U.S. patent application number 14/702967 was filed with the patent office on 2016-01-28 for multi-api loading prodrugs.
The applicant listed for this patent is Alkermes Pharma Ireland Limited. Invention is credited to Laura Cook Blumberg, Tarek A. Zeidan.
Application Number | 20160024011 14/702967 |
Document ID | / |
Family ID | 46314485 |
Filed Date | 2016-01-28 |
United States Patent
Application |
20160024011 |
Kind Code |
A1 |
Zeidan; Tarek A. ; et
al. |
January 28, 2016 |
Multi-API Loading Prodrugs
Abstract
The present invention accomplishes this by having multiple
molecules of parent drugs attached to carrier moieties and by
extending the period during which the parent drug is released and
absorbed after administration to the patient and providing a longer
duration of action per dose than the parent drug itself. Prodrug
conjugates are suitable for sustained delivery of heteroaryl,
lactam-amide-, imide-, sulfonamide-, carbamate-, urea-, benzamide-,
acylaniline-, cyclic amide- and tertiary amine-containing parent
drugs that are substituted at the amide nitrogen or oxygen atom
with labile aldehyde-linked prodrug moieties. The carrier groups of
the prodrugs can be hydrophobic to reduce the polarity and
solubility of the parent drug under physiological conditions.
Inventors: |
Zeidan; Tarek A.;
(Watertown, MA) ; Blumberg; Laura Cook; (Lincoln,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alkermes Pharma Ireland Limited |
Dublin 4 |
|
IE |
|
|
Family ID: |
46314485 |
Appl. No.: |
14/702967 |
Filed: |
May 4, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13335405 |
Dec 22, 2011 |
|
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14702967 |
|
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61427026 |
Dec 23, 2010 |
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Current U.S.
Class: |
514/220 ;
514/252.11; 540/557; 544/357 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 31/04 20180101; A61P 25/18 20180101; A61P 37/08 20180101; A61P
9/00 20180101; C07D 401/14 20130101; C07D 417/14 20130101; C07D
471/04 20130101; A61P 1/04 20180101; C07D 263/58 20130101; C07D
277/34 20130101; C07D 215/227 20130101; A61P 9/12 20180101; C07D
519/00 20130101; A61P 25/16 20180101; A61P 25/24 20180101; A61P
3/10 20180101; A61P 25/00 20180101; A61P 11/06 20180101 |
International
Class: |
C07D 215/227 20060101
C07D215/227; C07D 519/00 20060101 C07D519/00 |
Claims
1-15. (canceled)
16. A prodrug conjugate, having the formula: ##STR00531##
##STR00532## ##STR00533## wherein each R.sub.50, R.sub.51,
R.sub.52, R.sub.53, R.sub.54 and R.sub.55 is independently selected
from hydrogen, halogen, --OR.sub.10, --SR.sub.10,
--NR.sub.10R.sub.11--, optionally substituted aliphatic, optionally
substituted aryl or aryl or optionally substituted heterocyclyl;
alternatively, two or more R.sub.50, R.sub.51, R.sub.52, R.sub.53,
R.sub.54 and R.sub.55 together form an optionally substituted ring;
each R.sub.100, R.sub.101, R.sub.102, and R.sub.103 are
independently selected from absent, hydrogen, halogen, --OR.sub.10,
--SR.sub.10, --NR.sub.10R.sub.11--, optionally substituted
aliphatic, optionally substituted aryl or optionally substituted
heterocyclyl; alternatively, two R.sub.100, and R.sub.101 together
form an optionally substituted ring; h is 3or 4; X.sub.100 is
--CH-- or --N--; C1 is a carrier moiety; and, X.sub.2 is selected
from direct bond, O, S or NR.sub.20.
17. A prodrug conjugate of claim 16, having the formula:
##STR00534## wherein n is selected from 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29 and 30.
18. A prodrug conjugate, having the formula: ##STR00535## wherein
Cy.sub.2 is an optionally substituted heterocyclic ring; and
X.sub.5 is selected from absent, --S--, --O--, --S(O)--,
--S(O).sub.2--, --N(R.sub.10)--, --C(O)--,
--C(OR.sub.10)(R.sub.11)--, --[C(R.sub.10)(R.sub.11)].sub.v--,
--O[C(R.sub.10)(R.sub.11)].sub.v--,
--O[C(R.sub.10)(R.sub.11)].sub.vO--,
--S[C(R.sub.10)(R.sub.11)].sub.vO--,
--NR.sub.12[C(R.sub.10)(R.sub.11)].sub.vO--,
--NR.sub.12[C(R.sub.10)(R.sub.11)].sub.vS--,
--S[C(R.sub.10)(R.sub.11)].sub.v--,
--C(O)[C(R.sub.10)(R.sub.11)].sub.v--, and
--C(R.sub.10)(R.sub.11).dbd.C(R.sub.10)(R.sub.11)--; wherein v is
0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; C1 is a carrier moiety; and,
X.sub.2 is selected from direct bond, O, S or NR.sub.20.
19. The prodrug conjugate, having the formula: ##STR00536## wherein
A.sub.1, B.sub.1 and E.sub.1 together with the nitrogen they are
attached to form a tertiary amine containing first biologically
active molecule; A.sub.2, B.sub.2 and E.sub.2 together with the
nitrogen they are attached to form a tertiary amine containing
second biologically active molecule; X is a pharmaceutically
acceptable counterion; X.sub.1 is selected from O or S; X.sub.2 is
selected from direct bond, O, S or NR.sub.20 wherein R.sub.20 is
selected from hydrogen, halogen, aliphatic, substituted aliphatic,
aryl or substituted aryl; and C1 represents a carrier group.
20-27. (canceled)
28. The prodrug conjugate, having the formula: ##STR00537## wherein
API-1 is a biologically active moiety; and API-2 is a biologically
active moiety and is the same or different from API-1; and API-3 is
a biologically active moiety and is the same or different from
API-1 and API-2.
29. (canceled)
30. A method for sustained delivery of a parent drug to a patient
comprising administering a prodrug compound of claim 1, wherein
upon administration to the patient, release of the parent drug from
the prodrug is sustained.
31-33. (canceled)
34. A method of synthesizing a compound of formula I, IA or IB
comprising the steps of reacting a dicarboxylic acid containing
compound with thionyl chloride followed by reacting with
formaldehyde or trioxane to yield chloromethyl ester which is
reacted with a biologically active compound to give said compound
of formula I, IA, IB.
35-80. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/335,405, filed Dec. 22, 2011, which claims the benefit of
U.S. Provisional Application No. 61/427,026, filed on Dec. 23,
2010. The entire teachings of the above applications are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to prodrugs that can be linked
to multiple drug molecules.
BACKGROUND OF THE INVENTION
[0003] Drug delivery systems are often critical for the safe and
effective administration of a biologically active agent. Perhaps
the importance of these systems is best realized when patient
compliance and consistent dosing are taken under consideration. For
instance, reducing the dosing requirement for a drug from
four-times-a-day to a single dose per day would have significant
value in terms of ensuring patient compliance and optimizing
therapy. Many of the currently administered prodrugs and
formulations require large amounts of drug/excipient/prodrug
mixtures for administration.
[0004] Optimization of a drug's bioavailability has many potential
benefits. For patient convenience and enhanced compliance it is
generally recognized that less frequent dosing is desirable. By
extending the period through which the drug is released, a longer
duration of action per dose is expected. This will then lead to an
overall improvement of dosing parameters such as taking a drug once
a day where it has previously required four doses per day or dosing
once a week or even less frequently when daily dosing was
previously required. Many drugs are presently dosed once per day,
but not all of these drugs have pharmacokinetic properties that are
suitable for dosing intervals of exactly twenty-four hours.
Extending the period through which these drugs are released would
also be beneficial.
[0005] One of the fundamental considerations in drug therapy
involves the relationship between blood levels and therapeutic
activity. For most drugs, it is of primary importance that serum
levels remain between a minimally effective concentration and a
potentially toxic level. In pharmacokinetic terms, the peaks and
troughs of a drug's blood levels ideally fit well within the
therapeutic window of serum concentrations. For certain therapeutic
agents, this window is so narrow that dosage formulation becomes
critical.
[0006] In an attempt to address the need for improved
bioavailability, several drug release modulation technologies have
been developed. For example, poorly soluble
5,5-diphenylimidazolidine-2,4-diones have been derivatized into
phosphate ester prodrugs to improve solubility (Stella et al., U.S.
Pat. No. 4,260,769, 1981). Enteric coatings have been used as a
protector of pharmaceuticals in the stomach and microencapsulating
active agents using proteinaceous microspheres, liposomes or
polysaccharides have been effective in abating enzymatic
degradation of the active agent. Enzyme inhibiting adjuvants have
also been used to prevent enzymatic degradation.
[0007] A wide range of pharmaceutical formulations provide
sustained release through microencapsulation of the active agent in
amides of dicarboxylic acids, modified amino acids or thermally
condensed amino acids. Slow release rendering additives can also be
intermixed with a large array of active agents in tablet
formulations. Many of these formulations, however, deliver
relatively low amounts of parent drugs in comparison with the
overall weight of the formulations.
[0008] While microencapsulation and enteric coating technologies
impart enhanced stability and time-release properties to active
agent substances these technologies suffer from several
shortcomings. Incorporation of the active agent is often dependent
on diffusion into the microencapsulating matrix, which may not be
quantitative and may complicate dosage reproducibility. In
addition, encapsulated drugs rely on diffusion out of the matrix or
degradation of the matrix, or both, which is highly dependent on
the chemical properties and water solubility of the active agent.
Conversely, water-soluble microspheres swell by an infinite degree
and, unfortunately, may release the active agent in bursts with
limited active agent available for sustained release. Furthermore,
in some technologies, control of the degradation process required
for active agent release is unreliable. For example, because an
enterically coated active agent depends on pH to release the active
agent and pH and residence time varies, the release rate is
difficult to control.
[0009] Several implantable drug delivery systems have utilized
polypeptide attachment to drugs. Additionally, other large
polymeric carriers incorporating drugs into their matrices are used
as implants for the gradual release of drugs. Yet another
technology combines the advantages of covalent drug attachment with
liposome formation where the active ingredient is attached to
highly ordered lipid films.
[0010] There is a generally recognized need for sustained delivery
of drugs that reduces the daily dosing requirement and allows for
controlled and sustained release of the parent drug and also avoids
irregularities of release and cumbersome formulations encountered
with typical dissolution controlled sustained release methods.
Furthermore, there is a need to accomplish the above listed goals
with high relative ratios of parent drugs in relation to the dry
weight of the formulation.
SUMMARY OF THE INVENTION
[0011] The present invention accomplishes this by having multiple
molecules of parent drugs attached to carrier moieties and by
extending the period during which the parent drug is released and
absorbed after administration to the patient and providing a longer
duration of action per dose than the parent drug itself. In one
embodiment, the compounds suitable for use in the methods of the
invention are derivatives of heteroaryl, lactam-, amide-, imide-,
sulfonamide-, carbamate-, urea-, benzamide-, N-acylaniline-, and
cyclic amide-, and tertiary amine containing parent drugs that are
substituted at a nitrogen or oxygen atom with a labile
aldehyde-linked prodrug moieties. In one embodiment, the prodrug
moieties are hydrophobic and reduce the polarity and solubility of
the parent drug under physiological conditions.
[0012] In one embodiment, the invention provides a prodrug compound
of Formula I, IA or IB:
##STR00001## [0013] wherein a is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15 or 16; [0014] e is selected from 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; [0015] f is selected from 0,
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein
the sum of e and f is at least two; [0016] each R.sub.1 and R.sub.2
is independently selected hydrogen, halogen, --OR.sub.20,
--SR.sub.20, --NR.sub.20R.sub.21, --C(O)R.sub.20, --C(O)OR.sub.20,
--C(O)NR.sub.20R.sub.21, --N(R.sub.20)C(O)R.sub.21, --CF.sub.3,
--CN, --NO.sub.2, --N.sub.3, acyl, optionally substituted alkoxy,
optionally substituted alkylamino, optionally substituted
dialkylamino, optionally substituted alkylthio, optionally
substituted alkylsulfonyl, optionally substituted aliphatic,
optionally substituted aryl and optionally substituted
heterocyclyl; [0017] wherein each R.sub.20 and R.sub.21 is
independently selected from hydrogen, halogen, aliphatic,
substituted aliphatic, aryl and substituted aryl; [0018] X.sub.1 is
selected from O or S; [0019] X.sub.2 is selected from direct bond,
O, S or NR.sub.20; [0020] C1 is a carrier moiety; and [0021] each
API is independently a biologically active moiety. [0022] The
invention further relates to prodrugs of secondary amine containing
drugs of Formula LI:
##STR00002##
[0023] In one embodiment, each API is the same biologically active
moiety. In another embodiment, the API groups represent two or more
different biologically active moieties.
[0024] The invention further provides a method for sustained
delivery of a parent drug by the administration of a conjugate of
the parent drug with a labile moiety, wherein the conjugate is
represented by Formula I, IA or IB.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present provides a method for attaching multiple parent
drugs (biologically active moieties) to a carrier moiety resulting
in a conjugate that can undergo spontaneous or enzyme assisted
cleavage in physiological conditions to release the parent drug. In
one embodiment, the release of the parent drug is sustained
release. The sustained release is accomplished by extending the
period during which the parent drug is released and absorbed after
administration to the patient and providing a longer duration of
action per dose than the parent drug itself. In one embodiment, the
prodrug moieties are hydrophobic and reduce the polarity and
solubility of the parent drug under physiological conditions.
[0026] One of the challenges for delivering a prodrug is the high
amount of prodrug needed to be dosed compared to the parent drug
due to the higher molecular weight of the prodrug compared to the
parent drug. Having a multivalent carrier moiety that can link two
or more parent drug moieties can decrease the dose load. Also, such
a multivalent carrier can link two different APIs. For example,
molecules of Aripiprazole and Dehydroaripiprazole can be linked to
the same carrier moiety. In another embodiment, two molecules can
be linked to the same carrier so that they will be released through
different mechanisms. For example, a quaternary ammonium prodrug
can easily hydrolyze in physiological conditions. On the other
hand, a parent drug linked through another functional group that
relies on enzymatic action might release more slowly. Thus, two
parent drugs can be linked to a single carrier moiety, the first
via a quaternary ammonium group on one end and the second through a
labile functional group. This allows one to tailor the release of
the two parent drugs, with faster delivery of one parent drug
compared to the other based on chemical reactivity and/or enzymatic
activity.
[0027] In one embodiment, the invention provides a prodrug compound
of Formula I, IA or IB:
##STR00003## [0028] wherein a is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15 or 16; [0029] e is selected from 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; [0030] f is selected from 0,
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein
the sum of e and f is at least two; [0031] each R.sub.1 and R.sub.2
is independently selected hydrogen, halogen, --OR.sub.20,
--SR.sub.20, --NR.sub.20R.sub.21, --C(O)R.sub.20, --C(O)OR.sub.20,
--C(O)NR.sub.20R.sub.21, --N(R.sub.20)C(O)R.sub.21, --CF.sub.3,
--CN, --NO.sub.2, --N.sub.3, acyl, optionally substituted alkoxy,
optionally substituted alkylamino, optionally substituted
dialkylamino, optionally substituted alkylthio, optionally
substituted alkylsulfonyl, optionally substituted aliphatic,
optionally substituted aryl and optionally substituted
heterocyclyl; [0032] wherein each R.sub.20 and R.sub.21 is
independently selected from hydrogen, halogen, aliphatic,
substituted aliphatic, aryl and substituted aryl; [0033] X.sub.1 is
selected from O or S; [0034] X.sub.2 is selected from direct bond,
O, S or NR.sub.20; [0035] C1 is a carrier; and [0036] each API is
independently a biologically active moiety.
[0037] The invention further relates to prodrugs of secondary amine
containing drugs of Formula LI:
##STR00004##
[0038] The invention further provides a method for sustained
delivery of a parent drug by the administration of a multivalent
conjugate of the parent drug with a labile moiety, wherein the
conjugate is represented by Formula I, IA, IB or LI.
[0039] In some embodiments, C1 is selected from optionally
substituted aliphatic, aryl or substituted aryl. In some
embodiments, C1 is selected from optionally substituted
C.sub.1-C.sub.30 alkyl, optionally substituted C.sub.2-C.sub.30
alkenyl, optionally substituted C.sub.1-C.sub.30 alkynyl,
optionally substituted C.sub.1-C.sub.30 aryl. In some embodiments,
C1 is selected from optionally substituted bicyclic heteroaryl
group selected from benzofuran, benzothiophene, indole,
benzimidazole, indazole, benzotriazole, pyrrolo[2,3]pyridine,
imidazopyridine, pyrazolopyridine, isoindole, quinoline,
isoquinoline, quinazoline, quinoxaline, phthalazine, indazole,
purine, indolizine, indole, indoline, isoindoline, benzofuran and
chromene. In some embodiments, C1 is a polyethyleneglycol group
having a molecular weight of about 400 dalton to about 100,000
dalton.
[0040] In some embodiments, C1 is selected from:
##STR00005##
wherein c is selected from 0, 1, 2, 3 and 4; g is an integer from 1
to about 1,000; each b and d is independently selected from 0, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13; s and t are each
independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29 and 30; each R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
R.sub.15, and R.sub.16 is independently selected from absent,
hydrogen, halogen, --OR.sub.20, --SR.sub.20, --NR.sub.20R.sub.21,
--C(O)R.sub.20, --C(O)OR.sub.20, --C(O)NR.sub.20R.sub.21,
--N(R.sub.20)C(O)R.sub.21, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3,
acyl, optionally substituted alkoxy, optionally substituted
alkylamino, optionally substituted dialkylamino, optionally
substituted alkylthio, optionally substituted alkylsulfonyl,
optionally substituted aliphatic, optionally substituted aryl and
optionally substituted heterocyclyl; wherein each R.sub.20 and
R.sub.21 is independently selected from hydrogen, halogen,
aliphatic, substituted aliphatic, aryl and substituted aryl;
alternatively two R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
R.sub.15, and R.sub.16 together with the atoms to which they are
attached may form an optionally substituted 3, 4, 5, 6 or 7
membered carbocyclic or heterocyclyl ring.
[0041] In some embodiments, C1 is a dendrimer.
[0042] In some embodiments, the invention relates to a prodrug
conjugate of Formula II:
##STR00006##
wherein, each X.sub.1 is independently selected from S or O; each
X.sub.2 is selected from absent, O, S or NR.sub.20 wherein R.sub.20
is selected from hydrogen, halogen, aliphatic, substituted
aliphatic, aryl or substituted aryl; API-1 is a biologically active
moiety; and API-2 is a biologically active moiety and is the same
or different from API-1.
[0043] In some embodiments, the invention relates to a prodrug
conjugate having the formula:
##STR00007##
wherein A.sub.1 and B.sub.1 together with the nitrogen they are
attached to form a first biologically active molecule; and, A.sub.2
and B.sub.2 together with the nitrogen they are attached to form a
second biologically active molecule.
[0044] In some embodiments, the invention relates to a prodrug
conjugate having the formula:
##STR00008##
wherein A.sub.1 and B.sub.1 together with the nitrogen they are
attached to form a first biologically active molecule; and, A.sub.2
and B.sub.2 together with the nitrogen they are attached to form a
second biologically active molecule.
[0045] In some embodiments, the invention relates to a prodrug
conjugate having the formula:
##STR00009##
wherein n is an integer between about 1 and about 50; each R.sub.10
and R.sub.11 is independently selected from absent, hydrogen,
halogen, --OR.sub.20, --SR.sub.20, --NR.sub.20R.sub.21,
--C(O)R.sub.20, --C(O)OR.sub.20, --C(O)NR.sub.20R.sub.21,
--N(R.sub.20)C(O)R.sub.21, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3,
acyl, optionally substituted alkoxy, optionally substituted
alkylamino, optionally substituted dialkylamino, optionally
substituted alkylthio, optionally substituted alkylsulfonyl,
optionally substituted aliphatic, optionally substituted aryl or
optionally substituted heterocyclyl; wherein each R.sub.20 and
R.sub.21 is selected from hydrogen, halogen, aliphatic, substituted
aliphatic, aryl or substituted aryl; alternatively two R.sub.10 and
R.sub.11 together with the atoms to which they are attached may
form an optionally substituted 3, 4, 5, 6 or 7 membered carbocyclic
or heterocyclyl ring.
[0046] In some embodiments, the invention relates to a prodrug of a
secondary amine containing parent drug having the formula:
##STR00010##
wherein n is an integer between about 1 and about 50; each R.sub.10
and R.sub.11 is independently selected from absent, hydrogen,
halogen, --OR.sub.20, --SR.sub.20, --NR.sub.20R.sub.21,
--C(O)R.sub.20, --C(O)OR.sub.20, --C(O)NR.sub.20R.sub.21,
--N(R.sub.20)C(O)R.sub.21, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3,
acyl, optionally substituted alkoxy, optionally substituted
alkylamino, optionally substituted dialkylamino, optionally
substituted alkylthio, optionally substituted alkylsulfonyl,
optionally substituted aliphatic, optionally substituted aryl or
optionally substituted heterocyclyl; wherein each R.sub.20 and
R.sub.21 is selected from hydrogen, halogen, aliphatic, substituted
aliphatic, aryl or substituted aryl; alternatively two R.sub.10 and
R.sub.11 together with the atoms to which they are attached may
form an optionally substituted 3, 4, 5, 6 or 7 membered carbocyclic
or heterocyclyl ring.
[0047] In a preferred embodiment, n is an integer between about 4
and about 26.
[0048] In some embodiments, the invention relates to a prodrug
conjugate with three drug moieties attached to a carrier group. For
example, three parent drug moieties can be attached to an aconitic
acid based carrier:
##STR00011##
[0049] Other tricarboxylic acid compounds such as citric acid,
isocitric acid, and trimesic acid can be used as carriers. In one
embodiment, the invention relates to prodrugs having the
formula:
##STR00012##
[0050] API-1 and API-2 are as defined above, and API-3 is a
biologically active moiety and is the same or different from API-1,
and API-2.
Prodrugs of Lac Tam, Cyclic Urea, Imide and Carbamate Containing
Pharmacophores
[0051] In one embodiment, the compounds of the invention are
derivatives of lactam-, imide-, carbamate-, and cyclic urea-,
-containing parent drugs that are substituted at the amide nitrogen
or oxygen atom with labile aldehyde-linked prodrug moieties.
[0052] In some embodiments, the invention relates to a prodrug
conjugate having the formula:
##STR00013##
[0053] wherein h is 3 or 4;
##STR00014## ##STR00015##
wherein each R.sub.100, R.sub.101, R.sub.102, and R.sub.103 is
independently selected from absent, hydrogen, halogen, --OR.sub.10,
--SR.sub.10, --NR.sub.10R.sub.11--, optionally substituted
aliphatic, optionally substituted aryl or optionally substituted
heterocyclyl; alternatively, two R.sub.100, and R.sub.101 together
form an optionally substituted carbocyclic or heterocyclyl ring; C1
is as previously defined; and,
X.sub.100 is --CH-- or --N--.
[0054] In some embodiments, the invention relates to a prodrug
conjugates having the formula:
##STR00016##
wherein D together with oxygen to which it is attached forms a
biologically active moiety; and, D.sub.2 together with oxygen to
which it is attached forms a biologically active moiety; and C1 is
as previously defined.
[0055] In some embodiments, the invention relates to a prodrug
conjugate having the formula:
##STR00017##
wherein n is selected from 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and
30.
[0056] In one embodiment, the parent drug moieties (APIs) are
selected from Table 1. In one embodiment, the prodrug is a compound
of Formula II wherein API-1 and API-2 are selected from Table-1. In
one embodiment both API-1 and API-2 represent the same parent
drug.
TABLE-US-00001 TABLE 1 ##STR00018## 1 ##STR00019## 2 ##STR00020## 3
##STR00021## 4 ##STR00022## 5 ##STR00023## 6 ##STR00024## 7
##STR00025## 8 ##STR00026## 9 ##STR00027## 10 ##STR00028## 11
##STR00029## 12
[0057] In one embodiment, the parent drug moieties (APIs), are
selected from Table 2. In one embodiment, the prodrug is a compound
of Formula II wherein API-1 and API-2 are selected from Table-2. In
one embodiment both API-1 and API-2 represent the same parent
drug.
TABLE-US-00002 TABLE 2 ##STR00030## 1 ##STR00031## 2 ##STR00032## 3
##STR00033## 4 ##STR00034## 5 ##STR00035## 6 ##STR00036## 7
##STR00037## 8 ##STR00038## 9 ##STR00039## 10 ##STR00040## 11
##STR00041## 12 ##STR00042## 13 ##STR00043## 14 ##STR00044## 15
##STR00045## 16 ##STR00046## 17 ##STR00047## 18 ##STR00048## 19
##STR00049## 20 ##STR00050## 21 ##STR00051## 22 ##STR00052## 23
##STR00053## 24 ##STR00054## 25 ##STR00055## 26 ##STR00056## 27
##STR00057## 28 ##STR00058## 29 ##STR00059## 30 ##STR00060## 31
##STR00061## 32 ##STR00062## 33 ##STR00063## 34 ##STR00064## 35
##STR00065## 36 ##STR00066## 37 ##STR00067## 38 ##STR00068## 39
##STR00069## 40 ##STR00070## 41 ##STR00071## 42 ##STR00072## 43
##STR00073## 44 ##STR00074## 45 ##STR00075## 46 ##STR00076## 47
##STR00077## 48 ##STR00078## 49 ##STR00079## 50 ##STR00080## 51
##STR00081## 52 ##STR00082## 53 ##STR00083## 53 ##STR00084## 54
[0058] In one embodiment, the parent drug moieties (APIs) are
selected from Table 3. In one embodiment, the prodrug is a compound
of Formula II wherein API-1 and API-2 are selected from Table 3. In
one embodiment both API-1 and API-2 represent the same parent
drug.
TABLE-US-00003 TABLE 3 ##STR00085## 1 ##STR00086## 2 ##STR00087## 3
##STR00088## 4 ##STR00089## 5 ##STR00090## 6 ##STR00091## 7
##STR00092## 8 ##STR00093## 9 ##STR00094## 10 ##STR00095## 11
##STR00096## 12 ##STR00097## 13 ##STR00098## 14 ##STR00099## 15
##STR00100## 16 ##STR00101## 17 ##STR00102## 18 ##STR00103## 19
##STR00104## 20
Prodrugs of Acylanilines
[0059] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of acylaniline-,
-containing parent drugs that are substituted at the amide nitrogen
or oxygen atom with labile aldehyde-linked prodrug moieties.
[0060] In one embodiment, compounds of the present invention are
represented by Formula III below, or its geometric isomers,
enantiomers, diastereomers, racemates, pharmaceutically acceptable
salts and solvates thereof:
##STR00105##
wherein each R.sub.50, R.sub.51, R.sub.52, R.sub.53, R.sub.54 and
R.sub.55 is independently selected from hydrogen, halogen,
--OR.sub.10, --SR.sub.10, --NR.sub.10R.sub.11--, optionally
substituted aliphatic, optionally substituted aryl or optionally
substituted heterocyclyl; alternatively, two or more R.sub.50,
R.sub.51, R.sub.52, R.sub.53, R.sub.54 and R.sub.55 together form
an optionally substituted ring.
[0061] In one embodiment, the parent drug moieties (APIs), are
selected from Table 4. In one embodiment, the prodrug is a compound
of Formula II wherein API-1 and API-2 are independently selected
from Table-4. In one embodiment both API-1 and API-2 represent the
same parent drug.
TABLE-US-00004 TABLE 4 ##STR00106## 1 ##STR00107## 2 ##STR00108## 3
##STR00109## 4 ##STR00110## 5 ##STR00111## 6 ##STR00112## 7
##STR00113## 8 ##STR00114## 9 ##STR00115## 10 ##STR00116## 11
##STR00117## 12 ##STR00118## 13 ##STR00119## 14 ##STR00120## 15
##STR00121## 16 ##STR00122## 17 ##STR00123## 18 ##STR00124## 19
##STR00125## 20 ##STR00126## 21 ##STR00127## 22 ##STR00128## 23
##STR00129## 24 ##STR00130## 25 ##STR00131## 26 ##STR00132## 27
##STR00133## 28 ##STR00134## 29 ##STR00135## 30 ##STR00136## 31
##STR00137## 32 ##STR00138## 33 ##STR00139## 34 ##STR00140## 35
##STR00141## 36 ##STR00142## 37 ##STR00143## 38 ##STR00144## 39
##STR00145## 40 ##STR00146## 41 ##STR00147## 42 ##STR00148## 43
##STR00149## 44 ##STR00150## 45 ##STR00151## 46 ##STR00152## 47
##STR00153## 48 ##STR00154## 49 ##STR00155## 50 ##STR00156## 51
##STR00157## 52 ##STR00158## 53 ##STR00159## 54 ##STR00160## 55
##STR00161## 56 ##STR00162## 57 ##STR00163## 58 ##STR00164## 59
##STR00165## 60 ##STR00166## 61 ##STR00167## 62 ##STR00168## 63
##STR00169## 64 ##STR00170## 65 ##STR00171## 66 ##STR00172## 67
##STR00173## 68 ##STR00174## 69 ##STR00175## 70 ##STR00176## 71
##STR00177## 72 ##STR00178## 73 ##STR00179## 74 ##STR00180## 75
##STR00181## 76 ##STR00182## 77 ##STR00183## 78
Thiazolidinones
[0062] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of thioazolidine-,
-containing parent drugs that are substituted at an amide nitrogen
or oxygen atom with labile aldehyde-linked prodrug moieties.
[0063] In one embodiment, compounds of the present invention are
represented by Formula IV below, or its geometric isomers,
enantiomers, diastereomers, racemates, pharmaceutically acceptable
salts and solvates thereof:
##STR00184##
[0064] wherein Cy.sub.2 is an optionally substituted heterocyclic
ring; and X.sub.5 is selected from absent, --S--, --O--, --S(O)--,
--S(O).sub.2--, --N(R.sub.10)--, --C(O)--,
--C(OR.sub.10)(R.sub.11)--, --[C(R.sub.10)(R.sub.11)].sub.v--,
--O[C(R.sub.10)(R.sub.11)].sub.v--,
--O[C(R.sub.10)(R.sub.11)].sub.vO--,
--S[C(R.sub.10)(R.sub.11)].sub.vO--,
--NR.sub.12[C(R.sub.10)(R.sub.11)].sub.vO--,
--NR.sub.12[C(R.sub.10)(R.sub.11)].sub.vS--,
--S[C(R.sub.10)(R.sub.11)].sub.v--,
--C(O)[C(R.sub.10)(R.sub.11)].sub.v--, and
--C(R.sub.10)(R.sub.11).dbd.C(R.sub.10)(R.sub.11)--; wherein v is
0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[0065] In one embodiment, the parent drug moieties (APIs), are
independently selected from Table 5. In one embodiment, the prodrug
is a compound of Formula II wherein API-1 and API-2 are selected
from Table-5. In one embodiment both API-1 and API-2 represent the
same parent drug.
TABLE-US-00005 TABLE 5 ##STR00185## 1 ##STR00186## 2 ##STR00187## 3
##STR00188## 4 ##STR00189## 5 ##STR00190## 6 ##STR00191## 7
##STR00192## 8 ##STR00193## 9 ##STR00194## 10 ##STR00195## 11
##STR00196## 12 ##STR00197## 13 ##STR00198## 14 ##STR00199## 15
##STR00200## 16 ##STR00201## 17 ##STR00202## 18 ##STR00203## 19
##STR00204## 20 ##STR00205## 21
Barbiturates
[0066] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of barbiturates that are
substituted at an amide nitrogen or oxygen atom with labile
aldehyde-linked prodrug moieties.
[0067] In one embodiment, the parent drug moieties (APIs), are
selected from Table 6. In one embodiment, the prodrug is a compound
of Formula II wherein API-1 and API-2 are selected from Table-6. In
one embodiment both API-1 and API-2 represent the same parent
drug.
TABLE-US-00006 TABLE 6 ##STR00206## 1 ##STR00207## 2 ##STR00208## 3
##STR00209## 4 ##STR00210## 5 ##STR00211## 6 ##STR00212## 7
##STR00213## 8 ##STR00214## 9 ##STR00215## 10 ##STR00216## 11
##STR00217## 12 ##STR00218## 13 ##STR00219## 14 ##STR00220## 15
##STR00221## 16
wherein M is a pharmaceutically acceptable cation.
Prodrugs of Pyridone and Pyrimidine Containing Parent Drugs
[0068] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of pyridine and pyrimidine
containing parent drugs that are substituted at the amide nitrogen
or oxygen atom with labile aldehyde-linked prodrug moieties.
[0069] In one embodiment, the parent drug moieties (APIs), are
selected from Table 7. In one embodiment, the prodrug is a compound
of Formula II wherein API-1 and API-2 are selected from Table-7. In
one embodiment both API-1 and API-2 represent the same parent
drug.
TABLE-US-00007 TABLE 7 ##STR00222## 1 ##STR00223## 2 ##STR00224## 3
##STR00225## 4 ##STR00226## 5 ##STR00227## 6 ##STR00228## 7
##STR00229## 8 ##STR00230## 9 ##STR00231## 10 ##STR00232## 11
##STR00233## 12 ##STR00234## 13 ##STR00235## 14 ##STR00236## 15
##STR00237## 16
Prodrugs of Benzamide Parent Drugs
[0070] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of benzamide containing
parent drugs that are substituted at the amide nitrogen or oxygen
atom with labile aldehyde-linked prodrug moieties.
[0071] In one embodiment, the parent drug moieties (APIs) are
independently selected from Table 8. In one embodiment, the prodrug
is a compound of Formula II wherein API-1 and API-2 are selected
from Table-8. In one embodiment both API-1 and API-2 represent the
same parent drug.
TABLE-US-00008 TABLE 8 ##STR00238## 1 ##STR00239## 2 ##STR00240## 3
##STR00241## 4 ##STR00242## 5 ##STR00243## 6 ##STR00244## 7
##STR00245## 8 ##STR00246## 9 ##STR00247## 10 ##STR00248## 11
##STR00249## 12 ##STR00250## 13 ##STR00251## 14 ##STR00252## 15
##STR00253## 16 ##STR00254## 17 ##STR00255## 18 ##STR00256## 19
##STR00257## 20 ##STR00258## 21 ##STR00259## 22 ##STR00260## 23
##STR00261## 24 ##STR00262## 25 ##STR00263## 26 ##STR00264## 27
##STR00265## 28 ##STR00266## 29 ##STR00267## 30 ##STR00268## 31
##STR00269## 32 ##STR00270## 33 ##STR00271## 34 ##STR00272## 35
##STR00273## 36 ##STR00274## 37 ##STR00275## 38 ##STR00276## 39
##STR00277## 40 ##STR00278## 41 ##STR00279## 42
Prodrugs of Imide Containing Parent Drugs
[0072] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of imide containing parent
drugs that are substituted at the amide nitrogen or oxygen atom
with labile aldehyde-linked prodrug moieties.
[0073] In one embodiment, the parent drug moieties (APIs) are
independently selected from Table 9. In one embodiment, the prodrug
is a compound of Formula II wherein API-1 and API-2 are selected
from Table-9. In one embodiment both API-1 and API-2 represent the
same parent drug.
TABLE-US-00009 TABLE 9 ##STR00280## 1. ##STR00281## 2. ##STR00282##
3. ##STR00283## 4. ##STR00284## 5. ##STR00285## 6. ##STR00286## 7.
##STR00287## 8. ##STR00288## 9. ##STR00289## 10. ##STR00290## 11.
##STR00291## 12. ##STR00292## 13. ##STR00293## 14. ##STR00294## 15.
##STR00295## 16. ##STR00296## 17. ##STR00297## 18. ##STR00298## 19.
##STR00299## 20. ##STR00300## 21. ##STR00301## 22. ##STR00302## 23.
##STR00303## 24. ##STR00304## 25. ##STR00305## 26. ##STR00306## 27.
##STR00307## 28. ##STR00308## 29. ##STR00309## 30. ##STR00310## 31.
##STR00311## 32. ##STR00312## 33. ##STR00313## 34. ##STR00314## 35.
##STR00315## 36. ##STR00316## 37. ##STR00317## 38. ##STR00318## 39.
##STR00319## 40. ##STR00320## 41. ##STR00321## 42. ##STR00322## 43.
##STR00323## 44. ##STR00324## 45. ##STR00325## 46. ##STR00326## 47.
##STR00327## 48.
Prodrugs of Cyclic Ureas
[0074] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of cyclic urea-containing
parent drugs that are substituted at either of the urea nitrogens
or oxygen with labile aldehyde-linked prodrug moieties.
[0075] In one embodiment, the parent drug moieties (APIs), are
independently selected from Table 10. In one embodiment, the
prodrug is a compound of Formula II wherein API-1 and API-2 are
selected from Table-10. In one embodiment both API-1 and API-2
represent the same parent drug.
TABLE-US-00010 TABLE 10 No Structure 1 ##STR00328## 2 ##STR00329##
3 ##STR00330## 4 ##STR00331## 5 ##STR00332## 6 ##STR00333## 7
##STR00334## 8 ##STR00335## 9 ##STR00336## 10 ##STR00337## 11
##STR00338## 12 ##STR00339## 13 ##STR00340## 14 ##STR00341##
Prodrugs of Sulfonamide Parent Drugs
[0076] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of sulfonamide parent
drugs that are substituted at the sulfonamide nitrogen or oxygen
atom with labile aldehyde-linked prodrug moieties.
##STR00342##
wherein A and B together with the sulfonamide group forms the
parent drug; and, A2 and B2 together with the sulfonamide group
form the parent drug.
[0077] In one embodiment, the parent drug moieties (APIs), are
selected from Table 11. In one embodiment, the prodrug is a
compound of Formula II wherein API-1 and API-2 are independently
selected from Table-11. In one embodiment both API-1 and API-2
represent the same parent drug.
TABLE-US-00011 TABLE 11 ##STR00343## 1 ##STR00344## 2 ##STR00345##
3 ##STR00346## 4 ##STR00347## 5 ##STR00348## 6 ##STR00349## 7
##STR00350## 8 ##STR00351## 9 ##STR00352## 10 ##STR00353## 11
##STR00354## 12 ##STR00355## 13 ##STR00356## 14 ##STR00357## 15
##STR00358## 16 ##STR00359## 17 ##STR00360## 18 ##STR00361## 19
##STR00362## 20 ##STR00363## 21 ##STR00364## 22 ##STR00365## 23
##STR00366## 24 ##STR00367## 25 ##STR00368## 26 ##STR00369## 27
##STR00370## 28 ##STR00371## 29 ##STR00372## 30 ##STR00373## 31
##STR00374## 32 ##STR00375## 33 ##STR00376## 34 ##STR00377## 35
##STR00378## 36 ##STR00379## 37 ##STR00380## 38 ##STR00381## 39
##STR00382## 40 ##STR00383## 41 ##STR00384## 42 ##STR00385## 43
##STR00386## 44 ##STR00387## 45 ##STR00388## 46 ##STR00389## 47
##STR00390## 48 ##STR00391## 49 ##STR00392## 50 ##STR00393## 51
##STR00394## 52 ##STR00395## 53 ##STR00396## 54 ##STR00397## 55
##STR00398## 56 ##STR00399## 57 ##STR00400## 58 ##STR00401## 59
##STR00402## 60 ##STR00403## 61 ##STR00404## 62 ##STR00405## 63
##STR00406## 64 ##STR00407## 65 ##STR00408## 66 ##STR00409## 67
##STR00410## 68 ##STR00411## 69 ##STR00412## 70 ##STR00413## 71
##STR00414## 72
Prodrugs of Tertiary Amine Containing Parent Drugs
[0078] In some embodiments, the invention relates to a prodrug
conjugates having the Formula V:
##STR00415##
wherein A.sub.1, B.sub.1 and E.sub.1 together with the nitrogen
they are attached to form a tertiary amine containing first
biologically active molecule; A.sub.2, B.sub.2 and E.sub.2 together
with the nitrogen they are attached to form a tertiary amine
containing second biologically active molecule; X.sub.1 is selected
from O or S; X.sub.2 is selected from direct bond, O, S or
NR.sub.20 wherein R.sub.20 is selected from hydrogen, halogen,
aliphatic, substituted aliphatic, aryl or substituted aryl; X-- is
a pharmaceutically acceptable counterion; and, C1 represents a
carrier moiety.
[0079] In some embodiments, the invention relates to a prodrug
conjugates having the Formula VI:
##STR00416##
wherein n is an integer between 1 and 50; n, A.sub.1, E.sub.1,
B.sub.1, A.sub.2, E.sub.2, B.sub.2, X.sub.1, X.sub.2, R.sub.10,
R.sub.11 and X-- are as defined above.
[0080] In some embodiments, n is selected from 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29 and 30.
[0081] In some embodiments, the invention relates to a prodrug
conjugates having the Formula VII:
##STR00417##
n, A.sub.1, B.sub.1, A.sub.2, E.sub.2, B.sub.2, X.sub.1, X.sub.2,
and X-- are as defined above.
[0082] The tertiary amine-containing parent drug may be any
tertiary amine-containing drug that induces a desired local or
systemic effect. Such drugs include broad classes of compounds. In
general, this includes: analgesic agents; anesthetic agents;
antiarthritic agents; respiratory drugs, including antiasthmatic
agents; anticancer agents, including antineoplastic agents;
anticholinergics; anticonvulsants; antidepressants; antidiabetic
agents; antidiarrheals; antihelminthics; antihistamines;
antihyperlipidemic agents; antihypertensive agents; anti-infective
agents such as antibiotics and antiviral agents; antiinflammatory
agents; antimigraine preparations; antinauseants; antiparkinsonism
drugs; antipruritics; antipsychotics; antipyretics; antispasmodics;
antitubercular agents; antiulcer agents; antiviral agents;
anxiolytics; appetite suppressants; attention deficit disorder
(ADD) and attention deficit hyperactivity disorder (ADHD) drugs;
cardiovascular preparations including calcium channel blockers, CNS
agents; beta-blockers and antiarrhythmic agents; central nervous
system stimulants; cough and cold preparations, including
decongestants; diuretics; genetic materials; gastrointestinal (GI)
motility agents; herbal remedies; hormones; hormonolytics;
hypnotics; hypoglycemic agents; immunosuppressive agents;
leukotriene inhibitors; mitotic inhibitors; muscle relaxants;
narcotic antagonists; nicotine; nutritional agents, such as
vitamins, essential amino acids and fatty acids; ophthalmic drugs
such as antiglaucoma agents; parasympatholytics; peptide drugs;
psychostimulants; sedatives; steroids; sympathomimetics;
tranquilizers; and vasodilators including general coronary,
peripheral and cerebral.
[0083] Examples of tertiary amine-containing antibiotic parent
drugs from which the prodrugs of the invention may be derived
include: clindamycin, ofloxacin/levofloxacin, pefloxacin,
quinupristine, rolitetracycline, and cefotiam.
[0084] Examples of tertiary amine-containing antifungal parent
drugs from which the prodrugs of the invention may be derived
include: butenafine, naftifine, and terbinafine.
[0085] Examples of tertiary amine-containing antimalarials and
antiprotozoals parent drugs from which the prodrugs of the
invention may be derived include: amodiaquine, quinacrine,
sitamaquine, quinine.
[0086] Examples of tertiary amine-containing HIV protease inhibitor
parent drugs from which the prodrugs of the invention may be
derived include: saquinavir, indinavir, atazanavir and nelfinavir.
Anti-HIV drugs also include maraviroc and aplaviroc for inhibition
of HIV entry.
[0087] Examples of tertiary amine-containing
anticonvulsants/antispasmodics parent drugs from which the prodrugs
of the invention may be derived include: atropine, darifenancin;
dicyclomine; hyoscayamine, tiagabine, flavoxate; and alverine.
[0088] Examples of tertiary-amine containing antidepressant parent
drugs from which the prodrugs of the invention are derived include:
amitriptyline, adinazolam, citalopram, cotinine, clomipramine,
doxepin, escitalopram, femoxetine, imipramine, minaprine,
moclobemide, mianserin, mirtazapine, nefazodone, nefopam,
pipofenazine, promazine, ritanserin, trazodone, trimipramine and
venlafaxine.
[0089] Examples of tertiary amine-containing antiemetic parent
drugs from which the prodrugs of the invention are derived include:
aprepitant, buclizine, cilansetron, cyclizine, dolasetron,
granisetron, meclizine, ondansetron, palonosetron, ramosetron,
thiethylperazine, trimethobenzamide, scopolamine, and
prochlorperazine.
[0090] Examples of tertiary amine-containing antihistamine parent
drugs from which the prodrugs of the invention are derived include:
acetprometazine, azatadine, azelastine, brompheniramine,
carbinoxamine, chlorpheniramine, clemastine, dexobrompheniramine,
diphenhydramine, diphenylpyraline, doxepin, emadastine, loratadine,
mequitazine, olopatadine, phenindamine, pheniramine, promethazine,
tripelennamine, triprolidine, astemizole, cetirizine, fexofenadine,
terfenadine, latrepirdine, ketotifen, cyproheptadine, hydroxyzine,
clobenzepam doxylamine, cinnarizine, orphenadrine.
[0091] Examples of tertiary amine-containing antiparkinsonian
parent drugs from which prodrugs of the invention are derived
include: cabergoline, ethopropazine, pergolide, selegiline,
metixene, biperiden, cycrimine, procycladine and apomorphine.
[0092] Examples of tertiary amine-containing antipsychotic parent
drugs from which prodrugs of the invention are derived include:
acetophenazine, amisulpride, aripiprazole, bifeprunox, blonanserin,
cariprazine, carphenazine, clopenthixol, clozapine, dehydro
aripiprazole, someperidone, droperidol, flupenthixol, fluphenazine,
fluspirilene, haloperidol, iloperidone, lurasidone, mesoridazine,
molindole, nemanopride, olanzapine, perospirone, perphenazine,
PF-00217830 (Pfizer), pipotiazine, propericiazine, quetiapine,
remoxipride, risperidone, sertindole, SLV-313 (Solvay/Wyeth),
sulpiride, thioproperazine, thioridazine, thiothixene,
trifluoperazine, ziprasidone, zotepine, pimozide, benzquinamide,
triflupromazine, tetrabenazine, melperon, asenapine,
chlorprothixene, spiperone and chlorpromazine.
[0093] Examples of tertiary amine-containing anxiolytic parent
drugs from which prodrugs of the invention are derived include:
buspirone, and loxapine.
[0094] Examples of tertiary amine-containing nootroopic (memory and
cognitive enhancers) parent drugs from which prodrugs of the
invention are derived include: donepezil, galantamine,
latrepirdine, nicotine, TC-5616 (Targacept, Inc.) having the IUPAC
name:
N-[(2S,3S)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofur-
an-2-carboxamide.
[0095] Examples of tertiary amine-containing parent drugs for
erectile dysfunction from which prodrugs of the invention are
derived include: apomorphine and sildenafil.
[0096] Examples of tertiary amine-containing parent drugs for
migraine headache from which prodrugs of the invention are derived
include: almotriptan, naratriptan, rizatriptan, sumatriptan,
zolmitriptan, dihydroergotamine, ergotamine, eletripan and
lisuride.
[0097] Examples of tertiary amine-containing parent drugs for the
treatment of alcoholism from which prodrugs of the invention are
derived include: naloxone and naltrexone. Other narcotic antagonist
amine containing parent drugs for treatment of substance abuse from
which prodrugs of the invention are derived include: levallorphan,
nalbuphine, nalorphine and nalmefene.
[0098] Examples of a tertiary amine-containing parent drug for the
treatment of addiction from which a prodrug of the invention is
derived include: buprenorphine, isomethadone, levomethadyl acetate,
methadyl acetate, nor-acetyl levomethadol, and normethadone.
[0099] Examples of tertiary amine-containing muscle relaxant parent
drugs from which prodrugs are derived include: cyclobenzaprine,
nefopam, tolperisone, orphenadrine, and quinine.
[0100] Examples of tertiary amine-containing nonsteroidal
anti-inflammatory parent drugs from which prodrugs of the invention
are derived include: etodolac, meloxicam, ketorolac, lornoxicam and
tenoxicam. Examples of tertiary amine-containing opioid parent
drugs from which prodrugs of the invention are derived include
alfentanil, anileridine, buprenorphine, butorphanol, clonitazene,
codeine, dihydrocodeine, dihydromorphin, fentanyl, hydromorphone,
meperidine, metazocine, methadone, morphine, oxycodone,
hyrdocodone, oxymorphone, pentazocine, remifentanil, and
sufentanil.
[0101] Examples of other tertiary amine-containing analgesic parent
drugs from which prodrugs of the invention are derived include:
methotrimeprazine, tramadol, nefopam, phenazocine, propiram,
quinupramine, thebaine and propoxyphene.
[0102] Examples of tertiary amine-containing sedatives/hypnotics
from which the prodrugs of the invention may be derived include:
eszopiclone, flurazepam, propiomazine, and zopiclone.
[0103] Examples of tertiary amine-containing local analgesic parent
drugs from which prodrugs of the invention are derived include:
bupivacaine, dexmedetomidine, dibucaine, dyclonine, lodicaine,
mepivacaine, procaine, and tapentadol and ropivacaine.
[0104] Examples of tertiary amine-containing antianginals from
which the prodrugs of the invention may be derived include:
ranozaline, bepridil.
[0105] Examples of tertiary amine-containing antiarrhythmics from
which the prodrugs of the invention may be derived include:
amiodarone, aprindine, encainide, moricizine, procainamide,
diltiazem, verapamil, bepridil.
[0106] Examples of tertiary amine-containing antihypertensives from
which the prodrugs of the invention may be derived include:
azelnidipine, deserpidine, ketanserin, reserpine, and
sildenafil.
[0107] Examples of tertiary amine-containing antithrombotics from
which the prodrugs of the invention may be derived include:
clopidogrel and ticlopidine.
[0108] Examples of tertiary amine-containing antineoplastic parent
drugs from which prodrugs of the invention are derived include:
dasatinib, flavopiridol, gefitinib, imatinib, sunitinib, topotecan,
vinblastine, vincristine, fincesine, vinorelbine, vinorelbine,
tamoxifen, tremifene, and tesmilifene.
[0109] Examples of tertiary amine-containing drugs parent drugs for
use in treating irritable bowel syndrome (IBS) from which the
prodrugs of the invention are derived include asimadoline.
[0110] Examples of other tertiary amine-containing parent drugs
from which the prodrugs of the invention are derived include:
antimuscarinics and anticholinergics such as benzotropine,
procyclidine and trihexylphanidyl; alpha andrenergic blockers such
as dapiprazole, dexmedetomidine and nicergoline; anorexics such as
diethylpropian, benzapehtamine, phendimetrazine, and sibutramine;
antidiarrhels such as diphenoxylate and loperamide, antikinetic and
antihypertensives such as clonidine; antiosteoporotics such as
raloxifene; antipruritics such as methyldilazine; antitussives such
as dextromethorphan; antiulceratives such as pirenzepine;
cholinesterase inhibitors such as galantamine; gastroprokinetics
such as alvimopan, cisapride, and piboserod; miglustat for treating
glycosphingolipid lysosomal storage disorder; clomifene as gonad
stimulating prinicipal; neuromuscular blockers such as
dihydro-beta-erythrodoidine, niotropics such as rivastigmine,
oxytocics such as methylergonovine; antiametics such as
chloroquine; respiratory stimulants such as doxapram; muscarinic
receptor antagonists for treating urinary incontinence such as
oxybutynin and solifenacin; calcium channel blockers such as
flunarizine; anthelmintics such as diethylcarbamazine and
quinacrine; miotics such as physostigmine; neuroprotectives such as
lubeluzole; immunosuppressants such as mycophenolate mofetil; and
stimulants such as nicotine.
[0111] Preferred tertiary amine-containing parent drugs from which
prodrugs of the invention are derived include: amisulpride,
aripiprazole, asenapine, cariprazine, citalopram,
dehydroaripiprazole, escitalopram, galantamine, iloperidone,
latrepirdine, olanzapine, paliperidone, perospirone, risperidone,
and ziprasidone.
[0112] The present invention is intended to encompass any parent
drug compound or any substituted parent drug compound which
contains a tertiary amine group and which is biologically active
and can be derivatized according to the present invention to afford
the corresponding prodrugs. While the tertiary amine-containing
parent drugs from which the prodrugs of the invention may be
derived are numerous, many of the chemical structures of the
prodrugs of the invention can be characterized by certain general
structure types. One type includes those wherein the tertiary amine
nitrogen is part of a cyclic (including bicyclic or tricyclic)
aliphatic group such as piperidine, piperazine, morpholine,
pyrrolidine, azapine, and diazapine. Another type includes those
wherein the tertiary amine nitrogen is part of an alkyl amine group
such as a diethyl and/or dimethyl amine.
[0113] In some embodiments, the invention relates to a prodrug
conjugates having the Formula VIII:
##STR00418##
wherein A-- is a pharmaceutically acceptable counterion; and
X.sub.1, and X.sub.2, are as defined above.
[0114] In one embodiment, the parent drug moieties (APIs) are
independently selected from Table 12. In one embodiment, the
prodrug is a compound of Formula II wherein API-1 and API-2 are
selected from Table-12. In one embodiment both API-1 and API-2
represent the same parent drug.
TABLE-US-00012 TABLE 12 ##STR00419## ##STR00420## ##STR00421##
##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426##
##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431##
##STR00432## ##STR00433## ##STR00434## ##STR00435## ##STR00436##
##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441##
##STR00442## ##STR00443##
Prodrugs of Heteroaryl Parent Drugs
[0115] In one embodiment, the compounds suitable for use in the
methods of the invention are derivatives of heteroaryl
NH-containing parent drugs that are substituted at the NH nitrogen
atom with labile prodrug moieties. Preferably, the prodrug moieties
are hydrophobic and reduce the solubility at physiological pH (pH
7.0), as well as modulate polarity and lipophilicity parameters of
the prodrug as compared to the parent drug.
[0116] In one embodiment, the invention provides a prodrug compound
of Formula IX:
##STR00444##
or a pharmaceutically acceptable salt thereof, wherein each of
X.sub.10 to X.sub.17 is independently N or CR, provided that at
least one of X.sub.10-X.sub.17 is CR. The R groups combine to form
the portion of the prodrug compound in addition to the
five-membered heteroaromatic ring. For example, the R groups can be
independently hydrogen, optionally substituted aliphatic, aromatic,
heteroaromatic or a combination thereof. The R groups can also be
taken together with the carbon atoms to which they are attached to
form one or more optionally substituted fused ring systems.
[0117] In a preferred embodiment, the invention relates to a
prodrug conjugate of Formula X:
##STR00445##
wherein, n, X.sub.10-X.sub.17, X.sub.1, X.sub.2, R.sub.10, and
R.sub.11 are as defined above.
[0118] Heteroaromatic NH-containing parent drugs include broad
classes of compounds. In general, this includes: analgesic agents;
anesthetic agents; antiarthritic agents; respiratory drugs,
including antiasthmatic agents; anticancer agents, including
antineoplastic agents; anticholinergics; anticonvulsants;
antidepressants; antidiabetic agents; antidiarrheals;
antihelminthics; antihistamines; antihyperlipidemic agents;
antihypertensive agents; anti-infective agents such as antibiotics
and antiviral agents; antiinflammatory agents; antimigraine
preparations; antinauseants; antiparkinsonism drugs; antipruritics;
antipsychotics; antipyretics; antispasmodics; antitubercular
agents; antiulcer agents; antiviral agents; anxiolytics; appetite
suppressants; attention deficit disorder (ADD) and attention
deficit hyperactivity disorder (ADHD) drugs; cardiovascular
preparations including calcium channel blockers, CNS agents;
beta-blockers and antiarrhythmic agents; central nervous system
stimulants; nootropics; cough and cold preparations, including
decongestants; diuretics; genetic materials; herbal remedies;
hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive
agents; leukotriene inhibitors; mitotic inhibitors; muscle
relaxants; narcotic antagonists; opioid agonists; nicotine;
nutritional agents, such as vitamins, essential amino acids and
fatty acids; ophthalmic drugs such as antiglaucoma agents;
parasympatholytics; peptide drugs; psychostimulants; sedatives;
steroids; sympathomimetics; tranquilizers; and vasodilators
including general coronary, peripheral and cerebral.
[0119] Specific heteroaromatic NH-containing parent drugs represent
a variety of drug classes. Such drugs include tranquilizers and
sedatives, such as mepiprazole and dexmedetomidine; anthelmintic
agents, such as albendazole, carbendazole, cyclobendazole,
mebendazole and thiabendazole; antimigraine agents, such as
almotriptan, dolasetron, eletriptan, lisuride, naratriptan,
rizatriptan, sumatriptan, frovatriptan, zolmitriptan and
ergotamine; treatments for irritable bowel syndrome, such as
alosetron; antiviral agents, such as delavirdine and atevirdine;
antihypertensive agents, such as bopindolol, bucindolol,
candesartan, deserpidine, mibefradil, ergoloid mesylate, indoramin,
irbesartan, mepindolol, olmesartan, reserpine, rescinnamine,
losartan, tasosartan, valsartan, raubasine, syrosingopine,
carmoxirole and rescimetol; anti-Parkinson agents, such as
cabergoline, pergolide, bromocriptine and terguride;
bronchodilators, such as ambuphylline; antiulcerative agents, such
as cimetidine, lansoprazole, omeprazole, pantaprozole and
rabeprazole; antibacterial agents, such as cefatrizine and
daptomycin; oxytocic agents, such as ergonovine and
methylergonovine; analgesics, such as etodolac; antineoplastic
agents, such as liarozole, pemetrexed, thiamiprine, vinblastine,
vincristine, vindesine, vinorelbine, voacamine and venflunine;
antidepressants, such as oxypertine, indalpine and roxindole;
anti-allergic agents, such as pemirolast, tazanolast and traxanox;
cardiotonic agents, such as pimobendan and sulmazole;
antiasthmatics, such as pranlukast; antiemetics, such as
ramosetron, tropisetron and alizapride; vasodilators, such as
bendazole and tadalafil; anti-gout agents, such as allopurinol;
antirheumatic agents, such as azathioprine; mydriatics, such as
yohimbine; therapies for congestive heart failure, such as
conivaptan; and hormonal agents, such as adrenoglomerulotropin,
octreotide, somatostatin, exenatide, teriparatide, leuprorelin and
goserelin.
[0120] In one embodiment, the parent drug is a peptide comprising
at least one heteroaromatic NH group. Such peptides include
peptides comprising from 2 to about 50, from 2 to about 40, from 2
to about 20 or from 2 to about 12 amino acid residues, including at
least one residue selected from tryptophan and histidine. Suitable
peptides include, but are not limited to, thyrotropin releasing
hormone (TRH), exenatide, daptomycin, octreotide, somatostatin,
teriparatide, leuprorelin and goserelin.
[0121] While the heteroaromatic NH-containing parent drugs from
which the prodrugs of the invention may be derived are numerous,
many of the chemical structures of the prodrugs of the invention
can be characterized by certain general structure types. One type
includes compounds wherein the heteroaromatic group is a pyrrole
group. Another type includes compounds wherein the heteroaromatic
group is an imidazole group. Another type includes compounds
wherein the heteroaromatic group is a 1,2,3- or 1,2,4-triazole
group. Another type includes compounds wherein the heteroaromatic
group is a tetrazole group. Another type includes compounds wherein
the heteroaromatic group is a benzimidazole group. Another type
includes compounds wherein the heteroaromatic group is an indole
group. Another type includes compounds wherein the heteroaromatic
group is a pyrazole group.
[0122] Benzimidazole-containing parent drugs which can be modified
to produce prodrugs of the invention include albenazole,
carbendazole, cyclobendazole, lansoprazole, liarozole, mebendazole,
mizolastine, omeprazole, pantaprazole, pimobendan, rabeprazole,
thiabendazole, bendazol and mibepradil. Preferred
benzimidazole-containing drugs include lansoprazole, mibefradil and
pimobendan.
[0123] Imidazole-containing parent drugs which can be modified to
produce prodrugs of the invention include alosetron, ambuphylline,
cimetidine, conivaptan, dexmedetomidine, ramosetron, thiamiprine,
sulmazole, azathioprine, exenatide, teriparatide, thyrotropin
releasing hormone (TRH), goserelin and leuprorelin. Preferred
imidazole-containing drugs include conivaptan, sulmazole and
azathioprine.
[0124] Indole-containing parent drugs which can be modified to
produce prodrugs of the invention include almotriptan, atevirdine,
bopindolol, bromocriptine, bucindolol, cabergoline, delavirdine,
deserpidine, dolasetron, eletriptan, ergoloid mesylate, ergonovine,
etodolac, frovatriptan, indoramin, lisuride, mepidolol,
methylergonovine, naratriptan, oxypertine, pemetrexed, pergolide,
rescinnamine, reserpine, rizatriptan, sumatriptan, tadalafil,
tropisetron, adrenoglomerulotriptan, bromocriptine, ergotamine,
indalpine, raubasine, reserpiline, roxindole, syrosingopine,
terguride, vinblastine, vincristine, vindesine, vinorelbine,
voacamine, vinflunineatevirdine, carmoxirole, rescimetol,
yohimbine, zolmitriptan, octreotide, somatostatin, exenatide,
teriparatide, daptomycin, leuprorelin and goserelin. Preferred
indole-containing drugs include bopindolol, bucindolol,
cabergoline, dolasetron, indoramin, oxypertine, pergolide,
rescinnamine, reserpine, atevirdine, carmoxirole and
rescimetol.
[0125] Pyrazole-containing parent drugs which can be modified to
produce prodrugs of the invention include mepiprazole and
allopurinlol.
[0126] Tetrazole-containing parent drugs which can be modified to
produce prodrugs of the invention include candesartan, irbesartan,
losartan, olmesartan, pemirolast, pranlukast, tasosartan, traxanox
and valsartan.
[0127] Triazole-containing parent drugs which can be modified to
produce prodrugs of the invention include cefatrizine and
alizapride.
[0128] Particularly preferred parent drugs which can be modified
according to the invention include bopindolol, bucindolol,
cabergoline, candesartan, cefatrizine, conivaptan, indoramin,
irbesartan, lansoprazole, mibefradil, olmesartan, oxypertine,
pemirolast, pergolide, pimobendan, rescinnamine, reserpine,
valsartan, sulmazole, azathioprine, atevirdine, carmoxirole and
rescimetol.
[0129] In one embodiment, the parent drug moieties (APIs) are
selected from Table 13. In one embodiment, the prodrug is a
compound of Formula II wherein API-1 and API-2 are selected from
Table 13. In one embodiment both API-1 and API-2 represent the same
parent drug.
TABLE-US-00013 TABLE 13 ##STR00446## ##STR00447## ##STR00448##
##STR00449## ##STR00450## ##STR00451## ##STR00452## ##STR00453##
##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458##
##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463##
##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468##
##STR00469## ##STR00470##
[0130] In another aspect of the invention a general method to
synthesize prodrugs that can be linked to multiple drug molecules
is provided (Scheme 1).
##STR00471##
[0131] wherein each LG-1 and LG-2 is independently a leaving group,
preferably a chloride, bromide or iodide.
[0132] In another aspect of the invention a general method to
synthesize prodrugs that can be linked to two parent drug molecules
through alkyl group is provided (Scheme 2). The same methodology
can be used to synthesize prodrugs with branched and substituted
alkyl groups.
##STR00472##
wherein n is an integer between about 1 and about 50, preferably
between about 4 and about 26.
[0133] In one embodiment, the dicarboxylic acid from Scheme 2 is
selected from oxalic acid, malonic acid, succinic acid, glutaric
acid, adipic acid, pimelic acid, suberic acid, azelaic acid,
sebacic acid, undecanedioic acid, dodecanedioic acid, ortho-, para-
or meta-phthalic acid, maleic acid, fumaric acid, glutaconic acid,
traumatic acid or muconic acid. In one embodiment, the dicarboxylic
acid is reacted with one mole equivalent or less of thionyl
chloride to give a mixture of mono and disubstituted acid chloride.
In another embodiment, the dicarobxylic acid is reacted with two or
more mole equivalents of thionyl chloride. The acid chlorides can
be converted to chloromethyl esters by reacting with trioxane or
paraformaldehyde using zirconium tetrachloride as the Lewis acid.
(Mudryk, B. et. al., Tetrahedron Letters 43(36), 2002, 6317-6318).
The chloromethyl esters can be reacted with reactive APIs, such as
amine containing pharmacophores to give the final conjugates.
Methods for attaching biologically active agents containing amine
groups through labile groups are disclosed in U.S. application Ser.
No. 12/823,102. The methods described therein can be adapted to
convert dicarboxylic acid containing carrier groups herein.
[0134] In another aspect of the invention a general method to
synthesize prodrugs of aripiprazole that can be linked to two
aripiprazole molecules through alkyl group is provided (Scheme 3).
The invention further provides a prodrug of aripiprazole selected
from Table 14.
##STR00473##
TABLE-US-00014 TABLE A Compound No. Structure 1 ##STR00474## 2
##STR00475## 3 ##STR00476## 4 ##STR00477## 5 ##STR00478## 6
##STR00479## 7 ##STR00480## 8 ##STR00481## 9 ##STR00482## 10
##STR00483## 11 ##STR00484## 12 ##STR00485##
[0135] In one embodiment, the compounds of Formula I, IA or IB are
less soluble, and are preferably at least an order of magnitude
less soluble, as compared to the parent drug from which they were
derived. In one embodiment, the prodrugs of Formula I, IA or IB
have an aqueous solubility of less than about 0.5 mg/ml, preferably
less than about 0.1 mg/mL, preferably less than about 0.01 mg/mL,
preferably less than about 0.001 mg/mL, preferably less than about
0.0001 mg/mL and even more preferably less than about 0.00001 mg/ml
when solubility is measured in a phosphate buffer (pH 7.4) at room
temperature.
[0136] In a preferred embodiment, a compound of the invention
provides sustained delivery of the parent drug over hours, days,
weeks or months when administered, for example, orally or
parenterally, to a subject. For example, the compounds can provide
sustained delivery of the parent drug for at least 8, 12, 24, 36 or
48 hours or at least 4, 7, 15, 30, 60, 75 or 90 days or longer.
Without being bound by a theory, it is believed that the compounds
of the invention form an insoluble depot upon parenteral
administration, for example subcutaneous, intramuscular or
intraperitoneal injection. In one embodiment a prodrug of the
invention may further comprise a sustained release delivery system
for providing additional protection of the prodrug from enzymatic
or chemical degradation.
[0137] In another embodiment, the invention provides a method for
sustained delivery of a parent lactam, amide, imide, sulfonamide,
carbamate, urea, benzamide, or acylaniline containing drug to a
subject in need thereof. Each of these groups comprises an amidic
N--H group. The method comprises administering to the subject an
effective amount of a prodrug formed by substituting on the NH
group a labile, hydrophobic aldehyde-linked prodrug moiety wherein
the prodrug has reduced solubility under physiological conditions
compared to the parent drug and provides for longer sustained
therapeutic levels of the parent drug following administration than
observed levels following administration of the parent drug. In a
preferred embodiment, the amidic N--H group has a pKa of about 5 to
about 22, preferably about 5 to about 21, and preferably about 5 to
about 20.
Prodrugs of Secondary Amine Drugs
[0138] The invention further relates to prodrugs of secondary amine
containing drugs of Formula LI:
##STR00486##
[0139] In some embodiments, the invention relates to a prodrug
conjugate having the formula:
##STR00487##
wherein A.sub.1 and B.sub.1 together with the nitrogen they are
attached to form a first biologically active molecule; and, A.sub.2
and B.sub.2 together with the nitrogen they are attached to form a
second biologically active molecule.
[0140] In some embodiments, the invention relates to a prodrug of a
secondary amine containing parent drug having the Formula LI-A:
##STR00488##
wherein n is an integer between about 1 and about 50;
X.sub.1 is S or O;
[0141] X.sub.2 is selected from direct bond, O, S or NR.sub.20;
each R.sub.10 and R.sub.11 is independently selected from absent,
hydrogen, halogen, --OR.sub.20, --SR.sub.20, --NR.sub.20R.sub.21,
--C(O)R.sub.20, --C(O)OR.sub.20, --C(O)NR.sub.20R.sub.21,
--N(R.sub.20)C(O)R.sub.21, --CF.sub.3, --CN, --NO.sub.2, --N.sub.3,
acyl, optionally substituted alkoxy, optionally substituted
alkylamino, optionally substituted dialkylamino, optionally
substituted alkylthio, optionally substituted alkylsulfonyl,
optionally substituted aliphatic, optionally substituted aryl or
optionally substituted heterocyclyl; wherein each R.sub.20 and
R.sub.21 is selected from hydrogen, halogen, aliphatic, substituted
aliphatic, aryl or substituted aryl; alternatively two R.sub.10 and
R.sub.11 together with the atoms to which they are attached may
form an optionally substituted 3, 4, 5, 6 or 7 membered carbocyclic
or heterocyclyl ring.
[0142] In a preferred embodiment, n is selected from 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
26, 27, 28, 29 and 30.
[0143] The secondary amine-containing parent drugs (designated in
Formula LI as API-1 and API-2) can be any secondary
amine-containing parent drug that induces a desired local or
systemic effect. Such parent drugs include broad classes of
compounds. Several examples include: respiratory drugs, including
antiasthmatic agents; analgesic agents; antidepressants;
antianginal agents; antiarrhythmic agents; antihypertensive agents;
antidiabetic agents; antihistamines; anti-infective agents such as
antibiotics; antiinflammatory agents; antiparkinsonism drugs;
antipsychotics; antipyretic agents; antiulcer agents; attention
deficit hyperactivity disorder (ADHD) drugs; central nervous system
stimulants; cough and cold preparations, including decongestants;
and psychostimulants.
[0144] Examples of secondary-amine containing parent drugs from
which prodrugs of the invention may be derived include: alprenolol,
acebutolol, amidephrine, amineptine, amosulalol, amoxapine,
amphetaminil, atenolol, atomoxetine, balofloxacin, bamethan,
befunolol, benazepril, benfluorex, benzoctamine, betahistine,
betaxolol, bevantolol, bifemelane, bisoprolol, brinzolamide,
bufeniode, butethamine, camylofine, carazolol, carticaine,
carvedilol, cephaeline, ciprofloxacin, clozapine, clobenzorex,
clorprenaline, cyclopentamine, delapril, demexiptiline, denopamine,
desipramine, desloratadine (clarinex), diclofenac, dimetofrine,
dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide,
droprenilamine, duloxetine, eltoprazine, enalapril, enoxacin,
epinephrine, ertapenem, esaprazole, esmolol, etoxadrol, fasudil,
fendiline, fenethylline, fenfluramine, fenoldopam, fenoterol,
fenproporex, flecainide, fluoxetine, formoterol, frovatriptan,
gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline,
imidapril, indalpine, indecainide, indeloxazine hydrochloride,
isoxsuprine, ispronicline, labetalol, landiolol, lapatinib,
levophacetoperane, lisinopril, lomefloxacin, lotrafiban,
maprotiline, mecamylamine, mefloquine, mepindolol, meropenem,
metapramine, metaproterenol, methoxyphenamine, dtmp (dextrorotary
methylphenidate), methylphenidate, metipranolol, metoprolol,
mitoxantrone, mivazerol, moexipril, moprolol, moxifloxacin,
nebivolol, nifenalol, nipradilol, norfloxacin, nortriptyline,
nylidrin, olanzapine, oxamniquine, oxprenolol, oxyfedrine,
paroxetine, perhexiline, phenmetrazine, phenylephrine,
phenylpropylmethylamine, pholedrine, picilorex, pimefylline,
pindolol, pipemidic acid, piridocaine, practolol, pradofloxacin,
pramipexole, pramiverin, prenalterol, prenylamine, prilocaine,
procaterol, pronethalol, propafenone, propranolol, propylhexedrine,
protokylol, protriptyline, pseudoephedrine, reboxetine, rasagiline,
(r)-rasagiline, repinotan, reproterol, rimiterol, ritodrine,
safinamide, salbutamol/albuterol, salmeterol, sarizotan,
sertraline, silodosin, sotalol, soterenol, sparfloxacin, spirapril,
sulfinalol, synephrine, tamsulosin, tebanicline, tianeptine,
tirofiban, tretoquinol, trimetazidine, troxipide, varenicline
(champix), vildagliptin, viloxazine, viquidil and xamoterol.
[0145] Preferred secondary amine-containing parent drugs from which
prodrugs of the invention are derived include atenolol,
atomoxetine, clozapine, desipramine, desloratadine (clarinex),
diclofenac, doripenem, duloxetine, enalapril, ertapenem,
fluoxetine, metoprolol, mecamylamine, meropenem, methylphenidate,
dtmp (dextrorotary methylphenidate), olanzapine, paroxetine,
pramipexole, rasagiline, .RTM.-RASAGILINE, salbutamol/albuterol,
tamsulosin, varenicline (hantix), and vildagliptin. In a more
preferred embodiment, the secondary amine-containing parent drug is
selected from clozapine, duloxetine, mecamylamine, pramipexole,
rasagiline, .RTM.-RASAGILINE, and olanzapine.
[0146] In one embodiment, the parent drug moieties (APIs) are
selected from Table 14. In one embodiment, the prodrug is a
compound of Formula LI or LI-A wherein API-1 and API-2 are selected
from Table 14. In one embodiment both API-1 and API-2 represent the
same parent drug.
TABLE-US-00015 TABLE 14 ##STR00489## ##STR00490## ##STR00491##
##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496##
##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501##
##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506##
##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511##
##STR00512## ##STR00513## ##STR00514##
[0147] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00515##
[0148] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00516##
[0149] In a preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00517##
[0150] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00518##
[0151] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00519##
[0152] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00520##
[0153] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00521##
[0154] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00522##
[0155] In a more preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00523##
[0156] In a preferred embodiment, the invention relates to a
prodrug of olanzapine represented by formula:
##STR00524##
Synthesis of Compounds
[0157] Generally, the compounds of the invention can be synthesized
by the method set forth in Schemes 3A and 3B where derivatization
of olanzapine is illustrated.
##STR00525##
##STR00526##
[0158] Schemes 3A and 3B illustrate the synthesis of a compound of
Formula LI by condensation of the parent drug, olanzapine, with
chloromethyl chloroformate, followed by condensation with a
carboxylic acid.
DEFINITIONS
[0159] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification and claims, unless
otherwise limited in specific instances, either individually or as
part of a larger group.
[0160] The terms "API", "biologically active moiety", "drug moiety"
and "parent drug moiety" are used interchangeably to refer to the
structure of a parent drug molecule which is present in a prodrug
conjugate of the invention. As will be understood by one of skill
in the art, in certain embodiments, linking the drug molecule to a
carrier moiety proceeds via substitution at an oxygen or nitrogen
atom of the parent drug molecule with loss of a hydrogen atom. In
these embodiments, the parent drug moiety is the radical resulting
from removal of the O--H or N--H hydrogen atom from the parent drug
molecule. In certain embodiments, the carrier moiety is linked to
the parent drug molecule without any loss of atoms from the parent
drug molecule. In these embodiments, the parent drug moiety
includes the entire structure of the parent drug compound. For
example, in case of a tertiary amine parent drug that is converted
to a quaternary prodrug conjugate a loss of hydrogen from the
parent drug doesn't occur.
[0161] The term "aliphatic group" or "aliphatic" refers to a
non-aromatic moiety that may be saturated (e.g., single bond) or
contain one or more units of unsaturation, e.g., double and/or
triple bonds. An aliphatic group may be straight chained, branched
or cyclic, contain carbon, hydrogen or, optionally, one or more
heteroatoms and may be substituted or unsubstituted. In addition to
aliphatic hydrocarbon groups, aliphatic groups include, for
example, polyalkoxyalkyls, such as polyalkylene glycols,
polyamines, and polyimines, for example. Such aliphatic groups may
be further substituted. It is understood that aliphatic groups may
include alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, and substituted or unsubstituted
cycloalkyl groups as described herein.
[0162] The term "acyl" refers to a carbonyl substituted with
hydrogen, alkyl, partially saturated or fully saturated cycloalkyl,
partially saturated or fully saturated heterocycle, aryl, or
heteroaryl. For example, acyl includes groups such as
(C.sub.1-C.sub.6) alkanoyl (e.g., formyl, acetyl, propionyl,
butyryl, valeryl, caproyl, t-butylacetyl, etc.),
(C.sub.3-C.sub.6)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),
heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,
pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl,
piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), aroyl (e.g.,
benzoyl) and heteroaroyl (e.g., thiophenyl-2-carbonyl,
thiophenyl-3-carbonyl, furanyl-2-carbonyl, furanyl-3-carbonyl,
1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,
benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,
cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl
group may be any one of the groups described in the respective
definitions. When indicated as being "optionally substituted", the
acyl group may be unsubstituted or optionally substituted with one
or more substituents (typically, one to three substituents)
independently selected from the group of substituents listed below
in the definition for "substituted" or the alkyl, cycloalkyl,
heterocycle, aryl and heteroaryl portion of the acyl group may be
substituted as described above in the preferred and more preferred
list of substituents, respectively.
[0163] The term "alkyl" is intended to include both branched and
straight chain, substituted or unsubstituted saturated aliphatic
hydrocarbon radicals/groups having the specified number of carbons.
Preferred alkyl groups comprise about 1 to about 24 carbon atoms
("C.sub.1-C.sub.24") preferably about 7 to about 24 carbon atoms
("C.sub.7-C.sub.24"), preferably about 8 to about 24 carbon atoms
("C.sub.8-C.sub.24"), preferably about 9 to about 24 carbon atoms
("C.sub.9-C.sub.24"). Other preferred alkyl groups comprise at
about 1 to about 8 carbon atoms ("C.sub.1-C.sub.8") such as about 1
to about 6 carbon atoms ("C.sub.1-C.sub.6"), or such as about 1 to
about 3 carbon atoms ("C.sub.1-C.sub.3"). Examples of
C.sub.1-C.sub.6 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,
neopentyl and n-hexyl radicals.
[0164] The term "alkenyl" refers to linear or branched radicals
having at least one carbon-carbon double bond. Such radicals
preferably contain from about two to about twenty-four carbon atoms
("C.sub.2-C.sub.24") preferably about 7 to about 24 carbon atoms
("C.sub.7-C.sub.24"), preferably about 8 to about 24 carbon atoms
("C.sub.8-C.sub.24"), and preferably about 9 to about 24 carbon
atoms ("C.sub.9-C.sub.24"). Other preferred alkenyl radicals are
"lower alkenyl" radicals having two to about ten carbon atoms
("C.sub.2-C.sub.10") such as ethenyl, allyl, propenyl, butenyl and
4-methylbutenyl. Preferred lower alkenyl radicals include 2 to
about 6 carbon atoms ("C.sub.2-C.sub.6"). The terms "alkenyl", and
"lower alkenyl", embrace radicals having "cis" and "trans"
orientations, or alternatively, "E" and "Z" orientations.
[0165] The term "alkynyl" refers to linear or branched radicals
having at least one carbon-carbon triple bond. Such radicals
preferably contain from about two to about twenty-four carbon atoms
("C.sub.2-C.sub.24") preferably about 7 to about 24 carbon atoms
("C.sub.7-C.sub.24"), preferably about 8 to about 24 carbon atoms
("C.sub.8-C.sub.24"), and preferably about 9 to about 24 carbon
atoms ("C.sub.9-C.sub.24"). Other preferred alkynyl radicals are
"lower alkynyl" radicals having two to about ten carbon atoms such
as propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and
1-pentynyl. Preferred lower alkynyl radicals include 2 to about 6
carbon atoms ("C.sub.2-C.sub.6").
[0166] The term "cycloalkyl" refers to saturated carbocyclic
radicals having three to about twelve carbon atoms
("C.sub.3-C.sub.12"). The term "cycloalkyl" embraces saturated
carbocyclic radicals having three to about twelve carbon atoms.
Examples of such radicals include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
[0167] The term "cycloalkenyl" refers to partially unsaturated
carbocyclic radicals having three to twelve carbon atoms.
Cycloalkenyl radicals that are partially unsaturated carbocyclic
radicals that contain two double bonds (that may or may not be
conjugated) can be called "cycloalkyldienyl". More preferred
cycloalkenyl radicals are "lower cycloalkenyl" radicals having four
to about eight carbon atoms. Examples of such radicals include
cyclobutenyl, cyclopentenyl and cyclohexenyl.
[0168] The term "alkylene," as used herein, refers to a divalent
group derived from a straight chain or branched saturated
hydrocarbon chain having the specified number of carbons atoms.
Examples of alkylene groups include, but are not limited to,
ethylene, propylene, butylene, 3-methyl-pentylene, and
5-ethyl-hexylene.
[0169] The term "alkenylene," as used herein, denotes a divalent
group derived from a straight chain or branched hydrocarbon moiety
containing the specified number of carbon atoms having at least one
carbon-carbon double bond. Alkenylene groups include, but are not
limited to, for example, ethenylene, 2-propenylene, 2-butenylene,
1-methyl-2-buten-1-ylene, and the like.
[0170] The term "alkynylene," as used herein, denotes a divalent
group derived from a straight chain or branched hydrocarbon moiety
containing the specified number of carbon atoms having at least one
carbon-carbon triple bond. Representative alkynylene groups
include, but are not limited to, for example, propynylene,
1-butynylene, 2-methyl-3-hexynylene, and the like.
[0171] The term "alkoxy" refers to linear or branched
oxy-containing radicals each having alkyl portions of one to about
twenty-four carbon atoms or, preferably, one to about twelve carbon
atoms. More preferred alkoxy radicals are "lower alkoxy" radicals
having one to about ten carbon atoms and more preferably having one
to about eight carbon atoms. Examples of such radicals include
methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
[0172] The term "alkoxyalkyl" refers to alkyl radicals having one
or more alkoxy radicals attached to the alkyl radical, that is, to
form monoalkoxyalkyl and dialkoxyalkyl radicals.
[0173] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendent manner or
may be fused. The term "aryl" embraces aromatic radicals such as
phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
[0174] The terms "heterocyclyl", "heterocycle" "heterocyclic" or
"heterocyclo" refer to saturated, partially unsaturated and
unsaturated heteroatom-containing ring-shaped radicals, which can
also be called "heterocyclyl", "heterocycloalkenyl" and
"heteroaryl" correspondingly, where the heteroatoms may be selected
from nitrogen, sulfur and oxygen. Examples of saturated
heterocyclyl radicals include saturated 3 to 6-membered
heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.,
pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.);
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2
oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl, etc.);
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.).
Examples of partially unsaturated heterocyclyl radicals include
dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
Heterocyclyl radicals may include a pentavalent nitrogen, such as
in tetrazolium and pyridinium radicals. The term "heterocycle" also
embraces radicals where heterocyclyl radicals are fused with aryl
or cycloalkyl radicals. Examples of such fused bicyclic radicals
include benzofuran, benzothiophene, and the like.
[0175] The term "heteroaryl" refers to unsaturated aromatic
heterocyclyl radicals. Examples of heteroaryl radicals include
unsaturated 3 to 6 membered heteromonocyclic group containing 1 to
4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,
pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl
(e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,
etc.) tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.),
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to
6-membered heteromonocyclic group containing a sulfur atom, for
example, thienyl, etc.; unsaturated 3- to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.) etc.; unsaturated condensed heterocyclyl group containing 1
to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., benzoxazolyl,
benzoxadiazolyl, etc.); unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.)
etc.; unsaturated condensed heterocyclyl group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl,
benzothiadiazolyl, etc.) and the like.
[0176] The term "heterocycloalkyl" refers to
heterocyclo-substituted alkyl radicals. More preferred
heterocycloalkyl radicals are "lower heterocycloalkyl" radicals
having one to six carbon atoms in the heterocyclo radical.
[0177] The term "alkylthio" refers to radicals containing a linear
or branched alkyl radical, of one to about ten carbon atoms
attached to a divalent sulfur atom. Preferred alkylthio radicals
have alkyl radicals of one to about twenty-four carbon atoms or,
preferably, one to about twelve carbon atoms. More preferred
alkylthio radicals have alkyl radicals which are "lower alkylthio"
radicals having one to about ten carbon atoms. Most preferred are
alkylthio radicals having lower alkyl radicals of one to about
eight carbon atoms. Examples of such lower alkylthio radicals
include methylthio, ethylthio, propylthio, butylthio and
hexylthio.
[0178] The terms "aralkyl" or "arylalkyl" refer to aryl-substituted
alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl,
phenylethyl, and diphenylethyl.
[0179] The term "aryloxy" refers to aryl radicals attached through
an oxygen atom to other radicals.
[0180] The terms "aralkoxy" or "arylalkoxy" refer to aralkyl
radicals attached through an oxygen atom to other radicals.
[0181] The term "aminoalkyl" refers to alkyl radicals substituted
with amino radicals. Preferred aminoalkyl radicals have alkyl
radicals having about one to about twenty-four carbon atoms or,
preferably, one to about twelve carbon atoms. More preferred
aminoalkyl radicals are "lower aminoalkyl" that have alkyl radicals
having one to about ten carbon atoms. Most preferred are aminoalkyl
radicals having lower alkyl radicals having one to eight carbon
atoms. Examples of such radicals include aminomethyl, aminoethyl,
and the like.
[0182] The term "alkylamino" denotes amino groups which are
substituted with one or two alkyl radicals. Preferred alkylamino
radicals have alkyl radicals having about one to about twenty
carbon atoms or, preferably, one to about twelve carbon atoms. More
preferred alkylamino radicals are "lower alkylamino" that have
alkyl radicals having one to about ten carbon atoms. Most preferred
are alkylamino radicals having lower alkyl radicals having one to
about eight carbon atoms. Suitable lower alkylamino may be
monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such
as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino
or the like.
[0183] The term "substituted" refers to the replacement of one or
more hydrogen radicals in a given structure with the radical of a
specified substituent including, but not limited to: halo, alkyl,
alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio,
alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl,
arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,
aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro,
alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl,
aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,
carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,
heteroaryl, heterocyclic, and aliphatic. It is understood that the
substituent may be further substituted.
[0184] For simplicity, chemical moieties that are defined and
referred to throughout can be univalent chemical moieties (e.g.,
alkyl, aryl, etc.) or multivalent moieties under the appropriate
structural circumstances clear to those skilled in the art. For
example, an "alkyl" moiety can be referred to a monovalent radical
(e.g. CH.sub.3--CH.sub.2--), or in other instances, a bivalent
linking moiety can be "alkyl," in which case those skilled in the
art will understand the alkyl to be a divalent radical (e.g.,
--CH.sub.2--CH.sub.2--), which is equivalent to the term
"alkylene." Similarly, in circumstances in which divalent moieties
are required and are stated as being "alkoxy", "alkylamino",
"aryloxy", "alkylthio", "aryl", "heteroaryl", "heterocyclic",
"alkyl" "alkenyl", "alkynyl", "aliphatic", or "cycloalkyl", those
skilled in the art will understand that the terms alkoxy",
"alkylamino", "aryloxy", "alkylthio", "aryl", "heteroaryl",
"heterocyclic", "alkyl", "alkenyl", "alkynyl", "aliphatic", or
"cycloalkyl" refer to the corresponding divalent moiety.
[0185] The terms "halogen" or "halo" as used herein, refers to an
atom selected from fluorine, chlorine, bromine and iodine.
[0186] The terms "compound" "drug", and "prodrug" as used herein
all include pharmaceutically acceptable salts, co-crystals,
solvates, hydrates, polymorphs, enantiomers, diastereoisomers,
racemates and the like of the compounds, drugs and prodrugs having
the formulas as set forth herein.
[0187] Substituents indicated as attached through variable points
of attachments can be attached to any available position on the
ring structure.
[0188] As used herein, the term "effective amount of the subject
compounds," with respect to the subject method of treatment, refers
to an amount of the subject compound which, when delivered as part
of desired dose regimen, brings about management of the disease or
disorder to clinically acceptable standards.
[0189] "Treatment" or "treating" refers to an approach for
obtaining beneficial or desired clinical results in a patient. For
purposes of this invention, beneficial or desired clinical results
include, but are not limited to, one or more of the following:
alleviation of symptoms, diminishment of extent of a disease,
stabilization (i.e., not worsening) of a state of disease,
preventing spread (i.e., metastasis) of disease, preventing
occurrence or recurrence of disease, delay or slowing of disease
progression, amelioration of the disease state, and remission
(whether partial or total).
[0190] The term "labile" as used herein refers to the capacity of
the prodrug of the invention to undergo enzymatic and/or chemical
cleavage in vivo thereby forming the parent drug. As used herein
the term "prodrug" means a compounds as disclosed herein which is a
labile derivative compound of a parent drug which when administered
to a patient in vivo becomes cleaved by chemical and/or enzymatic
hydrolysis thereby forming the parent drug such that a sufficient
amount of the compound intended to be delivered to the patient is
available for its intended therapeutic use in a sustained release
manner.
[0191] The term "dendrimer" refers to a class of highly branched,
often spherical, macromolecular polymers that exhibit greater
monodispersity (i.e., a smaller range of molecular weights, sizes,
and shapes) than linear polymers of similar size. These
three-dimensional oligomeric structures are prepared by reiterative
reaction sequences starting from a core molecule (such as
diaminobutane or ethylenediamine) that has multiple reactive
groups. When monomer units, also having multiple reactive groups,
are reacted with the core, the number of reactive groups comprising
the outer bounds of the dendrimer increases. Successive layers of
monomer molecules may be added to the surface of the dendrimer,
with the number of branches and reactive groups on the surface
increasing geometrically each time a layer is added. The number of
layers of monomer molecules in a dendrimer may be referred to as
the "generation" of the dendrimer. The total number of reactive
functional groups on a dendrimer's outer surface ultimately depends
on the number of reactive groups possessed by the core, the number
of reactive groups possessed by the monomers that are used to grow
the dendrimer, and the generation of the dendrimer.
Pharmaceutical Compositions
[0192] The pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound of the
present invention formulated together with one or more
pharmaceutically acceptable carriers or excipients.
[0193] As used herein, the term "pharmaceutically acceptable
carrier or excipient" means a non-toxic, inert solid, semi-solid,
gel or liquid filler, diluent, encapsulating material or
formulation auxiliary of any type. Some examples of materials which
can serve as pharmaceutically acceptable carriers are sugars such
as lactose, glucose and sucrose; cyclodextrins such as
alpha-(.alpha.), beta-(.beta.) and gamma-(.gamma.) cyclodextrins;
starches such as corn starch and potato starch; cellulose and its
derivatives such as sodium carboxymethyl cellulose, ethyl cellulose
and cellulose acetate; powdered tragacanth; malt; gelatin; talc;
excipients such as cocoa butter and suppository waxes; oils such as
peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,
corn oil and soybean oil; glycols such as propylene glycol; esters
such as ethyl oleate and ethyl laurate; agar; buffering agents such
as magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0194] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. In a preferred embodiment, administration is parenteral
administration by injection.
[0195] The pharmaceutical compositions of this invention may
contain any conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants or vehicles. In some cases, the pH of the
formulation may be adjusted with pharmaceutically acceptable acids,
bases or buffers to enhance the stability of the formulated
compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0196] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0197] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable suspension or emulsion, such as INTRALIPID.RTM.,
LIPOSYN.RTM. or OMEGAVEN.RTM., or solution, in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. INTRALIPID.RTM. is an intravenous fat
emulsion containing 10-30% soybean oil, 1-10% egg yolk
phospholipids, 1-10% glycerin and water. LIPOSYN.RTM. is also an
intravenous fat emulsion containing 2-15% safflower oil, 2-15%
soybean oil, 0.5-5% egg phosphatides 1-10% glycerin and water.
OMEGAVEN.RTM. is an emulsion for infusion containing about 5-25%
fish oil, 0.5-10% egg phosphatides, 1-10% glycerin and water. Among
the acceptable vehicles and solvents that may be employed are
water, Ringer's solution, USP and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any
bland fixed oil can be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid are used
in the preparation of injectables.
[0198] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0199] Additional sustained release in accordance with the
invention may be accomplished by the use of a liquid suspension of
crystalline or amorphous material with poor water solubility. The
rate of absorption of the drug then depends upon its rate of
dissolution, which, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered drug form is accomplished by dissolving
or suspending the drug in an oil vehicle. Injectable depot forms
are made by forming microencapsule matrices of the drug in
biodegradable polymers such as polylactide-polyglycolide. Depending
upon the ratio of drug to polymer and the nature of the particular
polymer employed, the rate of drug release can be controlled.
Examples of other biodegradable polymers include poly(orthoesters)
and poly(anhydrides). Depot injectable formulations are also
prepared by entrapping the drug in liposomes or microemulsions that
are compatible with body tissues.
[0200] In one preferred embodiment, the formulation provides a
sustained release delivery system that is capable of minimizing the
exposure of the prodrug to water. This can be accomplished by
formulating the prodrug with a sustained release delivery system
that is a polymeric matrix capable of minimizing the diffusion of
water into the matrix. Suitable polymers comprising the matrix
include polylactide (PLA) polymers and the lactide/glycolide (PLGA)
co-polymers.
[0201] Alternatively, the sustained release delivery system may
comprise poly-anionic molecules or resins that are suitable for
injection or oral delivery. Suitable polyanionic molecules include
cyclodextrins and polysulfonates formulated to form a poorly
soluble mass that minimizes exposure of the prodrug to water and
from which the prodrug slowly leaves.
[0202] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0203] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0204] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0205] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions that can be used include
polymeric substances and waxes.
[0206] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[0207] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0208] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
[0209] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0210] For pulmonary delivery, a therapeutic composition of the
invention is formulated and administered to the patient in solid or
liquid particulate form by direct administration e.g., inhalation
into the respiratory system. Solid or liquid particulate forms of
the active compound prepared for practicing the present invention
include particles of respirable size: that is, particles of a size
sufficiently small to pass through the mouth and larynx upon
inhalation and into the bronchi and alveoli of the lungs. Delivery
of aerosolized therapeutics, particularly aerosolized antibiotics,
is known in the art (see, for example U.S. Pat. No. 5,767,068 to
VanDevanter et al., U.S. Pat. No. 5,508,269 to Smith et al., and WO
98/43650 by Montgomery, all of which are incorporated herein by
reference). A discussion of pulmonary delivery of antibiotics is
also found in U.S. Pat. No. 6,014,969, incorporated herein by
reference.
[0211] By a "therapeutically effective amount" of a prodrug
compound of the invention is meant an amount of the compound which
confers a therapeutic effect on the treated subject, at a
reasonable benefit/risk ratio applicable to any medical treatment.
The therapeutic effect may be objective (i.e., measurable by some
test or marker) or subjective (i.e., subject gives an indication of
or feels an effect).
[0212] In accordance with the invention, the therapeutically
effective amount of a prodrug of the invention is typically based
on the target therapeutic amount of the parent drug. Information
regarding dosing and frequency of dosing is readily available for
many parent drugs from which the prodrugs of the invention are
derived and the target therapeutic amount can be calculated for
each prodrug of the invention. In accordance with the invention,
the same dose of a prodrug of the invention provides a longer
duration of therapeutic effect as compared to the parent drug. Thus
if a single dose of the parent drug provides 12 hours of
therapeutic effectiveness, a prodrug of that same parent drug in
accordance with the invention that provides therapeutic
effectiveness for greater than 12 hours will be considered to
achieve a "sustained release".
[0213] The precise dose of a prodrug of the invention depends upon
several factors including the nature and dose of the parent drug
and the chemical characteristics of the prodrug moiety linked to
the parent drug. Ultimately, the effective dose and dose frequency
of a prodrug of the invention will be decided by the attending
physician within the scope of sound medical judgment. The specific
therapeutically effective dose level and dose frequency for any
particular patient will depend upon a variety of factors including
the disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or contemporaneously with the specific compound employed; and like
factors well known in the medical arts.
Examples
STEP 1: Synthesis of
7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4--
dihydroquinolin-2(1H)-one
##STR00527##
[0214] Procedure:
[0215] A mixture of Aripiprazole (5.2 g, 0.012 mol), triethylamine
(0.25 mL, 0.0018 mol), 37% aqueous formaldehyde solution (18.5 mL)
and dimethylformamide (50 mL) was heated at 80.degree. C. for 48
hours. After 48 hours the reaction mixture was cooled to ambient
temperature, diluted with ethyl acetate (200 mL) and washed with
water (2.times.200 mL) and brine (2.times.200 mL). The organic
phase was dried with sodium sulphate, filtered and concentrated in
vacuo to give hemi-aminal as a white solid [5.6 g, containing 43%
Aripiprazole and 56% hemi-aminal (as per LCMS analysis)].
Synthesis of Bis((7-(4-(4-(2,3-dichlorophenyl) piperazin-1-yl)
butoxy)-2oxo-3,4-dihydroquinolin-1(2H)-yl)methyl) decanedioate
##STR00528##
[0216] Procedure:
[0217] A solution of Step-1 reaction mixture (1.0 g, 0.0021 mol) in
dichloromethane (20 mL) was stirred at 25.degree. C. under nitrogen
atmosphere. Triethylamine (1.45 mL, 0.0105 mol) was added drop wise
to the above solution at 25.degree. C. and the resulting reaction
mixture was allowed to stir at the same temperature for next 10
minutes. After 10 minutes a solution of sebacoyl chloride in
dichloromethane (0.223 mL, 0.00105 mol sebacoyl chloride in 2.2 mL
dichloromethane) was added drop wise to the above reaction mixture
at 25.degree. C. The resulting clear reaction mixture was warmed to
45.degree. C. whereby it was allowed to stir for next 2 hours. The
reaction mixture was partitioned between dichloromethane (100 mL)
and water (200 mL) and the aqueous layer was extracted with
dichloromethane (2.times.100 mL). The combined organic fractions
were washed with brine (100 mL), dried over sodium sulphate,
filtered and concentrated in vacuo. The product was purified by
flash chromatography using dichloromethane: methanol as mobile
phase and the desired product eluted at around 1.5% methanol in
dichloromethane to provide Compound-6 [0.3 g, 22% yield].
[0218] .sup.1H NMR (DMSO, 400 MHz) .delta. 1.171 (s, 8H), 1.44-1.49
(m, 4H), 1.56-1.61 (m, 4H), 1.69-1.76 (m, 4H), 2.29 (t, 4H), 2.37
(t, 4H), 2.57 (t, 4H), 2.80 (t, 4H), 2.95 (broad s, 8H), 3.35
(broad s, 8H), 3.97 (t, 4H), 5.86 (broad s, 4H), 6.63-6.65 (m, 4H),
7.09-7.14 (m, 4H), 7.27-7.31 (m, 4H); m/z (M.sup.+H) 1123.
Synthesis of Compound-7: Bis((7-(4-(4-(2,3-dichlorophenyl)
piperazin-1-yl) butoxy)-2oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)
dodecanedioate
##STR00529##
[0219] Procedure:
[0220] A solution of Step-1 (1.0 g, 0.0021 mol) in dichloromethane
(20 mL) was stirred at 25.degree. C. under nitrogen atmosphere.
Triethylamine (1.45 mL, 0.0105 mol) was added drop wise to the
above solution at 25.degree. C. and the resulting reaction mixture
was allowed to stir at the same temperature for next 10 minutes.
After 10 minutes a solution of dodecandioyl dichloride in
dichloromethane (0.280 g, 0.00105 mol dodecandioyl dichloride in
2.5 mL dichloromethane) was added drop wise to the above reaction
mixture at 25.degree. C. The resulting clear reaction mixture was
warmed to 45.degree. C. whereby it was allowed to stir for next 2
hours. The reaction mixture was partitioned between dichloromethane
(100 mL) and water (200 mL) and the aqueous layer was extracted
with dichloromethane (2.times.100 mL). The combined organic were
washed with brine (100 mL), dried over sodium sulphate, filtered
and concentrated in vacuo. The product was purified by flash
chromatography using dichloromethane: methanol as mobile phase and
the desired product eluted at around 1.5% methanol in
dichloromethane. Distillation of the product fractions provided
Compound-7 [0.160 g, 11% yield].
[0221] .sup.1H NMR (DMSO, 400 MHz) .delta. 1.16-1.18 (s, 12H),
1.47-1.50 (m, 4H), 1.57-1.62 (m, 4H), 1.71-1.75 (m, 4H), 2.28-2.32
(t, 4H), 2.38 (t, 4H), 2.57 (t, 4H), 2.80 (t, 4H), 2.95 (broad s,
8H), 3.34 (broad s, 8H), 3.97 (t, 4H), 5.86 (broad s, 4H),
6.63-6.65 (m, 4H), 7.10-7.15 (m, 4H), 7.28-7.31 (m, 4H); m/z
(M.sup.+H) 1149.7.
Synthesis of Compound-8
Synthesis of Tetradecandioyl Dichloride
[0222] Oxalyl chloride (1.35 mL, 0.015 mol) was added drop wise to
a solution of Tetradecandioyl dichloride (1.0 g, 0.0039 mol) in
dichloromethane at 25.degree. C. After the addition was completed,
the reaction mixture was stirred at same temperature for 2 hours,
the reaction mixture was partitioned between dichloromethane (100
mL) and water (200 mL), the aqueous layer was extracted with
dichloromethane (2.times.100 mL). The combined organic extracts
were washed with brine (200 mL), dried over sodium sulphate
filtered and concentrated in vacuo to provide the desired product
(0.9 g, 90% yield) as a colorless liquid which was used directly
for the next step without further purification.
Synthesis of Bis((7-(4-(4-(2,3-dichlorophenyl) piperazin-1-yl)
butoxy)-2oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)tetradecanedioate
##STR00530##
[0224] A solution of Step-1 (1.0 g, 0.0021 mol) in dichloromethane
(20 mL) was stirred at 25.degree. C. under nitrogen atmosphere.
Triethylamine (1.45 mL g, 0.0105 mol) was added drop wise to the
above solution at 25.degree. C. and the resulting reaction mixture
was allowed to stir at the same temperature for next 10 minutes.
After 10 minutes a solution of tetradecandioyl dichloride in
dichloromethane (0.308 g, 0.00105 mol tetradecandioyl dichloride in
3.0 mL dichloromethane) was added drop wise to the above reaction
mixture at 25.degree. C. The resulting clear reaction mixture was
warmed to 45.degree. C. whereby it was allowed to stir for next 2
hours. The reaction mixture was partitioned between dichloromethane
(100 mL) and water (200 mL) and the aqueous layer was extracted
with dichloromethane (2.times.100 mL). The combined organic were
washed with brine (200 mL), dried over sodium sulphate, filtered
and concentrated in vacuo. The product was purified by flash
chromatography using dichloromethane: methanol as mobile phase and
the desired product eluted at around 1.8% methanol in
dichloromethane to provide Compound-8 [0.170 g, 12% yield].
[0225] .sup.1H NMR (DMSO, 400 MHz) .delta. 1.16-1.24 (m 18H),
1.47-1.51 (m, 4H), 1.57-1.62 (m, 4H), 1.70-1.75 (m, 4H), 2.30 (t,
4H), 2.38 (t, 4H), 2.57 (t, 4H), 2.80 (t, 4H), 2.96 (broad s, 8H),
3.34 (broad s, 8H), 3.97 (t, 4H), 5.86 (broad s, 4H), 6.654 (m,
4H), 7.10-7.15 (m, 4H), 7.27-7.31 (m, 4H); m/z (M.sup.+H)
1177.9.
[0226] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *