkyl carboxamidobenzyl
Tetrahydropyrimidinone cycloalkyl carboxamidobutyl-2- yl
Tetrahydropyrimidinone cycloalkyl isobutyramido
Tetrahydropyrimidinone cycloalkyl isobutoxy Tetrahydropyrimidinone
cycloalkyl carboethoxy Tetrahydropyrimidinone cycloalkyl carboxyl
Tetrahydropyrimidinone cycloalkyl amino Dehydropiperidinedione
cycloalkyl hydroxy Dehydropiperidinedione cycloalkyl
isobutylsulfonyl Dehydropiperidinedione cycloalkyl trifluoromethyl
Dehydropiperidinedione cycloalkyl carboxamidobenzyl
Dehydropiperidinedione cycloalkyl carboxamidobutyl-2- yl
Dehydropiperidinedione cycloalkyl isobutyramido
Dehydropiperidinedione cycloalkyl isobutoxy Dehydropiperidinedione
cycloalkyl carboethoxy Dehydropiperidinedione cycloalkyl carboxyl
Dehydropiperidinedione cycloalkyl amino Dihydropyridazinone
cycloalkyl hydroxy Dihydropyridazinone cycloalkyl isobutylsulfonyl
Dihydropyridazinone cycloalkyl trifluoromethyl Dihydropyridazinone
cycloalkyl carboxamidobenzyl Dihydropyridazinone cycloalkyl
carboxamidobutyl-2- yl Dihydropyridazinone cycloalkyl isobutyramido
Dihydropyridazinone cycloalkyl isobutoxy Dihydropyridazinone
cycloalkyl carboethoxy Dihydropyridazinone cycloalkyl carboxyl
Dihydropyridazinone cycloalkyl amino Dihydroisoxazinone cycloalkyl
hydroxy Dihydroisoxazinone cycloalkyl isobutylsulfonyl
Dihydroisoxazinone cycloalkyl trifluoromethyl Dihydroisoxazinone
cycloalkyl carboxamidobenzyl Dihydroisoxazinone cycloalkyl
carboxamidobutyl-2- yl Dihydroisoxazinone cycloalkyl isobutyramido
Dihydroisoxazinone cycloalkyl isobutoxy Dihydroisoxazinone
cycloalkyl carboethoxy Dihydroisoxazinone cycloalkyl carboxyl
Dihydroisoxazinone cycloalkyl amino Tetrahydrotriazinedione
cycloalkyl hydroxy Tetrahydrotriazinedione cycloalkyl
isobutylsulfonyl Tetrahydrotriazinedione cycloalkyl trifluoromethyl
Tetrahydrotriazinedione cycloalkyl carboxamidobenzyl
Tetrahydrotriazinedione cycloalkyl carboxamidobutyl-2- yl
Tetrahydrotriazinedione cycloalkyl isobutyramido
Tetrahydrotriazinedione cycloalkyl isobutoxy
Tetrahydrotriazinedione cycloalkyl carboethoxy
Tetrahydrotriazinedione cycloalkyl carboxyl Tetrahydrotriazinedione
cycloalkyl amino Tetrahydrotriazinone cycloalkyl hydroxy
Tetrahydrotriazinone cycloalkyl isobutylsulfonyl
Tetrahydrotriazinone cycloalkyl trifluoromethyl
Tetrahydrotriazinone cycloalkyl carboxamidobenzyl
Tetrahydrotriazinone cycloalkyl carboxamidobutyl-2- yl
Tetrahydrotriazinone cycloalkyl isobutyramido Tetrahydrotriazinone
cycloalkyl isobutoxy Tetrahydrotriazinone cycloalkyl carboethoxy
Tetrahydrotriazinone cycloalkyl carboxyl Tetrahydrotriazinone
cycloalkyl amino Piperidine cycloalkyl hydroxy Piperidine
cycloalkyl isobutylsulfonyl Piperidine cycloalkyl trifluoromethyl
Piperidine cycloalkyl carboxamidobenzyl Piperidine cycloalkyl
carboxamidobutyl-2- yl Piperidine cycloalkyl isobutyramido
Piperidine cycloalkyl isobutoxy Piperidine cycloalkyl carboethoxy
Piperidine cycloalkyl carboxyl Piperidine cycloalkyl amino
Piperazine cycloalkyl hydroxy Piperazine cycloalkyl
isobutylsulfonyl Piperazine cycloalkyl trifluoromethyl Piperazine
cycloalkyl carboxamidobenzyl Piperazine cycloalkyl
carboxamidobutyl-2- yl Piperazine cycloalkyl isobutyramido
Piperazine cycloalkyl isobutoxy Piperazine cycloalkyl carboethoxy
Piperazine cycloalkyl carboxyl Piperazine cycloalkyl amino
Piperidinone substituted hydroxy cycloalkyl Piperidinone
substituted isobutylsulfonyl cycloalkyl Piperidinone substituted
trifluoromethyl cycloalkyl Piperidinone substituted
carboxamidobenzyl cycloalkyl Piperidinone substituted
carboxamidobutyl-2- cycloalkyl yl Piperidinone substituted
isobutyramido cycloalkyl Piperidinone substituted isobutoxy
cycloalkyl Piperidinone substituted carboethoxy cycloalkyl
Piperidinone substituted carboxyl cycloalkyl Piperidinone
substituted amino cycloalkyl Dihydropyrimidinone substituted
hydroxy cycloalkyl Dihydropyrimidinone substituted isobutylsulfonyl
cycloalkyl Dihydropyrimidinone substituted trifluoromethyl
cycloalkyl Dihydropyrimidinone substituted carboxamidobenzyl
cycloalkyl Dihydropyrimidinone substituted carboxamidobutyl-2-
cycloalkyl yl Dihydropyrimidinone substituted isobutyramido
cycloalkyl Dihydropyrimidinone substituted isobutoxy cycloalkyl
Dihydropyrimidinone substituted carboethoxy cycloalkyl
Dihydropyrimidinone substituted carboxyl cycloalkyl
Dihydropyrimidinone substituted amino cycloalkyl
Tetrahydropyrimidinone substituted hydroxy cycloalkyl
Tetrahydropyrimidinone substituted isobutylsulfonyl cycloalkyl
Tetrahydropyrimidinone substituted trifluoromethyl cycloalkyl
Tetrahydropyrimidinone substituted carboxamidobenzyl cycloalkyl
Tetrahydropyrimidinone substituted carboxamidobutyl-2- cycloalkyl
yl Tetrahydropyrimidinone substituted isobutyramido cycloalkyl
Tetrahydropyrimidinone substituted isobutoxy cycloalkyl
Tetrahydropyrimidinone substituted carboethoxy cycloalkyl
Tetrahydropyrimidinone substituted carboxyl cycloalkyl
Tetrahydropyrimidinone substituted amino cycloalkyl
Dehydropiperidinedione substituted hydroxy cycloalkyl
Dehydropiperidinedione substituted isobutylsulfonyl cycloalkyl
Dehydropiperidinedione substituted trifluoromethyl cycloalkyl
Dehydropiperidinedione substituted carboxamidobenzyl cycloalkyl
Dehydropiperidinedione substituted carboxamidobutyl-2- cycloalkyl
yl Dehydropiperidinedione substituted isobutyramido cycloalkyl
Dehydropiperidinedione substituted isobutoxy cycloalkyl
Dehydropiperidinedione substituted carboethoxy cycloalkyl
Dehydropiperidinedione substituted carboxyl cycloalkyl
Dehydropiperidinedione substituted amino cycloalkyl
Dihydropyridazinone substituted hydroxy cycloalkyl
Dihydropyridazinone substituted isobutylsulfonyl cycloalkyl
Dihydropyridazinone substituted trifluoromethyl cycloalkyl
Dihydropyridazinone substituted carboxamidobenzyl cycloalkyl
Dihydropyridazinone substituted carboxamidobutyl-2- cycloalkyl yl
Dihydropyridazinone substituted isobutyramido cycloalkyl
Dihydropyridazinone substituted isobutoxy cycloalkyl
Dihydropyridazinone substituted carboethoxy cycloalkyl
Dihydropyridazinone substituted carboxyl cycloalkyl
Dihydropyridazinone substituted amino cycloalkyl Dihydroisoxazinone
substituted hydroxy cycloalkyl Dihydroisoxazinone substituted
isobutylsulfonyl cycloalkyl Dihydroisoxazinone substituted
trifluoromethyl cycloalkyl Dihydroisoxazinone substituted
carboxamidobenzyl cycloalkyl Dihydroisoxazinone substituted
carboxamidobutyl-2- cycloalkyl yl Dihydroisoxazinone substituted
isobutyramido cycloalkyl Dihydroisoxazinone substituted isobutoxy
cycloalkyl Dihydroisoxazinone substituted carboethoxy cycloalkyl
Dihydroisoxazinone substituted carboxyl cycloalkyl
Dihydroisoxazinone substituted amino cycloalkyl
Tetrahydrotriazinedione substituted hydroxy cycloalkyl
Tetrahydrotriazinedione substituted isobutylsulfonyl cycloalkyl
Tetrahydrotriazinedione substituted trifluoromethyl cycloalkyl
Tetrahydrotriazinedione substituted carboxamidobenzyl cycloalkyl
Tetrahydrotriazinedione substituted carboxamidobutyl-2- cycloalkyl
yl Tetrahydrotriazinedione substituted isobutyramido cycloalkyl
Tetrahydrotriazinedione substituted isobutoxy cycloalkyl
Tetrahydrotriazinedione substituted carboethoxy cycloalkyl
Tetrahydrotriazinedione substituted carboxyl cycloalkyl
Tetrahydrotriazinedione substituted amino cycloalkyl
Tetrahydrotriazinone substituted hydroxy cycloalkyl
Tetrahydrotriazinone substituted isobutylsulfonyl cycloalkyl
Tetrahydrotriazinone substituted trifluoromethyl cycloalkyl
Tetrahydrotriazinone substituted carboxamidobenzyl cycloalkyl
Tetrahydrotriazinone substituted carboxamidobutyl-2- cycloalkyl yl
Tetrahydrotriazinone substituted isobutyramido cycloalkyl
Tetrahydrotriazinone substituted isobutoxy cycloalkyl
Tetrahydrotriazinone substituted carboethoxy cycloalkyl
Tetrahydrotriazinone substituted carboxyl cycloalkyl
Tetrahydrotriazinone substituted amino cycloalkyl Piperidine
substituted hydroxy cycloalkyl Piperidine substituted
isobutylsulfonyl cycloalkyl Piperidine substituted trifluoromethyl
cycloalkyl Piperidine substituted carboxamidobenzyl cycloalkyl
Piperidine substituted carboxamidobutyl-2- cycloalkyl yl Piperidine
substituted isobutyramido cycloalkyl Piperidine substituted
isobutoxy cycloalkyl Piperidine substituted
carboethoxy cycloalkyl Piperidine substituted carboxyl cycloalkyl
Piperidine substituted amino cycloalkyl Piperazine substituted
hydroxy cycloalkyl Piperazine substituted isobutylsulfonyl
cycloalkyl Piperazine substituted trifluoromethyl cycloalkyl
Piperazine substituted carboxamidobenzyl cycloalkyl Piperazine
substituted carboxamidobutyl-2- cycloalkyl yl Piperazine
substituted isobutyramido cycloalkyl Piperazine substituted
isobutoxy cycloalkyl Piperazine substituted carboethoxy cycloalkyl
Piperazine substituted carboxyl cycloalkyl Piperazine substituted
amino cycloalkyl
[0146] In a preferred embodiment, the compounds correspond to any
of Formulae A, B, C, or D and the core, Z.sub.1 and R.sub.44 are as
identified in Table 2.
2TABLE 2 Core Z.sub.1 R.sub.44 Piperidinone methyl, ethyl,
isopropyl, hydroxy cyclopropyl, cyclobutyl, or phenyl Piperidinone
methyl, ethyl, isopropyl, isobutylsulfonyl cyclopropyl, cyclobutyl,
or phenyl Piperidinone methyl, ethyl, isopropyl, trifluoromethyl
cyclopropyl, cyclobutyl, or phenyl Piperidinone methyl, ethyl,
isopropyl, carboxamidobenzyl cyclopropyl, cyclobutyl, or phenyl
Piperidinone methyl, ethyl, isopropyl, carboxamidobutyl-
cyclopropyl, cyclobutyl, 2-yl or phenyl Piperidinone methyl, ethyl,
isopropyl, isobutyramido cyclopropyl, cyclobutyl, or phenyl
Piperidinone methyl, ethyl, isopropyl, carboethoxy cyclopropyl,
cyclobutyl, or phenyl Piperidinone methyl, ethyl, isopropyl,
carboxyl cyclopropyl, cyclobutyl, or phenyl Piperidinone methyl,
ethyl, isopropyl, amino cyclopropyl, cyclobutyl, or phenyl
Dihydropyrimidinone methyl, ethyl, isopropyl, hydroxy cyclopropyl,
cyclobutyl, or phenyl Dihydropyrimidinone methyl, ethyl, isopropyl,
isobutylsulfonyl cyclopropyl, cyclobutyl, or phenyl
Dihydropyrimidinone methyl, ethyl, isopropyl, trifluoromethyl
cyclopropyl, cyclobutyl, or phenyl Dihydropyrimidinone methyl,
ethyl, isopropyl, carboxamidobenzyl cyclopropyl, cyclobutyl, or
phenyl Dihydropyrimidinone methyl, ethyl, isopropyl,
carboxamidobutyl- cyclopropyl, cyclobutyl, 2-yl or phenyl
Dihydropyrimidinone methyl, ethyl, isopropyl, isobutyramido
cyclopropyl, cyclobutyl, or phenyl Dihydropyrimidinone methyl,
ethyl, isopropyl, isobutoxy cyclopropyl, cyclobutyl, or phenyl
Dihydropyrimidinone methyl, ethyl, isopropyl, carboethoxy
cyclopropyl, cyclobutyl, or phenyl Dihydropyrimidinone methyl,
ethyl, isopropyl, carboxyl cyclopropyl, cyclobutyl, or phenyl
Dihydropyrimidinone methyl, ethyl, isopropyl, amino cyclopropyl,
cyclobutyl, or phenyl Tetrahydropyrimidinone methyl, ethyl,
isopropyl, hydroxy cyclopropyl, cyclobutyl, or phenyl
Tetrahydropyrimidinone methyl, ethyl, isopropyl, isobutylsulfonyl
cyclopropyl, cyclobutyl, or phenyl Tetrahydropyrimidinone methyl,
ethyl, isopropyl, trifluoromethyl cyclopropyl, cyclobutyl, or
phenyl Tetrahydropyrimidinone methyl, ethyl, isopropyl,
carboxamidobenzyl cyclopropyl, cyclobutyl, or phenyl
Tetrahydropyrimidinone methyl, ethyl, isopropyl, carboxamidobutyl-
cyclopropyl, cyclobutyl, 2-yl or phenyl Tetrahydropyrimidinone
methyl, ethyl, isopropyl, isobutyramido cyclopropyl, cyclobutyl, or
phenyl Tetrahydropyrimidinone methyl, ethyl, isopropyl, isobutoxy
cyclopropyl, cyclobutyl, or phenyl Tetrahydropyrimidinone methyl,
ethyl, isopropyl, carboethoxy cyclopropyl, cyclobutyl, or phenyl
Tetrahydropyrimidinone methyl, ethyl, isopropyl, carboxyl
cyclopropyl, cyclobutyl, or phenyl Tetrahydropyrimidinone methyl,
ethyl, isopropyl, amino cyclopropyl, cyclobutyl, or phenyl
Dehydropiperidinedione methyl, ethyl, isopropyl, hydroxy
cyclopropyl, cyclobutyl, or phenyl Dehydropiperidinedione methyl,
ethyl, isopropyl, isobutylsulfonyl cyclopropyl, cyclobutyl, or
phenyl Dehydropiperidinedione methyl, ethyl, isopropyl,
trifluoromethyl cyclopropyl, cyclobutyl, or phenyl
Dehydropiperidinedione methyl, ethyl, isopropyl, carboxamidobenzyl
cyclopropyl, cyclobutyl, or phenyl Dehydropiperidinedione methyl,
ethyl, isopropyl, carboxamidobutyl- cyclopropyl, cyclobutyl, 2-yl
or phenyl Dehydropiperidinedione methyl, ethyl, isopropyl,
isobutyramido cyclopropyl, cyclobutyl, or phenyl
Dehydropiperidinedione methyl, ethyl, isopropyl, isobutoxy
cyclopropyl, cyclobutyl, or phenyl Dehydropiperidinedione methyl,
ethyl, isopropyl, carboethoxy cyclopropyl, cyclobutyl, or phenyl
Dehydropiperidinedione methyl, ethyl, isopropyl, carboxyl
cyclopropyl, cyclobutyl, or phenyl Dehydropiperidinedione methyl,
ethyl, isopropyl, amino cyclopropyl, cyclobutyl, or phenyl
Dihydropyridazinone methyl, ethyl, isopropyl, hydroxy cyclopropyl,
cyclobutyl, or phenyl Dihydropyridazinone methyl, ethyl, isopropyl,
isobutylsulfonyl cyclopropyl, cyclobutyl, or phenyl
Dihydropyridazinone methyl, ethyl, isopropyl, trifluoromethyl
cyclopropyl, cyclobutyl, or phenyl Dihydropyridazinone methyl,
ethyl, isopropyl, carboxamidobenzyl cyclopropyl, cyclobutyl, or
phenyl Dihydropyridazinone methyl, ethyl, isopropyl,
carboxamidobutyl- cyclopropyl, cyclobutyl, 2-yl or phenyl
Dihydropyridazinone methyl, ethyl, isopropyl, isobutyramido
cyclopropyl, cyclobutyl, or phenyl Dihydropyridazinone methyl,
ethyl, isopropyl, isobutoxy cyclopropyl, cyclobutyl, or phenyl
Dihydropyridazinone methyl, ethyl, isopropyl, carboethoxy
cyclopropyl, cyclobutyl, or phenyl Dihydropyridazinone methyl,
ethyl, isopropyl, carboxyl cyclopropyl, cyclobutyl, or phenyl
Dihydropyridazinone methyl, ethyl, isopropyl, amino cyclopropyl,
cyclobutyl, or phenyl Dihydroisoxazinone methyl, ethyl, isopropyl,
hydroxy cyclopropyl, cyclobutyl, or phenyl Dihydroisoxazinone
methyl, ethyl, isopropyl, isobutylsulfonyl cyclopropyl, cyclobutyl,
or phenyl Dihydroisoxazinone methyl, ethyl, isopropyl,
trifluoromethyl cyclopropyl, cyclobutyl, or phenyl
Dihydroisoxazinone methyl, ethyl, isopropyl, carboxamidobenzyl
cyclopropyl, cyclobutyl, or phenyl Dihydroisoxazinone methyl,
ethyl, isopropyl, carboxamidobutyl- cyclopropyl, cyclobutyl, 2-yl
or phenyl Dihydroisoxazinone methyl, ethyl, isopropyl,
isobutyramido cyclopropyl, cyclobutyl, or phenyl Dihydroisoxazinone
methyl, ethyl, isopropyl, isobutoxy cyclopropyl, cyclobutyl, or
phenyl Dihydroisoxazinone methyl, ethyl, isopropyl, carboethoxy
cyclopropyl, cyclobutyl, or phenyl Dihydroisoxazinone methyl,
ethyl, isopropyl, carboxyl cyclopropyl, cyclobutyl, or phenyl
Dihydroisoxazinone methyl, ethyl, isopropyl, amino cyclopropyl,
cyclobutyl, or phenyl Tetrahydrotriazinedione methyl, ethyl,
isopropyl, hydroxy cyclopropyl, cyclobutyl, or phenyl
Tetrahydrotriazinedione methyl, ethyl, isopropyl, isobutylsulfonyl
cyclopropyl, cyclobutyl, or phenyl Tetrahydrotriazinedione methyl,
ethyl, isopropyl, trifluoromethyl cyclopropyl, cyclobutyl, or
phenyl Tetrahydrotriazinedione methyl, ethyl, isopropyl,
carboxamidobenzyl cyclopropyl, cyclobutyl, or phenyl
Tetrahydrotriazinedione methyl, ethyl, isopropyl, carboxamidobutyl-
cyclopropyl, cyclobutyl, 2-yl or phenyl Tetrahydrotriazinedione
methyl, ethyl, isopropyl, isobutyramido cyclopropyl, cyclobutyl, or
phenyl Tetrahydrotriazinedione methyl, ethyl, isopropyl, isobutoxy
cyclopropyl, cyclobutyl, or phenyl Tetrahydrotriazinedione methyl,
ethyl, isopropyl, carboethoxy cyclopropyl, cyclobutyl, or phenyl
Tetrahydrotriazinedione methyl, ethyl, isopropyl, carboxyl
cyclopropyl, cyclobutyl, or phenyl Tetrahydrotriazinedione methyl,
ethyl, isopropyl, amino cyclopropyl, cyclobutyl, or phenyl
Tetrahydrotriazinone methyl, ethyl, isopropyl, hydroxy cyclopropyl,
cyclobutyl, or phenyl Tetrahydrotriazinone methyl, ethyl,
isopropyl, isobutylsulfonyl cyclopropyl, cyclobutyl, or phenyl
Tetrahydrotriazinone methyl, ethyl, isopropyl, trifluoromethyl
cyclopropyl, cyclobutyl, or phenyl Tetrahydrotriazinone methyl,
ethyl, isopropyl, carboxamidobenzyl cyclopropyl, cyclobutyl, or
phenyl Tetrahydrotriazinone methyl, ethyl, isopropyl,
carboxamidobutyl- cyclopropyl, cyclobutyl, 2-yl or phenyl
Tetrahydrotriazinone methyl, ethyl, isopropyl, isobutyramido
cyclopropyl, cyclobutyl, or phenyl Tetrahydrotriazinone methyl,
ethyl, isopropyl, isobutoxy cyclopropyl, cyclobutyl, or phenyl
Tetrahydrotriazinone methyl, ethyl, isopropyl, carboethoxy
cyclopropyl, cyclobutyl, or phenyl Tetrahydrotriazinone methyl,
ethyl, isopropyl, carboxyl cyclopropyl, cyclobutyl, or phenyl
Tetrahydrotriazinone methyl, ethyl, isopropyl, amino cyclopropyl,
cyclobutyl, or phenyl Piperidine methyl, ethyl, isopropyl, hydroxy
cyclopropyl, cyclobutyl, or phenyl Piperidine methyl, ethyl,
isopropyl, isobutylsulfonyl cyclopropyl, cyclobutyl, or phenyl
Piperidine methyl, ethyl, isopropyl, trifluoromethyl cyclopropyl,
cyclobutyl, or phenyl Piperidine methyl, ethyl, isopropyl,
carboxamidobenzyl cyclopropyl, cyclobutyl, or phenyl Piperidine
methyl, ethyl, isopropyl, carboxamidobutyl- cyclopropyl,
cyclobutyl, 2-yl or phenyl Piperidine methyl, ethyl, isopropyl,
isobutyramido cyclopropyl, cyclobutyl, or phenyl Piperidine methyl,
ethyl, isopropyl, isobutoxy cyclopropyl, cyclobutyl, or phenyl
Piperidine methyl, ethyl, isopropyl, carboethoxy cyclopropyl,
cyclobutyl, or phenyl Piperidine methyl, ethyl, isopropyl, carboxyl
cyclopropyl, cyclobutyl, or phenyl Piperidine methyl, ethyl,
isopropyl, amino cyclopropyl, cyclobutyl, or phenyl Piperazine
methyl, ethyl, isopropyl, hydroxy cyclopropyl, cyclobutyl, or
phenyl Piperazine methyl, ethyl, isopropyl, isobutylsulfonyl
cyclopropyl, cyclobutyl, or phenyl Piperazine methyl, ethyl,
isopropyl, trifluoromethyl cyclopropyl, cyclobutyl, or phenyl
Piperazine methyl, ethyl, isopropyl, carboxamidobenzyl cyclopropyl,
cyclobutyl, or phenyl Piperazine methyl, ethyl, isopropyl,
carboxamidobutyl- cyclopropyl, cyclobutyl, 2-yl or phenyl
Piperazine methyl, ethyl, isopropyl, isobutyramido cyclopropyl,
cyclobutyl, or phenyl Piperazine methyl, ethyl, isopropyl,
isobutoxy cyclopropyl, cyclobutyl, or phenyl Piperazine methyl,
ethyl, isopropyl, carboethoxy cyclopropyl, cyclobutyl, or phenyl
Piperazine methyl, ethyl, isopropyl, carboxyl cyclopropyl,
cyclobutyl, or phenyl Piperazine methyl, ethyl, isopropyl, amino
cyclopropyl, cyclobutyl, or phenyl
[0147] For convenience, each of the core heterocyclic rings and
R.sub.44 moieties identified in Tables 1 and 2 are set forth
below.
Heterocyclic Core Ring Structures
[0148] 16
R.sub.44 Moieties
[0149] 17
[0150] In another preferred embodiment, the compounds corresponding
to either of formulas (1) and (2) are selected from the group of
compounds illustrated in Table 3 below wherein for any given
compound, Z.sub.1 is isopropyl, cyclopropyl, cyclobutyl,
trifluoroethyl, or carboxymethyl.
3TABLE 3 Com- pound No. Compound 1 18 2 19 3 20 4 21 5 22 6 23 7 24
8 25 9 26 10 27
[0151] Any prodrug compound of the present invention having one or
more prodrug moieties as part of the molecule, can be converted
under physiological conditions to the biologically active drug by a
number of chemical and biological mechanisms. In general terms, as
detailed above, these prodrug conversion mechanisms are hydrolysis,
reduction, oxidation, and elimination. For illustrative purposes,
the following paragraphs detail prodrugs in which the prodrug
moiety is covalently bonded to the amidine group on Z.sub.3.
[0152] In one embodiment, conversion of the prodrug to the
biologically active drug can be accomplished by hydrolysis of the
prodrug moiety provided the prodrug moiety is chemically or
enzymatically hydrolyzable with water. The reaction with water
typically results in removal of the prodrug moiety and liberation
of the biologically active drug. By way of example, a hydrolyzable
prodrug derivative at the amidine group may be a carbonyl
derivative such as N-acyl. Hydrolysis results in freeing the
amidine group of the drug by removal of the acyl as carbon acid.
Other suitable hydrolyzable prodrug derivatives include carbonyl,
thiocarbonyl, imine, enamine, and oxygenated sulfur.
[0153] Yet another aspect of the invention provides conversion of
the prodrug to the biologically active drug by reduction of the
prodrug moiety. Typically in this embodiment, the prodrug moiety is
reducible under physiological conditions in the presence of a
reducing enzymatic process. The reduction preferably results in
removal of the prodrug moiety and liberation of the biologically
active drug. An example of a reducible prodrug derivative at the
amidine group is an oxygen containing group in which an oxygen is
directly attached to the amidine. Reduction results in freeing the
amidine group of the drug by removal of oxygen as water or an
alcohol. Generally speaking, other suitable reducible prodrug
derivatives include a nitrogen containing group, and a sulfur
containing group, provided both nitrogen and sulfur are each
preferably in their most reduced state.
[0154] In another aspect of the invention, conversion of the
prodrug to the biologically active drug can also be accomplished by
oxidation of the prodrug moiety. Typically in this embodiment, the
prodrug moiety is oxidizable under physiological conditions in the
presence of an oxidative enzymatic process. The oxidation
preferably results in removal of the prodrug moiety and liberation
of the biologically active drug. An example of an oxidizable
prodrug derivative at the amidine group is a hydrocarbyl containing
unsaturation in the carbon beta to the carbon directly connected to
the amidine group. Oxidation results in forming an oxygenated
intermediate that breaks down, thereby freeing the amidine group of
the drug with concurrent hydrolysis of the oxygenated hydrocarbyl
residue. Other suitable oxidizable prodrug derivatives of the
amidine include saturated hydrocarbyl, unsaturated substituted
hydrocarbyl, aryl, and aralkyl.
[0155] A further aspect of the invention encompasses conversion of
the prodrug to the biologically active drug by elimination of the
prodrug moiety. Generally speaking, in this embodiment the prodrug
moiety is removed under physiological conditions with a chemical or
biological reaction. The elimination results in removal of the
prodrug moiety and liberation of the biologically active drug. By
way of example, an eliminateable prodrug derivative at the amidine
group is a hydrocarbyl containing an unsaturated electron
withdrawing group bonded to the carbon beta to the carbon directly
connected to the amidine. More specifically, for illustration
purposes and exemplification, the hydrocarbyl group could have a
cyano group beta to the carbon directly bonded to the amidino
group. Elimination results in the freeing of the amidine group of
the drug with concurrent removal of the unsaturated hydrocarbyl
residue derived from the prodrug moiety. Other suitable
eliminateable prodrug derivatives of the amidine include a
hydrocarbyl substituted at the beta carbon with carbonyl,
alkoxycarbonyl, amidocarbonyl, nitro, or sulfonyl or an alkyl group
substituted with oxygen, nitrogen or sulfur at the carbon directly
bonded to the amidine group.
[0156] Any prodrug compound of the present invention may undergo
any combination of the above detailed mechanisms to convert the
prodrug to the biologically active compound. For example, a
particular compound may undergo hydrolysis, oxidation, elimination,
and reduction to convert the prodrug to the biologically active
compound. Equally, a particular compound may undergo only one of
these mechanisms to convert the prodrug to the biologically active
compound.
[0157] As a further embodiment, compounds of the present invention
or a pharmaceutically-acceptable salt thereof, comprise a treatment
and prophylaxis for thrombotic events resulting from coronary
artery disease, cerebrovascular disease and other coagulation
cascade related disorders in a subject, comprising administering to
the subject having such disorder a therapeutically-effective amount
of compounds of the present invention or a
pharmaceutically-acceptable salt thereof.
[0158] In another aspect of the invention, the compounds may also
be used whenever inhibition of blood coagulation is required such
as to prevent coagulation of stored whole blood and to prevent
coagulation in other biological samples for testing or storage.
Thus coagulation inhibitors of the present inhibition can be added
to or contacted with stored whole blood and any medium containing
or suspected of containing plasma coagulation factors and in which
it is desired that blood coagulation be inhibited, e.g. when
contacting the mammal's blood with material selected from the group
consisting of vascular grafts, stents, orthopedic prothesis,
cardiac prosthesis, and extracorporeal circulation systems.
[0159] Compounds of the invention are capable of inhibiting
activity of serine proteases related to the coagulation cascade,
and thus could be used in the manufacture of a medicament, a method
for the prophylactic or therapeutic treatment of diseases mediated
by coagulation cascade serine proteases, such as inhibiting the
formation of blood platelet aggregates, inhibiting the formation of
fibrin, inhibiting thrombus formation, and inhibiting embolus
formation in a mammal, in blood, in blood products, and in
mammalian organs. The compounds also can be used for treating or
preventing unstable angina, refractory angina, myocardial
infarction, transient ischemic attacks, atrial fibrillation,
thrombotic stroke, embolic stroke, deep vein thrombosis,
disseminated intravascular coagulation, ocular build up of fibrin,
and reocclusion or restenosis of recanalized vessels in a mammal.
The compounds also can be used to study the mechanism of action of
coagulation cascade serine proteases to enable the design of better
inhibitors and development of better assay methods. The compounds
would be also useful in prevention of cerebral vascular accident
(CVA) or stroke.
[0160] Also included in the family of compounds are the
pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salt" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
formulas (1), (2), or (3) may be prepared from an inorganic acid or
from an organic acid. Examples of such inorganic acids are
hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric
and phosphoric acid. Appropriate organic acids may be selected from
aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,
carboxylic and sulfonic classes of organic acids, examples of which
are formic, acetic, propionic, succinic, glycolic, gluconic,
lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic,
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic,
embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic,
sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic
acid. Suitable pharmaceutically-acceptable base addition salts of
compounds of formulas (1), (2), or (3) include metallic salts made
from aluminum, calcium, lithium, magnesium, potassium, sodium and
zinc or organic salts made from N,N'-dibenzylethyleneldiamine,
choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procain. All of these salts may be prepared
by conventional means from the corresponding compound by reacting,
for example, the appropriate acid or base with the compound of the
present invention.
[0161] The present invention also comprises a pharmaceutical
composition comprising a therapeutically-effective amount of the
compound in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
Pharmaceutical compositions of the present invention can comprise
the active compounds in association with one or more non-toxic,
pharmaceutically-acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The active compounds of
the present invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment
intended.
[0162] The active compounds and composition may, for example, be
administered orally, intravascularly, intraperitoneally,
subcutaneously, intramuscularly, oculary, or topically. For
treating ocular build up of fibrin, the compounds may be
administered intraocularly or topically as well as orally or
parenterally.
[0163] The compounds can be administered in the form of a depot
injection or implant preparation which may be formulated in such a
manner as to permit a sustained release of the active ingredient.
The active ingredient can be compressed into pellets or small
cylinders and implanted subcutaneously or intramusculary as depot
injections or implants. Implants may employ inert materials such as
biodegradable polymers or synthetic silicones, for example,
Silastic, silicone rubber or other silicon containing polymers.
[0164] The compounds can also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles and multilamellar vesicles. Liposomes
can be formed from a variety of phospholipids, such as cholesterol,
stearylamine or phosphatidylcholines.
[0165] The compounds may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules
are coupled. The compounds may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxy-propyl-methacrylamide-phenol,
polyhydroxyethyl-aspartamide-phenol, or
ployethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds may be coupled to a class of
biodegradable polymers useful in achieving controlled release of a
drug, for example, polylactic acid, polyglycolic acid, copolymers
of polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross linked or
amphitpathic block copolymers of hydrogels.
[0166] For oral administration, the pharmaceutical composition may
be in the form of, for example, tablets, capsules (each of which
includes sustained release or timed release formulations), pills,
powders, granules, elixers, tinctures, suspensions, liquids
including syrups, and emulsions. The pharmaceutical composition is
preferably made in the form of a dosage unit containing a
particular amount of the active ingredient. Examples of such dosage
units are tablets or capsules. The active ingredient may also be
administered by injection as a composition wherein, for example,
saline, dextrose or water may be used as a suitable carrier.
[0167] The amount of therapeutically active compounds which are
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely.
[0168] The pharmaceutical compositions may contain active
ingredients in the range of about 0.1 to 2000 mg, and preferably in
the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100
mg/kg body weight, and preferably between about 0.5 and about 20
mg/kg body weight, may be appropriate. The daily dose can be
administered in one to four doses per day.
[0169] The compounds may be formulated in topical ointment or
cream, or as a suppository, containing the active ingredients in a
total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to
20% w/w and most preferably 0.4 to 15% w/w. When formulated in an
ointment, the active ingredients may be employed with either
paraffinic or a water-miscible ointment base.
[0170] Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[0171] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[0172] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as diisoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0173] For therapeutic purposes, the active compounds of the
present invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0174] In practicing the methods of the present invention for the
treatment and prevention of a variety of thrombotic conditions
resulting from coronary artery and cerebrovascular disease, the
compounds and pharmaceutical compositions of the present invention
are administered alone or in combination with one another, or in
combination with other therapeutics or in vivo diagnostic agents.
The coagulation cascade inhibitors of the present invention can
also be co-administered with suitable anti-platelet aggregation
agents, including, but not limited to ticlopidine, clopidrogel, or
aspirin, fibrinogen receptor antagonists (e.g., to treat or prevent
unstable angina or to prevent reocculsion after angioplasty and
restenosis), anti-coagulants such as warfarin or heparins,
thrombolytic agents such as plasminogen activators or streptokinase
to achieve synergistic effects in the treatment of various
pathologies, lipid lowering agents including
antihypercholesterolemics (e.g., HMG CoA reductase inhibitors such
as mevastatin, lovastatin, simvastatin, pravastatin, and
fluvastatin, HMG CoA synthatase inhibitors, etc.), anti-diabetic
drugs, or other cardiovascular agents (loop diuretics, thiazide
type diuretics, nitrates, aldosterone antagonistics (i.e.,
spironolactone and eplerenone), angiotensin converting enzyme (ACE)
inhibitors, angiotensin II receptor antagonists, beta-blockers,
antiarrythmics, anti-hypertension agents, and calcium channel
blockers) to treat or prevent atheriosclerosis. For example,
patients suffering from coronary artery disease, and patients
subjected to angioplasty procedures, would benefit from
coadministration of fibrinogen receptor antagonists and coagulation
cascade inhibitors of the present invention. Also, coagulation
cascade inhibitors could enhance the efficiency of tissue
plasminogen activator-mediated thrombolytic reperfusion.
[0175] Typical doses of coagulation cascade inhibitors of the
present invention with other suitable anti-platelet agents,
anticoagulation agents, cardiovascular therapeutic agents, or
thrombolytic agents may be the same as those doses of coagulation
cascade inhibitors administered without coadministration of
additional anti-platelet agents, anticoagulation agents,
cardiovascular therapeutic agents, or thrombolytic agents, or may
be substantially less than those doses of coagulation cascade
inhibitors administered without coadministration of additional
anti-platelet agents, anticoagulation agents, cardiovascular
therapeutic agents, or thrombolytic agents, depending on a
patient's therapeutic needs.
[0176] Compounds of the present invention can exist in tautomeric,
geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-geometric
isomers, E- and Z-geometric isomers, R- and S-enantiomers,
diastereomers, d-isomers, l-isomers, the racemic mixtures thereof
and other mixtures thereof, as falling within the scope of the
invention. Pharmaceutically acceptable salts of such tautomeric,
geometric or stereoisomeric forms are also included within the
invention.
[0177] The terms "cis" and "trans", as used herein, denote a form
of geometric isomerism in which two carbon atoms connected by a
double bond will each have a hydrogen atom on the same side of the
double bond ("sis") or on opposite sides of the double bond
("trans").
[0178] Some of the compounds described contain alkenyl groups, and
are meant to include both cis and trans or "E" and "Z" geometric
forms.
[0179] Some of the compounds described contain one or more
stereocenters and are meant to include R, S, and mixtures of R and
S forms for each stereocenter present.
[0180] The present novel methods preferably employ compounds which
selectively inhibit human TF-VIIa over the inhibition of both human
Thrombin II and human factor Xa. Preferably, the compounds have a
human TF-VIIa IC.sub.50 of less than 0.5 uM and also have a
selectivity ratio of TF-VIIa inhibition over both human Thrombin II
and human factor Xa inhibition of at least 10, and more preferably
at least 100. Even more preferably, the compounds have a human
TF-VIIa IC.sub.50 of less than 0.1 uM and also have a selectivity
ratio of TF-VIIa inhibition over both human Thrombin II and human
factor Xa inhibition of at least 300, more preferably at least
1000, and most preferably at least 10,000.
[0181] All mentioned references are incorporated by reference as if
here written.
[0182] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations. Without further elaboration, it is
believed that one skilled in the art can, using the preceding
descriptions, utilize the present invention to its fullest extent.
Compounds containing multiple variations of the structural
modifications illustrated in the Schemes are also contemplated.
Those skilled in the art will readily understand that known
variations of the conditions and processes of the following
preparative procedures can be used to prepare these compounds.
GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES
[0183] The compounds of the present invention can be synthesized,
for example, according to the following procedures and Schemes
given below.
[0184] Abbreviations used in the schemes and tables include: "AA"
represents amino acids, "AcCN" represents acetonitrile, "AcOH"
represents acetic acid, "BINAP" represents
2,2'-bis(diphenylphosphino)-1,1'-binaphth- yl, "BnOH" represents
benzyl alcohol, "BnCHO" represents 2-phenylethanal, "BnSO.sub.2Cl"
represents benzylsulfonyl chloride, "Boc" represents
tert-butyloxycarbonyl, "BOP" represents
benzotriazol-1-yl-oxy-tris-(dimet- hylamino), "bu" represents
butyl, "dba" represents dibenzylidene-acetone, "DCC" represents
1,3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or
methylene chloride, "DIBAH" or "DIBAL" represents
diisobutylaluminum hydride, "DMF" represents dimethylformamide,
"DMSO" represents dimethylsulfoxide, "DPPA" represents
diphenylphosphoryl azide", "EDC" represents
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex.
No." represents Example Number, "Fmoc" represents
9-fluorenylmethoxycarbonyl, "HOBt" represents
hydroxybenzoltriazole", "LDA" represents lithium diisopropylamide,
"MW" represents molecular weight, "NMM" represents
N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH"
represents a phthaloyl group, "pnZ" represents
4-nitrobenzyloxy-carbonyl, "PTC" represents a phase transfer
catalyst, "py" represents pyridine, "RNH.sub.2" represents a
primary organic amine, "SEM" represents
2-(trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" represents
paratoluenesulfonic acid, "TBAF" represents tetrabutylammonium
fluoride, "TBTU" represents
2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium
tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents
trifluoroacetic acid, "THF" represents tetrahydrofuran, "TMS"
represents trimethylsilyl, "TMSCN" represents trimethylsilyl
cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl.
[0185] A specific synthetic process, useful in the preparation of
many of the heterocyclic compounds of the present invention, is the
arylation or heteroarylation of an intermediate compound
characterized by having a suitable leaving group on a sp.sup.2
hybridized carbon of a heterocyclic ring or a cyclodalkenyl ring.
In the product of the reaction, the leaving group is replaced by an
aryl group or a heteroaryl group. Suitable leaving groups for the
reaction include chloro, bromo, iodo, methylthio, and triflates.
The heterocyclic ring or the cycloalkenyl ring with the leaving
group will preferably have an acetic acid group or a derivative
thereof bonded to a ring atom alpha to the bromo and a substituted
or unsubstituted amino group bonded to a ring atom that is both
beta to the carbon having the acetic acid group and gamma to the
bromo substituted ring carbon. The aryl group that is reacted at
the sp.sup.2 hybridized carbon is generally an aryl boronic acid or
an ester of the aryl boronic acid; similarly, heteroaryl boronic
acids or esters of these boronic acids can be used in the same
manner as aryl boronates. The aryl and heteroaryl boronates may be
substituted or unsubstituted. The aryl or heteroaryl becomes bonded
to the sp.sup.2 hybridized carbon at the point at which the boron
was attached to the aryl or heteroaryl ring. Aryl and heteroaryl
organoSn compounds can also be used instead of the corresponding
boronates.
[0186] Suitable reaction conditions for carrying out this
transformation include:
[0187] 1. Pd[P(phenyl).sub.3].sub.4, 2M Na.sub.2CO.sub.3,
60-75.degree. C., dimethoxyethane (DME), H.sub.2O, N.sub.2;
[0188] 2. Pd[P(phenyl).sub.3].sub.4, Cs.sub.2CO.sub.3, dioxane,
100.degree. C.;
[0189] 3. Pd[P(phenyl).sub.3].sub.4, Cu(I)-2-thiophenecarboxylate,
70-75.degree. C., anhydrous THF, argon;
[0190] 4. Z4-Sn(n-butyl).sub.3], Pd[P(phenyl).sub.3].sub.4, LiCl,
anhydrous dioxane, 85.degree. C., argon or N.sub.2.
[0191] The organo palladium (Pd[P(phenyl)3]4) compound is used
catalytically in a ratio of 1 to 40 mole %. The carbonate base is
normally used in an excess of 1.2 to 2 molar equivalents. Suitable
solvents include dimethoxyethane (DME), dioxane, 1-propanol, and
tetrahydrofuran. The temperature of the reaction is normally in the
range of from about 50 to 100.degree. C.
Cu(I)-2-thiophenecarboxylate (Cu(I)-TC) is normally used in a mole
% of 110-150.
[0192] Schemes 2, 4, 5 and 6 show specific applications of this
specific synthetic process. Procedures for preparing the
intermediate heterocyclic or cycloalkenyl ring. compounds having a
suitable leaving group on sp.sup.2 hybridized carbon and useful as
suitable intermediates in this specific synthetic process are given
in the schemes and examples listed above.
[0193] As used in the schemes and examples, L.sub.3, Z.sub.1,
Z.sub.3, Z.sub.4, and R.sub.44, along with any other variable
depicted, encompass each group described for each particular
variable for each embodiment of compounds having any of the
formulas detailed herein. Further, Z.sub.5 and Z.sub.6 are
independently hydrogen or halogen, R.sub.4a and R.sub.4b are
hydrogen, and L.sub.6 is a bond. 28 2930 31 32 33 3435363738 394041
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