U.S. patent application number 14/776713 was filed with the patent office on 2016-01-28 for compounds and uses thereof for the modulation of hemoglobin.
This patent application is currently assigned to Global Blood Therapeutics, Inc.. The applicant listed for this patent is GLOBAL BLOOD THERAPEUTICS, INC.. Invention is credited to Stephen L. GWALTNEY, II, Jason R. HARRIS, Zhe LI, Brian W. METCALF.
Application Number | 20160024127 14/776713 |
Document ID | / |
Family ID | 51529912 |
Filed Date | 2016-01-28 |
United States Patent
Application |
20160024127 |
Kind Code |
A1 |
HARRIS; Jason R. ; et
al. |
January 28, 2016 |
COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN
Abstract
Provide herein are compounds and pharmaceutical compositions
suitable as modulators of hemoglobin, methods and intermediates for
their preparation, and methods for their use in treating disorders
mediated by hemoglobin and disorders that would benefit from tissue
and/or cellular oxygenation.
Inventors: |
HARRIS; Jason R.; (South San
Francisco, CA) ; METCALF; Brian W.; (South San
Francisco, CA) ; LI; Zhe; (South San Francisco,
CA) ; GWALTNEY, II; Stephen L.; (South San Francisco,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLOBAL BLOOD THERAPEUTICS, INC. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Global Blood Therapeutics,
Inc.
South San Francisco
CA
|
Family ID: |
51529912 |
Appl. No.: |
14/776713 |
Filed: |
March 10, 2014 |
PCT Filed: |
March 10, 2014 |
PCT NO: |
PCT/US2014/022742 |
371 Date: |
September 14, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13815810 |
Mar 15, 2013 |
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14776713 |
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14010455 |
Aug 26, 2013 |
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13815810 |
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Current U.S.
Class: |
514/89 ; 514/341;
546/22; 546/275.4 |
Current CPC
Class: |
C07F 9/65583 20130101;
C07D 401/04 20130101 |
International
Class: |
C07F 9/6558 20060101
C07F009/6558; C07D 401/04 20060101 C07D401/04 |
Claims
1. A compound of formula (I): ##STR00070## or an N oxide thereof,
or a pharmaceutically acceptable salt of each thereof, wherein A is
selected from the group consisting of: ##STR00071## wherein R.sup.1
is C.sub.1-C.sub.6 alkyl optionally substituted with 3-6 fluoro
atoms; R.sup.2 is hydrogen or C.sub.1-C.sub.6 alkyl; R.sup.3 is
C.sub.1-C.sub.6 alkyl; each R.sup.4 independently is hydrogen or
C.sub.1-C.sub.6 alkyl; ring B is ##STR00072## or ring B together
with A is: ##STR00073## X is oxygen. S, SO, or SO.sub.2; ring C is
selected from the group consisting of; ##STR00074## wherein R.sup.5
is selected from the group consisting of hydrogen; C.sub.1-C.sub.6
alkoxy, optionally substituted with a C.sub.1-C.sub.6 alkoxy group
or with up to 3 fluoro atoms; C.sub.1-C.sub.6 alkyl; and halo;
R.sup.6 is hydrogen or halo; R is hydrogen, a phosphate, a
diphosphate, a phosphonate or a phosphoramidate containing moiety,
or another promoiety; provided that the compound of formula (I)
comprises at least 1 OR group where R is not hydrogen.
2. The compound of claim 1, of formula (II): ##STR00075## wherein R
and R.sup.1 are defined as in claim 1.
3. The compound of claim 1 or 2, wherein R is --C(O)R.sup.31,
C(O)OR.sup.31, or CONR.sup.13R.sup.14 wherein each R.sup.31 is
independently a C.sub.1-C.sub.6 alkyl; C.sub.3-C.sub.8 cycloalkyl,
4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing
at least 1 basic nitrogen moiety; and R.sup.13 and R.sup.14
independently are C.sub.1-C.sub.6, alkyl; C.sub.3-C.sub.8
cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered
heteroaryl, containing at least 1 basic nitrogen moiety; or
R.sup.13 and R.sup.14 together with the nitrogen atom they are
bonded to for a 4-9 member heterocycle substituted with at least 1
amino, C.sub.1-C.sub.6 alkyl amino, or di C.sub.1-C.sub.6
alkylamino group.
4. The compound of claim 1 or 2, wherein R.sup.1 is isopropyl.
5. A compound of formula (II): ##STR00076## wherein R is phosphate.
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35, or
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35; and wherein m, R.sup.1,
R.sup.34 and R.sup.35 are defined as tabulated below:
TABLE-US-00005 R m R.sup.34 R.sup.35 NR.sup.34R.sup.35
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 1 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 2 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 3 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 4 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 1 ##STR00077##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 2 ##STR00078##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 3 ##STR00079##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 4 ##STR00080##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 2 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 3 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 4 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 2 ##STR00081##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 3 ##STR00082##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 4 ##STR00083##
P(O)(OH).sub.2
an N oxide thereof, or a pharmaceutically acceptable salt of each
thereof.
6. A compound of formula (IV): ##STR00084## or a pharmaceutically
acceptable salt thereof, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl optionally substituted with 1-3
C.sub.6-C.sub.12 aryl groups, optionally substituted;
C.sub.6-C.sub.12aryl, optionally substituted; and a protecting
group; and z is 1, 2 or 3.
7. The compound of claim 6, wherein the compound is of formula
(V-A): ##STR00085## or a pharmaceutically acceptable salt
thereof.
8. The compound of claim 6 of formula (V-B) ##STR00086## or a
pharmaceutically acceptable salt thereof.
9. A composition comprising a compound of any one of claims 1-5 and
7-8 and at least one pharmaceutically acceptable excipient.
10. A method for increasing oxygen affinity of hemoglobin S in a
subject, the method comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of any one
of claims 1-5 and 7-8 or the composition of claim 9.
11. A method for treating oxygen deficiency associated with sickle
cell anemia, the method comprising administering to a subject in
need thereof a therapeutically effective amount of a compound of
any one of claims 1-5 and 7-8 or the composition of claim 9.
Description
FIELD OF THE INVENTION
[0001] This invention provides compounds and pharmaceutical
compositions suitable for use as allosteric modulators of
hemoglobin, methods and intermediates for their preparation, and
methods for their use in treating disorders mediated by hemoglobin
and disorders that would benefit from tissue and/or cellular
oxygenation.
STATE OF THE ART
[0002] Sickle cell disease is a disorder of the red blood cells,
found particularly among those of African and Mediterranean
descent. The basis for sickle cell disease is found in sickle
hemoglobin (HbS), which contains a point mutation relative to the
prevalent peptide sequence of hemoglobin (Hb).
[0003] Hemoglobin (Hb) transports oxygen molecules from the lungs
to various tissues and organs throughout the body. Hemoglobin binds
and releases oxygen through conformational changes. Sickle
hemoglobin (HbS) contains a point mutation where glutamic acid is
replaced with valine, allowing HbS to become susceptible to
polymerization to give the HbS containing red blood cells their
characteristic sickle shape. The sickled cells are also more rigid
than normal red blood cells, and their lack of flexibility can lead
to blockage of blood vessels. U.S. Pat. No. 7,160,910 discloses
compounds that are allosteric modulators of hemoglobin. However, a
need exists for additional therapeutics that can treat disorders
that are mediated by Hb or by abnormal Hb such as HbS.
SUMMARY OF THE INVENTION
[0004] This invention relates generally to compounds and
pharmaceutical compositions suitable as allosteric modulators of
hemoglobin. In some aspects, this invention relates to methods for
treating disorders mediated by hemoglobin and disorders that would
benefit from tissue and/or cellular oxygenation.
[0005] In certain aspects of the invention, a compound of formula
(I) is provided:
##STR00001##
[0006] or an N oxide thereof, or a pharmaceutically acceptable salt
of each thereof, wherein A is selected from the group consisting
of:
##STR00002##
[0007] wherein R.sup.1 is C.sub.1-C.sub.6 alkyl optionally
substituted with 3-6 fluoro atoms;
[0008] R.sup.2 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0009] R.sup.3 is C.sub.1-C.sub.6 alkyl;
[0010] each R.sup.4 independently is hydrogen or C.sub.1-C.sub.6
alkyl;
[0011] ring B is
##STR00003##
[0012] or ring B together with A is:
##STR00004##
[0013] and stereoisomers thereof;
[0014] X is oxygen, S, SO, or SO.sub.2;
[0015] ring C is selected from the group consisting of:
##STR00005##
[0016] wherein R.sup.5 is selected from the group consisting of
hydrogen; C.sub.1-C.sub.6 alkoxy, optionally substituted with a
C.sub.1-C.sub.6 alkoxy group or with up to 3 fluoro atoms;
C.sub.1-C.sub.6 alkyl; and halo;
[0017] R.sup.6 is hydrogen or halo;
[0018] R is hydrogen, a phosphate, a diphosphate, a phosphonate or
a phosphoramidate containing moiety, or another promoiety;
[0019] provided that the compound of formula (I) comprises at least
1 OR group where R is not hydrogen.
[0020] In another aspect, this invention provides a compound of
formula (II):
[0021] wherein
##STR00006##
[0022] R is hydrogen, a phosphate or a diphosphate containing
moiety, or another promoiety; and
[0023] R.sup.1 is C.sub.1-C.sub.6 alkyl optionally substituted with
3-6 fluoro atoms;
[0024] provided that the compound of formula (I) comprises at least
1 OR group where R is not hydrogen.
[0025] In further aspects, this invention provides a compound of
formula (I) or formula (II),
[0026] wherein R is --COR.sup.31, C(O)OR.sup.31, or CONR.sup.13
R.sup.14.
[0027] each R.sup.31 is independently a C.sub.1-C.sub.6 alkyl;
C.sub.3-C.sub.8 cycloalkyl, 4-9 membered heterocycle. or a 5-10
membered heteroaryl, containing at least 1 basic nitrogen moiety;
and
[0028] R.sup.13 and R.sup.14 independently are C.sub.1-C.sub.6
alkyl; C.sub.3-C.sub.8 cycloalkyl, 4-9 membered heterocycle, or a
5-10 membered heteroaryl, containing at least 1 basic nitrogen
moiety; or R.sup.13 and R.sup.14 together with the nitrogen atom
they are bonded to for a 4-9 member heterocycle substituted with at
least 1 amino, C.sub.1-C.sub.6 alkyl amino, or di C.sub.1-C.sub.6
alkylamino group,
[0029] In one embodiment, this invention provides a compound of
formula (I) or formula (II), wherein R.sup.1 is isopropyl.
[0030] In certain aspects, this invention provides a compound of
formula (II):
##STR00007##
wherein R is phosphate, C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35, or
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35; and wherein m, R.sup.1,
R.sup.34 and R.sup.35 are defined as tabulated below:
TABLE-US-00001 R m R.sup.34 R.sup.35 NR.sup.34R.sup.35
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 1 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 2 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 3 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 4 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 1 ##STR00008##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 2 ##STR00009##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 3 ##STR00010##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 4 ##STR00011##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 2 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 3 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 4 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 2 ##STR00012##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 3 ##STR00013##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 4 ##STR00014##
P(O)(OH).sub.2
an N oxide thereof, or a pharmaceutically acceptable salt of each
thereof.
[0031] This invention arises in part out of the discovery that a
phosphate prodrug of a compound of formula (III):
##STR00015##
provides enhanced aqueous solubility while providing a whole blood
exposure equivalent to that of the compound of formula (III) upon
oral administration. This invention relates generally to compounds
and pharmaceutical compositions suitable for use as allosteric
modulators of hemoglobin. In some aspects, this invention relates
to methods for treating disorders mediated by hemoglobin and
disorders that would benefit from tissue and/or cellular
oxygenation.
[0032] In a further aspect of the invention, a compound of formula
(IV) is provided:
##STR00016##
or a salt, or a pharmaceutically acceptable salt thereof.
[0033] In further aspects of the invention, a composition is
provided where the composition comprises any of the compounds
disclosed herein, and at least one pharmaceutically acceptable
excipient.
[0034] In further aspects of the invention, a method is provided
for increasing oxygen affinity of hemoglobin S in a subject, the
method comprising administering to a subject in need thereof a
therapeutically effective amount of any of the compounds or
compositions disclosed herein.
[0035] In further aspects of the invention, a method is provided
for treating oxygen deficiency associated with sickle cell anemia,
the method comprising administering to a subject in need thereof a
therapeutically effective amount of any of the compounds or
compositions disclosed herein. Methods for increasing oxygen
affinity of hemoglobin S and methods for treating oxygen deficiency
associated with sickle cell anemia are well known and/or will be
apparent to the skilled artisan in view of this disclosure.
BRIEF DESCRIPTION OF THE FIGURE
[0036] FIG. 1 graphically illustrates the in vivo release of the
compound of formula (III) from a monophosphate prodrug compound
(V-B) of this invention, when administered at 10 mg/kg to a test
subject.
DETAILED DESCRIPTION OF THE INVENTION
[0037] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a solvent" includes a plurality of such
solvents,
[0038] As used herein, the term "comprising" or "comprises" is
intended to mean that the compositions and methods include the
recited elements, but not excluding others. "Consisting essentially
of" when used to define compositions and methods, shall mean
excluding other elements of any essential significance to the
combination for the stated purpose. Thus, a composition or process
consisting essentially of the elements as defined herein would not
exclude other materials or steps that do not materially affect the
basic and novel characteristic(s) of the claimed invention.
"Consisting of" shall mean excluding more than trace elements of
other ingredients and substantial method steps. Embodiments defined
by each of these transition terms are within the scope of this
invention.
[0039] Unless otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used
in the specification and claims are to be understood as being
modified in ail instances by the term "about. " Accordingly, unless
indicated to the contrary, the numerical parameters set forth in
the following specification and attached claims are approximations.
Each numerical parameter should at least be construed in light of
the number of reported significant digits and by applying ordinary
rounding techniques. The term "about" when used before a numerical
designation, e.g., temperature, time, amount, and concentration,
including range, indicates approximations which may vary by (+) or
(-) 10%, 5 % or 1%.
[0040] As used herein, C.sub.m-C.sub.n, such as C.sub.1-C.sub.12,
C.sub.1-C.sub.8, or C.sub.1-C.sub.6 when used before a group refers
to that group containing m to n carbon atoms.
[0041] The term "alkoxy" refers to O-alkyl.
[0042] The term "alkyl" refers to monovalent saturated aliphatic
hydrocarbyl groups having from 1 to 12 carbon atoms (i.e.,
C.sub.1-C.sub.12 alkyl) or 1 to 8 carbon atoms (i.e.,
C.sub.1-C.sub.8 alkyl , or 1 to 4 carbon atoms. This term includes,
by way of example, linear and branched hydrocarbyl groups such as
methyl (CH.sub.3--), ethyl (CH.sub.3CH2--), n-propyl
(CH.sub.3CH.sub.2CH.sub.2--), isopropyl ((CH.sub.3).sub.2CH--),
n-butyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2--), isobutyl
((CH.sub.3).sub.2CHCH.sub.2--), sec-butyl
((CH.sub.3)CH.sub.3CH.sub.2)CH--), t-butyl (CH.sub.3).sub.3C--),
n-pentyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and
neopentyl ((CH.sub.3).sub.3CCH.sub.2--).
[0043] The term "aryl" refers to a monovalent, aromatic mono- or
bicyclic ring having 6-10ring carbon atoms. Examples of aryl
include phenyl and naphthyl. The condensed ring may or may not be
aromatic provided that the point of attachment is at an aromatic
carbon atom. For example, and without limitation, the following is
an aryl group:
##STR00017##
[0044] The term "--CO.sub.2H ester" refers to an ester formed
between the --CO.sub.2H group and an alcohol, preferably an
aliphatic alcohol. A preferred example included --CO.sub.2R.sup.E,
wherein R.sup.E is alkyl or aryl group optionally substituted with
an amino group.
[0045] The term "chiral moiety" refers to a moiety that is chiral.
Such a moiety can possess one or more asymmetric centers.
Preferably, the chiral moiety is enantiomerically enriched, and
more preferably a single enantiomer. Non limiting examples of
chiral moieties include chiral carboxylic acids, chiral amines,
chiral amino acids, such as the naturally occurring amino acids,
chiral alcohols including chiral steroids, and the likes.
[0046] The term "cycloalkyl;" refers to a monovalent, preferably
saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12
ring carbon atoms. While cycloalkyl, refers preferably to saturated
hydrocarbyl rings, as used herein, it also includes rings
containing 1-2carbon-carbon double bonds. Nonlimiting examples of
cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl adamentyl, and the like. The condensed
rings may or may not be non-aromatic hydrocarbyl rings provided
that the point of attachment is at a cycloalkyl carbon atom. For
example, and without limitation, the following is a cycloalkyl
group:
##STR00018##
[0047] The term "halo" refers to F, Cl, Br, and/or I.
[0048] The term "heteroaryl" refers to a monovalent, aromatic
mono-, bi or tricyclic ring having 2-16 ring carbon atoms and 1-8
ring heteroatoms selected preferably from N, O, S, and P and
oxidized forms of N, S, and P, provided that the ring contains at
least 5 ring atoms. Nonlimiting examples of heteroaryl include
furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the
like. The condensed rings may or may not be a heteroatom containing
aromatic ring provided that the point of attachment is a heteroaryl
atom. For example, and without limitation, the following is a
heteroaryl group:
##STR00019##
[0049] The term "heterocyclyl" or heterocycle refers to a
non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring
carbon atoms and 1-8 ring heteroatoms selected preferably from N,
O, S, and P and oxidized forms of N, S, and P, provided that the
ring contains at least 3 ring atoms. While heterocyclyl preferably
refers to saturated ring systems, it also includes ring systems
containing 1-3 double bonds, provided that they ring is
non-aromatic. Nonlimiting examples of heterocyclyl include,
azaiactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl,
telrahydrofuranyl, and tetrahydropyranyl. The condensed rings may
or may not contain a non-aromatic heteroatom containing ring
provided that the point of attachment is a heterocyclyl group. For
example, and without limitation, the following is a heterocyclyl
group:
##STR00020##
[0050] The term "hydrolyzing" refers to breaking an R.sup.H--CO--,
R.sup.H--O--CS--, or an R.sup.H--O--SO.sub.2-- moiety to an
R.sup.H--OH, preferably by adding water across the broken bond. A
hydrolyzing is performed using various methods well known to the
skilled artisan, non limiting examples of which include acidic and
basic hydrolysis.
[0051] The term "oxo" refers to a C--O group, and to a substitution
of 2 geminal hydrogen atoms with a C.dbd.O group.
[0052] The term "optionally substituted" refers to a substituted or
unsubstituted group. The group may be substituted with one or more
substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.
Preferably, the substituents are selected from the group consisting
of oxo, halo, --CN, NO.sub.2, --N.sub.2+, --CO.sub.2R.sup.100 ,
--OR.sup.100, --SR.sup.100, --SOR.sup.100, --SO.sub.2R.sup.100,
--NR.sup.101R.sup.102, 13 CONR.sup.101R.sup.102,
--SO.sub.2NR.sup.101R.sup.102, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, --CR.sup.100.dbd.C(R.sup.100).sub.2,
--CCR.sup.100, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
heterocyclyl, C.sub.6-C.sub.12 aryl and C.sub.2-C.sub.12
heteroaryl, wherein each R.sup.100 independently is hydrogen or
C.sub.1-C.sub.8 cycloalkyl; C.sub.3-C.sub.12 cycloalkyl;
C.sub.3-C.sub.10 heterocyclyl; C.sub.6-C.sub.12 aryl; or
C.sub.2-C.sub.12 heteroaryl; wherein each alkyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl is optionally substituted with
1-3 halo, 1-3 C.sub.1-C.sub.6 alkyl, 1-3 C.sub.1-C.sub.6 haloalkyl
or 1-3 C.sub.1-C.sub.6 alkoxy groups. Preferably, the substituents
are selected from the group consisting of chloro, fluoro.
--OCH.sub.3, methyl, ethyl, iso-propyl, cyclopropyl, vinyl,
ethynyl, --CO.sub.2H, --CO.sub.2CH.sub.3, --OCF.sub.3, --CF; and
--OCHF.sub.2.
[0053] As used herein, R.sup.101 and R.sup.102 independently is
hydrogen; C.sub.1-C.sub.8 alkyl, optionally substituted with
--CO.sub.2H or an ester thereof C.sub.1-C.sub.6 alkoxy, oxo,
--CR.sup.103.dbd.C(R.sup.103).sub.2, --CCR, C.sub.3-C.sub.10
cycloalkyl, C.sub.3-C.sub.10 heterocyclyl, C.sub.6-C.sub.12 aryl,
or C.sub.2-C.sub.12 heteroaryl, wherein each R.sup.103
independently is hydrogen or C.sub.1-C.sub.8 alkyl;
C.sub.3-C.sub.12 cycloalkyl; C.sub.3-C.sub.10 heterocyclyl;
C.sub.6-C.sub.12 aryl; or C.sub.2-C.sub.12 heteroaryl; wherein each
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with 1-3 alkyl groups or 1-3 halo groups, or R.sup.101
and R.sup.102 together with the nitrogen atom they are attached to
form a 5-7 membered heterocycle.
[0054] The term "protecting group"as used herein, is well known in
the art and includes those described in detail in Protecting Groups
in Organic Synthesis. T. W. Greene and P. G. M. Wuts. 3.sup.rd
edition, John Wiley & Sons, 1999, and subsequent revisions, the
entirety of each of which is incorporated herein by reference.
Suitable protecting groups include benzyl, methyl, methoxymethyl
(MOM), methylthiomethyl (MTM), t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),
p-methoxybenzyloxymethyl (PMBM), (4-memoxyphenoxy)methyl (p-AOM),
guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),
siloxymethyl, 2-methoxyethoxymethyl (MEM),
2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,
2(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP),
3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP),
4-methoxytetrahydrothiopyranyl, 4-methoxyetrahydrothiopyranyl
S,S-dioxide, 1-[(2-chloro-4methyl)phenyl]4-methoxypiperidin-4-yl
(CTMP), 1,4-dioxan 2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7a
octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido. diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenylmethyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl
)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl,
benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl
(TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS),
diethylisopropylsilyl (DEIPS), dimethylthexylsilyl,
t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS),
tribenzysily, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsily
(DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl
carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl
p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl
p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate,
alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl
S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl
dithiocarbonate,2-iodobenzoate, 4-azidobutyiate,
4-nitro-4-methylpentanoate, o-dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(
methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxycarbonyl)benzoate, .alpha.-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsultenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts). For protecting 1,2- or 1,3-diols, the protecting groups
include methylene acetal, ethylidene acetal, 1-t-butylethylidene
ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene
acetal, 2,2,2-trichloroethylidene acetal, acetonide,
cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene
ketal, benzyl idene acetal, p-methoxybenzylidene acetal,
2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal,
2-nitrobenzylidene acetal, melhoxymethylene acetal, ethoxymethylene
acetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho
ester, 1-ethoxyethyfidine ortho ester, 1,2-dimethoxyethylidene
ortho ester, .alpha.-methoxybenzylidene ortho ester,
1-(N,N-dimethylamino)ethylidene derivative,
.alpha.-(N,N'-dimethylamino)benzylidene derivative,
2-oxacyclopentylidene ortho ester, di-t-butylsilylene group (DTBS),
1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),
tetra-t-butoxydisiloxane-1,3-diylidene derivative (TBDS), cyclic
carbonates, cyclic boronates, ethyl boronate, and phenyl
boronate.
[0055] The term "pharmaceutically acceptable" refers to safe and
non-toxic for in vivo, preferably, human administration.
[0056] The term "pharmaceutically acceptable salt" refers to a salt
that is pharmaceutically acceptable.
[0057] The term "salt" refers to an ionic compound formed between
an acid and a base. When the compound provided herein contains an
acidic functionality, such salts include, without limitation,
alkali metal, alkaline earth metal, and ammonium salts. As used
herein, ammonium salts include, salts containing protonated
nitrogen bases and alkylated nitrogen bases. Exemplary, and
non-limiting cations useful in pharmaceutically acceptable salts
include Na, K, Rb, Cs, NH.sub.4, Ca, Ba, imidazolium, and ammonium
cations based on naturally occurring amino acids. When the
compounds utilized herein contain basic functionally, such salts
include, without limitation, salts of organic acids, such as
carboxylic acids and sulfonic acids, and mineral acids, such as
hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
Exemplary and non-limiting anions useful in pharmaceutically
acceptable salts include oxalate, maleate, acetate, propionate,
succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and
tribasic phosphate, mesylate, tosylate, and the likes.
[0058] The terms "treat", "treating" or "treatment", as used
herein, include alleviating, abating or ameliorating a disease or
condition or one or more symptoms thereof, preventing additional
symptoms, ameliorating or preventing the underlying metabolic
causes of symptoms, inhibiting the disease or condition, e.g.,
arresting or suppressing the development of the disease or
condition, relieving the disease or condition, causing regression
of the disease or condition, relieving a condition caused by the
disease or condition, or suppressing the symptoms of the disease or
condition, and are intended to include prophylaxis. The terms also
include relieving the disease or conditions, e.g., causing the
regression of clinical symptoms. The terms further include
achieving a therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the individual, notwithstanding
that the individual is still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions are
administered to an individual at risk of developing a particular
disease, or to an individual reporting one or more of the
physiological symptoms of a disease, even though a diagnosis of
this disease has not been made.
[0059] The terms "preventing" or "prevention" refer to a reduction
in risk of acquiring a disease or disorder (i.e., causing at least
one of the clinical symptoms of the disease not to develop in a
subject that may be exposed to or predisposed to the disease but
does not yet experience or display symptoms of the disease). The
terms further include causing the clinical symptoms not to develop,
for example in a subject at risk of suffering from such a disease
or disorder, thereby substantially averting onset of the disease or
disorder.
[0060] The term "effective amount" refers to an amount that is
effective for the treatment of a condition or disorder by an
intranasal administration of a compound or composition described
herein. In some embodiments, an effective amount of any of the
compositions or dosage forms described herein is the amount used to
treat a disorder mediated by hemoglobin or a disorder that would
benefit from tissue and/or cellular oxygenation of any of the
compositions or dosage forms described herein to a subject in need
thereof.
[0061] The term "carrier" as used herein, refers to relatively
nontoxic chemical compounds or agents that facilitate the
incorporation of a compound into cells, e.g., red blood cells, in
tissues.
[0062] As used herein, a "prodrug" is a compound that, after
administration, is metabolized or otherwise converted to an active
or more active form with respect to at least one property. To
produce a prodrug, a pharmaceutically active compound can be
modified chemically to render it less active or inactive, but the
chemical modification is such that an active form of the compound
is generated by metabolic or other biological processes. A prodrug
may have, relative to the drug, altered metabolic stability or
transport characteristics, fewer side effects or lower toxicity.
For example, see the reference Nogrady, 1985, Medicinal Chemistry A
Biochemical Approach, Oxford University Press, New York, pages
388-392. Prodrugs can also be prepared using compounds that are not
drugs.
[0063] The invention provides prodrugs of substituted benzaldehyde
compounds that increase oxygen affinity of hemoglobin S. The
structures of the compounds, and derivatives thereof, as well as
methods of their synthesis, pharmaceutical formulations thereof and
methods of use are also provided.
Compounds
[0064] In certain aspects of the invention, a compound of formula
(I) is provided:
##STR00021##
[0065] or an N oxide thereof, or a pharmaceutically acceptable salt
of each thereof, wherein
[0066] A is selected from the group consisting of:
##STR00022##
[0067] wherein R.sup.1 is C.sub.1-C.sub.6 alkyl optionally
substituted with 3-6 fluoro atoms;
[0068] R.sup.2 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0069] R.sup.3 is C.sub.1-C.sub.6 alkyl;
[0070] each R.sup.4 independently is hydrogen or C.sub.1-C.sub.6
alkyl:
[0071] ring B is
##STR00023##
[0072] or ring B together with A is:
##STR00024##
[0073] X is oxygen, S, SO, or SO.sub.2;
[0074] ring C is selected from the group consisting of:
##STR00025##
[0075] wherein R.sup.5 is selected from the group consisting of
hydrogen; C.sub.1-C.sub.6 alkoxy, optionally substituted with a
C.sub.1-C.sub.6 alkoxy group or with up to 3 fluoro atoms;
C.sub.1-C.sub.6 alkyl; and halo;
[0076] R.sup.6 is hydrogen or halo;
[0077] R is hydrogen, a phosphate, a diphosphate, a phosphonate or
a phosphoramidate containing moiety, or another promoiety;
[0078] provided that the compound of formula (I) comprises at least
1 OR group where R is not hydrogen; and
[0079] the promoieties are structurally and functionally defined
herein.
[0080] In certain embodiments, a compound of formula (II) is
provided:
##STR00026##
[0081] wherein
[0082] R is hydrogen, a phosphate, a diphosphate, a phosphonate or
a phosphoramidate containing moiety, or another promoiety;
[0083] R.sup.1 is C.sub.1-C.sub.6 alkyl optionally substituted with
3-6 fluoro atoms;
[0084] provided that the compound of formula (I) comprises at least
1 OR group where R is not hydrogen and
[0085] the promoieties are structurally and functionally defined
herein.
[0086] In one aspect, R is hydrogen, a phosphate, a diphosphate, a
phosphonate or a phosphoramidate containing moiety, or another
promoiety or prodrug moiety. Preferably the prodrug moiety imparts
at least a 2 fold, more preferably a 4 fold, enhanced solubility
and/or bioavailability to the active moiety (where R is hydrogen),
and more preferably is hydrolyzed in vivo. The promoieties are
structurally and functionally defined herein.
[0087] In one embodiments, R is --COR.sup.90 , CO.sub.2R.sup.91, or
CONR.sup.92R.sup.93 wherein
[0088] R.sup.90 and R.sup.91 independently are C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, 4-9 membered heterocycle, or a
5-10 membered heteroaryl, each containing at least 1 basic nitrogen
moiety; and
[0089] R.sup.92 and R.sup.93 independently are C.sub.1-C.sub.6
alkyl; C.sub.3-.sub.8 cycloalkyl, 4-9 membered heterocycle, or a
5-10 membered heteroaryl, each containing at least 1 basic nitrogen
moiety; or R.sup.92 and R.sup.93 together with the nitrogen atom
they are bonded to for a 4-9 member heterocycle substituted with at
least 1 amino, C.sub.1-C.sub.6 alkyl amino, or di C.sub.1-C.sub.6
alkylamino group.
[0090] In certain embodiments. R is --C(O)R.sup.31, C(O).sup.31, or
CONR.sup.13R.sup.14,
[0091] each R.sup.31 is independently a C.sub.1-C.sub.6 alkyl;
C.sub.3-C.sub.8 cycloalkyl, 4-9 membered heterocycle, or a 5-10
membered heteroaryl, containing at least 1 basic nitrogen moiety;
and
[0092] R.sup.13 and R.sup.14 independently are C.sub.1-C.sub.6
alkyl; C.sub.3-C.sub.8 cycloalkyl, 4-9 membered hetcrocycle, or a
5-10 membered heteroaryl, containing at least 1 basic nitrogen
moiety; or R.sup.13 and R.sup.14 together with the nitrogen atom
they are bonded to for a 4-9 member hetcrocycle substituted with at
least 1 amino, C.sub.1-C.sub.6 alkyl amino, or di C.sub.1-C.sub.6
alkylamino group.
[0093] Preferably, R is isopropyl.
[0094] In one aspect, R is C(O)OR.sup.31, C(S)OR.sup.31,
C(O)SR.sup.31 or COR.sup.31, wherein R.sup.31 is as defined
herein,
[0095] In one embodiment, R.sup.31 is a group of the formula
(CR.sup.32R.sup.33).sub.eNR.sup.34R.sup.35, wherein
[0096] each R.sup.32 and R.sup.33 is independently H, a
C.sub.1-C.sub.8 alkyl, C.sub.3C.sub.9 heterocyclyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.9 heteroaryl or
R.sup.32 and R.sup.33 together with the carbon atom they are bond
to form a C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl,
C.sub.3-C.sub.9 heterocyclyl or C.sub.3-C.sub.9 heteroaryl ring
system, or 2 adjacent R.sup.32 moieties or 2 adjacent R.sup.33
moieties together with the carbon atom they are bond to form a
C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.9
heterocyclyl or C.sub.3-C.sub.9 heteroaryl ring system;
[0097] each R.sup.34 and R.sup.35 is a C.sub.1-C.sub.8 alkyl,
C3-C.sub.9 heterocyclyl, C.sub.3-C.sub.8 cycloalkyl, or R.sup.34
and R.sup.35 together with the nitrogen atom they are bond to form
a C.sub.3-C.sub.8 cycloalkyl or C.sub.3C.sub.9 heterocyclyl ring
system;
[0098] each heterocyclic and heteroaryl ring system is optionally
substituted with C.sub.1-C.sub.3 alkyl, --OH, amino and carboxyl
groups; and
[0099] e is an integer of from 1 to 4.
[0100] In some less preferred embodiments R.sup.34 and R.sup.35 can
be hydrogen.
[0101] In one embodiment, the subscript e is preferably 2 and each
R.sup.32 and R.sup.33 is preferably independently selected from the
group, H, CH.sub.3, and a member in which R.sup.32 and R.sup.33 are
joined together to form a cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, or 1,1-dioxo-hexahydro-1A.sup.6-thiopyran-4-yl or
tetrahydropyran-4-yl group.
[0102] With regard to the prodrug group, preferred embodiments are
compounds wherein NR.sup.34R.sup.35 is morpholino.
[0103] In one embodiment, R is:
##STR00027##
[0104] wherein
[0105] each R.sup.32 and R.sup.33 is independently H,
C.sub.1-C.sub.8 alkyl, or optionally, if both present on the same
substituent, may be joined together to form a C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.9 heterocyclyl or
C.sub.3-C.sub.9 heteroaryl ring system.
[0106] Within this embodiment, each R.sup.32 and R.sup.33 is
independently, H, CH.sub.3, or are joined together to form a
cyclopropyl, cyclopbutyl, cyclopentyl, cyclohexyl,
1,1-dioxo-hexahydro-1.lamda..sup.6-thiopyran-4-yl or
tetrahydropyran-4-yl group,
[0107] In a preferred embodiment, linkage of the prodrug moiety to
the rest of the active molecule is stable enough so that the serum
half life of the prodrug is from about 8 to about 24 hours.
[0108] In an embodiment of the invention, the prodrug moiety
comprises a tertiary amine having a pKa near the physiological pH
of 7.5. Any amines having a pKa within 1 unit of 7.5 are suitable
alternatives amines for this purpose. The amine may be provided by
the amine of a morpholino group. This pKa range of 6.5 to 8.5
allows for significant concentrations of the basic neutral amine to
be present in the mildly alkaline small intestine. The basic,
neutral form of the amine prodrug is lipophilic and is absorbed
through the wall of the small intestine into the blood. Following
absorption into the bloodstream, the prodrug moiety is cleaved by
esterases which are naturally present in the serum to release an
active compound.
[0109] Examples of R include, without limitation:
##STR00028## ##STR00029##
[0110] In another embodiment, R is as tabulated below;
TABLE-US-00002 R m R.sup.34 R.sup.35 NR.sup.34R.sup.35
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 1 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 2 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 3 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 4 Me Me
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 1 ##STR00030##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 2 ##STR00031##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 3 ##STR00032##
C(O)(CH.sub.2).sub.mNR.sup.34R.sup.35 4 ##STR00033##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 2 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 3 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 4 Me Me
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 2 ##STR00034##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 3 ##STR00035##
C(O)O(CH.sub.2).sub.mNR.sup.34R.sup.35 4 ##STR00036##
P(O)(OH).sub.2
[0111] an N oxide thereof, or a pharmaceutically acceptable salt of
each thereof.
[0112] In another aspect, R is,
##STR00037##
[0113] wherein
[0114] R.sup.16 is lower alkyl (e.g. C.sub.1-C.sub.6 alkyl).
[0115] In yet another aspect, R is:
##STR00038##
[0116] wherein X.sup.1, Y.sup.1 and X.sup.2 are as defined
herein.
[0117] In one embodiment, X.sup.1 is selected from the group
consisting O, S, and NR.sup.37 wherein R.sup.37 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0118] Y.sup.1 is --C(R.sup.38).sub.2 or a sugar moiety, wherein
each R.sup.38 is independently hydrogen or C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl;
[0119] X.sup.2 is selected from the group consisting of halogen,
C.sub.1-C.sub.6 alkoxy, diacylglycerol, amino, C.sub.1-C.sub.6
alkylamino, C.sub.1-C.sub.6 dialkylamino, C.sub.1-C.sub.6
alkylthio, a PEG moiety, a bile acid moiety, a sugar moiety, an
amino acid moiety, a di- or tri-peptide, a PEG carboxylic acid, and
--U--V wherein
[0120] U is O or S; and
[0121] V is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.9 heteroaryl,
C(W.sup.2)X.sup.3, PO(X.sup.3).sub.2, and SO.sub.2X.sup.3;
[0122] wherein W.sup.2 isO or NR.sup.39
[0123] wherein R.sup.39 is hydrogen or C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3C.sub.9 hetrocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl; and
[0124] each X.sup.3 is independently amino, hydroxyl, mercapto,
(C.sub.1-C.sub.6 alkyl, heteroalkyl, cycloalkyl, hetrocyclyl, aryl,
or heteroaryl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 dialkylamino. C.sub.1-C.sub.6 alkylthio, a bile
acid based alkoxy group, a sugar moiety, a PEG moiety, and
--O--CH.sub.2--CH(OR.sup.40)CH.sub.2X.sup.4R.sup.40.
[0125] wherein:
[0126] X.sup.4 is selected from the group consisting of O, S,
S.dbd.O, and SO.sub.2; and
[0127] each R.sup.40 is independently C.sub.10-C.sub.22 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl,
C.sub.1-C.sub.8 alkylene, or C.sub.1-C.sub.8 heteroalkylene.
[0128] Each heterocyclic and heteroaryl ring system is optionally
substituted with C.sub.1-C.sub.3 alkyl, --OH, amino and carboxyl
groups.
[0129] In one embodiment, the present invention utilizes the
following Y.sup.1 groups: CH.sub.2, CHMe, CH(isopropyl),
CH(tertiarybutyl), C(Me).sub.2, C(Et).sub.2 , C(isopropyl).sub.2,
and C(propyl).sub.2.
[0130] In another embodiment, the present invention utilizes the
following X.sup.2 groups:
##STR00039##
[0131] --OMe, --OEt, --O-isopropyl, O-isobutyl, O-tertiarybutyl,
--O--COMe, --O--C(.dbd.O)(isopropyl), --O--C(.dbd.O)(isobutyl),
--O--C(.dbd.O)(tertiarybutyl), --O--C(.dbd.O)--NMe.sub.2,
--O--C(.dbd.O)--NHMe, --O--C(.dbd.O)--NH.sub.2,
--O--C(.dbd.O)--N(H)--CH(R.sup.41)--CO.sub.22Et wherein R.sup.41 is
a side chain C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.9 heterocyclyl
group selected from the side chain groups present in essential
amino acids; --O--P(.dbd.O)(OMe).sub.2,
--O--P(.dbd.O)(O-isopropyl).sub.2, and
--O--P(.dbd.O)(O-isobutyl).sub.2. Each heterocyclic is optionally
substituted with one or more, preferably, 1-3. C.sub.1-C.sub.3
alkyl, --OH, amino and/or carboxyl groups.
[0132] In another embodiment. In one embodiment. R is:
##STR00040##
[0133] wherein
[0134] X.sup.3 is independently C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cyloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl; and
[0135] R.sup.42 is independently hydrogen or C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl.
[0136] Each heterocyclic is optionally substituted with one or
more, preferably, 1-3, C.sub.1-C.sub.3 alkyl, --OH, amino and/or
carboxyl groups.
[0137] In one embodiment, R is:
##STR00041##
[0138] wherein
[0139] each X.sup.3 is independently amino, hydroxyl, mercapto,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9
heterocyclyl, C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6
dialkylamino, C.sub.1-C.sub.6 alkylthio, a bile acid based alkoxy
group, a sugar moiety, a PEG moiety, and
--O--CH.sub.2--CH(OR.sup.40)CH.sub.2X.sup.4R.sup.40,
[0140] wherein:
[0141] X.sup.4 is selected from the group consisting of O, S,
S.dbd.O, and SO.sub.2 ; and
[0142] each R.sup.40 is independently C.sub.10-C.sub.22 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.9 heteroaryl, C.sub.1-C.sub.8
alkylene, or C.sub.1-C.sub.8 heteroalkylene; and
[0143] R.sup.42 is independently hydrogen or C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl.
[0144] In some embodiments, R.sup.42 is independently hydrogen or
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9
heterocyclyl, C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl;
and each X.sup.3 independently is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6
dialkylamino, or C.sub.1-C.sub.6 alkylthio.
[0145] In some embodiments, R is represented by the following
structures:
##STR00042## ##STR00043##
[0146] wherein, in the above examples, R.sup.43 is
C.sub.10-C.sub.22 alkyl or alkylene, R.sup.44 is H or
C.sub.1-C.sub.6 alkyl and R.sup.45 represents side chain alkyl
groups present in naturally occurring alpha amino acids;
##STR00044##
[0147] wherein R.sup.46 is (CH.sub.2).sub.n, f=2-4, and
CO--R.sup.47 --NH.sub.2 represents an aminoacyl group; or
##STR00045##
[0148] wherein R.sup.46 is (CH.sub.2).sub.n, n=2-4, R.sup.47 is
(CH.sub.2).sub.n, n=1-3 and R.sup.49 is O or NMe.
[0149] In one embodiment, R is:
##STR00046##
[0150] In one aspect, R is
--C(R.sup.200R.sup.201)O(R.sup.202R.sup.203)P(O)OR.sup.204NR.sup.205
R.sup.206 , wherein each R.sup.200, R.sup.201, R.sup.202,
R.sup.203, R.sup.204 R.sup.205 and R.sup.206 is independently H, a
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.9
heteroaryl, wherein each alkyl, heterocyclyl, cycloalkyl, aryl, and
heteroaryl is optionally substituted.
[0151] In some embodiments, R is
--CH(R.sup.201)OCH.sub.2P(O)OR.sup.204NHR.sup.206, wherein
R.sup.201 is C.sub.1-C.sub.8 alkyl, R.sup.204 is phenyl, optionally
substituted. In one embodiment.R.sup.206 is
--CHR.sup.207C(O)OR.sup.208 wherein R.sup.207 is selected from the
group consisting of the naturally occurring amino acid side chains
and --CO.sub.2H esters thereof and R.sup.208 is C.sub.1-C.sub.8
alkyl. In one embodiment, R.sup.206 is C.sub.1-c.sub.6 alkyl,
optionally substituted with 1-3. CO.sub.2H, SH, NH.sub.2 ,
C.sub.6-C.sub.10 aryl, and C.sub.2-C.sub.10 heteroaryl.
[0152] In one embodiment, R is:
##STR00047##
[0153] In one embodiment, R is:
##STR00048##
[0154] wherein Y.sup.1 is --C(R.sup.38).sub.2, wherein each
R.sup.38 is independently hydrogen or C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.9 heterocyclyl,
C.sub.6-C.sub.10 aryl, or C.sub.3-C.sub.9 heteroaryl.
[0155] Various polyethylene glycol (PEG) moieties and synthetic
methods related to them that can be used or adapted to make
compounds of the invention are described in U.S. Pat. Nos.
6,608,076; 6,395,266; 6,194,580; 6,153,655; 6,127,355; 6,111,107;
5,965,566; 5,880,131; 5,840,900; 6,011,042 and 5,681,567.
[0156] In one embodiment, R is
##STR00049##
[0157] wherein
[0158] R.sup.50 is --OH or hydrogen;
[0159] R.sup.51 is --OH, or hydrogen;
[0160] W is --CH(CH.sub.3)W.sup.1;
[0161] wherein W.sup.1 is a substituted C.sub.1-C.sub.8 alkyl group
containing a moiety which is optionally negatively charged at
physiological pH,
[0162] said moiety is selected from the group consisting of
CO.sub.2H, SO.sub.3H, SO.sub.2H, --P(O)(OR.sup.52)(OH),
--OP(O)(OR.sup.52)(OH), and OSO.sub.3H,
[0163] wherein R.sup.52 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl. C.sub.3C.sub.9 heterocyclyl, C.sub.6-C.sub.10 aryl, or
C.sub.3-C.sub.9 heteroaryl.
[0164] Each heterocyclic and heteroaryl ring system is optionally
substituted with one or more, preferably 1-3, C.sub.1-C.sub.3 ,
alkyl, --OH, amino and/or carboxyl groups.
[0165] In one embodiment, R is:
##STR00050##
wherein R.sup.53 is H or C.sub.1-C.sub.6 alkyl.
[0166] In another aspect, R is SO.sub.3H.
[0167] In another aspect, R comprises a cleavable linker, wherein
the term "cleavable linker" refers to a linker which has a short
half life in vivo. The breakdown of the linker Z in a compound
releases or generates the active compound. In one embodiment, the
cleavable linker has a half life of less than ten hours. In one
embodiment, the cleavable linker has a half life of less than an
hour. In one embodiment, the half life of the cleavable linker is
between one and fifteen minutes. In one embodiment, the cleavable
linker has at least one connection with the structure:
C*--C(.dbd.X*)X*--C* wherein C* is a substituted or unsubstituted
methylene group, and X* is S or O. In one embodiment, the cleavable
linker has at least one C*--C(--O)O--C* connection. In one
embodiment, the cleavable linker has at least one
(C*--C(.dbd.O)S--C* connection. In one embodiment, the cleavable
linker has at least one --C(.dbd.O)N*--C*--SO.sub.2--N*-connection,
wherein N* is --NH-- or C.sub.1-C.sub.6 alkylamino. In one
embodiment, the cleavable linker is hydrolyzed by an esterase
enzyme.
[0168] In one embodiment, the linker is a self-immolating linker,
such as that disclosed in U.S. patent publication 2002/0147138, to
Firestone: PCT Appl. No. US05/08161 and PCT Pub. No. 2004/087075.
In another embodiment, the linker is a substrate for enzymes. See
generally Rooseboom et al., 2004, Pharmacol. Rev. 56:53-102.
[0169] In certain aspects of the invention, prodrugs of a compound
of formula (III) are provided:
##STR00051##
or a pharmaceutical acceptable salt thereof.
[0170] In further aspects of the invention, a compound of formula
(IV) is provided:
##STR00052##
or a pharmaceutically acceptable salt thereof, wherein [0171]
R.sup.11 and R.sup.12 are independently selected from the group
consisting of hydrogen, [0172] C.sub.1-C.sub.6 alkyl optionally
substituted with 1-3 C.sub.6-C.sub.12 aryl groups, optionally
substituted; [0173] C.sub.6-C.sub.12 aryl, optionally substituted;
and [0174] a protecting group; and [0175] z is 1, 2 or 3.
[0176] In some embodiments, z is 1. In some embodiments, z is 2. In
some embodiments, z is 3.
[0177] In one embodiment, a compound of formula (V) is
provided:
##STR00053##
[0178] or a pharmaceutically acceptable salt thereof.
[0179] In some embodiments, R.sup.11 and R.sup.12 are independently
C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.11 and R.sup.12
are selected from methyl, ethyl, or propyl. In some embodiments,
R.sup.11 and R.sup.12 are methyl. In some embodiments, R.sup.11 and
R.sup.12 are ethyl. In some embodiments, R.sup.11 and R.sup.12 are
propyl. In some embodiments, R.sup.11 and R.sup.12 are
C.sub.1-C.sub.6 alkyl substituted with 1-3 C.sub.6-C.sub.12 aryl
groups, optionally substituted, in some embodiments. R.sup.11 and
R.sup.12 are methyl substituted with 1-3 phenyl groups, optionally
substituted. In some embodiments, R.sup.11 and R.sup.12 are methyl
substituted with a phenyl group, optionally substituted with 1-3
groups selected from the group consisting of C.sub.1C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halo and nitro.
[0180] In some embodiments, R.sup.11 and R.sup.12 are independently
C.sub.6-C.sub.12 aryl, optionally substituted with 1-3 groups
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halo and nitro. In some embodiments,
R.sup.11 and R.sup.12 are phenyl substituted with 1-3 groups
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halo and nitro. In some embodiments,
R.sup.11 and R.sup.12 are phenyl.
[0181] In some embodiments, R.sup.11 and R.sup.12 independently are
protecting groups. In some embodiments, the protecting groups are
selected independently from the group consisting of 2-cyanoethyl,
2-cyano-1,1-dimethylethyl, 2-Benzamidoethyl, allyl,
4-methylthio-1-butyl, 2-(trimethylsilyl)ethyl,
2-(triphenylsilyl)ethyl 2,2,2,-trichloroethyl, 4-methoxybenzyl,
4-nitrobenzyl, 2,4-dinitrobenzyl, 4-chlorobenzyl and
fluorenyl-9-methyl.
[0182] In one aspect, provided herein is a compound of formula
(V-A):
##STR00054##
or a pharmaceutically acceptable salt thereof.
[0183] In one additional aspect, provided herein is a compound of
formula (V-B)
##STR00055##
or a pharmaceutically acceptable salt thereof.
Pharmaceutical Compositions
[0184] In another aspect, this invention provides a composition
comprising any of the compounds described herein, and a
pharmaceutically acceptable excipient.
[0185] Such compositions can be formulated for different routes of
administration. Although compositions suitable for oral delivery
will probably be used most frequently, other routes that may be
used include transdermal, intravenous, intraarterial, pulmonary,
rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal,
intracutaneous, intracranial, and subcutaneous routes. Suitable
dosage forms for administering any of the compounds described
herein include tablets, capsules, pills, powders, aerosols,
suppositories, parenterals, and oral liquids, including
suspensions, solutions and emulsions. Sustained release dosage
forms may also be used, for example, in a transdermal patch form.
All dosage forms may be prepared using methods that are standard in
the art (see e.g., Remington's Pharmaceutical Sciences. 16.sup.th
ed., A. Oslo editor. Easton Pa. 1980).
[0186] Pharmaceutically acceptable excipients are non-toxic, aid
administration, and do not adversely affect the therapeutic benefit
of the compound of this invention. Such excipients may be any
solid, liquid, semi-solid or, in the case of an aerosol
composition, gaseous excipient that is generally available to one
of skill in the art. Pharmaceutical compositions in accordance with
the invention are prepared by conventional means using methods
known in the art.
[0187] The compositions disclosed herein may be used in conjunction
with any of the vehicles and excipients commonly employed in
pharmaceutical preparations, e.g., talc, gum arabic, lactose,
starch, magnesium stearate, cocoa butter, aqueous or non-aqueous
solvents, oils, paraffin derivatives, glycols, etc. Coloring and
flavoring agents may also be added to preparations, particularly to
those for oral administration. Solutions can be prepared using
water or physiologically compatible organic solvents such as
ethanol, 1,2,-propylene glycol, polyglycols, dimethylsuifoxide,
fatty alcohols, triglycerides, partial esters of glycerin and the
like.
[0188] Solid pharmaceutical excipients include starch, cellulose,
hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin,
malt, rice, flour, chalk, silica gel, magnesium stearate. sodium
stearate, glycerol monostearate, sodium chloride, dried skim milk
and the like. Liquid and semisolid excipients may be selected from
glycerol, propylene glycol, water, ethanol and various oils,
including those of petroleum, animal, vegetable or synthetic
origin. e.g., peanut oil, soybean oil, mineral oil, sesame oil,
etc. In certain embodiments, the compositions provided herein
comprises one or more of .alpha.-tocopherol, gum arable, and/or
hydroxypropyl cellulose.
[0189] In one embodiment, this invention provides sustained release
formulations such as drug depots or patches comprising an effective
amount of a compound provided herein. In another embodiment, the
patch further comprises gum Arabic or hydroxy propyl cellulose
separately or in combination, in the presence of alpha-tocopherol.
Preferably, the hydroxypropyl cellulose has an average MW of from
10,000 to 100,000. In a more preferred embodiment, the
hydroxypropyl cellulose has an average MW of from 5,000 to
50,000.
[0190] Compounds and pharmaceutical compositions of this invention
maybe used alone or in combination with other compounds. When
administered with another agent, the co-administration can be in
any manner in which the pharmacological effects of both are
manifest in the patient at the same time. Thus, co-administration
does not require that a single pharmaceutical composition, the same
dosage form, or even the same route of administration be used for
administration of both the compound of this invention and the other
agent or that the two agents be administered at precisely the same
time. However, co-administration will be accomplished most
conveniently by the same dosage form and the same route of
administration, at substantially the same time. Obviously, such
administration most advantageously proceeds by delivering both
active ingredients simultaneously in a novel pharmaceutical
composition in accordance with the present invention.
Methods of Treatment
[0191] In aspects of the invention, a method is provided for
increasing tissue and/or cellular oxygenation, the method
comprising administering to a subject in need thereof a
therapeutically effective amount of any of the compounds or
compositions described herein.
[0192] In aspects of the invention, a method is provided for
increasing oxygen affinity of hemoglobin S in a subject, the method
comprising administering to a subject in need thereof a
therapeutically effective amount of any of the compounds or
compositions described herein.
[0193] In aspects of the invention, a method is provided for
treating a condition associated with oxygen deficiency, the method
comprising administering to a subject in need thereof a
therapeutically effective amount of any of the compounds or
compositions described herein.
[0194] In further aspects of the invention, a method is provided
for treating oxygen deficiency associated with sickle cell anemia,
the method comprising administering to a subject in need thereof a
therapeutically effective amount of any of the compounds or
compositions described herein.
[0195] In further aspects of the invention, a method is provided
for treating sickle cell disease, the method comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound of any of the compounds or
compositions described herein, in still further aspects of the
invention, a method is provided for treating cancer, a pulmonary
disorder, stroke, high altitude sickness, an ulcer, a pressure
sore, Alzheimer's disease, acute respiratory disease syndrome, and
a wound, the method comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of any of
the compounds or compositions described herein.
Synthetic Methods
[0196] Certain methods for making the compounds described herein
are also provided. The reactions are preferably carried out in a
suitable inert solvent that will be apparent to the skilled artisan
upon reading this disclosure, for a sufficient period of time to
ensure substantial completion of the reaction as observed by thin
layer chromatography, .sup.1H-NMR, etc. If needed to speed up the
reaction, the reaction mixture can be heated, as is well known to
the skilled artisan. The final and the intermediate compounds are
purified, if necessary, by various art known methods such as
crystallization, precipitation, column chromatography, and the
likes, as will be apparent to the skilled artisan upon reading this
disclosure.
[0197] An illustrative and non-limiting method for synthesizing a
compound of formula (I), is schematically shown below.
[0198] Throughout the application, the following abbreviations have
the following meanings. If not defined, the terms have their
generally accepted meanings. [0199] .degree. C.=degrees Celsius
[0200] RT=Room temperature [0201] min=minute(s) [0202] h=hour(s)
[0203] .mu.L=Microliter [0204] ml=Milliliter [0205] mmol=Millimole
[0206] eq=Equivalent [0207] mg=Milligram [0208] ppm=Parts per
million [0209] LC-MS=Liquid chromatography-mass spectrometry [0210]
HPLC=High performance liquid chromatography [0211] NMR=Nuclear
magnetic resonance [0212] Ph.sub.3PBr.sub.2=Triphenlylphosphine
dibromide [0213] DMF=N,N-Dimethylformamide [0214]
DCM=Dichloromethane [0215] THF=Tetrahydrofuran [0216]
DIAD=Diisopropyl azodicarboxylate [0217] DEAD=Diethyl
azodicarboxylate [0218] PEG=Polyethylene glycol [0219]
H.beta.CD=Hydroxy-propyl-.beta.-cyclodextrin
[0220] In the following Schemes, "A" refers to substituent "A" as
described herein. refers aryl or heteroaryl members of substituent
"A" as described herein. and refer to rings B and C as described
herein.
##STR00056##
[0221] General method A (Scheme 1) for preparing
aryloxy/heteroarylether analogs (4a/4b) from substituted methylene
alcohol (1) and hydroxyl (hetero)aryl aldehyde derivatives (3a/3b).
A hydroxyl (hetero)arylaldehyde derivatives (3a/3b) (0.1-2 mmol)
mixture with substituted methylene alcohol (1) (0.8 to 1.2 eq) and
PPh.sub.3 (1-1.5 eq) in anhydrous THF (1-1 OmL) was stirred under
nitrogen until complete dissolution. The solution was cooled to
0.degree. C. on ice bath and DIAD or DEAD (1.1 eq) in THF or
toluene was added dropwise over a 1-20 min period. The ice cooling
bath was allowed to expire over 90 min and the mixture was stirred
at RT for 2-48 hours. The mixture was stirred for 10 min, then
filtered through a pad of silica. The silica was washed with ethyl
acetate 2-20 mL. The combined filtrates were evaporated and the
residue was dried on highvac. The residue was purified by
preparative HPLC or flash silica gel chromatography.
[0222] General method A (Scheme 1) for preparing
aryloxy/heteroarylether analogs (4a/4b) from substituted methylene
halide (2) and hydroxyl (hetero)aryl aldehyde derivatives (3a/3b).
A mixture of hydroxyl (hetero)arylaldehyde derivatives (3a/3b)
(0.1-2 mmol, 1-4 eq.), substituted methylene chloride or bromide
(2) (1 eq), and K.sub.2CO.sub.3 (2-5 eq) (catalytic amount of NaI
or Bu.sub.4NI may also be added) in DMF or acetonitrile (1 to 10
mL) was stirred at RT or heating up to 120.degree. C. for 0.5-8 h
under nitrogen atmosphere. In workup A, water was added to the
reaction mixture, the precipitated product was collected, washed
with water, and then subjected to preparative HPLC or flash silica
gel chromatography purification. In workup B (for products that did
not precipitate), diluted HCl or aqueous NH.sub.4Cl was added at
0.degree. C. to adjusted the pH to .about.7, the reaction mixture
was partitioned between ethyl acetate or dichloromethane and
aqueous sodium chloride and the organic layer separated, dried, and
solvent removed under vacuum to afford crude product which was
purified by automated silica gel column chromatography using
appropriate solvents mixture (e.g., ethyl acetate/hexanes).
[0223] General method C for preparing substituted methylene
chloride (2a). To a solution of substituted methylene alcohol (1)
(0.1 to 2 mmol) in DCM (1-10 mL) was added SOCl .sub.2 dropwise (2
eq to 5 eq ) at 0.degree. C. or RT, The reaction mixture was
stirred at RT for 10 min to 6 h, or until reaction is judged
complete (LC/MS). The reaction mixture is concentrated to dryness
over a rotavap. The crude chloride residue was suspended in
toluene, sonicated and concentrated to dryness. The process was
repeated three times and dried under vacuum to give the substituted
methylene chloride (2), usually as an off-white solid, which was
used for next step without further purification. Alternatively, a
solution of aqueous 1N Na.sub.2CO.sub.3 is then added to produce a
solution of pH .about.8, the mixture was extracted with DCM
(3.times.10-50 mL), dried over sodium sulfate, and concentrated to
the crude substituted methylene chloride (2a), which is then
purified by column chromatography on silica gel (0-100% ethyl
acetate-hexanes).
[0224] General method D for preparing substituted methylene bromide
(2b). To a solution of substituted methylene alcohol (1) (0.1 to 2
mmol) in DCM (1-10 mL) was added Ph.sub.3PBr.sub.2 dropwise (2 eq
to 5 eq ) at 0.degree. C. or RT. The reaction mixture was stirred
at RT for 10 min to 2 h, or until reaction is judged complete
(LC/MS). The reaction mixture is concentrated to dryness over a
rotavap. The residue purified by column chromatography on silica
gel (0-100% ethyl acetate-hexanes) to afford the pure bromide
2b.
[0225] Syntheses of the ester prodrugs start with the free
carboxylic acid bearing the tertiary amine. The free acid is
activated for ester formation in an aprotic solvent and then
reacted with a free alcohol group in the presence of an inert base,
such as triethyl amine, to provide the ester prodrug. Activating
conditions for the carboxylic acid include forming the acid
chloride using oxalyl chloride or thionyl chloride in an aprotic
solvent, optionally with a catalytic amount of dimethyl formamide,
followed by evaporation. Examples of aprotic solvents, include, but
are not limited to methylene chloride, tetrahydrofuran, and the
like. Alternatively, activations can be performed in situ by using
reagents such as BOP (benzotriazol-1-yloxylris(dimethylamino)
phosphonium hexafluorolphosphate, and the like (see Nagy et al,
1993. Proc. Natl. Acad. Sci. USA 90:6373-6376) followed by reaction
with the free alcohol. Isolation of the ester products can be
affected by extraction with an organic solvent, such as ethyl
acetate or methylene chloride, against, a mildly acidic aqueous
solution; followed by base treatment of the acidic aqueous phase so
as to render it basic; followed by extraction with an organic
solvent, for example ethyl acetate or methylene chroride;
evaporation of the organic solvent layer; and recrystallization
from a solvent, such as ethanol. Optionally, the solvent can be
acidified with an acid, such as HCl or acetic acid to provide a
pharmaceutically acceptable salt thereof. Alternatively the crude
reaction can be passed over an ion exchange column bearing sulfonic
acid groups in the protonated form, washed with deionized water,
and eluted with aqueous ammonia; followed by evaporation.
[0226] Suitable free acids bearing the tertiary amine are
commercially available, such as 2-(N-morpholino)-propionic acid,
N,N-dimethyl-beta-alanine. and the like. Non-commercial acids can
be synthesized in straightforward manner via standard literature
procedures.
[0227] Carbonate and carbamate prodrugs can be prepared in an
analogous way, for example, amino alcohols and diamines can be
activated using activating agents such as phosgene or carbonyl
diimidazole, to provide an activated carbonates, which in turn can
react with the alcohol and/or the phenolic hydroxy group on the
compounds utilized herein to provide carbonate and carbamate
prodrugs.
[0228] Various protecting groups and synthetic methods related to
them that can be used or adapted to make compounds of the invention
can be adapted from the references Testa et al., Hydrolysis in Drug
and Prodrug Metabolism, June 2003, Wiley-VCH. Zurich, 419-534 and
Beaumont et al., Curr. Drug Metab. 2003. 4:461-85.
[0229] Scheme 2 below provides a method of synthesizing an
acyloxymethyl version of a prodrug by adapting a method from the
reference Sobolev et al., 2002, J. Org. Chem. 67:401-410.
##STR00057##
[0230] wherein R.sup.51 is C.sub.1-C.sub.6 alkyl.
[0231] Scheme 3 below provides a method for synthesizing a
phosphonooxymethyl version of a prodrug by adapting a method from
Mantyla et al., 2004, J. Med. Chem. 47:188-195.
##STR00058##
[0232] Scheme 4 below provides a method of synthesizing an
alkyloxymethyl version of a prodrug
##STR00059##
[0233] wherein R.sup.52 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.9 heterocyclyl, C.sub.6-C.sub.10 aryl, or
C.sub.3-C.sub.9 heteroaryl.
[0234] The compound of formula (III) was synthesized as
schematically described below and elaborated thereafter.
##STR00060##
EXAMPLE 1
Synthesis of Compound 15
##STR00061##
[0236] To a solution of 2-bromobenzene-1,3-diol (5 g, 26.45 mmol)
in DCM (50 ml) at 0.degree. C. was added DIPFEA ( 11.54 mL, 66.13
mmol) and MOMCl (4.42 ml, 58.19 mmol). The mixture was stirred at
0.degree. C. for 1.5 h, and then warmed to room temperature. The
solution was diluted with DCM, washed with sat. NaHCO.sub.3, brine,
dried and concentrated to give crude product, which was purified by
column (hexanes/EtOAc=4:1) to give desired product 15.58
g(90%).
EXAMPLE 2
Synthesis of Compound 13 from 15
##STR00062##
[0238] To a solution of 2-bromo-1.3-bis(methoxymethoxy)benzene (15)
(19.9 g, 71.8 mmol) in THF (150 mL) at -78.degree. C. was added
BuLi (2.5 M, 31.6 mL, 79.0 mmol) dropwise. The solution was stirred
at -78.degree. C. for 25 min (resulting white cloudy mixture), then
it was warmed to 0.degree. C. and stirred for 25 min. The reaction
mixture slowly turns homogenous. To the solution was added DMF at
0.degree. C. After 25 min. HPLC showed reaction completed. The
mixture was quenched with sat. NH4Cl (150 mL), diluted with ether
(300 mL). The organic layer was separated, aq. layer was further
extracted with ether (2.times.200 mL), and organic layer was
combined, washed with brine, dried and concentrated to give crude
product, which was triturated to give 14.6 g desired product. The
filtrate was then concentrated and purified by column to give
additional 0.7 g, total mass is 15.3 g.
EXAMPLE 3
Synthesis of Compound 13 from Resorcinol 11
##STR00063##
[0240] A three-necked round-bottom flask equipped with mechanical
stirrer was charged with 0.22 mol of NaH (50 % suspension in
mineral oil) under nitrogen atmosphere. NaH was washed with 2
portions (100 mL) of n-hexane and then with 300 mL of dry diethyl
ether; then 80 mL of anhydrous DMF was added. Then 0.09 mol of
resorcinol 11, dissolved in 100mL of diethyl ether was added
dropwise and the mixture was left under stirring at it for 30min.
Then 0.18 mol of MOMCl was slowly added. After 1 h under stirring
at it, 250 mL of water was added and the organic layer was
extracted with diethyl ether, The extracts were washed with brine,
dried (Na.sub.2SO.sub.4)then concentrated to give the crude product
that was purified by silica gel chromatography to give compound 12
(93 % yield).
[0241] A three-necked round-bottom flask was charged with 110 mL of
n-hexane, 0.79 mol of BuLi and 9.4 mL of tetramethylethylendiamine
(TMEDA) under nitrogen atmosphere, the mixture was cooled at
-10.degree. C. and 0.079 mol of bis-phenyl ether 12 was slowly
added. The resulting mixture was left under magnetic stirring at
-10.degree. C. for 2 h. Then the temperature was raised to
0.degree. C. and 0.067 mol of DMF was added dropwise. After 1 h,
aqueous HCl was added until the pH was acidic; the mixture was then
extracted with ethyl ether. The combined extracts were washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated to give aldehyde
13 (84%).
[0242] 2.6-bis(methoxymethoxy )benzaldehyde (13); mp 58-59.degree.
C. (n-hexane); IR (KBr) n; 1685 (C.dbd.O) cm.sup.-1; .sup.1H-NMR
(400 MHz, CDCl) .delta. 3.51 (s, 6H, 2 OCH.sub.3), 5.28 (s, 4H, 2
OCH.sub.2O), 6.84 (d, 2H, J=8.40 Hz, H-3, H-5), 7.41 (t, 1H, J=8.40
Hz, H-4), 10.55 (s, 1H, CHO); MS, m/e (relative intensity) 226
(M+,3), 180 (4), 164 (14), 122 (2), 92 (2), 45 (100); Anal. Calc'd,
for C.sub.11H.sub.14O.sub.5; C58.40; H. 6.24. Found: C, 57.98; H,
6.20.
EXAMPLE 4
The Synthesis of Compound 16
##STR00064##
[0244] To a solution of 2,6-bis(methoxymethoxy)benzaldehyde (13) (1
5.3 g, 67.6 mmol) in THF (105 mL) (solvent was purged with N.sub.2)
was added cone. HCl (12N, 7 mL) under N.sub.2, then it was further
stirred under N.sub.2 for 1.5 h. To the solution was added brine
(109 mL) and ether (150 ml). The organic layer was separated and
the aqueous layer was further extracted with ether (2.times.200
mL). The organic layer was combined, washed with brine, dried and
concentrated to give crude product, which was purified by column
(300 g, hexanes/EtOAc=85:15) to give desired product 16 (9.9 g) as
yellow liquid.
EXAMPLE 5
Synthesis of Compound 17
##STR00065##
[0246] To a solution of 2-hydroxy-6-(methoxymethoxy)benzaldehyde
(16) (10.88 g, 59.72 mmol) in DMF (120 mL) (DMF solution was purged
with N.sub.2 for 10 min) was added K.sub.2CO.sub.3 (32.05 g. 231.92
mmol) and 3-(chloromethyl)-2-( 1-isopropyl-1H-pyrazol-5-yl)pyridine
hydrochloride (10) (15.78 g, 57.98 mmol). The mixture was heated at
65.degree. C. for 1.5 h, cooled to rt, poured into ice water (800
mL). The precipitated solids were isolated by filtration, dried and
concentrated to give desired product (17, 18 g).
EXAMPLE 6
Synthesis of Compound (III)
##STR00066##
[0248] To a solution of 2-((2-( 1-isopropyl
-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde
(17) (18 g, 47.19 mmol) in THF (135 mL, solution was purged with
N.sub.2) was added cone. HCl (12N, 20 mL). The solution was stirred
at rt for 3 h when HPLC showed the reaction complete. The mixture
was added to a solution of NaHCO.sub.3 (15 g) in water (1.2 L), and
the resulting precipitate was collected by filtration, dried to
give crude solid, which was further purified by column
(DCM/EtOAc=60:40) to give pure product (15.3 g).
EXAMPLE 7
Synthesis of Compound III (Free Base) and its HCl Salt Form
[0249] Compound (III) free base (40 g) was obtained from the
coupling of the alcohol intermediate 7 and
2,6-dihydroxybenzaldedhye 9 under Mitsunobu conditions. A procedure
is also provided below:
##STR00067##
EXAMPLE8
Synthesis of Compound (III) by Mitsunobu Coupling
[0250] Into a 2000-mL three neck round-bottom flask, which was
purged and maintained with an inert atmosphere of nitrogen, was
placed a solution of
[2[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g,
322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL).
2,6-Dihydroxybenzaidehyde (9) (49.2 g, 356.21 mmol. 1.10 equiv) and
PPh.sub.3 (101 g, 385.07 mmol, 1.20 equiv) were added to the
reaction mixture. This was followed by the addition of a solution
of DIAD (78.1 g, 386.23 mmol. 1.20 equiv) in tetrahydrofuran (200
ml) dropwise with stirring. The resulting solution was stirred
overnight at room temperature. The resulting solution was diluted
with 500 ml of H.sub.2O. The resulting solution was extracted with
3.times.500 ml of dichloromethane and the combined organic layers
were dried over sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with EA:PE (1:50-1:3)
as eluent to yield the crude product. The crude product was
re-crystallized from i-propanol/H.sub.2O in the ratio of 1/1.5.
This resulted in 40 g (37%) of
2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)ben-
zaldehyde as a light yellow solid. The compound exhibited a melting
point of 80-82.degree. C. MS (ES, m/z); 338.1 [M+1], .sup.1H NMR
(300 MHz, DMSO-d6) .delta. 11.72(s, 1H), 10.21(s, 1H), 8.76(d,
J=3.6 Hz, 1H), 8.24(d, J=2.7 Hz, 1H),7.55(m, 3H), 6.55(m,3H), 5.21
(s. 2H), 4.65 (m, 1H), 1.37(d, J=5.1 Hz, 6H), .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8,
1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H),
7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H),
6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz, 1H),
1.50 (d, J=6.6 Hz, 6H).
[0251] In another approach, multiple batches of Compound (III) free
base are prepared in multi gram quantities (20 g), The advantage of
this route is the use of mono-protected 2,6-dihydroxybenzaldehyde
(16), which effectively eliminates the possibility of
bis-alkylation side product. The mono-MOM ether of
2,6-dihydroxybenzaldehyde (16) can be obtained from two starting
points, bromoresorcinol (14) or resorcinol (11) [procedures
described in the Journal of Organic Chemistry, 74(11), 4311-4317;
2009]. All steps and procedures are provided below. Due to the
presence of phenolic aldehyde group, precautions (i.e., carry out
all reactions under inert gas such as nitrogen) should be taken to
avoid oxidation of the phenol and/or aldehyde group.
EXAMPLE 9
Monophosphate Prodrug Formation
##STR00068##
[0253] To a solution of 2-hydroxy-6-((2-(
1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (1.06
g, 3.13 mmol)in dry acetonitrile was added
N-ethyl-N-isopropylpropan-2-amine (1.10 ml., 6.27 mmol),
N,N-dimethylpyridin-4-amine (0.038 g, 0.31 mmol) and carbon
tetrachloride (1.52 mL, 15.7 mmol). The resulting mixture was
purged with argon gas (15 minutes), cooled (-10.degree. C.) and
dibenzyl phosphonate (0.73 mL, 3.3 mmol) was added dropwise over 10
minutes. After 1 h the reaction mixture was diluted with sat'd
KH.sub.2PO.sub.4 and extracted with EtOAc. The combined organic
layers were washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo. Purification by silica gel chromatography
(10-100%-EtOAc/hexanes) provided dibenzyl (2-formyl-3-((2-(
1-isopropyl-1H-pyraol-5-yl)pyridin-3-yl)methoxy)phenyl) phosphate
(1.2 g, 65% yield), .sup.1H NMR (400 MHz, Chloroform-d) .delta.
10.39 (s, 1H), 8.72 (dd, J=4.8. 1.7 Hz, 1H), 8.17 (ddt, J=7.9, 1.5,
0.7 Hz, 1H), 7.61 (dd, J=1.9, 0.5 Hz, 1H), 7.44 (dd, J=7.9. 4.8
Hiz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.36-7.29 (m, 10H), 7.02 (dt,
J=8.4, 1.0 Hz, 1H), 6.66 (dt., J=8.6, 0.8 Hz, 1H), 6.35 (d, J=1.9
Hz, 1H), 5.19 (d, J=1.5 Hz, 2H), 5.17 (d, J=1.3 Hz, 2H), 5.06 (s,
2H), 4.66-4.58 (m, 1H), 1.47 (d, J=6.6 Hz, 6H), .sup.31P NMR (162
MHz, Chloroform-d) .delta. -7.09. MS (ES) for
C.sub.33H.sub.32N.sub.3O.sub.6P: 598 (MH.sup.+).
##STR00069##
[0254] To a solution of (2-formyl-3-((2-(
1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)phenyl) phosphate
(0.600 g. 1.00 mmol) in MeOH (15 mL) was added Pd (10% on carbon,
50 mg). The reaction vessel was evacuated and then purged with an
atmosphere of hydrogen three times. After 1 hour, the vessel was
evacuated and purged with N.sub.2 three times and filtered over
Celite. The filter cake was washed with MeOH and the combined
filtrates were concentrated. The resulting residue was purified by
preparatory HPLC to yield
2-formyl-3-((2-(1-isopropyl-1H-pyraol-5-yl)pyridin-3-yl)methoxy)phenyl
dihydrogen phosphate (32 mg, 8% yield), .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.29 (s, 1H), 8,71 (dd, J=4.7, 1.7 Hz, 1H),
8.27(dd, J=7.9. 1.7 Hz, 1H), 7.59-7.49 (m, 3H), 6.99 (d, J=8.3 Hz,
1H), 6.86 (d, J=8.5 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H), 5,11 (s, 2H),
4.63 (p, J=6.6 Hz, 1H) 1.33 (d, J.times.6.6 Hz, 7H), .sup.31P NMR
(162 MHz, DMSO-d.sub.6) .delta.-6.46, MS (ES) for
C.sub.19H.sub.20N.sub.3O.sub.6P; 418 (MH.sup.+).
EXAMPLE 10
Advantageous Pharinacokinetic Properties of the Monophosphate
Prodrug
[0255] A sodium salt of the monophosphate prodrug compound (Formula
(V-B)) was administered orally to rats in a dose of 10 mg/kg (5
mL/kg). The vehicle administered was dimethylacetamide:PEG400:30%
H.beta.CD (5:25:70). The pharmacokinetic results are tabulated
below and graphically illustrated in FIG. 1.
TABLE-US-00003 Blood AUCall AUC(0-.infin.) T1/2 Tmax Cmax Cmax (hr
* ng/ (hr * ng/ B/P Animal_# (hr) (hr) (ng/mL) (uM) mL) mL) Ratio 7
12.5 3 27500 81.5 464873 668159 50.9 8 24.0 4 29700 88.0 577713
1190229 67.1 9 19.2 8 21200 62.8 411205 740923 28.3 Mean 18.6 6.67
26133 77.5 484597 866437 48.7 SD 5.78 2.31 4412 13.1 84988 282762
19.5 % CV 31.1 34.6 16.6 16.9 17.5 32.6 39.9
TABLE-US-00004 Plasma T1/2 Tmax Cmax Cmax AUCall AUC(0-.infin.)
Animal_# (hr) (hr) (ng/mL) (uM) (hr * ng/mL) (hr * ng/mL) 7 19.3
0.5 1170 3.47 11315 17405 8 26.4 1 1380 4.09 11355 22007 9 28.1 1
1920 5.69 17414 36253 Mean 24.6 0.833 1490 4.42 13361 25222 SD 4.67
0.289 387 1.15 3510 9827 % CV 19.0 34.6 26.0 26.0 26.3 39.0
[0256] The monophospate prodrug was efficiently con veiled to
compound of formula (III). At the monophosphate dose administered,
the whole blood Cmax of the compound of formula (III) was about 78
uM which is equivalent to the Cmax achieved following
administration of the compound of formula (III) at the same
dose.
[0257] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
[0258] Throughout the description of this invention, reference is
made to various patent applications and publications, each of which
are herein incorporated by reference in their entirety.
* * * * *