U.S. patent application number 13/794380 was filed with the patent office on 2014-06-05 for solid forms of a thiophosphoramidate nucleotide prodrug.
The applicant listed for this patent is Vertex Pharmaceuticals Incorporated. Invention is credited to Lori Ann Ferris, Young Chun Jung, Anuj K. Kuldipkumar, Ales Medek, Praveen Mudunuri, William Aloysius Nugent, Michael Waldo, David Richard Willcox.
Application Number | 20140154210 13/794380 |
Document ID | / |
Family ID | 47997873 |
Filed Date | 2014-06-05 |
United States Patent
Application |
20140154210 |
Kind Code |
A9 |
Kuldipkumar; Anuj K. ; et
al. |
June 5, 2014 |
Solid Forms of a Thiophosphoramidate Nucleotide Prodrug
Abstract
The present application relates to solid state forms, for
example, crystalline forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate, pharmaceutical compositions that can include one or
more solid forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate, and methods of treating or ameliorating diseases
and/or conditions with one or more solid forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate. Also disclosed herein are methods of treating
diseases and/or conditions with one or more solid forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate in combination with one or more other agents.
Inventors: |
Kuldipkumar; Anuj K.;
(Medford, MA) ; Medek; Ales; (Winchester, MA)
; Ferris; Lori Ann; (Medford, MA) ; Mudunuri;
Praveen; (Waltham, MA) ; Jung; Young Chun;
(Lexington, MA) ; Willcox; David Richard;
(Wellesley, MA) ; Waldo; Michael; (Grafton,
MA) ; Nugent; William Aloysius; (Manomet,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vertex Pharmaceuticals Incorporated |
Cambridge |
MA |
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20130266538 A1 |
October 10, 2013 |
|
|
Family ID: |
47997873 |
Appl. No.: |
13/794380 |
Filed: |
March 11, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61613972 |
Mar 21, 2012 |
|
|
|
Current U.S.
Class: |
424/85.7 ;
424/85.4; 514/51; 536/26.8 |
Current CPC
Class: |
C07H 19/06 20130101;
A61K 31/7056 20130101; A61K 38/00 20130101; A61K 31/706 20130101;
A61K 45/06 20130101; A61P 31/14 20180101; C07H 19/10 20130101; A61K
31/7072 20130101; A61K 31/7068 20130101; C07B 2200/13 20130101;
A61K 31/7072 20130101; A61K 2300/00 20130101; A61K 31/7056
20130101; A61K 2300/00 20130101; A61K 31/7064 20130101 |
Class at
Publication: |
424/85.7 ;
536/26.8; 514/51; 424/85.4 |
International
Class: |
C07H 19/10 20060101
C07H019/10; A61K 45/06 20060101 A61K045/06; A61K 31/7072 20060101
A61K031/7072 |
Claims
1-85. (canceled)
86.
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)th-
iophosphoramidate characterized as Form J.
87. Form J of claim 86, wherein the Form J is characterized by one
or more peaks in an X-ray powder diffraction pattern, wherein the
one or more peaks is selected from a peak from about 5.9 to about
6.3 degrees, a peak from about 7.3 to about 7.7 degrees, a peak
from about 11.9 to about 12.3 degrees, a peak from about 13.1 to
about 13.5 degrees, a peak from about 13.8 to about 14.2 degrees, a
peak from about 18.3 to about 18.7 degrees, a peak from about 22.4
to about 22.8 degrees, a peak from about 33.0 to about 33.4
degrees, a peak from about 33.8 to about 34.2 degrees, and a peak
from about 35.1 to about 35.5 degrees.
88. Form J of claim 86, wherein the Form J is characterized by one
or more peaks in an X-ray powder diffraction pattern, wherein the
one or more peaks is selected from a peak at about 6.1 degrees, a
peak at about 7.5 degrees, a peak at about 12.1 degrees, a peak at
about 13.3 degrees, a peak at about 14.0 degrees, a peak at about
18.5 degrees, a peak at about 22.6 degrees, a peak at about 33.2
degrees, a peak at about 34.0 degrees, and a peak at about 35.3
degrees.
89. Form J of claim 88, wherein the Form J is characterized by a
peak at about 6.1 degrees, a peak at about 7.5 degrees, a peak at
about 12.1 degrees, a peak at about 13.3 degrees, a peak at about
14.0 degrees, and a peak at about 18.5 degrees in an X-ray powder
diffraction pattern.
90. Form J of claim 89, wherein the Form J is characterized by a
peak at about 6.1 degrees, a peak at about 7.5 degrees, a peak at
about 12.1 degrees, a peak at about 13.3 degrees, a peak at about
14.0 degrees, a peak at about 18.5 degrees, a peak at about 22.6
degrees, a peak at about 33.2 degrees, a peak at about 34.0
degrees, and a peak at about 35.3 degrees in an X-ray powder
diffraction pattern.
91. Form J of claim 86, wherein the Form J is characterized by an
X-ray powder diffraction pattern of FIG. 20.
92. Form J of claim 86, wherein the Form J is characterized by a
melting temperature of about 126.degree. C.
93. Form J of claim 86, wherein the Form J is characterized by a
DSC thermogram of FIG. 21.
94. Form J of claim 86, wherein the Form J is characterized by one
or more peaks in a .sup.13C NMR solid state spectrum, wherein the
one or more peaks is selected from a peak at about 175.6 ppm, a
peak at about 141.4 ppm, a peak at about 127.8 ppm, a peak at about
123.4 ppm, a peak at about 103.1 ppm, a peak at about 83.5 ppm, a
peak at about 81.1 ppm, a peak at about 62.2 ppm, a peak at about
25.6 ppm, and a peak at about 19.6 ppm.
95. Form J of claim 94, wherein the Form J is characterized by a
peak at about 83.5 ppm, a peak at about 81.1 ppm, a peak at about
62.2 ppm, and a peak at about 25.6 ppm in a .sup.13C NMR solid
state spectrum.
96. Form J of claim 95, wherein the Form J is characterized by a
peak at about 175.6 ppm, a peak at about 141.4 ppm, a peak at about
127.8 ppm, a peak at about 123.4 ppm, a peak at about 103.1 ppm, a
peak at about 83.5 ppm, a peak at about 81.1 ppm, a peak at about
62.2 ppm, a peak at about 25.6 ppm, and a peak at about 19.6 ppm in
a .sup.13C NMR solid state spectrum.
97. Form J of claim 86, wherein the Form J is characterized by a
.sup.13C NMR solid state spectrum of FIG. 22.
98-140. (canceled)
141. A process for producing the compound according to claim 86,
comprising a) contacting Amorphous Form O with ethanol to form a
mixture; and b) isolating Form J from said mixture.
142. The process of claim 141, wherein the mixture is stirred at
room temperature for about 12 hours before isolating Form J.
143-156. (canceled)
157. A pharmaceutical composition comprising the compound according
to claim 86.
158. The pharmaceutical composition according to claim 157, further
comprising one or more additional agents.
159. The pharmaceutical composition according to claim 158, wherein
the one or more agents is selected from the group consisting of an
interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase
inhibitor, a NS5A inhibitor, an antiviral compound, a compound of
Formula (BB) and a compound of Formula (DD), or a pharmaceutically
acceptable salt any of the aforementioned compounds.
160. The pharmaceutical composition of claim 159, wherein the one
or more agents is selected from the group consisting of Compound
1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010,
1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021,
1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032,
1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043,
1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054,
1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065,
1066, 8001, 8002, 8003, 8004, 8005, 8006, 8007, 8008, 8009, 8010,
8011 and 8012, or a pharmaceutically acceptable salt of any of the
aforementioned compounds.
161. The pharmaceutical composition of claim 159, wherein the one
or more agents is selected from Pegylated interferon-alpha-2a
(brand name PEGASYS.RTM.), ribavirin, Pegylated interferon-alpha-2b
(brand name PEG-INTRON.RTM.), a HCV protease inhibitor, a HCV
polymerase inhibitor, and a NS5A inhibitor.
162-172. (canceled)
173. A method of ameliorating or treating a HCV infection
comprising administering to a subject suffering from the HCV
infection an effective amount of the compound according to claim
86, or a pharmaceutically acceptable salt thereof.
174. (canceled)
175. A method for inhibiting replication of a hepatitis C virus
comprising contacting a cell infected with the hepatitis C virus
with an effective amount of the compound according to claim 86, or
a pharmaceutically acceptable salt thereof.
176. (canceled)
177. (canceled)
178. A method of ameliorating or treating a HCV infection
comprising administering to a subject suffering from the HCV
infection an effective amount of the compound according to claim
86, or a pharmaceutically acceptable salt thereof, in combination
with one or more agents selected from the group consisting of an
interferon, ribavirin, a HCV protease inhibitor, a HCV polymerase
inhibitor, a NS5A inhibitor, an antiviral compound, a compound of
Formula (BB) and a compound of Formula (DD), or a pharmaceutically
acceptable salt any of the aforementioned compounds.
179. The method of claim 178, wherein the one or more agents are
selected from the group consisting of Compound 1000, 1001, 1002,
1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013,
1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024,
1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035,
1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046,
1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057,
1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 8001, 8002,
8003, 8004, 8005, 8006, 8007, 8008, 8009, 8010, 8011 and 8012, or a
pharmaceutically acceptable salt of any of the aforementioned
compounds.
180. The method of claim 178, wherein the one or more agents is
selected from Pegylated interferon-alpha-2a (brand name
PEGASYS.RTM.), ribavirin, Pegylated interferon-alpha-2b (brand name
PEG-INTRON.RTM.), a HCV protease inhibitor, a HCV polymerase
inhibitor, or and a NS5A inhibitor.
181. The method according to claim 178, wherein the one or more
agents is a compound of Formula (BB), ##STR00009## or a
pharmaceutically acceptable salt thereof, wherein B.sup.BB1 can be
an optionally substituted heterocyclic base or an optionally
substituted heterocyclic base with a protected amino group;
X.sup.BB can be O (oxygen) or S (sulfur); R.sup.BB1 can be selected
from --Z.sup.BB--R.sup.BB9, an optionally substituted N-linked
amino acid and an optionally substituted N-linked amino acid ester
derivative; Z.sup.BB can be selected from O (oxygen), S (sulfur)
and N(R.sup.BB10); R.sup.BB2 and R.sup.BB3 can be independently
selected from hydrogen, an optionally substituted C.sub.1-6 alkyl,
an optionally substituted C.sub.2-6 alkenyl, an optionally
substituted C.sub.2-6 alkynyl, an optionally substituted C.sub.1-6
haloalkyl and an optionally substituted aryl(C.sub.1-6alkyl); or
R.sup.BB2 and R.sup.BB3 can be taken together to form a group
selected from an optionally substituted C.sub.3-6 cycloalkyl, an
optionally substituted C.sub.3-6 cycloalkenyl, an optionally
substituted C.sub.3-6 aryl and an optionally substituted
C.sub.3-6heteroaryl; R.sup.BB4 can be selected from hydrogen,
halogen, azido, cyano, an optionally substituted C.sub.1-6 alkyl,
an optionally substituted C.sub.2-6 alkenyl, an optionally
substituted C.sub.2-6 alkynyl and an optionally substituted
allenyl; R.sup.BB5 can be hydrogen or an optionally substituted
C.sub.1-6 alkyl; R.sup.BB6 can be selected from hydrogen, halogen,
azido, amino, cyano, an optionally substituted C.sub.1-6 alkyl,
--OR.sup.BB11 and --OC(.dbd.O)R.sup.BB12; R.sup.BB7 can be selected
from hydrogen, halogen, azido, cyano, an optionally substituted
C.sub.1-6 alkyl, --OR.sup.BB13 and --OC(.dbd.O)R.sup.BB14;
R.sup.BB8 can be selected from hydrogen, halogen, azido, cyano, an
optionally substituted C.sub.1-6 alkyl, --OR.sup.BB15 and
--OC(.dbd.O)R.sup.BB16; R.sup.BB9 can be selected from an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted heterocyclyl, an optionally substituted
aryl(C.sub.1-6alkyl), an optionally substituted
heteroaryl(C.sub.1-6alkyl) and an optionally substituted
heterocyclyl(C.sub.1-6alkyl); R.sup.BB10 can be selected from
hydrogen, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted heterocyclyl, an
optionally substituted aryl(C.sub.1-6alkyl), an optionally
substituted heteroaryl(C.sub.1-6alkyl) and an optionally
substituted heterocyclyl(C.sub.1-6alkyl); R.sup.BB11, R.sup.BB13
and R.sup.BB15 can be independently hydrogen or an optionally
substituted C.sub.1-6 alkyl; and R.sup.BB12, R.sup.BB14 and
R.sup.BB16 can be independently an optionally substituted C.sub.1-6
alkyl or an optionally substituted C.sub.3-6 cycloalkyl.
182. The method according to claim 178, wherein the one or more
agents is a compound of Formula (DD), ##STR00010## or a
pharmaceutically acceptable salt thereof, wherein each can be
independently a double or single bond; A.sup.DD1 can be selected
from C (carbon), O (oxygen) and S (sulfur); B.sup.DD1 can be an
optionally substituted heterocyclic base or a derivative thereof;
D.sup.DD1 can be selected from C.dbd.CH.sub.2, CH.sub.2, O
(oxygen), S (sulfur), CHF, and CF.sub.2; R.sup.DD1 can be hydrogen,
an optionally substituted alkyl, an optionally substituted
cycloalkyl, an optionally substituted aralkyl,
dialkylaminoalkylene, alkyl-C(.dbd.O)--, aryl-C(.dbd.O)--,
alkoxyalkyl-C(.dbd.O)--, aryloxyalkyl-C(.dbd.O)--, alkylsulfonyl,
arylsulfonyl, aralkylsulfonyl, ##STR00011## an --O--linked amino
acid, diphosphate, triphosphate or derivatives thereof; R.sup.DD2
and R.sup.DD3 can be each independently selected from hydrogen, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl and
an optionally substituted C.sub.1-6 haloalkyl, provided that at
least one of R.sup.DD2 and R.sup.DD3 cannot be hydrogen; or
R.sup.DD2 and R.sup.DD3 are taken together to form a group selected
from among C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6
aryl, and a C.sub.3-6 heteroaryl; R.sup.DD4 and R.sup.DD9 can be
independently selected from hydrogen, halogen, --NH.sub.2,
--NHR.sup.DDa1, NR.sup.DDa1R.sup.DDb1, --OR.sup.DDa1,
--SR.sup.DDa1, --CN, --NC, --N.sub.3, --NO.sub.2,
--N(R.sup.DDc1)--NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--OR.sup.DDa1, --S--SR.sup.DDa1,
--C(.dbd.O)R.sup.DDa1, --C(.dbd.O)OR.sup.DDa1,
--C(.dbd.O)NR.sup.DDa1R.sup.DDb1, --O--(C.dbd.O)R.sup.DDa1,
--O--C(.dbd.O)OR.sup.DDa1, --O--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--S(.dbd.O)R.sup.DDa1, S(.dbd.O).sub.2R.sup.DDa1,
--O--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl, an
optionally substituted aralkyl and an --O-linked amino acid;
R.sup.DD5, R.sup.DD6 and R.sup.DD7 can be independently absent or
selected from hydrogen, halogen, --NH.sub.2, --NHR.sup.DDa1,
NR.sup.DDa1R.sup.DDb1, --OR.sup.DDa1, --SR.sup.DDa1, --CN, --NC,
--N.sub.3, --NO.sub.2, --N(R.sup.DDc1)--NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--OR.sup.DDa1, --S--SR.sup.DDa1,
--C(.dbd.O)R.sup.DDa1, --C(.dbd.O)OR.sup.DDa1,
--C(.dbd.O)NR.sup.DDa1R.sup.DDb1, --O--(C.dbd.O)R.sup.DDa1,
--O--C(.dbd.O)OR.sup.DDa1, --O--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--S(.dbd.O)R.sup.DDa1, S(.dbd.O).sub.2R.sup.DDa1,
--O--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl, an
optionally substituted aralkyl and an --O-linked amino acid; or
R.sup.DD6 and R.sup.DD7 taken together form --O--C(.dbd.O)--O--;
R.sup.DD8 can be absent or selected from the group consisting of
hydrogen, halogen, --NH.sub.2, --NHR.sup.DDa1,
NR.sup.DDa1R.sup.DDb1, --OR.sup.DDa1, --SR.sup.DDa1, --CN, --NC,
--N.sub.3, --NO.sub.2, --N(R.sup.DDc1)--NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--OR.sup.DDa1, --S--SR.sup.DDa1,
--C(.dbd.O)R.sup.DDa1, --C(.dbd.O)OR.sup.DDa1,
--C(.dbd.O)NR.sup.DDa1R.sup.DDb1, --O--(C.dbd.O)OR.sup.DDa1,
--O--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--S(.dbd.O)R.sup.DDa1, S(.dbd.O).sub.2R.sup.DDa1,
--O--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDv1,
--N(R.sup.DDc1)--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl, an
optionally substituted haloalkyl, an optionally substituted
hydroxyalkyl and an --O-linked amino acid, or when the bond to
R.sup.DD7 indicated by is a double bond, then R.sup.DD7 is a
C.sub.2-6 alkylidene and R.sup.DD8 is absent; R.sup.DDa1,
R.sup.DDb1 and R.sup.DDc1 can be each independently selected from
hydrogen, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted aryl, an optionally substituted heteroaryl,
an optionally substituted aralkyl and an optionally substituted
heteroaryl(C.sub.1-6 alkyl); R.sup.DD10 can be selected from
O.sup.-, --OH, an optionally substituted aryloxy or aryl-O--,
##STR00012## alkyl-C(.dbd.O)--O--CH.sub.2--O--,
alkyl-C(.dbd.O)--S--CH.sub.2CH.sub.2--O-- and an --N-linked amino
acid; R.sup.DD11 can be selected from O.sup.-, --OH, an optionally
substituted aryloxy or aryl-O--, ##STR00013##
alkyl-C(.dbd.O)--O--CH.sub.2--O--,
alkyl-C(.dbd.O)--S--CH.sub.2CH.sub.2--O-- and an --N-linked amino
acid; each R.sup.DD12 and each R.sup.DD13 can be independently
--C.ident.N or an optionally substituted substituent selected from
C.sub.1-8 organylcarbonyl, C.sub.1-8 alkoxycarbonyl and C.sub.1-8
organylaminocarbonyl; each R.sup.DD14 can be hydrogen or an
optionally substituted C.sub.1-6-alkyl; each m.sup.DD can be
independently 1 or 2, and if both R.sup.DD10 and R.sup.DD11 are
##STR00014## each R.sup.DD12, each R.sup.DD13, each R.sup.DD14 and
each m.sup.DD can be the same or different.
183. The method according to claim 178, wherein the one or more
agents is Compound 1012 ##STR00015##
184. The method according to claim 178, wherein the one or more
agents is Compound 1042 ##STR00016##
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. 119(e) to
U.S. provisional application No. 61/613,972, filed on Mar. 21,
2012. The entire contents of which is incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present application relates to solid state forms, for
example, crystalline forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate, pharmaceutical compositions that can include one or
more solid forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate, and methods of treating or ameliorating diseases
and/or conditions with one or more solid forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate. Also disclosed herein are methods of treating
diseases and/or conditions with one or more solid forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate in combination with one or more other agents.
BACKGROUND
[0003] Nucleoside analogs are a class of compounds that have been
shown to exert antiviral and anticancer activity both in vitro and
in vivo, and thus, have been the subject of widespread research for
the treatment of viral infections and cancer. Nucleoside analogs
are usually therapeutically inactive compounds that are converted
by host or viral enzymes to their respective active
anti-metabolites, which, in turn, may inhibit polymerases involved
in viral or cell proliferation. The activation occurs by a variety
of mechanisms, such as the addition of one or more phosphate groups
and, or in combination with, other metabolic processes.
SUMMARY
[0004] Some embodiments disclosed herein generally relate to solid
forms of
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thi-
ophosphoramidate (hereinafter "Compound 1") which has the structure
below:
##STR00001##
[0005] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form A.
[0006] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form B.
[0007] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form C.
[0008] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form D.
[0009] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form E.
[0010] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form F.
[0011] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form G.
[0012] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form H.
[0013] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form I.
[0014] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form J.
[0015] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form K.
[0016] In some embodiments, Compound 1 can be
T-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thiopho-
sphoramidate characterized as Form L.
[0017] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form M.
[0018] In some embodiments, Compound 1 can be
T-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thiopho-
sphoramidate characterized as Form N.
[0019] In some embodiments, Compound 1 can be
T-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thiopho-
sphoramidate characterized as Amorphous Form 0.
[0020] Some embodiments disclosed herein generally relate to a
process for producing Form
[0021] A that can include:
[0022] a) contacting Compound 1 with a first amount of ethyl
acetate to form a mixture;
[0023] b) heating the mixture until the solids are dissolved;
[0024] c) cooling the mixture to allow precipitation of a
solid;
[0025] d) optionally adding a second amount of ethyl acetate and
repeating steps a, b and c; and
[0026] e) isolating Form A from said mixture.
[0027] Some embodiments disclosed herein generally relate to a
process for producing Form J that can include:
[0028] a) contacting Amorphous Form O with ethanol to form a
mixture; and
[0029] b) isolating Form J from said mixture.
[0030] Some embodiments disclosed herein generally relate to a
process for producing a solvated solid form of Compound 1 that can
include:
[0031] a) contacting Compound 1 with a solvent to form a mixture;
and
[0032] b) isolating the solvated solid form of Compound 1 from said
mixture.
[0033] Some embodiments disclosed herein generally relate to a
method of ameliorating or treating a viral infection (for example,
a HCV infection) in a subject, said method can include
administering to said subject an effective amount of one or more
solid forms of Compound 1 as described herein.
[0034] Some embodiments disclosed herein relate to a pharmaceutical
composition that can include one or more solid forms of Compound 1
as described herein.
[0035] Some embodiments disclosed herein generally relate to a
pharmaceutical composition that can include one or more solid forms
of Compound 1, and one or more additional agent(s).
[0036] Some embodiments disclosed herein relate to a method of
ameliorating and/or treating a HCV infection that can include
administering to a subject identified as suffering from the HCV
infection an effective amount of a compound described herein or a
pharmaceutically acceptable salt thereof (for example, one or more
solid forms of Compound 1, or a pharmaceutically acceptable salt
thereof), or a pharmaceutical composition that includes one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, in combination with an
agent selected from an interferon, ribavirin, a HCV protease
inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an other
antiviral compound, a compound of Formula (BB) and a compound of
Formula (DD), or a pharmaceutically acceptable salt of any of the
foregoing.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1 is an XRPD spectrum of Form A.
[0038] FIG. 2 is a DSC spectrum of Form A.
[0039] FIG. 3 is a .sup.13C ssNMR spectrum of Form A.
[0040] FIG. 4 is an XRPD spectrum of Form B.
[0041] FIG. 5 is a .sup.13C ssNMR spectrum of Form B.
[0042] FIG. 6 is an XRPD spectrum of Form C.
[0043] FIG. 7 is a .sup.13C ssNMR spectrum of Form C.
[0044] FIG. 8 is an XRPD spectrum of Form D.
[0045] FIG. 9 is a .sup.13C ssNMR spectrum of Form D.
[0046] FIG. 10 is an XRPD spectrum of a mixture of Form A and Form
E.
[0047] FIG. 11 is a .sup.13C ssNMR spectrum of a mixture of Form A
and Form E.
[0048] FIG. 12 is an XRPD spectrum of a mixture of Form A and Form
F.
[0049] FIG. 13 is a .sup.13C ssNMR spectrum of a mixture of Form A
and Form F.
[0050] FIG. 14 is an XRPD spectrum of Form G.
[0051] FIG. 15 is a .sup.13C ssNMR spectrum of Form G.
[0052] FIG. 16 is an XRPD spectrum of Form H.
[0053] FIG. 17 is a .sup.13C ssNMR spectrum of Form H.
[0054] FIG. 18 is an XRPD spectrum of Form I.
[0055] FIG. 19 is a .sup.13C ssNMR spectrum of Form I.
[0056] FIG. 20 is an XRPD spectrum of Form J.
[0057] FIG. 21 is a DSC spectrum of Form J.
[0058] FIG. 22 is a .sup.13C ssNMR spectrum of Form J.
[0059] FIG. 23 is an XRPD spectrum of Form K.
[0060] FIG. 24 is a .sup.13C ssNMR spectrum of Form K.
[0061] FIG. 25 is an XRPD spectrum of Form L.
[0062] FIG. 26 is a .sup.13C ssNMR spectrum of Form L.
[0063] FIG. 27 is an XRPD spectrum of Form M.
[0064] FIG. 28 is a .sup.13C ssNMR spectrum of Form M.
[0065] FIG. 29 is an XRPD spectrum of Form N.
[0066] FIG. 30 is a .sup.13C ssNMR spectrum of Form N.
[0067] FIG. 31 is an XRPD spectrum of Amorphous Form 0.
[0068] FIG. 32 shows examples of additional agents that can be used
to treat HCV.
[0069] FIG. 33 shows examples of Compounds of Formula (BB).
[0070] FIG. 34 shows the generic Formula (DD).
DETAILED DESCRIPTION
Definitions
[0071] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art. All patents, applications, published
applications and other publications referenced herein are
incorporated by reference in their entirety unless stated
otherwise. In the event that there are a plurality of definitions
for a term herein, those in this section prevail unless stated
otherwise. As used herein, the following definitions shall apply
unless otherwise indicated.
[0072] The term "crystalline" refers to a substance that has its
atoms, molecules or ions packed in a regularly ordered
three-dimensional pattern. The term "substantially crystalline"
refers to a substance where a substantial portion of the substance
is crystalline. For example, substantially crystalline materials
can have more than about 85% crystallinity (e.g., more than about
90% crystallinity, more than about 95% crystallinity, or more than
about 99% crystallinity).
[0073] The chemical elements are identified in accordance with the
Periodic Table of the Elements, CAS version, Handbook of Chemistry
and Physics, 75th Ed. Additionally, general principles of organic
chemistry are described in "Organic Chemistry", Thomas Sorrell,
University Science Books, Sausalito: 1999, and "March's Advanced
Organic Chemistry", 5th Ed., Ed.: Smith, M. B. and March, J., John
Wiley & Sons, New York: 2001, the entire contents of which are
hereby incorporated by reference.
[0074] As used herein, the abbreviations for any protective groups,
amino acids and other compounds, are, unless indicated otherwise,
in accord with their common usage, recognized abbreviations, or the
IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.
11:942-944 (1972)).
[0075] The term "nucleoside" refers to a compound composed of an
optionally substituted pentose moiety or modified pentose moiety
attached to a heterocyclic base or tautomer thereof via a
N-glycosidic bond, such as attached via the 9-position of a
purine-base or the 1-position of a pyrimidine-base. Examples
include, but are not limited to, a ribonucleoside comprising a
ribose moiety and a deoxyribonucleoside comprising a deoxyribose
moiety. A modified pentose moiety is a pentose moiety in which an
oxygen atom has been replaced with a carbon and/or a carbon has
been replaced with a sulfur or an oxygen atom. A "nucleoside" is a
monomer that can have a substituted base and/or sugar moiety.
Additionally, a nucleoside can be incorporated into larger DNA
and/or RNA polymers and oligomers. In some instances, the
nucleoside can be a nucleoside analog drug.
[0076] The term "pharmaceutically acceptable salt" refers to a salt
of a compound that does not cause significant irritation to an
organism to which it is administered and does not abrogate the
biological activity and properties of the compound. In some
embodiments, the salt is an acid addition salt of the compound.
Pharmaceutical salts can be obtained by reacting a compound with
inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or
hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
Pharmaceutical salts can also be obtained by reacting a compound
with an organic acid such as aliphatic or aromatic carboxylic or
sulfonic acids, for example formic, acetic, succinic, lactic,
malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,
ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic
acid. Pharmaceutical salts can also be obtained by reacting a
compound with a base to form a salt such as an ammonium salt, an
alkali metal salt, such as a sodium or a potassium salt, an
alkaline earth metal salt, such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
C.sub.1-C.sub.7 alkylamine, cyclohexylamine, triethanolamine,
ethylenediamine, and salts with amino acids such as arginine and
lysine.
[0077] As used herein, the term "room temperature" refers to a
temperature in the range of about 20.degree. C. to about 25.degree.
C., such as a temperature in the range of about 21.degree. C. to
about 23.degree. C.
[0078] Terms and phrases used in this application, and variations
thereof, especially in the appended claims, unless otherwise
expressly stated, should be construed as open ended as opposed to
limiting. As examples of the foregoing, the term `including` should
be read to mean `including, without limitation,` `including but not
limited to,` or the like; the term `comprising` as used herein is
synonymous with `including,` `containing,` or `characterized by,`
and is inclusive or open-ended and does not exclude additional,
unrecited elements or method steps; the term `having` should be
interpreted as `having at least;` the term `includes` should be
interpreted as `includes but is not limited to;` the term `example`
is used to provide exemplary instances of the item in discussion,
not an exhaustive or limiting list thereof; and use of terms like
`preferably,` `preferred,``desired,` or `desirable,` and words of
similar meaning should not be understood as implying that certain
features are critical, essential, or even important to the
structure or function of the invention, but instead as merely
intended to highlight alternative or additional features that may
or may not be utilized in a particular embodiment of the invention.
In addition, the term "comprising" is to be interpreted
synonymously with the phrases "having at least" or "including at
least". When used in the context of a process, the term
"comprising" means that the process includes at least the recited
steps, but may include additional steps. When used in the context
of a compound, composition or device, the term "comprising" means
that the compound, composition or device includes at least the
recited features or components, but may also include additional
features or components. Likewise, a group of items linked with the
conjunction `and` should not be read as requiring that each and
every one of those items be present in the grouping, but rather
should be read as `and/or` unless expressly stated otherwise.
Similarly, a group of items linked with the conjunction `or` should
not be read as requiring mutual exclusivity among that group, but
rather should be read as `and/or` unless expressly stated
otherwise.
[0079] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations may be expressly set forth
herein for sake of clarity. The indefinite article "a" or "an" does
not exclude a plurality. The mere fact that certain measures are
recited in mutually different dependent claims does not indicate
that a combination of these measures cannot be used to advantage.
Any reference signs in the claims should not be construed as
limiting the scope.
[0080] It is understood that, in any compound described herein
having one or more chiral centers, if an absolute stereochemistry
is not expressly indicated, then each center may independently be
of R-configuration or S-configuration or a mixture thereof. Thus,
the compounds provided herein may be enantiomerically pure,
enantiomerically enriched, racemic mixture, diastereomerically
pure, diastereomerically enriched, or a stereoisomeric mixture. In
addition it is understood that, in any compound described herein
having one or more double bond(s) generating geometrical isomers
that can be defined as E or Z, each double bond may independently
be E or Z a mixture thereof. Unless otherwise stated, all
tautomeric forms of Compound 1 are intended to be included.
[0081] Likewise, it is understood that, in any compound described,
all tautomeric forms are also intended to be included. For example
all tautomers of phosphate groups are intended to be included.
Furthermore, all tautomers of heterocyclic bases known in the art
are intended to be included, including tautomers of natural and
non-natural purine-bases and pyrimidine-bases.
[0082] It is to be understood that where compounds disclosed herein
have unfilled valencies, then the valencies are to be filled with
hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and
hydrogen-2 (deuterium).
[0083] It is understood that the compounds described herein can be
labeled isotopically. Substitution with isotopes such as deuterium
may afford certain therapeutic advantages resulting from greater
metabolic stability, such as, for example, increased in vivo
half-life or reduced dosage requirements. Each chemical element as
represented in a compound structure may include any isotope of said
element. For example, in a compound structure a hydrogen atom may
be explicitly disclosed or understood to be present in the
compound. At any position of the compound that a hydrogen atom may
be present, the hydrogen atom can be any isotope of hydrogen,
including but not limited to hydrogen-1 (protium) and hydrogen-2
(deuterium). Thus, reference herein to a compound encompasses all
potential isotopic forms unless the context clearly dictates
otherwise.
[0084] It is understood that the methods and combinations described
herein include crystalline forms (also known as polymorphs, which
include the different crystal packing arrangements of the same
elemental composition of a compound), amorphous phases, salts,
solvates, and hydrates. In some embodiments, the compounds
described herein exist in solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, or the like. In other
embodiments, the compounds described herein exist in unsolvated
form. Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and may be formed during the process of
crystallization with pharmaceutically acceptable solvents such as
water, ethanol, or the like. Hydrates are formed when the solvent
is water, or alcoholates are formed when the solvent is alcohol. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the compounds and methods
provided herein.
[0085] Where a range of values is provided, it is understood that
the upper and lower limit, and each intervening value between the
upper and lower limit of the range is encompassed within the
embodiments.
Example Embodiments of Compound 1
[0086] All XRPD spectra provided herein are measured on a degrees
2-Theta scale, and all .sup.13C solid state NMR's are referenced to
adamantane at 29.5 ppm.
[0087] Form A
[0088] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form A.
[0089] In some embodiments, Form A can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
6.8 to about 7.2 degrees, a peak in the range of from about 8.3 to
about 8.7 degrees, a peak in the range of from about 15.6 to about
16.0 degrees, a peak in the range of from about 21.2 to about 21.6
degrees, a peak in the range of from about 21.8 to about 22.2
degrees, a peak in the range of from about 22.4 to about 22.8
degrees, and a peak in the range of from about 23.1 to about 23.5
degrees.
[0090] In some embodiments, Form A can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
6.8 to about 7.2 degrees, a peak in the range of from about 8.3 to
about 8.7 degrees, a peak in the range of from about 15.6 to about
16.0 degrees and a peak in the range of from about 21.2 to about
21.6 degrees.
[0091] In some embodiments, Form A can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 7.0 degrees, a peak
at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about
21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6
degrees, and a peak at about 23.3 degrees.
[0092] In some embodiments, Form A can be characterized by a peak
at about 8.5 degrees, a peak at about 15.8 degrees, and a peak at
about 21.4 degrees in an X-ray powder diffraction pattern.
[0093] In some embodiments, Form A can be characterized by a peak
at about 8.5 degrees, a peak at about 15.8 degrees, a peak at about
21.4 degrees, a peak at about 22.0 degrees, a peak at about 22.6
degrees, and a peak at about 23.3 degrees in an X-ray powder
diffraction pattern.
[0094] In some embodiments, Form A can be characterized by a peak
at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about
15.8 degrees, and a peak at about 21.4 degrees in an X-ray powder
diffraction pattern.
[0095] In some embodiments, Form A can be characterized by a peak
at about 7.0 degrees, a peak at about 8.5 degrees, a peak at about
15.8 degrees, a peak at about 21.4 degrees, a peak at about 22.0
degrees, a peak at about 22.6 degrees, and a peak at about 23.3
degrees in an X-ray powder diffraction pattern.
[0096] In some embodiments, Form A can exhibit an X-ray powder
diffraction pattern as shown in FIG. 1.
[0097] In some embodiments, Form A can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00001 No. 2-Theta .degree. Intensity % 1 7.0* 91.8 2 8.5*
100.0 3 10.0 70.0 4 11.0 73.4 5 14.7 90.3 6 15.5 76.7 7 15.8* 79.6
8 16.6 90.9 9 17.8 81.1 10 18.0 99.2 11 18.8 72.2 12 19.9 76.1 13
20.8 73.5 14 21.4* 77.0 15 22.0** 68.9 16 22.6** 73.0 17 23.3**
68.8 18 25.8 71.7 19 28.7 67.4 Peaks with an asterisk (*) are major
peaks Peaks with a double asterisk (**) are secondary peaks
[0098] In some embodiments, Form A can be characterized by a DSC
thermogram as shown in FIG. 2. In some embodiments, Form A can be
characterized by a melting point in the range of from about
137.degree. C. to about 139.degree. C. In other embodiments, Form A
can be characterized by a melting point of about 138.degree. C. In
some embodiments, Form A can be characterized by a melting point of
about 138.4.degree. C. In some embodiments, Form A can be
characterized by an endotherm in the range of from about
137.degree. C. to about 139.degree. C. In other embodiments, Form A
can be characterized by an endotherm of about 138.degree. C. In
some embodiments, Form A can be characterized by an endotherm of
about 138.4.degree. C.
[0099] In some embodiments, Form A can be characterized by a peak
at about 130.4 ppm, a peak at about 69.5 ppm, a peak at about 66.9
ppm, and a peak at about 20.6 ppm in a .sup.13C NMR solid state
spectrum.
[0100] In some embodiments, Form A can be characterized by a peak
at about 172.0 ppm, a peak at about 146.6 ppm, a peak at about
130.4 ppm, a peak at about 104.1 ppm, a peak at about 69.5 ppm, a
peak at about 66.9 ppm, and a peak at about 20.6 ppm in a .sup.13C
NMR solid state spectrum.
[0101] In some embodiments, Form A can exhibit a .sup.13C NMR solid
state spectrum as shown in FIG. 3.
[0102] In some embodiments, Form A can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00002 .nu.(F1) Intensity Peak # [ppm] [rel] 1 173.0 24.12
2 172.0* 23.11 3 170.2 24.80 4 151.3 28.62 5 150.5 38.71 6 146.6*
14.23 7 143.9 12.74 8 130.4* 36.15 9 126.2 27.80 10 122.9 3.91 11
120.4 33.00 12 104.1* 23.68 13 102.2 23.18 14 92.8 20.65 15 92.2
17.13 16 84.1 27.03 17 79.7 68.89 18 75.0 28.02 19 73.5 33.05 20
69.5* 34.76 21 69.2 27.63 22 66.9* 40.98 23 50.4 22.59 24 21.9
100.00 25 20.6* 39.44 Peaks with an asterisk (*) are major
peaks
[0103] Form B
[0104] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form B.
[0105] In some embodiments, Form B can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
5.5 to about 5.9 degrees, a peak in the range of from about 9.2 to
about 9.6 degrees, a peak in the range of from about 16.8 to about
17.2 degrees, and a peak in the range of from about 26.0 to about
26.4 degrees.
[0106] In some embodiments, Form B can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 5.7 degrees, a peak
at about 9.4 degrees, a peak at about 17.0 degrees, and a peak at
about 26.2 degrees.
[0107] In some embodiments, Form B can be characterized by a peak
at about 5.7 degrees, a peak at about 9.4 degrees, a peak at about
17.0 degrees, and a peak at about 26.2 degrees in an X-ray powder
diffraction pattern.
[0108] In some embodiments, Form B can be characterized by an X-ray
diffraction pattern of FIG. 4.
[0109] In some embodiments, Form B can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00003 No. 2-Theta .degree. Intensity % 1 5.720* 71.8 2
9.395* 31.2 3 17.042* 100.0 4 26.219* 28.5 Peaks with an asterisk
(*) are major peaks
[0110] In some embodiments, Form B can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.2 ppm, a peak at
about 129.9 ppm, a peak at about 118.3 ppm, a peak at about 68.5
ppm, a peak at about 27.1 ppm, or a peak at about 19.5 ppm.
[0111] In some embodiments, Form B can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.2 ppm, a peak at
about 129.9 ppm, a peak at about 118.3 ppm, a peak at about 72.3
ppm, a peak at about 68.5 ppm, a peak at about 49.2 ppm, a peak at
about 27.1 ppm and a peak at about 19.5 ppm. In some embodiments,
Form B can be a methyl tert-butyl solvate.
[0112] In some embodiments, Form B can be characterized by a peak
at about 118.3 ppm, a peak at about 68.5 ppm, and a peak at about
27.1 ppm in a .sup.13C NMR solid state spectrum.
[0113] In some embodiments, Form B can be characterized by a peak
at about 173.2 ppm, a peak at about 129.9 ppm, a peak at about
118.3 ppm, a peak at about 68.5 ppm, a peak at about 27.1 ppm, and
a peak at about 19.5 ppm in a .sup.13C NMR solid state
spectrum.
[0114] In some embodiments, Form B can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 5.
[0115] In some embodiments, Form B (methyl tert-butyl ether
solvate) can be characterized by one or more peaks in a .sup.13C
NMR solid state spectrum selected from the table below.
TABLE-US-00004 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.2* 55.0 2
169.9 24.91 3 151.1 50.46 4 144.7 20.81 5 129.9* 100.00 6 123.3
47.74 7 118.3* 77.98 8 103.5 41.84 9 92.8 29.78 10 82.4 43.94 11
79.8 88.11 12 74.1 57.28 13 72.3* 20.83 14 68.5* 76.94 15 68.1
67.80 16 50.9 12.62 17 50.3 27.03 18 49.2* 57.83 19 27.1* 61.90 20
22.6 76.64 21 22.2 75.51 22 22.0 16.01 23 21.7 65.44 24 19.5* 52.58
Peaks with an asterisk (*) are major peaks
[0116] In some embodiments, Form B can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 170.3 ppm, a peak at
about 150.5 ppm, a peak at about 129.8 ppm, a peak at about 118.2
ppm, a peak at about 79.8 ppm, a peak at about 27.2 ppm, and a peak
at about 21.8 ppm.
[0117] In other embodiments, Form B can be a cyclohexane
solvate.
[0118] In some embodiments, Form B can be characterized by a peak
at about 150.5 ppm, a peak at about 129.8 ppm, a peak at about
118.2 ppm, and a peak at about 21.8 ppm in a .sup.13C NMR solid
state spectrum.
[0119] In some embodiments, Form B can be characterized by a peak
at about 170.3 ppm, a peak at about 150.5 ppm, a peak at about
129.8 ppm, a peak at about 118.2 ppm, a peak at about 79.8 ppm, a
peak at about 27.2 ppm, and a peak at about 21.8 ppm in a .sup.13C
NMR solid state spectrum.
[0120] In some embodiments, Form B (cyclohexane solvate) can be
characterized by one or more peaks in a 13C NMR solid state
spectrum selected from the table below.
TABLE-US-00005 .nu.(F1) Intensity Peak # [ppm] [rel] 1 172.6 20.01
2 170.3* 26.09 3 150.5* 39.10 4 146.6 15.32 5 144.4 12.23 6 129.8*
31.00 7 126.3 25.02 8 122.6 15.89 9 120.4 26.04 10 118.2* 30.57 11
104.1 18.00 12 102.2 17.34 13 92.8 19.56 14 84.2 16.62 15 79.8*
53.48 16 75.0 22.56 17 73.6 20.49 18 69.5 21.11 19 68.1 19.74 20
66.9 21.59 21 64.0 13.37 22 50.5 20.41 23 40.8 12.34 24 27.2* 21.00
25 21.8* 100.00 26 18.6 15.87 Peaks with an asterisk (*) are major
peaks
[0121] Form C
[0122] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form C.
[0123] In some embodiments, Form C can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
4.8 to about 5.2 degrees, a peak in the range of from about 6.4 to
about 6.8 degrees, a peak in the range of from about 8.0 to about
8.4 degrees, a peak in the range of from about 9.0 to about 9.4
degrees, a peak in the range of from about 9.4 to about 9.8
degrees, a peak in the range of from about 16.1 to about 16.5
degrees, and a peak in the range of from about 22.1 to about 22.5
degrees.
[0124] In some embodiments, Form C can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 5.0 degrees, a peak
at about 6.6 degrees, a peak at about 8.2 degrees, a peak at about
9.2 degrees, a peak at about 9.6 degrees, a peak at about 16.3
degrees, and a peak at about 22.3 degrees.
[0125] In some embodiments, Form C can be characterized by a peak
at about 5.0 degrees, a peak at about 6.6 degrees, a peak at about
8.2 degrees, and a peak at about 22.3 degrees in an X-ray powder
diffraction pattern.
[0126] In some embodiments, Form C can be characterized by a peak
at about 5.0 degrees, a peak at about 6.6 degrees, a peak at about
8.2 degrees, a peak at about 9.2 degrees, a peak at about 9.6
degrees, a peak at about 16.3 degrees, and a peak at about 22.3
degrees in an X-ray powder diffraction pattern.
[0127] In some embodiments, Form C can be characterized by an X-ray
powder diffraction pattern of FIG. 6.
[0128] In some embodiments, Form C can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00006 No. 2-Theta .degree. Intensity % 1 4.980* 27.4 2
6.573* 31.0 3 8.174* 39.0 4 9.151** 47.4 5 9.585** 56.2 6 16.337**
62.7 7 22.340* 28.1 Peaks with an asterisk (*) are major peaks
Peaks with a double asterisk (**) are secondary peaks
[0129] In some embodiments, Form C can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.7 ppm, a peak at
about 151.9 ppm, a peak at about 103.2 ppm, a peak at about 83.3
ppm, a peak at about 80.8 ppm, a peak at about 73.3 ppm, a peak at
about 25.1 ppm, and a peak at about 20.1 ppm.
[0130] In some embodiments, Form C can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.7 ppm, a peak at
about 151.9 ppm, a peak at about 103.2 ppm, a peak at about 83.3
ppm, a peak at about 80.8 ppm, a peak at about 73.3 ppm, a peak at
about 63.8 ppm, a peak at about 25.1 ppm, and a peak at about 20.1
ppm.
[0131] In some embodiments, Form C can be characterized by a peak
at about 173.7 ppm, a peak at about 83.3 ppm, a peak at about 80.8
ppm, and a peak at about 25.1 ppm in a .sup.13C NMR solid state
spectrum.
[0132] In some embodiments, Form C can be characterized by a peak
at about 173.7 ppm, a peak at about 151.9 ppm, a peak at about
103.2 ppm, a peak at about 83.3 ppm, a peak at about 80.8 ppm, a
peak at about 73.3 ppm, a peak at about 25.1 ppm, and a peak at
about 20.1 ppm in a .sup.13C NMR solid state spectrum.
[0133] In some embodiments, Form C can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 7.
[0134] In some embodiments, Form C can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00007 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.7* 72.2 2
163.6 27.15 3 162.7 27.66 4 152.6 33.02 5 151.9* 39.39 6 151.3
17.72 7 150.4 19.06 8 144.1 20.92 9 140.7 19.90 10 129.6 32.86 11
126.7 18.14 12 126.1 20.87 13 125.5 22.15 14 123.3 27.16 15 122.8
35.54 16 103.2* 40.00 17 102.5 24.12 18 101.9 21.60 19 93.3 34.02
20 92.4 35.66 21 83.3* 51.71 22 81.5 57.50 23 80.8* 54.60 24 80.3
75.92 25 73.3* 88.51 26 69.4 39.18 27 68.3 39.61 28 65.5 23.22 29
64.9 26.70 30 63.8* 54.98 31 51.8 21.78 32 50.6 28.73 33 25.1*
71.94 34 20.8 88.14 35 20.1* 100.00 36 18.8 24.24 Peaks with an
asterisk (*) are major peaks
[0135] Form D
[0136] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form D.
[0137] In some embodiments, Form D can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
7.9 to about 8.3 degrees, a peak in the range of from about 13.2 to
about 13.6 degrees, a peak in the range of from about 14.2 to about
14.6 degrees, a peak in the range of from about 17.0 to about 17.4
degrees, a peak in the range of from about 29.4 to about 29.8
degrees, and a peak in the range of from about 34.8 to about 35.2
degrees.
[0138] In some embodiments, Form D can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 8.1 degrees, a peak
at about 13.4 degrees, a peak at about 14.4 degrees, a peak at
about 17.2 degrees, a peak at about 29.6 degrees, and a peak at
about 35.0 degrees.
[0139] In some embodiments, Form D can be characterized by a peak
at about 8.1 degrees, a peak at about 13.4 degrees, a peak at about
29.6 degrees, and a peak at about 35.0 degrees in an X-ray powder
diffraction pattern.
[0140] In some embodiments, Form D can be characterized by a peak
at about 8.1 degrees, a peak at about 13.4 degrees, a peak at about
14.4 degrees, a peak at about 17.2 degrees, a peak at about 29.6
degrees, and a peak at about 35.0 degrees in an X-ray powder
diffraction pattern.
[0141] In some embodiments, Form D can be characterized by an X-ray
powder diffraction pattern of FIG. 8.
[0142] In some embodiments, Form D can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00008 No. 2-Theta .degree. Intensity % 1 8.105* 55.6 2
13.357* 44.1 3 14.424** 100.0 4 17.215** 66.0 5 29.590* 29.1 6
35.019* 25.3 Peaks with an asterisk (*) are major peaks Peaks with
a double asterisk (**) are secondary peaks
[0143] In some embodiments, Form D can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 139.1 ppm, a peak at
about 125.3 ppm, a peak at about 120.8 ppm, a peak at about 105.2
ppm, a peak at about 72.8 ppm, a peak at about 67.5 ppm, and a peak
at about 63.0 ppm.
[0144] In some embodiments, Form D can be characterized by a peak
at about 125.3 ppm, a peak at about 105.2 ppm, a peak at about 72.8
ppm, and a peak at about 67.5 ppm in a .sup.13C NMR solid state
spectrum.
[0145] In some embodiments, Form D can be characterized by a peak
at about 139.1 ppm, a peak at about 125.3 ppm, a peak at about
120.8 ppm, a peak at about 105.2 ppm, a peak at about 72.8 ppm, a
peak at about 67.5 ppm, and a peak at about 63.0 ppm in a .sup.13C
NMR solid state spectrum.
[0146] In some embodiments, Form D can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 9.
[0147] In some embodiments, Form D can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00009 .nu.(F1) Intensity Peak # [ppm] [rel] 1 172.5 31.47
2 170.3 39.91 3 163.0 36.97 4 152.7 57.96 5 150.4 41.72 6 143.3
19.06 7 139.1* 20.55 8 130.9 74.16 9 130.2 33.92 10 125.3* 71.51 11
124.4 39.60 12 120.8* 61.60 13 105.2* 73.13 14 92.3 31.47 15 91.0
29.46 16 81.8 47.28 17 79.9 100.00 18 78.5 65.96 19 73.6 52.41 20
72.8* 51.48 21 69.4 48.17 22 67.5* 45.52 23 63.0* 84.89 24 53.6
23.06 25 50.8 25.81 26 23.7 50.37 27 22.8 89.54 28 22.0 51.17 29
21.3 98.72 30 20.8 54.41 31 18.3 54.61 Peaks with an asterisk (*)
are major peaks
[0148] Form E
[0149] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form E.
[0150] In some embodiments, Form E can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
7.6 to about 8.0 degrees, a peak in the range of from about 10.4 to
about 10.8 degrees, a peak in the range of from about 12.7 to about
13.1 degrees, a peak in the range of from about 21.4 to about 21.8
degrees, a peak in the range of from about 24.3 to about 24.7
degrees, and a peak in the range of from about 24.8 to about 25.2
degrees.
[0151] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form E.
[0152] In some embodiments, Form E can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
7.6 to about 8.0 degrees, a peak in the range of from about 12.7 to
about 13.1 degrees, a peak in the range of from about 21.4 to about
21.8 degrees, and a peak in the range of from about 24.8 to about
25.2 degrees.
[0153] In some embodiments, Form E can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 7.8 degrees, a peak
at about 10.6 degrees, a peak at about 12.9 degrees, a peak at
about 21.6 degrees, a peak at about 24.5 degrees, and a peak at
about 25.0 degrees.
[0154] In some embodiments, Form E can be characterized by a peak
at about 7.8 degrees, a peak at about 10.6 degrees, a peak at about
12.9 degrees, a peak at about 21.6 degrees, a peak at about 24.5
degrees, and a peak at about 25.0 degrees in an X-ray powder
diffraction pattern.
[0155] In some embodiments, Form E can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak from about 7.6 to about 8.0
degrees, a peak from about 10.4 to about 10.8 degrees, a peak from
about 12.7 to about 13.1 degrees, a peak from about 24.3 to about
24.7 degrees, and a peak from about 24.8 to about 25.2 degrees.
[0156] In some embodiments, Form E can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 7.8 degrees, a peak
at about 10.6 degrees, a peak at about 12.9 degrees, a peak at
about 24.5 degrees, and a peak at about 25.0 degrees.
[0157] In some embodiments, Form E can be characterized by a peak
at about 7.8 degrees, a peak at about 12.9 degrees, and a peak at
about 25.0 degrees in an X-ray powder diffraction pattern.
[0158] In some embodiments, Form E can be characterized by a peak
at about 7.8 degrees, a peak at about 12.9 degrees, a peak at about
21.6 degrees and a peak at about 25.0 degrees in an X-ray powder
diffraction pattern.
[0159] In some embodiments, Form E can be characterized by a peak
at about 7.8 degrees, a peak at about 10.6 degrees, a peak at about
12.9 degrees, a peak at about 24.5 degrees, and a peak at about
25.0 degrees in an X-ray powder diffraction pattern.
[0160] In some embodiments, Form E can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00010 No. 2-Theta .degree. Intensity % 1 7.765* 58.9 2
10.563** 22.3 3 12.901* 40.7 4 21.571* 26.4 5 24.466** 51.4 6
25.016* 31.6 Peaks with an asterisk (*) are major peaks Peaks with
a double asterisk (**) are secondary peaks
[0161] In some embodiments, Form E can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.0 ppm, a peak at
about 150.7 ppm, a peak at about 130.2 ppm, a peak at about 118.3
ppm, a peak at about 73.9 ppm, a peak at about 67.0 ppm, and a peak
at about 22.0 ppm.
[0162] In some embodiments, Form E can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.0 ppm, a peak at
about 150.7 ppm, a peak at about 130.2 ppm, a peak at about 118.3
ppm, a peak at about 73.9 ppm, a peak at about 68.0 ppm, a peak at
about 67.0 ppm, and a peak at about 22.0 ppm.
[0163] In some embodiments, Form E can be characterized by a peak
at about 130.2 ppm, a peak at about 118.3 ppm, a peak at about 73.9
ppm, and a peak at about 67.0 ppm in a .sup.13C NMR solid state
spectrum.
[0164] In some embodiments, Form E can be characterized by a peak
at about 173.0 ppm, a peak at about 150.7 ppm, a peak at about
130.2 ppm, a peak at about 118.3 ppm, a peak at about 73.9 ppm, a
peak at about 67.0 ppm, and a peak at about 22.0 ppm in a .sup.13C
NMR solid state spectrum.
[0165] In some embodiments, Form E can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.0 ppm, a peak at
about 150.7 ppm, a peak at about 118.3 ppm, or a peak at about 73.9
ppm. In some embodiments, Form E can be characterized by a peak at
about 118.3 ppm, and a peak at about 73.9 ppm in a .sup.13C NMR
solid state spectrum. In some embodiments, Form E can be
characterized by a peak at about 173.0 ppm, a peak at about 150.7
ppm, a peak at about 118.3 ppm, and a peak at about 73.9 ppm in a
.sup.13C NMR solid state spectrum.
[0166] In some embodiments, Form E can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00011 .nu.(F1) Intensity Peak # [ppm] [rel] 1 173.0* 56.27
2 172.1 10.64 3 170.1 29.76 4 151.3 14.75 5 150.7* 55.30 6 146.7
6.43 7 145.2 17.07 8 144.0 6.43 9 130.2* 78.40 10 126.2 14.42 11
123.7 34.51 12 120.5 15.84 13 118.3* 65.27 14 104.1 11.22 15 103.2
33.55 16 102.2 11.20 17 92.7 28.19 18 84.1 12.31 19 82.4 35.17 20
80.1 73.44 21 79.8 36.49 22 75.0 14.45 23 73.9* 48.37 24 69.2 53.62
25 68.0* 59.07 26 67.0* 32.83 27 50.4 28.84 28 22.0* 100.00 29 21.7
93.59 30 21.4 58.58 31 20.6 18.91 32 19.4 40.73 Peaks with an
asterisk (*) are major peaks
[0167] Form F
[0168] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form F.
[0169] In some embodiments, Form F can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
5.8 to about 6.2 degrees, a peak in the range of from about 6.8 to
about 7.2 degrees, a peak in the range of from about 17.3 to about
17.7 degrees, and a peak in the range of from about 17.8 to about
18.2 degrees.
[0170] In some embodiments, Form F can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 6.0 degrees, a peak
at about 7.0 degrees, a peak at about 17.5 degrees, and a peak at
about 18.0 degrees.
[0171] In some embodiments, Form F can be characterized by a peak
at about 7.8 degrees, a peak at about 12.9 degrees, a peak at about
21.6 degrees, and a peak at about 25.0 degrees in an X-ray powder
diffraction pattern.
[0172] In some embodiments, Form F can be characterized by a peak
at about 6.0 degrees, a peak at about 7.0 degrees, a peak at about
17.5 degrees, and a peak at about 18.0 degrees in an X-ray powder
diffraction pattern.
[0173] In some embodiments, Form F can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00012 No. 2-Theta .degree. Intensity % 1 6.090* 100.0 2
6.970* 32.4 3 17.538* 30.7 4 18.048* 56.0 Peaks with an asterisk
(*) are major peaks
[0174] In some embodiments, Form F can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 170.2 ppm, a peak at
about 150.5 ppm, a peak at about 130.4 ppm, a peak at about 79.7
ppm, a peak at about 73.5 ppm, a peak at about 66.9 ppm, a peak at
about 21.8 ppm, and a peak at about 20.6 ppm.
[0175] In some embodiments, Form F can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 170.2 ppm, a peak at
about 150.5 ppm, a peak at about 130.4 ppm, a peak at about 79.7
ppm, a peak at about 73.5 ppm, a peak at about 68.2 ppm, a peak at
about 66.9 ppm, a peak at about 25.7 ppm, a peak at about 21.8 ppm,
and a peak at about 20.6 ppm.
[0176] In some embodiments, Form F can be characterized by a peak
at about 130.4 ppm, a peak at about 73.5 ppm, a peak at about 66.9
ppm, and a peak at about 20.6 ppm in a .sup.13C NMR solid state
spectrum. In still a further embodiment, Form F can be
characterized by a peak at about 6.1 degrees in an X-ray powder
diffraction pattern.
[0177] In some embodiments, Form F can be characterized by a peak
at about 170.2 ppm, a peak at about 150.5 ppm, a peak at about
130.4 ppm, a peak at about 79.7 ppm, a peak at about 73.5 ppm, a
peak at about 66.9 ppm, a peak at about 21.8 ppm, and a peak at
about 20.6 ppm in a .sup.13C NMR solid state spectrum.
[0178] In some embodiments, Form F can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 170.2 ppm, a peak at
about 150.5 ppm, a peak at about 79.7 ppm, a peak at about 73.5
ppm, or a peak at about 21.8 ppm. In some embodiments, Form F can
be characterized by a peak at about 73.5 ppm in a .sup.13C NMR
solid state spectrum. In some embodiments, Form F can be
characterized by a peak at about 170.2 ppm, a peak at about 150.5
ppm, a peak at about 79.7 ppm, a peak at about 73.5 ppm, and a peak
at about 21.8 ppm in a .sup.13C NMR solid state spectrum.
[0179] In some embodiments, Form F can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00013 .nu.(F1) Intensity Peak # [ppm] [rel] 1 173.0 21.53
2 172.0 24.07 3 170.2* 27.88 4 151.3 28.85 5 150.5* 40.71 6 146.6
11.13 7 145.2 6.82 8 143.9 11.03 9 130.4* 33.74 10 126.2 25.38 11
123.1 8.05 12 120.4 29.96 13 104.0 20.89 14 103.2 9.89 15 102.2
20.47 16 92.8 22.77 17 92.2 18.97 18 84.0 21.12 19 81.9 7.45 20
79.7* 71.06 21 75.0 24.15 22 73.5* 30.33 23 69.5 29.78 24 69.2
27.71 25 68.2* 20.78 26 66.9* 34.82 27 50.4 28.03 28 25.7* 7.70 29
21.8* 100.00 30 20.6* 39.64 Peaks with an asterisk (*) are major
peaks
[0180] Form G
[0181] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form G.
[0182] In some embodiments, Form G can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
5.7 to about 6.1 degrees, a peak in the range of from about 7.3 to
about 7.7 degrees, a peak in the range of from about 7.6 to about
8.0 degrees, a peak in the range of from about 12.3 to about 12.7
degrees, a peak in the range of from about 17.5 to about 17.9
degrees, and a peak in the range of from about 18.0 to about 18.4
degrees.
[0183] In some embodiments, Form G can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
5.7 to about 6.1 degrees, a peak in the range of from about 7.3 to
about 7.7 degrees, a peak in the range of from about 7.6 to about
8.0 degrees and a peak in the range of from about 17.5 to about
17.9 degrees.
[0184] In some embodiments, Form G can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 5.9 degrees, a peak
at about 7.5 degrees, a peak at about 7.8 degrees, a peak at about
12.5 degrees, a peak at about 17.7 degrees, and a peak at about
18.2 degrees.
[0185] In some embodiments, Form G can be characterized by a peak
at about 5.9 degrees, a peak at about 7.5 degrees, a peak at about
7.8 degrees, and a peak at about 17.7 degrees in an X-ray powder
diffraction pattern.
[0186] In some embodiments, Form G can be characterized by a peak
at about 5.9 degrees, a peak at about 7.5 degrees, a peak at about
7.8 degrees, a peak at about 12.5 degrees, a peak at about 17.7
degrees, and a peak at about 18.2 degrees in an X-ray powder
diffraction pattern.
[0187] In some embodiments, Form G can be characterized by an X-ray
powder diffraction pattern of FIG. 14.
[0188] In some embodiments, Form G can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00014 No. 2-Theta .degree. Intensity % 1 5.857* 100.0 2
7.498* 41.6 3 7.835* 32.1 4 12.522** 23.5 5 17.733* 53.0 6 18.193**
23.5 Peaks with an asterisk (*) are major peaks Peaks with a double
asterisk (**) are secondary peaks
[0189] In some embodiments, Form G can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 172.9 ppm, a peak at
about 150.8 ppm, a peak at about 130.4 ppm, a peak at about 119.6
ppm, a peak at about 118.7 ppm, a peak at about 83.1 ppm, a peak at
about 69.0 ppm, and a peak at about 20.4 ppm.
[0190] In some embodiments, Form G can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 172.9 ppm, a peak at
about 150.8 ppm, a peak at about 130.4 ppm, a peak at about 119.6
ppm, a peak at about 118.7 ppm, a peak at about 83.1 ppm, a peak at
about 69.0 ppm, a peak at about 54.2 ppm, and a peak at about 20.4
ppm.
[0191] In some embodiments, Form G can be characterized by a peak
at about 119.6 ppm, a peak at about 118.7 ppm, a peak at about 83.1
ppm, and a peak at about 69.0 ppm in a .sup.13C NMR solid state
spectrum.
[0192] In some embodiments, Form G can be characterized by a peak
at about 172.9 ppm, a peak at about 150.8 ppm, a peak at about
130.4 ppm, a peak at about 119.6 ppm, a peak at about 118.7 ppm, a
peak at about 83.1 ppm, a peak at about 69.0 ppm, and a peak at
about 20.4 ppm in a .sup.13C NMR solid state spectrum.
[0193] In some embodiments, Form G can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 15.
[0194] In some embodiments, Form G can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00015 .nu.(F1) Intensity Peak [ppm] [rel] 1 172.9* 47.8 2
172.5 60.77 3 170.1 31.87 4 150.8* 97.73 5 145.6 17.22 6 143.7
10.94 7 130.4* 78.80 8 123.6 13.92 9 122.8 39.28 10 122.2 22.62 11
119.6* 30.97 12 118.7* 83.25 13 103.6 49.34 14 103.2 27.56 15 93.1
34.63 16 92.6 30.12 17 83.1* 44.78 18 82.6 41.59 19 80.2 49.48 20
79.9 89.47 21 79.5 48.95 22 74.4 42.00 23 73.5 36.87 24 73.3 36.16
25 69.0* 46.99 26 68.8 93.22 27 68.5 53.49 28 68.3 50.90 29 68.0
70.75 30 54.2* 17.40 31 50.5 44.46 32 23.4 36.90 33 22.9 82.85 34
22.6 100.00 35 21.8 87.94 36 21.4 85.89 37 20.4* 70.1 38 20.1 39.2
Peaks with an asterisk (*) are major peaks
[0195] Form H
[0196] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form H.
[0197] In some embodiments, Form H can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
7.9 to about 8.3 degrees, a peak in the range of from about 13.8 to
about 14.2 degrees, a peak in the range of from about 17.0 to about
17.4 degrees, and a peak in the range of from about 19.9 to about
20.3 degrees.
[0198] In some embodiments, Form H can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 8.1 degrees, a peak
at about 14.0 degrees, a peak at about 17.2 degrees, and a peak at
about 20.1 degrees.
[0199] In some embodiments, Form H can be characterized by a peak
at about 8.1 degrees, a peak at about 14.0 degrees, a peak at about
17.2 degrees, and a peak at about 20.1 degrees in an X-ray powder
diffraction pattern.
[0200] In some embodiments, Form H can be characterized by an X-ray
powder diffraction pattern of FIG. 16.
[0201] In some embodiments, Form H can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00016 No. 2-Theta .degree. Intensity % 1 8.132* 81.7 2
14.020* 34.6 3 17.226* 61.7 4 20.902* 27.3 Peaks with an asterisk
(*) are major peaks
[0202] In some embodiments, Form H can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.4 ppm, a peak at
about 153.4 ppm, a peak at about 152.2 ppm, a peak at about 129.8
ppm, a peak at about 119.8 ppm, a peak at about 104.6 ppm, a peak
at about 79.4 ppm, and a peak at about 20.6 ppm.
[0203] In some embodiments, Form H can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.4 ppm, a peak at
about 153.4 ppm, a peak at about 152.2 ppm, a peak at about 129.8
ppm, a peak at about 119.8 ppm, a peak at about 104.6 ppm, a peak
at about 79.4 ppm, a peak at about 20.6 ppm, and a peak at about
2.2 ppm.
[0204] In some embodiments, Form H can be characterized by a peak
at about 173.4 ppm, a peak at about 153.4 ppm, a peak at about
119.8 ppm, and a peak at about 104.6 ppm in a .sup.13C NMR solid
state spectrum.
[0205] In some embodiments, Form H can be characterized by a peak
at about 173.4 ppm, a peak at about 153.4 ppm, a peak at about
152.2 ppm, a peak at about 129.8 ppm, a peak at about 119.8 ppm, a
peak at about 104.6 ppm, a peak at about 79.4 ppm, and a peak at
about 20.6 ppm in a .sup.13C NMR solid state spectrum.
[0206] In some embodiments, Form H can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 17.
[0207] In some embodiments, Form H can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00017 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.4* 70.7 2
164.4 44.87 3 153.4* 31.83 4 152.2* 61.17 5 141.4 42.94 6 129.8*
70.37 7 123.6 53.72 8 119.8* 55.92 9 104.6* 76.16 10 92.3 56.76 11
82.6 35.67 12 81.9 32.74 13 79.4* 100.00 14 73.4 96.98 15 68.9
54.71 16 61.7 73.15 17 53.6 47.24 18 23.4 79.96 19 22.9 86.96 20
21.6 41.15 21 20.6* 90.05 22 2.2* 14.59 Peaks with an asterisk (*)
are major peaks
[0208] Form I
[0209] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form I.
[0210] In some embodiments, Form I can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
6.2 to about 6.6 degrees, a peak in the range of from about 9.1 to
about 9.5 degrees, a peak in the range of from about 10.6 to about
11.0 degrees, and a peak in the range of from about 11.6 to about
12.0 degrees.
[0211] In some embodiments, Form I can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 6.4 degrees, a peak
at about 9.3 degrees, a peak at about 10.8 degrees, and a peak at
about 11.8 degrees.
[0212] In some embodiments, Form I can be characterized by a peak
at about 6.4 degrees, a peak at about 9.3 degrees, a peak at about
10.8 degrees, and a peak at about 11.8 degrees in an X-ray powder
diffraction pattern.
[0213] In some embodiments, Form I can be characterized by an X-ray
powder diffraction pattern of FIG. 18.
[0214] In some embodiments, Form I can be characterized by one or
more peaks in an X-ray powder diffraction pattern selected from the
table below.
TABLE-US-00018 No. 2-Theta .degree. Intensity % 1 6.434* 59.2 2
9.283* 30.8 3 10.831* 55.3 4 11.794* 28.3 Peaks with an asterisk
(*) are major peaks
[0215] In some embodiments, Form I can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.0 ppm, a peak at
about 152.1 ppm, a peak at about 126.1 ppm, a peak at about 102.7
ppm, a peak at about 74.5 ppm, a peak at about 71.2 ppm, a peak at
about 63.3 ppm, and a peak at about 23.3 ppm.
[0216] In some embodiments, Form I can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.1 ppm, a peak at
about 168.6 ppm, a peak at about 152.1 ppm, a peak at about 123.6
ppm, a peak at about 102.6 ppm, a peak at about 71.4 ppm, a peak at
about 63.5 ppm, a peak at about 61.9 ppm, a peak at about 22.4 ppm,
and a peak at about 15.5 ppm. In some embodiments, Form I can be an
ethyl acetate solvate.
[0217] In some embodiments, Form I (ethyl acetate solvate) can be
characterized by one or more peaks in a .sup.13C NMR solid state
spectrum selected from the table below.
TABLE-US-00019 .nu.(F1) Intensity Peak [ppm] [rel] 1 174.2 27.6 2
173.1* 34.33 3 170.3 20.24 4 168.6* 20.76 5 152.1* 41.55 6 151.1
35.37 7 144.9 20.96 8 143.6 18.23 9 129.4 12.59 10 126.1 23.63 11
123.6* 24.98 12 119.3 10.42 13 102.6* 56.41 14 93.2 22.66 15 91.1
23.83 16 81.7 36.81 17 80.6 41.38 18 79.6 68.17 19 74.3 34.18 20
73.2 33.47 21 71.4* 32.36 22 69.3 33.35 23 68.7 34.79 24 63.5*
32.91 25 61.9* 21.88 26 51.3 22.60 27 50.5 21.35 28 22.4* 100.00 29
20.1 52.23 30 15.5* 16.24 Peaks with an asterisk (*) are major
peaks
[0218] In some embodiments, Form I can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.0 ppm, a peak at
about 168.4 ppm, a peak at about 152.1 ppm, a peak at about 126.1
ppm, a peak at about 102.7 ppm, a peak at about 74.5 ppm, a peak at
about 71.2 ppm, a peak at about 63.3 ppm, and a peak at about 23.3
ppm. In some embodiments, Form I can be an isopropyl acetate
solvate.
[0219] In some embodiments, Form I can be characterized by a peak
at about 102.7 ppm, a peak at about 74.5 ppm, a peak at about 71.2
ppm, and a peak at about 63.3 ppm in a .sup.13C NMR solid state
spectrum.
[0220] In some embodiments, Form I can be characterized by a peak
at about 173.0 ppm, a peak at about 152.1 ppm, a peak at about
126.1 ppm, a peak at about 102.7 ppm, a peak at about 74.5 ppm, a
peak at about 71.2 ppm, a peak at about 63.3 ppm, and a peak at
about 23.3 ppm in a .sup.13C NMR solid state spectrum.
[0221] In some embodiments, Form I can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 19.
[0222] In some embodiments, Form I (isopropyl acetate solvate) can
be characterized by one or more peaks in a .sup.13C NMR solid state
spectrum selected from the table below.
TABLE-US-00020 .nu.(F1) Intensity Peak [ppm] [rel] 1 174.2 28.4 2
173.0* 35.35 3 170.1 18.49 4 168.4* 18.99 5 152.1* 44.16 6 151.0
35.26 7 144.8 19.59 8 143.5 18.22 9 129.9 26.35 10 126.1* 27.72 11
123.4 33.24 12 122.8 27.21 13 119.6 9.23 14 102.7* 56.58 15 93.2
23.93 16 91.1 24.94 17 81.6 37.12 18 80.5 42.31 19 79.6 73.82 20
74.5* 37.87 21 73.2 37.91 22 71.2* 34.86 23 69.3 62.97 24 68.8
39.70 25 63.3* 34.57 26 51.1 22.87 27 50.3 19.47 28 23.3* 100.00 29
22.8 76.24 30 21.9 75.98 31 21.4 42.76 32 20.4 36.17 33 20.0 38.34
Peaks with an asterisk (*) are major peaks
[0223] Form J
[0224] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form J.
[0225] In some embodiments, Form J can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
5.9 to about 6.3 degrees, a peak in the range of from about 7.3 to
about 7.7 degrees, a peak in the range of from about 11.9 to about
12.3 degrees, a peak in the range of from about 13.1 to about 13.5
degrees, a peak in the range of from about 13.8 to about 14.2
degrees, a peak in the range of from about 18.3 to about 18.7
degrees, a peak in the range of from about 22.4 to about 22.8
degrees, a peak in the range of from about 33.0 to about 33.4
degrees, a peak in the range of from about 33.8 to about 34.2
degrees, and a peak in the range of from about 35.1 to about 35.5
degrees.
[0226] In some embodiments, Form J can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
5.9 to about 6.3 degrees, a peak in the range of from about 7.3 to
about 7.7 degrees, a peak in the range of from about 11.9 to about
12.3 degrees, a peak in the range of from about 13.1 to about 13.5
degrees, a peak in the range of from about 13.8 to about 14.2
degrees and a peak in the range of from about 18.3 to about 18.7
degrees.
[0227] In some embodiments, Form J can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 6.1 degrees, a peak
at about 7.5 degrees, a peak at about 12.1 degrees, a peak at about
13.3 degrees, a peak at about 14.0 degrees, a peak at about 18.5
degrees, a peak at about 22.6 degrees, a peak at about 33.2
degrees, a peak at about 34.0 degrees, and a peak at about 35.3
degrees.
[0228] In some embodiments, Form J can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 6.1 degrees, a peak
at about 7.5 degrees, a peak at about 12.1 degrees, a peak at about
13.3 degrees, a peak at about 14.0 degrees, and a peak at about
18.5 degrees.
[0229] In some embodiments, Form J can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 6.1 degrees, a peak
at about 7.5 degrees, a peak at about 12.1 degrees, a peak at about
13.3 degrees, a peak at about 14.0 degrees, a peak at about 18.5
degrees, a peak at about 22.6 degrees, a peak at about 33.2
degrees, a peak at about 34.0 degrees, and a peak at about 35.3
degrees.
[0230] In some embodiments, Form J can be characterized by an X-ray
powder diffraction pattern of FIG. 20.
[0231] In some embodiments, Form J can be characterized by one or
more XRPD peaks selected from the table below.
TABLE-US-00021 No. 2-Theta .degree. Intensity % 1 6.1* 69.2 2 7.5*
54.4 3 9.0 21.2 4 9.9 21.2 5 10.8 34.0 6 11.1 44.2 7 11.4 26.5 8
12.1* 100.0 9 12.9 24.6 10 13.3* 31.2 11 14.0* 27.2 12 14.8 28.3 13
15.1 30.2 14 15.4 29.5 15 16.1 33.0 16 16.7 41.0 17 17.6 29.8 18
18.0 54.6 19 18.5* 47.3 20 18.9 25.6 21 19.4 41.6 22 19.6 35.8 23
20.3 43.5 24 20.7 59.8 25 21.1 43.8 26 21.7 35.5 27 22.6** 30.1 28
22.3 24.3 29 23.8 23.1 30 24.7 32.7 31 25.2 23.7 32 25.7 20.8 33
26.6 26.7 34 27.5 24.3 35 27.8 23.6 36 28.3 20.7 37 29.6 22.9 38
32.2 20.3 39 33.2** 21.5 40 34.0** 19.2 41 35.3** 19.3 42 35.4 19.4
43 36.5 19.0 Peaks with an asterisk (*) are major peaks Peaks with
a double asterisk (**) are secondary peaks
[0232] In some embodiments, Form J can be characterized by a DSC
thermogram as shown in FIG. 21. In some embodiments, Form J can be
characterized by a DSC thermogram showing a first endotherm in the
range of about 121.degree. C. to about 127.degree. C. (for example,
at about 126.degree. C.). In some embodiments, Form J can be
characterized by a DSC thermogram showing an exotherm in the range
of about 127.degree. C. to about 132.degree. C. (for example, at
about 129.degree. C.). In some embodiments, Form J can be
characterized by a DSC thermogram showing a second endotherm in the
range of about 135.degree. C. to about 142.degree. C. (for example,
at about 138.degree. C.). In some embodiments, Form J can be
characterized by a DSC thermogram showing a first melting
temperature in the range of about 121.degree. C. to about
127.degree. C. (for example, at about 126.degree. C.). In some
embodiments, Form J can be characterized by a DSC thermogram
showing a recrystallization at a temperature in the range of about
127.degree. C. to about 132.degree. C. (for example, at about
129.degree. C.). In some embodiments, Form J can be characterized
by a DSC thermogram showing a second melting temperature in the
range of about 135.degree. C. to about 142.degree. C. (for example,
at about 138.degree. C.). In some embodiments, Form J can be
characterized by a melting temperature in the range of about
121.degree. C. to about 127.degree. C. (for example, at about
126.degree. C.).
[0233] In some embodiments, Form J can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 175.6 ppm, a peak at
about 141.4 ppm, a peak at about 127.8 ppm, a peak at about 123.4
ppm, a peak at about 103.1 ppm, a peak at about 83.5 ppm, a peak at
about 81.1 ppm, a peak at about 62.2 ppm, a peak at about 25.6 ppm,
and a peak at about 19.6 ppm.
[0234] In some embodiments, Form J can be characterized by a peak
at about 83.5 ppm, a peak at about 81.1 ppm, a peak at about 62.2
ppm, and a peak at about 25.6 ppm in a .sup.13C NMR solid state
spectrum.
[0235] In some embodiments, Form J can be characterized by a peak
at about 175.6 ppm, a peak at about 141.4 ppm, a peak at about
127.8 ppm, a peak at about 123.4 ppm, a peak at about 103.1 ppm, a
peak at about 83.5 ppm, a peak at about 81.1 ppm, a peak at about
62.2 ppm, a peak at about 25.6 ppm, and a peak at about 19.6 ppm in
a .sup.13C NMR solid state spectrum.
[0236] In some embodiments, Form J can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 22.
[0237] In some embodiments, Form J can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00022 .nu.(F1) Intensity Peak [ppm] [rel] 1 175.6* 26.8 2
172.6 39.76 3 165.8 13.72 4 162.9 22.43 5 162.5 16.16 6 153.0 15.82
7 152.8 15.88 8 151.5 29.40 9 151.1 11.45 10 150.7 36.85 11 150.1
21.71 12 141.4* 19.34 13 140.1 11.81 14 131.1 29.77 15 129.7 35.60
16 129.5 26.33 17 127.8* 25.20 18 127.1 17.58 19 126.3 27.54 20
123.8 29.09 21 123.4* 32.43 22 122.8 26.21 23 103.1* 37.64 24 101.3
27.86 25 93.8 22.55 26 93.3 16.53 27 91.7 18.80 28 83.5* 35.20 29
81.1* 35.52 30 80.7 100.00 31 79.8 28.76 32 78.6 42.08 33 74.4
37.67 34 73.4 41.04 35 73.1 28.84 36 72.3 39.74 37 70.1 57.8 38
63.7 44.0 39 62.2* 33.4 40 53.1 21.6 41 52.5 16.9 42 50.8 15.9 43
25.6* 36.7 44 23.7 60.6 45 23.0 34.4 46 22.5 64.4 47 22.1 46.4 48
21.7 36.1 49 19.6* 34.5 50 18.8 34.8 51 18.4 29.1 Peaks with an
asterisk (*) are major peaks
[0238] Form K
[0239] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form K.
[0240] In some embodiments, Form K can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
22.4 to about 22.8 degrees, a peak in the range of from about 27.1
to about 27.5 degrees, a peak in the range of from about 28.1 to
about 28.5 degrees, and a peak in the range of from about 31.0 to
about 31.4 degrees.
[0241] In some embodiments, Form K can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 22.6 degrees, a peak
at about 27.3 degrees, a peak at about 28.3 degrees, and a peak at
about 31.2 degrees.
[0242] In some embodiments, Form K can be characterized by a peak
at about 22.6 degrees, a peak at about 27.3 degrees, a peak at
about 28.3 degrees, and a peak at about 31.2 degrees in an X-ray
powder diffraction pattern.
[0243] In some embodiments, Form K can be characterized by an X-ray
powder diffraction pattern of FIG. 23.
[0244] In some embodiments, Form K can be characterized by one or
more XRPD peaks selected from the table below.
TABLE-US-00023 No. 2-Theta .degree. Intensity % 1 22.620* 27.5 2
27.257* 26.7 3 28.272* 25.0 4 31.216* 27.0 Peaks with an asterisk
(*) are major peaks
[0245] In some embodiments, Form K can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.9 ppm, a peak at
about 173.4 ppm, a peak at about 151.8 ppm, a peak at about 150.5
ppm, a peak at about 101.9 ppm, a peak at about 92.0 ppm, a peak at
about 73.5 ppm, a peak at about 22.1 ppm, and a peak at about 20.4
ppm.
[0246] In some embodiments, Form K can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.9 ppm, a peak at
about 173.4 ppm, a peak at about 151.8 ppm, a peak at about 150.5
ppm, a peak at about 101.9 ppm, a peak at about 92.0 ppm, a peak at
about 80.4 ppm, a peak at about 73.5 ppm, a peak at about 22.1 ppm,
and a peak at about 20.4 ppm.
[0247] In some embodiments, Form K can be characterized by a peak
at about 173.9 ppm, a peak at about 173.4 ppm, a peak at about
101.9 ppm, and a peak at about 92.0 ppm in a .sup.13C NMR solid
state spectrum.
[0248] In some embodiments, Form K can be characterized by a peak
at about 173.9 ppm, a peak at about 173.4 ppm, a peak at about
151.8 ppm, a peak at about 150.5 ppm, a peak at about 101.9 ppm, a
peak at about 92.0 ppm, a peak at about 73.5 ppm, a peak at about
22.1 ppm, and a peak at about 20.4 ppm in a .sup.13C NMR solid
state spectrum.
[0249] In some embodiments, Form K can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 24.
[0250] In some embodiments, Form K can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00024 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.9* 40.0 2
173.4* 39.97 3 169.9 23.72 4 168.7 24.10 5 151.8* 45.42 6 150.5*
44.95 7 144.6 27.19 8 144.1 24.43 9 129.8 17.44 10 126.2 30.54 11
125.8 20.97 12 122.5 16.21 13 101.9* 81.01 14 93.4 34.58 15 92.0*
35.25 16 81.6 54.04 17 80.4* 88.61 18 79.7 51.32 19 78.6 62.92 20
73.5* 72.84 21 70.6 49.15 22 69.5 50.72 23 68.1 46.78 24 63.6 47.15
25 50.8 55.38 26 23.2 76.97 27 22.8 67.52 28 22.1* 100.00 29 20.7
68.21 30 20.4* 97.77 Peaks with an asterisk (*) are major peaks
[0251] Form L
[0252] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form L.
[0253] In some embodiments, Form L can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
5.5 to about 5.9 degrees, a peak in the range of from about 5.8 to
about 6.2 degrees, a peak in the range of from about 15.0 to about
15.4 degrees, and a peak in the range of from about 15.9 to about
16.3 degrees.
[0254] In some embodiments, Form L can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 5.7 degrees, a peak
at about 6.0 degrees, a peak at about 15.2 degrees, and a peak at
about 16.1 degrees.
[0255] In some embodiments, Form L can be characterized by a peak
at about 5.7 degrees, a peak at about 6.0 degrees, a peak at about
15.2 degrees, and a peak at about 16.1 degrees in an X-ray powder
diffraction pattern.
[0256] In some embodiments, Form L can be characterized by an X-ray
powder diffraction pattern of FIG. 25.
[0257] In some embodiments, Form L can be characterized by one or
more XRPD peaks selected from the table below.
TABLE-US-00025 No. 2-Theta .degree. Intensity % 1 5.662* 27.0 2
6.036* 27.2 3 15.174* 100.0 4 16.102* 56.5 Peaks with an asterisk
(*) are major peaks
[0258] In some embodiments, Form L can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.2 ppm, a peak at
about 151.4 ppm, a peak at about 140.9 ppm, a peak at about 118.5
ppm, a peak at about 81.5 ppm, a peak at about 80.1 ppm, a peak at
about 73.4 ppm, a peak at about 61.6 ppm, and a peak at about 20.9
ppm.
[0259] In some embodiments, Form L can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 173.2 ppm, a peak at
about 151.4 ppm, a peak at about 140.9 ppm, a peak at about 118.5
ppm, a peak at about 81.5 ppm, a peak at about 80.1 ppm, a peak at
about 73.4 ppm, a peak at about 61.6 ppm, a peak at about 20.9 ppm,
and a peak at about 1.6 ppm.
[0260] In some embodiments, Form L can be characterized by a peak
at about 81.5 ppm, a peak at about 80.1 ppm, a peak at about 61.6
ppm, and a peak at about 20.9 ppm in a .sup.13C NMR solid state
spectrum.
[0261] In some embodiments, Form L can be characterized by a peak
at about 173.2 ppm, a peak at about 151.4 ppm, a peak at about
140.9 ppm, a peak at about 118.5 ppm, a peak at about 81.5 ppm, a
peak at about 80.1 ppm, a peak at about 73.4 ppm, a peak at about
61.6 ppm, and a peak at about 20.9 ppm in a .sup.13C NMR solid
state spectrum.
[0262] In some embodiments, Form L can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 26.
[0263] In some embodiments, Form L can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00026 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.2* 32.2 2
172.6 13.04 3 164.3 20.50 4 152.9 15.62 5 152.3 18.02 6 151.4*
22.38 7 150.8 10.20 8 150.6 15.53 9 142.9 7.14 10 140.9* 17.32 11
130.3 17.85 12 129.9 17.36 13 125.7 15.60 14 124.7 11.99 15 123.4
12.87 16 118.5* 18.82 17 103.8 8.86 18 103.3 18.66 19 102.9 15.60
20 101.5 12.23 21 92.7 29.36 22 92.3 25.58 23 81.5* 51.96 24 80.1*
100.00 25 73.4* 51.97 26 69.9 17.16 27 69.3 27.18 28 68.0 11.49 29
63.0 15.93 30 61.9 24.74 31 61.6* 32.16 32 54.0 18.79 33 53.0 14.69
34 52.2 16.30 35 23.7 12.59 36 23.3 12.87 37 23.0 28.2 38 22.5 42.2
39 22.0 47.5 40 21.4 43.2 41 20.9* 50.2 42 20.2 17.4 43 19.8 22.2
44 19.2 15.2 45 18.9 14.8 46 1.6* 12.9 Peaks with an asterisk (*)
are major peaks
[0264] Form M
[0265] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form M.
[0266] In some embodiments, Form M can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
6.1 to about 6.5 degrees, a peak in the range of from about 13.0 to
about 13.4 degrees, a peak in the range of from about 22.0 to about
22.4 degrees, and a peak in the range of from about 23.3 to about
23.7 degrees.
[0267] In some embodiments, Form M can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 6.3 degrees, a peak
at about 13.2 degrees, a peak at about 22.2 degrees, and a peak at
about 23.5 degrees.
[0268] In some embodiments, Form M can be characterized by a peak
at about 6.3 degrees, a peak at about 13.2 degrees, a peak at about
22.2 degrees, and a peak at about 23.5 degrees in an X-ray powder
diffraction pattern.
[0269] In some embodiments, Form M can be characterized by an X-ray
powder diffraction pattern of FIG. 27.
[0270] In some embodiments, Form M can be characterized by one or
more XRPD peaks selected from the table below.
TABLE-US-00027 No. 2-Theta .degree. Intensity % 1 6.274* 66.2 2
13.200* 40.5 3 22.225* 50.0 4 23.520* 38.7 Peaks with an asterisk
(*) are major peaks
[0271] In some embodiments, Form M can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 174.0 ppm, a peak at
about 170.5 ppm, a peak at about 129.5 ppm, a peak at about 79.6
ppm, a peak at about 69.7 ppm, a peak at about 63.2 ppm, a peak at
about 51.8 ppm, a peak at about 24.0 ppm, and a peak at about 19.5
ppm.
[0272] In some embodiments, Form M can be characterized by a peak
at about 69.7 ppm, a peak at about 63.2 ppm, a peak at about 51.8
ppm, and a peak at about 24.0 ppm in a .sup.13C NMR solid state
spectrum.
[0273] In some embodiments, Form M can be characterized by a peak
at about 174.0 ppm, a peak at about 170.5 ppm, a peak at about
129.5 ppm, a peak at about 79.6 ppm, a peak at about 69.7 ppm, a
peak at about 63.2 ppm, a peak at about 51.8 ppm, a peak at about
24.0 ppm, and a peak at about 19.5 ppm in a .sup.13C NMR solid
state spectrum.
[0274] In some embodiments, Form M can be characterized by a
.sup.13C NMR solid state spectrum of FIG. 28.
[0275] In some embodiments, Form M can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00028 .nu.(F1) Intensity Peak [ppm] [rel] 1 174.0* 31.8 2
173.2 13.03 3 172.3 7.89 4 170.5* 25.18 5 163.6 11.98 6 163.0 24.93
7 162.4 16.01 8 152.8 24.75 9 151.8 15.28 10 151.3 19.55 11 150.7
13.04 12 150.3 26.82 13 149.8 8.82 14 149.3 28.40 15 141.0 21.01 16
138.9 14.25 17 131.3 17.74 18 130.3 11.77 19 129.5* 32.91 20 127.0
27.77 21 126.6 24.70 22 124.7 17.32 23 124.0 14.60 24 122.4 15.29
25 121.3 12.07 26 118.5 11.42 27 103.5 34.79 28 102.7 10.83 29
102.2 27.86 30 101.7 8.62 31 92.5 36.95 32 83.2 31.87 33 81.5 45.71
34 80.6 14.75 35 80.1 18.58 36 79.6* 100.00 37 74.3 44.8 38 73.3
44.3 39 70.5 10.0 40 69.7* 44.6 41 67.5 8.1 42 64.5 8.8 43 64.0 9.6
44 63.2* 39.5 45 61.4 8.0 46 53.3 20.6 47 51.8* 33.6 48 24.0* 37.0
49 23.7 47.1 50 23.3 62.9 51 22.4 67.7 52 21.9 44.5 53 21.6 52.4 54
20.5 8.9 55 19.5* 49.4 Peaks with an asterisk (*) are major
peaks
[0276] Form N
[0277] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Form N.
[0278] In some embodiments, Form N can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak in the range of from about
12.2 to about 12.6 degrees, a peak in the range of from about 15.1
to about 15.5 degrees, a peak in the range of from about 16.9 to
about 17.3 degrees, and a peak in the range of from about 17.7 to
about 18.1 degrees.
[0279] In some embodiments, Form N can be characterized by one or
more peaks in an X-ray powder diffraction pattern, wherein the one
or more peaks is selected from a peak at about 12.4 degrees, a peak
at about 15.3 degrees, a peak at about 17.1 degrees, and a peak at
about 17.9 degrees.
[0280] In some embodiments, Form N can be characterized by a peak
at about 12.4 degrees, a peak at about 15.3 degrees, a peak at
about 17.1 degrees, and a peak at about 17.9 degrees in an X-ray
powder diffraction pattern.
[0281] In some embodiments, Form N can be characterized by an X-ray
powder diffraction pattern of FIG. 29.
[0282] In some embodiments, Form N can be characterized by one or
more XRPD peaks selected from the table below.
TABLE-US-00029 No. 2-Theta .degree. Intensity % 1 12.419* 25.7 2
15.310* 41.7 3 17.149* 76.6 4 17.873* 57.0 Peaks with an asterisk
(*) are major peaks
[0283] In some embodiments, Form N can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 172.6 ppm, a peak at
about 130.4 ppm, a peak at about 129.2 ppm, a peak at about 128.4
ppm, a peak at about 82.2 ppm, a peak at about 74.0 ppm, a peak at
about 67.7 ppm, and a peak at about 21.3 ppm.
[0284] In some embodiments, Form N can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum, wherein the one
or more peaks is selected from a peak at about 172.6 ppm, a peak at
about 130.4 ppm, a peak at about 129.5 ppm, a peak at about 129.2
ppm, a peak at about 128.4 ppm, a peak at about 82.2 ppm, a peak at
about 74.0 ppm, a peak at about 67.7 ppm, and a peak at about 21.3
ppm.
[0285] In some embodiments, Form N can be characterized by a peak
at about 129.2 ppm, a peak at about 128.4 ppm, a peak at about 82.2
ppm, and a peak at about 67.7 ppm in a .sup.13C NMR solid state
spectrum.
[0286] In some embodiments, Form N can be characterized by a peak
at about 172.6 ppm, a peak at about 130.4 ppm, a peak at about
129.2 ppm, a peak at about 128.4 ppm, a peak at about 82.2 ppm, a
peak at about 74.0 ppm, a peak at about 67.7 ppm, and a peak at
about 21.3 ppm in a .sup.13C NMR solid state spectrum.
[0287] In some embodiments, Form N can be characterized by a
.sup.13C solid state NMR solid state spectrum of FIG. 30.
[0288] In some embodiments, Form N can be characterized by one or
more peaks in a .sup.13C NMR solid state spectrum selected from the
table below.
TABLE-US-00030 .nu.(F1) Intensity Peak [ppm] [rel] 1 172.6* 60.5 2
170.3 21.21 3 169.9 20.31 4 151.5 28.70 5 151.1 40.12 6 150.6 26.12
7 145.2 33.34 8 130.4* 78.13 9 129.5* 87.88 10 129.2* 70.02 11
128.4* 64.31 12 125.5 40.20 13 124.4 31.97 14 124.2 31.70 15 120.8
66.36 16 120.0 74.60 17 103.5 40.76 18 103.2 33.90 19 92.8 37.18 20
82.6 41.88 21 82.2* 37.02 22 79.6 64.84 23 79.3 68.37 24 74.0*
88.74 25 68.6 28.92 26 68.4 57.45 27 68.1 92.39 28 67.7* 51.91 29
50.2 29.20 30 23.0 54.35 31 22.3 18.31 32 21.8 60.50 33 21.3*
100.00 34 21.1 61.99 35 20.6 18.12 36 20.2 58.39 37 19.3 34.4 Peaks
with an asterisk (*) are major peaks
[0289] Amorphous Form O
[0290] In some embodiments, Compound 1 can be
2'-C-methyluridine-5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thioph-
osphoramidate characterized as Amorphous Form 0.
[0291] In some embodiments, the Amorphous Form O contains less than
about 30% crystallinity. In other embodiments, the Amorphous Form O
contains less than about 15% crystallinity. In still other
embodiments, the Amorphous Form O contains less than about 1.0%
crystallinity. In yet still other embodiments, the Amorphous Form O
contains substantially no crystallinity. In some embodiments, the
Amorphous Form O is substantially amorphous. In other embodiments,
the Amorphous Form O is completely amorphous (i.e., 100%
amorphous).
[0292] Some embodiments described herein relate to a process for
producing Form A that can include: [0293] a) contacting Compound 1
with a first amount of ethyl acetate to form a mixture; [0294] b)
heating the mixture until the solids are dissolved; [0295] c)
cooling the mixture to allow precipitation of a solid; [0296] d)
optionally adding a second amount of ethyl acetate and repeating
steps a, b and c; and [0297] e) isolating the solid Form A from
said mixture.
[0298] In some embodiments, the temperature in step b) can be in
the range of from about 55.degree. C. to about 65.degree. C. (for
example, about 60.degree. C.).
[0299] In some embodiments, the temperature in step c) can be in
the range of from about 18.degree. C. to about 24.degree. C. (for
example, about 21.degree. C.). In some embodiments, the temperature
in step c) can be room temperature (RT).
[0300] In some embodiments, the second amount of ethyl acetate in
step d) can be approximately equal to the first amount of ethyl
acetate used in step a). In other embodiments, the second amount of
ethyl acetate in step d) can be up to five times the first amount
of ethyl acetate used in step a). In other still other embodiments,
the second amount of ethyl acetate in step d) can be less than the
first amount of ethyl acetate used in step a). In some embodiments,
the first amount of ethyl acetate in step a) can be in the range of
from about 1 mL to about 3 mL per gram of Compound 1. In some
embodiments, the first amount of ethyl acetate in step a) can be
about 2 mL per gram of Compound 1.
[0301] In some embodiments, steps a, b and c can be repeated at
least one time. In other embodiments, steps a, b and c can be
repeated at least 2 times. In some embodiments, steps a, b and c
can be repeated one time.
[0302] In some embodiments, Form A can be isolated from the mixture
by filtration.
[0303] Other embodiments described herein relate to a process for
producing Form J, that can include
[0304] a) contacting Amorphous Form O with ethanol to form a
mixture; and
[0305] b) isolating Form J from said mixture.
[0306] In some embodiments, the mixture can be stirred at room
temperature for about 12 hours before isolating Form J. In some
embodiments, the mixture can be stirred at a temperature in the
range of about 20.degree. C. to about 30.degree. C. for about 12
hours before isolating Form J.
[0307] In some embodiments, about 100 mg of Amorphous Form O can be
contacted with an amount of ethanol in the range of from about 100
.mu.L to about 200 .mu.L of ethanol. In other embodiments, about
100 mg of Amorphous Form O can be contacted with about 150 .mu.L of
ethanol. In some embodiments, the ethanol can be HPLC grade
ethanol.
[0308] In some embodiments, Form J can be isolated from the mixture
by filtration.
[0309] Still other embodiments described herein relate to a process
for producing a solvated solid form of Compound 1, that can
include
[0310] a) contacting Compound 1 with a solvent to form a mixture;
and
[0311] b) isolating the solvated solid form of Compound 1 from said
mixture.
[0312] In some embodiments, the solvated solid form of Compound 1
can be isolated from the mixture by a method selected from
filtration and evaporation.
[0313] In some embodiments, the solvent can be MTBE, cyclohexane,
nitromethane, acetonitrile, dioxane, THF, dichloromethane, ethyl
acetate, isopropyl acetate, chloroform, chlorobenzene,
1,2-dichloroethane, 1,2,3-trichloroethane, or toluene.
[0314] In some embodiments, the solvent can be MTBE or cyclohexane
and the solvated solid form can be Form B. In other embodiments,
the solvent can be nitromethane and the solvated solid form can be
Form C. In still other embodiments, the solvent can be dioxane and
the solvated solid form can be Form E. In yet still other
embodiments, the solvent can be THF and the solvated solid form can
be Form F. In some embodiments, the solvent can be dichloromethane
and the solvated solid form can be Form G. In other embodiments,
the solvent can be acetonitrile and the solvated solid form can be
Form H or Form L. In still other embodiments, the solvent can be
ethyl acetate or isopropyl acetate and the solvated solid form can
be Form I. In yet still other embodiments, the solvent can be
chloroform, chlorobenzene, 1,2-dichloroethane or
1,2,3-trichloroethane and the solvated solid form can be Form K. In
some embodiments, the solvent can be toluene and the solvated solid
form can be Form N.
[0315] In some embodiments, the mixture can be sonicated before
isolating the solvated solid form.
[0316] In some embodiments, the amount of solvent added in step a)
above is in the range of from about 0.5 mL to about 10 mL per gram
of Compound 1. In some embodiments, the amount of solvent added in
step a) above is about 0.83 mL per gram of Compound 1. In other
embodiments, the amount of solvent added in step a) above is about
1.0 mL per gram of Compound 1. In still other embodiments, the
amount of solvent added in step a) above is about 1.5 mL per gram
of Compound 1. In yet still other embodiments, the amount of
solvent added in step a) above is about 1.9 mL per gram of Compound
1. In some embodiments, the amount of solvent added in step a)
above is about 2.0 mL per gram of Compound 1. In other embodiments,
the amount of solvent added in step a) above is about 2.5 mL per
gram of Compound 1. In still other embodiments, the amount of
solvent added in step a) above is about 3.3 mL per gram of Compound
1. In yet still other embodiments, the amount of solvent added in
step a) above is about 4.0 mL per gram of Compound 1. In some
embodiments, the amount of solvent added in step a) above is about
5.0 mL per gram of Compound 1. In other embodiments, the amount of
solvent added in step a) above is about 6.1 mL per gram of Compound
1. In still other embodiments, the amount of solvent added in step
a) above is about 10.0 mL per gram of Compound 1.
[0317] In some embodiments, the process further can include
removing the solvent from the solvated solid form of Compound 1,
including one or more of those described herein, to provide a
desolvated solid form of Compound 1. In some embodiments, the
desolvated solid form of Compound 1 can be Form D. In other
embodiments, the desolvated solid form of Compound 1 can be Form
M.
[0318] Uses, Formulation and Administration
[0319] Pharmaceutically Acceptable Compositions
[0320] Some embodiments described herein generally relate to a
pharmaceutical composition that can include one or more solid forms
of Compound 1 as described herein, and optionally comprise a
pharmaceutically acceptable carrier, adjuvant or vehicle.
[0321] Other embodiments described herein relate to a
pharmaceutical composition that can include one or more solid forms
of Compound 1, and one or more additional agent(s). In some
embodiments, the one or more additional agent(s) can be selected
from Pegylated interferon-alpha-2a (brand name PEGASYS.RTM.) and
ribavirin, Pegylated interferon-alpha-2b (brand name
PEG-INTRON.RTM.) and ribavirin, a HCV protease inhibitor, a HCV
polymerase inhibitor, and a NS5A inhibitor.
[0322] In some embodiments, the one or more agents can be selected
from an interferon, ribavirin, a HCV protease inhibitor, a HCV
polymerase inhibitor, a NS5A inhibitor, an antiviral compound, a
compound of Formula (BB) and a compound of Formula (DD), or a
pharmaceutically acceptable salt any of the aforementioned
compounds.
[0323] In some embodiments, the one or more agents can be selected
from Compounds 1000-1066 and 8001-8012, or a pharmaceutically
acceptable salt of any of the aforementioned compounds.
[0324] In some embodiments, including those embodiments described
previously, the pharmaceutical composition can include a single
diastereomer of Compound 1, or a pharmaceutically acceptable salt
thereof, (for example, a single diastereomer is present in the
pharmaceutical composition at a concentration of greater than 99%
compared to the total concentration of the diastereomers of
Compound 1). In other embodiments, the pharmaceutical composition
can include a mixture of diastereomers of Compound 1, or a
pharmaceutically acceptable salt thereof. For example, the
pharmaceutical composition can include a concentration of one
diastereomer of >50%, .gtoreq.60%, .gtoreq.70%, .gtoreq.80%,
.gtoreq.90%, .gtoreq.95%, or .gtoreq.98%, as compared to the total
concentration of diastereomers of Compound 1. In some embodiments,
the pharmaceutical composition includes a 1:1 mixture of two
diastereomers of Compound 1, or a pharmaceutically acceptable salt
thereof.
[0325] The term "pharmaceutical composition" refers to a mixture of
one or more compounds or forms disclosed herein with other chemical
components, such as diluents or carriers. The pharmaceutical
composition facilitates administration of the compound to an
organism. Pharmaceutical compositions can also be obtained by
reacting compounds with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid and salicylic acid. Pharmaceutical
compositions will generally be tailored to the specific intended
route of administration.
[0326] The term "physiologically acceptable" defines a carrier,
diluent or excipient that does not abrogate the biological activity
and properties of the compound.
[0327] As used herein, a "carrier" refers to a compound that
facilitates the incorporation of a compound into cells or tissues.
For example, without limitation, dimethyl sulfoxide (DMSO) is a
commonly utilized carrier that facilitates the uptake of many
organic compounds into cells or tissues of a subject.
[0328] As used herein, a "diluent" refers to an ingredient in a
pharmaceutical composition that lacks pharmacological activity but
may be pharmaceutically necessary or desirable. For example, a
diluent may be used to increase the bulk of a potent drug whose
mass is too small for manufacture and/or administration. It may
also be a liquid for the dissolution of a drug to be administered
by injection, ingestion or inhalation. A common form of diluent in
the art is a buffered aqueous solution such as, without limitation,
phosphate buffered saline that mimics the composition of human
blood.
[0329] As used herein, an "excipient" refers to an inert substance
that is added to a pharmaceutical composition to provide, without
limitation, bulk, consistency, stability, binding ability,
lubrication, disintegrating ability etc., to the composition. A
"diluent" is a type of excipient.
[0330] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical
compositions where they are mixed with other active ingredients, as
in combination therapy, or carriers, diluents, excipients or
combinations thereof. Proper formulation is dependent upon the
route of administration chosen. Techniques for formulation and
administration of the compounds described herein are known to those
skilled in the art.
[0331] The pharmaceutical compositions disclosed herein may be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tableting
processes. Additionally, the active ingredients are contained in an
amount effective to achieve its intended purpose. Many of the
compounds used in the pharmaceutical combinations disclosed herein
may be provided as salts with pharmaceutically compatible
counterions.
[0332] Multiple techniques of administering a compound exist in the
art including, but not limited to, oral, rectal, topical, aerosol,
injection and parenteral delivery, including intramuscular,
subcutaneous, intravenous, intramedullary injections, intrathecal,
direct intraventricular, intraperitoneal, intranasal and
intraocular injections.
[0333] One may also administer the compound in a local rather than
systemic manner, for example, via injection of the compound
directly into the infected area, often in a depot or sustained
release formulation. Furthermore, one may administer the compound
in a targeted drug delivery system, for example, in a liposome
coated with a tissue-specific antibody. The liposomes will be
targeted to and taken up selectively by the organ.
[0334] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions that can
include a compound described herein formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated
condition.
[0335] Uses of the Solid Forms and Pharmaceutically Acceptable
Compositions
[0336] Some embodiments disclosed herein relate to a method of
treating and/or ameliorating a disease or condition that can
include administering to a subject an effective amount of one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein.
[0337] Some embodiments disclosed herein relates to a method of
ameliorating or treating a viral infection that can include
administering to a subject suffering from the viral infection an
effective amount of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein. Other embodiments described
herein relate to the use of an effective amount of one or more
solid forms of Compound 1 as described herein in the preparation of
a medicament for ameliorating or treating a viral infection. Still
other embodiments described herein relate to one or more solid
forms of Compound 1 as described herein, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes one or more solid forms of Compound 1 as described herein,
that can be used for ameliorating and/or treating a viral infection
by administering an effective amount of said compound(s). In some
embodiments, the viral infection can be a hepatitis C viral (HCV)
infection.
[0338] Some embodiments disclosed herein relate to methods of
ameliorating and/or treating a viral infection that can include
contacting a cell infected with the virus with an effective amount
of one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein. Other embodiments described herein relate to
using one or more compounds described herein, or a pharmaceutically
acceptable salt of a compound described herein, in the manufacture
of a medicament for ameliorating and/or treating a viral infection
that can include contacting a cell infected with the virus with an
effective amount of said compound(s). Still other embodiments
described herein relate to one or more compounds described herein,
or a pharmaceutically acceptable salt of a compound described
herein, that can be used for ameliorating and/or treating a viral
infection by contacting a cell infected with the virus with an
effective amount of said compound(s). In some embodiments, the
compound can be one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein. In other embodiments, the compound
can be a mono-, di- and/or tri-phosphate of one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein. In some
embodiments, the virus can be a HCV virus.
[0339] Some embodiments disclosed herein relate to methods of
inhibiting replication of a virus that can include contacting a
cell infected with the virus with an effective amount of one or
more compounds described herein, or a pharmaceutically acceptable
salt of a compound described herein, or a pharmaceutical
composition that includes one or more compounds described herein,
or a pharmaceutically acceptable salt thereof. Other embodiments
described herein relate to using one or more compounds described
herein, or a pharmaceutically acceptable salt of a compound
described herein, in the manufacture of a medicament for inhibiting
replication of a virus that can include contacting a cell infected
with the virus with an effective amount of said compound(s). Still
other embodiments described herein relate to a compound described
herein, or a pharmaceutically acceptable salt of a compound
described herein, that can be used for inhibiting replication of a
virus by contacting a cell infected with the virus with an
effective amount of said compound(s). In some embodiments, the
compound can be one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein. In other embodiments, the compound
can be a mono-, di- and/or tri-phosphate of one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein. In some
embodiments, the virus can be a HCV virus.
[0340] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can inhibit an RNA
dependent RNA polymerase. In some embodiments, one or more solid
forms of Compound 1 as described herein, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes one or more solid forms of Compound 1 as described herein,
can inhibit a HCV polymerase (for example, NS5B polymerase). Some
embodiments described herein relate to a method for inhibiting NS5B
polymerase activity of a virus that can include contacting a cell
(such as a cell infected with HCV) with an effective amount of a
compound described herein, whereby inhibiting the NS5B polymerase
activity of the virus (for example, HCV). Other embodiments
described herein relate to the use of an effective amount of a
compound as described as described herein for preparing a
medicament for inhibiting NS5B polymerase activity of a virus, such
as the NS5B polymerase activity of a hepatitis C virus. Still other
embodiments described herein relate to a compound described herein,
or a pharmaceutically acceptable salt of a compound described
herein, that can be used for inhibiting NS5B polymerase activity
that can include contacting a cell (such as a cell infected with
HCV) an effective amount of said compound(s). In some embodiments,
the compound can be one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein. In other embodiments, the
compound can be a mono-, di- and/or tri-phosphate of one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein. In some embodiments, the virus can be a HCV
virus.
[0341] HCV is an enveloped positive strand RNA virus in the
Flaviviridae family. There are various nonstructural proteins of
HCV, such as NS2, NS3, NS4A, NS4B, NS5A, and NS5B. NS5B is believed
to be an RNA-dependent RNA polymerase involved in the replication
of HCV RNA.
[0342] Some embodiments described herein relate to a method of
treating HCV infection in a subject suffering from a HCV infection
that can include administering to the subject an effective amount
of one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein. Other embodiments described herein relate to the
use of an effective amount of a compound as described as described
herein for preparing a medicament for treating HCV infection in a
subject suffering from a HCV infection. Still other embodiments
described herein relate to a compound described herein, or a
pharmaceutically acceptable salt of a compound described herein,
that can be used for treating HCV infection in a subject suffering
from a HCV infection that can include administering an effective
amount of said compound(s).
[0343] There are a variety of genotypes of HCV, and a variety of
subtypes within each genotype. For example, at present it is known
that there are eleven (numbered 1 through 11) main genotypes of
HCV, although others have classified the genotypes as 6 main
genotypes. Each of these genotypes is further subdivided into
subtypes (1a-1c; 2a-2c; 3a-3b; 4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a;
10a; and 11a). In some embodiments, an effective amount of one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be effective to treat at least one genotype
of HCV. In some embodiments, a compound described herein (for
example, one or more solid forms of Compound 1 as described herein,
or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein) can be effective to treat all 11 genotypes of
HCV. In some embodiments, a compound described herein (for example,
one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein) can be effective to treat 3 or more, 5 or more, 7
or more of 9 more genotypes of HCV. In some embodiments, one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein is more effective against a larger number of HCV
genotypes than the standard of care. In some embodiments, one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, is more effective against a particular HCV
genotype than the standard of care (such as genotype 1, 2, 3, 4, 5
and/or 6).
[0344] Various indicators for determining the effectiveness of a
method for treating a HCV infection are known to those skilled in
the art. Example of suitable indicators include, but are not
limited to, a reduction in viral load, a reduction in viral
replication, a reduction in time to seroreversion (virus
undetectable in patient serum), an increase in the rate of
sustained viral response to therapy, a reduction of morbidity or
mortality in clinical outcomes, a reduction in the rate of liver
function decrease; stasis in liver function; improvement in liver
function; reduction in one or more markers of liver dysfunction,
including alanine transaminase, aspartate transaminase, total
bilirubin, conjugated bilirubin, gamma glutamyl transpeptidase,
and/or other indicator of disease response. Similarly, successful
therapy with an effective amount of a compound or a pharmaceutical
composition described herein (for example, one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein) can reduce the
incidence of liver cancer in HCV patients.
[0345] Some embodiments described herein relate to a method of
treating a condition selected from liver fibrosis, liver cirrhosis,
and liver cancer in a subject suffering from one or more of the
aforementioned liver conditions that can include administering to
the subject an effective amount of a compound or a pharmaceutical
composition described herein (for example, one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein). One cause of
the liver fibrosis, liver cirrhosis, and/or liver cancer can be a
HCV infection. Some embodiments described herein relate to a method
of increasing liver function in a subject having a HCV infection
that can include administering to the subject an effective amount
of a compound or a pharmaceutical composition described herein (for
example, one or more solid forms of Compound 1 as described herein,
or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein). Also contemplated is a method for reducing or
eliminating further virus-caused liver damage in a subject having
an HCV infection by administering to the subject an effective
amount of a compound or a pharmaceutical composition described
herein (for example, one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein). In some embodiments, this
method comprises slowing or halting the progression of liver
disease. In other embodiments, the course of the disease is
reversed, and stasis or improvement in liver function is
contemplated.
[0346] In some embodiments, an effective amount of one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, is an amount that is effective to reduce viral
titers undetectable levels, for example, to about 100 to about 500,
to about 50 to about 100, to about 10 to about 50, or to about 15
to about 25 international units/mL serum. In some embodiments, an
effective amount of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein, is an amount that is effective
to reduce viral load compared to the viral load before
administration of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein. For example, wherein the viral
load is measured before administration of one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, and again after
completion of the treatment regime with one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein (for example, 1
month after completion). In some embodiments, an effective amount
of one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof; or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be an amount that is effective to reduce
viral load to lower than about 100 genome copies/mL serum. In some
embodiments, an effective amount of one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, is an amount
that is effective to achieve a reduction in viral titer in the
serum of the subject in the range of about 1.5-log to about a
2.5-log reduction, about a 3-log to about a 4-log reduction, or a
greater than about 5-log reduction compared to the viral load
before administration of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein. For example, the viral load can
be measured before administration of one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, and again after
completion of the treatment regime with one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein (for example, 1
month after completion).
[0347] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can result in at least a
1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction
in the replication of HCV relative to pre-treatment levels in a
subject, as determined after completion of the treatment regime
(for example 1 month after completion). In some embodiments, one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can result in a reduction of the replication of
HCV relative to pre-treatment levels in the range of about 2 to
about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold,
or about 50 to about 100 fold. In some embodiments, one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can result in a reduction of HCV replication in
the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5
to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of HCV
replication compared to the reduction of HCV reduction achieved by
pegylated interferon in combination with ribavirin, administered
according to the standard of care, or may achieve the same
reduction as that standard of care therapy in a shorter period of
time, for example, in one month, two months, or three months, as
compared to the reduction achieved after six months of standard of
care therapy with ribavirin and pegylated interferon.
[0348] In some embodiments, an effective amount of one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, is an amount that is effective to achieve a
sustained viral response, for example, non-detectable or
substantially non-detectable HCV RNA (e.g., less than about 500,
less than about 400, less than about 200, or less than about 100
genome copies per milliliter serum) is found in the subject's serum
for a period of at least about one month, at least about two
months, at least about three months, at least about four months, at
least about five months, or at least about six months following
cessation of therapy.
[0349] In some embodiments, an effective amount one or more solid
forms of Compound 1 as described herein, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes one or more solid forms of Compound 1 as described herein,
can reduce a level of a marker of liver fibrosis by at least about
10%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55%, at least about 60%, at least about
65%, at least about 70%, at least about 75%, or at least about 80%,
or more, compared to the level of the marker in an untreated
subject, or to a placebo-treated subject. Methods of measuring
serum markers are known to those skilled in the art and include
immunological-based methods, e.g., enzyme-linked immunosorbent
assays (ELISA), radioimmunoassays, and the like, using antibody
specific for a given serum marker. A non-limiting list of examples
of markers include measuring the levels of serum alanine
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline
phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and total
bilirubin (TBIL) using known methods. In general, an ALT level of
less than about 45 IU/L (international units/liter), an AST in the
range of 10-34 IU/L, ALP in the range of 44-147 IU/L, GGT in the
range of 0-51 IU/L, TBIL in the range of 0.3-1.9 mg/dL is
considered normal. In some embodiments, an effective amount of one
or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein is an amount effective to reduce ALT, AST, ALP,
GGT and/or TBIL levels to with what is considered a normal
level.
[0350] Subjects who are clinically diagnosed with HCV infection
include "naive" subjects (e.g., subjects not previously treated for
HCV, particularly those who have not previously received
IFN-alpha-based and/or ribavirin-based therapy) and individuals who
have failed prior treatment for HCV ("treatment failure" subjects).
Treatment failure subjects include "non-responders" (i.e., subjects
in whom the HCV titer was not significantly or sufficiently reduced
by a previous treatment for HCV (.ltoreq.0.5 log IU/mL), for
example, a previous IFN-alpha monotherapy, a previous IFN-alpha and
ribavirin combination therapy, or a previous pegylated IFN-alpha
and ribavirin combination therapy); and "relapsers" (i.e., subjects
who were previously treated for HCV, for example, who received a
previous IFN-alpha monotherapy, a previous IFN-alpha and ribavirin
combination therapy, or a previous pegylated IFN-alpha and
ribavirin combination therapy, whose HCV titer decreased, and
subsequently increased).
[0351] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be administered to a
treatment failure subject suffering from HCV. In some embodiments,
one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered to a non-responder subject
suffering from HCV. In some embodiments, one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, can be
administered to a relapsed subject suffering from HCV.
[0352] After a period of time, infectious agents can develop
resistance to one or more therapeutic agents. The term "resistance"
as used herein refers to a viral strain displaying a delayed,
lessened and/or null response to a therapeutic agent(s). For
example, after treatment with an antiviral agent, the viral load of
a subject infected with a resistant virus may be reduced to a
lesser degree compared to the amount in viral load reduction
exhibited by a subject infected with a non-resistant strain. In
some embodiments, one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein, can be administered to a subject
infected with an HCV strain that is resistant to one or more
different anti-HCV agents. In some embodiments, development of
resistant HCV strains is delayed when patients are treated with one
or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, compared to the development of HCV strains
resistant to other HCV drugs.
[0353] In some embodiments, an effective amount of one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered to a subject for whom other
anti-HCV medications are contraindicated. For example,
administration of pegylated interferon alpha in combination with
ribavirin is contraindicated in subjects with hemoglobinopathies
(e.g., thalassemia major, sickle-cell anemia) and other subjects at
risk from the hematologic side effects of current therapy. In some
embodiments, one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein, can be provided to a subject that
is hypersensitive to interferon or ribavirin.
[0354] Some subjects being treated for HCV experience a viral load
rebound. The term "viral load rebound" as used herein refers to a
sustained .gtoreq.0.5 log IU/mL increase of viral load above nadir
before the end of treatment, where nadir is a .gtoreq.0.5 log IU/mL
decrease from baseline. In some embodiments, one or more solid
forms of Compound 1 as described herein, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes one or more solid forms of Compound 1 as described herein,
can be administered to a subject experiencing viral load rebound,
or can prevent such viral load rebound when used to treat the
subject.
[0355] The standard of care for treating HCV has been associated
with several side effects (adverse events). In some embodiments,
one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can decrease the number and/or severity of side
effects that can be observed in HCV patients being treated with
ribavirin and pegylated interferon according to the standard of
care. Examples of side effects include, but are not limited to
fever, malaise, tachycardia, chills, headache, arthralgias,
myalgias, fatigue, apathy, loss of appetite, nausea, vomiting,
cognitive changes, asthenia, drowsiness, lack of initiative,
irritability, confusion, depression, severe depression, suicidal
ideation, anemia, low white blood cell counts, and thinning of
hair. In some embodiments, one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein, can be provided to a subject
that discontinued a HCV therapy because of one or more adverse
effects or side effects associated with one or more other HCV
agents.
[0356] Table 1 provides some embodiments of one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, compared to the
standard of care. Examples include the following: in some
embodiments, one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein, results in a percentage of
non-responders that is 10% less than the percentage of
non-responders receiving the standard of care; in some embodiments,
one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, results number of side effects that is in the
range of about 10% to about 30% less than compared to the number of
side effects experienced by a subject receiving the standard of
care; and in some embodiments, one or more solid forms of Compound
1 as described herein, or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition that includes one or more
solid forms of Compound 1 as described herein, results a severity
of a side effect (such as one of those described herein) that is
25% less than compared to the severity of the same side effect
experienced by a subject receiving the standard of care. Methods of
quantifying the severity of a side effect are known to those
skilled in the art.
TABLE-US-00031 TABLE 1 Percentage Percentage of non- Percentage of
Percentage of of viral load Number of Severity of responders
relapsers resistance rebound side effects side effects 10% less 10%
less 10% less 10% less 10% less 10% less 25% less 25% less 25% less
25% less 25% less 25% less 40% less 40% less 40% less 40% less 40%
less 40% less 50% less 50% less 50% less 50% less 50% less 50% less
60% less 60% less 60% less 60% less 60% less 60% less 70% less 70%
less 70% less 70% less 70% less 70% less 80% less 80% less 80% less
80% less 80% less 80% less 90% less 90% less 90% less 90% less 90%
less 90% less about 10% to about 10% about 10% about 10% to about
10% to about 10% to about 30% to about to about about 30% about 30%
about 30% less 30% less 30% less less less less about 20% to about
20% about 20% about 20% to about 20% to about 20% to about 50% to
about to about about 50% about 50% about 50% less 50% less 50% less
less less less about 30% to about 30% about 30% about 30% to about
30% to about 30% to about 70% to about to about about 70% about 70%
about 70% less 70% less 70% less less less less about 20% to about
20% about 20% about 20% to about 20% to about 20% to about 80% to
about to about about 80% about 80% about 80% less 80% less 80% less
less less less
[0357] As used herein, a "subject" refers to an animal that is the
object of treatment, observation or experiment. "Animal" includes
cold- and warm-blooded vertebrates and invertebrates such as fish,
shellfish, reptiles and, in particular, mammals. "Mammal" includes,
without limitation, mice, rats, rabbits, guinea pigs, dogs, cats,
sheep, goats, cows, horses, primates, such as monkeys, chimpanzees,
and apes, and, in particular, humans. In some embodiments, the
subject is human.
[0358] As used herein, the terms "treating," "treatment,"
"therapeutic," or "therapy" do not necessarily mean total cure or
abolition of the disease or condition. Any alleviation of any
undesired signs or symptoms of a disease or condition, to any
extent can be considered treatment and/or therapy. Furthermore,
treatment may include acts that may worsen the patient's overall
feeling of well-being or appearance.
[0359] The term "effective amount" is used to indicate an amount of
an active compound, or pharmaceutical agent, that elicits the
biological or medicinal response indicated. For example, an
effective amount of compound can be the amount needed to prevent,
alleviate or ameliorate symptoms of disease or prolong the survival
of the subject being treated This response may occur in a tissue,
system, animal or human and includes alleviation of the signs or
symptoms of the disease being treated. Determination of an
effective amount is well within the capability of those skilled in
the art, in view of the disclosure provided herein. The effective
amount of the compounds disclosed herein required as a dose will
depend on the route of administration, the type of animal,
including human, being treated, and the physical characteristics of
the specific animal under consideration. The dose can be tailored
to achieve a desired effect, but will depend on such factors as
weight, diet, concurrent medication and other factors which those
skilled in the medical arts will recognize.
[0360] As will be readily apparent to one skilled in the art, the
useful in vivo dosage to be administered and the particular mode of
administration will vary depending upon the age, weight, the
severity of the affliction, and mammalian species treated, the
particular compounds employed, and the specific use for which these
compounds are employed. The determination of effective dosage
levels, that is the dosage levels necessary to achieve the desired
result, can be accomplished by one skilled in the art using routine
methods, for example, human clinical trials and in vitro
studies.
[0361] The dosage may range broadly, depending upon the desired
effects and the therapeutic indication. Alternatively dosages may
be based and calculated upon the surface area of the patient, as
understood by those of skill in the art. Although the exact dosage
will be determined on a drug-by-drug basis, in most cases, some
generalizations regarding the dosage can be made. The daily dosage
regimen for an adult human patient may be, for example, an oral
dose of between 0.01 mg and 3000 mg of each active ingredient,
preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage
may be a single one or a series of two or more given in the course
of one or more days, as is needed by the subject. In some
embodiments, the compounds will be administered for a period of
continuous therapy, for example for a week or more, or for months
or years. In some embodiments, one or more solid forms of Compound
1 as described herein, or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition that includes one or more
solid forms of Compound 1 as described herein, can be administered
less frequently compared to the frequency of administration of an
agent within the standard of care. In some embodiments, one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered one time per day. For
example, one or more solid forms of Compound 1 as described herein,
or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered one time per day to a subject
suffering from a HCV infection. In some embodiments, the total time
of the treatment regime with one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can less compared to the
total time of the treatment regime with the standard of care.
[0362] In instances where human dosages for compounds have been
established for at least some condition, those same dosages may be
used, or dosages that are between about 0.1% and 500%, more
preferably between about 25% and 250% of the established human
dosage. Where no human dosage is established, as will be the case
for newly-discovered pharmaceutical compositions, a suitable human
dosage can be inferred from ED.sub.50 or ID.sub.50 values, or other
appropriate values derived from in vitro or in vivo studies, as
qualified by toxicity studies and efficacy studies in animals.
[0363] In cases of administration of a pharmaceutically acceptable
salt, dosages may be calculated as the free base. As will be
understood by those of skill in the art, in certain situations it
may be necessary to administer one or more solid forms of Compound
1 as described herein, or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition that includes one or more
solid forms of Compound 1 as described herein in amounts that
exceed, or even far exceed, the above-stated, preferred dosage
range in order to effectively and aggressively treat particularly
aggressive diseases or infections.
[0364] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety which are sufficient to
maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will
depend on individual characteristics and route of administration.
However, HPLC assays or bioassays can be used to determine plasma
concentrations. Dosage intervals can also be determined using MEC
value. Compositions should be administered using a regimen which
maintains plasma levels above the MEC for 10-90% of the time,
preferably between 30-90% and most preferably between 50-90%. In
cases of local administration or selective uptake, the effective
local concentration of the drug may not be related to plasma
concentration.
[0365] It should be noted that the attending physician would know
how to and when to terminate, interrupt, or adjust administration
due to toxicity or organ dysfunctions. Conversely, the attending
physician would also know to adjust treatment to higher levels if
the clinical response were not adequate (precluding toxicity). The
magnitude of an administrated dose in the management of the
disorder of interest will vary with the severity of the condition
to be treated and to the route of administration. The severity of
the condition may, for example, be evaluated, in part, by standard
prognostic evaluation methods. Further, the dose and perhaps dose
frequency, will also vary according to the age, body weight, and
response of the individual patient. A program comparable to that
discussed above may be used in veterinary medicine.
[0366] Compounds disclosed herein can be evaluated for efficacy and
toxicity using known methods. For example, the toxicology of a
particular compound, or of a subset of the compounds, sharing
certain chemical moieties, may be established by determining in
vitro toxicity towards a cell line, such as a mammalian, and
preferably human, cell line. The results of such studies are often
predictive of toxicity in animals, such as mammals, or more
specifically, humans. Alternatively, the toxicity of particular
compounds in an animal model, such as mice, rats, rabbits, or
monkeys, may be determined using known methods. The efficacy of a
particular compound may be established using several recognized
methods, such as in vitro methods, animal models, or human clinical
trials. When selecting a model to determine efficacy, the skilled
artisan can be guided by the state of the art to choose an
appropriate model, dose, route of administration and/or regime.
[0367] Combination Therapies
[0368] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be used in combination
with one or more additional agent(s).
[0369] Examples of additional agents that can be used in
combination with one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein, include, but are not limited to,
agents currently used in a conventional standard of care for
treating HCV, HCV protease inhibitors, HCV polymerase inhibitors,
NS5A inhibitors, other antiviral compounds, compounds of Formula
(BB) (including pharmaceutically acceptable salts and
pharmaceutical compositions that can include a compound of Formula
(BB), or a pharmaceutically acceptable salt thereof), compounds of
Formula (DD) (including pharmaceutically acceptable salts and
pharmaceutical compositions that can include a compound of Formula
(DD), or a pharmaceutically acceptable salt thereof), and/or
combinations thereof. In some embodiments, one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, can be used
with one, two, three or more additional agents described herein. In
some embodiments, one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein, can be used in combination with
an agent(s) currently used in a conventional standard of care
therapy. For example, for the treatment of HCV, a compound
disclosed herein can be used in combination with Pegylated
interferon-alpha-2a (brand name PEGASYS.RTM.) and ribavirin, or
Pegylated interferon-alpha-2b (brand name PEG-INTRON.RTM.) and
ribavirin.
[0370] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be substituted for an
agent currently used in a conventional standard of care therapy.
For example, for the treatment of HCV, one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, can be used in
place of ribavirin.
[0371] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be used in combination
with an interferon, such as a pegylated interferon. Examples of
suitable interferons include, but are not limited to, Pegylated
interferon-alpha-2a (brand name PEGASYS.RTM.), Pegylated
interferon-alpha-2b (brand name PEG-INTRON.RTM.), interferon
alfacon-1 (brand name INFERGEN.RTM.), pegylated interferon lambda
and/or a combination thereof.
[0372] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be used in combination
with a HCV protease inhibitor. A non-limiting list of example HCV
protease inhibitors include the following: VX-950
(TELAPREVIR.RTM.), MK-5172, ABT-450, BILN-2061, BI-201335,
BMS-650032, SCH 503034 (BOCEPREVIR.RTM.), GS-9256, GS-9451,
IDX-320, ACH-1625, ACH-2684, TMC-435, ITMN-191 (DANOPREVIR.RTM.)
and/or a combination thereof.
[0373] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be used in combination
with a HCV polymerase inhibitor. In some embodiments, the HCV
polymerase inhibitor can be a nucleoside inhibitor. In other
embodiments, the HCV polymerase inhibitor can be a non-nucleoside
inhibitor. Examples of suitable nucleoside inhibitors include, but
are not limited to, RG7128, PSI-7851, PSI-7977, PSI-352938,
PSI-661, 4'-azidouridine (including known prodrugs of
4'-azidouridine), GS-6620, and TMC649128 and/or combinations
thereof. A non-limiting list of example nucleoside inhibitors as
provided in FIG. 32. Examples of suitable non-nucleoside inhibitors
include, but are not limited to, ABT-333, ANA-598, VX-222, HCV-796,
BI-207127, GS-9190, PF-00868554 (FILIBUVIR.RTM.), VX-497 and/or
combinations thereof. A non-limiting list of example non-nucleoside
as provided in FIG. 32.
[0374] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be used in combination
with a NS5A inhibitor. A non-limiting list of example NS5A
inhibitors include BMS-790052, GSK-2336805, ACH-3102, PPI-461,
ACH-2928, GS-5885, BMS-824393 and/or combinations thereof. A
non-limiting list of example NS5A inhibitors as provided in FIG.
32.
[0375] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be used in combination
with other antiviral compounds. Examples of other antiviral
compounds include, but are not limited to, Debio-025, MIR-122
and/or combinations thereof. A non-limiting list of example other
antiviral compounds are provided in FIG. 32.
[0376] A non-limiting list of additional agents that can be used in
combination with more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein, include the following compounds
provided in FIG. 32: 1000, 1001, 1002, 1003, 1004, 1005, 1006,
1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017,
1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028,
1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039,
1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050,
1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061,
1062, 1063, 1064, 1065, and 1066.
[0377] In some embodiments, one or more solid forms of Compound 1,
or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be used in
combination with a compound of Formula (BB), or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes a compound of Formula (BB), or a pharmaceutically
acceptable salt thereof (see, U.S. Publication No. 2012/0165286,
filed Dec. 20, 2011 the contents of which are incorporated by
reference in its entirety):
##STR00002##
[0378] wherein B.sup.BB1 can be an optionally substituted
heterocyclic base or an optionally substituted heterocyclic base
with a protected amino group; X.sup.BB can be O (oxygen) or S
(sulfur); R.sup.BB1 can be selected from --Z.sup.BB--R.sup.BB9, an
optionally substituted N-linked amino acid and an optionally
substituted N-linked amino acid ester derivative; Z.sup.BB can be
selected from O (oxygen), S (sulfur) and N(R.sup.BB10); R.sup.BB2
and R.sup.BB3 can be independently selected from hydrogen, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl, an
optionally substituted C.sub.1-6 haloalkyl and an optionally
substituted aryl(C.sub.1-6alkyl); or R.sup.BB2 and R.sup.BB3 can be
taken together to form a group selected from an optionally
substituted C.sub.3-6 cycloalkyl, an optionally substituted
C.sub.3-6 cycloalkenyl, an optionally substituted C.sub.3-6 aryl
and an optionally substituted C.sub.3-6heteroaryl; R.sup.BB4 can be
selected from hydrogen, halogen, azido, cyano, an optionally
substituted C.sub.1-6 alkyl, an optionally substituted C.sub.2-6
alkenyl, an optionally substituted C.sub.2-6 alkynyl and an
optionally substituted allenyl; R.sup.BB5 can be hydrogen or an
optionally substituted C.sub.1-6 alkyl; R.sup.BB6 can be selected
from hydrogen, halogen, azido, amino, cyano, an optionally
substituted C.sub.1-6 alkyl, --OR.sup.BBI11 and
--OC(.dbd.O)R.sup.B12; R.sup.BB7 can be selected from hydrogen,
halogen, azido, cyano, an optionally substituted C.sub.1-6 alkyl,
--OR.sup.BB13 and --OC(.dbd.O)R.sup.BB14; R.sup.BB8 can be selected
from hydrogen, halogen, azido, cyano, an optionally substituted
C.sub.1-6 alkyl, --OR.sub.BB15 and --OC(.dbd.O)R.sup.BB16;
R.sup.BB9 can be selected from an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted heterocyclyl, an
optionally substituted aryl(C.sub.1-6alkyl), an optionally
substituted heteroaryl(C.sub.1-6alkyl) and an optionally
substituted heterocyclyl(C.sub.1-6alkyl); R.sup.BB10 can be
selected from hydrogen, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted heterocyclyl, an
optionally substituted aryl(C.sub.1-6alkyl), an optionally
substituted heteroaryl(C.sub.1-6alkyl) and an optionally
substituted heterocyclyl(C.sub.1-6alkyl); R.sup.BB11, R.sup.BB13
and R.sup.BB15 can be independently hydrogen or an optionally
substituted C.sub.1-6 alkyl; and R.sup.BB12, R.sup.BB14 and
R.sup.BB16 can be independently an optionally substituted C.sub.1-6
alkyl or an optionally substituted C.sub.3-6 cycloalkyl. In some
embodiments, at least one of R.sup.BB2 and R.sup.BB3 is not
hydrogen. A non-limiting list of example compounds of Formula (BB)
includes the compound numbered 8001-8012 in FIG. 33.
[0379] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be used in combination
with a compound of Formula (DD), or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes a
compound of Formula (DD), or a pharmaceutically acceptable salt
thereof (see, U.S. Publication No. 2010/0249068, filed Mar. 19,
2010, the contents of which are incorporated by reference in its
entirety):
##STR00003##
[0380] wherein each can be independently a double or single bond;
A.sup.DD1 can be selected from C (carbon), O (oxygen) and S
(sulfur); B.sup.DD1 can be an optionally substituted heterocyclic
base or a derivative thereof; D.sup.DD1 can be selected from
C.dbd.CH.sub.2, CH.sub.2, O (oxygen), S (sulfur), CHF, and
CF.sub.2; R.sup.DD1 can be hydrogen, an optionally substituted
alkyl, an optionally substituted cycloalkyl, an optionally
substituted aralkyl, dialkylaminoalkylene, alkyl-C(.dbd.O)--,
aryl-C(.dbd.O)--, alkoxyalkyl-C(.dbd.O)--,
aryloxyalkyl-C(.dbd.O)--, alkylsulfonyl, arylsulfonyl,
aralkylsulfonyl,
##STR00004##
an --O-linked amino acid, diphosphate, triphosphate or derivatives
thereof; R.sup.DD2 and R.sup.DD3 can be each independently selected
from hydrogen, an optionally substituted C.sub.1-6 alkyl, an
optionally substituted C.sub.2-6 alkenyl, an optionally substituted
C.sub.2-6 alkynyland an optionally substituted C.sub.1-6 haloalkyl,
provided that at least one of R.sup.DD2 and R.sup.DD3 cannot be
hydrogen; or R.sup.DD2 and R.sup.DD3 are taken together to form a
group selected from among C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkenyl, C.sub.3-6 aryl, and a C.sub.3-6 heteroaryl; R.sup.DD4
and R.sup.DD9 can be independently selected from hydrogen, halogen,
--NH.sub.2, --NHR.sup.DDa1, NR.sup.DDa1R.sup.DDb1, --OR.sup.DDa1,
--SR.sup.DDa1, --CN, --NC, --N.sub.3, --NO.sub.2,
--N(R.sup.DDc1)--NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--OR.sup.DDa1, --S--SR.sup.DDa1,
--C(.dbd.O)R.sup.DDa1, --C(.dbd.O)OR.sup.DDa1,
--C(.dbd.O)NR.sup.DDa1R.sup.DDb1, --O--(C.dbd.O)R.sup.DDa1,
--O--C(.dbd.O)OR.sup.DDa1, --O--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--S(.dbd.O)R.sup.DDa1, S(.dbd.O).sub.2R.sup.DDa1,
--O--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl, an
optionally substituted aralkyl and an --O-linked amino acid;
R.sup.DD5, R.sup.DD6 and R.sup.DD7 can be independently absent or
selected from hydrogen, halogen, --NH.sub.2, --NHR.sup.DDa1,
NR.sup.DDa1R.sup.DDb1, --OR.sup.DDa1, --SR.sup.DDa1, --CN, --NC,
--N.sub.3, --NO.sub.2, --N(R.sup.DDc1)--NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--OR.sup.DDa1, --S--SR.sup.DDa1,
--C(.dbd.O)R.sup.DDa1, --C(.dbd.O)OR.sup.DDa1,
--C(.dbd.O)NR.sup.DDa1R.sup.DDb1, --O--(C.dbd.O)R.sup.DDa1,
--O--C(.dbd.O)OR.sup.DDa1, --O--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--S(.dbd.O)R.sup.DDa1, S(.dbd.O).sub.2R.sup.DDa1,
--O--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl, an
optionally substituted aralkyl and an --O-linked amino acid; or
R.sup.DD6 and R.sup.DD7 taken together form --O--C(.dbd.O)--O--;
R.sup.DD8 can be absent or selected from the group consisting of
hydrogen, halogen, --NH.sub.2, --NHR.sup.DDa1,
NR.sup.DDa1R.sup.DDb1, --OR.sup.DDa1, --SR.sup.DDa1, --CN, --NC,
--N.sub.3, --NO.sub.2, --N(R.sup.DDc1)--NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--OR.sup.DDa1, --S--SR.sup.DDa1,
--C(.dbd.O)R.sup.DDa1, --C(.dbd.O)OR.sup.DDa1,
--C(.dbd.O)NR.sup.DDa1R.sup.DDb1, --O--(C.dbd.O)R.sup.DDa1,
--O--C(.dbd.O)OR.sup.DDa1, --O--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--C(.dbd.O)NR.sup.DDa1R.sup.DDb1,
--S(.dbd.O)R.sup.DDa1, S(.dbd.O).sub.2R.sup.DDa1,
--O--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1,
--N(R.sup.DDc1)--S(.dbd.O).sub.2NR.sup.DDa1R.sup.DDb1--, an
optionally substituted C.sub.1-6 alkyl, an optionally substituted
C.sub.2-6 alkenyl, an optionally substituted C.sub.2-6 alkynyl, an
optionally substituted haloalkyl, an optionally substituted
hydroxyalkyl and an --O-linked amino acid, or when the bond to
R.sup.DD7 indicated by is a double bond, then R.sup.DD7 is a
C.sub.2-6 alkylidene and R.sup.DD8 is absent; R.sup.DDa1,
R.sup.DDb1 and R.sup.DDc1 can be each independently selected from
hydrogen, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted aryl, an optionally substituted heteroaryl,
an optionally substituted aralkyl and an optionally substituted
heteroaryl(C.sub.1-6 alkyl); R.sup.DD10 can be selected from
O.sup.-, --OH, an optionally substituted aryloxy or aryl-O--,
##STR00005##
alkyl-C(.dbd.O)--O--CH.sub.2--O--,
alkyl-C(.dbd.O)--S--CH.sub.2CH.sub.2--O-- and an --N-linked amino
acid; R.sup.DD11 can be selected from O.sup.-, --OH, an optionally
substituted aryloxy or aryl-O--,
##STR00006##
alkyl-C(.dbd.O)--O--CH.sub.2--O--,
alkyl-C(.dbd.O)--S--CH.sub.2CH.sub.2--O-- and an --N-linked amino
acid; each R.sup.DD12 and each R.sup.DD13 can be independently
--C.ident.N or an optionally substituted substituent selected from
C.sub.1-8 organylcarbonyl, C.sub.1-8 alkoxycarbonyl and C.sub.1-8
organylaminocarbonyl; each R.sup.DD14 can be hydrogen or an
optionally substituted C.sub.1-6-alkyl; each m.sup.DD can be
independently 1 or 2, and if both R.sup.DD10 and R.sup.DD11 are
##STR00007##
each R.sup.DD12, each R.sup.DD13, each R.sup.DD14 and each m.sup.DD
can be the same or different. In some embodiments, R.sup.DD8 can be
halogen, --OR.sup.DDa1, an optionally substituted C.sub.1-6 alkyl,
an optionally substituted C.sub.2-6 alkenyl, an optionally
substituted C.sub.2-6 alkynyl and an optionally substituted
C.sub.1-6 haloalkyl.
[0381] Additional examples of compounds that can be used in
combination with one or more solid forms of Compound 1 described
herein, or a pharmaceutically acceptable salt thereof, include
those described in the following: WO 99/07733 (Boehringer
Ingelheim), WO 99/07734 (Boehringer Ingelheim), WO 00/09558
(Boehringer Ingelheim), WO 00/09543 (Boehringer Ingelheim), WO
00/59929 (Boehringer Ingelheim), WO 02/060926 (BMS), WO 2006/039488
(Vertex), WO 2005/077969 (Vertex), WO 2005/035525 (Vertex), WO
2005/028502 (Vertex), WO 2005/007681 (Vertex), WO 2004/092162
(Vertex), WO 2004/092161 (Vertex), WO 2003/035060 (Vertex), WO
03/087092 (Vertex), WO 02/18369 (Vertex), WO 98/17679 (Vertex), WO
03/010140 (Boehringer Ingelheim), WO 03/026587 (Bristol Myers
Squibb), WO 02/100846 A1, WO 02/100851 A2, WO 01/85172 A1 (GSK), WO
02/098424 A1 (GSK), WO 00/06529 (Merck), WO 02/06246 A1 (Merck), WO
01/47883 (Japan Tobacco), WO 03/000254 (Japan Tobacco), EP 1 256
628 A2 (Agouron), WO 01/90121 A2 (Idenix), WO 02/069903 A2
(Biocryst Pharmaceuticals Inc.), WO 02/057287 A2 (Merck/Isis), WO
02/057425 A2 (Merck/lsis), WO 2010/117635, WO 2010/117977, WO
2010/117704, WO 2010/1200621, WO 2010/096302, WO 2010/017401, WO
2009/102633, WO 2009/102568, WO 2009/102325, WO 2009/102318, WO
2009/020828, WO 2009/020825, WO 2008/144380, WO 2008/021936, WO
2008/021928, WO 2008/021927, WO 2006/133326, WO 2004/014852, WO
2004/014313, WO 2010/096777, WO 2010/065681, WO 2010/065668, WO
2010/065674, WO 2010/062821, WO 2010/099527, WO 2010/096462, WO
2010/091413, WO 2010/094077, WO 2010/111483, WO 2010/120935, WO
2010/126967, WO 2010/132538, WO 2010/122162 and WO 2006/019831 (PTC
therapeutics), wherein all the aforementioned are hereby
incorporated by reference for the limited purpose of the chemical
structures and chemical compounds disclosed therein.
[0382] Further examples of compounds that can be used in
combination with one or more solid forms of Compound 1 described
herein, or a pharmaceutically acceptable salt thereof, include the
following: R1626, R1479 (Roche), MK-0608 (Merck), R1656,
(Roche-Pharmasset), Valopicitabine (Idenix), JTK-002/003, JTK-109
(Japan Tobacco), GS-7977(Gilead), EDP-239 (Enanta), PPI-1301
(Presido Pharmaceuticals), (Gao M. et al. Nature, 465, 96-100
(2010)), JTK-853 (Japan Tobacco), RO-5303253 Hoffmann-La Roche),
IDX-184 (Idenix Pharmaceuticals), class I interferons (such as
alpha-interferons, beta-interferons, delta-interferons,
omega-interferons, tau-inteferons, x-interferons, consensus
interferons and asialo-interferons), class II interferons (such as
gamma-interferons), pegylated interferons, interferon alpha 1A,
interferon alpha 1 B, interferon alpha 2A, and interferon alpha 2B,
thalidomide, IL-2; hematopoietins, IMPDH inhibitors (for example,
Merimepodib (Vertex Pharmaceuticals Inc.)), natural interferon
(such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, and a blend of
natural interferons), natural interferon alpha (ALFERON, Hemispherx
Biopharma, Inc.), interferon alpha n1 from lymphblastoid cells
(WELLFERON, Glaxo Wellcome), oral alpha interferon, Peg-interferon,
Peg-interferon alpha 2a (PEGASYS, Roche), recombinant interferon
alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX,
Aradigm), Peg-interferon alpha 2b (ALBUFERON, Human Genome
Sciences/Novartis, PEGINTRON, Schering), recombinant interferon
alpha 2b (INTRON A, Schering), pegylated interferon alpha 2b
(PEG-INTRON, Schering, VIRAFERONPEG, Schering), interferon beta-1a
(REBIF, Serono, Inc. and Pfizer), consensus interferon alpha
(INFERGEN, Valeant Pharmaceutical), interferon gamma-1b (ACTIMMUNE,
Intermune, Inc.), synthetic thymosin alpha 1 (ZADAXIN, SciClone
Pharmaceuticals Inc.), an antisense agent (for example,
ISIS-14803), SCH-6, ITMN-B (InterMune), GS9132 (Gilead), ISIS-14803
(ISIS Pharmaceuticals), ribavirin, amantadine, merimepodib,
Levovirin, Viramidine, maxamine, silybum marianum, interleukine-12,
amantadine, ribozyme, thymosin, N-acetyl cysteine and
cyclosporin.
[0383] Some embodiments described herein relate to a method of
ameliorating or treating a viral infection that can include
contacting a cell infected with the viral infection with an
effective amount of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, in
combination with one or more agents selected from an interferon,
ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a
NS5A inhibitor, an antiviral compound, a mono-, di, and/or
tri-phosphate thereof, a compound of Formula (BB), and a compound
of Formula (DD), or a pharmaceutically acceptable salt of any of
the aforementioned compounds.
[0384] Some embodiments described herein relate to a method of
ameliorating or treating a viral infection that can include
administering to a subject suffering from the viral infection an
effective amount of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, in
combination with one or more agents selected from an interferon,
ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a
NS5A inhibitor, an antiviral compound, a compound of Formula (BB),
and a compound of Formula (DD), or a pharmaceutically acceptable
salt of any of the aforementioned compounds.
[0385] Some embodiments described herein relate to a method of
inhibiting viral replication of a virus that can include contacting
a cell infected with the virus with an effective amount of one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, in combination with one
or more agents selected from an interferon, ribavirin, a HCV
protease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor,
an antiviral compound, a compound of Formula (BB), and a compound
of Formula (DD), or a pharmaceutically acceptable salt of any of
the aforementioned compounds.
[0386] Some embodiments described herein relate to the use of a
compound described herein, or a pharmaceutically acceptable salt
thereof, in the preparation of a medicament for ameliorating or
treating a HCV infection, wherein the medicament can be
manufactured for use in combination with one or more agents
selected from an interferon, ribavirin, a HCV protease inhibitor, a
HCV polymerase inhibitor, a NS5A inhibitor, an antiviral compound,
a compound of Formula (BB) and a compound of Formula (DD), or a
pharmaceutically acceptable salt any of the aforementioned
compounds.
[0387] Other embodiments described herein relate to the use of a
compound described herein, or a pharmaceutically acceptable salt
thereof, in the preparation of a medicament for contacting a cell
infected with a hepatitis C virus, wherein the medicament can be
manufactured for use in combination with one or more agents
selected from the group consisting of an interferon, ribavirin, a
HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A
inhibitor, an antiviral compound, a compound of Formula (BB), and a
compound of Formula (DD), or a pharmaceutically acceptable salt any
of the aforementioned compounds.
[0388] Other embodiments described herein relate to the use of a
compound described herein, or a pharmaceutically acceptable salt
thereof, in the preparation of a medicament for inhibiting viral
replication of a virus (for example, HCV), wherein the medicament
can be manufactured for use in combination with one or more agents
selected from the group consisting of an interferon, ribavirin, a
HCV protease inhibitor, a HCV polymerase inhibitor, a NS5A
inhibitor, an antiviral compound, a compound of Formula (BB), and a
compound of Formula (DD), or a pharmaceutically acceptable salt any
of the aforementioned compounds.
[0389] In some embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be administered with
one or more additional agent(s) together in a single pharmaceutical
composition. In some embodiments, one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, can be
administered with one or more additional agent(s) as two or more
separate pharmaceutical compositions. For example, one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered in one pharmaceutical
composition, and at least one of the additional agents can be
administered in a second pharmaceutical composition. If there are
at least two additional agents, one or more of the additional
agents can be in a first pharmaceutical composition that includes
one or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, and at least one of the other additional agent(s)
can be in a second pharmaceutical composition.
[0390] In some embodiments, one or more solid forms of Compound 1
described herein can be used in combination with VX-950
(TELAPREVIR.RTM.) for treating and/or ameliorating HCV, inhibiting
NS5B activity of HCV and/or inhibiting replication of HCV. In some
embodiments, Form J can be used in combination with VX-950
(TELAPREVIR.RTM.) for treating and/or ameliorating HCV, inhibiting
NS5B activity of HCV and/or inhibiting replication of HCV. In some
embodiments, one or more solid forms of Compound 1 described herein
can be used in combination with VX-222 for treating and/or
ameliorating HCV, inhibiting NS5B activity of HCV and/or inhibiting
replication of HCV. In some embodiments, Form J can be used in
combination with VX-222 for treating and/or ameliorating HCV,
inhibiting NS5B activity of HCV and/or inhibiting replication of
HCV.
[0391] The dosing amount(s) and dosing schedule(s) when using one
or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, and one or more additional agents are within the
knowledge of those skilled in the art. For example, when performing
a conventional standard of care therapy using art-recognized dosing
amounts and dosing schedules, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be administered in
addition to that therapy, or in place of one of the agents of a
combination therapy, using effective amounts and dosing protocols
as described herein.
[0392] The order of administration of one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, with one or
more additional agent(s) can vary. In some embodiments, one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered prior to all additional
agents. In other embodiments, one or more solid forms of Compound 1
as described herein, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition that includes one or more solid
forms of Compound 1 as described herein, can be administered prior
to at least one additional agent. In still other embodiments, one
or more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered concomitantly with one or
more additional agent(s). In yet still other embodiments, one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, can be administered subsequent to the
administration of at least one additional agent. In some
embodiments, one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein, can be administered subsequent to
the administration of all additional agents.
[0393] In some embodiments, the combination of one or more solid
forms of Compound 1 as described herein, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes one or more solid forms of Compound 1 as described herein,
in combination with one or more additional agent(s) in FIGS. 32-34
(including pharmaceutically acceptable salts and prodrugs thereof)
can result in an additive effect. In some embodiments, the
combination one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein, in combination with one or more
additional agent(s) in FIGS. 32-34 (including pharmaceutically
acceptable salts and prodrugs thereof) can result in a synergistic
effect. In some embodiments, the combination of one or more solid
forms of Compound 1 as described herein, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition that
includes one or more solid forms of Compound 1 as described herein,
in combination with one or more additional agent(s) in FIGS. 32-34
(including pharmaceutically acceptable salts and prodrugs thereof)
can result in a strongly synergistic effect. In some embodiments,
the combination of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein, in combination with one or more
additional agent(s) in FIGS. 32-34 (including pharmaceutically
acceptable salts and prodrugs thereof) is not antagonistic.
[0394] As used herein, the term "antagonistic" means that the
activity of the combination of compounds is less compared to the
sum of the activities of the compounds in combination when the
activity of each compound is determined individually (i.e. as a
single compound). As used herein, the term "synergistic effect"
means that the activity of the combination of compounds is greater
than the sum of the individual activities of the compounds in the
combination when the activity of each compound is determined
individually. As used herein, the term "additive effect" means that
the activity of the combination of compounds is about equal to the
sum of the individual activities of the compound in the combination
when the activity of each compound is determined individually.
[0395] A potential advantage of utilizing one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, in combination
with one or more additional agent(s) in FIGS. 32-34 (including
pharmaceutically acceptable salts and prodrugs thereof) may be a
reduction in the required amount(s) of one or more compounds of
FIGS. 32-34 (including pharmaceutically acceptable salts and
prodrugs thereof) that is effective in treating a disease condition
disclosed herein (for example, HCV), as compared to the amount
required to achieve same therapeutic result when one or more
compounds of FIGS. 32-34 (including pharmaceutically acceptable
salts and prodrugs thereof) are administered without one or more
solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein. For example, the amount of a compound in FIGS.
32-34 (including a pharmaceutically acceptable salt and prodrug
thereof), can be less compared to the amount of the compound in
FIGS. 32-34 (including a pharmaceutically acceptable salt and
prodrug thereof), needed to achieve the same viral load reduction
when administered as a monotherapy. Another potential advantage of
utilizing one or more solid forms of Compound 1 as described
herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition that includes one or more solid forms of
Compound 1 as described herein, in combination with one or more
additional agent(s) in FIGS. 32-34 (including pharmaceutically
acceptable salts and prodrugs thereof) is that the use of two or
more compounds having different mechanism of actions can create a
higher barrier to the development of resistant viral strains
compared to the barrier when a compound is administered as
monotherapy.
[0396] Additional advantages of utilizing one or more solid forms
of Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, in combination
with one or more additional agent(s) in FIGS. 32-34 (including
pharmaceutically acceptable salts and prodrugs thereof) may include
little to no cross resistance between one or more solid forms of
Compound 1 as described herein, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition that includes one or
more solid forms of Compound 1 as described herein, and one or more
additional agent(s) in FIGS. 32-34 (including pharmaceutically
acceptable salts and prodrugs thereof) thereof; different routes
for elimination of one or more solid forms of Compound 1 as
described herein, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition that includes one or more solid forms
of Compound 1 as described herein, and one or more additional
agent(s) in FIGS. 32-34 (including pharmaceutically acceptable
salts and prodrugs thereof); little to no overlapping toxicities
between one or more solid forms of Compound 1 as described herein,
or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, and one or more additional agent(s) in FIGS.
32-34 (including pharmaceutically acceptable salts and prodrugs
thereof); little to no significant effects on cytochrome P450;
and/or little to no pharmacokinetic interactions between one or
more solid forms of Compound 1 as described herein, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition that includes one or more solid forms of Compound 1 as
described herein, and one or more additional agent(s) in FIGS.
32-34 (including pharmaceutically acceptable salts and prodrugs
thereof).
[0397] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
EXAMPLES
[0398] Methods & Materials
[0399] XRPD (X-Ray Powder Diffraction)
[0400] Unless otherwise specified, samples were scanned on the
Bruker D8 Discover operated at 40 kV, 35 mA. Two frames were
registered with an exposure of 120 seconds. Data were integrated
over the range of 4.5.degree.-39.0.degree. 2 theta with a step size
of 0.02.degree. and merged into one continuous pattern. All XRPD
spectra provided herein are measured on a degrees 2-Theta
scale.
[0401] Differential Scanning Calorimetry (DSC)
[0402] The following DSC method was used:
[0403] 1: Data storage: Off
[0404] 2: Equilibrate at -20.00.degree. C. or 25.00.degree. C.
[0405] 3: Modulate +/-1.00.degree. C. every 60 seconds
[0406] 4: Isothermal for 5.00 min
[0407] 5: Data storage: On
[0408] 6: Ramp 2.00-3.00.degree. C./min to 250.00.degree. C.
[0409] Solid State Nuclear Magnetic Spectroscopy
[0410] Samples were packed into Bruker-Biospin 4 mm ZrO.sub.2
rotors (approximately 65 mg or less each depending on sample
availability). The rotors were spun inside a Bruker-Biospin 4 mm
HFX probe, which was placed in 400 MHz Bruker-Biospin wide bore
magnet. Magic angle spinning (MAS) speed of typically 12.5 kHz was
used (10.0 kHz if a suspension was characterized instead of a dry
powder). The samples were referenced to adamantane at 29.5 ppm. The
proton relaxation time was measured using .sup.1H MAS T.sub.1
saturation recovery relaxation experiment in order to set up proper
recycle delay of the .sup.13C cross-polarization (CP) MAS
experiment. The CP contact time was set to 2 ms. A CP proton pulse
with linear ramp (from 50% to 100%) was employed. The Hartmann-Hahn
match was optimized on external reference sample of glycine. SPINAL
64 decoupling was used with the field strength of approximately 90
kHz.
[0411] Synthesis of Compound 1 and the Solid Forms of Compound
1.
Example 1
Synthesis of 2'-C-methyluridine
5'-(O-phenyl-N--(S)-1-(isopropoxycarbonyl)ethyl)thiophosphoramidate
(Compound 1)
##STR00008##
[0413] Step 1: Compound 3b-1--
[0414] To a suspension of 2'-methyluridine (20 g, 77.52 mmol) in
dry CH.sub.3CN (200 mL) were added cyclopentanone (20 mL) and
trimethylorthoformate (20 mL) followed by p-toluenesulfonic acid
monohydrate (7.4 g, 38.76 mmol). The reaction mixture was stirred
at 40.degree. C. overnight. The solvent was evaporated. The residue
was dissolved in ethyl acetate and washed with brine. The organic
layer was dried and evaporated to give pure 3b-1 as a white solid
(14.5 g, 57.7%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.8.86 (s,
1H), 7.67 (d, J=8.0 Hz, 1H), 6.06 (s, 1H), 5.73 (d, J=8.0 Hz, 1H),
4.50 (d, J=4.8 Hz, 1H), 4.21 (m, 1H), 4.02-3.86 (m, 2H), 2.17 (m,
1H), 1.98, 1.83, 1.68 (m, 8H), 1.30 (s, 3H).
[0415] Step 2: Compound 3b-2--
[0416] To a suspension of 3b-1 (20 g, 61.7 mmol) in dry CH.sub.3CN
(100 mL) was added N-methylimidazole (50 mL) and 2b (80 g, 249.2
mmol). The reaction mixture was stirred at 70.degree. C. for 2 h.
Solvent was removed and the residue was dissolved in ethyl acetate
(500 mL). The solution was washed with brine, dried and evaporated.
The residue was purified on a silica gel column (20-50%
ethylacetate (EA) in petroleum ether (PE)) to give 3b-2 as a white
foam (two isomers, 12.5 g, 33%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta.8.79-8.92 (m, 1H), 7.55 (m, 1H), 7.34 (m, 2H), 7.20 (m, 3H),
6.09 (d, J=13.6 Hz, 1H), 5.70-5.61 (m, 1H), 5.06-5.01 (m, 1H),
4.38-4.09 (m, 6H), 2.08 (m, 1H), 1.96 (m, 1H), 1.73 (m, 2H), 1.66
(m, 5H), 1.39 (m, 3H), 1.23 (m, 9H); .sup.31P NMR (CDCl.sub.3, 162
MHz) .delta.67.62, 67.31.
[0417] Step 3: Compound 1(rac)--
[0418] Compound 3b-2 (10 g, 16.4 mmol) was suspended in 100 mL of
80% formic acid and the reaction mixture was stirred at 50.degree.
C. for 1.5 hours. Solvent was evaporated and the residue was
co-evaporated with toluene to remove traces of acid and water. The
residue was purified by RP HPLC (0.5% HCOOH in MeCN and water as
mobile phase) to give Compound 1(rac) (a mixture of two
P-diastereomers, 5.6 g, 63%). .sup.1H NMR (CD.sub.3OD, 400 MHz)
.delta. 7.79, 7.87 (2d, J=8.0 Hz, 1H), 7.18-7.38 (m, 5H), 5.98,
6.01 (2s, 1H), 5.59, 5.63 (2d, J=8.0 Hz, 1H), 4.95-5.05 (m, 1H),
4.51-4.56 (m, 1H), 4.30-4.44 (m, 1H), 4.05-4.17 (m, 2H), 3.82-3.87
(m, 1H), 1.34, 1.38 (2d, J=7.2 Hz, 3H), 1.17, 1.25 (2d, J=6.0 Hz,
6H), 1.24, 125 (2s, 3H); .sup.31P NMR (CD.sub.3OD, 162 MHz)
.delta.68.17, 68.40; ESI-LCMS: m/z 544.0 [M+H].sup.+.
[0419] Step 4: Separation of Compound 1 and Compound 1--
[0420] Compound 1(rac) was separated into its diastereomers by two
methods: (a) supercritical fluid chromatography (SFC) and (b)
crystallization.
[0421] (a) Via SFC:
[0422] Compound 1(rac) (440 mg, consisting of both Compound 1 and
Compound 1a in .about.1:1 ratio) was subjected to separation by SFC
(chiral PAK AD, 5 um. 250*30 mm using 25% MeOH and 75% CO.sub.2 as
mobile phase) to give Compound 1a (123.8 mg) and Compound 1 (162.5
mg) as a white solid; Compound 1a: .sup.1H NMR (CD.sub.3OD, 400
MHz) .delta.7.87 (d, J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz, 2H), 7.28
(d, J=8.8 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.01 (s, 1H), 5.62 (d,
J=8.0 Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.92 (m, 1H), 4.44-4.39 (m,
1H), 4.16-4.13 (m, 1H), 4.10-4.05 (m, 1H), 3.86 (d, J=9.2 Hz, 1H),
1.34 (d, J=7.2 Hz, 3H), 1.25 (d, J=6.4 Hz, 6H), 1.16 (s, 3H);
.sup.31P NMR (CD.sub.3OD, 162 MHz) .delta.68.18; ESI-LCMS: m/z=544
[M+H].sup.+. Compound 1: .sup.1H NMR (CD.sub.3OD, 400 MHz)
.delta.7.89 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 2H), 7.30 (d,
J=8.4 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 5.99 (s, 1H), 5.60 (d, J=8.4
Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.51 (m, 1H), 4.35-4.30 (m, 1H),
4.14-4.10 (m, 2H), 3.83 (d, J=9.2 Hz, 1H), 1.39 (d, J=7.2 Hz, 3H),
1.25 (d, J=6.4 Hz, 6H), 1.17 (s, 3H); .sup.31P NMR (CD.sub.3OD, 162
MHz) .delta.68.42; ESI-LCMS: m/z=566 [M+Na].sup.+.
[0423] (b) Via Crystallization:
[0424] Method 1:
[0425] Compound 1(rac) as a mixture of diastereomers (1:1, 10 g)
was dissolved in 100 mL of dichloromethane (DCM)/ether (1:3).
Hexane was added dropwise until the solution became cloudy. The
solution was left at (room temperature) RT for 5 h and overnight at
-20.degree. C. Precipitated crystals were recrystallized from
DCM/ether 1:3 v/v, and one more time from DCM/ether 1:2. Compound
1a (3 g) was obtained as a pure single diastereomer. The mother
liquor after first crystallization was concentrated, and then
dissolved in isopropanol. Hexane was added (30% by volume). The
clear solution was left overnight at RT to produce a small amount
of crystals, which were used as seeds. The mother liquor was
evaporated and crystallized 2 times from hexane/isopropanol (4:1)
to give 2.3 g of Compound 1.
[0426] Method 2:
[0427] 50 g of Compound 1(rac) was added to 100 mL of DCM and
allowed to stir. After brief stirring almost all of the material
was dissolved (<100 mg remained suspended). This was filtered
and 300 mL of MTBE added while stirring. About 25 mg of Compound 1
was added as seeds and the solution cooled to 3.degree. C.
overnight. Significant precipitation was observed. The cold mixture
was filtered and the solid washed with 25 mL of MTBE but not
filtered dry. The product was dried on a rotvac at 8 torr and
30.degree. C. This material was recrystallized one additional time
using the procedure outline above with precipitation being observed
upon the addition of 100 mg of the product from the first
crystallization as seeds. XRPD indicated that the material
recovered was amorphous. Additional solids had precipitated from
the supernatant and were collected by filtration. These were then
rinsed with 25 mL of MTBE and dried. .sup.31P NMR showed that this
material was Compound 1 with about 4% of Compound 1a.
Example 2
Synthesis of Amorphous Form O
[0428] 350 mg of Compound 1 was weighed and added to 8 mL of a 1:1
DCM/Methanol (HPLC grade) solution in a vial. The contents were
allowed to stir until a clear solution was obtained. This solution
was spray dried on a Buchi B-290 Mini with a condenser attached.
The resulting spray dried solid was further dried in a vacuum oven
at RT overnight to remove any residual solvent. The parameters of
the Buchi B-290 Mini are listed below:
[0429] Nitrogen flow: 10 L/min;
[0430] Nitrogen max pressure: 10 psi;
[0431] CO.sub.2 max pressure: 15 psi;
[0432] Inlet temperature: 95-100.degree. C.;
[0433] Outlet temperature: 50.degree. C.;
[0434] Aspirator: 100%;
[0435] Pump: 30%; and
[0436] Nozzle: 1.5
Example 3
Synthesis of Form A
[0437] To 1 g of Compound 1 was added 2 mL of ethyl acetate and the
mixture was heated to 35.degree. C. and stirred until all solids
had dissolved. The mixture was then allowed to cool to room
temperature to allow the solids to precipitate out of solution. An
additional 2 mL of ethyl acetate was then added to the mixture, and
the mixture was again heated to 35.degree. C. until all solids
dissolved. The mixture was allowed to cool to allow the solids to
precipitate out of solution as above. The solid Form A was then
collected by filtration.
[0438] Representative XRPD peaks for Form A are shown in the table
below. Form A can be identified and/or characterized by one or more
of the peaks in the table below.
TABLE-US-00032 No. 2-Theta .degree. Intensity % 1 7.0* 91.8 2 8.5*
100.0 3 10.0 70.0 4 11.0 73.4 5 14.7 90.3 6 15.5 76.7 7 15.8* 79.6
8 16.6 90.9 9 17.8 81.1 10 18.0 99.2 11 18.8 72.2 12 19.9 76.1 13
20.8 73.5 14 21.4* 77.0 15 22.0** 68.9 16 22.6** 73.0 17 23.3**
68.8 18 25.8 71.7 19 28.7 67.4 Peaks with an asterisk (*) are major
peaks Peaks with a double asterisk (**) are secondary peaks
[0439] Representative peaks from the .sup.13C NMR solid state
spectrum of Form A are shown in the table below. Form A can be
identified and/or characterized by one or more of the peaks
selected from the table below.
TABLE-US-00033 .nu.(F1) Intensity Peak # [ppm] [rel] 1 173.0 24.12
2 172.0* 23.11 3 170.2 24.80 4 151.3 28.62 5 150.5 38.71 6 146.6*
14.23 7 143.9 12.74 8 130.4* 36.15 9 126.2 27.80 10 122.9 3.91 11
120.4 33.00 12 104.1* 23.68 13 102.2 23.18 14 92.8 20.65 15 92.2
17.13 16 84.1 27.03 17 79.7 68.89 18 75.0 28.02 19 73.5 33.05 20
69.5* 34.76 21 69.2 27.63 22 66.9* 40.98 23 50.4 22.59 24 21.9
100.00 25 20.6* 39.44 Peaks with an asterisk (*) are major
peaks
Example 4
[0440] Synthesis of the Form B (methyl tert-butyl ether solvate)
and Form B (cyclohexane solvate). Form B (methyl tert-butyl ether
solvate) and Form B (cyclohexane solvate) were determined to be
isostructural by XRPD analysis.
Example 4a
Synthesis of Form B (Methyl Tert-Butyl Ether Solvate)
[0441] To a vial containing 20 mg of Form A was added 200 .mu.L of
HPLC grade methyl tert-butyl ether (MTBE). The vial was stirred at
an intermediate speed (250 rpm) on a stir plate at RT for 3 weeks.
The mixture was filtered through a 0.22 .mu.m PVDF filter to
provide Form B (methyl tert-butyl ether solvate).
[0442] Representative peaks from the .sup.13C NMR solid state
spectrum of Form B (methyl tert-butyl ether solvate) are shown in
the table below. Form B (methyl tert-butyl ether solvate) can be
identified and/or characterized by one or more of the peaks
selected from the table below.
TABLE-US-00034 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.2* 55.0 2
169.9 24.91 3 151.1 50.46 4 144.7 20.81 5 129.9* 100.00 6 123.3
47.74 7 118.3* 77.98 8 103.5 41.84 9 92.8 29.78 10 82.4 43.94 11
79.8 88.11 12 74.1 57.28 13 72.3* 20.83 14 68.5* 76.94 15 68.1
67.80 16 50.9 12.62 17 50.3 27.03 18 49.2* 57.83 19 27.1* 61.90 20
22.6 76.64 21 22.2 75.51 22 22.0 16.01 23 21.7 65.44 24 19.5* 52.58
Peaks with an asterisk (*) are major peaks
[0443] Representative peaks from the XRPD spectrum of Form B
(methyl tert-butyl ether solvate) are shown in the table below.
Form B (methyl tert-butyl ether solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00035 No. 2-Theta .degree. Intensity % 1 5.720* 71.8 2
9.395* 31.2 3 17.042* 100.0 4 26.219* 28.5 Peaks with an asterisk
(*) are major peaks
Example 4b
Synthesis of Form B (Cyclohexane Solvate)
[0444] To a vial containing 20 mg of Form A was added 200 .mu.l of
HPLC grade cyclohexane. The vial was stirred at an intermediate
speed (250 rpm) on a stir plate at RT for 3 weeks. The mixture was
filtered through a 0.22 .mu.m PVDF filter to provide Form B
(cyclohexane solvate).
[0445] Representative peaks from the .sup.13C NMR solid state
spectrum of Form B (cyclohexane solvate) are shown in the table
below. Form B (cyclohexane solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00036 .nu.(F1) Intensity Peak # [ppm] [rel] 1 172.6 20.01
2 170.3* 26.09 3 150.5* 39.10 4 146.6 15.32 5 144.4 12.23 6 129.8*
31.00 7 126.3 25.02 8 122.6 15.89 9 120.4 26.04 10 118.2* 30.57 11
104.1 18.00 12 102.2 17.34 13 92.8 19.56 14 84.2 16.62 15 79.8*
53.48 16 75.0 22.56 17 73.6 20.49 18 69.5 21.11 19 68.1 19.74 20
66.9 21.59 21 64.0 13.37 22 50.5 20.41 23 40.8 12.34 24 27.2* 21.00
25 21.8* 100.00 26 18.6 15.87 Peaks with an asterisk (*) are major
peaks
[0446] Representative peaks from the XRPD spectrum of Form B
(cyclohexane solvate) are shown in the table below. Form B
(cyclohexane solvate) can be identified and/or characterized by one
or more of the peaks selected from the table below.
TABLE-US-00037 No. 2-Theta .degree. Intensity % 1 5.720* 71.8 2
9.395* 31.2 3 17.042* 100.0 4 26.219* 28.5 Peaks with an asterisk
(*) are major peaks
Example 5
Synthesis of Form C (Nitromethane Solvate)
[0447] To a vial containing 20 mg of Form A was added 100 .mu.L of
HPLC grade nitromethane. The vial was stirred at an intermediate
speed (250 rpm) on a stir plate at RT for 3 weeks. The mixture was
filtered through a 0.22 .mu.m PVDF filter to provide Form C.
[0448] Representative peaks from the .sup.13C NMR solid state
spectrum of Form C (nitromethane solvate) are shown in the table
below. Form C (nitromethane solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00038 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.7* 72.2 2
163.6 27.15 3 162.7 27.66 4 152.6 33.02 5 151.9* 39.39 6 151.3
17.72 7 150.4 19.06 8 144.1 20.92 9 140.7 19.90 10 129.6 32.86 11
126.7 18.14 12 126.1 20.87 13 125.5 22.15 14 123.3 27.16 15 122.8
35.54 16 103.2* 40.00 17 102.5 24.12 18 101.9 21.60 19 93.3 34.02
20 92.4 35.66 21 83.3* 51.71 22 81.5 57.50 23 80.8* 54.60 24 80.3
75.92 25 73.3* 88.51 26 69.4 39.18 27 68.3 39.61 28 65.5 23.22 29
64.9 26.70 30 63.8* 54.98 31 51.8 21.78 32 50.6 28.73 33 25.1*
71.94 34 20.8 88.14 35 20.1* 100.00 36 18.8 24.24 Peaks with an
asterisk (*) are major peaks
[0449] Representative peaks from the XRPD spectrum of Form C
(nitromethane solvate) are shown in the table below. Form C
(nitromethane solvate) can be identified and/or characterized by
one or more of the peaks selected from the table below.
TABLE-US-00039 No. 2-Theta .degree. Intensity % 1 4.980* 27.4 2
6.573* 31.0 3 8.174* 39.0 4 9.151** 47.4 5 9.585** 56.2 6 16.337**
62.7 7 22.340* 28.1 Peaks with an asterisk (*) are major peaks
Peaks with a double asterisk (**) are secondary peaks
Example 6
Synthesis of Form D (Desolvated Acetonitrile Solvate)
[0450] To a vial containing 50 mg of Form A was added 100 .mu.L of
HPLC grade acetonitrile (ACN) and stirred at RT until all solids
dissolved. The vial was then stirred at an intermediate speed (250
rpm) on a stir plate at 5.degree. C. for 3 weeks. The mixture was
filtered through a 0.22 .mu.m PVDF filter, and the isolated solid
was dried at RT and atmospheric pressure until the solid was
substantially desolvated to provide Form D (desolvated acetonitrile
solvate).
[0451] Representative peaks from the .sup.13C NMR solid state
spectrum of Form D (desolvated acetonitrile solvate) are shown in
the table below. Form D (desolvated acetonitrile solvate) can be
identified and/or characterized by one or more of the peaks
selected from the table below.
TABLE-US-00040 .nu.(F1) Intensity Peak # [ppm] [rel] 1 172.5 31.47
2 170.3 39.91 3 163.0 36.97 4 152.7 57.96 5 150.4 41.72 6 143.3
19.06 7 139.1* 20.55 8 130.9 74.16 9 130.2 33.92 10 125.3* 71.51 11
124.4 39.60 12 120.8* 61.60 13 105.2* 73.13 14 92.3 31.47 15 91.0
29.46 16 81.8 47.28 17 79.9 100.00 18 78.5 65.96 19 73.6 52.41 20
72.8* 51.48 21 69.4 48.17 22 67.5* 45.52 23 63.0* 84.89 24 53.6
23.06 25 50.8 25.81 26 23.7 50.37 27 22.8 89.54 28 22.0 51.17 29
21.3 98.72 30 20.8 54.41 31 18.3 54.61 Peaks with an asterisk (*)
are major peaks
[0452] Representative peaks from the XRPD spectrum of Form D
(desolvated acetonitrile solvate) are shown in the table below.
Form D (desolvated acetonitrile solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00041 No. 2-Theta .degree. Intensity % 1 8.105* 55.6 2
13.357* 44.1 3 14.424** 100.0 4 17.215** 66.0 5 29.590* 29.1 6
35.019* 25.3 Peaks with an asterisk (*) are major peaks Peaks with
a double asterisk (**) are secondary peaks
Example 7
Synthesis of a Mixture of Form E (Dioxane Solvate) and Form A
[0453] To a vial containing 40 mg of Form A was added 100 .mu.L of
HPLC grade dioxane. The vial was stirred at an intermediate speed
(250 rpm) on a stir plate at 5.degree. C. for 24 hours. 100 .mu.L
of HPLC grade heptane was then added, and the vial was sonicated in
a ultrasonicator for 2 minutes. The mixture was then stirred at
5.degree. C. for an additional 3 weeks. The vial was then uncapped
and placed in the open air to evaporate the solvent and provide a
solid mixture of Form E (dioxane solvate) and Form A.
[0454] Representative peaks from the .sup.13C NMR solid state
spectrum of Form E (dioxane solvate) are shown in the table below.
Form E (dioxane solvate) can be identified and/or characterized by
one or more of the peaks selected from the table below.
TABLE-US-00042 .nu.(F1) Intensity Peak # [ppm] [rel] 1 173.0* 56.27
2 172.1 10.64 3 170.1 29.76 4 151.3 14.75 5 150.7* 55.30 6 146.7
6.43 7 145.2 17.07 8 144.0 6.43 9 130.2* 78.40 10 126.2 14.42 11
123.7 34.51 12 120.5 15.84 13 118.3* 65.27 14 104.1 11.22 15 103.2
33.55 16 102.2 11.20 17 92.7 28.19 18 84.1 12.31 19 82.4 35.17 20
80.1 73.44 21 79.8 36.49 22 75.0 14.45 23 73.9* 48.37 24 69.2 53.62
25 68.0* 59.07 26 67.0* 32.83 27 50.4 28.84 28 22.0* 100.00 29 21.7
93.59 30 21.4 58.58 31 20.6 18.91 32 19.4 40.73 Peaks with an
asterisk (*) are major peaks
[0455] Representative peaks from the XRPD spectrum of Form E
(dioxane solvate) are shown in the table below. Form E (dioxane
solvate) can be identified and/or characterized by one or more of
the peaks selected from the table below.
TABLE-US-00043 No. 2-Theta .degree. Intensity % 1 7.765* 58.9 2
10.563** 22.3 3 12.901* 40.7 4 21.571* 26.4 5 24.466** 51.4 6
25.016* 31.6 Peaks with an asterisk (*) are major peaks Peaks with
a double asterisk (**) are secondary peaks
Example 8
Synthesis of a Mixture of Form F (Tetrahydrofuran Solvate) and Form
A
[0456] To a vial containing 60 mg of Form A was added 200 .mu.L of
HPLC grade tetrahydrofuran (THF). The vial was stirred at an
intermediate speed (250 rpm) on a stir plate at RT for 3 weeks. The
vial was then uncapped and placed in the open air to evaporate the
solvent and provide a solid mixture of Form F (tetrahydrofuran
solvate) and Form A.
[0457] Representative peaks from the .sup.13C NMR solid state
spectrum of Form F (tetrahydrofuran solvate) are shown in the table
below. Form F (tetrahydrofuran solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00044 .nu.(F1) Intensity Peak # [ppm] [rel] 1 173.0 21.53
2 172.0 24.07 3 170.2* 27.88 4 151.3 28.85 5 150.5* 40.71 6 146.6
11.13 7 145.2 6.82 8 143.9 11.03 9 130.4* 33.74 10 126.2 25.38 11
123.1 8.05 12 120.4 29.96 13 104.0 20.89 14 103.2 9.89 15 102.2
20.47 16 92.8 22.77 17 92.2 18.97 18 84.0 21.12 19 81.9 7.45 20
79.7* 71.06 21 75.0 24.15 22 73.5* 30.33 23 69.5 29.78 24 69.2
27.71 25 68.2* 20.78 26 66.9* 34.82 27 50.4 28.03 28 25.7* 7.70 29
21.8* 100.00 30 20.6* 39.64 Peaks with an asterisk (*) are major
peaks
[0458] Representative peaks from the XRPD spectrum of Form F
(tetrahydrofuran solvate) are shown in the table below. Form F
(tetrahydrofuran solvate) can be identified and/or characterized by
one or more of the peaks selected from the table below.
TABLE-US-00045 No. 2-Theta .degree. Intensity % 1 6.090* 100.0 2
6.970* 32.4 3 17.538* 30.7 4 18.048* 56.0 Peaks with an asterisk
(*) are major peaks
Example 9
Synthesis of Form G (Dichloromethane Solvate)
[0459] To a vial containing 50 mg of Amorphous Form O was added 50
.mu.L of HPLC grade dichloromethane (DCM). The vial was stirred at
an intermediate speed (250 rpm) on a stir plate at RT for 1 hour.
An aliquot (.about.25 .mu.L) was placed in a capillary tube which
was then sealed off at both ends. The capillary tube was placed on
an XRPD holder and analyzed (an acquisition time of 600 seconds was
used for each frame).
[0460] Representative peaks from the .sup.13C NMR solid state
spectrum of Form G (dichloromethane solvate) are shown in the table
below. Form G (dichloromethane solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00046 .nu.(F1) Intensity Peak [ppm] [rel] 1 172.9* 47.8 2
172.5 60.77 3 170.1 31.87 4 150.8* 97.73 5 145.6 17.22 6 143.7
10.94 7 130.4* 78.80 8 123.6 13.92 9 122.8 39.28 10 122.2 22.62 11
119.6* 30.97 12 118.7* 83.25 13 103.6 49.34 14 103.2 27.56 15 93.1
34.63 16 92.6 30.12 17 83.1* 44.78 18 82.6 41.59 19 80.2 49.48 20
79.9 89.47 21 79.5 48.95 22 74.4 42.00 23 73.5 36.87 24 73.3 36.16
25 69.0* 46.99 26 68.8 93.22 27 68.5 53.49 28 68.3 50.90 29 68.0
70.75 30 54.2* 17.40 31 50.5 44.46 32 23.4 36.90 33 22.9 82.85 34
22.6 100.00 35 21.8 87.94 36 21.4 85.89 37 20.4* 70.1 38 20.1 39.2
Peaks with an asterisk (*) are major peaks
[0461] Representative peaks from the XRPD spectrum of Form G
(dichloromethane solvate) are shown in the table below. Form G
(dichloromethane solvate) can be identified and/or characterized by
one or more of the peaks selected from the table below.
TABLE-US-00047 No. 2-Theta .degree. Intensity % 1 5.857* 100.0 2
7.498* 41.6 3 7.835* 32.1 4 12.522** 23.5 5 17.733* 53.0 6 18.193**
23.5 Peaks with an asterisk (*) are major peaks Peaks with a double
asterisk (**) are secondary peaks
Example 10
Synthesis of Form H (Acetonitrile Solvate)
[0462] To a vial containing 120 mg of Amorphous Form O was added
100 .mu.L of HPLC grade acetonitrile (ACN), and the mixture was
stirred at RT until the solids dissolved. The vial was then
sonicated in an ultrasonicator for 2 minutes, and the mixture was
then stirred at an intermediate speed (250 rpm) on a stir plate at
RT for 5 minutes. The mixture was filtered through a 0.22 .mu.m
PVDF filter to provide Form H (acetonitrile solvate).
[0463] Representative peaks from the .sup.13C NMR solid state
spectrum of Form H (acetonitrile solvate) are shown in the table
below. Form H (acetonitrile solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00048 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.4* 70.7 2
164.4 44.87 3 153.4* 31.83 4 152.2* 61.17 5 141.4 42.94 6 129.8*
70.37 7 123.6 53.72 8 119.8* 55.92 9 104.6* 76.16 10 92.3 56.76 11
82.6 35.67 12 81.9 32.74 13 79.4* 100.00 14 73.4 96.98 15 68.9
54.71 16 61.7 73.15 17 53.6 47.24 18 23.4 79.96 19 22.9 86.96 20
21.6 41.15 21 20.6* 90.05 22 2.2* 14.59 Peaks with an asterisk (*)
are major peaks
[0464] Representative peaks from the XRPD spectrum of Form H
(acetonitrile solvate) are shown in the table below. Form H
(acetonitrile solvate) can be identified and/or characterized by
one or more of the peaks selected from the table below.
TABLE-US-00049 No. 2-Theta .degree. Intensity % 1 8.132* 81.7 2
14.020* 34.6 3 17.226* 61.7 4 20.902* 27.3 Peaks with an asterisk
(*) are major peaks
Example 11
[0465] Synthesis of the isostructural Form I (isopropyl acetate
solvate) and Form I (ethyl acetate solvate). Form I (isopropyl
acetate solvate) and Form I (ethyl acetate solvate) were determined
to be isostructural by XRPD analysis.
Example 11a
Synthesis of Form I (Isopropyl Acetate Solvate)
[0466] To a vial containing 33 mg of Amorphous Form O was added
2004 of HPLC grade isopropyl acetate (IPAC). The mixture was then
stirred at an intermediate speed (250 rpm) on a stir plate at RT
for 2 hours. The mixture was filtered through a 0.22 .mu.m PVDF
filter to provide Form I (isopropyl acetate solvate).
[0467] Representative peaks from the .sup.13C NMR solid state
spectrum of Form I (isopropyl acetate solvate) are shown in the
table below. Form I (isopropyl acetate solvate) can be identified
and/or characterized by one or more of the peaks selected from the
table below.
TABLE-US-00050 .nu.(F1) Intensity Peak [ppm] [rel] 1 174.2 28.4 2
173.0* 35.35 3 170.1 18.49 4 168.4* 18.99 5 152.1* 44.16 6 151.0
35.26 7 144.8 19.59 8 143.5 18.22 9 129.9 26.35 10 126.1* 27.72 11
123.4 33.24 12 122.8 27.21 13 119.6 9.23 14 102.7* 56.58 15 93.2
23.93 16 91.1 24.94 17 81.6 37.12 18 80.5 42.31 19 79.6 73.82 20
74.5* 37.87 21 73.2 37.91 22 71.2* 34.86 23 69.3 62.97 24 68.8
39.70 25 63.3* 34.57 26 51.1 22.87 27 50.3 19.47 28 23.3* 100.00 29
22.8 76.24 30 21.9 75.98 31 21.4 42.76 32 20.4 36.17 33 20.0 38.34
Peaks with an asterisk (*) are major peaks
[0468] Representative peaks from the XRPD spectrum of Form I
(isopropyl acetate solvate) are shown in the table below. Form I
(isopropyl acetate solvate) can be identified and/or characterized
by one or more of the peaks selected from the table below.
TABLE-US-00051 No. 2-Theta .degree. Intensity % 1 6.434* 59.2 2
9.283* 30.8 3 10.831* 55.3 4 11.794* 28.3 Peaks with an asterisk
(*) are major peaks
Example 11b
Synthesis of Form I (Ethyl Acetate Solvate)
[0469] To a vial containing 33 mg of Amorphous Form O was added
2004 of HPLC grade ethyl acetate. The mixture was then stirred at
an intermediate speed (250 rpm) on a stir plate at RT for 2 hours.
The mixture was filtered through a 0.22 .mu.m PVDF filter to
provide Form I (ethyl acetate solvate).
[0470] Representative peaks from the .sup.13C NMR solid state
spectrum of Form I (ethyl acetate solvate) are shown in the table
below. Form I (ethyl acetate solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00052 .nu.(F1) Intensity Peak [ppm] [rel] 1 174.2 27.6 2
173.1* 34.33 3 170.3 20.24 4 168.6* 20.76 5 152.1* 41.55 6 151.1
35.37 7 144.9 20.96 8 143.6 18.23 9 129.4 12.59 10 126.1 23.63 11
123.6* 24.98 12 119.3 10.42 13 102.6* 56.41 14 93.2 22.66 15 91.1
23.83 16 81.7 36.81 17 80.6 41.38 18 79.6 68.17 19 74.3 34.18 20
73.2 33.47 21 71.4* 32.36 22 69.3 33.35 23 68.7 34.79 24 63.5*
32.91 25 61.9* 21.88 26 51.3 22.60 27 50.5 21.35 28 22.4* 100.00 29
20.1 52.23 30 15.5* 16.24
[0471] Representative peaks from the XRPD spectrum of Form I (ethyl
acetate solvate) are shown in the table below. Form I (ethyl
acetate solvate) can be identified and/or characterized by one or
more of the peaks selected from the table below.
TABLE-US-00053 No. 2-Theta .degree. Intensity % 1 6.434* 59.2 2
9.283* 30.8 3 10.831* 55.3 4 11.794* 28.3 Peaks with an asterisk
(*) are major peaks
Example 12
Synthesis of Form J
[0472] To a vial containing 100 mg of Amorphous Form O was added
150 .mu.L of HPLC grade ethanol. The contents of the vial was
stirred at an intermediate speed (250 rpm) on a stir plate at RT
overnight. The mixture was filtered through a 0.22 .mu.m PVDF
filter to provide Form J.
[0473] Representative peaks from the XRPD spectrum of Form J are
shown in the table below. Form J can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00054 No. 2-Theta .degree. Intensity % 1 6.1* 69.2 2 7.5*
54.4 3 9.0 21.2 4 9.9 21.2 5 10.8 34.0 6 11.1 44.2 7 11.4 26.5 8
12.1* 100.0 9 12.9 24.6 10 13.3* 31.2 11 14.0* 27.2 12 14.8 28.3 13
15.1 30.2 14 15.4 29.5 15 16.1 33.0 16 16.7 41.0 17 17.6 29.8 18
18.0 54.6 19 18.5* 47.3 20 18.9 25.6 21 19.4 41.6 22 19.6 35.8 23
20.3 43.5 24 20.7 59.8 25 21.1 43.8 26 21.7 35.5 27 22.6** 30.1 28
22.3 24.3 29 23.8 23.1 30 24.7 32.7 31 25.2 23.7 32 25.7 20.8 33
26.6 26.7 34 27.5 24.3 35 27.8 23.6 36 28.3 20.7 37 29.6 22.9 38
32.2 20.3 39 33.2** 21.5 40 34.0** 19.2 41 35.3** 19.3 42 35.4 19.4
43 36.5 19.0 Peaks with an asterisk (*) are major peaks Peaks with
a double asterisk (**) are secondary peaks
[0474] Representative peaks from the .sup.13C NMR solid state
spectrum of Form J are shown in the table below. Form J can be
identified and/or characterized by one or more of the peaks
selected from the table below.
TABLE-US-00055 .nu.(F1) Intensity Peak [ppm] [rel] 1 175.6* 26.8 2
172.6 39.76 3 165.8 13.72 4 162.9 22.43 5 162.5 16.16 6 153.0 15.82
7 152.8 15.88 8 151.5 29.40 9 151.1 11.45 10 150.7 36.85 11 150.1
21.71 12 141.4* 19.34 13 140.1 11.81 14 131.1 29.77 15 129.7 35.60
16 129.5 26.33 17 127.8* 25.20 18 127.1 17.58 19 126.3 27.54 20
123.8 29.09 21 123.4* 32.43 22 122.8 26.21 23 103.1* 37.64 24 101.3
27.86 25 93.8 22.55 26 93.3 16.53 27 91.7 18.80 28 83.5* 35.20 29
81.1* 35.52 30 80.7 100.00 31 79.8 28.76 32 78.6 42.08 33 74.4
37.67 34 73.4 41.04 35 73.1 28.84 36 72.3 39.74 37 70.1 57.8 38
63.7 44.0 39 62.2* 334 40 53.1 21.6 41 52.5 16.9 42 50.8 15.9 43
25.6* 36.7 44 23.7 60.6 45 23.0 34.4 46 22.5 64.4 47 22.1 46.4 48
21.7 36.1 49 19.6* 34.5 50 18.8 34.8 51 18.4 29.1 Peaks with an
asterisk (*) are major peaks
Example 13
Synthesis of Form K (Chloroform Solvate)
[0475] To a vial containing 80 mg of Form J was added 200 .mu.L of
HPLC grade chloroform. The vial was sonicated in an ultrasonicator
for 1 minute, and the mixture was then stirred at an intermediate
speed (250 rpm) on a stir plate at RT overnight. An aliquot (-25
.mu.L) was placed on a holder and analyzed by XRPD.
[0476] Representative peaks from the .sup.13C NMR solid state
spectrum of Form K are shown in the table below. Form K can be
identified and/or characterized by one or more of the peaks
selected from the table below.
TABLE-US-00056 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.9* 40.0 2
173.4* 39.97 3 169.9 23.72 4 168.7 24.10 5 151.8* 45.42 6 150.5*
44.95 7 144.6 27.19 8 144.1 24.43 9 129.8 17.44 10 126.2 30.54 11
125.8 20.97 12 122.5 16.21 13 101.9* 81.01 14 93.4 34.58 15 92.0*
35.25 16 81.6 54.04 17 80.4* 88.61 18 79.7 51.32 19 78.6 62.92 20
73.5* 72.84 21 70.6 49.15 22 69.5 50.72 23 68.1 46.78 24 63.6 47.15
25 50.8 55.38 26 23.2 76.97 27 22.8 67.52 28 22.1* 100.00 29 20.7
68.21 30 20.4* 97.77 Peaks with an asterisk (*) are major peaks
[0477] Representative peaks from the XRPD spectrum of Form K are
shown in the table below. Form K can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00057 No. 2-Theta .degree. Intensity % 1 22.620* 27.5 2
27.257* 26.7 3 28.272* 25.0 4 31.216* 27.0 Peaks with an asterisk
(*) are major peaks
Example 14
Synthesis of Form L (Acetonitrile Solvate)
[0478] To a vial containing 80 mg of Form J was added 150 .mu.L of
HPLC grade acetonitrile (ACN). The vial was sonicated in an
ultrasonicator for 1 minute, and the mixture was then stirred at an
intermediate speed (250 rpm) on a stir plate at RT for 2 days. The
resulting solid Form L (acetonitrile solvate) in the mixture was
analyzed by XRPD as a suspension without isolation of the
solid.
[0479] Representative peaks from the .sup.13C NMR solid state
spectrum of Form L (acetonitrile solvate) are shown in the table
below. Form L (acetonitrile solvate) can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00058 .nu.(F1) Intensity Peak [ppm] [rel] 1 173.2* 32.2 2
172.6 13.04 3 164.3 20.50 4 152.9 15.62 5 152.3 18.02 6 151.4*
22.38 7 150.8 10.20 8 150.6 15.53 9 142.9 7.14 10 140.9* 17.32 11
130.3 17.85 12 129.9 17.36 13 125.7 15.60 14 124.7 11.99 15 123.4
12.87 16 118.5* 18.82 17 103.8 8.86 18 103.3 18.66 19 102.9 15.60
20 101.5 12.23 21 92.7 29.36 22 92.3 25.58 23 81.5* 51.96 24 80.1*
100.00 25 73.4* 51.97 26 69.9 17.16 27 69.3 27.18 28 68.0 11.49 29
63.0 15.93 30 61.9 24.74 31 61.6* 32.16 32 54.0 18.79 33 53.0 14.69
34 52.2 16.30 35 23.7 12.59 36 23.3 12.87 37 23.0 28.2 38 22.5 42.2
39 22.0 47.5 40 21.4 43.2 41 20.9* 50.2 42 20.2 17.4 43 19.8 22.2
44 19.2 15.2 45 18.9 14.8 46 1.6* 12.9
[0480] Representative peaks from the XRPD spectrum of Form L
(acetonitrile solvate) are shown in the table below. Form L
(acetonitrile solvate) can be identified and/or characterized by
one or more of the peaks selected from the table below.
TABLE-US-00059 No. 2-Theta .degree. Intensity % 1 5.662* 27.0 2
6.036* 27.2 3 15.174* 100.0 4 16.102* 56.5 Peaks with an asterisk
(*) are major peaks
Example 15
Synthesis of Form M
[0481] Form L, as produced above, was isolated from the mixture and
placed in a vacuum overnight until the solid was substantially
desolvated, to provide Form M.
[0482] Representative peaks from the .sup.13C NMR solid state
spectrum of Form M are shown in the table below. Form M can be
identified and/or characterized by one or more of the peaks
selected from the table below.
TABLE-US-00060 .nu.(F1) Intensity Peak [ppm] [rel] 1 174.0* 31.8 2
173.2 13.03 3 172.3 7.89 4 170.5* 25.18 5 163.6 11.98 6 163.0 24.93
7 162.4 16.01 8 152.8 24.75 9 151.8 15.28 10 151.3 19.55 11 150.7
13.04 12 150.3 26.82 13 149.8 8.82 14 149.3 28.40 15 141.0 21.01 16
138.9 14.25 17 131.3 17.74 18 130.3 11.77 19 129.5* 32.91 20 127.0
27.77 21 126.6 24.70 22 124.7 17.32 23 124.0 14.60 24 122.4 15.29
25 121.3 12.07 26 118.5 11.42 27 103.5 34.79 28 102.7 10.83 29
102.2 27.86 30 101.7 8.62 31 92.5 36.95 32 83.2 31.87 33 81.5 45.71
34 80.6 14.75 35 80.1 18.58 36 79.6* 100.00 37 74.3 44.8 38 73.3
44.3 39 70.5 10.0 40 69.7* 44.6 41 67.5 8.1 42 64.5 8.8 43 64.0 9.6
44 63.2* 39.5 45 61.4 8.0 46 53.3 20.6 47 51.8* 33.6 48 24.0* 37.0
49 23.7 47.1 50 23.3 62.9 51 22.4 67.7 52 21.9 44.5 53 21.6 52.4 54
20.5 8.9 55 19.5* 49.4 Peaks with an asterisk (*) are major
peaks
[0483] Representative peaks from the XRPD spectrum of Form M are
shown in the table below. Form M can be identified and/or
characterized by one or more of the peaks selected from the table
below.
TABLE-US-00061 No. 2-Theta .degree. Intensity % 1 6.274* 66.2 2
13.200* 40.5 3 22.225* 50.0 4 23.520* 38.7 Peaks with an asterisk
(*) are major peaks
Example 16
Synthesis of Form N (Toluene Solvate)
[0484] To a vial containing 50 mg of Amorphous Form O was added 200
.mu.L of HPLC grade toluene. The vial was sonicated in an
ultrasonicator for 1 minute, and the mixture was then stirred at an
intermediate speed (250 rpm) on a stir plate at RT for 3 days. The
resulting solid Form N (toluene solvate) in the mixture was
analyzed by XRPD (Bruker D8 Discover; 40 kV, 35 mA; single frame
registered with an exposure of 120 seconds) as a suspension without
isolation of the solid.
[0485] Representative peaks from the .sup.13C NMR solid state
spectrum of Form N (toluene solvate) are shown in the table below.
Form N (toluene solvate) can be identified and/or characterized by
one or more of the peaks selected from the table below.
TABLE-US-00062 .nu.(F1) Intensity Peak [ppm] [rel] 1 172.6* 60.5 2
170.3 21.21 3 169.9 20.31 4 151.5 28.70 5 151.1 40.12 6 150.6 26.12
7 145.2 33.34 8 130.4* 78.13 9 129.5* 87.88 10 129.2* 70.02 11
128.4* 64.31 12 125.5 40.20 13 124.4 31.97 14 124.2 31.70 15 120.8
66.36 16 120.0 74.60 17 103.5 40.76 18 103.2 33.90 19 92.8 37.18 20
82.6 41.88 21 82.2* 37.02 22 79.6 64.84 23 79.3 68.37 24 74.0*
88.74 25 68.6 28.92 26 68.4 57.45 27 68.1 92.39 28 67.7* 51.91 29
50.2 29.20 30 23.0 54.35 31 22.3 18.31 32 21.8 60.50 33 21.3*
100.00 34 21.1 61.99 35 20.6 18.12 36 20.2 58.39 37 19.3 34.4 Peaks
with an asterisk (*) are major peaks
[0486] Representative peaks from the XRPD spectrum of Form N
(toluene solvate) are shown in the table below. Form N (toluene
solvate) can be identified and/or characterized by one or more of
the peaks selected from the table below.
TABLE-US-00063 No. 2-Theta .degree. Intensity % 1 12.419* 25.7 2
15.310* 41.7 3 17.149* 76.6 4 17.873* 57.0 Peaks with an asterisk
(*) are major peaks
Example 17
HCV Replicon Assay
[0487] Cells
[0488] Huh-7 cells containing the self-replicating, subgenomic HCV
replicon with a stable luciferase (LUC) reporter were cultured in
Dulbecco's modified Eagle's medium (DMEM) containing 2 mM
L-glutamine and supplemented with 10% heat-inactivated fetal bovine
serum (FBS), 1% penicillin-streptomyocin, 1% nonessential amino
acids, and 0.5 mg/mL G418.
[0489] Determination of Anti-HCV Activity
[0490] Determination of 50% inhibitory concentration (EC.sub.50) of
compounds in HCV replicon cells were performed by the following
procedure. On the first day, 5,000 HCV replicon cells were plated
per well in a 96-well plate. On the following day, test compounds
were solubilized in 100% DMSO to 100.times. the desired final
testing concentration. Each compound was then serially diluted
(1:3) up to 9 different concentrations. Compounds in 100% DMSO are
reduced to 10% DMSO by diluting 1:10 in cell culture media. The
compounds were diluted to 10% DMSO with cell culture media, which
were used to dose the HCV replicon cells in 96-well format. The
final DMSO concentration was 1%. The HCV replicon cells were
incubated at 37.degree. C. for 72 hours. At 72 hours, cells were
processed when the cells are still subconfluent. Compounds that
reduce the LUC signal are determined by Bright-Glo Luciferase Assay
(Promega, Madison, Wis.). Percent Inhibition was determined for
each compound concentration in relation to the control cells
(untreated HCV replicon) to calculate the EC.sub.50.
[0491] Compound 1 was determined to have an EC.sub.50 of less than
1 .mu.M by the above procedure.
* * * * *