U.S. patent application number 15/205395 was filed with the patent office on 2016-11-03 for substituted tetrahydroisoquinoline compounds as factor xia inhibitors.
The applicant listed for this patent is Bristol-Myers Squibb Company. Invention is credited to Marta Dabros, Michael J. Orwat, Donald J.P. Pinto, Leon M. Smith, II, Shefali Srivastava, Chenkou Wei.
Application Number | 20160318904 15/205395 |
Document ID | / |
Family ID | 47080863 |
Filed Date | 2016-11-03 |
United States Patent
Application |
20160318904 |
Kind Code |
A1 |
Orwat; Michael J. ; et
al. |
November 3, 2016 |
SUBSTITUTED TETRAHYDROISOQUINOLINE COMPOUNDS AS FACTOR XIA
INHIBITORS
Abstract
The present invention provides compounds of Formula (I):
##STR00001## or stereoisomers, pharmaceutically acceptable salts
thereof, wherein all of the variables are as defined herein. These
compounds are inhibitors of factor XIa and/or plasma kallikrein
which may be used as medicaments.
Inventors: |
Orwat; Michael J.; (New
Hope, PA) ; Pinto; Donald J.P.; (Churchville, PA)
; Smith, II; Leon M.; (Somerset, NJ) ; Srivastava;
Shefali; (Jaipur, IN) ; Dabros; Marta; (Foster
City, CA) ; Wei; Chenkou; (Princeton Junction,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company |
Princeton |
NJ |
US |
|
|
Family ID: |
47080863 |
Appl. No.: |
15/205395 |
Filed: |
July 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14886415 |
Oct 19, 2015 |
9447110 |
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15205395 |
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14617979 |
Feb 10, 2015 |
9192607 |
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14886415 |
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14117513 |
Nov 13, 2013 |
9000172 |
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PCT/US2012/059969 |
Oct 12, 2012 |
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14617979 |
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61547292 |
Oct 14, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
C07D 487/10 20130101; C07D 487/08 20130101; A61K 31/551 20130101;
A61P 7/02 20180101; C07D 471/10 20130101; C07D 491/113 20130101;
A61K 31/496 20130101; A61K 31/55 20130101; A61K 31/541 20130101;
C07D 491/10 20130101; C07D 401/14 20130101; C07B 2200/13 20130101;
C07D 487/04 20130101; C07D 413/14 20130101; C07D 217/26 20130101;
A61K 31/4725 20130101; C07D 491/107 20130101; C07D 401/04 20130101;
C07D 401/10 20130101 |
International
Class: |
C07D 401/14 20060101
C07D401/14 |
Claims
1. Form HCl:SA-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid, which is characterized by a powder X-ray diffraction
pattern substantially in accordance with that shown in FIG. 1.
2. Form HCl:SA-1 according to claim 1 having a powder X-ray
diffraction pattern comprising four or more 2.theta. values
(CuK.alpha. .lamda.=1.5418 .ANG.): 6.0, 8.3, 8.7, 12.3, 16.2, 16.7,
17.5, 19.9, and 20.4.
3. Form HCl:SA-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid according to claim 1, which is characterized by unit
cell parameters substantially equal to the following: Cell
dimensions: a=8.3746(2) .ANG. b=20.2236(5) .ANG. c=21.3099(6) .ANG.
.alpha.=90.degree. .beta.=90.degree. .gamma.=90.degree. Space
group: P2(1)2(1)2(1) Molecules/asymmetric unit: 1 wherein
measurement of the crystalline form is at a temperature of about
23.degree. C.
4. Form HCl:SA-1 according to claim 3, which is characterized by
fractional atomic coordinates substantially as listed in Table
2.
5. Form HCl:SA-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid, to claim 3 which is characterized by unit cell
parameters substantially as listed in Table 4.
6. Form H.5-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid, which is characterized by a powder X-ray diffraction
pattern substantially in accordance with that shown in FIG. 2.
7. Form H.5-1 according to claim 6 having a powder X-ray
diffraction pattern comprising four or more 2.theta. values
(CuK.alpha. .lamda.=1.5418 .ANG.): 5.9, 7.2, 12.0, 15.7, 17.2,
18.9, 20.3, 24.2, and 26.1.
8. Form H.5-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid according to claim 6, which is characterized by unit
cell parameters substantially equal to the following: Cell
dimensions: a=13.6547(3) .ANG. b=18.7590(3) .ANG. c=24.7370(5)
.ANG. .alpha.=90.degree. .beta.=90.degree. .gamma.=90.degree. Space
group: 12(1)2(1)2(1) Molecules/asymmetric unit: 1 Density
(calculated): 1.401 Mg/m.sup.3 wherein measurement of the
crystalline form is at a temperature of about 23.degree. C.
9. Form H.5-1 according to claim 8, which is characterized by
fractional atomic coordinates substantially as listed in Table
1.
10. Form P13 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid, which is characterized by a powder X-ray diffraction
pattern substantially in accordance with that shown in FIG. 3.
11. Form P13 according to claim 10 having a powder X-ray
diffraction pattern comprising four or more 2.theta. values
(CuK.alpha. .lamda.=1.5418 .ANG.): 8.4, 8.9, 12.7, and 17.9.
12. The Form according to claim 1 in substantially pure form.
13. The Form according to claim 12, wherein substantially pure is
greater than 90 percent pure.
14. A pharmaceutical composition comprising a therapeutically
effective amount of crystalline Form H.5-1 of
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid of claim 6 and a pharmaceutically acceptable
carrier.
15. A pharmaceutical composition comprising a therapeutically
effective amount of crystalline Form P13 of
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid of claim 10 and a pharmaceutically acceptable
carrier.
16. A pharmaceutical composition comprising a therapeutically
effective amount of crystalline Form HCl:SA-1 of
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid of claim 1 and a pharmaceutically acceptable
carrier.
17. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically
effective amount of crystalline Form according to claim 16.
18. A method according to claim 17, wherein the thromboembolic
disorder is selected from the group consisting of arterial
cardiovascular thromboembolic disorders, venous cardiovascular
thromboembolic disorders, and thromboembolic disorders in the
chambers of the heart.
19. A method according to claim 17, wherein the thromboembolic
disorder is selected from unstable angina, an acute coronary
syndrome, atrial fibrillation, first myocardial infarction,
recurrent myocardial infarction, ischemic sudden death, transient
ischemic attack, stroke, atherosclerosis, peripheral occlusive
arterial disease, venous thrombosis, deep vein thrombosis,
thrombophlebitis, arterial embolism, coronary arterial thrombosis,
cerebral arterial thrombosis, cerebral embolism, kidney embolism,
pulmonary embolism, and thrombosis resulting from (a) prosthetic
valves or other implants, (b) indwelling catheters, (c) stents, (d)
cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures
in which blood is exposed to an artificial surface that promotes
thrombosis.
20. A process for preparing crystalline forms of Compound (I)
according to claim 1, comprising a step of slurrying Compound (I)
in a solvent selected from: acetone, methanol, ethanol,
CH.sub.2Cl.sub.2, DMF, NMP, MEK, 2-BuOH, IPA, IpOAc, MTBE, EtOAc,
and BuOAc.
21. A pharmaceutical composition comprising a therapeutically
effective amount of amorphous form of
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid and a pharmaceutically acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/886,415, filed Oct. 19, 2015, now allowed, which is a
continuation of U.S. application Ser. No. 14/617,979 (U.S. Pat. No.
9,192,607), filed Feb. 10, 2015, which is a continuation of U.S.
application Ser. No. 14/117,513 (U.S. Pat. No. 9,000,172), filed
Nov. 13, 2013, which is the 371 National Stage of International
Application No. PCT/US2012/059969, filed Oct. 12, 2012, which
claims the priority benefit of U.S. Provisional Application No.
61/547,292, filed Oct. 14, 2011, the contents of all of which are
herein incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention provides novel substituted
tetrahydroisoquinoline (THQ) compounds, and their analogues
thereof, which are inhibitors of factor XIa or plasma kallikrein,
compositions containing them, and methods of using them, for
example, for the treatment or prophylaxis of thromboembolic
disorders.
BACKGROUND OF THE INVENTION
[0003] Thromboembolic diseases remain the leading cause of death in
developed countries despite the availability of anticoagulants such
as warfarin (COUMADIN.RTM.), heparin, low molecular weight heparins
(LMWH), and synthetic pentasaccharides and antiplatelet agents such
as aspirin and clopidogrel (PLAVIX.RTM.). The oral anticoagulant
warfarin, inhibits the post-translational maturation of coagulation
factors VII, IX, X and prothrombin, and has proven effective in
both venous and arterial thrombosis. However, its usage is limited
due to its narrow therapeutic index, slow onset of therapeutic
effect, numerous dietary and drug interactions, and a need for
monitoring and dose adjustment. Thus discovering and developing
safe and efficacious oral anticoagulants for the prevention and
treatment of a wide range of thromboembolic disorders has become
increasingly important.
[0004] One approach is to inhibit thrombin generation by targeting
the inhibition of coagulation factor XIa (FXIa). Factor XIa is a
plasma serine protease involved in the regulation of blood
coagulation, which is initiated in vivo by the binding of tissue
factor (TF) to factor VII (FVII) to generate factor VIIa (FVIIa).
The resulting TF:FVIIa complex activates factor IX (FIX) and factor
X (FX) that leads to the production of factor Xa (FXa). The
generated FXa catalyzes the transformation of prothrombin into
small amounts of thrombin before this pathway is shut down by
tissue factor pathway inhibitor (TFPI). The process of coagulation
is then further propagated via the feedback activation of Factors
V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. et
al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) The
resulting burst of thrombin converts fibrinogen to fibrin that
polymerizes to form the structural framework of a blood clot, and
activates platelets, which are a key cellular component of
coagulation (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)).
Therefore, factor XIa plays a key role in propagating this
amplification loop and is thus an attractive target for
anti-thrombotic therapy.
SUMMARY OF THE INVENTION
[0005] The present invention provides novel substituted
tetrahydroisoquinoline compounds, and their analogues thereof,
including stereoisomers, tautomers, pharmaceutically acceptable
salts, or solvates thereof, which are useful as selective
inhibitors of serine protease enzymes, especially factor XIa and/or
plasma kallikrein.
[0006] The present invention also provides processes and
intermediates for making the compounds of the present
invention.
[0007] The present invention also provides pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and
at least one of the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof.
[0008] The compounds of the invention may be used in the treatment
and/or prophylaxis of thromboembolic disorders.
[0009] The compounds of the present invention may be used in
therapy.
[0010] The compounds of the present invention may be used for the
manufacture of a medicament for the treatment and/or prophylaxis of
a thromboembolic disorder.
[0011] The compounds of the invention can be used alone, in
combination with other compounds of the present invention, or in
combination with one or more, preferably one to two, other
agent(s).
[0012] These and other features of the invention will be set forth
in expanded form as the disclosure continues.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The invention is illustrated by reference to the
accompanying drawings described below.
[0014] FIG. 1 shows the observed and calculated (room temperature)
powder X-ray diffraction patterns (CuK.alpha. .lamda.=1.5418 .ANG.)
of Form HCl:SA-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0015] FIG. 2 shows the observed and calculated (room temperature)
powder X-ray diffraction patterns (CuK.alpha. .lamda.=1.5418 .ANG.)
of Form H.5-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0016] FIG. 3 shows the observed powder X-ray diffraction patterns
(CuK.alpha. .lamda.=1.5418 .ANG.) of Form P13 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0017] FIG. 4 is a differential scanning calorimetry thermogram of
Form HCl:SA-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0018] FIG. 5 is a differential scanning calorimetry thermogram of
Form P13 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0019] FIG. 6 is a differential scanning calorimetry thermogram of
Form H.5-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0020] FIG. 7 is a thermogravimetric analysis thermogram of Form
HCl:SA-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0021] FIG. 8 is a thermogravimetric analysis thermogram of Form
P13 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0022] FIG. 9 is a thermogravimetric analysis thermogram of Form
H.5-1 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid.
[0023] FIG. 10 is a C-13 CPMASA spectrum diagram of Form P13 of
crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid. The spinning sidebands are labeled with "ssb."
[0024] FIG. 11 is a F-19 CPMAS spectrum (with proton decoupling)
diagram of Form P13 of crystalline
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid. The spinning side bands are labeled and were
confirmed by varying the spinning speed.
DETAILED DESCRIPTION OF THE INVENTION
I. Compounds of the Invention
[0025] In a first aspect, the present invention provides compounds
of Formula (I):
##STR00002##
or stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof, wherein:
[0026] ring A is C.sub.3-6 carbocycle;
[0027] ring B is 4- to 7-membered heterocycle containing carbon
atoms and 0-3 additional heteroatoms selected from the group
consisting of N, NR.sup.6, O, and S(O).sub.p; optionally, ring B
forms a fused ring or spiro ring with a 4- to 7-membered
heterocycle containing carbon atoms and 1-3 heteroatoms selected
from the group consisting of NR.sup.6, O, and S(O).sub.p; ring B,
including the fused ring or spiro ring is substituted with 1-3
R.sup.5;
[0028] L is selected from the group consisting of:
--CHR.sup.10CHR.sup.10--, --CR.sup.10.dbd.CR.sup.10--,
--C.ident.C--, --CHR.sup.10NH--, --NHCHR.sup.10--, --SCH.sub.2--,
--CH.sub.2S--, --SO.sub.2CH.sub.2--, --CH.sub.2SO.sub.2--,
--NHCH.sub.2--, and --CH.sub.2NH--;
[0029] R.sup.1, at each occurrence, is selected from the group
consisting of: H, halo, C.sub.1-6 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkylthio, OH, SH, CHF.sub.2, CF.sub.3, OCF.sub.3, CN,
NH.sub.2, COC.sub.1-4 alkyl, CO.sub.2(C.sub.1-4 alkyl),
--CH.sub.2CO.sub.2H, --CH.sub.2CO.sub.2(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), and --SO.sub.2NH.sub.2, and
--C(.dbd.NH)NH.sub.2;
[0030] R.sup.2 is selected from the group consisting of: H, halo,
CN, OH, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-6haloalkyl,
C.sub.1-6haloalkoxy, CO(C.sub.1-4 alkyl), CONH.sub.2, CO.sub.2H,
CH.sub.2NH.sub.2, and a 5- to 7-membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p, wherein said heterocycle is substituted with 0-2
R.sup.2a;
[0031] R.sup.2a, at each occurrence, is selected from the group
consisting of: H, halo, C.sub.1-4 alkyl, --CH.sub.2OH, C.sub.1-4
alkoxy, OH, CF.sub.3, OCF.sub.3, CN, NH.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), CO(C.sub.1-4 alkyl), --CONH.sub.2,
--CH.sub.2OH, --CH.sub.2OC.sub.1-4alkyl, --CH.sub.2NH.sub.2--,
CONH(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
--SO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-4 alkyl), and --SO.sub.2N(C.sub.1-4
alkyl).sub.2;
[0032] R.sup.3 is selected from the group consisting of: C.sub.1-6
alkyl substituted with 1-3 R.sup.3a, --(CH.sub.2).sub.n--C.sub.3-10
carbocycle substituted with 0-3 R.sup.3a or --(CH.sub.2).sub.n-5-10
membered heterocycle containing carbon atoms and 1-4 heteroatoms
selected from the group consisting of N, NR.sup.7, O, and
S(O).sub.p; wherein said heterocycle is substituted with 0-3
R.sup.3a;
[0033] R.sup.3a, at each occurrence, is selected from the group
consisting of: .dbd.O, halo, C.sub.1-4 alkyl, OH, C.sub.1-4 alkoxy,
CN, NH.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl), CONH.sub.2,
CONH(C.sub.1-6 alkyl), CON(C.sub.1-4 alkyl).sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl),
--CONHCO.sub.2C.sub.1-4 alkyl, --CONH--C.sub.1-4
alkylene-NHCO(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-CONH.sub.2, --NHCOC.sub.1-4 alkyl, --NHCO.sub.2(C.sub.1-4
alkyl), --C.sub.1-4 alkylene-NHCO.sub.2C.sub.1-4 alkyl, R.sup.f,
CONHR.sup.f, and --CO.sub.2R.sup.f;
[0034] R.sup.4, at each occurrence, is selected from the group
consisting of: H, halo and C.sub.1-4 alkyl;
[0035] R.sup.5, at each occurrence, is selected from the group
consisting of: H, .dbd.O, halo, C.sub.1-4 alkyl, OH, CN, NH.sub.2,
--N(C.sub.1-4 alkyl).sub.2, NO.sub.2, C.sub.1-4 alkoxy,
--OCO(C.sub.1-4 alkyl), --O--C.sub.1-4 alkylene-O(C.sub.1-4 alkyl),
--O--C.sub.1-4 alkylene-N(C.sub.1-4 alkyl).sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--(CH.sub.2).sub.2CONH.sub.2, --CONR.sup.9(C.sub.1-4 alkyl),
--CONR.sup.9--C.sub.1-4 alkylene-O(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --CONR.sup.9--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CON(C.sub.1-4 alkyl)-C.sub.1-4
alkylene-O(C.sub.1-4 alkyl), --CONR.sup.9--C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), --NR.sup.9COC.sub.1-4 alkyl,
--NR.sup.9CO.sub.2C.sub.1-4 alkyl, --NR.sup.9CONH(C.sub.1-4 alkyl),
--NR.sup.9CONR.sup.9--C.sub.1-4 alkylene-CO.sub.2C.sub.1-4 alkyl,
--NR.sup.9--C.sub.1-4 alkylene-N(C.sub.1-4 alkyl).sub.2, R.sup.8,
--OR.sup.8, --O--C.sub.1-4 alkylene-R.sup.8, --CO.sub.2R.sup.8,
--CONR.sup.9R.sup.8, --NR.sup.9COR.sup.8,
--NR.sup.9CO.sub.2R.sup.8, and --NR.sup.9CONR.sup.9R.sup.8;
[0036] R.sup.6 is selected from the group consisting of: H,
C.sub.1-4 alkyl, --CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4
alkyl), --CONH.sub.2, --CO--C.sub.1-4 alkylene-N(C.sub.1-4
alkyl).sub.2, --(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--CONR.sup.9(C.sub.1-4 alkyl), --CONR.sup.9--C.sub.1-4
alkylene-O(C.sub.1-4 alkyl), --CONR.sup.9--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONR.sup.9--C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
R.sup.8, --COR.sup.8, --CO.sub.2R.sup.8, and
--CONR.sup.9R.sup.8;
[0037] R.sup.7, at each occurrence, is selected from the group
consisting of: H, C.sub.1-4 alkyl, COC.sub.1-4 alkyl,
CO.sub.2(C.sub.1-4 alkyl), CO.sub.2Bn, --CONH--C.sub.1-4
alkylene-CO.sub.2C.sub.1-4 alkyl, phenyl, benzyl, and
--CO.sub.2--C.sub.1-4 alkylene-aryl;
[0038] R.sup.8, at each occurrence, is selected from the group
consisting of: --(CH.sub.2).sub.n--C.sub.3-10 carbocycle
substituted with 0-3 R.sup.e and --(CH.sub.2).sub.n-5-10 membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of N, NR.sup.d, 0, and S(O).sub.p;
wherein said carbocycle and heterocycle are optionally substituted
with .dbd.O;
[0039] R.sup.9, at each occurrence, is selected from the group
consisting of: H and C.sub.1-4alkyl;
[0040] R.sup.10, at each occurrence, is selected from the group
consisting of: H, halo, OH, and C.sub.1-4 alkyl;
[0041] R.sup.c is, independently at each occurrence, selected from
the group consisting of: H, C.sub.1-4 alkyl, COC.sub.1-4 alkyl,
CO.sub.2C.sub.1-4 alkyl, and CO.sub.2Bn;
[0042] R.sup.d is, independently at each occurrence, selected from
the group consisting of: H, C.sub.1-4 alkyl, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-CO.sub.2C.sub.1-4 alkyl, CO.sub.2Bn, R.sup.f, and
CONHR.sup.f;
[0043] R.sup.e is, independently at each occurrence, selected from
the group consisting of: .dbd.O, halo, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, OCF.sub.3, NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2,
CO(C.sub.1-4 alkyl), CO(C.sub.1-4 haloalkyl), CO.sub.2(C.sub.1-4
alkyl), CONH.sub.2, --CONH(C.sub.1-4 alkyl), --CONHPh,
--CON(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4
alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4 alkylene-N(C.sub.1-4
alkyl).sub.2, --CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(C.sub.1-4 alkyl), R.sup.f, COR.sup.f, CO.sub.2R.sup.f
and CONHR.sup.f;
[0044] R.sup.f is, independently at each occurrence, selected from
the group consisting of: --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of N, NR.sup.c, O, and S(O).sub.p;
wherein each ring moiety is substituted with 0-2 R.sup.g;
[0045] R.sup.g is, independently at each occurrence, selected from
the group consisting of: .dbd.O, halo, C.sub.1-4 alkyl, OH,
C.sub.1-4 alkoxy, and NHCO(C.sub.1-4 alkyl);
[0046] n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
and
[0047] p, at each occurrence, is selected from 0, 1, and 2.
[0048] In a second aspect, the present invention provides compounds
of Formula (I) or stereoisomers, tautomers, pharmaceutically
acceptable salts thereof, within the scope of the first aspect,
wherein:
[0049] ring A is C.sub.3-6 carbocycle;
[0050] ring B is 4- to 7-membered heterocycle containing carbon
atoms and 0-3 additional heteroatoms selected from the group
consisting of N, NR.sup.6, O, and S(O).sub.p; optionally, ring B
forms a fused ring or spiro ring with a 4- to 7-membered
heterocycle containing carbon atoms and 1-3 heteroatoms selected
from the group consisting of NR.sup.6, O, and S(O).sub.p; ring B,
including the fused ring or spiro ring is substituted with 1-3
R.sup.5;
[0051] L is selected from the group consisting of: a bond,
--CHR.sup.10CHR.sup.10--, --CR.sup.10.dbd.CR.sup.10--, and
--C.ident.C--;
[0052] R.sup.1, at each occurrence, is selected from the group
consisting of: H, halo, C.sub.1-2 alkyl, --O(C.sub.1-4 alkyl), CN,
--CH.sub.2NH.sub.2, and --C(.dbd.NH)NH.sub.2;
[0053] R.sup.2 is independently selected from the group consisting
of: H, halo, CN, OH C.sub.1-6 alkyl, C.sub.1-4 alkoxy,
C.sub.1-6haloalkyl, C.sub.1-6haloalkoxy, CO(C.sub.1-4 alkyl),
CONH.sub.2, CO.sub.2H and a 5- to 7-membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NH, N(C.sub.1-4
alkyl), O, and S(O).sub.p, wherein said heterocycle is substituted
with 1-2 R.sup.2a;
[0054] R.sup.2a, at each occurrence, is selected from the group
consisting of: H, halo, C.sub.1-4 alkyl, CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2, --CH.sub.2OH,
--CH.sub.2OC.sub.1-4alkyl, and --CH.sub.2NH.sub.2;
[0055] R.sup.3 is selected from the group consisting of: C.sub.1-6
alkyl substituted with 1-3 R.sup.3a, C.sub.3-10 carbocycle
substituted with 1-3 R.sup.3a, and 5-10 membered heterocycle
containing carbon atoms and 1-4 heteroatoms selected from the group
consisting of N, NR.sup.7, O, and S(O).sub.p; wherein said
heterocycle is substituted with 1-3 R.sup.3a;
[0056] R.sup.3a, at each occurrence, is selected from the group
consisting of: H, halo, C.sub.1-4 alkyl, --OH, C.sub.1-4 alkoxy,
--CN, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO.sub.2--C.sub.1-4
alkylene-O(C.sub.1-4 alkyl), --CO.sub.2--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH.sub.2, --CONH(C.sub.1-6
alkyl), --CON(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), --CONHCO.sub.2C.sub.1-4 alkyl,
--CONH--C.sub.1-4 alkylene-NHCO(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-CONH.sub.2, --NHCOC.sub.1-4 alkyl, --NHCO.sub.2(C.sub.1-4
alkyl), R.sup.8, --CONHR.sup.8, and --CO.sub.2R.sup.8;
[0057] R.sup.4, at each occurrence, is selected from the group
consisting of: H, halo, and C.sub.1-4 alkyl;
[0058] R.sup.5, at each occurrence, is selected from the group
consisting of: H, .dbd.O, halo, C.sub.1-4 alkyl, OH, CN, NH.sub.2,
--N(C.sub.1-4 alkyl).sub.2, NO.sub.2, C.sub.1-4 alkoxy,
--OCO(C.sub.1-4 alkyl), --O--C.sub.1-4 alkylene-O(C.sub.1-4 alkyl),
--O--C.sub.1-4 alkylene-N(C.sub.1-4 alkyl).sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--(CH.sub.2).sub.2CONH.sub.2, --CONR.sup.9(C.sub.1-4 alkyl),
--CONR.sup.9--C.sub.1-4 alkylene-O(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --CONR.sup.9--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CON(C.sub.1-4 alkyl)-C.sub.1-4
alkylene-O(C.sub.1-4 alkyl), --CONR.sup.9--C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), --NR.sup.9COC.sub.1-4 alkyl,
--NR.sup.9CO.sub.2C.sub.1-4 alkyl, --NR.sup.9CONH(C.sub.1-4 alkyl),
--NR.sup.9CONR.sup.9--C.sub.1-4 alkylene-CO.sub.2C.sub.1-4 alkyl,
--NR.sup.9--C.sub.1-4 alkylene-N(C.sub.1-4 alkyl).sub.2, R.sup.8,
--OR.sup.8, --O--C.sub.1-4 alkylene-R.sup.8, --CO.sub.2R.sup.8,
--CONR.sup.9R.sup.8, --NR.sup.9COR.sup.8,
--NR.sup.9CO.sub.2R.sup.8, and --NR.sup.9CONR.sup.9R.sup.8;
[0059] R.sup.6 is selected from the group consisting of: H,
C.sub.1-4 alkyl, --CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4
alkyl), --CONH.sub.2, --CO--C.sub.1-4 alkylene-N(C.sub.1-4
alkyl).sub.2, --(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--CONR.sup.9(C.sub.1-4 alkyl), --CONR.sup.9--C.sub.1-4
alkylene-O(C.sub.1-4 alkyl), --CONR.sup.9--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONR.sup.9--C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
R.sup.8, --COR.sup.8, --CO.sub.2R.sup.8, and
--CONR.sup.9R.sup.8;
[0060] R.sup.7, at each occurrence, is selected from the group
consisting of: H, C.sub.1-4 alkyl, --CO.sub.2(C.sub.1-4 alkyl), and
--CO.sub.2--C.sub.1-4 alkylene-aryl;
[0061] R.sup.8, at each occurrence, is selected from the group
consisting of: --(CH.sub.2).sub.n--C.sub.3-10 carbocycle and
--(CH.sub.2).sub.n-5-10 membered heterocycle containing carbon
atoms and 1-4 heteroatoms selected from the group consisting of N,
NH, N(C.sub.1-4 alkyl), O, and S(O).sub.p; wherein said carbocycle
and heterocycle are substituted with .dbd.O;
[0062] R.sup.9, at each occurrence, is selected from the group
consisting of: H and C.sub.1-4alkyl;
[0063] R.sup.10, at each occurrence, is selected from the group
consisting of: H and F;
[0064] n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
and
[0065] p, at each occurrence, is selected from 0, 1, and 2.
[0066] In a third aspect, the present invention includes compounds
of Formula (II):
##STR00003##
or stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof, within the scope of the second aspect,
wherein:
[0067] W is selected from the group consisting of
CR.sup.5bR.sup.5c, O, S(O).sub.p, and NR.sup.6;
[0068] R.sup.4a, R.sup.4b, R.sup.4c, and Rod are independently
selected from the group consisting of: H, F, and C.sub.1-4
alkyl;
[0069] R.sup.5a is selected from the group consisting of: H and
.dbd.O;
[0070] R.sup.5b and R.sup.5c are independently selected from the
group consisting of: H, halo, C.sub.1-4 alkyl, OH, CN, NH.sub.2,
--N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, --OCO--C.sub.1-4
alkyl, --O--C.sub.1-4alkylene-N(C.sub.1-4 alkyl).sub.2,
--O--C.sub.1-4alkylene-O(C.sub.1-4 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2, --CONR.sup.9(C.sub.1-4
alkyl), --CON(C.sub.1-4 alkyl).sub.2, R.sup.8, --OR.sup.8,
--COR.sup.8, and --CO.sub.2R.sup.8;
[0071] optionally, R.sup.5b and R.sup.5c together with the carbon
atom to which they are attached form a 4-7 membered heterocyclic
ring containing carbon atoms and 1-4 heteroatoms selected from the
group consisting of N, NR.sup.6, O, and S(O).sub.p; wherein said
heterocycle is unsubstituted or substituted with .dbd.O.
[0072] q, at each occurrence, is selected from 0, 1, and 2; and
[0073] r, at each occurrence, is selected from 0, 1, and 2.
[0074] In a fourth aspect, the present invention includes compounds
of Formula (III):
##STR00004##
or stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof, within the scope of the third aspect,
wherein:
[0075] R.sup.1a is selected from the group consisting of: H, halo,
C.sub.1-2 alkyl, and methoxy;
[0076] R.sup.1b is selected from the group consisting of: H and
halo;
[0077] R.sup.2 is independently selected from the group consisting
of: H, F, CN, OH, C.sub.1-4 alkoxy, --CHF.sub.2, --CF.sub.3,
--CH.sub.2NH.sub.2, --OCHF.sub.2, --CO(C.sub.1-4 alkyl),
--CONH.sub.2, --COOH, triazole substituted with R.sup.2a, and
tetrazole substituted with R.sup.2a;
[0078] R.sup.3 is selected from the group consisting of: phenyl
substituted with 1-2 R.sup.3a, C.sub.3-6 cycloalkyl substituted
with 1-2 R.sup.3a, heterocycle substituted with 1-2 R.sup.3a;
wherein said heterocycle is selected from the group consisting of:
piperidinyl, pyridyl, indolyl, and indazolyl.
[0079] In a fifth aspect, the present invention includes compounds
of Formula (IV):
##STR00005##
or stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof, within the scope of the fourth aspect,
wherein:
##STR00006##
is selected from the group consisting of:
##STR00007##
[0080] R.sup.3 is selected from the group consisting of: phenyl
substituted with 1-2 R.sup.3a, pyridyl substituted with 1-2
R.sup.3a, C.sub.3-6 cycloalkyl substituted with 1-2 R.sup.3a,
##STR00008##
[0081] R.sup.7 is selected from the group consisting of: H and
C.sub.1-4 alkyl.
[0082] In a sixth aspect, the present invention includes compounds
of Formula (V):
##STR00009##
or stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof, within the scope of the fifth aspect,
wherein:
[0083] R.sup.3 is selected from the group consisting of: phenyl
substituted with 1-2 R.sup.3a and pyridyl substituted with 1-2
R.sup.3a;
##STR00010##
is selected from the group consisting of:
##STR00011##
[0084] R.sup.3a, at each occurrence, is selected from the group
consisting of: H, halo, C.sub.1-4 alkyl, OH, C.sub.1-4 alkoxy, CN,
NH.sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H, --CO.sub.2(C.sub.1-4
alkyl), --CO.sub.2(CH.sub.2).sub.1-2O(C.sub.1-4 alkyl),
--CO.sub.2(CH.sub.2).sub.1-2CON(C.sub.1-4 alkyl).sub.2,
--CONH.sub.2, CONH(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), R.sup.8, --CONHR.sup.8, and
--CO.sub.2R.sup.8
[0085] R.sup.5b and R.sup.5c are independently selected from the
group consisting of: H, C.sub.1-4 alkyl, OH, CN, NH.sub.2,
--N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, --OCO--C.sub.1-4
alkyl, --CO.sub.2H, --CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONR.sup.9(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
R.sup.8, --OR.sup.8, --COR.sup.8, and --CO.sub.2R.sup.8;
[0086] optionally, R.sup.5b and R.sup.5c together with the carbon
atom to which they are both attached form a 5-6 membered
heterocyclic ring containing carbon atoms and 1-4 heteroatoms
selected from the group consisting of N, NR.sup.6, O, and
S(O).sub.p; wherein said heterocycle is unsubstituted or
substituted with .dbd.O; and
[0087] R.sup.6 is selected from the group consisting of: H,
C.sub.1-4 alkyl, --CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4
alkyl), --CO--C.sub.1-4 alkylene-N(C.sub.1-4 alkyl).sub.2,
--CONH.sub.2, --(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--CONH(C.sub.1-4 alkyl), --CONH--C.sub.1-4 alkylene-O(C.sub.1-4
alkyl), --CONH--C.sub.1-4 alkylene-N(C.sub.1-4 alkyl).sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl),
--CONH(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2, R.sup.8,
--COR.sup.8, and --CO.sub.2R.sup.8.
[0088] In a seventh aspect, the present invention includes
compounds of Formula (VI):
##STR00012##
or stereoisomers, tautomers, pharmaceutically acceptable salts
thereof, within the scope of the sixth aspect, wherein:
[0089] R.sup.1b is independently selected from the group consisting
of: H and F;
[0090] R.sup.3a is selected from the group consisting of: H, halo,
CN, CO.sub.2H, --CO.sub.2(C.sub.1-4 alkyl),
--CO.sub.2(CH.sub.2).sub.1-2O(C.sub.1-4 alkyl),
--CO.sub.2(CH.sub.2).sub.1-2CON(C.sub.1-4 alkyl).sub.2,
--CONH.sub.2, --CONH(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4
alkyl), --CO.sub.2(C.sub.3-6 cycloalkyl),
--CO.sub.2(CH.sub.2).sub.1-2Ph, and
--CO.sub.2(CH.sub.2).sub.1-2triazole.
[0091] In an eighth aspect, the present invention includes
compounds of Formula (VI), or stereoisomers, tautomers,
pharmaceutically acceptable salts, or solvates thereof, within the
scope of the seventh aspect, wherein:
##STR00013##
is selected from the group consisting of:
##STR00014## ##STR00015## ##STR00016##
[0092] R.sup.3a is independently selected from the group consisting
of: H, F, Cl, CN, CO.sub.2H, --CO.sub.2Me, --CO.sub.2Et,
--CO.sub.2(i-Pr), --CO.sub.2(t-Bu), --CO.sub.2(n-Bu),
--CO.sub.2(i-Bu), --CO.sub.2(CH.sub.2).sub.2OMe,
--CO.sub.2CH.sub.2CON(Me).sub.2, --NHCO.sub.2Me,
--CO.sub.2CH.sub.2(phenyl), --CO.sub.2(C.sub.3-6 cycloalkyl), and
--CO.sub.2(CH.sub.2).sub.2-triazole; and
[0093] R.sup.6 is selected from the group consisting of: H,
C.sub.1-4 alkyl, --CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4
alkyl), --COCH.sub.2N(C.sub.1-4 alkyl).sub.2,
--(CH.sub.2).sub.1-2N(C.sub.1-4 alkyl).sub.2, --CONH(C.sub.1-4
alkyl), --CONH--C.sub.1-4 alkylene-O(C.sub.1-4 alkyl),
--CONH--C.sub.1-4 alkylene-N(C.sub.1-4 alkyl).sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), --CH.sub.2Ph,
and --CO.sub.2--C.sub.1-4 alkylene-Ph.
[0094] In a ninth aspect, the present invention includes compounds
of Formula (VII):
##STR00017##
or stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof, within the scope of the second aspect,
wherein:
[0095] R.sup.1b is selected from the group consisting of: H and
F;
##STR00018##
is selected from the group consisting of:
##STR00019## ##STR00020##
[0096] R.sup.2 is selected from the group consisting of: H, F, CN,
COMe, OH, OMe, OCHF.sub.2, CHF.sub.2, CF.sub.3, and tetrazole;
[0097] R.sup.3 is selected from the group consisting of: phenyl
substituted with 1-2 R.sup.3a, cyclohexyl,
##STR00021##
[0098] R.sup.3a is independently selected from the group consisting
of: H, F, Cl, CN, CO.sub.2H, --CH.sub.2CO.sub.2H, CO.sub.2Me,
--CO.sub.2Et, --CO.sub.2(i-Pr), --CO.sub.2(t-Bu), --CO.sub.2(n-Bu),
--CO.sub.2(i-Bu), --CO.sub.2(CH.sub.2).sub.2OMe,
--CO.sub.2CH.sub.2CON(Me).sub.2, --NHCO.sub.2Me,
--CO.sub.2(CH.sub.2).sub.2-triazole, and
--CO.sub.2(cyclopentyl);
[0099] R.sup.4c and R.sup.4d are independently selected from the
group consisting of: H and Me;
[0100] R.sup.5b and R.sup.5c are, independently selected from the
group consisting of: H, F, Me, Et, i-propyl, CN, OH, --OMe,
--CO.sub.2Me, --CO.sub.2Et, --CON(Me).sub.2, NH.sub.2,
--N(Me).sub.2, O(CH.sub.2)N(Me).sub.2, --O(CH.sub.2)OMe,
##STR00022##
[0101] R.sup.6 is selected from the group consisting of: H, Me,
--CO.sub.2Me, --CO.sub.2(t-butyl), --COMe, --COM-Me,
--CONH(CH.sub.2).sub.2CO.sub.2Et, CONH(CH.sub.2).sub.2N(Me).sub.2,
--CO.sub.2CH.sub.2Ph, --(CH.sub.2).sub.2N(Me).sub.2, and
--CH.sub.2Ph; and
[0102] R.sup.7 is selected from the group consisting of: H and
Me;
[0103] q, at each occurrence, is selected from 0, 1, and 2; and
[0104] r, at each occurrence, is selected from 0, 1, and 2.
[0105] In a tenth aspect, the present invention includes compounds
of Formula (VIII):
##STR00023##
or stereoisomers, tautomers, pharmaceutically acceptable salt
thereof, within the scope of the ninth aspect wherein:
[0106] R.sup.2 is selected from the group consisting of: H, F, CN,
COMe, OH, OMe, OCHF.sub.2, CHF.sub.2, CF.sub.3, and tetrazole;
[0107] R.sup.3a is selected from the group consisting of: H, F, Cl,
CN, CO.sub.2H, --CH.sub.2CO.sub.2H, CO.sub.2Me, --CO.sub.2Et,
--CO.sub.2(i-Pr), --CO.sub.2(t-Bu), --CO.sub.2(n-Bu),
--CO.sub.2(i-Bu), and --NHCO.sub.2Me;
[0108] R.sup.6 is selected from the group consisting of: H, Me,
--CO.sub.2Me, --CO.sub.2(t-butyl), --COMe, and --CONHMe;
[0109] q is 1 or 2; and
[0110] r is 1 or 2.
[0111] In an eleventh aspect, the present invention includes
compounds of Formula (VIII):
##STR00024##
or stereoisomers, tautomers, pharmaceutically acceptable salts
thereof, wherein:
[0112] R.sup.1a is selected from the group consisting of: H, Cl,
C.sub.1-2 alkyl, and methoxy;
[0113] R.sup.1b is selected from the group consisting of: H and
F;
[0114] R.sup.6 is selected from the group consisting of: H,
C.sub.1-4 alkyl, --CO(C.sub.1-4 alkyl), CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(CH.sub.2).sub.0-2NH(C.sub.1-4
alkyl), and --CO(CH.sub.2).sub.0-2N(C.sub.1-4 alkyl).sub.2;
[0115] R.sup.3a is selected from the group consisting of: H, F, Cl,
CN, CO.sub.2H, --CO.sub.2Et, and --CO.sub.2(t-Bu).
[0116] In a twelfth aspect, the present invention includes
compounds of Formula (I) or stereoisomers, tautomers,
pharmaceutically acceptable salts thereof, within the scope of the
first aspect, wherein:
[0117] ring B is heteroaryl or bridged heterocycle, each containing
carbon atoms and 0-2 additional heteroatoms selected from the group
consisting of N, NH, O, and S(O)p, and each substituted with 1-3
R.sup.5;
[0118] R.sup.2 is selected from the group consisting of: H, F, CN,
--CO(C.sub.1-4 alkyl), OH, --O(C.sub.1-4 alkyl), --OCHF.sub.2,
--CHF.sub.2, --CF.sub.3, triazole, and tetrazole, wherein said
triazole and tetrazole are substituted with 0-2 R.sup.2a; and
[0119] R.sup.5, at each occurrence, is selected from the group
consisting of: H, .dbd.O, halo, C.sub.1-4 alkyl, OH, CN, NH.sub.2,
--N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, --CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2, --CONR.sup.9(C.sub.1-4
alkyl), --CON(C.sub.1-4 alkyl).sub.2, R.sup.8, and --COR.sup.8.
[0120] In another embodiment, ring A is phenyl.
[0121] In another embodiment, ring A is cyclohexyl.
In another aspect, ring A is
##STR00025##
wherein R.sup.1 is, independently at each occurrence, selected from
the group consisting of: halogen, C.sub.1-4 alkyl, OH, C.sub.1-4
alkoxy, CO(C.sub.1-4 alkyl), CN, CH.sub.2F, CHF.sub.2, OCHF.sub.2,
and --CH.sub.2NHCO.sub.2(C.sub.1-4 alkyl), a 5- to 7-membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected
from N, NR.sup.c, O, and S(O).sub.p, wherein said heterocycle is
substituted with 0-2 R.sup.2a.
[0122] In another aspect, ring A is
##STR00026##
is independently selected from the group consisting of:
##STR00027## ##STR00028##
[0123] In another embodiment, L is independently selected from the
group consisting of: a bond, --CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--C(Me).dbd.CH--, --C.ident.C--, and --CH.sub.2NH--.
[0124] In another embodiment, L is independently selected from the
group consisting of: a bond, --CH.sub.2CH.sub.2--, --CH.dbd.CH--,
and --C(Me).dbd.CH.
[0125] In another embodiment, L is independently selected from the
group consisting of: a bond, --CH.sub.2CH.sub.2-- and
--CH.dbd.CH--.
[0126] In another embodiment, L is --CH.dbd.CH--.
[0127] In another embodiment, ring B is
##STR00029##
wherein R.sup.6 is methyl or ethyl; q and r are independently
selected from 0, 1, and 2.
[0128] In another embodiment, ring B is
##STR00030##
[0129] In another embodiment, ring B is substituted pyrazole.
[0130] In another embodiment, ring B is
##STR00031##
[0131] In another embodiment, R.sup.3 is C.sub.1-4 alkyl
substituted with R.sup.3a.
[0132] In another embodiment, R.sup.3 is phenyl substituted with
R.sup.3a.
[0133] In another embodiment, R.sup.3 is cyclohexyl substituted
with R.sup.3a.
[0134] In another embodiment, R.sup.3 is a heterocycle substituted
with R.sup.3a and selected from:
##STR00032##
[0135] In another embodiment, R.sup.3 is
##STR00033##
substituted with R.sup.3a.
[0136] In another embodiment, ring B is
##STR00034##
wherein R.sup.6 is methyl or ethyl, q and r are independently an
integer selected from 1 and 2; R.sup.2 is selected from the group
consisting of: H, F, CN, COMe, OH, OMe, OCHF.sub.2, CHF.sub.2,
CF.sub.3, and tetrazole; R.sup.3 is phenyl substituted with
R.sup.3a, wherein R.sup.3a is selected from the group consisting
of: H, F, Cl, CN, CO.sub.2H, --CH.sub.2CO.sub.2H, CO.sub.2Me,
--CO.sub.2Et, --CO.sub.2(i-Pr), --CO.sub.2(t-Bu), --CO.sub.2(n-Bu),
--CO.sub.2(i-Bu), -- and NHCO.sub.2Me;
[0137] In another aspect, the present invention provides a compound
selected from the exemplified examples or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate
thereof.
[0138] In another aspect, the present invention provides a compound
selected from any subset list of compounds within the scope of the
exemplified examples or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof.
[0139] In another embodiment, the compounds of the present
invention have Factor XIa Ki values .ltoreq.10 .mu.M.
[0140] In another embodiment, the compounds of the present
invention have Factor XIa Ki values .ltoreq.1 .mu.M.
[0141] In another embodiment, the compounds of the present
invention have Factor XIa Ki values .ltoreq.0.5 .mu.M.
[0142] In another embodiment, the compounds of the present
invention have Factor XIa Ki values .ltoreq.0.1 .mu.M.
II. Other Embodiments of the Invention
[0143] In another embodiment, the present invention provides a
composition comprising at least one of the compounds of the present
invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate thereof.
[0144] In another embodiment, the present invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and at least one of the compounds of the present invention
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,
or a solvate, thereof.
[0145] In another embodiment, the present invention provides a
pharmaceutical composition, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of at
least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof.
[0146] In another embodiment, the present invention provides a
process for making a compound of the present invention.
[0147] In another embodiment, the present invention provides an
intermediate for making a compound of the present invention.
[0148] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s). In a preferred embodiment, the present
invention provides pharmaceutical composition, wherein the
additional therapeutic agent(s) are an anti-platelet agent or a
combination thereof. Preferably, the anti-platelet agent(s) are
clopidogrel and/or aspirin, or a combination thereof.
[0149] In another embodiment, the present invention provides a
method for the treatment and/or prophylaxis of a thromboembolic
disorder comprising administering to a patient in need of such
treatment and/or prophylaxis a therapeutically effective amount of
at least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof.
[0150] In another embodiment, the present invention provides a
compound of the present invention or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof, for use in
therapy.
[0151] In another embodiment, the present invention provides a
compound of the present invention or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof, for use in
therapy for the treatment and/or prophylaxis of a thromboembolic
disorder.
[0152] In another embodiment, the present invention also provides
the use of a compound of the present invention or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate thereof,
for the manufacture of a medicament for the treatment and/or
prophylaxis of a thromboembolic disorder.
[0153] In another embodiment, the present invention provides a
method for treatment and/or prophylaxis of a thromboembolic
disorder, comprising: administering to a patient in need thereof a
therapeutically effective amount of a first and second therapeutic
agent, wherein the first therapeutic agent is a compound of the
present invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate thereof, and the second therapeutic
agent is at least one agent selected from a second factor XIa
inhibitor, an anti-coagulant agent, an anti-platelet agent, a
thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic
agent. Preferably, the second therapeutic agent is at least one
agent selected from warfarin, unfractionated heparin, low molecular
weight heparin, synthetic pentasaccharide, hirudin, argatroban,
aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate,
droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine,
clopidogrel, tirofiban, eptifibatide, abciximab, melagatran,
desulfatohirudin, tissue plasminogen activator, modified tissue
plasminogen activator, antistreplase, urokinase, and streptokinase.
Preferably, the second therapeutic agent is at least one
anti-platelet agent. Preferably, the anti-platelet agent(s) are
clopidogrel and/or aspirin, or a combination thereof.
[0154] The thromboembolic disorder includes arterial cardiovascular
thromboembolic disorders, venous cardiovascular thromboembolic
disorders, arterial cerebrovascular thromboembolic disorders, and
venous cerebrovascular thromboembolic disorders. Examples of the
thromboembolic disorder include, but are not limited to, unstable
angina, an acute coronary syndrome, atrial fibrillation, first
myocardial infarction, recurrent myocardial infarction, ischemic
sudden death, transient ischemic attack, stroke, atherosclerosis,
peripheral occlusive arterial disease, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism, coronary arterial
thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney
embolism, pulmonary embolism, and thrombosis resulting from medical
implants, devices, or procedures in which blood is exposed to an
artificial surface that promotes thrombosis.
[0155] In another embodiment, the present invention provides a
method for the treatment and/or prophylaxis of an inflammatory
disorder comprising: administering to a patient in need of such
treatment and/or prophylaxis a therapeutically effective amount of
at least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof. Examples of the inflammatory disorder include, but
are not limited to, sepsis, acute respiratory distress syndrome,
and systemic inflammatory response syndrome.
[0156] In another embodiment, the present invention provides a
combined preparation of a compound of the present invention and
additional therapeutic agent(s) for simultaneous, separate or
sequential use in therapy.
[0157] In another embodiment, the present invention provides a
combined preparation of a compound of the present invention and
additional therapeutic agent(s) for simultaneous, separate or
sequential use in treatment and/or prophylaxis of a thromboembolic
disorder.
[0158] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof. This invention encompasses all combinations of preferred
aspects of the invention noted herein. It is understood that any
and all embodiments of the present invention may be taken in
conjunction with any other embodiment or embodiments to describe
additional embodiments. It is also to be understood that each
individual element of the embodiments is its own independent
embodiment. Furthermore, any element of an embodiment is meant to
be combined with any and all other elements from any embodiment to
describe an additional embodiment.
III. Chemistry
[0159] Throughout the specification and the appended claims, a
given chemical formula or name shall encompass all stereo and
optical isomers and racemates thereof where such isomers exist.
Unless otherwise indicated, all chiral (enantiomeric and
diastereomeric) and racemic forms are within the scope of the
invention. Many geometric isomers of C.dbd.C double bonds, C.dbd.N
double bonds, ring systems, and the like can also be present in the
compounds, and all such stable isomers are contemplated in the
present invention. Cis- and trans- (or E- and Z-) geometric isomers
of the compounds of the present invention are described and may be
isolated as a mixture of isomers or as separated isomeric forms.
The present compounds can be isolated in optically active or
racemic forms. Optically active forms may be prepared by resolution
of racemic forms or by synthesis from optically active starting
materials. All processes used to prepare compounds of the present
invention and intermediates made therein are considered to be part
of the present invention. When enantiomeric or diastereomeric
products are prepared, they may be separated by conventional
methods, for example, by chromatography or fractional
crystallization. Depending on the process conditions the end
products of the present invention are obtained either in free
(neutral) or salt form. Both the free form and the salts of these
end products are within the scope of the invention. If so desired,
one form of a compound may be converted into another form. A free
base or acid may be converted into a salt; a salt may be converted
into the free compound or another salt; a mixture of isomeric
compounds of the present invention may be separated into the
individual isomers. Compounds of the present invention, free form
and salts thereof, may exist in multiple tautomeric forms, in which
hydrogen atoms are transposed to other parts of the molecules and
the chemical bonds between the atoms of the molecules are
consequently rearranged. It should be understood that all
tautomeric forms, insofar as they may exist, are included within
the invention.
[0160] The term "stereoisomer" refers to isomers of identical
constitution that differ in the arrangement of their atoms in
space. Enantiomers and diastereomers are examples of stereoisomers.
The term "enantiomer" refers to one of a pair of molecular species
that are mirror images of each other and are not superimposable.
The term "diastereomer" refers to stereoisomers that are not mirror
images. The term "racemate" or "racemic mixture" refers to a
composition composed of equimolar quantities of two enantiomeric
species, wherein the composition is devoid of optical activity.
[0161] The symbols "R" and "S" represent the configuration of
substituents around a chiral carbon atom(s). The isomeric
descriptors "R" and "S" are used as described herein for indicating
atom configuration(s) relative to a core molecule and are intended
to be used as defined in the literature (IUPAC Recommendations
1996, Pure and Applied Chemistry, 68, 2193-2222 (1996)).
[0162] The term "chiral" refers to the structural characteristic of
a molecule that makes it impossible to superimpose it on its mirror
image. The term "homochiral" refers to a state of enantiomeric
purity. The term "optical activity" refers to the degree to which a
homochiral molecule or nonracemic mixture of chiral molecules
rotates a plane of polarized light.
[0163] As used herein, the term "alkyl" or "alkylene" is intended
to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms. For
example, "C.sub.1 to C.sub.10 alkyl" or "C.sub.1-10 alkyl" (or
alkylene), is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, and C.sub.10
alkyl groups. Additionally, for example, "C.sub.1 to C.sub.6 alkyl"
or "C.sub.1-C.sub.6 alkyl" denotes alkyl having 1 to 6 carbon
atoms. Alkyl group can be unsubstituted or substituted with at
least one hydrogen being replaced by another chemical group.
Example alkyl groups include, but are not limited to, methyl (Me),
ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g.,
n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl,
neopentyl). When "C.sub.0 alkyl" or "C.sub.0 alkylene" is used, it
is intended to denote a direct bond.
[0164] Alkenyl" or "alkenylene" is intended to include hydrocarbon
chains of either straight or branched configuration having the
specified number of carbon atoms and one or more, preferably one to
two, carbon-carbon double bonds that may occur in any stable point
along the chain. For example, "C.sub.2 to C.sub.6 alkenyl" or
"C.sub.2-6 alkenyl" (or alkenylene), is intended to include
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkenyl groups.
Examples of alkenyl include, but are not limited to, ethenyl,
1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3,
pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
2-methyl-2-propenyl, and 4-methyl-3-pentenyl.
[0165] "Alkynyl" or "alkynylene" is intended to include hydrocarbon
chains of either straight or branched configuration having one or
more, preferably one to three, carbon-carbon triple bonds that may
occur in any stable point along the chain. For example, "C.sub.2 to
C.sub.6 alkynyl" or "C.sub.2-6 alkynyl" (or alkynylene), is
intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6
alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and
hexynyl.
[0166] The term "alkoxy" or "alkyloxy" refers to an --O-alkyl
group. "C.sub.1 to C.sub.6 alkoxy" or "C.sub.1-6 alkoxy" (or
alkyloxy), is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6 alkoxy groups. Example alkoxy groups
include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or
"thioalkoxy" represents an alkyl group as defined above with the
indicated number of carbon atoms attached through a sulphur bridge;
for example methyl-S-- and ethyl-S--.
[0167] "Halo" or "halogen" includes fluoro, chloro, bromo, and
iodo. "Haloalkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, substituted with 1 or more
halogens. Examples of haloalkyl include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl,
pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,
heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl
also include "fluoroalkyl" that is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms, substituted with 1 or
more fluorine atoms.
[0168] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group
as defined above with the indicated number of carbon atoms attached
through an oxygen bridge. For example, "C.sub.1 to C.sub.6
haloalkoxy" or "C.sub.1-6 haloalkoxy", is intended to include
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 haloalkoxy
groups. Examples of haloalkoxy include, but are not limited to,
trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.
Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a
haloalkyl group as defined above with the indicated number of
carbon atoms attached through a sulphur bridge; for example
trifluoromethyl-S--, and pentafluoroethyl-S--.
[0169] The term "cycloalkyl" refers to cyclized alkyl groups,
including mono-, bi- or poly-cyclic ring systems. "C.sub.3 to
C.sub.7 cycloalkyl" or "C.sub.3-7 cycloalkyl" is intended to
include C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7 cycloalkyl
groups. Example cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
Branched cycloalkyl groups such as 1-methylcyclopropyl and
2-methylcyclopropyl are included in the definition of
"cycloalkyl".
[0170] As used herein, "carbocycle" or "carbocyclic residue" is
intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered
monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered
bicyclic or tricyclic hydrocarbon ring, any of which may be
saturated, partially unsaturated, unsaturated or aromatic. Examples
of such carbocycles include, but are not limited to, cyclopropyl,
cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl,
cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,
adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown
above, bridged rings are also included in the definition of
carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles,
unless otherwise specified, are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term
"carbocycle" is used, it is intended to include "aryl". A bridged
ring occurs when one or more carbon atoms link two non-adjacent
carbon atoms. Preferred bridges are one or two carbon atoms. It is
noted that a bridge always converts a monocyclic ring into a
tricyclic ring. When a ring is bridged, the substituents recited
for the ring may also be present on the bridge.
[0171] As used herein, the term "bicyclic carbocycle" or "bicyclic
carbocyclic group" is intended to mean a stable 9- or 10-membered
carbocyclic ring system that contains two fused rings and consists
of carbon atoms. Of the two fused rings, one ring is a benzo ring
fused to a second ring; and the second ring is a 5- or 6-membered
carbon ring which is saturated, partially unsaturated, or
unsaturated. The bicyclic carbocyclic group may be attached to its
pendant group at any carbon atom which results in a stable
structure. The bicyclic carbocyclic group described herein may be
substituted on any carbon if the resulting compound is stable.
Examples of a bicyclic carbocyclic group are, but not limited to,
naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and
indanyl.
[0172] "Aryl" groups refer to monocyclic or polycyclic aromatic
hydrocarbons, including, for example, phenyl, naphthyl, and
phenanthranyl. Aryl moieties are well known and described, for
example, in Hawley's Condensed Chemical Dictionary (13th Ed.),
Lewis, R. J., ed., J. Wiley & Sons, Inc., New York (1997).
"C.sub.6 or C.sub.10 aryl" or "C.sub.6-10 aryl" refers to phenyl
and naphthyl. Unless otherwise specified, "aryl", "C.sub.6 or
C.sub.10 aryl" or "C.sub.6-10 aryl" or "aromatic residue" may be
unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3
groups, OH, OCH.sub.3, Cl, F, Br, I, CN, NO.sub.2, NH.sub.2,
N(CH.sub.3)H, N(CH.sub.3).sub.2, CF.sub.3, OCF.sub.3,
C(.dbd.O)CH.sub.3, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CO.sub.2H, and
CO.sub.2CH.sub.3.
[0173] The term "benzyl," as used herein, refers to a methyl group
on which one of the hydrogen atoms is replaced by a phenyl group,
wherein said phenyl group may optionally be substituted with 1 to 5
groups, preferably 1 to 3 groups, OH, OCH.sub.3, Cl, F, Br, I, CN,
NO.sub.2, NH.sub.2, N(CH.sub.3)H, N(CH.sub.3).sub.2, CF.sub.3,
OCF.sub.3, C(.dbd.O)CH.sub.3, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CO.sub.2H, and
CO.sub.2CH.sub.3.
[0174] As used herein, the term "heterocycle" or "heterocyclic
group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered
monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or
14-membered polycyclic heterocyclic ring that is saturated,
partially unsaturated, or fully unsaturated, and that contains
carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected
from the group consisting of N, O and S; and including any
polycyclic group in which any of the above-defined heterocyclic
rings is fused to a benzene ring. The nitrogen and sulfur
heteroatoms may optionally be oxidized (i.e., N.fwdarw.O and
S(O).sub.p, wherein p is 0, 1 or 2). The nitrogen atom may be
substituted or unsubstituted (i.e., N or NR wherein R is H or
another substituent, if defined). The heterocyclic ring may be
attached to its pendant group at any heteroatom or carbon atom that
results in a stable structure. The heterocyclic rings described
herein may be substituted on carbon or on a nitrogen atom if the
resulting compound is stable. A nitrogen in the heterocycle may
optionally be quaternized. It is preferred that when the total
number of S and O atoms in the heterocycle exceeds 1, then these
heteroatoms are not adjacent to one another. It is preferred that
the total number of S and O atoms in the heterocycle is not more
than 1. When the term "heterocycle" is used, it is intended to
include heteroaryl.
[0175] Examples of heterocycles include, but are not limited to,
acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,
isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl,
isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,
oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl,
pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl,
2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Also included are fused ring and spiro compounds containing, for
example, the above heterocycles.
[0176] Examples of 5- to 10-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl,
1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,
benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,
isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl,
isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,
imidazolopyridinyl, and pyrazolopyridinyl.
[0177] Examples of 5- to 6-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included
are fused ring and spiro compounds containing, for example, the
above heterocycles.
[0178] As used herein, the term "bicyclic heterocycle" or "bicyclic
heterocyclic group" is intended to mean a stable 9- or 10-membered
heterocyclic ring system which contains two fused rings and
consists of carbon atoms and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of N, O and S. Of
the two fused rings, one ring is a 5- or 6-membered monocyclic
aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered
heteroaryl ring or a benzo ring, each fused to a second ring. The
second ring is a 5- or 6-membered monocyclic ring which is
saturated, partially unsaturated, or unsaturated, and comprises a
5-membered heterocycle, a 6-membered heterocycle or a carbocycle
(provided the first ring is not benzo when the second ring is a
carbocycle).
[0179] The bicyclic heterocyclic group may be attached to its
pendant group at any heteroatom or carbon atom which results in a
stable structure. The bicyclic heterocyclic group described herein
may be substituted on carbon or on a nitrogen atom if the resulting
compound is stable. It is preferred that when the total number of S
and O atoms in the heterocycle exceeds 1, then these heteroatoms
are not adjacent to one another. It is preferred that the total
number of S and O atoms in the heterocycle is not more than 1.
[0180] Examples of a bicyclic heterocyclic group are, but not
limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,
1,2,3,4-tetrahydro-quinoxalinyl, and
1,2,3,4-tetrahydro-quinazolinyl.
[0181] As used herein, the term "aromatic heterocyclic group" or
"heteroaryl" is intended to mean stable monocyclic and polycyclic
aromatic hydrocarbons that include at least one heteroatom ring
member such as sulfur, oxygen, or nitrogen. Heteroaryl groups
include, without limitation, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,
imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl,
benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl,
carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and
benzodioxane. Heteroaryl groups are substituted or unsubstituted.
The nitrogen atom is substituted or unsubstituted (i.e., N or NR
wherein R is H or another substituent, if defined). The nitrogen
and sulfur heteroatoms may optionally be oxidized (i.e., N.fwdarw.O
and S(O).sub.p, wherein p is 0, 1 or 2).
[0182] Bridged rings are also included in the definition of
heterocycle. A bridged ring occurs when one or more atoms (i.e., C,
O, N, or S) link two non-adjacent carbon or nitrogen atoms.
Examples of bridged rings include, but are not limited to, one
carbon atom, two carbon atoms, one nitrogen atom, two nitrogen
atoms, and a carbon-nitrogen group. It is noted that a bridge
always converts a monocyclic ring into a tricyclic ring. When a
ring is bridged, the substituents recited for the ring may also be
present on the bridge.
[0183] The term "counterion" is used to represent a negatively
charged species such as chloride, bromide, hydroxide, acetate, and
sulfate.
[0184] When a dotted ring is used within a ring structure, this
indicates that the ring structure may be saturated, partially
saturated or unsaturated.
[0185] As referred to herein, the term "substituted" means that at
least one hydrogen atom is replaced with a non-hydrogen group,
provided that normal valencies are maintained and that the
substitution results in a stable compound. When a substituent is
keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced.
Keto substituents are not present on aromatic moieties. When a ring
system (e.g., carbocyclic or heterocyclic) is said to be
substituted with a carbonyl group or a double bond, it is intended
that the carbonyl group or double bond be part (i.e., within) of
the ring. Ring double bonds, as used herein, are double bonds that
are formed between two adjacent ring atoms (e.g., C.dbd.C, C.dbd.N,
or N.dbd.N).
[0186] In cases wherein there are nitrogen atoms (e.g., amines) on
compounds of the present invention, these may be converted to
N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or
hydrogen peroxides) to afford other compounds of this invention.
Thus, shown and claimed nitrogen atoms are considered to cover both
the shown nitrogen and its N-oxide (N.fwdarw.O) derivative.
[0187] When any variable occurs more than one time in any
constituent or formula for a compound, its definition at each
occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-3 R groups, then said group may optionally be
substituted with up to three R groups, and at each occurrence R is
selected independently from the definition of R. Also, combinations
of substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0188] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom in which such substituent is bonded to the rest
of the compound of a given formula, then such substituent may be
bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0189] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms that are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
and/or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0190] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic groups such as amines; and
alkali or organic salts of acidic groups such as carboxylic acids.
The pharmaceutically acceptable salts include the conventional
non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. For example, such conventional non-toxic salts include those
derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, and isethionic.
[0191] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound that contains
a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
18th Edition, Mack Publishing Company, Easton, Pa. (1990), the
disclosure of which is hereby incorporated by reference.
[0192] In addition, compounds of formula I may have prodrug forms.
Any compound that will be converted in vivo to provide the
bioactive agent (i.e., a compound of formula I) is a prodrug within
the scope and spirit of the invention. Various forms of prodrugs
are well known in the art. For examples of such prodrug
derivatives, see: [0193] a) Design of Prodrugs, Bundgaard, H., ed.,
Elsevier (1985), and Methods in Enzymology, 112:309-396, Widder, K.
et al., eds., Academic Press (1985); [0194] b) Bundgaard, H.,
Chapter 5, "Design and Application of Prodrugs," A Textbook of Drug
Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al.,
eds., Harwood Academic Publishers (1991); [0195] c) Bundgaard, H.,
Adv. Drug Deliv. Rev., 8:1-38 (1992); [0196] d) Bundgaard, H. et
al., J. Pharm. Sci., 77:285 (1988); and [0197] e) Kakeya, N. et
al., Chem. Pharm. Bull., 32:692 (1984).
[0198] Compounds containing a carboxy group can form
physiologically hydrolyzable esters that serve as prodrugs by being
hydrolyzed in the body to yield formula I compounds per se. Such
prodrugs are preferably administered orally since hydrolysis in
many instances occurs principally under the influence of the
digestive enzymes. Parenteral administration may be used where the
ester per se is active, or in those instances where hydrolysis
occurs in the blood. Examples of physiologically hydrolyzable
esters of compounds of formula I include C.sub.1-6alkyl,
C.sub.1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,
methoxymethyl, C.sub.1-6 alkanoyloxy-C.sub.1-6alkyl (e.g.,
acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl),
C.sub.1-6alkoxycarbonyloxy-C.sub.1-6alkyl (e.g.,
methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
glycyloxymethyl, phenylglycyloxymethyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well known
physiologically hydrolyzable esters used, for example, in the
penicillin and cephalosporin arts. Such esters may be prepared by
conventional techniques known in the art.
[0199] Preparation of prodrugs is well known in the art and
described in, for example, Medicinal Chemistry: Principles and
Practice, King, F. D., ed. The Royal Society of Chemistry,
Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and
Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA
and Wiley-VCH, Zurich, Switzerland (2003); The Practice of
Medicinal Chemistry, Wermuth, C. G., ed., Academic Press, San
Diego, Calif. (1999).
[0200] The present invention is intended to include all isotopes of
atoms occurring in the present compounds. Isotopes include those
atoms having the same atomic number but different mass numbers. By
way of general example and without limitation, isotopes of hydrogen
include deuterium and tritium. Isotopes of carbon include .sup.13C
and .sup.14C. Isotopically-labeled compounds of the invention can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described
herein, using an appropriate isotopically-labeled reagent in place
of the non-labeled reagent otherwise employed. Such compounds have
a variety of potential uses, e.g., as standards and reagents in
determining the ability of a potential pharmaceutical compound to
bind to target proteins or receptors, or for imaging compounds of
this invention bound to biological receptors in vivo or in
vitro.
[0201] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent. It is preferred
that compounds of the present invention do not contain a N-halo,
S(O).sub.2H, or S(O)H group.
[0202] The term "solvate" means a physical association of a
compound of this invention with one or more solvent molecules,
whether organic or inorganic. This physical association includes
hydrogen bonding. In certain instances the solvate will be capable
of isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid. The
solvent molecules in the solvate may be present in a regular
arrangement and/or a non-ordered arrangement. The solvate may
comprise either a stoichiometric or nonstoichiometric amount of the
solvent molecules. "Solvate" encompasses both solution-phase and
isolable solvates. Exemplary solvates include, but are not limited
to, hydrates, ethanolates, methanolates, and isopropanolates.
Methods of solvation are generally known in the art.
[0203] Abbreviations as used herein, are defined as follows:
"1.times." for once, "2.times." for twice, "3.times." for thrice,
".degree. C." for degrees Celsius, "eq" for equivalent or
equivalents, "g" for gram or grams, "mg" for milligram or
milligrams, "L" for liter or liters, "mL" for milliliter or
milliliters, ".mu.L" for microliter or microliters, "N" for normal,
"M" for molar, "mmol" for millimole or millimoles, "min" for minute
or minutes, "h" for hour or hours, "rt" for room temperature, "RT"
for retention time, "atm" for atmosphere, "psi" for pounds per
square inch, "conc." for concentrate, "sat" or "sat'd" for
saturated, "MW" for molecular weight, "mp" for melting point, "ee"
for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry,
"ESI" for electrospray ionization mass spectroscopy, "HR" for high
resolution, "HRMS" for high resolution mass spectrometry, "LCMS"
for liquid chromatography mass spectrometry, "HPLC" for high
pressure liquid chromatography, "RP HPLC" for reverse phase HPLC,
"TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear
magnetic resonance spectroscopy, "nOe" for nuclear Overhauser
effect spectroscopy, ".sup.1H" for proton, ".delta." for delta, "s"
for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m"
for multiplet, "br" for broad, "Hz" for hertz, and ".alpha.",
".beta.", "R", "S", "E", and "Z" are stereochemical designations
familiar to one skilled in the art.
TABLE-US-00001 Me Methyl Et Ethyl Pr Propyl i-Pr Isopropyl Bu Butyl
i-Bu Isobutyl t-Bu tert-butyl Ph Phenyl Bn Benzyl Boc or BOC
tert-butyloxycarbonyl AcOH or HOAc acetic acid AlCl.sub.3 aluminum
chloride AIBN Azobisisobutyronitrile BBr.sub.3 boron tribromide
BCl.sub.3 boron trichloride BEMP
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-
diazaphosphorine BOP reagent
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate Burgess reagent
1-methoxy-N-triethylammoniosulfonyl-methanimidate CBz
Carbobenzyloxy DCM or CH.sub.2Cl.sub.2 Dichloromethane CH.sub.3CN
or ACN Acetonitrile CDCl.sub.3 deutero-chloroform CHCl.sub.3
Chloroform mCPBA or m- meta-chloroperbenzoic acid CPBA
Cs.sub.2CO.sub.3 cesium carbonate Cu(OAc).sub.2 copper (II) acetate
Cy.sub.2NMe N-cyclohexyl-N-methylcyclohexanamine DBU
1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2 dichloroethane DEA
Diethylamine Dess-Martin
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one DIC
or DIPCDI Diisopropylcarbodiimide DIEA, DIPEA diisopropylethylamine
(Hunig's base) DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane
DMF dimethyl formamide DMSO dimethyl sulfoxide cDNA complimentary
DNA Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane DuPhos
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene EDC
N-(3-dimthylaminopropyl)-N'-ethylcarbodiimide EDCI
N-(3-dimthylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDTA
ethylenediaminetetraacetic acid (S,S)-
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-
EtDuPhosRh(I) cyclooctadiene)rhodium(I) trifluoromethanesulfonate
Et.sub.3N or TEA Triethylamine EtOAc ethyl acetate Et.sub.2O
diethyl ether EtOH Ethanol GMF glass microfiber filter Grubbs (II)
(1,3-bis(2,4,6-trimethylphenyl)-2-
imidazolidinylidene)dichloro(phenylmethylene)
(triycyclohexylphosphine)ruthenium HCl hydrochloric acid HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate HEPES
4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid Hex Hexane HOBt
or HOBT 1-hydroxybenzotriazole H.sub.2SO.sub.4 sulfuric acid
K.sub.2CO.sub.3 potassium carbonate KOAc potassium acetate
K.sub.3PO.sub.4 potassium phosphate LAH lithium aluminum hydride LG
leaving group LiOH lithium hydroxide MeOH Methanol MgSO.sub.4
magnesium sulfate MsOH or MSA methylsulfonic acid NaCl sodium
chloride NaH sodium hydride NaHCO.sub.3 sodium bicarbonate
Na.sub.2CO.sub.3 sodium carbonate NaOH sodium hydroxide
Na.sub.2SO.sub.3 sodium sulfite Na.sub.2SO.sub.4 sodium sulfate NBS
N-bromosuccinimide NCS N-chlorosuccinimide NH.sub.3 Ammonia
NH.sub.4Cl ammonium chloride NH.sub.4OH ammonium hydroxide OTf
triflate or trifluoromethanesulfonate Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) Pd(OAc).sub.2
palladium(II) acetate Pd/C palladium on carbon Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
Ph.sub.3PCl.sub.2 triphenylphosphine dichloride PG protecting group
POCl.sub.3 phosphorus oxychloride i-PrOH or IPA Isopropanol PS
Polystyrene SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride SiO.sub.2
silica oxide SnCl.sub.2 tin(II) chloride TBAI tetra-n-butylammonium
iodide TFA trifluoroacetic acid THF tetrahydrofuran TMSCHN.sub.2
trimethylsilyldiazomethane T3P propane phosphonic acid anhydride
TRIS tris (hydroxymethyl) aminomethane
[0204] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or by variations thereof as appreciated by those skilled in the
art. Preferred methods include, but are not limited to, those
described below. The reactions are performed in a solvent or
solvent mixture appropriate to the reagents and materials employed
and suitable for the transformations being effected. It will be
understood by those skilled in the art of organic synthesis that
the functionality present on the molecule should be consistent with
the transformations proposed. This will sometimes require a
judgment to modify the order of the synthetic steps or to select
one particular process scheme over another in order to obtain a
desired compound of the invention.
[0205] It will also be recognized that another major consideration
in the planning of any synthetic route in this field is the
judicious choice of the protecting group used for protection of the
reactive functional groups present in the compounds described in
this invention. An authoritative account describing the many
alternatives to the trained practitioner is Greene et al.
(Protective Groups in Organic Synthesis, 3rd Ed.,
Wiley-Interscience (1999)).
IV. Biology
[0206] While blood coagulation is essential to the regulation of an
organism's hemostasis, it is also involved in many pathological
conditions. In thrombosis, a blood clot, or thrombus, may form and
obstruct circulation locally, causing ischemia and organ damage.
Alternatively, in a process known as embolism, the clot may
dislodge and subsequently become trapped in a distal vessel, where
it again causes ischemia and organ damage. Diseases arising from
pathological thrombus formation are collectively referred to as
thromboembolic disorders which include acute coronary syndrome,
unstable angina, myocardial infarction, thrombosis in the cavity of
the heart, ischemic stroke, deep vein thrombosis, peripheral
occlusive arterial disease, transient ischemic attack, and
pulmonary embolism. In addition, thrombosis occurs on artificial
surfaces in contact with blood, including catheters, stents,
artificial heart valves, and hemodialysis membranes.
[0207] Some conditions contribute to the risk of developing
thrombosis, for example, alterations of the vessel wall, changes in
the flow of blood, and alterations in the composition of the
vascular compartment. These risk factors are collectively known as
Virchow's triad. (Hemostasis and Thrombosis, Basic Principles and
Clinical Practice, 5th Ed., p. 853, Colman, R. W. et al., eds.,
Lippincott Williams & Wilkins (2006))
[0208] Antithrombotic agents are frequently given to patients at
risk of developing thromboembolic disease because of the presence
of one or more predisposing risk factors from Virchow's triad to
prevent formation of an occlusive thrombus (primary prevention).
For example, in an orthopedic surgery setting (e.g., hip and knee
replacement), an antithrombotic agent is frequently administered
prior to a surgical procedure. The antithrombotic agent
counterbalances the prothrombotic stimulus exerted by vascular flow
alterations (stasis), potential surgical vessel wall injury, as
well as changes in the composition of the blood due to the acute
phase response related to surgery. Another example of the use of an
antithrombotic agent for primary prevention is dosing with aspirin,
a platelet activation inhibitor, in patients at risk for developing
thrombotic cardiovascular disease. Well recognized risk factors in
this setting include age, male gender, hypertension, diabetes
mellitus, lipid alterations, and obesity.
[0209] Antithrombotic agents are also indicated for secondary
prevention, following an initial thrombotic episode. For example,
patients with mutations in factor V (also known as factor V Leiden)
and additional risk factors (e.g., pregnancy) are dosed with
anticoagulants to prevent the reoccurrence of venous thrombosis.
Another example entails secondary prevention of cardiovascular
events in patients with a history of acute myocardial infarction or
acute coronary syndrome. In a clinical setting, a combination of
aspirin and clopidogrel (or other thienopyridines) may be used to
prevent a second thrombotic event.
[0210] Antithrombotic agents are also given to treat the disease
state (i.e., by arresting its development) after it has already
started. For example, patients presenting with deep vein thrombosis
are treated with anticoagulants (i.e., heparin, warfarin, or LMWH)
to prevent further growth of the venous occlusion. Over time, these
agents also cause a regression of the disease state because the
balance between prothrombotic factors and
anticoagulant/profibrinolytic pathways is changed in favor of the
latter. Examples on the arterial vascular bed include the treatment
of patients with acute myocardial infarction or acute coronary
syndrome with aspirin and clopidogrel to prevent further growth of
vascular occlusions and eventually leading to a regression of
thrombotic occlusions.
[0211] Thus, antithrombotic agents are used widely for primary and
secondary prevention (i.e., prophylaxis or risk reduction) of
thromboembolic disorders, as well as treatment of an already
existing thrombotic process. Drugs that inhibit blood coagulation,
or anticoagulants, are "pivotal agents for prevention and treatment
of thromboembolic disorders" (Hirsh, J. et al., Blood, 105:453-463
(2005)).
[0212] An alternative way of initiation of coagulation is operative
when blood is exposed to artificial surfaces (e.g., during
hemodialysis, "on-pump" cardiovascular surgery, vessel grafts,
bacterial sepsis), on cell surfaces, cellular receptors, cell
debris, DNA, RNA, and extracellular matrices. This process is also
termed contact activation. Surface absorption of factor XII leads
to a conformational change in the factor XII molecule, thereby
facilitating activation to proteolytic active factor XII molecules
(factor XIIa and factor XIIf). Factor XIIa (or XIIf) has a number
of target proteins, including plasma prekallikrein and factor XI.
Active plasma kallikrein further activates factor XII, leading to
an amplification of contact activation. Alternatively, the serine
protease prolylcarboxylpeptidase can activate plasma kallikrein
complexed with high molecular weight kininogen in a multiprotein
complex formed on the surface of cells and matrices (Shariat-Madar
et al., Blood, 108:192-199 (2006)). Contact activation is a surface
mediated process responsible in part for the regulation of
thrombosis and inflammation, and is mediated, at least in part, by
fibrinolytic, complement, kininogen/kinin, and other humoral and
cellular pathways (for review, Coleman, R., "Contact Activation
Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott
Williams & Wilkins (2001); Schmaier, A. H., "Contact
Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)). The
biological relevance of the contact activation system for
thromboembolic diseases is supported by the phenotype of factor XII
deficient mice. More specifically, factor XII deficient mice were
protected from thrombotic vascular occlusion in several thrombosis
models as well as stroke models and the phenotype of the XII
deficient mice was identical to XI deficient mice (Renne et al., J.
Exp. Med., 202:271-281 (2005); Kleinschmitz et al., J. Exp. Med.,
203:513-518 (2006)). The fact that factor XI is down-stream from
factor XIIa, combined with the identical phenotype of the XII and
XI deficient mice suggest that the contact activation system could
play a major role in factor XI activation in vivo.
[0213] Factor XI is a zymogen of a trypsin-like serine protease and
is present in plasma at a relatively low concentration. Proteolytic
activation at an internal R369-I370 bond yields a heavy chain (369
amino acids) and a light chain (238 amino acids). The latter
contains a typical trypsin-like catalytic triad (H413, D464, and
S557). Activation of factor XI by thrombin is believed to occur on
negatively charged surfaces, most likely on the surface of
activated platelets. Platelets contain high affinity (0.8 nM)
specific sites (130-500/platelet) for activated factor XI. After
activation, factor XIa remains surface bound and recognizes factor
IX as its normal macromolecular substrate. (Galiani, D., Trends
Cardiovasc. Med., 10:198-204 (2000))
[0214] In addition to the feedback activation mechanisms described
above, thrombin activates thrombin activated fibrinolysis inhibitor
(TAFI), a plasma carboxypeptidase that cleaves C-terminal lysine
and arginine residues on fibrin, reducing the ability of fibrin to
enhance tissue-type plasminogen activator (tPA) dependent
plasminogen activation. In the presence of antibodies to FXIa, clot
lysis can occur more rapidly independent of plasma TAFI
concentration. (Bouma, B. N. et al., Thromb. Res., 101:329-354
(2001)). Thus, inhibitors of factor XIa are expected to be
anticoagulant and profibrinolytic.
[0215] Further evidence for the anti-thromboembolic effects of
targeting factor XI is derived from mice deficient in factor XI. It
has been demonstrated that complete fXI deficiency protected mice
from ferric chloride (FeCl.sub.3)-induced carotid artery thrombosis
(Rosen et al., Thromb. Haemost., 87:774-777 (2002); Wang et al., J.
Thromb. Haemost., 3:695-702 (2005)). Also, factor XI deficiency
rescues the perinatal lethal phenotype of complete protein C
deficiency (Chan et al., Amer. J. Pathology, 158:469-479 (2001)).
Furthermore, baboon cross-reactive, function blocking antibodies to
human factor XI protect against baboon arterial--venous shunt
thrombosis (Gruber et al., Blood, 102:953-955 (2003)). Evidence for
an antithrombotic effect of small molecule inhibitors of factor XIa
is also disclosed in published U.S. Patent Application No.
2004/0180855A1. Taken together, these studies suggest that
targeting factor XI will reduce the propensity for thrombotic and
thromboembolic diseases.
[0216] Genetic evidence indicates that factor XI is not required
for normal homeostasis, implying a superior safety profile of the
factor XI mechanism compared to competing antithrombotic
mechanisms. In contrast to hemophilia A (factor VIII deficiency) or
hemophilia B (factor IX deficiency), mutations of the factor XI
gene causing factor XI deficiency (hemophilia C) result in only a
mild to moderate bleeding diathesis characterized primarily by
postoperative or posttraumatic, but rarely spontaneous hemorrhage.
Postoperative bleeding occurs mostly in tissue with high
concentrations of endogenous fibrinolytic activity (e.g., oral
cavity, and urogenital system). The majority of the cases are
fortuitously identified by preoperative prolongation of aPTT
(intrinsic system) without any prior bleeding history.
[0217] The increased safety of inhibition of XIa as an
anticoagulation therapy is further supported by the fact that
Factor XI knock-out mice, which have no detectable factor XI
protein, undergo normal development, and have a normal life span.
No evidence for spontaneous bleeding has been noted. The aPTT
(intrinsic system) is prolonged in a gene dose-dependent fashion.
Interestingly, even after severe stimulation of the coagulation
system (tail transection), the bleeding time is not significantly
prolonged compared to wild-type and heterozygous litter mates.
(Gailani, D., Frontiers in Bioscience, 6:201-207 (2001); Gailani,
D. et al., Blood Coagulation and Fibrinolysis, 8:134-144 (1997).)
Taken together, these observations suggest that high levels of
inhibition of factor XIa should be well tolerated. This is in
contrast to gene targeting experiments with other coagulation
factors, excluding factor XII.
[0218] In vivo activation of factor XI can be determined by complex
formation with either C1 inhibitor or alpha 1 antitrypsin. In a
study of 50 patients with acute myocardial infarction (AMI),
approximately 25% of the patients had values above the upper normal
range of the complex ELISA. This study can be viewed as evidence
that at least in a subpopulation of patients with AMI, factor XI
activation contributes to thrombin formation (Minnema, M. C. et
al., Arterioscler. Thromb. Vasc. Biol., 20:2489-2493 (2000)). A
second study establishes a positive correlation between the extent
of coronary arteriosclerosis and factor XIa in complex with alpha 1
antitrypsin (Murakami, T. et al., Arterioscler. Thromb. Vasc.
Biol., 15:1107-1113 (1995)). In another study, Factor XI levels
above the 90th percentile in patients were associated with a
2.2-fold increased risk for venous thrombosis (Meijers, J. C. M. et
al., N. Engl. J. Med., 342:696-701 (2000)).
[0219] Plasma kallikrein is a zymogen of a trypsin-like serine
protease and is present in plasma at 35 to 50 .mu.g/mL. The gene
structure is similar to that of factor XI. Overall, the amino acid
sequence of plasma kallikrein has 58% homology to factor XI.
Proteolytic activation by factor XIIa at an internal I389-R390 bond
yields a heavy chain (371 amino acids) and a light chain (248 amino
acids). The active site of plasma kallikrein is contained in the
light chain. The light chain of plasma kallikrein reacts with
protease inhibitors, including alpha 2 macroglobulin and
C1-inhibitor. Interestingly, heparin significantly accelerates the
inhibition of plasma kallikrein by antithrombin III in the presence
of high molecular weight kininogen (HMWK). In blood, the majority
of plasma kallikrein circulates in complex with HMWK. Plasma
kallikrein cleaves HMWK to liberate bradykinin. Bradykinin release
results in increase of vascular permeability and vasodilation (for
review, Coleman, R., "Contact Activation Pathway", Hemostasis and
Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001);
Schmaier A. H., "Contact Activation", Thrombosis and Hemorrhage,
pp. 105-128 (1998)).
[0220] Also, it is preferred to find new compounds with improved
activity in in vitro clotting assays, compared with known serine
protease inhibitors, such as the activated partial thromboplastin
time (aPTT) or prothrombin time (PT) assay. (for a description of
the aPTT and PT assays see, Goodnight, S. H. et al., "Screening
Tests of Hemostasis", Disorders of Thrombosis and Hemostasis: A
Clinical Guide, 2nd Ed., pp. 41-51, McGraw-Hill, New York
(2001)).
[0221] It is also desirable and preferable to find compounds with
advantageous and improved characteristics compared with known
serine protease inhibitors, in one or more of the following
categories that are given as examples, and are not intended to be
limiting: (a) pharmacokinetic properties, including oral
bioavailability, half life, and clearance; (b) pharmaceutical
properties; (c) dosage requirements; (d) factors that decrease
blood concentration peak-to-trough characteristics; (e) factors
that increase the concentration of active drug at the enzyme; (f)
factors that decrease the liability for clinical drug-drug
interactions; (g) factors that decrease the potential for adverse
side-effects, including selectivity versus other biological
targets; and (h) factors that improve manufacturing costs or
feasibility, (i) factors that are ideal for use as a parenteral
agent such as solubility profile and pharmocokinetics.
[0222] Pre-clinical studies demonstrated significant antithrombotic
effects of small molecule factor XIa inhibitors in rabbit and rat
model of arterial thrombosis, at doses that preserved hemostasis.
(Wong P. C. et al., American Heart Association Scientific Sessions,
Abstract No. 6118, Nov. 12-15, 2006; Schumacher, W. et al., Journal
of Thrombosis and Haemostasis, Vol. 3 (Suppl. 1):P1228 (2005);
Schumacher, W. A. et al., European Journal of Pharmacology, pp.
167-174 (2007)). Furthermore, it was observed that in vitro
prolongation of the aPTT by specific XIa inhibitors is a good
predictor of efficacy in our thrombosis models. Thus, the in vitro
aPTT test can be used as a surrogate for efficacy in vivo.
[0223] As used herein, the term "patient" encompasses all mammalian
species.
[0224] As used herein, "treating" or "treatment" cover the
treatment of a disease-state in a mammal, particularly in a human,
and include: (a) inhibiting the disease-state, i.e., arresting it
development; and/or (b) relieving the disease-state, i.e., causing
regression of the disease state.
[0225] As used herein, "prophylaxis" or "prevention" covers the
preventive treatment of a subclinical disease-state in a mammal,
particularly in a human, aimed at reducing the probability of the
occurrence of a clinical disease-state. Patients are selected for
preventative therapy based on factors that are known to increase
risk of suffering a clinical disease state compared to the general
population. "Prophylaxis" therapies can be divided into (a) primary
prevention and (b) secondary prevention. Primary prevention is
defined as treatment in a subject that has not yet presented with a
clinical disease state, whereas secondary prevention is defined as
preventing a second occurrence of the same or similar clinical
disease state.
[0226] As used herein, "risk reduction" covers therapies that lower
the incidence of development of a clinical disease state. As such,
primary and secondary prevention therapies are examples of risk
reduction.
[0227] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention that is effective
when administered alone or in combination to inhibit factor XIa
and/or plasma kallikrein and/or to prevent or treat the disorders
listed herein. When applied to a combination, the term refers to
combined amounts of the active ingredients that result in the
preventive or therapeutic effect, whether administered in
combination, serially, or simultaneously.
[0228] The term "thrombosis", as used herein, refers to formation
or presence of a thrombus (pl. thrombi); clotting within a blood
vessel that may cause ischemia or infarction of tissues supplied by
the vessel. The term "embolism", as used herein, refers to sudden
blocking of an artery by a clot or foreign material that has been
brought to its site of lodgment by the blood current. The term
"thromboembolism", as used herein, refers to obstruction of a blood
vessel with thrombotic material carried by the blood stream from
the site of origin to plug another vessel. The term "thromboembolic
disorders" entails both "thrombotic" and "embolic" disorders
(defined above).
[0229] The term "thromboembolic disorders" as used herein includes
arterial cardiovascular thromboembolic disorders, venous
cardiovascular or cerebrovascular thromboembolic disorders, and
thromboembolic disorders in the chambers of the heart or in the
peripheral circulation. The term "thromboembolic disorders" as used
herein also includes specific disorders selected from, but not
limited to, unstable angina or other acute coronary syndromes,
atrial fibrillation, first or recurrent myocardial infarction,
ischemic sudden death, transient ischemic attack, stroke,
atherosclerosis, peripheral occlusive arterial disease, venous
thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial
thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that
promotes thrombosis. The medical implants or devices include, but
are not limited to: prosthetic valves, artificial valves,
indwelling catheters, stents, blood oxygenators, shunts, vascular
access ports, ventricular assist devices and artificial hearts or
heart chambers, and vessel grafts. The procedures include, but are
not limited to: cardiopulmonary bypass, percutaneous coronary
intervention, and hemodialysis. In another embodiment, the term
"thromboembolic disorders" includes acute coronary syndrome,
stroke, deep vein thrombosis, and pulmonary embolism.
[0230] In another embodiment, the present invention provides a
method for the treatment of a thromboembolic disorder, wherein the
thromboembolic disorder is selected from unstable angina, an acute
coronary syndrome, atrial fibrillation, myocardial infarction,
transient ischemic attack, stroke, atherosclerosis, peripheral
occlusive arterial disease, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism, coronary arterial
thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney
embolism, pulmonary embolism, and thrombosis resulting from medical
implants, devices, or procedures in which blood is exposed to an
artificial surface that promotes thrombosis. In another embodiment,
the present invention provides a method for the treatment of a
thromboembolic disorder, wherein the thromboembolic disorder is
selected from acute coronary syndrome, stroke, venous thrombosis,
atrial fibrillation, and thrombosis resulting from medical implants
and devices.
[0231] In another embodiment, the present invention provides a
method for the primary prophylaxis of a thromboembolic disorder,
wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, myocardial
infarction, ischemic sudden death, transient ischemic attack,
stroke, atherosclerosis, peripheral occlusive arterial disease,
venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial
thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that
promotes thrombosis. In another embodiment, the present invention
provides a method for the primary prophylaxis of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from
acute coronary syndrome, stroke, venous thrombosis, and thrombosis
resulting from medical implants and devices.
[0232] In another embodiment, the present invention provides a
method for the secondary prophylaxis of a thromboembolic disorder,
wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, recurrent
myocardial infarction, transient ischemic attack, stroke,
atherosclerosis, peripheral occlusive arterial disease, venous
thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial
thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that
promotes thrombosis. In another embodiment, the present invention
provides a method for the secondary prophylaxis of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from
acute coronary syndrome, stroke, atrial fibrillation and venous
thrombosis.
[0233] The term "stroke", as used herein, refers to embolic stroke
or atherothrombotic stroke arising from occlusive thrombosis in the
carotid communis, carotid interna, or intracerebral arteries.
[0234] It is noted that thrombosis includes vessel occlusion (e.g.,
after a bypass) and reocclusion (e.g., during or after percutaneous
transluminal coronary angioplasty). The thromboembolic disorders
may result from conditions including but not limited to
atherosclerosis, surgery or surgical complications, prolonged
immobilization, arterial fibrillation, congenital thrombophilia,
cancer, diabetes, effects of medications or hormones, and
complications of pregnancy.
[0235] Thromboembolic disorders are frequently associated with
patients with atherosclerosis. Risk factors for atherosclerosis
include but are not limited to male gender, age, hypertension,
lipid disorders, and diabetes mellitus. Risk factors for
atherosclerosis are at the same time risk factors for complications
of atherosclerosis, i.e., thromboembolic disorders.
[0236] Similarly, arterial fibrillation is frequently associated
with thromboembolic disorders. Risk factors for arterial
fibrillation and subsequent thromboembolic disorders include
cardiovascular disease, rheumatic heart disease, nonrheumatic
mitral valve disease, hypertensive cardiovascular disease, chronic
lung disease, and a variety of miscellaneous cardiac abnormalities
as well as thyrotoxicosis.
[0237] Diabetes mellitus is frequently associated with
atherosclerosis and thromboembolic disorders. Risk factors for the
more common type 2 include but are not limited to are family
history, obesity, physical inactivity, race/ethnicity, previously
impaired fasting glucose or glucose tolerance test, history of
gestational diabetes mellitus or delivery of a "big baby",
hypertension, low HDL cholesterol, and polycystic ovary
syndrome.
[0238] Risk factors for congenital thrombophilia include gain of
function mutations in coagulation factors or loss of function
mutations in the anticoagulant- or fibrinolytic pathways.
[0239] Thrombosis has been associated with a variety of tumor
types, e.g., pancreatic cancer, breast cancer, brain tumors, lung
cancer, ovarian cancer, prostate cancer, gastrointestinal
malignancies, and Hodgkins or non-Hodgkins lymphoma. Recent studies
suggest that the frequency of cancer in patients with thrombosis
reflects the frequency of a particular cancer type in the general
population (Levitan, N. et al., Medicine (Baltimore), 78(5):285-291
(1999); Levine M. et al., N. Engl. J. Med., 334(11):677-681 (1996);
Blom, J. W. et al., JAMA, 293(6):715-722 (2005)). Hence, the most
common cancers associated with thrombosis in men are prostate,
colorectal, brain, and lung cancer, and in women are breast, ovary,
and lung cancer. The observed rate of venous thromboembolism (VTE)
in cancer patients is significant. The varying rates of VTE between
different tumor types are most likely related to the selection of
the patient population. Cancer patients at risk for thrombosis may
possess any or all of the following risk factors: (i) the stage of
the cancer (i.e., presence of metastases), (ii) the presence of
central vein catheters, (iii) surgery and anticancer therapies
including chemotherapy, and (iv) hormones and antiangiogenic drugs.
Thus, it is common clinical practice to dose patients having
advanced tumors with heparin or low molecular heparin to prevent
thromboembolic disorders. A number of low molecular heparin
preparations have been approved by the FDA for these
indications.
[0240] There are three main clinical situations when considering
the prevention of VTE in a medical cancer patient: (i) the patient
is bedridden for prolonged periods of time; (ii) the ambulatory
patient is receiving chemotherapy or radiation; and (iii) the
patient is with indwelling central vein catheters. Unfractionated
heparin (UFH) and low molecular weight heparin (LMWH) are effective
antithrombotic agents in cancer patients undergoing surgery.
(Mismetti, P. et al., British Journal of Surgery, 88:913-930
(2001).)
A. In Vitro Assays
[0241] The effectiveness of compounds of the present invention as
inhibitors of the coagulation factors XIa, VIIa, IXa, Xa, XIIa,
plasma kallikrein or thrombin, can be determined using a relevant
purified serine protease, respectively, and an appropriate
synthetic substrate. The rate of hydrolysis of the chromogenic or
fluorogenic substrate by the relevant serine protease was measured
both in the absence and presence of compounds of the present
invention. Hydrolysis of the substrate resulted in the release of
pNA (para nitroaniline), which was monitored spectrophotometrically
by measuring the increase in absorbance at 405 nm, or the release
of AMC (amino methylcoumarin), which was monitored
spectrofluorometrically by measuring the increase in emission at
460 nm with excitation at 380 nm. A decrease in the rate of
absorbance or fluorescence change in the presence of inhibitor is
indicative of enzyme inhibition. Such methods are known to one
skilled in the art. The results of this assay are expressed as the
inhibitory constant, K.sub.i.
[0242] Factor XIa determinations were made in 50 mM HEPES buffer at
pH 7.4 containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000
(polyethylene glycol; JT Baker or Fisher Scientific).
Determinations were made using purified human Factor XIa at a final
concentration of 75-200 pM (Haematologic Technologies) and the
synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; CHROMOGENIX.RTM.
or AnaSpec) at a concentration of 0.0002-0.001 M.
[0243] Factor VIIa determinations were made in 0.005 M calcium
chloride, 0.15 M sodium chloride, 0.05 M HEPES buffer containing
0.1% PEG 8000 at a pH of 7.5. Determinations were made using
purified human Factor VIIa (Haematologic Technologies) or
recombinant human Factor VIIa (Novo Nordisk) at a final assay
concentration of 1-5 nM, recombinant soluble tissue factor at a
concentration of 10-40 nM and the synthetic substrate
H-D-Ile-Pro-Arg-pNA (S-2288; CHROMOGENIX.RTM. or BMPM-2; AnaSpec)
at a concentration of 0.001-0.0075 M.
[0244] Factor IXa determinations were made in 0.005 M calcium
chloride, 0.1 M sodium chloride, 0.0001 M Refludan (Berlex), 0.05 M
TRIS base and 0.5% PEG 8000 at a pH of 7.4. Refludan was added to
inhibit small amounts of thrombin in the commercial preparations of
human Factor IXa. Determinations were made using purified human
Factor IXa (Haematologic Technologies) at a final assay
concentration of 20-100 nM and the synthetic substrate PCIXA2100-B
(CenterChem) or Pefafluor IXa 3688 (H-D-Leu-Ph'Gly-Arg-AMC;
CenterChem) at a concentration of 0.0004-0.0005 M.
[0245] Factor Xa determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG
8000. Determinations were made using purified human Factor Xa
(Haematologic Technologies) at a final assay concentration of
150-1000 pM and the synthetic substrate S-2222 (Bz-Ile-Glu
(gamma-OMe, 50%)-Gly-Arg-pNA; CHROMOGENIX.RTM.) at a concentration
of 0.0002-0.00035 M.
[0246] Factor XIIa determinations were made in 50 mM HEPES buffer
at pH 7.4 containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000.
Determinations were made using purified human Factor XIIa at a
final concentration of 4 nM (American Diagnostica) and the
synthetic substrate SPECTROZYME.RTM. #312 (pyroGlu-Pro-Arg-pNA;
American Diagnostica) at a concentration of 0.00015 M.
[0247] Plasma kallikrein determinations were made in 0.1 M sodium
phosphate buffer at a pH of 7.5 containing 0.1-0.2 M sodium
chloride and 0.5% PEG 8000. Determinations were made using purified
human kallikrein (Enzyme Research Laboratories) at a final assay
concentration of 200 pM and the synthetic substrate S-2302
(H-(D)-Pro-Phe-Arg-pNA; CHROMOGENIX.RTM.) at a concentration of
0.00008-0.0004 M. The K.sub.m value used for calculation of K.sub.i
was 0.00005 to 0.00007 M.
[0248] Thrombin determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG
8000. Determinations were made using purified human alpha thrombin
(Haematologic Technologies or Enzyme Research Laboratories) at a
final assay concentration of 200-250 pM and the synthetic substrate
S-2366 (pyroGlu-Pro-Arg-pNA; CHROMOGENIX.RTM.) at a concentration
of 0.0002-0.00026 M.
[0249] The Michaelis constant, K.sub.m, for substrate hydrolysis by
each protease, was determined at 25.degree. C. using the method of
Lineweaver and Burk. Values of K.sub.i were determined by allowing
the protease to react with the substrate in the presence of the
inhibitor. Reactions were allowed to go for periods of 20-180
minutes (depending on the protease) and the velocities (rate of
absorbance or fluorescence change versus time) were measured. The
following relationships were used to calculate K.sub.i values:
(v.sub.o-v.sub.s)/v.sub.s=I/(K.sub.i(1+S/K.sub.m)) for a
competitive inhibitor with one binding site; or
v.sub.s/v.sub.o=A+((B-A)/1+((IC.sub.50/(I).sub.n))); and
K.sub.i=IC.sub.50/(1+S/K.sub.m) for a competitive inhibitor
where:
[0250] v.sub.o is the velocity of the control in the absence of
inhibitor;
[0251] v.sub.s is the velocity in the presence of inhibitor;
[0252] I is the concentration of inhibitor;
[0253] A is the minimum activity remaining (usually locked at
zero);
[0254] B is the maximum activity remaining (usually locked at
1.0);
[0255] n is the Hill coefficient, a measure of the number and
cooperativity of potential inhibitor binding sites;
[0256] IC.sub.50 is the concentration of inhibitor that produces
50% inhibition under the assay conditions;
[0257] K.sub.i is the dissociation constant of the enzyme:inhibitor
complex;
[0258] S is the concentration of substrate; and
[0259] K.sub.m is the Michaelis constant for the substrate.
[0260] The selectivity of a compound may be evaluated by taking the
ratio of the K.sub.i value for a given protease with the K.sub.i
value for the protease of interest (i.e., selectivity for FXIa
versus protease P=K.sub.i for protease P/K.sub.i for FXIa).
Compounds with selectivity ratios >20 are considered selective.
Compounds with selectivity ratios >100 are preferred, and
compounds with selectivity ratios >500 are more preferred.
[0261] The effectiveness of compounds of the present invention as
inhibitors of coagulation can be determined using a standard or
modified clotting assay. An increase in the plasma clotting time in
the presence of inhibitor is indicative of anticoagulation.
Relative clotting time is the clotting time in the presence of an
inhibitor divided by the clotting time in the absence of an
inhibitor. The results of this assay may be expressed as
IC1.5.times. or IC2.times., the inhibitor concentration required to
increase the clotting time by 50 or 100 percent, respectively. The
IC1.5.times. or IC2.times. is found by linear interpolation from
relative clotting time versus inhibitor concentration plots using
inhibitor concentration that spans the IC1.5.times. or
IC2.times..
[0262] Clotting times are determined using citrated normal human
plasma as well as plasma obtained from a number of laboratory
animal species (e.g., rat, or rabbit). A compound is diluted into
plasma beginning with a 10 mM DMSO stock solution. The final
concentration of DMSO is less than 2%. Plasma clotting assays are
performed in an automated coagulation analyzer (Sysmex,
Dade-Behring, Ill.). Similarly, clotting times can be determined
from laboratory animal species or humans dosed with compounds of
the invention.
[0263] Activated Partial Thromboplastin Time (aPTT) is determined
using ALEXIN.RTM. (Trinity Biotech, Ireland) or ACTIN.RTM.
(Dade-Behring, Ill.) following the directions in the package
insert. Plasma (0.05 mL) is warmed to 37.degree. C. for 1 minute.
ALEXIN.RTM. or ACTIN.RTM. (0.05 mL) is added to the plasma and
incubated for an additional 2 to 5 minutes. Calcium chloride (25
mM, 0.05 mL) is added to the reaction to initiate coagulation. The
clotting time is the time in seconds from the moment calcium
chloride is added until a clot is detected.
[0264] Prothrombin Time (PT) is determined using thromboplastin
(Thromboplastin C Plus, Dade-Behring, Ill.) following the
directions in the package insert. Plasma (0.05 mL) is warmed to
37.degree. C. for 1 minute. Thromboplastin (0.1 mL) is added to the
plasma to initiate coagulation. The clotting time is the time in
seconds from the moment thromboplastin is added until a clot is
detected.
[0265] The Examples disclosed below were tested in the Factor XIa
assay described above and found having Factor XIa inhibitory
activity. A range of Factor XIa inhibitory activity (Ki values) of
.ltoreq.10 .mu.M (10000 nM) was observed. The results are shown in
Tables 1 and A. The activity ranges in Table A are: A is 500-5000
nanocromolar (nM); B is 100-500 nM; C is 5-10 nM; D is <5 nM.
Note that by using the Example Number in the tables the structures
of the compounds can be found herein.
TABLE-US-00002 TABLE 1 Example No. Factor XIa Ki (nM) 1 <5.00 4
10.26 7 49.73 13 <5.00 15 2440.00 16 2294.00 22 <5.00 28
1217.00 37 86.45 41 5641.00 43 20.60 52 <5.00 63 34.46 71 491.50
81 <5.00 90 314.00 94 <5.00 98 632.4 106 <5.00 119
<5.00 125 1006.00 128 132.70 131 <5.00 155 <5.00 169
516.80 175 <5.00 184 <5.00 189 1690.00 191 1051.00 193 107.30
196 843.70 198 5736.00 215 <5.00 216 955.00 228 <5.00 235
74.48 237 4617.00 240 47.10 250 <5.00 257 2570.00 266
<5.00
TABLE-US-00003 TABLE A Example No. Factor XIa Ki (nM) 2 B 3 D 5 C 6
C 8 C 9 C 10 C 11 D 12 C 14 D 17 C 18 D 19 C 20 C 21 D 23 C 24 C 25
C 26 C 27 D 29 C 30 B 31 D 32 B 33 C 34 D 35 D 36 B 38 C 39 C 40 D
42 C 44 C 45 C 46 D 47 D 48 B 49 D 50 B 51 C 53 D 54 D 55 B 56 C 57
C 58 B 59 C 60 D 61 C 62 D 64 D 65 C 66 C 67 B 68 B 69 B 70 B 72 A
73 A 74 B 75 B 76 A 77 B 78 D 79 D 80 D 82 D 83 D 84 D 85 D 86 D 87
D 88 C 89 D 91 C 92 D 93 C 95 D 96 D 97 D 99 D 100 D 101 D 102 C
103 D 104 D 105 D 107 C 108 D 109 C 110 C 111 A 112 D 113 B 114 D
115 D 116 D 117 D 118 C 120 D 121 D 122 D 123 D 124 D 126 D 127 D
129 D 130 D 132 B 133 D 134 D 135 D 136 D 137 D 138 D 139 D 140 D
141 D 142 D 143 D 144 D 145 D 146 D 147 D 148 D 149 D 150 D 151 D
152 D 153 C 154 D 156 C 157 C 158 D 159 D 160 C 161 D 162 D 163 C
164 D 165 C 166 C 167 C 168 D 170 D 171 C 172 D 173 C 174 D 176 D
177 C 178 D 179 B 180 D 181 C 182 C 183 B 185 C 186 A 187 B 188 D
190 C 192 C 194 D 195 D 197 C 199 D 200 B 201 D 202 B 203 C 204 D
205 C 206 D 207 C 208 D 209 D 210 D 211 D 212 D 213 D 214 D 217 D
218 D 219 D 220 D 221 C 222 D 223 D 224 C 225 D 226 C 227 D 229 B
230 B 231 B 232 C 233 C 234 C 236 C 238 C 239 D 241 D 242 B 243 D
244 D 245 D 246 D 247 D 248 D 249 D 251 D 252 D 253 C 254 D 255 D
256 D 258 D 259 D 260 D 261 D 262 D 263 D 264 D 265 D 267 D 268 D
269 D 270 D
B. In Vivo Assays
[0266] The effectiveness of compounds of the present invention as
antithrombotic agents can be determined using relevant in vivo
thrombosis models, including In Vivo Electrically-induced Carotid
Artery Thrombosis Models and In Vivo Rabbit Arterio-venous Shunt
Thrombosis Models.
a. In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT)
Model
[0267] The rabbit ECAT model, described by Wong et al. (J.
Pharmacol. Exp. Ther., 295:212-218 (2000)), can be used in this
study. Male New Zealand White rabbits are anesthetized with
ketamine (50 mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h
IM). These anesthetics are supplemented as needed. An
electromagnetic flow probe is placed on a segment of an isolated
carotid artery to monitor blood flow. Test agents or vehicle will
be given (i.v., i.p., s.c., or orally) prior to or after the
initiation of thrombosis. Drug treatment prior to initiation of
thrombosis is used to model the ability of test agents to prevent
and reduce the risk of thrombus formation, whereas dosing after
initiation is used to model the ability to treat existing
thrombotic disease. Thrombus formation is induced by electrical
stimulation of the carotid artery for 3 min at 4 mA using an
external stainless-steel bipolar electrode. Carotid blood flow is
measured continuously over a 90-min period to monitor
thrombus-induced occlusion. Total carotid blood flow over 90 min is
calculated by the trapezoidal rule. Average carotid flow over 90
min is then determined by converting total carotid blood flow over
90 min to percent of total control carotid blood flow, which would
result if control blood flow had been maintained continuously for
90 min. The ED.sub.50 (dose that increased average carotid blood
flow over 90 min to 50% of the control) of compounds are estimated
by a nonlinear least square regression program using the Hill
sigmoid E.sub.max equation (DeltaGraph; SPSS Inc., Chicago,
Ill.).
b. In Vivo Rabbit Arterio-Venous (AV) Shunt Thrombosis Model
[0268] The rabbit AV shunt model, described by Wong et al. (Wong,
P. C. et al., J. Pharmacol. Exp. Ther. 292:351-357 (2000)), can be
used in this study. Male New Zealand White rabbits are anesthetized
with ketamine (50 mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10
mg/kg/h IM). These anesthetics are supplemented as needed. The
femoral artery, jugular vein and femoral vein are isolated and
catheterized. A saline-filled AV shunt device is connected between
the femoral arterial and the femoral venous cannulae. The AV shunt
device consists of an outer piece of tygon tubing (length=8 cm;
internal diameter=7.9 mm) and an inner piece of tubing (length=2.5
cm; internal diameter=4.8 mm). The AV shunt also contains an
8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows
from the femoral artery via the AV-shunt into the femoral vein. The
exposure of flowing blood to a silk thread induces the formation of
a significant thrombus. Forty minutes later, the shunt is
disconnected and the silk thread covered with thrombus is weighed.
Test agents or vehicle will be given (i.v., i.p., s.c., or orally)
prior to the opening of the AV shunt. The percentage inhibition of
thrombus formation is determined for each treatment group. The
ID.sub.50 values (dose that produces 50% inhibition of thrombus
formation) are estimated by a nonlinear least square regression
program using the Hill sigmoid E.sub.max equation (DeltaGraph; SPSS
Inc., Chicago, Ill.).
[0269] The anti-inflammatory effect of these compounds can be
demonstrated in an Evans Blue dye extravasation assay using
C1-esterase inhibitor deficient mice. In this model, mice are dosed
with a compound of the present invention, Evans Blue dye is
injected via the tail vein, and extravasation of the blue dye is
determined by spectrophotometric means from tissue extracts.
[0270] The ability of the compounds of the current invention to
reduce or prevent the systemic inflammatory response syndrome, for
example, as observed during on-pump cardiovascular procedures, can
be tested in in vitro perfusion systems, or by on-pump surgical
procedures in larger mammals, including dogs and baboons. Read-outs
to assess the benefit of the compounds of the present invention
include for example reduced platelet loss, reduced platelet/white
blood cell complexes, reduced neutrophil elastase levels in plasma,
reduced activation of complement factors, and reduced activation
and/or consumption of contact activation proteins (plasma
kallikrein, factor XII, factor XI, high molecular weight kininogen,
C1-esterase inhibitors).
[0271] The compounds of the present invention may also be useful as
inhibitors of additional serine proteases, notably human thrombin,
human plasma kallikrein and human plasmin. Because of their
inhibitory action, these compounds are indicated for use in the
prevention or treatment of physiological reactions, including blood
coagulation, fibrinolysis, blood pressure regulation and
inflammation, and wound healing catalyzed by the aforesaid class of
enzymes. Specifically, the compounds have utility as drugs for the
treatment of diseases arising from elevated thrombin activity of
the aforementioned serine proteases, such as myocardial infarction,
and as reagents used as anticoagulants in the processing of blood
to plasma for diagnostic and other commercial purposes.
V. Pharmaceutical Compositions, Formulations and Combinations
[0272] The compounds of this invention can be administered in such
oral dosage forms as tablets, capsules (each of which includes
sustained release or timed release formulations), pills, powders,
granules, elixirs, tinctures, suspensions, syrups, and emulsions.
They may also be administered in intravenous (bolus or infusion),
intraperitoneal, subcutaneous, or intramuscular form, all using
dosage forms well known to those of ordinary skill in the
pharmaceutical arts. They can be administered alone, but generally
will be administered with a pharmaceutical carrier selected on the
basis of the chosen route of administration and standard
pharmaceutical practice.
[0273] The term "pharmaceutical composition" means a composition
comprising a compound of the invention in combination with at least
one additional pharmaceutically acceptable carrier. A
"pharmaceutically acceptable carrier" refers to media generally
accepted in the art for the delivery of biologically active agents
to animals, in particular, mammals, including, i.e., adjuvant,
excipient or vehicle, such as diluents, preserving agents, fillers,
flow regulating agents, disintegrating agents, wetting agents,
emulsifying agents, suspending agents, sweetening agents, flavoring
agents, perfuming agents, antibacterial agents, antifungal agents,
lubricating agents and dispensing agents, depending on the nature
of the mode of administration and dosage forms. Pharmaceutically
acceptable carriers are formulated according to a number of factors
well within the purview of those of ordinary skill in the art.
These include, without limitation: the type and nature of the
active agent being formulated; the subject to which the
agent-containing composition is to be administered; the intended
route of administration of the composition; and the therapeutic
indication being targeted. Pharmaceutically acceptable carriers
include both aqueous and non-aqueous liquid media, as well as a
variety of solid and semi-solid dosage forms. Such carriers can
include a number of different ingredients and additives in addition
to the active agent, such additional ingredients being included in
the formulation for a variety of reasons, e.g., stabilization of
the active agent, binders, etc., well known to those of ordinary
skill in the art. Descriptions of suitable pharmaceutically
acceptable carriers, and factors involved in their selection, are
found in a variety of readily available sources such as, for
example, Remington's Pharmaceutical Sciences, 18th Ed. (1990).
[0274] The dosage regimen for the compounds of the present
invention will, of course, vary depending upon known factors, such
as the pharmacodynamic characteristics of the particular agent and
its mode and route of administration; the species, age, sex,
health, medical condition, and weight of the recipient; the nature
and extent of the symptoms; the kind of concurrent treatment; the
frequency of treatment; the route of administration, the renal and
hepatic function of the patient, and the effect desired. A
physician or veterinarian can determine and prescribe the effective
amount of the drug required to prevent, counter, or arrest the
progress of the thromboembolic disorder.
[0275] By way of general guidance, the daily oral dosage of each
active ingredient, when used for the indicated effects, will range
between about 0.001 to about 1000 mg/kg of body weight, preferably
between about 0.01 to about 100 mg/kg of body weight per day, and
most preferably between about 0.1 to about 20 mg/kg/day.
Intravenously, the most preferred doses will range from about 0.001
to about 10 mg/kg/minute during a constant rate infusion. Compounds
of this invention may be administered in a single daily dose, or
the total daily dosage may be administered in divided doses of two,
three, or four times daily.
[0276] Compounds of this invention can also be administered by
parenteral administration (e.g., intra-venous, intra-arterial,
intramuscularly, or subcutaneously. When administered intra-venous
or intra-arterial, the dose can be given continuously or
intermittent. Furthermore, formulation can be developed for
intramuscularly and subcutaneous delivery that ensure a gradual
release of the active pharmaceutical ingredient.
[0277] Compounds of this invention can be administered in
intranasal form via topical use of suitable intranasal vehicles, or
via transdermal routes, using transdermal skin patches. When
administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
[0278] The compounds are typically administered in admixture with
suitable pharmaceutical diluents, excipients, or carriers
(collectively referred to herein as pharmaceutical carriers)
suitably selected with respect to the intended form of
administration, e.g., oral tablets, capsules, elixirs, and syrups,
and consistent with conventional pharmaceutical practices.
[0279] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic, pharmaceutically acceptable, inert carrier such
as lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like; for oral administration in liquid form, the oral drug
components can be combined with any oral, non-toxic,
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water, and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents, and coloring
agents can also be incorporated into the mixture. Suitable binders
include starch, gelatin, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum, and the like.
[0280] The compounds of the present invention 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.
[0281] Compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues. Furthermore, the compounds of
the present invention 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, polycyanoacylates, and crosslinked or
amphipathic block copolymers of hydrogels.
[0282] Dosage forms (pharmaceutical compositions) suitable for
administration may contain from about 1 milligram to about 1000
milligrams of active ingredient per dosage unit. In these
pharmaceutical compositions the active ingredient will ordinarily
be present in an amount of about 0.1-95% by weight based on the
total weight of the composition.
[0283] Gelatin capsules may contain the active ingredient and
powdered carriers, such as lactose, starch, cellulose derivatives,
magnesium stearate, stearic acid, and the like. Similar diluents
can be used to make compressed tablets. Both tablets and capsules
can be manufactured as sustained release products to provide for
continuous release of medication over a period of hours. Compressed
tablets can be sugar coated or film coated to mask any unpleasant
taste and protect the tablet from the atmosphere, or enteric coated
for selective disintegration in the gastrointestinal tract.
[0284] Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance.
[0285] In general, water, a suitable oil, saline, aqueous dextrose
(glucose), and related sugar solutions and glycols such as
propylene glycol or polyethylene glycols are suitable carriers for
parenteral solutions. Solutions for parenteral administration
preferably contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer substances.
Antioxidizing agents such as sodium bisulfite, sodium sulfite, or
ascorbic acid, either alone or combined, are suitable stabilizing
agents. Also used are citric acid and its salts and sodium EDTA. In
addition, parenteral solutions can contain preservatives, such as
benzalkonium chloride, methyl- or propyl-paraben, and
chlorobutanol.
[0286] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field.
[0287] Where the compounds of this invention are combined with
other anticoagulant agents, for example, a daily dosage may be
about 0.1 to about 100 milligrams of the compound of the present
invention and about 0.1 to about 100 milligrams per kilogram of
patient body weight. For a tablet dosage form, the compounds of
this invention generally may be present in an amount of about 5 to
about 100 milligrams per dosage unit, and the second anti-coagulant
in an amount of about 1 to about 50 milligrams per dosage unit.
[0288] Where the compounds of the present invention are
administered in combination with an anti-platelet agent, by way of
general guidance, typically a daily dosage may be about 0.01 to
about 25 milligrams of the compound of the present invention and
about 50 to about 150 milligrams of the anti-platelet agent,
preferably about 0.1 to about 1 milligrams of the compound of the
present invention and about 1 to about 3 milligrams of antiplatelet
agents, per kilogram of patient body weight.
[0289] Where the compounds of the present invention are
administered in combination with thrombolytic agent, typically a
daily dosage may be about 0.1 to about 1 milligrams of the compound
of the present invention, per kilogram of patient body weight and,
in the case of the thrombolytic agents, the usual dosage of the
thrombolytic agent when administered alone may be reduced by about
50-80% when administered with a compound of the present
invention.
[0290] Particularly when provided as a single dosage unit, the
potential exists for a chemical interaction between the combined
active ingredients. For this reason, when the compound of the
present invention and a second therapeutic agent are combined in a
single dosage unit they are formulated such that although the
active ingredients are combined in a single dosage unit, the
physical contact between the active ingredients is minimized (that
is, reduced). For example, one active ingredient may be enteric
coated. By enteric coating one of the active ingredients, it is
possible not only to minimize the contact between the combined
active ingredients, but also, it is possible to control the release
of one of these components in the gastrointestinal tract such that
one of these components is not released in the stomach but rather
is released in the intestines. One of the active ingredients may
also be coated with a material that affects a sustained-release
throughout the gastrointestinal tract and also serves to minimize
physical contact between the combined active ingredients.
Furthermore, the sustained-released component can be additionally
enteric coated such that the release of this component occurs only
in the intestine. Still another approach would involve the
formulation of a combination product in which the one component is
coated with a sustained and/or enteric release polymer, and the
other component is also coated with a polymer such as a low
viscosity grade of hydroxypropyl methylcellulose (HPMC) or other
appropriate materials as known in the art, in order to further
separate the active components. The polymer coating serves to form
an additional barrier to interaction with the other component.
[0291] These as well as other ways of minimizing contact between
the components of combination products of the present invention,
whether administered in a single dosage form or administered in
separate forms but at the same time by the same manner, will be
readily apparent to those skilled in the art, once armed with the
present disclosure.
[0292] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s) selected from potassium channel openers,
potassium channel blockers, calcium channel blockers, sodium
hydrogen exchanger inhibitors, antiarrhythmic agents,
antiatheroaclerotic agents, anticoagulants, antithrombotic agents,
prothrombolytic agents, fibrinogen antagonists, diuretics,
antihypertensive agents, ATPase inhibitors, mineralocorticoid
receptor antagonists, phosphodiesterase inhibitors, antidiabetic
agents, anti-inflammatory agents, antioxidants, angiogenesis
modulators, antiosteoporosis agents, hormone replacement therapies,
hormone receptor modulators, oral contraceptives, antiobesity
agents, antidepressants, antianxiety agents, antipsychotic agents,
antiproliferative agents, antitumor agents, antiulcer and
gastroesophageal reflux disease agents, growth hormone agents
and/or growth hormone secretagogues, thyroid mimetics,
anti-infective agents, antiviral agents, antibacterial agents,
antifungal agents, cholesterol/lipid lowering agents and lipid
profile therapies, and agents that mimic ischemic preconditioning
and/or myocardial stunning, or a combination thereof.
[0293] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s) selected from an anti-arrhythmic agent, an
anti-hypertensive agent, an anti-coagulant agent, an anti-platelet
agent, a thrombin inhibiting agent, a thrombolytic agent, a
fibrinolytic agent, a calcium channel blocker, a potassium channel
blocker, a cholesterol/lipid lowering agent, or a combination
thereof.
[0294] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s) selected from warfarin, unfractionated
heparin, low molecular weight heparin, synthetic pentasaccharide,
hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac,
indomethacin, mefenamate, dipyridamol, droxicam, diclofenac,
sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban,
eptifibatide, abciximab, melagatran, ximelagatran,
disulfatohirudin, tissue plasminogen activator, modified tissue
plasminogen activator, antistreplase, urokinase, and streptokinase,
or a combination thereof.
[0295] In another embodiment, the present invention provides a
pharmaceutical composition wherein the additional therapeutic agent
is an antihypertensive agent selected from ACE inhibitors, AT-1
receptor antagonists, beta-adrenergic receptor antagonists, ETA
receptor antagonists, dual ETA/AT-1 receptor antagonists, renin
inhibitors (alliskerin) and vasopepsidase inhibitors, an
antiarrythmic agent selected from IKur inhibitors, an anticoagulant
selected from thrombin inhibitors, antithrombin-III activators,
heparin co-factor II activators, other factor XIa inhibitors, other
kallikrein inhibitors, plasminogen activator inhibitor (PAI-1)
antagonists, thrombin activatable fibrinolysis inhibitor (TAFI)
inhibitors, factor VIIa inhibitors, factor IXa inhibitors, and
factor Xa inhibitors, or an antiplatelet agent selected from
GPIIb/IIIa blockers, GP Ib/IX blockers, protease activated receptor
1 (PAR-1) antagonists, protease activated receptor4 (PAR-4)
antagonists, prostaglandin E2 receptor EP3 antagonists, collagen
receptor antagonists, phosphodiesterase-III inhibitors, P2Y.sub.1
receptor antagonists, P2Y.sub.12 antagonists, thromboxane receptor
antagonists, cyclooxygense-1 inhibitors, and aspirin, or a
combination thereof.
[0296] In another embodiment, the present invention provides
pharmaceutical composition, wherein the additional therapeutic
agent(s) are an anti-platelet agent or a combination thereof.
[0297] In another embodiment, the present invention provides a
pharmaceutical composition, wherein the additional therapeutic
agent is the anti-platelet agent clopidogrel.
[0298] The compounds of the present invention can be administered
alone or in combination with one or more additional therapeutic
agents. By "administered in combination" or "combination therapy"
it is meant that the compound of the present invention and one or
more additional therapeutic agents are administered concurrently to
the mammal being treated. When administered in combination, each
component may be administered at the same time or sequentially in
any order at different points in time. Thus, each component may be
administered separately but sufficiently closely in time so as to
provide the desired therapeutic effect.
[0299] Compounds that can be administered in combination with the
compounds of the present invention include, but are not limited to,
anticoagulants, anti-thrombin agents, anti-platelet agents,
fibrinolytics, hypolipidemic agents, antihypertensive agents, and
anti-ischemic agents.
[0300] Other anticoagulant agents (or coagulation inhibitory
agents) that may be used in combination with the compounds of this
invention include warfarin, heparin (either unfractionated heparin
or any commercially available low molecular weight heparin, for
example LOVENOX.RTM.), synthetic pentasaccharide, direct acting
thrombin inhibitors including hirudin and argatroban, as well as
other factor VIIa inhibitors, factor IXa inhibitors, factor Xa
inhibitors (e.g., ARIXTRA.RTM., apixaban, rivaroxaban, LY-517717,
DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO
03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors,
and inhibitors of activated TAFI and PAI-1 known in the art.
[0301] The term anti-platelet agents (or platelet inhibitory
agents), as used herein, denotes agents that inhibit platelet
function, for example, by inhibiting the aggregation, adhesion or
granule-content secretion of platelets. Such agents include, but
are not limited to, the various known non-steroidal
anti-inflammatory drugs (NSAIDs) such as acetaminophen, aspirin,
codeine, diclofenac, droxicam, fentaynl, ibuprofen, indomethacin,
ketorolac, mefenamate, morphine, naproxen, phenacetin, piroxicam,
sufentanyl, sulfinpyrazone, sulindac, and pharmaceutically
acceptable salts or prodrugs thereof. Of the NSAIDs, aspirin
(acetylsalicylic acid or ASA) and piroxicam are preferred. Other
suitable platelet inhibitory agents include glycoprotein IIb/IIIa
antagonists (e.g., tirofiban, eptifibatide, abciximab, and
integrelin), thromboxane-A2-receptor antagonists (e.g., ifetroban),
thromboxane-A-synthetase inhibitors, phosphodiesterase-III
(PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE-V
inhibitors (such as sildenafil), protease-activated receptor 1
(PAR-1) antagonists (e.g., E-5555, SCH-530348, SCH-203099,
SCH-529153 and SCH-205831), and pharmaceutically acceptable salts
or prodrugs thereof.
[0302] Other examples of suitable anti-platelet agents for use in
combination with the compounds of the present invention, with or
without aspirin, are ADP (adenosine diphosphate) receptor
antagonists, preferably antagonists of the purinergic receptors
P2Y.sub.1 and P2Y.sub.12, with P2Y.sub.12 being even more
preferred. Preferred P2Y.sub.12 receptor antagonists include
clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, and
pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine
and clopidogrel are also preferred compounds since they are known
to be more gentle than aspirin on the gastro-intestinal tract in
use. Clopidogrel is an even more preferred agent.
[0303] A preferred example is a triple combination of a compound of
the present invention, aspirin, and another anti-platelet agent.
Preferably, the anti-platelet agent is clopidogrel or prasugrel,
more preferably clopidogrel.
[0304] The term thrombin inhibitors (or anti-thrombin agents), as
used herein, denotes inhibitors of the serine protease thrombin. By
inhibiting thrombin, various thrombin-mediated processes, such as
thrombin-mediated platelet activation (that is, for example, the
aggregation of platelets, and/or the secretion of platelet granule
contents including serotonin) and/or fibrin formation are
disrupted. A number of thrombin inhibitors are known to one of
skill in the art and these inhibitors are contemplated to be used
in combination with the present compounds. Such inhibitors include,
but are not limited to, boroarginine derivatives, boropeptides,
heparins, hirudin, argatroban, dabigatran, AZD-0837, and those
disclosed in WO 98/37075 and WO 02/044145, and pharmaceutically
acceptable salts and prodrugs thereof. Boroarginine derivatives and
boropeptides include N-acetyl and peptide derivatives of boronic
acid, such as C-terminal a-aminoboronic acid derivatives of lysine,
ornithine, arginine, homoarginine and corresponding isothiouronium
analogs thereof. The term hirudin, as used herein, includes
suitable derivatives or analogs of hirudin, referred to herein as
hirulogs, such as disulfatohirudin.
[0305] The term thrombolytic (or fibrinolytic) agents (or
thrombolytics or fibrinolytics), as used herein, denotes agents
that lyse blood clots (thrombi). Such agents include tissue
plasminogen activator (TPA, natural or recombinant) and modified
forms thereof, anistreplase, urokinase, streptokinase, tenecteplase
(TNK), lanoteplase (nPA), factor VIIa inhibitors, thrombin
inhibitors, inhibitors of factors IXa, Xa, and XIa, PAI-I
inhibitors (i.e., inactivators of tissue plasminogen activator
inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmin
inhibitors, and anisoylated plasminogen streptokinase activator
complex, including pharmaceutically acceptable salts or prodrugs
thereof. The term anistreplase, as used herein, refers to
anisoylated plasminogen streptokinase activator complex, as
described, for example, in European Patent Application No. 028,489,
the disclosure of which is hereby incorporated herein by reference
herein. The term urokinase, as used herein, is intended to denote
both dual and single chain urokinase, the latter also being
referred to herein as prourokinase.
[0306] Examples of suitable cholesterol/lipid lowering agents and
lipid profile therapies for use in combination with the compounds
of the present invention include HMG-CoA reductase inhibitors
(e.g., pravastatin, lovastatin, simvastatin, fluvastatin,
atorvastatin, rosuvastatin, and other statins), low-density
lipoprotein (LDL) receptor activity modulators (e.g., HOE-402,
PCSK9 inhibitors), bile acid sequestrants (e.g., cholestyramine and
colestipol), nicotinic acid or derivatives thereof (e.g.,
NIASPAN.RTM.), GPR109B (nicotinic acid receptor) modulators,
fenofibric acid derivatives (e.g., gemfibrozil, clofibrate,
fenofibrate and benzafibrate) and other peroxisome
proliferator-activated receptors (PPAR) alpha modulators, PPARdelta
modulators (e.g., GW-501516), PPARgamma modulators (e.g.,
rosiglitazone), compounds that have multiple functionality for
modulating the activities of various combinations of PPARalpha,
PPARgamma and PPARdelta, probucol or derivatives thereof (e.g.,
AGI-1067), cholesterol absorption inhibitors and/or Niemann-Pick
C1-like transporter inhibitors (e.g., ezetimibe), cholesterol ester
transfer protein inhibitors (e.g., CP-529414), squalene synthase
inhibitors and/or squalene epoxidase inhibitors or mixtures
thereof, acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1
inhibitors, ACAT2 inhibitors, dual ACAT1/2 inhibitors, ileal bile
acid transport inhibitors (or apical sodium co-dependent bile acid
transport inhibitors), microsomal triglyceride transfer protein
inhibitors, liver-X-receptor (LXR) alpha modulators, LXR beta
modulators, LXR dual alpha/beta modulators, FXR modulators, omega 3
fatty acids (e.g., 3-PUFA), plant stanols and/or fatty acid esters
of plant stanols (e.g., sitostanol ester used in BENECOL.RTM.
margarine), endothelial lipase inhibitors, and HDL functional
mimetics which activate reverse cholesterol transport (e.g., apoAI
derivatives or apoAI peptide mimetics).
[0307] The compounds of the present invention are also useful as
standard or reference compounds, for example as a quality standard
or control, in tests or assays involving the inhibition of
thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein. Such
compounds may be provided in a commercial kit, for example, for use
in pharmaceutical research involving thrombin, Factor VIIa, IXa,
Xa, XIa, and/or plasma kallikrein. XIa. For example, a compound of
the present invention could be used as a reference in an assay to
compare its known activity to a compound with an unknown activity.
This would ensure the experimentor that the assay was being
performed properly and provide a basis for comparison, especially
if the test compound was a derivative of the reference compound.
When developing new assays or protocols, compounds according to the
present invention could be used to test their effectiveness.
[0308] The compounds of the present invention may also be used in
diagnostic assays involving thrombin, Factor VIIa, IXa, Xa, XIa,
and/or plasma kallikrein. For example, the presence of thrombin,
Factor VIIa, IXa, Xa XIa, and/or plasma kallikrein in an unknown
sample could be determined by addition of the relevant chromogenic
substrate, for example S2366 for Factor XIa, to a series of
solutions containing test sample and optionally one of the
compounds of the present invention. If production of pNA is
observed in the solutions containing test sample, but not in the
presence of a compound of the present invention, then one would
conclude Factor XIa was present.
[0309] Extremely potent and selective compounds of the present
invention, those having K.sub.i values less than or equal to 0.001
.mu.M against the target protease and greater than or equal to 0.1
.mu.M against the other proteases, may also be used in diagnostic
assays involving the quantitation of thrombin, Factor VIIa, IXa,
Xa, XIa, and/or plasma kallikrein in serum samples. For example,
the amount of Factor XIa in serum samples could be determined by
careful titration of protease activity in the presence of the
relevant chromogenic substrate, S2366, with a potent and selective
Factor XIa inhibitor of the present invention.
[0310] The present invention also encompasses an article of
manufacture. As used herein, article of manufacture is intended to
include, but not be limited to, kits and packages. The article of
manufacture of the present invention, comprises: (a) a first
container; (b) a pharmaceutical composition located within the
first container, wherein the composition, comprises: a first
therapeutic agent, comprising: a compound of the present invention
or a pharmaceutically acceptable salt form thereof; and, (c) a
package insert stating that the pharmaceutical composition can be
used for the treatment of a thromboembolic and/or inflammatory
disorder (as defined previously). In another embodiment, the
package insert states that the pharmaceutical composition can be
used in combination (as defined previously) with a second
therapeutic agent to treat a thromboembolic and/or inflammatory
disorder. The article of manufacture can further comprise: (d) a
second container, wherein components (a) and (b) are located within
the second container and component (c) is located within or outside
of the second container. Located within the first and second
containers means that the respective container holds the item
within its boundaries.
[0311] The first container is a receptacle used to hold a
pharmaceutical composition. This container can be for
manufacturing, storing, shipping, and/or individual/bulk selling.
First container is intended to cover a bottle, jar, vial, flask,
syringe, tube (e.g., for a cream preparation), or any other
container used to manufacture, hold, store, or distribute a
pharmaceutical product.
[0312] The second container is one used to hold the first container
and, optionally, the package insert. Examples of the second
container include, but are not limited to, boxes (e.g., cardboard
or plastic), crates, cartons, bags (e.g., paper or plastic bags),
pouches, and sacks. The package insert can be physically attached
to the outside of the first container via tape, glue, staple, or
another method of attachment, or it can rest inside the second
container without any physical means of attachment to the first
container. Alternatively, the package insert is located on the
outside of the second container. When located on the outside of the
second container, it is preferable that the package insert is
physically attached via tape, glue, staple, or another method of
attachment. Alternatively, it can be adjacent to or touching the
outside of the second container without being physically
attached.
[0313] The package insert is a label, tag, marker, etc. that
recites information relating to the pharmaceutical composition
located within the first container. The information recited will
usually be determined by the regulatory agency governing the area
in which the article of manufacture is to be sold (e.g., the United
States Food and Drug Administration). Preferably, the package
insert specifically recites the indications for which the
pharmaceutical composition has been approved. The package insert
may be made of any material on which a person can read information
contained therein or thereon. Preferably, the package insert is a
printable material (e.g., paper, plastic, cardboard, foil,
adhesive-backed paper or plastic, etc.) on which the desired
information has been formed (e.g., printed or applied).
[0314] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments that
are given for illustration of the invention and are not intended to
be limiting thereof. The following Examples have been prepared,
isolated and characterized using the methods disclosed herein.
VI. General Synthesis Including Schemes
[0315] The compounds of the present invention may be synthesized by
many methods available to those skilled in the art of organic
chemistry (Maffrand, J. P. et al., Heterocycles, 16(1):35-7
(1981)). General synthetic schemes for preparing compounds of the
present invention are described below. These schemes are
illustrative and are not meant to limit the possible techniques one
skilled in the art may use to prepare the compounds disclosed
herein. Different methods to prepare the compounds of the present
invention will be evident to those skilled in the art.
Additionally, the various steps in the synthesis may be performed
in an alternate sequence in order to give the desired compound or
compounds.
[0316] Examples of compounds of the present invention prepared by
methods described in the general schemes are given in the
intermediates and examples section set out hereinafter. Example
compounds are typically prepared as racemic mixtures. Preparation
of homochiral examples may be carried out by techniques known to
one skilled in the art. For example, homochiral compounds may be
prepared by separation of racemic products by chiral phase
preparative HPLC. Alternatively, the example compounds may be
prepared by methods known to give enantiomerically enriched
products. These include, but are not limited to, the incorporation
of chiral auxiliary functionalities into racemic intermediates
which serve to control the diastereoselectivity of transformations,
providing enantio-enriched products upon cleavage of the chiral
auxiliary.
[0317] Scheme 1 illustrates a few approaches to the synthesis of
compounds of Formula (I). Amide 1c can be prepared by amide
coupling of commercially available or readily accessible acid 1a
and readily accessible aniline 1b using methods commonly used in
the literature, such as T3P/base, HOAt/EDC/base and/or POCl.sub.3,
pyridine. Deprotection of the protecting group PG.sub.1 using
appropriate conditions known to those in the art of organic
synthesis, followed by coupling with acid 1e can yield compounds of
formula 1g. Alternatively, coupling of amine 1d with acid 1e
followed by deprotection can give acid 1f. The coupling of acid 1f
with amine 1b under standard peptide coupling procedures can yield
compounds of formula 1g. Appropriate functionalization of
intermediates used in this invention to prepare compounds of
formula 1g can be achieved through the Suzuki, Buchwald, Ullman or
Mitsunobu reactions or simple reactions known to those in the
art.
##STR00035##
[0318] Scheme 2 describes an alternative method to access compounds
of this invention. Reaction of acid 1e, isocyanide 2a, and imine 2b
can give Ugi product 2d (Schuster, I. et al., Letters in Organic
Chemistry, 4(2):102-108 (2007)). Selective oxidation of
tetrahydroisoquinoline 2c using known methods such as MnO.sub.2
(Aoyama, T. et al., Synlett, 1:35-36 (1998)) can yield imine 2b,
which can then be used via the three component Ugi coupling
procedures described above. The Ugi coupling procedures can be used
extensively with other imino derived intermediates contained in
this invention. Further manipulations of the Ugi derived products
can afford compounds of this invention.
##STR00036##
[0319] Scheme 3 describes methods for preparing the
tetrahydroisoquinoline intermediate 3c and 3e. Method A uses
Bischler-Napieralski cyclization to access compounds such as
intermediate 3c (Al-Hiari, Y. M. et al., Journal of Heterocyclic
Chemistry, 42(4): 647-659 (2005)) or 3e (Zalan, Z. et al.,
Tetrahedron, 62(12): 2883-2891 (2006)). Method B uses the
Friedel-Crafts alkylation reaction to access compounds such as
intermediate 3c (Topsom, R. D. et al., Journal of the Chemical
Society [Section] D: Chemical Communications, 15:799 (1971)).
Alternatively, as described in Method C, cyclization of
intermediate 3h and 3-aminopropanol (3i) can afford 3j. Reduction
with NaBH.sub.4, followed by PCC oxidation gave .beta.-amino
aldehyde, which can be converted to 3c under basic conditions
(Umetsu, K.; Asao, N., Tetrahedron Letters, 49(17): 2722-2725
(2008)). In Method D, lactam 3l can be synthesized from ketone 3k
by the Beckmann rearrangement. Reduction of 3l can afford
intermediates such as 3c (Vernier, J. et al., WO 2008024398
(2008)). In Method E, the dihydroisoquinoline carbaldehyde (3m) was
converted to 3c under basic conditions (Martin, S. et al., WO
2006134143 (2006)). In Method F, dihydroisoquinolinethione was
converted to 3c treating the thione 3o with bromopropene followed
by treatment with perchloric acid and sodium borohydride (Mohinder,
B, et al., Indian Journal of Chemistry, Section B: Organic
Chemistry Including Medicinal Chemistry, 18B (4); 312-15
(1979)).
##STR00037## ##STR00038## ##STR00039##
[0320] Preparation of substituted THQ analogs is shown in Scheme 4.
Bromide 4a can be converted to nitrile 4b under lithiation
conditions. Hydrolysis under basic conditions should lead to acid
4c, which can be converted to carbamate 4e via Curtius
rearrangement. Formation of the THQ intermediate 4f can then be
accomplished by treatment with paraformaldehyde in a mixture of
acetic and sulfuric acid (Bigge, C. F. et al, Bioorganic &
Medicinal Chemistry Letters, 3(1): 39-42 (1993)). Deprotection of
carbamate 4f followed by protection with Boc.sub.2O should afford
intermediate 4h, which can be subjected to the Suzuki cross
coupling reaction with an appropriate boronate or boronic acid or
the Stille coupling procedures known to those in the art.
##STR00040##
[0321] Purification of intermediates and final products was carried
out via either normal or reverse phase chromatography. Normal phase
chromatography was carried out using prepacked SiO.sub.2 cartridges
eluting with either gradients of hexanes and EtOAc or DCM and MeOH
unless otherwise indicated. Reverse phase preparative HPLC was
carried out using C18 columns eluting with gradients of Solvent A
(90% water, 10% MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH,
0.1% TFA, UV 220 nm) or with gradients of Solvent A (90% water, 10%
ACN, 0.1% TFA) and Solvent B (10% water, 90% ACN, 0.1% TFA, UV 220
nm) or with gradients of Solvent A (98% water, 2% ACN, 0.05% TFA)
and Solvent B (98% ACN, 2% water, 0.05% TFA, UV 220 nm).
[0322] Unless otherwise stated, analysis of final products was
carried out by reverse phase analytical HPLC.
[0323] Method A: A majority of analytical HPLC runs were: SunFire
(4.6.times.150 mm) (15 min gradient--95:5 H.sub.2O/ACN-to 95:5
ACN/H.sub.2O-0.05% TFA).
[0324] Method B: A minority of analytical HPLC runs were: Zorbax
(4.6.times.75 mm) (8 min gradient--10:90 MeOH/H.sub.2O to 90:10
MeOH/H.sub.2O, 0.2% H.sub.3PO.sub.4)
[0325] A majority of mass spectra runs were run using Phenomenex
Luna C18 (2.times.30 mm) (2 min gradient 90% H.sub.2O/10% MeOH/0.1%
TFA to 90% MeOH/10% H.sub.2O/0.1% TFA)
Intermediate 1: (E)-2,5-Dioxopyrrolidin-1-yl
3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylate
##STR00041##
[0327] The synthesis was described as Intermediate 1 in PCT
International Application, WO 2009/114677 published Sep. 17,
2009.
Intermediate 2: (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic
acid
##STR00042##
[0329] The synthesis was described as Intermediate 1B in PCT
International Application, WO 2009/114677 published Sep. 17,
2009.
Intermediate 3:
(E)-3-(3-Chloro-2-fluoro-6-tetrazol-1-yl-phenyl)-acrylic acid
2,5-dioxo-pyrrolidin-1-yl ester
##STR00043##
[0331] Intermediate 3A:
(E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid:
The synthesis of Intermediate 3A was described as Intermediate 7 in
PCT International Application, WO 2009/114677 published Sep. 17,
2009.
[0332] Intermediate 3: To a slightly turbid mixture of Intermediate
3A (1.0 g, 3.72 mmol) in THF (18.70 mL) and DMF (1.870 mL) was
added 1-hydroxypyrrolidine-2,5-dione (0.471 g, 4.09 mmol) and DIC
(0.638 mL, 4.09 mmol). The reaction was stirred at rt and a white
precipitate formed overtime. The solid was collected by suction
filtration and washed with MeOH and H.sub.2O. The crude product was
then air-dried and finally dried under vacuum to give Intermediate
3 (0.98 g, 72%), as a white solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.92 (s, 1H), 8.06 (t, J=8.12 Hz, 1H), 7.72
(d, J=8.80 Hz, 1H), 7.36 (d, J=16.23 Hz, 1H), 6.81 (d, J=16.51 Hz,
1H), 2.84 (s, 4H) ppm. MS (ESI) m/z: 366.2 (M+H).sup.+.
Intermediate 4: (E)-3-(2-acetyl-5-chlorophenyl)acrylic acid
##STR00044##
[0334] Intermediate 4A: (E)-tert-butyl
3-(2-acetyl-5-chlorophenyl)acrylate: To a degassed solution of
1-(2-bromo-4-chlorophenyl)ethanone (1.0 g, 4.28 mmol),
tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate (1.255
mL, 8.57 mmol) in DMF (10 mL) was added palladium on carbon (0.456
g, 0.428 mmol) and palladium (II) acetate (0.096 g, 0.428 mmol).
The reaction mixture was warmed to 100.degree. C. After 16 h, the
reaction was cooled to rt and filtered. The solid was rinsed with
DMF and the filtrate was diluted with EtOAc and washed with
H.sub.2O (2.times.) followed by brine. The crude product was then
dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification by normal phase chromatography afforded Intermediate
4A (0.760 g, 63%), as a brown oil. MS (ESI) m/z: 225.0
(M-C4H8+H).sup.+.
[0335] Intermediate 4: A solution of Intermediate 4A (0.048 g,
0.171 mmol) in 50% TFA/DCM (2 mL) was stirred at rt. After 1 h, the
reaction was concentrated to give Intermediate 4 (0.038 g, 100%) as
a yellow solid. The material was carried onto the next step without
further purification. MS (ESI) m/z: 225.1 (M+H).sup.+.
Intermediate 5:
(E)-3-(5-chloro-4-fluoro-2-(1H-tetrazol-1-yl)phenyl)acrylic
acid
##STR00045##
[0337] Intermediate 5A: 4-chloro-5-fluoro-2-iodoaniline: To
4-chloro-3-fluoroaniline (25 g, 0.17 mmol) in 250 mL of H.sub.2O
was added NaHCO.sub.3 (21.6 g, 0.25 mmol). After cooling to
0.degree. C., iodine (43.5 g, 0.17 mmol) was added. After 18 h at
rt, an additional 10.8 g of iodine was added and the reaction was
stirred overnight. The reaction was extracted with DCM (4.times.250
mL), the combined organics were washed with sodium thiosulfate
solution (2.times.250 mL) and brine (2.times.250 mL) and dried
(Na.sub.2SO.sub.4). Purification by silica gel chromatography gave
47 g of Intermediate 5A. MS (ESI) m/z: 145.2 (M+H).sup.+.
[0338] Intermediate 5B:
1-(4-chloro-5-fluoro-2-iodophenyl)-1H-tetrazole: To Intermediate 5A
(47 g, 17.3 mmol) in AcOH (470 mL) was added NaN.sub.3 (33.76 g,
51.9 mmol) and trimethyl orthoformate (56.8 mL, 51.9 mmol). After
30 h, the reaction was poured into ice H.sub.2O, the solids were
filtered-off and washed with petroleum ether to afford 49 g
Intermediate 5B. MS (ESI) m/z: 324.8 (M+H).sup.+.
[0339] Intermediate 5C: (E)-methyl
3-(5-chloro-4-fluoro-2-(1H-tetrazol-1-yl)phenyl)acrylate: A
solution of Intermediate 5B (100 g, 324.4 mmol) in ACN (1000 mL)
was degassed with N2. TEA (64 mL) and methyl acrylate (60 mL) were
added and the reaction was further degassed. Pd(OAc).sub.2 (8 g,
11.8 mmol) was added and the reaction was heated to 85.degree. C.
for 18 h. The reaction was concentrated and the residue was diluted
with H.sub.2O. The aqueous layer was extracted with EtOAc and the
combined organics were washed with brine. Purification by silica
gel chromatography gave 25 g Intermediate 5C. MS (ESI) m/z: 283.0
(M+H).sup.+.
[0340] Intermediate 5:
(E)-3-(5-chloro-4-fluoro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid:
To Intermediate 5C (5 g, 17.7 mmol) in MeOH (50 mL) and THF (25 mL)
was added 10% NaOH solution (25 mL). After 2 h, the reaction was
concentrated and the residue was diluted with H.sub.2O. The pH was
adjusted to 2 to 3 with 1.5N HCl and the resultant solid was
filtered and washed with petroleum ether to afford 2 g of
Intermediate 5. MS (ESI) m/z: 269.0 (M+H).sup.+.
Intermediate 6: tert-Butyl 4-isocyanobenzoate
##STR00046##
[0342] Intermediate 6A: tert-Butyl 4-formamidobenzoate: Combined
tert-butyl 4-aminobenzoate (15.3 g, 79 mmol), DMAP (1.935 g, 15.84
mmol), N-methylmorpholine (15.67 mL, 143 mmol) in DCM (120 mL) and,
after cooling to 0.degree. C., slowly added formic acid (9.11 mL,
238 mmol). After stirring for 18 h, the reaction was concentrated
and then partitioned with 1N HCl (100 mL) and EtOAc (200 mL). The
aqueous layer was extracted with EtOAc (100 mL). The combined
organic layer was washed with brine (50 mL) and dried (MgSO.sub.4).
The desired product was collected as yellow syrup (16 g).
[0343] Intermediate 6: To Intermediate 6A in THF (300 mL) was added
TEA (33 mL, 238 mmol) and the after cooling to 0.degree. C.,
POCl.sub.3 (7.3 mL, 79 mmol) was slowly added and the reaction was
stirred at room temperature. After 24 h, the reaction was
partitioned between EtOAc (200 mL) and aqueous NaHCO.sub.3 (100
mL). The aqueous layer was extracted with EtOAc (100 mL). The
combined organic layer was washed with brine (50 mL) and dried
(MgSO.sub.4). Purification by normal phase chromatography afforded
10.4 g (64.6%) of intermediate 6 as a green solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta..quadrature. 8.02 (d, J=8.59 Hz, 2H), 7.41
(d, J=8.34 Hz, 2H), 1.60 (s, 9H) ppm.
Intermediate 7: 4-Isocyanobenzonitrile
##STR00047##
[0345] Intermediate 7 was prepared in a similar manner as
Intermediate 6 from 4-isocyanoaniline. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.68-7.84 (m, 2H) 7.51 (d, J=8.34 Hz, 2H)
ppm.
Intermediate 8: tert-Butyl 6-isocyano-1H-indazole-1-carboxylate
##STR00048##
[0347] Intermediate 8 was prepared in a similar manner as
Intermediate 6 from tert-butyl 6-amino-1H-indazole-1-carboxylate.
.sup.1H NMR (400 MHz, CDCl.sub.3) 8.28 (1H, s), 8.20 (1H, s), 7.76
(1H, d, J=8.34 Hz), 7.28-7.40 (1H, m), 1.74 (9H, s) ppm. MS (ESI)
m/z: 144 (M+H-Boc).sup.+.
Intermediate 9: Ethyl 4-isocyanobenzoate
##STR00049##
[0349] Intermediate 9 was prepared in a similar manner as
Intermediate 6. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40 (t,
J=7.20 Hz, 3H) 4.40 (q, J=7.24 Hz, 2H) 7.44 (d, J=8.59 Hz, 2H)
8.00-8.17 (m, 2H) ppm. MS (ESI) m/z: 176 (M+H).sup.+.
Intermediate 10: Methyl 4-isocyanophenylcarbamate
##STR00050##
[0351] Intermediate 10A: 1-Boc-methyl 4-aminophenylcarbamate: To
tert-butyl 4-aminophenylcarbamate (2.1 g, 10.08 mmol) in a
separatory funnel with DCM (75 mL) and saturated aqueous
NaHCO.sub.3 (25 mL) was added methyl chloroformate (0.937 mL, 12.10
mmol). After shaking for 10 min a thick pink gel formed. The solid
was filtered off and dried. The aqueous layer was extracted with
DCM (50 mL) and dried (MgSO.sub.4). All solids collected were
combined to afford 2.6 g of Intermediate 10A. .sup.1H NMR (400 MHz,
MeOD) .delta. 7.32 (4H, s), 3.73 (3H, s), 1.53 (9H, s) ppm.
[0352] Intermediate 10B: methyl 4-aminophenylcarbamate:
Intermediate 10A (2.6 g, 9.77 mmol) was deprotected with 30% TFA in
DCM (40 mL). After 2 h, the reaction was concentrated and the
residue was partitioned with EtOAc (75 mL) and saturated
NaHCO.sub.3 (50 mL). The organic layer was washed with brine (20
mL) and dried (MgSO.sub.4). Crude Intermediate 10B was carried onto
the next step. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.86
(1H, s), 7.56 (2H, d, J=8.84 Hz), 7.28 (2H, d, J=8.84 Hz), 6.90
(2H, s), 3.68 (3H, s) ppm.
[0353] Intermediate 10C: methyl 4-formamidophenylcarbamate: Crude
Intermediate 10B was heated to reflux in ethyl formate for several
days. The solvent was removed and the residue was purified by
silica gel chromatography to afford 2.9 g of Intermediate 10C as
brown oil. MS (ESI) m/z: 195.0 (M+H).sup.+.
[0354] Intermediate 10 was made in a similar manner as Intermediate
6 to afford 0.31 g (17.8%) of a tan solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.45 (2H, d, J=8.8 Hz), 7.33-7.41 (2H, m), 6.73
(1H, br. s.), 3.82 (3H, s) ppm.
Intermediate 11: benzyl 6-isocyano-1H-indazole-1-carboxylate
##STR00051##
[0356] Intermediate 11 was made in a similar manner as Intermediate
6 and Intermediate 8 starting from benzyl
6-amino-1H-indazole-1-carboxylate: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.31 (1H, s), 8.21 (1H, s), 7.76 (1H, d, J=8.34
Hz), 7.54 (2H, d, J=6.82 Hz), 7.30-7.47 (4H, m), 5.56 (2H, s) ppm.
MS (ESI) m/z: 234 (M+H-CO2).sup.+.
Intermediate 12: (E)-3-(6-acetyl-3-chloro-2-fluorophenyl)acrylic
acid
##STR00052##
[0358] Intermediate 12A: 2-bromo-4-chloro-3-fluorobenzoic acid: To
a cooled (-78.degree. C.) solution of DIEA (4.9 mL, 48 mmol) in THF
was added dropwise n-BuLi (132 mL, 2.3 eq, 2.5 M). The mixture was
stirred at -30.degree. C. for 30 min. Again the reaction mixture
was cooled to -78.degree. C., and a solution of
4-chloro-3-fluorobenzoic acid (25 g, 143 mmol) in THF was added
over 1 h. The reaction was stirred at -78.degree. C. overnight. The
next day a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g,
267 mmol) in THF was added and the reaction was stirred at
-78.degree. C. for further 2 h and then rt for 4 h. The reaction
mixture was quenched with H.sub.2O, organic layer was separated and
aqueous layer washed with Et.sub.2O. Aqueous layer acidified with
1.5 N HCl and extracted in EtOAc (2.times.200 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated to afford
Intermediate 12A (30 g, 83.3%). MS (ESI) m/z: 252.6
(M-H).sup.+.
[0359] Intermediate 12B: Diethyl
2-((2-bromo-4-chloro-3-fluorophenyl) (hydroxy)methylene)malonate:
To a suspension of Intermediate 12A (14.6 g, 57 mmol) in DCM (200
mL) was added thionyl chloride (6.6 mL, 88 mmol). The mixture was
stirred at reflux for 3 h. Solvent was removed and the residue was
dried in vacuum to give the acid chloride as a light brown solid.
To a cooled (0.degree. C.) suspension of sodium hydride (3.66 g
(60%), 91.5 mmol) in THF was added a solution of diethyl malonate
(0.612 g, 3.82 mmol) in THF (5 mL). After 10 min, a solution of the
acid chloride (16.4 g, 60 mmol) in THF (160 mL) was added slowly.
Following the addition, the reaction was warmed to rt. After 30
min, the solvent was removed and the residue was treated with cold
(0.degree. C.) 1.2 M HCl (150 mL). The mixture was extracted with
EtOAc (3.times.250 mL). The combined organic layers were washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
to give Intermediate 12B (20 g, 87%) as a solid. MS (ESI) m/z: 395
(M+H).sup.+.
[0360] Intermediate 12C:
1-(2-Bromo-4-chloro-3-fluorophenyl)ethanone: A solution of
Intermediate 12B (18.6 g, 47 mmol) in AcOH (200 mL), H.sub.2O (150
mL) and H2504 (2.0 mL) was stirred at 110.degree. C. for 4 h. Most
of the solvent was removed and the residue was diluted with EtOAc
(400 mL), washed with H.sub.2O (5.times.20 mL), saturated
NaHCO.sub.3, 1N NaOH, and brine. The solvent was removed to give
Intermediate 12C (10 g, 84% yield) as a low melting solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.42 (q, J=6.8, 6.4 Hz, 1H),
7.24 (q, J=6.4, 5.2 Hz, 1H), 2.5 (s, 3H) ppm.
[0361] Intermediate 12D: (E)-tert-Butyl
3-(6-acetyl-3-chloro-2-fluorophenyl)acrylate: To a mixture of
Intermediate 12C (50 g, 198 mmol), tert-butyl acrylate (50.9 g, 397
mmol) and TEA (55 mL, 397 mmol) in DMF (500 mL) was added
Pd(OAc).sub.2 (8.9 g, 39.7 mmol). The resulting mixture was stirred
at 90.degree. C. overnight. The reaction was cooled to rt,
filtered, and the filtrate was concentrated. Purification by column
chromatography gave Intermediate 12D (30 g, 51%) as a light yellow
solid. MS (ESI) m/z: 242.7 (M+H).sup.+.
[0362] Intermediate 12: A solution of Intermediate 12D (25 g, 84
mmol) in DCM (330 mL) and TFA (330 mL) was stirred at rt. After 1.5
h, the solvent was concentrated to give Intermediate 12 (19.5 g,
97%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.69 (bs, 1H), 7.80-7.76 (m, 2H), 7.62 (d, J=12.1 Hz, 1H), 6.30
(dd, J=2.4, 2.0 Hz, 1H), 2.6 (s, 3H) ppm. MS (ESI) m/z: 241
(M-H).sup.+.
Intermediate 13: (E)-3-(3-Chloro-6-cyano-2-fluorophenyl)acrylic
acid
##STR00053##
[0364] Intermediate 13: 2-Bromo-4-chloro-3-fluorobenzamide: To a
solution of 2-bromo-4-chloro-3-fluorobenzoic acid (20 g, 0.078 mol)
in DCM (200 mL) was added thionyl chloride (14.7 g, 0.125 mol)
followed by DMF (29.5 g, 0.5 moles) and the reaction was heated to
reflux for 4 h. The reaction was then cooled to 0.degree. C. and
NH.sub.3 gas was bubbled in until the pH was basic. After 30 min,
the reaction mixture was quenched with H.sub.2O and extracted with
DCM. The combined organics were washed with H.sub.2O, brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to yield the crude
product. The crude product was finally suspended in petroleum ether
and filtered to afford 16.5 g of Intermediate 13A. MS (ESI) m/z:
250.0 (M+H).sup.+.
[0365] Intermediate 13B: 2-Bromo-4-chloro-3-fluorobenzonitrile: To
Intermediate 13A (10 g, 39 mmol) was added POCl.sub.3 (100 mL) and
NaOH (5 g, 87 mmol) and the reaction was heated to 110.degree. C.
for 2 h. The reaction mixture was concentrated and the residue was
quenched with ice water. Extracted with EtOAc and the combined
organics were washed with 10% NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford 8.5 g of
13B. MS (ESI) m/z: 232.9 (M+H).sup.+.
[0366] Intermediate 13C: (E)-Methyl
3-(3-chloro-6-cyano-2-fluorophenyl)acrylate: Combined Intermediate
13B (7 g, 29.9 mmol), tetrabutylammonium bromide (9.6 g, 29.9
mmol), NaHCO.sub.3 (6.2 g, 74.8 mmol), methyl acrylate (5.2 g, 59.8
mmol) and Pd(OAc).sub.2 in DMF (50 mL). After stirring at rt for 18
h, the reaction was heated to 90.degree. C. for 4 h. The reaction
was then cooled to rt and filtered through Celite.RTM..
Purification by normal phase chromatography afforded 3.5 g of
Intermediate 13C. MS (ESI) m/z: 257 (M+H.sub.2O).sup.+.
[0367] Intermediate 13: To Intermediate 13C (0.5 g, 2.0 mmol) in
THF (15 mL) and MeOH (5 mL) was added 1N LiOH (5 mL, 5 mmol). After
2 h, the volatile solvents were removed and the aqueous layer was
extracted with EtOAc. The aqueous layer was acidified and extracted
with EtOAc and the combined organics were washed with H.sub.2O,
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to
afford 0.3 g of Intermediate 13. MS (ESI) m/z: 226.2
(M+2+H).sup.+.
Intermediate 14: (E)-3-(5-Chloro-2-(difluoromethyl)phenyl)acrylic
acid
##STR00054##
[0369] Intermediate 14A:
2-Bromo-4-chloro-1-(difluoromethyl)benzene: To a solution of
2-bromo-4-chlorobenzaldehyde (1 g, 4.56 mmol) in DCM (15 mL) was
added DAST (0.903 mL, 6.83 mmol) at 0.degree. C. The reaction was
allowed to warm to rt and stirred overnight. The reaction mixture
was diluted with EtOAc, washed with saturated NaHCO.sub.3 and
brine. The organic phase was dried over MgSO.sub.4, filtered and
concentrated to give Intermediate 14A (0.88 g. 80%) as a clear oil.
MS (ESI) m/z: 261.2 (M+Na).sup.+.
[0370] Intermediate 14B: (E)-tert-Butyl
3-(5-chloro-2-(difluoromethyl)phenyl) acrylate: To a solution of
Intermediate 14A (0.88 g, 3.64 mmol) in DMF (10 mL) was added
tert-butyl acrylate (1.401 g, 10.93 mmol), TEA (1.270 mL, 9.11
mmol) and Pd(OAc).sub.2 (0.082 g, 0.364 mmol). The reaction was
warmed to 90.degree. C. After 5 h, the reaction was cooled to rt
and then filtered to remove the solid. The filtrate was diluted
with EtOAc, washed with 1M HCl, saturated NaHCO.sub.3, and brine.
The organic phase was dried over MgSO.sub.4, filtered and
concentrated. Purification by normal phase chromatography gave
Intermediate 14B (232 mg, 22%) as a tan oil. MS (ESI) m/z: 233.1
(M-tBu).sup.+.
[0371] Intermediate 14: To a solution of Intermediate 14B (232 mg,
0.804 mmol) in DCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol). The
reaction was stirred under argon at rt. After 1 h, the solvent was
removed and residue was dried to give Intermediate 14 (191 mg,
100%) as tan solid. .sup.1H NMR (400 MHz, MeOD) .delta. 7.99 (dt,
J=15.8, 1.5 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J=8.3 Hz, 1H),
7.55-7.48 (m, 1H), 7.01 (t, J=54.6 Hz, 1H), 6.51 (d, J=15.8 Hz,
1H). 19F NMR (376 MHz, MeOD) .quadrature..delta. -111.67 (s, 2F)
ppm. MS (ESI) m/z: 233.1 (M+H).sup.+.
Intermediate 15: (E)-3-(5-Chloro-2-(difluoromethoxy)phenyl)acrylic
acid
##STR00055##
[0373] Intermediate 15A (E)-tert-Butyl
3-(5-chloro-2-(difluoromethoxy)phenyl) acrylate: To a solution of
potassium tert-butoxide (0.407 g, 3.63 mmol) in THF (10 mL) were
added tert-butyl 2-(dimethoxyphosphoryl)acetate (0.528 mL, 2.66
mmol) and 5-chloro-2-(difluoromethoxy)benzaldehyde (0.50 g, 2.420
mmol) at 0.degree. C. After 4 h, NH.sub.4Cl solution was added and
the reaction mixture was diluted with EtOAc, washed with saturated
NH.sub.4Cl solution, saturated NaHCO.sub.3, and brine. The organic
phase was dried over Na.sub.2SO.sub.4, filtered and concentrated.
The crude product was purified by normal phase chromatography to
yield Intermediate 15A as a white solid (550 mg, 74%). MS (ESI)
m/z: 327.0 (M+Na).sup.+. .sup.19F NMR (376 MHz, CDCl.sub.3) .delta.
-81.11 (1F, s) ppm.
[0374] Intermediate 15: To a solution of (E)-tert-butyl
3-(5-chloro-2-(difluoromethoxy) phenyl)acrylate (458 mg, 1.503
mmol) in DCM (4 mL) was added TFA (2.0 mL, 26.0 mmol). After 1 h,
the solvent was removed to give Intermediate 15 as a white solid.
MS (ESI) m/z: 249.0 (M+H).sup.+.
Intermediate 16:
(E)-3-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)acrylic acid
##STR00056##
[0376] Intermediate 16 was made in a similar manner as Intermediate
15 substituting 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde
for 5-chloro-2-(difluoromethoxy) benzaldehyde followed by TFA
deprotection. MS (ESI) m/z: 292 (M+Na).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.87 (1H, dd, J=16.17, 2.02 Hz), 7.49-7.62 (2H,
m), 6.67 (1H, dd, J=16.30, 1.39 Hz) ppm.
Intermediate 17:
1-cyclopentyl-3-(3,4-dihydroisoquinolin-5-yl)urea
##STR00057##
[0378] Intermediate 17A: 1-Cyclopentyl-3-(isoquinolin-5-yl)urea: To
isoquinolin-5-amine (0.23 g, 1.595 mmol) in DCM (5 mL) was added
DIEA (0.557 mL, 3.19 mmol) and isocyanatocyclopentane (0.180 mL,
1.595 mmol). After 24 h, the reaction was quenched with H.sub.2O
(15 mL) and extracted with EtOAc (3.times.30 mL). The combined
organic layers were washed with brine (10 mL) and dried
(MgSO.sub.4). The impure yellow solid was collected and was carried
onto the next step. MS (ESI) m/z: 256 (M+H).sup.+.
[0379] Intermediate 17B:
1-Cyclopentyl-3-(1,2,3,4-tetrahydroisoquinolin-5-yl)urea: 17A was
hydrogenated at 55 psi in EtOH (25 mL) in the presence of PtO.sub.2
(30 mg). After 24 h, the reaction was filtered through Celite.RTM.
and filtrate concentrated to give 0.389 g of Intermediate 17B as a
white oily solid. MS (ESI) m/z: 260.1 (M+H).sup.+.
[0380] Intermediate 17: Intermediate 17B was oxidized with
MnO.sub.2 (2.496 g, 28.7 mmol) in DCM (20 mL). After 24 h, the
reaction was filtered through Celite.RTM. and concentrated to 0.34
g (83%) of brown solid. MS (ESI) m/z: 258.1 (M+H).sup.+.
Intermediate 18: tert-butyl
4-(3,4-dihydroisoquinolin-5-yl)piperazine-1-carboxylate
##STR00058##
[0382] Intermediate 18A: tert-butyl
4-(1,2,3,4-tetrahydroisoquinolin-5-yl)piperazine-1-carboxylate: To
5-(piperazin-1-yl)isoquinoline, HCl (0.58 g, 2.322 mmol) and NaOH
(5.11 mL, 5.11 mmol) in dioxane (6 mL), cooled in ice bath, was
added Boc.sub.2O (0.539 mL, 2.322 mmol) in dioxane (6 mL). The
organics were stripped and the reaction was partitioned with
H.sub.2O (30 mL) and EtOAc (100 mL). The organic layer was washed
with brine (15 mL) and dried (MgSO.sub.4). Collected Boc-protected
compound as a yellow oil (0.86 g) which was then hydrogenated at 55
psi with PtO.sub.2 in EtOH. The crude product was then filtered
through Celite.RTM. and collected 0.73 g (99%) of the desired
product as a off-white solid. MS (ESI) m/z: 318.1 (M+H).sup.+.
[0383] Intermediate 18: Intermediate 18A was reduced and then
oxidized in a similar manner as described for Intermediate 17. MS
(ESI) m/z: 316.1 (M+H).sup.+.
Intermediate 19:
5-(4-Methylpiperazin-1-yl)-3,4-dihydroisoquinoline
##STR00059##
[0385] Intermediate 19A: 5-(4-Methylpiperazin-1-yl)isoquinoline: To
5-(piperazin-1-yl) isoquinoline, HCl (0.28 g, 1.121 mmol) in MeOH
(10 mL) was added sodium methoxide (1.026 mL, 4.48 mmol) and
paraformaldehyde (0.040 g, 1.332 mmol). After 30 min, sodium
borohydride (0.424 g, 11.21 mmol) was added to the above mixture.
The reaction was quenched with 1N NaOH (15 mL) and extracted with
EtOAc (3.times.30 mL). The combined organic layers were washed with
brine (15 mL) and dried (MgSO.sub.4) to afford 0.267 g of
Intermediate 19A as yellow oil. MS (ESI) m/z: 228.1
(M+H).sup.+.
[0386] Intermediate 19: Intermediate 19A was reduced and then
oxidized in a similar manner as described for Intermediate 17. MS
(ESI) m/z: 230.0 (M+H).sup.+.
Intermediate 20: Ethyl
3-(4-(3,4-dihydroisoquinolin-5-yl)piperazine-1-carboxamido)
propanoate
##STR00060##
[0388] 20A: Ethyl
3-(4-(isoquinolin-5-yl)piperazine-1-carboxamido)propanoate: To
5-(piperazin-1-yl)isoquinoline, HCl (0.216 g, 0.865 mmol) in DCM (5
mL) was added DIEA (0.302 mL, 1.730 mmol) and ethyl
3-isocyanatopropanoate (0.124 g, 0.865 mmol). The reaction was
quenched with H.sub.2O (10 mL) and extracted with DCM (3.times.20
mL). The combined organic layers were washed with brine (10 mL) and
dried (MgSO.sub.4) which afforded Intermediate 20A as a white solid
(0.39 g). MS (ESI) m/z: 357.0 (M+H).sup.+.
[0389] Intermediate 20: Intermediate 20A was reduced and then
oxidized in a similar manner as described for Intermediate 18. MS
(ESI) m/z: 359.0 (M+H).sup.+.
Intermediate 21: tert-butyl
4-(3,4-dihydroisoquinolin-5-yl)-3-oxopiperazine-1-carboxylate
##STR00061##
[0391] Intermediate 21A: tert-Butyl
4-(isoquinolin-5-yl)-3-oxopiperazine-1-carboxylate: To
5-bromoisoquinoline (0.3 g, 1.442 mmol) and tert-butyl
3-oxopiperazine-1-carboxylate (0.289 g, 1.442 mmol) was added DMSO
(4 mL), 1,10-phenanthroline (0.026 g, 0.144 mmol) and
K.sub.2CO.sub.3 (0.498 g, 3.60 mmol). The mixture was degassed for
10 min and then was added CuI (0.055 g, 0.288 mmol). The reaction
was heated in a sealed tube in oil bath at 130.degree. C. After 24
h, the reaction was incomplete. After cooling and degassing with
argon, more CuI was added and heating was repeated. After 24 h, the
reaction was quenched with dilute NH.sub.4OH (15 mL) and extracted
with EtOAc (3.times.30 mL). The combined organic layers were washed
with brine (15 mL) and dried (MgSO.sub.4). The crude product was
purified by normal phase chromatography followed by HPLC. After
partitioning with saturated NaHCO.sub.3 (15 mL) and EtOAc (50 mL),
organic layer was washed with brine and dried (MgSO.sub.4) to
afford 0.157 g (54%) of Intermediate 21A as a white solid. MS (ESI)
m/z: 328 (M+H).sup.+.
[0392] Intermediate 21 was prepared from Intermediate 21A as
described for Intermediate 18. MS (ESI) m/z: 330.1 (M+H).sup.+.
Intermediate 22:
1-(3,4-dihydroisoquinolin-5-yl)-4-methylpiperazin-2-one
##STR00062##
[0394] Intermediate 22 was prepared in a similar manner as
Intermediate 21 substituting 4-methylpiperazin-2-one for tert-butyl
3-oxopiperazine-1-carboxylate. MS (ESI) m/z: 244.1 (M+H).sup.+.
Intermediate 23: 4-(3,4-dihydroisoquinolin-5-yl)morpholin-3-one
##STR00063##
[0396] Intermediate 23 was prepared in the same manner as
Intermediate 22 substituting morpholin-3-one for tert-butyl
3-oxopiperazine-1-carboxylate. MS (ESI) m/z: 231.1 (M+H).sup.+.
Intermediate 24:
5-Bromo-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline
##STR00064##
[0398] Intermediate 24A:
3-(2-Bromophenyl)-2,2-dimethylpropanenitrile: To a solution of
isobutyronitrile (3.58 g, 52 mmol) in dry THF (30 mL) was added
LiHMDS (1.0 M in THF) (80 mL, 80 mmol) at 0.degree. C., stirred for
20 min, and to this solution was added
1-bromo-2-(bromomethyl)benzene (10 g, 40 mmol) in dry THF (70 mL).
After 3 h at rt, the reaction mixture was quenched with saturated
NH.sub.4Cl solution, extracted with EtOAc (2.times.), the combined
organics were washed with H.sub.2O, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give 9.5 g (99%) of
Intermediate 24A as red wine liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.57-7.60 (2H, m), 7.30-7.34 (1H, m), 7.12-7.17
(1H, m), 3.08 (2H, s), 1.4 (6H, s) ppm.
[0399] Intermediate 24B: 3-(2-Bromophenyl)-2,2-dimethylpropanoic
acid: To a solution of 24A (19 g, 79.83 mmol) in ethylene glycol
(100 mL) was added potassium hydroxide pellets (20 g, 359.24 mmol)
and the reaction was heated at 150.degree. C. for 48 h. The
reaction mixture was cooled, diluted with H.sub.2O and the aqueous
layer was washed with EtOAc (2.times.). The aqueous layer was
acidified with 1.5 N HCl, extracted with EtOAc (2.times.) and the
combined organics were washed with H.sub.2O, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
then purified by silica gel column chromatography to give 18.0 g,
(87.8%) of Intermediate 24B as a white solid. MS (ESI) m/z: 257
(M+H).sup.+.
[0400] Intermediate 24C:
1-Bromo-2-(2-isocyanato-2-methylpropyl)benzene: To a solution of
Intermediate 24B (9.0 g, 35.0 mmol) in toluene (80 mL) at 0.degree.
C., was added TEA (4.7 mL, 33.2 mmol) and, slowly,
diphenylphosphoryl azide (9.17 g, 33.2 mmol). After 45 min at
0.degree. C., the reaction was heated to reflux for 4 h. The
reaction mixture was cooled to rt, quenched with H.sub.2O, and
extracted with EtOAc (2.times.). The combined organics were washed
with saturated NaHCO.sub.3 solution, H.sub.2O, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give 8.0 g of
Intermediate 24C as colorless liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.37-7.59 (2H, m), 7.30 (1H, m), 7.14 (1H, m),
3.03 (2H, s), 1.41 (6H, s) ppm.
[0401] Intermediate 24D: Methyl
1-(2-bromophenyl)-2-methylpropan-2-ylcarbamate: To a stirred
solution of Intermediate 24C (8.0 g, 31.5 mmol) in dry THF (80 mL)
at 0.degree. C., was added MeOH (5.0 mL, 157.5 mmol) and, slowly,
NaH (60% in oil) (3.8 g, 94.5 mmol). After 3 h at rt, the reaction
was quenched with ice cold water and extracted with EtOAc twice.
The combined organics were washed with H.sub.2O, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give Intermediate
24D (8.5 g, 94.5%) as white solid. MS (ESI) m/z: 286.0
(M+H).sup.+.
[0402] Intermediate 24E: Methyl
5-bromo-3,3-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate: To
a solution of 24D (5.0 g, 17.5 mmol) in AcOH/H.sub.2SO.sub.4 (3:1;
15+5 mL) at 0.degree. C. was, slowly, added paraformaldehyde (0.524
g, 17.5 mmol). After 48 h at rt, the reaction mixture was quenched
with H.sub.2O, extracted with EtOAc (2.times.). The combined
organics were washed with saturated NaHCO.sub.3 solution, H.sub.2O,
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to
give 4.6 g of Intermediate 24E as a brown liquid. MS (ESI) m/z:
300.0 (M+H).sup.+.
[0403] Intermediate 24:
5-Bromo-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline: To a solution
of Intermediate 24E (4.6 g) in ethylene glycol (50 mL) was added
50% aqueous KOH solution (23 mL) and the reaction was heated at
150.degree. C. for 3 days. The reaction mixture was cooled, diluted
with H.sub.2O, extracted with EtOAc twice. The combined organics
were extracted with 1.5 N HCl solution, the aqueous layer was
basified with 10% NaOH solution, extracted with EtOAc twice and the
combined organics were washed with H.sub.2O, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give Intermediate 24
(1.5 g, 39.4%) as a brown liquid. MS (ESI) m/z: 242.2
(M+H).sup.+.
Example 1
(E)-4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(piperazin-1--
yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid,
TFA
##STR00065##
[0405] A mixture of Intermediate 18 (0.1 g, 0.317 mmol),
Intermediate 6 (0.064 g, 0.317 mmol) and Intermediate 2 (0.079 g,
0.317 mmol) were heated in EtOH (3 mL) to reflux for 24 h. The
reaction mixture was then cooled to rt and concentrated, followed
by treatment with TFA/DCM to give the desired product as a yellow
solid (0.018 g, 7.5%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.64 (1H, br. s.), 10.68 (1H, s), 9.79 (1H, s), 8.60 (2H, br. s.),
8.32 (1H, d, J=2.02 Hz), 7.75-7.89 (2H, m), 7.63-7.71 (2H, m), 7.60
(1H, d, J=8.84 Hz), 7.43 (1H, d, J=15.41 Hz), 7.32 (1H, d, J=7.58
Hz), 7.20 (1H, t, J=7.83 Hz), 6.97 (1H, d, J=8.08 Hz), 6.91 (1H, d,
J=15.41 Hz), 5.72 (1H, s), 4.23 (1H, d, J=5.56 Hz), 3.60-3.70 (1H,
m), 3.21 (4H, br. s.), 2.85-3.11 (6H, m) ppm. MS (ESI) m/z: 613.1
(M+H).sup.+. Analytical HPLC: RT=5.54 min.
[0406] The following examples in Table 2 were made by the Ugi
reaction as described in Example 1, using Intermediate 1,
Intermediate 2 or Intermediate 3A; the corresponding imine
intermediates, made in a similar manner as Intermediate 18, from
commercially available piperazines and 5-bromoisoquinoline; and the
appropriate isocyano benzoate intermediates.
##STR00066##
TABLE-US-00004 TABLE 2 Exam- ple # R R' R'' M + H RT 2 H Piperazine
##STR00067## 587.0 5.54 3 F Piperazine ##STR00068## 631.0 5.62 4 F
Piperazine ##STR00069## 660.1 5.40 5 F Piperazine ##STR00070##
605.1 6.06 6 F Piperazine ##STR00071## 612.1 5.88 7 F Piperazine
##STR00072## 687.2 7.08 8 F Piperazine ##STR00073## 587.3 5.93 9 F
Piperazine 6-indazole-1-CBz 761.2 6.63 10 F Boc- 6-indazole-1-tBoc
827.1 12.14 piperazine 11 F Piperazine 6-indazole 627.2 5.51
[0407] The following examples in Table 3 were obtained from HPLC
chiral separation of corresponding examples, or their intermediates
followed by deprotection, in Table 2.
##STR00074##
TABLE-US-00005 TABLE 3 Ex- am- ple # Stereochem R R' M + H RT 12 R
enantiomer.sup.a 2-F ##STR00075## 631.1 5.16 13 S enantiomer.sup.a
2-F ##STR00076## 631.1 5.16 14 S enantiomer.sup.b 4-F 6-indazole
627.1 5.75 15 R enantiomer.sup.b 4-F 6-indazole 627.1 5.70 16 R
enantiomer.sup.c 4-F ##STR00077## 631.0 5.30 17 S enantiomer.sup.c
4-F ##STR00078## 630.9 5.27 a: Chiral HPLC Methods: .sup.aChiralcel
OJ-H, 250 .times. 21 mm ID, 5 .mu.m using 25/25/50
MeOH--IPA-Heptane-0.1% DEA, then 50/50 EtOH--IPA-0.1% DEA at 18
mL/min. .sup.bChiracel OD 5 cm .times. 50 cm column and 20%
Heptane/80% (1:1 EtOH/MeOH) at 50 mL/min. .sup.cChiralpak AS-H, 2
.times. 15 cm using 30% IPA-0.1% DEA/CO.sub.2 (100 bar) at 60
mL/min.
[0408] The following examples in Table 4 were made by the Ugi
reaction, as shown in Example 1, using the corresponding imine
intermediate such as Intermediates 18, 19 or 20 or an imine made in
a similar manner as Intermediate 20 by substituting methyl
chloroformate for ethyl 3-isocyanatopropanoate. The acids,
Intermediates 1, 2 or 3A and the isonitriles, Intermediates 6, 7,
8, 9, 10, 11 or commercially available 1-fluoro-4-isocyanobenzene
were used as required. Final deprotection of the t-butyl esters or
carbamates with TFA/DCM yielded the final desired products as
described previously.
##STR00079##
TABLE-US-00006 TABLE 4 Example # R R' R'' M + H RT 18 F -4-PhCOOH
CH.sub.3 645.1 5.24 19 H -4-PhNHCOO CH.sub.3 CH.sub.3 656.1 5.8 20
F -4-PhCN CH.sub.3 626.2 5.10* 21 H -4-PhCOOH ##STR00080## 756.1
7.87 22 H -4-PhCOOH CH.sub.3OOC-- 671.1 8.49 23 H -4-PhNHCOO
CH.sub.3 ##STR00081## 785.1 8.20 24 F -4-PhNHCOO CH.sub.3
CH.sub.3OOC-- 660.1 5.43 25 F -4-PhF CH.sub.3OOC-- 663.4 9.50 26 F
-4-PhCN CH.sub.3OOC-- 670.1 9.93 27 F 6-indazole CH.sub.3 641.2
6.21 *method B
[0409] The examples in Table 5 were made in a similar manner as
Example 18 (Table 4) and separated by chiral HPLC.
##STR00082##
TABLE-US-00007 TABLE 5 Example # R' Stereochemistry M + H RT 28
COOEt R-enatiomer.sup.a 673.3 6.47 29 COOEt S-enatiomer.sup.a 673.3
6.46 30 COOH R-enatiomer.sup.a 645.3 5.20 31 COOH S-enatiomer.sup.a
645.3 5.20 .sup.aChiralpak IA SFC (250 .times. 21 mm) using 40%
EtOH-0.1% DEA/60% CO.sub.2 at 60 mL/min, 150 bar, 35.degree. C.
Example 32
(E)-4-(2-(3-(2-(Aminomethyl)-5-chlorophenyl)acryloyl)-5-(piperazin-1-yl)-1-
,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid, tri TFA
salt
##STR00083##
[0411] Example 32 was prepared in a similar manner as Example 1,
using Intermediate
(E)-3-(2-((tert-butoxycarbonylamino)methyl)-5-chlorophenyl)acrylic
acid in the Ugi reaction. .sup.1H NMR (400 MHz, MeOD) .delta. 7.98
(3H, d, J=8.84 Hz), 7.87 (1H, d, J=15.41 Hz), 7.69 (2H, d, J=8.84
Hz), 7.48-7.58 (2H, m), 7.29-7.45 (3H, m), 7.16 (1H, d, J=7.83 Hz),
5.86 (1H, s), 4.38-4.47 (1H, m), 4.30 (2H, s), 3.66-3.77 (1H, m),
3.38-3.52 (4H, m), 3.23-3.29 (4H, m), 3.15 (2H, d, J=177 Hz) ppm.
MS (ESI) m/z: 574.1 (M+H).sup.+. Analytical HPLC: RT=3.55 min.
Example 33
(E)-4-(2-(3-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(2-oxopiperid-
in-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic
acid
##STR00084##
[0413] 33A: 1-(Isoquinolin-5-yl)piperidin-2-one: To
isoquinolin-5-amine (0.24 g, 1.665 mmol) in THF (5 mL) was added
5-bromopentanoyl chloride (0.223 mL, 1.665 mmol) followed by
addition of THF (3 mL). The reaction was cooled with ice bath and
to the above solution was added 1M KOtBu in THF (3.66 mL, 3.66
mmol). After 24 h, the reaction was quenched with H.sub.2O (10 mL)
and extracted with EtOAc (3.times.20 mL). The combined organic
layers were washed with brine (10 mL) and dried (MgSO.sub.4) to
afford 0.4 g of 33A as a dark solid. MS (ESI) m/z: 227
(M+H).sup.+.
[0414] 33B: 1-(1,2,3,4-Tetrahydroisoquinolin-5-yl)piperidin-2-one:
33A was hydrogenated at 55 psi in EtOH (20 mL) in the presence of
PtO.sub.2 (30 mg). After 24 h, the reaction was filtered through
Celite.RTM. and concentrated to afford 0.4 g of dark oil as desired
product. MS (ESI) m/z: 231.3 (M+H).sup.+.
[0415] 33C: 1-(3,4-Dihydroisoquinolin-5-yl)piperidin-2-one: 33B
(0.38 g, 1.650 mmol) was oxidized with MnO.sub.2 to afford 0.36 g
of 33C as a dark oil. MS (ESI) m/z: 229.0 (M+H).sup.+.
[0416] Example 33 was made by the Ugi reaction combining 33C and
Intermediates 2 and 6 as previously described for Example 1
followed by TFA deprotection. .sup.1H NMR (400 MHz, MeOD) .delta.
9.54 (1H, s), 8.17 (1H, t, J=2.78 Hz), 7.90-8.03 (2H, m), 7.61-7.73
(3H, m), 7.56-7.60 (1H, m), 7.52 (1H, d, J=7.83 Hz), 7.29-7.44 (2H,
m), 7.14-7.27 (2H, m), 5.87-5.94 (1H, m), 4.19-4.32 (1H, m),
3.82-3.98 (1H, m), 3.63-3.73 (1H, m), 3.45-3.54 (1H, m), 2.98-3.11
(1H, m), 2.76-2.89 (1H, m), 2.50-2.62 (2H, m), 2.02 (4H, br. s)
ppm. MS (ESI) m/z: 626.0 (M+H).sup.+. Analytical HPLC: RT=7.46
min.
[0417] The following examples in Table 6 were made by Ugi reaction
as described in Example 1 using intermediate 33C and intermediates
1, 2, 3, 5 and 12 as appropriate. Deprotection with TFA/DCM was
carried out where necessary. Single enantiomers were isolated by
chiral HPLC.
##STR00085##
TABLE-US-00008 TABLE 6 Exam- ple # Stereochemistry R R' R'' M + H
RT 34 Racemic tetrazole 2-F COOH 644.1 7.50 35 S-enantiomer.sup.a
tetrazole 2-F COOH 644.1 7.62 36 R-enantiomer.sup.a tetrazole 2-F
COOH 644.1 7.69 37 S-enantiomer.sup.a tetrazole 2-F COOtBu 700.1
10.65 38 Racemic --COMe 2-F COOH 618.0 8.10 39 R-enantiomer.sup.a
--COMe 2-F COOH 618.0 5.68 40 S-enantiomer.sup.a --COMe 2-F COOH
618.0 5.68 41 R-enantiomer.sup.b tetrazole 4-F COOH 643.9 7.75 42
S-enantiomer.sup.b tetrazole 4-F COOH 643.9 7.76 43 Racemic
tetrazole 2-F COOEt 672.3 9.35 44 R-enantiomer.sup.c tetrazole 2-F
COOEt 672.3 9.02 45 S-enantiomer.sup.c tetrazole 2-F COOEt 672.3
9.06 .sup.aChiral HPLC using Chiralcel OD 5 .times. 50 cm using 20%
heptane and 80% (1:1MeOH/EtOH) at 50 mL/min. .sup.bChiralpak IA
SFC, 150 .times. 30 mm using 55% EtOH-0.1% DEA/45% CO.sub.2 at 70
mL/min, 100 Bar, 35.degree. C. .sup.cChiralpak AD-H, 250 .times. 21
mm 30 mm using 45% (4:1 IPA-EtOH-0.1% DEA + 3% H.sub.2O)/55%
CO.sub.2 at 60 mL/min, 100 Bar, 35.degree. C.
[0418] The following examples in Table 7 were made by Ugi reaction
as described in Example 1 using imine intermediates 19, 21, 22 or
23 and intermediates 6, 7, 8, 9, 10 or 11 as appropriate.
Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage
intermediate and then, deprotected where indicated.
##STR00086##
TABLE-US-00009 TABLE 7 Example # Stereochemistry R R' M + H RT 46
Racemic ##STR00087## -4-PhCOOH 646.0 7.04 47 Racemic ##STR00088##
##STR00089## 642.6 7.15 48 R-enantiomer.sup.a ##STR00090##
-4-PhCOOH 646.0 7.15 49 S-enantiomer.sup.a ##STR00091## -4-PhCOOH
646.0 7.15 50 S-enantiomer.sup.a ##STR00092## -4-PhCOOtBu 701.9
9.90 51 Racemic ##STR00093## -4-PhCOOEt 674.0 8.61 52 Racemic
##STR00094## -4-PhCOOH 779.1 8.76 53 Racemic ##STR00095##
##STR00096## 655.2 5.28 54 Racemic ##STR00097## -4-PhCOOH 645.0
5.20 55 Racemic ##STR00098## -4-PhCOOtBu 801.5 11.25 56 Racemic
##STR00099## -4-PhCOOEt 773.5 10.3 57 Racemic ##STR00100##
-4-PhCOOtBu 715.3 6.82 58 Racemic ##STR00101## -4-PhNHCOOCH.sub.3
661.0 9.33 59 Racemic ##STR00102## -4-PhCOOtBu 688.3 10.8 60
Racemic ##STR00103## 4-PhCOOH 632.2 8.40 61 R-enantiomer.sup.b
##STR00104## 4-PhCOOH 632.3 8.44 62 S-enantiomer.sup.b ##STR00105##
4-PhCOOH 632.3 8.44 63 Racemic ##STR00106## -4-PhCOOEt 660.3 10.6
64 Diastereomer ##STR00107## 4-PhCOOH 643.2 5.49 .sup.aChiracel OD
5 .times. 50 cm using 20% Heptane/80% 1:1 EtOH/MeOH at 50 mL/min.
.sup.bChiralpak 250 .times. 21 mm, using AD-H using 45% (1:1
EtOH--IPA-0.1% DEA)/55% CO.sub.2 at 60 mL/min, 100 bar, 35.degree.
C.
Example 65
(E)-4-(2-(3-(5-chloro-4-fluoro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(pip-
erazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic
acid, bis TFA Salt
##STR00108##
[0420] Example 65 was prepared in a similar manner as Example 1
substituting Intermediate 5 for Intermediate 2. .sup.1H NMR (500
MHz, MeOD) .delta. 10.22-10.48 (1H, m), 9.37-9.51 (1H, m),
8.11-8.28 (1H, m), 7.75-7.96 (2H, m), 7.45-7.66 (2H, m), 7.15-7.34
(2H, m), 6.97-7.18 (3H, m), 5.63-5.75 (1H, m), 4.09-4.32 (2H, m),
3.48-3.61 (2H, m), 3.24-3.43 (4H, m), 2.97-3.19 (4H, m) ppm. MS
(ESI) m/z: 631 (M+H).sup.+. Analytical HPLC: RT=5.55 min.
Example 66
(E)-N-(4-carbamoylphenyl)-2-(3-(5-chloro-4-fluoro-2-(1H-tetrazol-1-yl)phen-
yl)acryloyl)-5-(piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxami-
de, bis-TFA Salt
##STR00109##
[0422] 66A: (E)-tert-butyl
4-(1-(4-carbamoylphenylcarbamoyl)-2-(3-(5-chloro-4-fluoro-2-(1H-tetrazol--
1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)piperazine-1-carb-
oxylate: To Boc-protected Compound 65 (piperazine as Boc protected)
(0.2 g, 0.274 mmol) in DMF (2 mL) was added ammonium chloride
(0.022 g, 0.410 mmol), PyBOP (0.142 g, 0.274 mmol) and DIEA (0.072
mL, 0.410 mmol). After 24 h, the reaction was partitioned with
H.sub.2O (15 mL) and EtOAc (40 mL). The organic layer was washed
with H.sub.2O (2.times.10 mL), 10% LiCl (10 mL), brine (10 mL) and
dried (MgSO.sub.4). MS (ESI) m/z: 730.0 (M+H).sup.+.
[0423] Example 66: 66A was deprotected with 30% TFA/DCM (10 mL).
After 2 h, the reaction was concentrated and purified by reverse
phase HPLC and freeze-dried to afford 4.6 mg (1.8%) of example 66
as a tan solid. .sup.1H NMR (400 MHz, MeOD) .delta. 9.46 (1H, s),
8.14-8.26 (1H, m), 7.72 (2H, d, J=8.84 Hz), 7.49-7.63 (4H, m),
7.17-7.30 (2H, m), 7.00-7.14 (2H, m), 5.69 (1H, s), 4.14-4.28 (1H,
m), 3.50-3.67 (1H, m), 3.27-3.42 (4H, m), 2.99-3.17 (6H, m) ppm. MS
(ESI) m/z: 630.0 (M+H).sup.+. Analytical HPLC: RT=5.26 min.
[0424] The examples in Table 8 were prepared in a similar manner as
Example 66 using the appropriate amines in place of ammonium
chloride.
##STR00110##
TABLE-US-00010 TABLE 8 Example # R M + H RT 67 Cyclopropanamine
670.07 1.87* 68 2-(1H-imidazol-4-yl)ethanamine 724.13 1.66* 69
Aniline 706.11 2.25* 70 N-(4-aminophenyl)acetamide 763.26 1.88* 71
Ethyl 658.11 1.85* 72 N-(2-aminoethyl)acetamide 715.23 1.67* 73
3-aminopropanamide 701.14 1.64* 74 methyl 2-aminoacetate 702.12
1.83* 75 3-methoxyaniline 736.20 2.30* 76 Dimethylamine 658.1 5.52
77 Methylamine 643.9 5.38 * Column used: Supelco Ascentis Express
4.6 .times. 50 mm 2.7 uM C18. Mobile Phase: A = 5:95
Acetonitrile:H.sub.2O; B = 95:5 Acetrile:H.sub.2O; Modifier = 0.05%
TFA Wavelength: 220 nm. The remaining samples used method A.
Example 78
(E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-3,3-di-
methyl-5-(piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)ben-
zoic acid, bis-TFA Salt
##STR00111##
[0426] 78A: Benzyl
5-bromo-3,3-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate: To
intermediate 24 (900 mg, 3.75 mmol) in dry THF (9 mL), at 0.degree.
C., was added 10% aqueous NaOH (5.4 mL) followed by drop-wise
addition of benzyl chloroformate (0.6 mL, 4.12 mmol). After 48 h,
the reaction was quenched with ice cold H.sub.2O, extracted with
EtOAc (2.times.), the combined organics were washed with H.sub.2O,
brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification
by silica gel column chromatography afforded 78A (0.6 g, 42.8%) as
a white liquid. MS (ESI) m/z: 347.0 (M+H).sup.+.
[0427] 78B: Benzyl
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3,3-dimethyl-3,4-dihydroisoquin-
oline-2(1H)-carboxylate: To 78A (600 mg, 1.60 mmol) in toluene (5
mL) was added NaOtBu (215 mg, 2.24 mmol), tert-butyl
piperazine-1-carboxylate (358 mg, 1.92 mmol), Pd.sub.2(dba).sub.3
(3.6 mg, 0.004 mmol) and BINAP (7.4 mg, 0.012 mmol). The reaction
mixture was heated at 100.degree. C. in a sealed tube. After 18 h,
the reaction was cooled to rt, quenched with H.sub.2O, extracted
with EtOAc twice, the combined organics were washed with H.sub.2O,
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. Purification by silica gel column chromatography
afforded 78B (500 mg, 67%) as a green liquid. MS (ESI) m/z: 480.4
(M+H).sup.+.
[0428] 78C:
tert-Butyl-4-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)piperazine--
1-carboxylate: To 78B (340 mg) in EtOH (4 mL) was added 10% Pd/C
(68 mg, 20 vol) and the reaction was hydrogenated under 14 psi of
H2. After 3 h, the reaction was filtered through Celite.RTM. and
washed twice with MeOH. The combined organics were evaporated to
afford 78C (170 mg, 69.6%) as a white solid. MS (ESI) m/z: 346.2
(M+H).sup.+.
[0429] 78D:
tert-Butyl-4-(3,3-dimethyl-3,4-dihydroisoquinolin-5-yl)piperazine-1-carbo-
xylate: To a solution of 78C (170 mg, 0.49 mmol) in EtOH (2 mL) was
added iodine (281 mg, 2.21 mmol) and NaOAc (60 mg, 0.73 mmol) and
the reaction mixture was heated to 80.degree. C. After 3 h, the
solvent was evaporated and the residue was quenched with 10% sodium
thiosulphate solution and extracted twice with EtOAc and the
combined organics were washed with H.sub.2O. The organic layer was
extracted with 2 mL of 0.5 N HCl solution and the combined aqueous
layers were basified with ammonia solution and extracted with EtOAc
twice. The combined organics were washed with H.sub.2O, brine and
dried over Na.sub.2SO.sub.4, filtered and concentrated to give 78D
(90 mg, 53.2%). MS (ESI) m/z: 344.2 (M+H).sup.+.
[0430] Example 78 was prepared in an Ugi reaction in a similar
manner as Example 1 using 78D, Intermediate 3, and Intermediate 6
followed by TFA deprotection and HPLC purification. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.77 (1H, s), 10.48 (1H, s), 9.86
(1H, s), 8.63 (2H, bs), 7.88-7.97 (3H, m), 7.66 (3H, d, J=8.8 Hz),
7.53 (1H, d, J=7.6 Hz), 7.29 (1H, t, J=8.0 Hz), 7.07-7.11 (3.0H,
m), 5.74 (1H, bs), 3.20-3.23 (2H, m), 3.06-3.10 (2H, m), 2.94 (3H,
bs), 1.81 (3H, s), 1.11 (3H, s) ppm. LCMS m/z: 659.4 (M+H).sup.+.
Analytical HPLC: RT=7.62 min.
Example 79
(E)-4-(2-(3-(6-acetyl-3-chloro-2-fluorophenyl)acryloyl)-5-(4-methylpiperaz-
in-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid,
bis-TFA Salt
##STR00112##
[0432] Example 79 was prepared in a similar manner as Example 1
using Intermediate 19, Intermediate 6 and Intermediate 12 followed
by TFA deprotection. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.83 (1H, s), 9.51-9.65 (1H, m), 7.88 (2H, d, J=8.80 Hz),
7.73-7.79 (1H, m), 7.70 (2H, d, J=8.80 Hz), 7.56 (1H, d, J=15.68
Hz), 7.44 (1H, d, J=7.70 Hz), 7.28 (1H, t, J=7.84 Hz), 7.03-7.12
(2H, m), 5.85 (1H, s), 4.21 (1H, ddd, J=12.04, 5.16, 4.81 Hz),
3.59-3.67 (1H, m), 3.47-3.56 (2H, m), 3.18-3.31 (5H, m), 3.09-3.17
(1H, m), 2.99-3.05 (2H, m), 2.85-2.93 (4H, m), 2.59 (3H, s) ppm. MS
(ESI) m/z: 619 (M+H).sup.+. Analytical HPLC: RT=5.0 min.
Example 80
(E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-(-
pyrrolidin-1-yl)piperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxami-
do)benzoic acid, bis TFA Salt
##STR00113##
[0434] 80A: 5-(4-(Pyrrolidin-1-yl)piperidin-1-yl)isoquinoline: To
5-bromoisoquinoline (1 g, 4.81 mmol), 4-(pyrrolidin-1-yl)piperidine
(1.112 g, 7.21 mmol), and sodium tert-butoxide (0.647 g, 6.73
mmol), was added toluene (10 mL) and the mixture was degassed with
argon. BINAP (0.090 g, 0.144 mmol) and Pd.sub.2(dba).sub.3 (0.044
g, 0.048 mmol) were added and the reaction was heated to
130.degree. C. in a microwave for 20 min. Purification by normal
phase chromatography afforded 0.84 g (62.7%) of 80A as a tan solid.
MS (ESI) m/z: 282.1 (M+H).sup.+.
[0435] 80B:
5-(4-(Pyrrolidin-1-yl)piperidin-1-yl)-3,4-dihydroisoquinoline: 80A
was hydrogenated in the presence of PtO.sub.2 and then oxidized
with MnO.sub.2 to afford 0.85 g (62.8%) of 80B as a yellow oil. MS
(ESI) m/z: 284.2 (M+H).sup.+.
[0436] Example 80 was prepared by the Ugi reaction as in Example 1
using 80B and Intermediates 3A and 6 followed by TFA deprotection.
.sup.1H NMR (400 MHz, MeOD) .delta. 9.56 (1H, s), 7.95 (2H, d,
J=8.59 Hz), 7.72-7.85 (1H, m), 7.64 (2H, dd, J=8.72, 1.39 Hz), 7.49
(1H, dd, J=8.72, 1.39 Hz), 7.23-7.42 (2H, m), 7.14-7.23 (1H, m),
7.07 (1H, d, J=7.58 Hz), 6.91-7.05 (1H, m), 5.76 (1H, s), 4.12 (1H,
ddd, J=11.75, 4.67, 4.55 Hz), 3.72 (2H, br. s.), 3.41-3.57 (1H, m),
3.07-3.32 (7H, m), 2.90 (1H, t, J=11.24 Hz), 2.57-2.71 (1H, m),
2.14-2.38 (4H, m), 1.83-2.11 (4H, m) ppm. MS (ESI) m/z: 699.4
(M+H).sup.+. Analytical HPLC: RT=5.51 min.
[0437] The following examples in Table 9 were prepared in a similar
manner as Example 80 starting with the appropriate substituted
piperidine and isonitriles (Intermediates 6, 7, 8, 9, 10 or 11 or
commercial). Chiral separation was carried out using chiral HPLC on
late stage intermediates followed by deprotection and purification
where indicated.
##STR00114##
TABLE-US-00011 TABLE 9 Example # stereochemistry R R' M + H RT 81
Racemic ##STR00115## -4-PhCOOH 630.3 7.46 82 Racemic ##STR00116##
-4-Ph--F 673.4 6.83 83 Racemic ##STR00117## -4-PhCOOEt 727.4 6.70
84 Racemic ##STR00118## -4-PhCOOtBu 755.4 8.73 85 Racemic
##STR00119## 4-PhCN 680.4 6.47 86 S-enantiomer.sup.a ##STR00120##
-4-Ph--F 673.5 6.69 87 S-enantiomer.sup.a ##STR00121## -4-PhCOOH
699.4 5.90 88 R-enantiomer.sup.a ##STR00122## -4-PhCOOH 699.4 5.91
89 Racemic ##STR00123## -4-PhNHCOOCH.sub.3 728.5 6.10 90
R-enantiomer.sup.a ##STR00124## -4-Ph--F 673.5 6.85 91 Racemic
##STR00125## -4-PhCOOtBu 729.5 7.28 92 Racemic ##STR00126##
-4-PhCOOH 673.5 5.65 93 R-enantiomer.sup.b ##STR00127## -4-Ph-COOEt
727.6 6.88 94 S-enantiomer.sup.b ##STR00128## -4-Ph-COOEt 727.6
6.85 95 Racemic ##STR00129## -4-PhCOOH 706.3 9.61 96 Racemic
##STR00130## -4-PhCOOH 713.3 7.45 97 Racemic ##STR00131## -4-PhCOOH
645.4 5.19 98 R-enantiomer.sup.c ##STR00132## -4-PhNHCOOCH.sub.3
728.6 5.84 99 S-enantiomer.sup.c ##STR00133## -4-PhNHCOOCH.sub.3
728.6 5.89 100 Racemic ##STR00134## -4-PhCOOH 701.2 7.20 101
S-enantiomer.sup.h ##STR00135## -4-PhCOOH 701.2 7.26 102
R-enantiomer.sup.a ##STR00136## -4-PhCOOH 673.5 5.39 103
S-enantiomer.sup.a ##STR00137## -4-PhCOOH 673.5 5.37 104 Racemic
##STR00138## -4-Ph--Cl 689.5 6.94 105 Racemic ##STR00139##
-4-PhCOOnBu 755.6 7.65 106 Racemic ##STR00140## -4-PhCOOH 713.5
7.02 107 R-enantiomer.sup.e ##STR00141## -4-PhCOOH 713.5 6.98 108
S-enantiomer.sup.e ##STR00142## -4-PhCOOH 713.5 6.97 109 Racemic
##STR00143## -4-PhCOOEt 741.6 8.45 110 S-enantiomer ##STR00144##
-4-PhCOOEt 741.3 9.20 111 R-enantiomer.sup.a ##STR00145## -4-Ph--Cl
689.5 7.36 112 S-enantiomer.sup.a ##STR00146## -4-Ph--Cl 689.5 6.95
113 R-enantiomer.sup.a ##STR00147## -4-PhCOOnBu 755.6 8.03 114
S-enantiomer.sup.a ##STR00148## -4-PhCOOnBu 755.7 8.05 115 Racemic
##STR00149## -4-PhCOOH 713.5 6.70 116 Racemic ##STR00150##
-4-PhCOOH 672.5 9.62 117 Racemic ##STR00151## 4-PhCOOH 658.5 9.21
118 R-enantiomer.sup.c ##STR00152## -4-PhCOOH 713.5 7.27 119
S-enantiomer.sup.c ##STR00153## -4-PhCOOH 713.5 7.82 120 Racemic
##STR00154## ##STR00155## 709.3 5.76 121 Racemic ##STR00156##
-4-PhCOOH 789.6 8.55 122 Racemic ##STR00157## -4-PhCOOiPr 741.6
7.26 123 Racemic ##STR00158## -4-PhCOOiBu 755.6 7.69 124 Racemic
##STR00159## ##STR00160## 767.6 7.61 125 R-enantiomer.sup.d
##STR00161## -4-Ph--COOEt 741.5 9.13 126 S-enantiomer.sup.d
##STR00162## -4-Ph--COOEt 741.5 9.09 127 Racemic ##STR00163##
##STR00164## 709.6 7.01 128 R-enantiomer.sup.e ##STR00165##
-4-PhCOOEt 701.5 7.45 129 S-enantiomer.sup.e ##STR00166##
-4-PhCOOEt 701.5 7.45 130 Racemic ##STR00167## -4-PhCOOH 727.5 8.86
131 Racemic ##STR00168## -4-PhCOOH 727.5 8.37 132
R-enantiomer.sup.f ##STR00169## -4-PhCOOH 727.6 7.08 133
S-enantiomer.sup.f ##STR00170## -4-PhCOOH 727.6 10.69 ? 134 Racemic
##STR00171## -4-PhCOOEt 755.5 8.56 135 S-enantiomer.sup.f
##STR00172## -4-PhCOOEt 755.3 9.3 136 Racemic ##STR00173##
-4-PhCOOH 702.0 13.02 137 Racemic ##STR00174## -4-PhCOOH 688.3
10.47 138 Racemic ##STR00175## -4-PhCOOH 715.3 6.19 139
S-enantiomer.sup.k ##STR00176## -4-PhCOOH 715.4 6.20 140 Racemic
##STR00177## -4-PhCOOH 743.3 6.75 141 S-enantiomer.sup.f
##STR00178## -4-PhCOOH 743.3 7.24 142 Racemic ##STR00179##
-4-PhCOOH 688.4 10.36 143 S-enantiomer.sup.g ##STR00180## -4-PhCOOH
688.2 9.33 144 S-enantiomer ##STR00181## -4-PhCOOMe 702.3 2.18**
145 Racemic ##STR00182## -4-PhCOOH 700.2 8.75 146 Racemic
##STR00183## -4-PhCOOH 699.4 5.61 147 Racemic ##STR00184##
-4-PhCOOH 655.3 9.54 148 Racemic ##STR00185## -4-PhCOOH 646.3 6.94
149 S-enantiomer.sup.j ##STR00186## -4-PhCOOH 646.2 7.38 150
Racemic ##STR00187## -4-PhCOOH 660.3 9.37 151 S-enantiomer
##STR00188## -4-PhCOOH 660.3 8.45 152 Racemic ##STR00189##
-4-PhCOOH 741.4 7.89 .sup.aChiralpak AD-H, 250 X 21 mm ID, 5 .mu.m,
using 55/45 CO.sub.2/(1:1) EtOH-IPA-0.1% DEA at 60 mL/min, 150 bar
BP, 40.degree. C. .sup.bChiralpak AD-H, 250 X 21 mm ID, 5 .mu.m,
using 50/50 CO.sub.2/(1:1) EtOH-IPA-0.1% DEA at 90 mL/min, 150 bar
BP, 40.degree. C. .sup.cChiralpak AD-H, 250 X 21 mm ID, 5 .mu.m,
using 40/60 CO.sub.2/(1:1) EtOH-IPA-0.1% DEA at 60 mL/min, 125 bar
BP, 40.degree. C. .sup.dChiralpak AD-H, 150 X 20 mm ID, 5 .mu.m,
using 50/50 CO.sub.2/IPA-0.1% DEA at 55 mL/min, 150 bar BP,
35.degree. C. .sup.eChiralpak AS-H, 150 X 20 mm ID, 5 .mu.m, using
60/40 CO.sub.2/MeOH-0.1% DEA at 60 mL/min, 100 bar BP, 35.degree.
C. .sup.fChiralpak AD-H, 250 X 30 mm ID, 5 .mu.m, using 50/50
CO.sub.2/(1:1) EtOH-0.1% DEA at 100 mL/min, 150 bar BP, 40.degree.
C. .sup.gChiralpak AD-H, 150 X 21 mm ID, 5 .mu.m, using 55/45
CO.sub.2/(1:1) EtOH-IPA-0.1% DEA at 45 mL/min, 150 bar BP,
40.degree. C. .sup.hChiralpak AD-H, 150 X 21 mm ID, 5 .mu.m, using
50/50 CO.sub.2/(1:1) EtOH-IPA-0.1% DEA at 50 mL/min, 150 bar BP,
50.degree. C. .sup.iChiralpak OD-H, 250 X 30 cm ID, 5 .mu.m, using
65/35 CO.sub.2/EtOH-0.1% DIPA at 90 mL/min, 150 bar BP, 45.degree.
C. .sup.jChiralpak AD-H, 25 X 2 cm ID, 5 .mu.m, using 60/40
CO.sub.2/IPA-20 mM NH.sub.4OH at 50 mL/min, 100 bar BP.
.sup.kChiralcel OJ-H, 25 X 2 cm ID, 5 .mu.m, using 70/30
CO.sub.2/IPA-0.1% DEA at 70 mL/min, 100 bar BP. **LCMS retention
time.
[0438] The following examples in Table 10 were prepared in a
similar manner as Example 80 substituting Intermediate 3A for the
appropriate carboxylic acid listed and were separated by chiral
HPLC on late stage intermediates followed by deprotection and
purification where indicated.
##STR00190##
TABLE-US-00012 TABLE 10 Example Stereochemistry R R' M + H RT 153
Racemic ##STR00191## -4-PhCOOtBu 729.4 7.76 154 Racemic
##STR00192## -4-PhCOOH 673.5 6.07 155 Racemic ##STR00193##
-4-PhCOOH 656.5 6.18 156 Racemic ##STR00194## -4-PhCOOH 613.4 6.31
157 Racemic ##STR00195## -4-PhCOOH 647.5 7.45 158 Racemic
##STR00196## -4-PhCOOH 663.5 6.39 159 Racemic ##STR00197##
-4-PhCOOH 679.6 6.47 160 Racemic ##STR00198## -4-PhCOOEt 701.6 7.07
161 Racemic ##STR00199## -4-PhCOOH 661.2 6.99 162 Racemic
##STR00200## -4-PhCOOH 647.2 7.16 163 R-enantiomer.sup.a
##STR00201## -4-PhCOOH 656.4 5.99 164 S-enantiomer.sup.a
##STR00202## -4-PhCOOH 656.4 5.97 165 Racemic ##STR00203##
-4-PhCOOEt 684.5 9.90 166 S-enantiomer.sup.c ##STR00204##
-4-PhCOOEt 684.3 7.39 167 R-enantiomer.sup.a ##STR00205## -4-PhCOOH
673.4 5.83 168 S-enantiomer.sup.a ##STR00206## -4-PhCOOH 673.4 5.82
169 R-enantiomer.sup.a ##STR00207## -4-PhCOOEt 701.4 7.05 170
S-enantiomer.sup.a ##STR00208## -4-PhCOOEt 701.4 7.06 171
S-enantiomer ##STR00209## -4-PhCOOBzl 763.2 6.72* 172 S-enantiomer
##STR00210## -4-PhCOOCH2CON(CH.sub.3).sub.2 758.2 6.74 173
S-enantiomer ##STR00211## ##STR00212## 768.2 6.53 174 S-enantiomer
##STR00213## ##STR00214## 731.2 7.59 175 Racemic ##STR00215##
-4-PhCOOCH.sub.3 687.1 7.53 176 Racemic ##STR00216## -4-PhCOOH
699.5 8.26 177 S-enantiomer.sup.b ##STR00217## -4-PhCOOEt 727.5
9.14 178 S-enantiomer.sup.b ##STR00218## -4-PhCOOH 699.5 6.81 179
R-enantiomer.sup.b ##STR00219## -4-PhCOOH 699.5 6.84 180 Racemic
##STR00220## -4-PhCOOH 649.5 7.86 181 Racemic ##STR00221##
-4-PhCOOH 597.5 6.08 182 Racemic ##STR00222## -4-PhCOOH 633.5 6.87
.sup.aChiralpak AD-H, 250 X 21 cm ID, 5 .mu.m, using 50/50
CO.sub.2/EtOH-IPA-0.1% DEA at 60 mL/min, 125 bar BP, 40.degree. C.
.sup.bChiralpak AD-H, 250 X 21 cm ID, 5 .mu.m, using 60/40
CO.sub.2/EtOH-IPA-0.1% DEA at 45 mL/min, 150 bar BP, 50.degree. C.
.sup.cChiralcel OD-H, 250 X 30 mm ID, 5 .mu.m, using 55/45
CO.sub.2/EtOH-IPA-0.1% DEA at 85 mL/min, 100 bar BP, 40.degree. C.
*Method B
Example 183
(R,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-
-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)-
benzoic acid, TFA salt
##STR00223##
[0440] Example 57 (Table 7): (E)-tert-butyl
4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-meth-
yl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzo-
ate: Intermediate 3A (0.320 g, 1.192 mmol) and Intermediate 22
(0.29 g, 1.192 mmol) were combined in a vial in EtOH (5 mL) and
after 10 min., Intermediate 6 (0.315 g, 1.550 mmol) in EtOH (3 mL)
was added and reaction was heated at 55.degree. C. for 24 h. The
reaction was concentrated and the residue was purified by silica
gel column chromatography followed by reverse phase HPLC and
freeze-dried to afford 0.339 g (32.6%) of Example 57 (Table 7) as a
white solid. .sup.1H NMR (400 MHz, MeOD) .delta.: 9.44 (1H, s),
7.74-7.84 (2H, m), 7.62-7.73 (1H, m), 7.43-7.58 (3H, m), 7.37 (1H,
dd, J=8.72, 1.64 Hz), 7.31 (1H, td, J=7.83, 2.78 Hz), 7.19 (1H, t,
J=6.82 Hz), 6.98-7.11 (1H, m), 6.79-6.94 (1H, m), 5.80 (1H, s),
3.94-4.20 (3H, m), 3.84-3.95 (1H, m), 3.62-3.80 (3H, m), 3.53-3.64
(1H, m), 2.99 (3H, s), 2.92-2.96 (1H, m), 2.61-2.77 (1H, m), 1.47
(9H, d, J=2.02 Hz) ppm. MS (ESI) m/z: 715.3. Analytical HPLC:
RT=6.82 min.
[0441] Example 183 was prepared from Example 57 (Table 7) and
isolated as the first eluting peak after chiral HPLC separation
using Chiralpak AD-H, 250.times.30 mm, 5 .mu.m, using 60/40
CO.sub.2/1:1 EtOH-IPA-0.1% DEA at 90 mL/min, 150 bar BP, 35.degree.
C. followed by deprotection with TFA/DCM and HPLC purification to
afford 96.8 mgs (25.8%) of a white solid. .sup.1H NMR (400 MHz,
MeOD) .delta.: 9.44 (1H, s), 7.78-7.95 (2H, m), 7.69 (1H, td,
J=8.08, 2.53 Hz), 7.44-7.60 (3H, m), 7.27-7.41 (2H, m), 7.15-7.25
(1H, m), 6.98-7.11 (1H, m), 6.77-6.98 (1H, m), 5.78-5.88 (1H, m),
3.83-4.19 (4H, m), 3.64-3.80 (3H, m), 3.54-3.64 (1H, m), 3.03 (3H,
s), 2.93-3.00 (1H, m), 2.63-2.78 (1H, m) ppm MS (ESI) m/z: 659.3
(M+H).sup.+. Analytical HPLC: RT=4.90 min.
Example 184
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-
-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)-
benzoic acid, TFA salt
##STR00224##
[0443] Example 184 was isolated as the second eluting enantiomer
from Example 57 (Table 7) and deprotected and purified as described
in Example 183 to afford 104 mgs (27.7%) of a white solid. .sup.1H
NMR (400 MHz, MeOD) .delta.: 9.45 (1H, s), 7.79-7.92 (2H, m),
7.64-7.74 (1H, m), 7.44-7.62 (3H, m), 7.27-7.43 (2H, m), 7.15-7.24
(1H, m), 6.97-7.12 (1H, m), 6.72-6.90 (1H, m), 5.77-5.88 (1H, m),
3.82-4.17 (4H, m), 3.53-3.82 (4H, m), 2.99-3.03 (1H, m), 2.98 (3H,
s), 2.60-2.77 (1H, m) ppm. MS (ESI) m/z: 659.3 (M+H).sup.+.
Analytical HPLC: RT=4.94 min.
[0444] The following compounds listed in Table 11 were isolated
following chiral HPLC separation of the appropriate racemic example
listed.
##STR00225##
TABLE-US-00013 TABLE 11 Racemic Example # Example # Stereochemistry
R R' M + H RT 185 63 S-enantiomer.sup.a ##STR00226## --COOEt 660.4
10.13 186 63 R-enantiomer.sup.a ##STR00227## --COOEt 660.4 10.14
187 54 R-enantiomer.sup.b ##STR00228## --COOH 645.3 4.85 188 54
S-enantiomer.sup.b ##STR00229## --COOH 645.3 4.87 189 56
R-enantiomer.sup.c ##STR00230## --COOEt 672.3 5.80 190 56
S-enantiomer.sup.c ##STR00231## --COOEt 672.3 5.77 .sup.aChiralpak
IA, 250 .times. 30 mm, 5 .mu.m, using 60/40 CO.sub.2/1:1
EtOH--IPA-0.1% DEA at 90 mL/min, 150 bar BP, 35.degree. C.
.sup.bChiralpak IA, 250 .times. 21 mm, 5 .mu.m, using 55/45 to
60/40 CO.sub.2/1:1 EtOH--ACN at 40 mL/min, 150 bar BP, 35.degree.
C. .sup.cChiralpak AD-H, 250 .times. 21 mm, 5 .mu.m, using 55/45 to
60/40 CO.sub.2/1:1 EtOH--ACN at 40 mL/min, 150 bar BP, 35.degree.
C.
Example 191
(R,E)-Ethyl
4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-meth-
yl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzo-
ate, TFA Salt
##STR00232##
[0446] Example 191 was prepared as in Example 189 (Table 11) using
Intermediate 22, Intermediate 9 and Intermediate 3A to afford 84.4
mg (43%) as the first peak after chiral HPLC separation using
Chiralpak IA, 250.times.30 mm, 5 .mu.m, using 60/40 CO.sub.2/1:1
EtOH-IPA-0.1% DEA at 100 mL/min, 150 bar BP, 40.degree. C. .sup.1H
NMR (400 MHz, MeOD) .delta. 9.50 (1H, s), 7.85-7.96 (2H, m),
7.72-7.77 (1H, m), 7.61 (2H, dd, J=8.79, 6.05 Hz), 7.48-7.56 (1H,
m), 7.44 (1H, d, J=8.79 Hz), 7.35 (1H, td, J=7.83, 3.02 Hz),
7.16-7.27 (1H, m), 7.05-7.14 (1H, m), 6.94-7.05 (1H, m), 5.84 (1H,
d, J=7.70 Hz), 4.22-4.33 (2H, m), 4.09 (1H, s), 3.51-3.82 (2H, m),
3.43 (2H, br. s.), 2.94-3.07 (4H, m), 2.70-2.81 (1H, m), 2.55 (3H,
br. s.), 1.25 (3H, t, J=7.42 Hz) ppm. MS (ESI) m/z: 687.3
(M+H).sup.+. Analytical HPLC: RT=5.91 min.
Example 192
(S,E)-Ethyl
4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(4-meth-
yl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzo-
ate, TFA Salt
##STR00233##
[0448] Example 192 was prepared as in Example 190 (Table 11) using
Intermediate 22, Intermediate 9 and Intermediate 3A to afford 84.4
mg (43%) as the second peak after chiral HPLC separation using
Chiralpak IA, 250.times.30 mm, 5 .mu.m, using 60/40 CO.sub.2/1:1
EtOH-IPA-0.1% DEA at 100 mL/min, 150 bar BP, 40.degree. C. .sup.1H
NMR (400 MHz, MeOD) .delta.: 9.54 (1H, s), 7.90-7.99 (2H, m),
7.74-7.82 (1H, m), 7.61-7.70 (2H, m), 7.56 (1H, dd, J=19.24, 7.70
Hz), 7.47 (1H, d, J=8.79 Hz), 7.38 (1H, td, J=7.70, 3.85 Hz), 7.24
(1H, t, J=6.87 Hz), 6.98-7.16 (2H, m), 5.88 (1H, d, J=8.24 Hz),
4.26-4.38 (2H, m), 4.06-4.16 (1H, m), 3.60-3.81 (3H, m), 3.47-3.58
(1H, m), 3.02-3.16 (2H, m), 2.83-2.95 (2H, m), 2.75-2.85 (1H, m),
2.45 (3H, s), 1.36 (3H, t, J=7.15 Hz) ppm. MS (ESI) m/z: 687.3
(M+H).sup.+. Analytical HPLC: RT=5.90 min.
Example 193
(R,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-3,3--
dimethyl-5-(piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)
benzoic acid, bis-TFA salt
##STR00234##
[0450] Example 193 was prepared from Example 78 tert-butyl ester
intermediate by chiral HPLC separation using Chiralpak IA
(250.times.4.6) mm eluting with hexane:EtOH (50:50) and 0.2% DEA at
1 mL/min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.77 (1H,
s), 10.48 (1H, s), 9.86 (1H, s), 8.67 (2H, q), 7.95 (2H, t, J=8.4
Hz), 7.88 (1H, bs), 7.64 (3H, d, J=9.2 Hz), 7.53 (1H, d, J=7.6 Hz),
7.29 (1H, t, J=8.0 Hz), 7.07-7.11 (3.0H, m), 5.74 (1H, bs), 3.23
(2H, q), 3.08 (2H, t, J=12.4 Hz), 2.91-2.95 (3H, m), 1.81 (3H, s),
1.11 (3H, s) ppm. MS (ESI) m/z: 659.2 (M+H).sup.+. Analytical HPLC:
RT=11.26 min.
Example 194
(S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-3,3--
dimethyl-5-(piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)
benzoic acid, bis-TFA salt
##STR00235##
[0452] Example 194 was prepared from Example 78 tert-butyl ester
intermediate by chiral HPLC separation using Chiralpak IA
(250.times.4.6) mm eluting with hexane:EtOH (50:50) and 0.2% DEA at
1 mL/min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.77 (1H,
s), 10.51 (1H, s), 9.86 (1H, s), 8.68 (2H, bs), 7.95 (2H, t, J=8.4
Hz), 7.88 (1H, bs), 7.65 (3H, d, J=8.8 Hz), 7.52 (1H, d, J=7.6 Hz),
7.29 (1H, t, J=8.0 Hz), 7.09 (3H, t, J=9.2 Hz), 6.82 (1H, bs), 5.79
(1H, bs), 3.15-3.35 (2H, m), 3.10-2.80 (5H, m), 1.80 (3H, s), 1.10
(3H, s). MS (ESI) m/z: 659.2 (M+H).sup.+. Analytical HPLC: RT=11.28
min.
[0453] The following compounds listed in Table 12 were isolated
following chiral HPLC separation of the appropriate racemic example
listed.
##STR00236##
TABLE-US-00014 TABLE 12 Example # Stereochemistry R R' M + H RT 195
S-enantiomer.sup.a ##STR00237## --COOH 658.2 2.093 196
R-enantiomer.sup.a ##STR00238## --COOH 658 2 2.094 197
S-enantiomer.sup.b ##STR00239## --COOEt 688.2 2.141 198
R-enantiomer.sup.b ##STR00240## --COOEt 688.2 2.142 199
S-enantiomer.sup.c ##STR00241## --COOH 660.2 1.974 200
R-enantiomer.sup.c ##STR00242## --COOH 660.2 1.973 201
S-enantiomer.sup.d ##STR00243## --COOH 673.2 1.515 202
R-enantiomer.sup.d ##STR00244## --COOH 673.2 1.509 203
S-enantiomer.sup.d ##STR00245## --COOEt 701.2 1.746 204
S-enantiomer.sup.d ##STR00246## --COOH 701.2 1.859 205
R-enantiomer.sup.d ##STR00247## --COOH 701.2 1.858 1.
.sup.aChiralpak AD-H, 250 .times. 30 mm, 5 .mu.m, using 40/60
CO.sub.2/1:1 EtOH--IPA-0.1% DEA at 90.0 mL/min, 150 bar BP,
35.degree. C. 2. .sup.bChiralpak IA, 250 .times. 30 mm, 5 .mu.m,
using 60/40 CO.sub.2/1:1 EtOH--IPA-0.1% DEA at 90.0 mL/min, 150 bar
BP, 35.degree. C. 3. .sup.cChiralpak IA, 250 .times. 21 mm, 5
.mu.m, using 55/45 to 60/40 CO.sub.2/1:1 EtOH--ACN at 40.0 mL/min,
150 bar BP, 35.degree. C. 4. .sup.dChiralpak AD-H, 250 .times. 21
mm, 5 .mu.m, using 55/45 to 60/40 CO.sub.2/1:1 EtOH--ACN at 40.0
mL/min, 150 bar BP, 35.degree. C.
Example 206
4-((S)-2-((E)-3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5--
((S)-3-(dimethylamino)pyrrolidin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-ca-
rboxamido)benzoic acid, bis-TFA salt
##STR00248##
[0455] 206A:
(S)-1-(3,4-Dihydroisoquinolin-5-yl)-N,N-dimethylpyrrolidin-3-amine:
To 5-bromoisoquinoline (0.60 g, 2.88 mmol),
(S)--N,N-dimethylpyrrolidin-3-amine (0.428 g, 3.75 mmol),
Pd.sub.2(dba).sub.3 (0.053 g, 0.058 mmol), BINAP (0.072 g, 0.115
mmol), and sodium tert-butoxide (0.39 g, 4.04 mmol) was added
degassed toluene (10 mL) and the mixture was heated to 85.degree.
C. overnight. The reaction mixture was dissolved in EtOAc, washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. This intermediate was reduced and then, oxidized as
described in Example 1 to afford 206A (577 mg, 82%).
[0456] Example 206: 206A (0.25 g, 1.03 mmol), Intermediate 3A (0.28
g, 1.03 mmol), and Intermediate 6 (0.23 g, 1.13 mmol) were combined
in an Ugi reaction as described in Example 1 and then, deprotected
by TFA. Purification by reverse phase HPLC afforded Example 206 as
the first of two diastereomers. The compound was obtained as a
light yellow solid after lyophilization. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.78 (1H, s), 9.88 (1H, s), 7.97 (1H, t,
J=8.12 Hz), 7.87 (2H, d, J=8.80 Hz), 7.68 (3H, d, J=8.80 Hz), 7.30
(1H, d, J=7.70 Hz), 7.22 (1H, t, J=7.84 Hz), 7.03-7.09 (1H, m),
6.93-7.02 (2H, m), 5.75 (1H, s), 3.94-4.10 (1H, m), 3.20-3.55 (9H,
m), 2.79-3.06 (5H, m), 2.27-2.40 (1H, m), 2.06-2.21 (1H, m) ppm. MS
(ESI) m/z: 659.3 (M+H).sup.+. Analytical HPLC: RT=4.53 min.
Example 207
tert-butyl
4-((S)-2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)a-
cryloyl)-5-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1,2,3,4-tetrahydroisoqui-
noline-1-carboxamido)benzoate, bis TFA salt
##STR00249##
[0458] Example 207: 206A (0.25 g, 1.03 mmol), Intermediate 3A (0.28
g, 1.03 mmol), and Intermediate 6 (0.23 g, 1.13 mmol) were combined
in an Ugi reaction as described in Example 1. Purification by
reverse phase HPLC afforded Example 207. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.77 (1H, s), 9.86 (1H, s), 7.96 (1H, t,
J=8.25 Hz), 7.82 (2H, d, J=8.80 Hz), 7.67 (3H, d, J=9.08 Hz), 7.29
(1H, d, J=7.43 Hz), 7.17-7.25 (1H, m), 6.87-7.08 (3H, m), 5.75 (1H,
s), 3.92-4.07 (2H, m), 3.23-3.54 (4H, m), 2.80-3.05 (9H, m),
2.26-2.37 (1H, m), 2.09-2.19 (1H, m), 1.50-1.55 (9H, m) ppm. MS
(ESI) m/z: 715.5 (M+H).sup.+. Analytical HPLC: RT=8.68 min
Example 208
4-((R)-2-((E)-3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5--
((S)-3-(dimethylamino)pyrrolidin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-ca-
rboxamido)benzoic acid, bis-TFA salt
##STR00250##
[0460] Example 208 was obtained as the second eluting diastereomer
during the synthesis and purification of Example 206. The compound
was obtained as a light yellow solid after lyophilization. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 12.73 (1H, br. s.), 10.75 (1H,
s), 9.88 (1H, s), 7.97 (1H, t, J=8.12 Hz), 7.81-7.93 (2H, m),
7.63-7.72 (2H, m), 7.31 (1H, d, J=7.70 Hz), 7.21 (1H, t, J=7.84
Hz), 7.03-7.12 (1H, m), 6.91-7.00 (2H, m), 5.72 (1H, s), 4.03-4.19
(1H, m), 3.86-3.98 (1H, m), 3.37-3.49 (3H, m), 3.07-3.30 (5H, m),
2.81-2.92 (7H, m) ppm. MS (ESI) m/z: 659.3 (M+H).sup.+. Analytical
HPLC: RT=4.64 min.
Example 209
4-((R)-2-((E)-3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5--
((R)-3-(dimethylamino)pyrrolidin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-ca-
rboxamido)benzoic acid, bis TFA salt
##STR00251##
[0462] Example 209 was prepared in a similar manner as Example 206
substituting (R)--N,N-dimethylpyrrolidin-3-amine instead of
(S)--N,N-dimethylpyrrolidin-3-amine in Buchwald reaction. The
compound was the first eluting diastereomer during purification by
reverse phase prep HPLC. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.74 (1H, br. s.), 10.78 (1H, s), 9.88 (1H, s), 7.97 (1H,
t, J=8.12 Hz), 7.87 (1H, d, J=8.80 Hz), 7.67 (1H, d, J=8.80 Hz),
7.30 (1H, d, J=7.43 Hz), 7.21 (1H, t, J=7.84 Hz), 7.03-7.09 (1H,
m), 6.94-7.01 (2H, m), 5.75 (1H, s), 3.90-4.18 (2H, m), 3.40-3.56
(3H, m), 3.19-3.33 (5H, m), 2.80-2.98 (7H, m) ppm. MS (ESI) m/z:
659.3 (M+H).sup.+. Analytical HPLC: RT=4.57 min.
Example 210
4-((S)-2-((E)-3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5--
((R)-3-(dimethylamino)pyrrolidin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-ca-
rboxamido)benzoic acid, bis-TFA salt
##STR00252##
[0464] Example 210 was prepared in a similar manner as Example 206
substituting (R)--N,N-dimethylpyrrolidin-3-amine instead of
(S)--N,N-dimethylpyrrolidin-3-amine in Buchwald reaction. The
compound was the second eluting diastereomer during purification by
reverse phase prep HPLC. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 10.74 (1H, s), 9.87 (1H, s), 7.96 (1H, t, J=8.12 Hz),
7.83-7.88 (2H, m), 7.63-7.70 (3H, m), 7.27-7.34 (1H, m), 7.17-7.23
(1H, m), 7.02-7.10 (1H, m), 6.90-7.01 (2H, m), 5.71 (1H, s),
4.07-4.20 (1H, m), 3.84-3.98 (1H, m), 3.35-3.44 (3H, m), 3.09-3.29
(5H, m), 2.79-2.92 (7H, m) ppm. MS (ESI) m/z: 659.3 (M+H).sup.+.
Analytical HPLC: RT=4.64 min.
[0465] The following examples in Table 13 were made by Ugi reaction
as described in Example 1 using appropriate imine intermediates and
carboxylic acids (Intermediates 3A, 12, or 16). Deprotection with
TFA/DCM was carried out where necessary. Single enantiomers were
isolated by chiral HPLC at a protected late stage intermediate and
then, deprotected where indicated.
##STR00253##
TABLE-US-00015 TABLE 13 Ex- am- Stereo- ple # chemistry R R' M + H
RT 211 Racemic ##STR00254## -4-PhCOOH 648.3 9.53 212 S-
enantiomer.sup.a ##STR00255## -4-PhCOOH 648.2 10.61 213 Racemic
##STR00256## -4-PhCOOH 680.4 11.28 214 S- enantiomer.sup.b
##STR00257## -4-PhCOOH 680.4 7.80 .sup.aChiralpak AD-H, 250 .times.
21 mm ID, 45% (1:1 EtOH--IPA-0.1% DEA)/55% CO.sub.2 at 45 mL/min,
120 bar, 45.degree. C. .sup.bChiralpak AD-H, 250 .times. 21 mm ID,
45% (1:1 EtOH--IPA-0.1% DEA)/55% CO.sub.2 at 60 mL/min, 100 bar,
35.degree. C.
[0466] The following examples in Table 14 were made by Ugi reaction
as described in Example 18 using appropriate imine intermediates.
Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage
intermediate and then, deprotected where indicated.
##STR00258##
TABLE-US-00016 TABLE 14 Example # Stereochemistry R R' R'' M + H RT
215 Racemic ##STR00259## ##STR00260## -4-PhCOOH 655.4 8.19 216
R-enantiomer.sup.a ##STR00261## ##STR00262## -4-PhCOOH 654.3 9.43
217 S-enantiomer.sup.a ##STR00263## ##STR00264## -4-PhCOOH 654.3
8.19 218 Racemic ##STR00265## ##STR00266## -4-PhCOOH 675.3 7.97 219
S-enantiomer.sup.b ##STR00267## ##STR00268## -4-PhCOOH 675.3 8.31
220 Racemic ##STR00269## ##STR00270## -4-PhCOOH 689.3 7.15 221
R-enantiomer.sup.c ##STR00271## ##STR00272## -4-PhCOOH 687.5 8.50
222 S-enantiomer.sup.c ##STR00273## ##STR00274## -4-PhCOOH 687.3
10.88 223 Racemic ##STR00275## ##STR00276## -4-PhCOOH 673.5 6.67
224 Racemic ##STR00277## ##STR00278## -4-PhCOOH 639.5 6.33 225
Racemic ##STR00279## ##STR00280## -4-PhCOOH 680.4 10.55 226 Racemic
##STR00281## ##STR00282## -4-PhCOOEt 708.4 10.51 227 Racemic
##STR00283## ##STR00284## -4-PhCOOH 685.4 6.92 228 Racemic
##STR00285## ##STR00286## -4-PhCOOH 714.3 9.77 .sup.aChiralpak
IA-H, 150 .times. 21 cm ID, 45% (1:1 EtOH--IPA-0.1% DEA)/55%
CO.sub.2 at 70 mL/min, 100 bar, 35.degree. C. .sup.bChiralcel OD-H,
2 .times. 20 cm ID, 30% MeOH-0.1% DEA)/70% CO.sub.2 at 70 mL/min,
100 bar, 35.degree. C. .sup.cChiralpak AD-H, 250 .times. 21 cm ID,
45% (1:1 EtOH--IPA-0.1% DEA)/55% CO.sub.2 at 60 mL/min, 150 bar,
35.degree. C.
[0467] The following examples in Table 15 were made by Ugi reaction
as described in Example 1 using appropriate nitrile intermediates.
Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage
intermediate and then, deprotected where indicated.
##STR00287##
TABLE-US-00017 TABLE 15 Example Stereo- # chemistry R M + H RT 229
Racemic ##STR00288## 651.5 5.71 230 Racemic ##STR00289## 707.6 6.69
231 Racemic ##STR00290## 651.5 5.54 232 Racemic ##STR00291## 719.6
6.38 233 Racemic ##STR00292## 719.4 6.13 234 Racemic ##STR00293##
705.4 5.34 235 Racemic ##STR00294## 676.4 4.41 236 Racemic
##STR00295## 677.6 5.32 237 Racemic ##STR00296## 662.5 4.27 238
Racemic ##STR00297## 734.6 6.70 239 Racemic ##STR00298## 661.5 6.45
240 Racemic ##STR00299## 621.4 4.64
Example 241
(E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(3-(-
ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-
-carboxamido)benzoic acid
##STR00300##
[0469] 241A: A solution of isoquinolin-5-amine (1.442 g, 10 mmol)
in H.sub.2O (10 mL) containing concentrated HCl (3.0 mL, 36.5 mmol)
at 0.degree. C. was treated dropwise with a solution of sodium
nitrite (0.759 g, 11.00 mmol) in H.sub.2O (3 mL). After stirring
for an additional hour at 0.degree. C., the contents were
transferred to an addition funnel and added drop wise to a
vigorously stirred solution of tin(II) chloride dihydrate (5.64 g,
25.00 mmol) in concentrated HCl (25 mL) at 0.degree. C. After
stirring for 1 h, the pH was adjusted to 7-8 by adding 10 N NaOH
with cooling in an ice bath. The mixture was extracted with
CHCl.sub.3/MeOH (9:1). The combined organic extracts were dried
over MgSO.sub.4, filtered, and concentrated to give a light brown
solid. Ethyl 2,4-dioxovalerate (1.582 g, 10.00 mmol) was added to a
solution of the hydrazine in EtOH and heated at 80.degree. C. After
cooling to rt, the reaction mixture was concentrated. The residue
was dissolved in EtOAc (75 mL) and washed with saturated
NaHCO.sub.3 solution, H.sub.2O, brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude material was purified by
column chromatography. The desired product was isolated as a brown
solid. MS(ESI) m/z: 282.0 (M+H).sup.+.
[0470] 241B: Adam's Catalyst (0.061 g, 0.267 mmol) was added to a
solution of 241A (1.5 g, 5.33 mmol) in EtOH (50 mL) and stirred
under a hydrogen atmosphere (55 psi) overnight. The reaction
mixture was filtered through a plug of Celite.RTM., the filter-cake
rinsed with EtOH, and the combined filtrate concentrated. The
residue was dissolved in DCM (50 mL), treated with MnO.sub.2 (8.34
g, 96 mmol), and left to stir overnight. The reaction mixture was
filtered through a plug of Celite.RTM. and the filter cake rinsed
with DCM/MeOH (9:1). The combined filtrate was concentrated to
yield the desired product. MS(ESI) m/z: 284.1 (M+H).sup.+
[0471] 241C: 241B (0.150 g, 0.529 mmol) was dissolved in EtOH (10
mL), treated with intermediate 3A (0.142 g, 0.529 mmol) and
intermediate 6 (0.108 g, 0.529 mmol) and heated at 60.degree. C.
overnight. The reaction mixture was concentrated, dissolved in
EtOAc, washed with 1.5M K.sub.3PO.sub.4 solution, brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The t-butyl ester was
converted into the corresponding carboxylic acid by treatment with
50% TFA/DCM for 2 h. The reaction mixture was concentrated and
purified by reverse phase HPLC. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.89 (s, 1H), 9.85 (s, 1H), 8.00-7.80 (m, 4H), 7.75-7.62
(m, 3H), 7.55-7.46 (m, 1H), 7.41 (s, 1H), 7.14-7.05 (m, 1H),
7.01-6.91 (m, 1H), 6.78 (s, 1H), 5.96 (s, 1H), 4.29 (q, J=7.1 Hz,
2H), 4.11-3.99 (m, 1H), 3.77-3.59 (m, 1H), 2.81-2.67 (m, 1H),
2.44-2.30 (m, 1H), 2.11 (s, 3H), 1.29 (t, J=6.9 Hz, 3H) ppm.
MS(ESI) m/z: 699.1 (M+H).sup.+ Analytical HPLC: RT=9.10 min
Example 242
(E)-Ethyl
1-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)--
1-(4-fluorophenylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-methyl-1-
H-pyrazole-3-carboxylate
##STR00301##
[0473] 241B (0.150 g, 0.529 mmol) was dissolved in EtOH (10 mL),
treated with intermediate 3A (0.142 g, 0.529 mmol) and
1-fluoro-4-isocyanobenzene (0.064 g, 0.529 mmol) and heated at
60.degree. C. overnight. The reaction mixture was concentrated,
dissolved in EtOAc, washed with 1.5 M K.sub.3PO.sub.4 solution,
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
reaction mixture was concentrated and purified by reverse phase
HPLC. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.63 (1H, s),
9.85 (1H, s), 7.94 (1H, t, J=8.08 Hz), 7.81 (1H, d, J=7.83 Hz),
7.56-7.70 (3H, m), 7.49 (1H, t, J=7.83 Hz), 7.35-7.42 (1H, m),
7.04-7.22 (3H, m), 6.91-7.02 (1H, m), 6.78 (1H, s), 5.93 (1H, s),
4.28 (2H, q, J=7.07 Hz), 4.00-4.11 (1H, m), 3.62-3.75 (1H, m),
2.64-2.78 (1H, m), 2.29-2.41 (1H, m), 2.11 (2H, s), 1.29 (3H, t,
J=7.07 Hz) ppm. MS (ESI) m/z: 673.1 (M+H).sup.+ Analytical HPLC:
RT=10.54 min.
[0474] The following examples in Table 16 were made by Ugi reaction
as described in Example 1 using appropriate intermediates.
Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage
intermediate and then, deprotected where indicated.
##STR00302##
TABLE-US-00018 TABLE 16 Example # Stereochemistry R M + H RT 243
Diastereomer ##STR00303## 671.5 9.04 244 Diastereomer ##STR00304##
671.5 9.12 245 Diastereomer ##STR00305## 671.2 5.3* 246
Diastereomer ##STR00306## 671.5 5.97 247 Diastereomer ##STR00307##
657.1 6.62 248 Diastereomer ##STR00308## 715.4 9.72 249
Diastereomer ##STR00309## 699.4 8.25 250 Diastereomer ##STR00310##
714.4 7.90 251 Diastereomer ##STR00311## 742.4 5.87 252 Racemate
##STR00312## 685.2 4.98* *Method B
[0475] The following examples in Table 17 were made by Ugi reaction
as described in Example 1 using appropriate intermediates.
Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage
intermediate and then, deprotected where indicated.
##STR00313##
TABLE-US-00019 TABLE 17 Example # Stereochemistry R R' M + H RT 253
S-enantiomer.sup.a ##STR00314## 4-PhCOOEt 699.3 7.79 254
S-enantiomer.sup.a ##STR00315## 4-PhCOOH 671.3 6.64 255 Racemic
##STR00316## ##STR00317## 706.3 9.37 .sup.aKromasil cellulocoat,
250 x 4.6 mm ID, 40% (MeOH-0.1% DEA)/60% CO.sub.2 at 45 mL/min, 100
bar, 40.degree. C.
[0476] The following examples in Table 18 were made by Ugi reaction
as described in Example 1 using appropriate intermediates.
Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage
intermediate and then, deprotected where indicated.
##STR00318##
TABLE-US-00020 TABLE 18 Example # Stereochemistry R R' M + H RT 256
Racemic ##STR00319## 4-PhCOOH 645.2 5.42 257 Racemic ##STR00320##
4-PhCOOtBu 801.4 13.15 258 Racemic ##STR00321## 4-PhCOOH 644.3 7.82
259 Racemic ##STR00322## 4-PhCOOH 702.3 8.14 260 S-enantiomer.sup.a
##STR00323## 4-PhCOOH 645.2 5.02* 261 Racemic ##STR00324## 4-PhCOOH
759.3 5.46* 262 Racemic ##STR00325## 4-PhCOOH 659.2 4.90* 263
Racemic ##STR00326## 4-PhCOOH 730.3 5.06* 264 Racemic ##STR00327##
4-PhCOOH 673.3 8.36 265 S-enantiomer ##STR00328## 4-PhCOOH 659.2
6.75 266 S-enantiomer ##STR00329## 4-PhCOOH 730.4 6.33
.sup.aChiralpak AD-H, 150 x 21 mm ID, 45% (1:1 EtOH-IPA-0.1%
DEA)/55% CO.sub.2 at 45 mL/min, 150 bar, 40.degree. C. *Method
B
[0477] The following examples in Table 19 were made by Ugi reaction
as described in Example 206 using appropriate intermediates.
Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage
intermediate and then, deprotected where indicated.
##STR00330##
TABLE-US-00021 TABLE 19 Example # Stereochemistry R R' M + H RT 267
S-enantiomer.sup.a ##STR00331## ##STR00332## 691.3 5.86 268
S-enantiomer.sup.b ##STR00333## ##STR00334## 660.2 6.68 269 Racemic
##STR00335## ##STR00336## 678.2 8.44 270 S-enantiomer.sup.a
##STR00337## ##STR00338## 648.2 9.91 .sup.aChiralpak AD-H, 250 x 21
mm ID, 45% (1:1 EtOH-IPA-0.1% DEA)/55% CO.sub.2 at 65 mL/min, 150
bar, 45.degree. C. .sup.bChiralpak AD-H, 250 x 21 mm ID, 40% (1:1
EtOH-IPA-0.1% DEA)/60% CO.sub.2 at 65 mL/min, 150 bar, 45.degree.
C.
VII. Polymorphs
[0478] The compounds of the present invention may exist as
polymorphs. As used herein "polymorph" refers to crystalline forms
having the same chemical composition but different spatial
arrangements of the molecules, and/or ions forming the crystal. The
present invention provides crystalline forms as a pharmaceutically
acceptable form. The term "pharmaceutically acceptable", as used
herein, refers to those compounds, materials, compositions, and/or
dosage forms which are, within the scope of sound medical judgment,
suitable for contact with the tissues of human beings and animals
without excessive toxicity, irritation, allergic response, or other
problem complications commensurate with a reasonable benefit/risk
ratio.
[0479] In one embodiment, a compound of the present invention is in
substantially pure form. The term "substantially pure", as used
herein, means a compound having a purity greater than about 90%
including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99
weight %, and also including equal to about 100 weight % of the
compound, based on the weight of the compound. The remaining
material comprises other form(s) of the compound, and/or reaction
impurities and/or processing impurities arising from its
preparation. For example, a crystalline form of a compound may be
deemed substantially pure in that it has a purity greater than 90
weight %, as measured by means that are at this time known and
generally accepted in the art, where the remaining less than 10
weight % of material comprises other form(s) of the compound and/or
reaction impurities and/or processing impurities.
[0480] Samples of the crystalline forms may be provided with
substantially pure phase homogeneity, indicating the presence of a
dominant amount of a single crystalline form and optionally minor
amounts of one or more other crystalline forms. The presence of
more than one crystalline form in a sample may be determined by
techniques such as powder X-ray diffraction (PXRD) or solid state
nuclear magnetic resonance spectroscopy (SSNMR). For example, the
presence of extra peaks in the comparison of an experimentally
measured PXRD pattern with a simulated PXRD pattern may indicate
more than one crystalline form in the sample. The simulated PXRD
may be calculated from single crystal X-ray data. see Smith, D. K.,
"A FORTRAN Program for Calculating X-Ray Powder Diffraction
Patterns," Lawrence Radiation Laboratory, Livermore, Calif.,
UCRL-7196, April 1963. Preferably, the crystalline form has
substantially pure phase homogeneity as indicated by less than 10%,
preferably less than 5%, and more preferably less than 2% of the
total peak area in the experimentally measured PXRD pattern arising
from the extra peaks that are absent from the simulated XRPD
pattern. Most preferred is a crystalline form having substantially
pure phase homogeneity with less than 1% of the total peak area in
the experimentally measured PXRD pattern arising from the extra
peaks that are absent from the simulated PXRD pattern.
[0481] The crystalline forms may be prepared by a variety of
methods, including for example, crystallization or
recrystallization from a suitable solvent, sublimation, growth from
a melt, solid state transformation from another phase,
crystallization from a supercritical fluid, and jet spraying.
Techniques for crystallization or recrystallization of crystalline
forms from a solvent mixture include, for example, evaporation of
the solvent, decreasing the temperature of the solvent mixture,
crystal seeding a supersaturated solvent mixture of the molecule
and/or salt, freeze drying the solvent mixture, and addition of
antisolvents (countersolvents) to the solvent mixture. High
throughput crystallization techniques may be employed to prepare
crystalline forms including polymorphs.
[0482] Crystals of drugs, including polymorphs, methods of
preparation, and characterization of drug crystals are discussed in
Solid-State Chemistry of Drugs, S. R. Byrn, R. R. Pfeiffer, and J.
G. Stowell, 2.sup.nd Edition, SSCI, West Lafayette, Ind., 1999.
[0483] For crystallization techniques that employ solvent, the
choice of solvent or solvents is typically dependent upon one or
more factors, such as solubility of the compound, crystallization
technique, and vapor pressure of the solvent. Combinations of
solvents may be employed, for example, the compound may be
solubilized into a first solvent to afford a solution, followed by
the addition of an antisolvent to decrease the solubility of the
compound in the solution and to afford the formation of crystals.
An antisolvent is a solvent in which the compound has low
solubility. Suitable solvents for preparing crystals include polar
and nonpolar solvents.
[0484] In one method to prepare crystals, the compound of the
present invention is suspended and/or stirred in a suitable solvent
to afford a slurry, which may be heated to promote dissolution. The
term "slurry", as used herein, means a saturated solution of the
compound and a solvent at a given temperature. Suitable solvents in
this regard include, for example, polar aprotic solvents, and polar
protic solvents, and nonpolar solvents, and mixtures of two or more
of these.
[0485] Suitable polar aprotic solvents include, for example,
dicholomethane (CH.sub.2Cl.sub.2 or DCM), tetrahydrofuran (THF),
acetone, methyl ethyl ketone (MEK), dimethylformamide (DMF),
dimethylacetamide (DMAC),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),
formamide, N-methylacetamide, N-methylformamide, acetonitrile (ACN
or MeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate,
methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate
(IpOAc), butyl acetate (BuOAc), t-butyl acetate, hexachloroacetone,
dioxane, sulfolane, N,N-dimethylpropionamide, nitromethane,
nitrobenzene and hexamethylphosphoramide.
[0486] Suitable polar protic solvents include, for example,
alcohols and glycols, such as H.sub.2O, methanol, ethanol,
1-propanol, 2-propanol, isopropanol (IPA), 1-butanol (1-BuOH),
2-butanol (2-BuOH), i-butyl alcohol, t-butyl alcohol,
2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene
glycol, 2-methoxyethanol, 2-ethoxyethanol, diethylene glycol, 1-,
2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene
glycol monomethyl ether, diethylene glycol monoethyl ether,
cyclohexanol, benzyl alcohol, phenol, glycerol and methyl t-butyl
ether (MTBE).
[0487] Preferred solvents include, for example, acetone, H.sub.2O,
CH.sub.2Cl.sub.2, methanol, ethanol, MEK, IPA, and EtOAc.
[0488] Other solvents suitable for the preparation of slurries, in
addition to those exemplified above, would be apparent to one
skilled in the art, based on the present disclosure.
[0489] Seed crystals may be added to any crystallization mixture to
promote crystallization. As will be clear to the skilled artisan,
seeding is used as a means of controlling growth of a particular
crystalline form or as a means of controlling the particle size
distribution of the crystalline product. Accordingly, calculation
of the amount of seeds needed depends on the size of the seed
available and the desired size of an average product particle as
described, for example, in "Programmed cooling of batch
crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering
Science, 1971, 26, 369-377. In general, seeds of small size are
needed to effectively control the growth of crystals in the batch.
Seeds of small size may be generated by sieving, milling, or
micronizing of larger crystals, or by micro-crystallization of
solutions. Care should be taken that milling or micronizing of
crystals does not result in any change in crystallinity of the
desired crystal form or form conversions (i.e. change to amorphous
or to another polymorph).
[0490] A cooled mixture may be filtered under vacuum, and the
isolated solids may be washed with a suitable solvent, such as cold
recrystallization solvent, and dried under a nitrogen purge to
afford the desired crystalline form. The isolated solids may be
analyzed by a suitable spectroscopic or analytical technique, such
as SSNMR, DSC, PXRD, or the like, to assure formation of the
preferred crystalline form of the product. The resulting
crystalline form is typically produced in an amount of greater than
about 70 weight % isolated yield, but preferably greater than 90
weight % based on the weight of the compound originally employed in
the crystallization procedure. The product may be comilled or
passed through a mesh screen to delump the product, if
necessary.
[0491] Crystalline forms may be prepared directly from the reaction
medium of the final process step for preparing the compound of the
present invention. This may be achieved, for example, by employing
in the final process step a solvent or mixture of solvents from
which the compound may be crystallized. Alternatively, crystalline
forms may be obtained by distillation or solvent addition
techniques. Suitable solvents for this purpose include any of those
solvents described herein, including protic polar solvents such as
alcohols, and aprotic polar solvents such as ketones.
[0492] By way of general guidance, the reaction mixture may be
filtered to remove any undesired impurities, inorganic salts, and
the like, followed by washing with reaction or crystallization
solvent. The resulting solution may be concentrated to remove
excess solvent or gaseous constituents. If distillation is
employed, the ultimate amount of distillate collected may vary,
depending on process factors including, for example, vessel size,
stirring capability, and the like, by way of general guidance, the
reaction solution may be distilled to about 1/10 the original
volume before solvent replacement is carried out. The reaction may
be sampled and assayed to determine the extent of the reaction and
the wt % product in accordance with standard process techniques. If
desired, additional reaction solvent may be added or removed to
optimize reaction concentration. Preferably, the final
concentration is adjusted to about 50 wt % at which point a slurry
typically results.
[0493] It may be preferable to add solvents directly to the
reaction vessel without distilling the reaction mixture. Preferred
solvents for this purpose are those which may ultimately
participate in the crystalline lattice as discussed above in
connection with solvent exchange. Although the final concentration
may vary depending on desired purity, recovery and the like, the
final concentration of the in solution is preferably about 4% to
about 7%. The reaction mixture may be stirred following solvent
addition and simultaneously warmed. By way of illustration, the
reaction mixture may be stirred for about 1 hour while warming to
about 70.degree. C. The reaction is preferably filtered hot and
washed with either the reaction solvent, the solvent added or a
combination thereof. Seed crystals may be added to any
crystallization solution to initiate crystallization.
[0494] The various forms described herein may be distinguishable
from one another through the use of various analytical techniques
known to one of ordinary skill in the art. Such techniques include,
but are not limited to, solid state nuclear magnetic resonance
(SSNMR) spectroscopy, X-ray powder diffraction (PXRD), differential
scanning calorimetry (DSC), and/or thermogravimetric analysis
(TGA).
[0495] One of ordinary skill in the art will appreciate that an
X-ray diffraction pattern may be obtained with a measurement error
that is dependent upon the measurement conditions employed. In
particular, it is generally known that intensities in a X-ray
diffraction pattern may fluctuate depending upon measurement
conditions employed. It should be further understood that relative
intensities may also vary depending upon experimental conditions
and, accordingly, the exact order of intensity should not be taken
into account. Additionally, a measurement error of diffraction
angle for a conventional X-ray diffraction pattern is typically
about 5% or less, and such degree of measurement error should be
taken into account as pertaining to the aforementioned diffraction
angles. Consequently, it is to be understood that the crystal forms
of the instant invention are not limited to the crystal forms that
provide X-ray diffraction patterns completely identical to the
X-ray diffraction patterns depicted in the accompanying Figures
disclosed herein. Any crystal forms that provide X-ray diffraction
patterns substantially identical to those disclosed in the
accompanying Figures fall within the scope of the present
invention. The ability to ascertain substantial identities of X-ray
diffraction patterns is within the purview of one of ordinary skill
in the art.
[0496] The crystalline forms of the compound of the present
invention may be formulated into pharmaceutical compositions and/or
employed in therapeutic and/or prophylactic methods. These methods
include, but are not limited to, the administration of the
crystalline compound, alone or in combination with one or more
other pharmaceutically active agents, including agents that may be
useful in the treatment of the disorders mentioned herein.
[0497] The crystalline forms of the compound of the present
invention and pharmaceutical composition thereof may be useful in
inhibiting Factor XIa. Accordingly, the present invention provides
methods for the treatment and/or prevention of thromboembolic
disorders in mammals (i.e., factor XIa-associated disorders). In
general, a thromboembolic disorder is a circulatory disease caused
by blood clots (i.e., diseases involving fibrin formation, platelet
activation, and/or platelet aggregation). The term "thromboembolic
disorders" as used herein includes arterial cardiovascular
thromboembolic disorders, venous cardiovascular thromboembolic
disorders, and thromboembolic disorders in the chambers of the
heart. The term "thromboembolic disorders" as used herein also
includes specific disorders selected from, but not limited to,
unstable angina or other acute coronary syndromes, atrial
fibrillation, first or recurrent myocardial infarction, ischemic
sudden death, transient ischemic attack, stroke, atherosclerosis,
peripheral occlusive arterial disease, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism, coronary arterial
thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney
embolism, pulmonary embolism, and thrombosis resulting from (a)
prosthetic valves or other implants, (b) indwelling catheters, (c)
stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other
procedures in which blood is exposed to an artificial surface that
promotes thrombosis. It is noted that thrombosis includes occlusion
(e.g. after a bypass) and reocclusion (e.g., during or after
percutaneous transluminal coronary angioplasty). The thromboembolic
disorders may result from conditions including but not limited to
atherosclerosis, surgery or surgical complications, prolonged
immobilization, arterial fibrillation, congenital thrombophilia,
cancer, diabetes, effects of medications or hormones, and
complications of pregnancy. The anticoagulant effect of compounds
of the present invention is believed to be due to inhibition of
factor XIa or thrombin.
[0498] The methods preferably comprise administering to a patient a
pharmaceutically effective amount of the novel crystals of the
present invention, preferably in combination with one or more
pharmaceutically acceptable carriers and/or excipients. The
relative proportions of active ingredient and carrier and/or
excipient may be determined, for example, by the solubility and
chemical nature of the materials, chosen route of administration
and standard pharmaceutical practice.
[0499] The crystalline forms of the compound may be administered to
a patient in such oral dosage forms as tablets, capsules (each of
which includes sustained release or timed release formulations),
pills, powders, granules, elixirs, tinctures, suspensions, syrups,
and emulsions. They may also be administered in intravenous (bolus
or infusion), intraperitoneal, subcutaneous, or intramuscular form,
all using dosage forms well known to those of ordinary skill in the
pharmaceutical arts. They may be administered alone, but generally
will be administered with a pharmaceutical carrier selected on the
basis of the chosen route of administration and standard
pharmaceutical practice.
[0500] The dosage regimen for the crystalline forms of the compound
will, of course, vary depending upon known factors, such as the
pharmacodynamic characteristics of the particular agent and its
mode and route of administration; the species, age, sex, health,
medical condition, and weight of the recipient; the nature and
extent of the symptoms; the kind of concurrent treatment; the
frequency of treatment; the route of administration, the renal and
hepatic function of the patient, and the effect desired. A
physician or veterinarian can determine and prescribe the effective
amount of the drug required to prevent, counter, or arrest the
progress of the thromboembolic disorder. Obviously, several unit
dosage forms may be administered at about the same time. The dosage
of the crystalline form of the compound that will be most suitable
for prophylaxis or treatment may vary with the form of
administration, the particular crystalline form of the compound
chosen and the physiological characteristics of the particular
patient under treatment. Broadly, small dosages may be used
initially and, if necessary, increased by small increments until
the desired effect under the circumstances is reached.
[0501] By way of general guidance, in the adult, suitable doses may
range from about 0.001 to about 1000 mg/Kg body weight, and all
combinations and subcombinations of ranges and specific doses
therein. Preferred doses may be from about 0.01 to about 100 mg/kg
body weight per day by inhalation, preferably 0.1 to 70, more
preferably 0.5 to 20 mg/Kg body weight per day by oral
administration, and from about 0.01 to about 50, preferably 0.01 to
10 mg/Kg body weight per day by intravenous administration. In each
particular case, the doses may be determined in accordance with the
factors distinctive to the subject to be treated, such as age,
weight, general state of health and other characteristics which can
influence the efficacy of the medicinal product. The crystalline
forms of the compound may be administered in a single daily dose,
or the total daily dosage may be administered in divided doses of
two, three, or four times daily.
[0502] For oral administration in solid form such as a tablet or
capsule, the crystalline forms of the compound can be combined with
a non-toxic, pharmaceutically acceptable inert carrier, such as
lactose, starch, sucrose, glucose, methylcellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like.
[0503] Preferably, in addition to the active ingredient, solid
dosage forms may contain a number of additional ingredients
referred to herein as "excipients". These excipients include among
others diluents, binders, lubricants, glidants and disintegrants.
Coloring agents may also be incorporated. "Diluents", as used
herein, are agents which impart bulk to the formulation to make a
tablet a practical size for compression. Examples of diluents are
lactose and cellulose. "Binders", as used herein, are agents used
to impart cohesive qualities to the powered material to help ensure
the tablet will remain intact after compression, as well as
improving the free-flowing qualities of the powder. Examples of
typical binders are lactose, starch and various sugars.
"Lubricants", as used herein, have several functions including
preventing the adhesion of the tablets to the compression equipment
and improving the flow of the granulation prior to compression or
encapsulation. Lubricants are in most cases hydrophobic materials.
Excessive use of lubricants is undesired, however, as it may result
in a formulation with reduced disintegration and/or delayed
dissolution of the drug substance. "Glidants", as used herein,
refer to substances which may improve the flow characteristics of
the granulation material. Examples of glidants include talc and
colloidal silicon dioxide. "Disintegrants", as used herein, are
substances or a mixture of substances added to a formulation to
facilitate the breakup or disintegration of the solid dosage form
after administration. Materials that may serve as disintegrants
include starches, clays, celluloses, algins, gums and cross-linked
polymers. A group of disintegrants referred to as
"super-disintegrants" generally are used at a low level in the
solid dosage form, typically 1% to 10% by weight relative to the
total weight of the dosage unit. Croscarmellose, crospovidone and
sodium starch glycolate represent examples of a cross-linked
cellulose, a cross-linked polymer and a cross-linked starch,
respectively. Sodium starch glycolate swells seven- to twelve-fold
in less than 30 seconds effectively disintegrating the granulations
that contain it.
[0504] The disintegrant preferably used in the present invention is
selected from the group comprising modified starches,
croscarmellose sodium, carboxymethylcellulose calcium and
crospovidone. A more preferred disintegrant in the present
invention is a modified starch such as sodium starch glycolate.
[0505] Preferred carriers include capsules or compressed tablets
which contain the solid pharmaceutical dosage forms described
herein. Preferred capsule or compressed tablet forms generally
comprise a therapeutically effective amount of the crystalline
forms of the compound and one or more disintegrants in an amount
greater than about 10% by weight relative to the total weight of
the contents of the capsule or the total weight of the tablet.
[0506] Preferred capsule formulations may contain the crystalline
forms of the compound in an amount from about 5 to about 1000 mg
per capsule. Preferred compressed tablet formulations contain the
crystalline forms of the compound in an amount from about 5 mg to
about 800 mg per tablet. More preferred formulations contain about
50 to about 200 mg per capsule or compressed tablet. Preferably,
the capsule or compressed tablet pharmaceutical dosage form
comprises a therapeutically effective amount of the crystalline
forms; a surfactant; a disintegrant; a binder; a lubricant; and
optionally additional pharmaceutically acceptable excipients such
as diluents, glidants and the like; wherein the disintegrant is
selected from modified starches; croscarmellose sodium,
carboxymethylcellulose calcium and crospovidone.
[0507] For oral administration in liquid form, the crystalline
forms of the compound can be combined with any oral, non-toxic
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water and the like. The liquid composition may contain a
sweetening agent which to make the compositions more palatable. The
sweetening agent can be selected from a sugar such as sucrose,
mannitol, sorbitol, xylitol, lactose, etc. or a sugar substitute
such as cyclamate, saccaharin, aspartame, etc. If sugar substitutes
are selected as the sweetening agent the amount employed in the
compositions of the invention will be substantially less than if
sugars are employed. Taking this into account, the amount of
sweetening agent may range from about 0.1 to about 50% by weight,
and all combinations and subcombinations of ranges and specific
amounts therein. Preferred amounts range from about 0.5 to about
30% by weight.
[0508] The more preferred sweetening agents are the sugars and
particularly sucrose. The particle size of the powdered sucrose
used has been found to have a significant influence in the physical
appearance of the finished composition and its ultimate acceptance
for taste. The preferred particle size of the sucrose component
when used is in the range of from 200 to less than 325 mesh US
Standard Screen, and all combinations and subcombinations of ranges
and specific particle sizes therein.
[0509] Sterile injectable solutions may be prepared by
incorporating the crystalline forms of the compound in the required
amounts, in the appropriate solvent, with various of the other
ingredients enumerated herein, as required, followed by filtered
sterilization. Generally, dispersions may be prepared by
incorporating the sterilized active ingredient into a sterile
vehicle which contains the dispersion medium and any other required
ingredients. In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation
may include vacuum drying and the freeze drying technique which may
yield a powder of the active ingredient, plus any additional
desired ingredient from the previously sterile-filtered solution
thereof.
[0510] As would be apparent to a person of ordinary skill in the
art, once armed with the teachings of the present disclosure, when
dissolved, a crystalline compound loses its crystalline structure,
and is therefore considered to be a solution of the compound. All
forms of the present invention, however, may be used for the
preparation of liquid formulations in which the compound may be,
for example, dissolved or suspended. In addition, the crystalline
forms of the compound may be incorporated into solid
formulations.
[0511] The liquid compositions may also contain other components
routinely utilized in formulating pharmaceutical compositions. One
example of such components is lecithin. Its use in compositions of
the invention as an emulsifying agent in the range of from 0.05 to
1% by weight, and all combinations and subcombinations of ranges
and specific amounts therein. More preferably, emulsifying agents
may be employed in an amount of from about 0.1 to about 0.5% by
weight. Other examples of components that may be used are
antimicrobial preservatives, such as benzoic acid or parabens;
suspending agents, such as colloidal silicon dioxide; antioxidants;
topical oral anesthetics; flavoring agents; and colorants.
[0512] The selection of such optional components and their level of
use in the compositions of the invention is within the level of
skill in the art and will be even better appreciated from the
working examples provided hereinafter.
[0513] The crystalline forms of the compound may also be coupled
with soluble polymers as targetable drug carriers. Such polymers
can include polyvinylpyrrolidine pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethyl-aspartamidephenol or polyethylene oxide-polylysine
substituted with palmitolyl residues. Furthermore, the crystalline
compound 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 crosslinked or amphipathic block copolymers of hydrogels.
[0514] Gelatin capsules of the crystalline forms of the compound
may contain the crystalline compound and the liquid or solid
compositions described herein. Gelatin capsules may also contain
powdered carriers such as lactose, starch, cellulose derivatives,
magnesium stearate, stearic acid and the like. Similar diluents can
be used to make compressed tablets. Both tablets and capsules can
be manufactured as sustained release products to provide for
continuous release of medication over a period of hours. Tablets
can be sugar coated or film coated to mask any unpleasant taste and
to protect the tablet from the atmosphere or enteric coated for
selective disintegration in the gastrointestinal track.
[0515] In general, water, a suitable oil, saline, aqueous dextrose
(glucose), and related sugar solutions and glycols, such as
propylene glycol or polyethylene glycols are suitable carriers for
parenteral solutions. Solutions for parenteral solutions are
prepared by dissolving the crystalline compound in the carrier and,
if necessary, adding buffering substances. Anti-oxidizing agents
such as sodium bisulfate, sodium sulfite, or ascorbic acid either
alone or combined, are suitable stabilizing agents. Citric acid and
its salts and sodium EDTA may also be employed. Parenteral
solutions may also contain preservatives, such as benzalkonium
chloride, methyl- or propyl-paraben and chlorobutanol.
[0516] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Co., the
disclosures of which are hereby incorporated herein by reference,
in their entireties. Useful pharmaceutical dosage-forms for
administration of the compounds of this invention can be
illustrated as follows:
Capsules
[0517] A large number of unit capsules can be prepared by filling
standard two-piece hard gelatin capsules each with 100 mg of
powdered active ingredient (i.e., Factor XIa inhibitor), 150 mg of
lactose, 50 mg of cellulose, and 6 mg magnesium stearate.
Soft Gelatin Capsules
[0518] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil or olive oil can be prepared and
injected by means of a positive displacement pump into gelatin to
form soft gelatin capsules containing 100 mg of the active
ingredient. The capsules should then be washed and dried.
Tablets
[0519] A large number of tablets can be prepared by conventional
procedures so that the dosage unit is 100 mg of active ingredient,
0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate,
275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg
of lactose. Appropriate coatings may be applied to increase
palatability or delay absorption.
Suspension
[0520] An aqueous suspension can be prepared for oral
administration so that each 5 mL contain 25 mg of finely divided
active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg
of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025
mg of vanillin.
Injectable
[0521] A parenteral composition suitable for administration by
injection can be prepared by stirring 1.5% by weight of active
ingredient in 10% by volume propylene glycol and water. The
solution is sterilized by commonly used techniques.
Nasal Spray
[0522] An aqueous solution is prepared such that each 1 mL contains
10 mg of active ingredient, 1.8 mg methylparaben, 0.2 mg
propylparaben and 10 mg methylcellulose. The solution is dispensed
into 1 mL vials.
Lung Inhaler
[0523] A homogeneous mixture of the active ingredient in
polysorbate 80 is prepared such that the final concentration of the
active ingredient will be 10 mg per container and the final
concentration of polysorbate 80 in the container will be 1% by
weight. The mixture is dispensed into each can, the valves are
crimped onto the can and the required amount of
dichlorotetrafluoroethane is added under pressure.
[0524] The preferred crystalline form of the compound may serve as
component (a) of this invention and can independently be in any
dosage form, such as those described above, and can also be
administered in various combinations, as described above. In the
following description component (b) is to be understood to
represent one or more agents as described herein suitable for
combination therapy.
[0525] Thus, the crystalline forms of the compound may be used
alone or in combination with other diagnostic, anticoagulant,
antiplatelet, fibrinolytic, antithrombotic, and/or profibrinolytic
agents. For example, adjunctive administration of Factor XIa
inhibitors with standard heparin, low molecular weight heparin,
direct thrombin inhibitors (i.e. hirudin), aspirin, fibrinogen
receptor antagonists, streptokinase, urokinase and/or tissue
plasminogen activator may result in improved antithrombotic or
thrombolytic efficacy or efficiency. The crystals described herein
may be administered to treat thrombotic complications in a variety
of animals, such as primates, including humans, sheep, horses,
cattle, pigs, dogs, rats and mice. Inhibition of Factor XIa may be
useful not only in the anticoagulant therapy of individuals having
thrombotic conditions, but also when inhibition of blood
coagulation may be required, such as to prevent coagulation of
stored whole blood and to prevent coagulation in other biological
samples for testing or storage. Thus, any Factor XIa inhibitor,
including the crystalline forms of the compound as described
herein, can be added to or contacted with any medium containing or
suspected of containing Factor XIa and in which it may be desired
to inhibit blood coagulation.
[0526] The crystalline forms of the compound may be used in
combination with any antihypertensive agent or cholesterol or lipid
regulating agent, or concurrently in the treatment of restenosis,
atherosclerosis or high blood pressure. Some examples of agents
that may be useful in combination with a novel form of the compound
according to the present invention in the treatment of high blood
pressure include, for example, compounds of the following classes:
beta-blockers, ACE inhibitors, calcium channel antagonists and
alpha-receptor antagonists. Some examples of agents that may be
useful in combination with a compound according to the invention in
the treatment of elevated cholesterol levels or disregulated lipid
levels include compounds known to be HMGCoA reductase inhibitors,
or compounds of the fibrate class.
[0527] Accordingly, components (a) and (b) of the present invention
may be formulated together, in a single dosage unit (that is,
combined together in one capsule, tablet, powder, or liquid, etc.)
as a combination product. When component (a) and (b) are not
formulated together in a single dosage unit, the component (a) may
be administered at the same time as component (b) or in any order;
for example component (a) of this invention may be administered
first, followed by administration of component (b), or they may be
administered in the reverse order. If component (b) contains more
than one agent, these agents may be administered together or in any
order. When not administered at the same time, preferably the
administration of component (a) and (b) occurs less than about one
hour apart. Preferably, the route of administration of component
(a) and (b) is oral. Although it may be preferable that component
(a) and component (b) both be administered by the same route (that
is, for example, both orally) or dosage form, if desired, they may
each be administered by different routes (that is, for example, one
component of the combination product may be administered orally,
and another component may be administered intravenously) or dosage
forms.
[0528] Pharmaceutical kits which may be useful for the treatment of
various disorders, and which comprise a therapeutically effective
amount of a pharmaceutical composition comprising a novel form of
the compound in one or more sterile containers, are also within the
ambit of the present invention. The kits may further comprise
conventional pharmaceutical kit components which will be readily
apparent to those skilled in the art, once armed with the present
disclosure. Sterilization of the container may be carried out using
conventional sterilization methodology well known to those skilled
in the art.
Example 271
Preparation of Single Crystal Forms H.5-1 and HCl:SA-1
271A: Single Crystal X-Ray Measurement of Forms H.5-1 and
HCl:SA-1
[0529] Single crystal X-ray data were collected on a Bruker AXS
APEX II diffractometer with MicroStarH generator using Cu K.alpha.
radiation (.lamda.=1.5418 .ANG.). Indexing and processing of the
measured X-ray intensity data were carried out with the APEX2
software suite (Bruker AXS, Inc., Madison, Wis., USA). The
structure was solved by direct methods and refined on the basis of
observed reflections using SHELXTL crystallographic package (Bruker
AXS, Inc., Madison, Wis., USA). The derived atomic parameters
(coordinates and temperature factors) were refined through full
matrix least-squares. The function minimized in the refinements was
.SIGMA..sub.w(|F.sub.o|-|F.sub.c|).sup.2. R is defined as
.SIGMA..parallel.F.sub.o|-|F.sub.c.parallel./.SIGMA.|F.sub.o|,
while
R.sub.w=[.SIGMA..sub.w(|F.sub.o|-|F.sub.c|).sup.2/.SIGMA..sub.w|F.sub.o|.-
sup.2].sup.1/2, where w is an appropriate weighting function based
on errors in the observed intensities. Difference Fourier maps were
examined at all stages of refinement. All non-hydrogen atoms were
refined with anisotropic thermal displacement parameters. Hydrogen
atoms were calculated from an idealized geometry with standard bond
lengths and angles and refined using a riding model.
271B: Preparation of Single Crystal Form H.5-1
[0530] Crystal form H.5-1 (hemi-hydrate) was prepared by adding 3
mg of
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid to 0.7 mL of ethyl acetate and methanol solution
(1:1). Yellow prism shaped crystals were obtained after one day of
slow evaporation of solution at room temperature.
Crystal Structure Data:
[0531] Unit cell dimensions: a=13.6547(3) .ANG. b=18.7590(3) .ANG.
c=24.7370(5) .ANG. .alpha.=90.degree. .beta.=90.degree.
.gamma.=90.degree.
Volume=6336.3(2) .ANG..sup.3
[0532] Crystal system: Orthorhombic Space group: 12(1)2(1)2(1)
Molecules/asymmetric unit: 1 Density (calculated)=1.401 Mg/m.sup.3
Measurement of the crystalline form is at a temperature of about
23.degree. C.
TABLE-US-00022 TABLE 20 Atomic coordinates (.times.10.sup.4) and
equivalent isotropic displacement parameters (.ANG..sup.2 .times.
10.sup.3) for Compound (I) H.5-1. x y z U(eq)* Cl(1) 1142(1)
8638(1) 1383(1) 89(1) F(1) 1133(2) 7271(1) 862(1) 67(1) O(1)
1102(2) 5533(1) -724(1) 52(1) O(2) -779(1) 4373(1) 15(1) 48(1) O(3)
-4534(2) 4606(1) -1807(1) 62(1) O(4) -3952(2) 3964(2) -2477(1)
109(1) O(5) 3532(2) 3748(1) 1408(1) 63(1) N(1) 1127(2) 8164(1)
-968(1) 56(1) N(2) 1654(2) 7703(2) -1270(1) 73(1) N(3) 1416(3)
7825(2) -1768(2) 91(1) N(4) 759(3) 8363(2) -1810(1) 97(1) N(5)
1100(2) 5019(1) 102(1) 35(1) N(6) -311(2) 4095(1) -837(1) 46(1)
N(7) 2057(2) 3304(1) 1616(1) 43(1) N(8) 2218(2) 3810(1) 2664(1)
57(1) C(1) 1203(2) 8493(2) 699(1) 57(1) C(2) 1257(2) 9049(2) 342(2)
59(1) C(3) 1267(2) 8920(2) -203(2) 54(1) C(4) 1218(2) 8232(2)
-398(1) 46(1) C(5) 1210(2) 7639(1) -54(1) 41(1) C(6) 1193(2)
7804(2) 496(1) 49(1) C(7) 593(3) 8565(2) -1310(2) 81(1) C(8)
1150(2) 6900(1) -250(1) 42(1) C(9) 1279(2) 6305(1) 22(1) 45(1)
C(10) 1151(2) 5598(1) -230(1) 38(1) C(11) 947(2) 4321(1) -154(1)
33(1) C(12) 1229(2) 3707(1) 214(1) 36(1) C(13) 1543(2) 3812(1)
746(1) 35(1) C(14) 1604(2) 4554(1) 977(1) 38(1) C(15) 912(2)
5043(1) 686(1) 39(1) C(16) 1171(2) 3021(1) 5(1) 50(1) C(17) 1412(2)
2438(2) 321(1) 59(1) C(18) 1711(2) 2537(2) 845(1) 55(1) C(19)
1785(2) 3214(1) 1053(1) 41(1) C(20) -134(2) 4263(1) -318(1) 35(1)
C(21) -1221(2) 4098(2) -1108(1) 42(1) C(22) -1223(3) 3919(2)
-1650(1) 76(1) C(23) -2072(3) 3948(2) -1947(1) 78(1) C(24) -2943(2)
4163(2) -1711(1) 47(1) C(25) -2940(2) 4313(1) -1170(1) 40(1) C(26)
-2096(2) 4271(1) -864(1) 42(1) C(27) -3846(3) 4228(2) -2041(1)
57(1) C(28) 2912(2) 3605(2) 1747(1) 45(1) C(29) 3099(2) 3770(2)
2335(1) 56(1) C(30) 1304(2) 3112(2) 2016(1) 59(1) C(31) 1666(3)
3151(2) 2584(1) 67(1) C(32) 2477(4) 3923(2) 3236(1) 90(1) O(1S)
1006(2) 5000 2500 50(1) *U(eq) is defined as one third of the trace
of the orthogonalized U.sup.ij tensor.
271C: Preparation of Single Crystal Form HCl:SA-1
[0533] Crystal form HCl:SA-1 (solvated mono-HCl salt) was prepared
by adding 2 mg of Compound (I) to 0.7 mL of methanol, 2-butanone
and butyl acetate solution (2:1:1). Yellow prism shaped crystals
were obtained after one day of slow evaporation of solution at room
temperature.
Crystal Structure Data:
[0534] Unit cell dimensions: a=8.3746(2) .ANG. b=20.2236(5) .ANG.
c=21.3099(6) .ANG. .alpha.=90.degree. .beta.=90.degree.
.gamma.=90.degree.
Volume=3609.14(16) .ANG..sup.3
[0535] Crystal system: Orthorhombic Space group: P2(1)2(1)2(1)
Molecules/asymmetric unit: 1 Density (calculated)=1.368 Mg/m.sup.3
wherein measurement of the crystalline form is at a temperature of
about 23.degree. C.
TABLE-US-00023 TABLE 21 Atomic coordinates (.times.10.sup.4) and
equivalent isotropic displacement parameters (.ANG..sup.2 .times.
10.sup.3) for Compound (I) HCl:SA-1 x y z U(eq)* Cl(2) 4183(3)
7590(1) 7388(1) 73(1) C(1) 5350(8) 5357(3) -5(3) 58(2) C(2) 5189(9)
5113(3) 606(3) 62(2) C(3) 6122(9) 4563(3) 743(3) 62(2) C(4) 7131(8)
4259(3) 322(4) 63(2) C(5) 7186(9) 4508(4) -278(4) 71(2) C(6)
6312(9) 5055(4) -435(3) 72(2) C(7) 3624(12) 6026(4) -680(4) 87(2)
C(8) 4120(11) 5408(4) 1083(3) 76(2) C(9) 3311(10) 5137(4) 1500(4)
78(2) C(10) 2308(8) 5511(3) 1938(3) 57(2) C(11) 481(11) 4538(3)
1991(4) 79(2) C(12) -331(9) 4186(3) 2541(4) 71(2) C(13) -1725(8)
4599(3) 2754(3) 56(2) C(14) -1568(8) 5294(3) 2755(3) 51(2) C(15)
41(8) 5604(3) 2612(3) 50(2) C(16) -3161(9) 4326(3) 2946(3) 59(2)
C(17) -4444(9) 4719(4) 3106(3) 69(2) C(18) -4286(9) 5400(4) 3088(4)
70(2) C(19) -2842(8) 5689(3) 2911(3) 60(2) C(20) 938(8) 5679(3)
3244(3) 54(2) C(21) 971(8) 6440(3) 4151(3) 53(2) C(22) 2064(8)
6122(3) 4526(3) 61(2) C(23) 2282(8) 6336(4) 5147(3) 62(2) C(24)
1416(8) 6856(3) 5378(3) 54(2) C(25) 315(9) 7169(3) 4999(3) 64(2)
C(26) 103(9) 6969(3) 4387(3) 62(2) C(27) 1629(9) 7122(4) 6032(3)
67(2) C(28) -4232(14) 3275(4) 2493(4) 101(3) C(29) -3869(13)
2532(4) 2464(4) 96(3) C(30) -2699(9) 2550(3) 3483(3) 66(2) C(31)
-2625(9) 3285(3) 3458(3) 60(2) C(32) -5588(10) 2286(4) 3384(5)
102(3) Cl(1) 8255(3) 3595(1) 563(1) 95(1) F(1) 6062(6) 4310(2)
1340(2) 93(1) N(1) 4510(8) 5920(3) -180(3) 71(2) N(2) 4579(11)
6492(3) 148(3) 96(2) N(3) 3701(14) 6911(4) -149(5) 123(3) N(4)
3089(12) 6638(4) -679(4) 116(3) N(5) 1037(7) 5207(2) 2179(2) 58(1)
N(6) 645(7) 6263(2) 3524(2) 58(1) N(7) -3312(7) 3606(2) 2977(3)
60(1) N(8) -3972(7) 2250(3) 3097(3) 68(2) O(1) 2620(6) 6081(2)
2096(2) 70(1) O(2) 1744(6) 5235(2) 3465(2) 63(1) O(3) 971(7)
7602(3) 6233(2) 91(2) O(4) 2705(7) 6777(2) 6357(2) 81(2) O(5)
-1867(7) 3575(2) 3864(3) 80(2) O(1S) 8222(7) 5981(2) 1227(2) 70(1)
O(2S) 489(6) 5435(3) 69(3) 103(2) O(3SB) 9450(30) 6486(13) 631(17)
126(8) O(3SA) 9170(30) 6463(11) 1022(13) 136(7) O(3SC) 9560(30)
6237(13) 140(14) 137(8) *U(eq) is defined as one third of the trace
of the orthogonalized U.sup.ij tensor.
Example 272
272A: Preparation of Form HCl:SA-1
[0536] In a reactor, 415 g of dried crude Compound (I) was
dissolved in 9.0 kg of a solution of 200 Proof Ethanol and purified
water (70:30). The batch was heated to 66.degree. C. and polish
filtered into another reactor. 708 g of the Ethanol/water solution
was used to rinse the first reactor and transferred through the
filter into the reactor containing the solution mixture. The
temperature of the batch was lowered to 50.degree. C. and 2.24 g of
Compound (I) was added in one portion. After 30 minutes the batch
was cooled to 0.degree. C. over 4 h and allowed to age at that
temperature for 60 minutes. The temperature of the batch was then
increased to 50.degree. C. over a 2 h period and held for an
additional 30 minutes. Again, the batch temperature was then
reduced to 0.degree. C. over 4 h and 2.9 L of 200 Proof ethanol was
added to the batch. The slurry was filtered at 0.degree. C. and the
wet cake was washed twice with 0.9 L of 200 Proof ethanol. The wet
cake was dried in a vacuum oven at 40.degree. C. for a minimum of
12 h and until the ethanol content is <6.6 weight percent. The
obtained crystal was subjected to PXRD (GADDS-NB), hybrid PXRD
(from isostructural analog), DSC and TGA analyses and the results
are shown in FIGS. 1, 4, and 7.
[0537] PXRD data were obtained using a Bruker C2 GADDS. The
radiation was Cu K.alpha. (40 KV, 40 mA). The sample-detector
distance was 15 cm. Powder samples were placed in sealed glass
capillaries of 1 mm or less in diameter; the capillary was rotated
during data collection. Data were collected approximately for
2.ltoreq.2.theta..ltoreq.35.degree. with a sample exposure time of
at least 1000 seconds. The resulting two-dimensional diffraction
arcs were integrated to create a traditional 1-dimensional PXRD
pattern with a step size of 0.05 degrees 2.theta. in the
approximate range of 2 to 35 degrees 2.theta..
[0538] "Hybrid" simulated powder X-ray patterns were generated as
described in the literature (Yin. S.; Scaringe, R. P.; DiMarco, J.;
Galella, M. and Gougoutas, J. Z., American Pharmaceutical Review,
2003, 6, 2, 80). The room temperature cell parameters were obtained
by performing a cell refinement using the CellRefine.xls program.
Input to the program includes the 2-theta position of ca. 10
reflections, obtained from the experimental room temperature powder
pattern; the corresponding Miller indices, hkl, were assigned based
on the single-crystal data collected for an isostructural analog. A
crystal structure for the molecule of interest was generated in a
two step process: (1) by replacing the analog molecule in the
experimental analog crystal structure with the molecule of
interest. This step fixes the orientation and position of the
molecule of interest in the unit cell of the analog compound; (2)
Inserting the molecule of interest into the room temperature cell
obtained from the experimental PXRD of the molecule of interest, as
described above. In this step, the molecules are inserted in a
manner that retains the size and shape of the molecule and the
position of the molecules with respect to the cell origin, but,
allows intermolecular distances to expand/contract with the cell. A
new (hybrid) PXRD was calculated (by either of the software
programs, Alex or LatticeView) based on the crystal structure
generated as described above.
DSC (Open Pan)
[0539] DSC experiments were performed in a TA INSTRUMENTS.RTM.
model Q2000, Q1000 or 2920. The sample (about 2-10 mg) was weighed
in an aluminum pan and recorded accurately recorded to a hundredth
of a milligram, and transferred to the DSC. The instrument was
purged with nitrogen gas at 50 mL/min. Data were collected between
room temperature and 300.degree. C. at 10.degree. C./min heating
rate. The plot was made with the endothermic peaks pointing
down.
TGA (Open Pan)
[0540] TGA experiments were performed in a TA INSTRUMENTS.RTM.
model Q5000, Q500 or 2950. The sample (about 4-30 mg) was placed in
a platinum pan previously tared. The weight of the sample was
measured accurately and recorded to a thousandth of a milligram by
the instrument. The furnace was purged with nitrogen gas at 100
mL/min. Data were collected between room temperature and
300.degree. C. at 10.degree. C./min heating rate.
Example 273
273A: Preparation of Form H.5-1
[0541] 60 g of dried crude Compound (I) was dissolved in 240 mL of
200 Proof ethanol (4 mL/g) at room temperature. In one portion,
13.25 mL of triethylamine (1.1 equiv) was added and the reaction
mixture was aged for a minimum of 3 h. The solution was cooled to
0.degree. C. and remained at that temperature for a minimum of 30
min. The slurry was filtered and the solids were washed with 30 mL
of 200 Proof ethanol (0.5 mL/g). The wet cake was dissolved in 600
mL of purified water (10 mL/g) and stirred for a minimum of 30 min
at room temperature. The slurry was filtered and the solids were
washed with 120 mL of purified water (2 mL/g) and then 180 mL of
purified water (3 mL/g). The wet cake was dried at 45.degree. C.
under vacuum for a minimum of 12 h. The obtained crystal was
subjected to further analyses and the results are shown in FIGS. 2,
6, and 9.
Example 274
274A: Preparation of Form P13
[0542] A slurry of 6.8 g of Example 271 in 33 mL of methanol (4.9
mL/g) and 102 mL of dichlormethane (15 mL/g) was heated to
40.degree. C. and became a homogeneous solution. Atmospheric
distillation with constant volume addition of dichloromethane (136
mL) was performed over the next hour with batch temperature
maintained at 40.degree. C. The batch was cooled to 15.degree. C.,
and a solvent swap from dichloromethane/methanol solution to ethyl
acetate at constant volume was initiated under reduced pressure
(150 mmHg). The batch temperature was raised to 37.degree. C., 400
mL of ethyl acetate was used to complete the solvent swap with a
remainder of 136 mL of ethyl acetate in the reactor. The batch was
cooled to 20.degree. C. and allowed to age for 12 h. The slurry was
filtered and the resulting wet cake was dried at 50.degree. C.
under reduced pressure for 6 h. The dried material was subjected to
PXRD, Solid-State Nuclear Magnetic Resonance (SSNMR) and the
results are shown in FIGS. 3, 5, 8, 10, and 11.
[0543] Carbon cross polarization magic angle spinning (CPMAS) solid
state NMR experiments were conducted on a Bruker AV III instrument
operating at a proton frequency of 400.1 MHz. Solid samples were
spun at 13 KHz in a 4 mm ZrO.sub.2 rotor. The contact time was 3
milliseconds and was ramped on the proton channel from 50 to 100%.
(A. E. Bennett et al, J. Chem. Phys., 1995, 103, 6951), (G. Metz,
X. Wu and S. O. Smith, J. Magn. Reson. A, 1994, 110, 219-227). The
relaxation delay was maintained at 20 seconds. Proton decoupling
was applied using a TPPM sequence with a 4 microsecond pulse (62.5
KHz nominal band width). The spectral sweep width was 300 ppm
centered at 100 ppm. 4096 data points were acquired and zero filled
to 8192 prior to apodization with 20 Hz line broadening. Typically
2096 free induction decays were coadded. The spectra were
referenced indirectly to TMS using 3-methylglutaric acid (D.
Barich, E. Gorman, M. Zell, and E. Munson, Solid State Nuc. Mag.
Res., 2006, 30, 125-129). Approximately 70 mg of sample was used
for each experiment.
[0544] Fluorine magic angle spinning (MAS) solid state and cross
polarization magic angle spinning (CPMAS) solid state NMR
experiments were conducted on a Bruker AV III instrument operating
at a proton frequency of 400.1 MHz. Solid samples were spun at 11,
12 and 13 KHz in a 4 mm ZrO.sub.2 rotor. Data collected at 13 KHz
is reported. The relaxation delay was maintained at 30 seconds for
the MAS and 5 seconds for the CPMAS experiments. Proton decoupling
was applied to the CPMAS experiments using a TPPM sequence with a 4
microsecond pulse (62.5 KHz nominal band width). The spectral sweep
width was 500 ppm centered at -100 ppm. 4096 data points were
acquired and zero filled to 8192 prior to apodization with 20 Hz
line broadening. Typically 256 free induction decays were coadded.
The spectra were referenced indirectly to CCl.sub.3F using PTFE (at
-122 ppm).
[0545] Various crystalline forms of
(S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(-
4-methyl-2-oxopiperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido-
)benzoic acid and its solvates were prepared and their
characteristic peak positions are tabulated in Table 22. The unit
cell data and other properties for these examples are tabulated in
Tables 23-25. The unit cell parameters were obtained from single
crystal X-ray crystallographic analysis. A detailed account of unit
cells can be found in Chapter 3 of Stout & Jensen, "X-Ray
Structure Determination: A Practical Guide", (MacMillian,
1968).
TABLE-US-00024 TABLE 22 Characteristic diffraction peak positions
(degrees 2.theta. .+-. 0.1) @ RT, based on a high quality pattern
collected with a diffractometer (CuK.alpha.) with a spinning
capillary with 2.theta. calibrated with a NIST other suitable
standard. HCl:SA-1 Free Base H.5-1 Free Base P13 6.0 5.9 8.4 8.3
7.2 8.9 8.7 12.0 12.7 12.3 15.7 17.9 16.2 17.2 16.7 18.9 17.5 20.3
19.9 24.2 20.4 26.1
TABLE-US-00025 TABLE 23 Cell Parameters for Single crystal (input)
and hybrid (refined) for Form HCl: SA-1 Cell Parameter Input
Refined a (.ANG.) 8.3746 8.2562 b (.ANG.) 20.2236 20.2918 c (.ANG.)
21.3099 21.2423 .alpha..degree. 90 90 .beta..degree. 90 90
.gamma..degree. 90 90 Volume (.ANG..sup.3) 3609.14 3558.77
TABLE-US-00026 TABLE 24 Carbon Chemical Shifts (referenced to
external TMS) for P13 No. (ppm) 1 23.8 2 24.8 3 41.1 4 43.0 5 45.1
6 45.9 7 48.5 8 49.0 9 51.0 10 52.4 11 56.8 12 57.6 13 58.6 14 61.7
15 118.1 16 121.7 17 122.0 18 122.5 19 123.0 20 124.2 21 126.1 22
127.1 23 127.9 24 129.0 25 129.9 26 130.5 27 130.6 28 131.8 29
132.6 30 133.3 31 135.0 32 139.9 33 140.4 34 143.6 35 146.1 36
147.3 37 156.6 38 157.9 39 159.2 40 160.4 41 165.7 42 166.3 43
168.7 44 169.7 45 171.4
TABLE-US-00027 TABLE 25 F-19 Chemical Shifts (referenced to
external CCl.sub.3F) for P13 No. (ppm) 1 -109.8 2 -106.3
[0546] Numerous modifications and variations of the present
invention are possible in light of the above teachings. It is
therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise than as
specifically described herein.
* * * * *