U.S. patent application number 10/829896 was filed with the patent office on 2004-10-07 for orally administered dosage forms of gaba analog prodrugs having reduced toxicity.
Invention is credited to Cundy, Kenneth C., Gallop, Mark A..
Application Number | 20040198820 10/829896 |
Document ID | / |
Family ID | 27404495 |
Filed Date | 2004-10-07 |
United States Patent
Application |
20040198820 |
Kind Code |
A1 |
Cundy, Kenneth C. ; et
al. |
October 7, 2004 |
Orally administered dosage forms of gaba analog prodrugs having
reduced toxicity
Abstract
The present invention provides an extended release oral dosage
form of prodrugs of gabapentin and other GABA analogs, which dosage
forms exhibit reduced toxicity. The dosage forms are particularly
useful in administering those prodrugs of gabapentin and other GABA
analogs that are metabolized to form an aldehyde. The dosage forms
of the invention are useful for treating or preventing diseases
and/or disorders for which the parent gabapentin or other GABA
analog are known to be therapeutically effective.
Inventors: |
Cundy, Kenneth C.; (Redwood
City, CA) ; Gallop, Mark A.; (Los Altos, CA) |
Correspondence
Address: |
COOLEY GODWARD, LLP
3000 EL CAMINO REAL
5 PALO ALTO SQUARE
PALO ALTO
CA
94306
US
|
Family ID: |
27404495 |
Appl. No.: |
10/829896 |
Filed: |
April 21, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10829896 |
Apr 21, 2004 |
|
|
|
10170127 |
Jun 11, 2002 |
|
|
|
60297521 |
Jun 11, 2001 |
|
|
|
60298514 |
Jun 14, 2001 |
|
|
|
60366090 |
Mar 19, 2002 |
|
|
|
Current U.S.
Class: |
514/557 ;
514/666 |
Current CPC
Class: |
A61K 47/54 20170801;
C07D 213/79 20130101; A61P 25/28 20180101; A61K 31/341 20130101;
A61P 31/00 20180101; C07C 2601/14 20170501; C07D 317/40 20130101;
A61P 43/00 20180101; C07D 307/33 20130101; A61K 31/19 20130101;
C07C 201/12 20130101; A61P 29/00 20180101; A61P 25/22 20180101;
A61P 25/00 20180101; A61P 25/24 20180101; C07D 307/58 20130101;
A61K 31/197 20130101; A61P 19/02 20180101; C07D 213/80 20130101;
A61P 1/06 20180101; A61P 19/00 20180101; C07D 317/32 20130101; A61P
25/08 20180101; A61P 25/04 20180101; A61P 25/20 20180101; A61K
31/22 20130101; A61P 25/02 20180101; A61P 25/18 20180101; A61P
25/32 20180101; A61P 39/02 20180101; A61K 47/555 20170801; A61P
25/14 20180101; A61P 1/02 20180101; A61P 1/04 20180101; C07C 323/58
20130101; A61K 31/27 20130101; A61P 1/00 20180101; C07D 307/60
20130101; C07D 267/06 20130101; C07C 271/22 20130101; C07C 201/12
20130101; C07C 205/43 20130101 |
Class at
Publication: |
514/557 ;
514/666 |
International
Class: |
A61K 031/19; A61K
031/13 |
Claims
1. A method of reducing toxicity of an orally administered
therapeutic GABA analog, comprising: formulating the GABA analog as
a prodrug comprised of the therapeutic GABA analog covalently bound
to a cleavable promoiety; placing the prodrug in a sustained
release oral dosage form; introducing the dosage form into the
intestinal lumen of a patient by having the patient swallow the
dosage form; releasing the prodrug gradually into the intestinal
lumen of the patient over a period of hours; and cleaving the
promoiety from the prodrug to provide a therapeutic concentration
of the GABA analog in the plasma of the patient.
2. The method of claim 1, wherein the toxicity of the GABA analog
administered from said sustained release oral dosage form is less
than the toxicity of an equivalent dose of the GABA analog
administered from an immediate release oral dosage form.
3. The method of claim 1, wherein the toxicity of the promoiety
administered from said sustained oral release dosage form, and any
metabolites thereof, is less than the toxicity of the promoiety,
and any metabolites thereof, administered at an equivalent dose
from an immediate release oral dosage form.
4. The method of any of claims 1 to 3, wherein the promoiety
metabolizes to form an aldehyde.
5. The method of claim 4, wherein the aldehyde comprises
formaldehyde.
6. The method of any one of claims 1 to 3, wherein the promoiety
metabolizes to form an acid that depletes carnitine in said
patient.
7. The method of claim 6, wherein the acid comprises pivalic
acid.
8. The method of claim 1, wherein the period of hours comprises at
least about 6 hours.
9. The method of claim 1, wherein the period of hours comprises at
least about 8 hours.
10. The method of claim 1, wherein the period of hours comprises at
least about 12 hours.
11. The method of claim 1, wherein the dosage form releases from 0
to 20% of the prodrug in 0 to 2 hours, from 20 to 50% of the
prodrug in 2 to 12 hours, from 50 to 85% of the prodrug in 3 to 20
hours and greater than 75% of the prodrug in 5 to 18 hours.
12. The method of claim 1, wherein the concentration of the GABA
analog in plasma of the patient over time provides a curve of
concentration of the GABA analog in the plasma over time, the curve
having an area under the curve (AUC) which is proportional to the
dose of GABA analog administered.
13. The method of claim 12, wherein the curve has a maximum plasma
concentration (C.sub.max) which is proportional to the dose of GABA
analog administered.
14. The method of any one of claims 1, 12 or 13, wherein the
C.sub.max is less than 75% of the C.sub.max obtained from
administering an equivalent dose of the prodrug from an immediate
release oral dosage form, and the AUC is at least 50% of the AUC
obtained from administering an equivalent dose of the prodrug from
an immediate release oral dosage form.
15. The method of any one of claims 1, 12 or 13, wherein the
C.sub.max is less than 60% of the C.sub.max obtained from
administering an equivalent dose of the prodrug from an immediate
release oral dosage form, and the AUC is at least 75% of the AUC
obtained from administering an equivalent dose of the prodrug from
an immediate release oral dosage form.
16. The method of claim 14, wherein the AUC is substantially the
same as the AUC obtained from administering an equivalent dose of
the prodrug from an immediate release oral dosage form.
17. The method of claim 15, wherein the AUC is substantially the
same as the AUC obtained from administering an equivalent dose of
the prodrug from an immediate release oral dosage form.
18. An oral dosage form of a GABA analog prodrug, comprising: a
sustained release oral dosage form containing a GABA analog prodrug
comprised of a therapeutic GABA analog covalently bound to a
cleavable promoiety, the dosage form being adapted to be swallowed
by a patient in order to introduce the dosage form into an
intestinal lumen of the patient; the dosage form further being
adapted to release the prodrug gradually into the intestinal lumen
of the patient over a period of hours after said swallowing, said
gradual release causing the GABA analog to be cleaved from the
promoiety after said swallowing and providing a therapeutic
concentration of the GABA analog in the plasma of the patient.
19. The dosage form of claim 18, wherein the promoiety metabolizes
to form an aldehyde.
20. The dosage form of claim 19, wherein the aldehyde comprises
formaldehyde.
21. The dosage form of claim 18, wherein the promoiety metabolizes
to form an acid that depletes carnitine in said patient.
22. The dosage form of claim 20, wherein the acid comprises pivalic
acid.
23. The dosage form of claim 18, wherein the period of hours
comprises at least about 6 hours.
24. The dosage form of claim 18, wherein the period of hours
comprises at least about 8 hours.
25. The dosage form of claim 18, wherein the period of hours
comprises at least about 12 hours.
26. The dosage form of claim 18, wherein the dosage form releases
from 0 to 20% of the prodrug in 0 to 2 hours, from 20 to 50% of the
prodrug in 2 to 12 hours, from 50 to 85% of the prodrug in 3 to 20
hours and greater than 75% of the prodrug in 5 to 18 hours.
27. The dosage form of claim 18, wherein the dosage form, upon
swallowing, provides a curve of concentration of the GABA analog in
the plasma over time, the curve having an area under the curve
(AUC) which is proportional to the dose of GABA analog
administered.
28. The dosage form of claim 18, wherein the curve has a maximum
plasma concentration (C.sub.max) which is proportional to the dose
of GABA analog administered.
29. The dosage form of claim 27 or 28, wherein the C.sub.max is
less than 75% of the C.sub.max obtained from administering an
equivalent dose of the prodrug from an immediate release oral
dosage form and the AUC is at least 50% of an AUC obtained from
administering an equivalent dose of the prodrug from an immediate
release oral dosage form.
30. The dosage form of claim 27 or 28, wherein the C.sub.max is
less than 60% of the C.sub.max obtained from administering an
equivalent dose of the prodrug from an immediate release oral
dosage form, and the AUC is at least 75% of the AUC obtained from
administering an equivalent dose of the prodrug from an immediate
release oral dosage form.
31. The dosage form of claim 29, wherein the AUC is substantially
the same as the AUC obtained from administering an equivalent dose
of the prodrug from an immediate release oral dosage form.
32. The dosage form of claim 30, wherein the AUC is substantially
the same as the AUC obtained from administering an equivalent dose
of the prodrug from an immediate release oral dosage form.
33. The dosage form of claim 18, wherein the dosage form comprises
an osmotic dosage form.
34. The dosage form of claim 18, wherein the dosage form comprises
a prodrug-releasing polymer.
35. The dosage form of claim 18, wherein the dosage form comprises
a prodrug-releasing lipid.
36. The dosage form of claim 18, wherein the dosage form comprises
a prodrug-releasing wax.
37. The dosage form of claim 18, wherein the dosage form comprises
tiny timed-release pills.
38. The dosage form of claim 18, wherein the dosage form comprises
prodrug releasing beads.
39. A method of orally administering a GABA analog prodrug,
comprising: formulating the GABA analog as a prodrug comprised of
the therapeutic GABA analog covalently bound to a cleavable
promoiety; placing the prodrug in a sustained release oral dosage
form; introducing the dosage form into the intestinal lumen of a
patient by having the patient swallow the dosage form; releasing
the prodrug gradually from the swallowed dosage form into the
intestinal lumen of the patient over a period of hours; and
allowing the GABA analog to be cleaved from the promoiety after
said swallowing to provide a therapeutic concentration of the GABA
analog in the plasma of the patient.
40. The method of claim 39, wherein the promoiety metabolizes to
form an aldehyde.
41. The method of claim 40, wherein the aldehyde comprises
formaldehyde.
42. The method of claim 39, wherein the promoiety metabolizes to
form an acid that depletes carnitine in said patient.
43. The method of claim 39, wherein the period of hours comprises
at least about 6 hours.
44. The method of claim 39, wherein the period of hours comprises
at least about 8 hours.
45. The method of claim 39, wherein the period of hours comprises
at least about 12 hours.
46. The method of claim 39, wherein the dosage form releases from 0
to 20% of the prodrug in 0 to 2 hours, from 20 to 50% of the
prodrug in 2 to 12 hours, from 50 to 85% of the prodrug in 3 to 20
hours and greater than 75% of the prodrug in 5 to 18 hours.
47. The method of claim 39, wherein the concentration of the GABA
analog in plasma of the patient over time provides a curve of
concentration of the GABA analog in the plasma over time, the curve
having an area under the curve (AUC) which is proportional to the
dose of GABA analog administered.
48. The method of claim 39, wherein the curve has a maximum plasma
concentration (C.sub.max) which is proportional to the dose of GABA
analog administered.
49. The method of claim 47 or 48, wherein the C.sub.max is less
than 75% of the C.sub.max obtained from administering an equivalent
dose of the prodrug from an immediate release oral dosage form and
the AUC is at least 50% of an AUC obtained from administering an
equivalent dose of the prodrug from an immediate release oral
dosage form.
50. The method of claim 47 or 48, wherein the C.sub.max is less
than 60% of the C.sub.max obtained from administering an equivalent
dose of the prodrug from an immediate release oral dosage form and
the AUC is at least 75% of an AUC obtained from administering an
equivalent dose of the prodrug from an immediate release oral
dosage form.
51. The method of claim 49, wherein the AUC is substantially the
same as the AUC obtained from administering an equivalent dose of
the prodrug from an immediate release oral dosage form.
52. The method of claim 50, wherein the AUC is substantially the
same as the AUC obtained from administering an equivalent dose of
the prodrug from an immediate release oral dosage form
Description
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) from U.S. Provisional Application Serial No. 60/297,521
filed Jun. 11, 2001; U.S. Provisional Application Serial
No.60/298,514 filed Jun. 14, 2001; and U.S. Provisional Application
Serial No.60/366,090 filed Mar. 19, 2002, which are herein
incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to prodrugs of GABA
analogs which are adapted to be administered orally, and dosage
forms for administering these prodrugs of GABA analogs to reduce
their toxicity.
BACKGROUND OF THE INVENTION
[0003] Gamma (".gamma.")-aminobutyric acid ("GABA") is one of the
major inhibitory transmitters in the central nervous system of
mammals. GABA is not transported efficiently into the brain from
the bloodstream (i.e., GABA does not effectively cross the
blood-brain barrier). Consequently, brain cells provide virtually
all of the GABA found in the brain (GABA is biosynthesized by
decarboxylation of glutamic acid with pyridoxal phosphate).
[0004] GABA regulates neuronal excitability through binding to
specific membrane proteins (i.e., GABAA receptors), which results
in opening of an ion channel. The entry of chloride ion through the
ion channel leads to hyperpolarization of the recipient cell, which
consequently prevents transmission of nerve impulses to other
cells. Low levels of GABA have been observed in individuals
suffering from epileptic seizures, motion disorders (e.g., multiple
sclerosis, action tremors, tardive dyskinesia), panic, anxiety,
depression, alcoholism and manic behavior.
[0005] The implication of low GABA levels in a number of common
disease states and/or common medical disorders has stimulated
intensive interest in preparing GABA analogs, which have superior
pharmaceutical properties in comparison to GABA (e.g., the ability
to cross the blood brain barrier). Accordingly, a number of GABA
analogs, with considerable pharmaceutical activity have been
synthesized in the art (See, e.g., Satzinger et al., U.S. Pat. No.
4,024,175; Silverman et al., U.S. Pat. No. 5,563,175; Horwell et
al., U.S. Pat. No. 6,020,370; Silverman et al., U.S. Pat. No.
6,028,214; Horwell et al., U.S. Pat. No. 6,103,932; Silverman et
al., U.S. Pat. No. 6,117,906; Silverman, International Publication
No. WO 92/09560; Silverman et al., International Publication No. WO
93/23383; Horwell et al., International Publication No. WO
97/29101, Horwell et al., International Publication No. WO
97/33858; Horwell et al., International Publication No. WO
97/33859; Bryans et al., International Publication No. WO 98/17627;
Guglietta et al., International Publication No. WO 99/08671; Bryans
et al., International Publication No. WO 99/21824; Bryans et al.,
International Publication No. WO 99/31057; Belliotti et al.,
International Publication No. WO 99/31074; Bryans et al.,
International Publication No. WO 99/31075; Bryans et al.,
International Publication No. WO 99/61424; Bryans et al.,
International Publication No. WO 00/15611; Bryans, International
Publication No. WO 00/31020; Bryans et al., International
Publication No. WO 00/50027; and Bryans et al., International
Publication No. WO 02/00209).
[0006] However, many GABA analogs, including those described above
exhibit poor oral absorption across the gut wall. One potential
solution to the above problem is converting GABA analogs to
prodrugs of GABA analogs (Bryans et al., International Publication
No. WO 01/90052; U.K. Application GB 2,362,646; European
Applications EP 1,201,240 and 1,178,034; Yatvin et al., U.S. Pat.
No. 6,024,977; Gallop et al., U.S. patent application Ser. No.
______, entitled "Prodrugs of GABA Analogs, Compositions and Uses
Thereof"; Gallop et al International Publication No. WO 02/28881;
Gallop et al, International Publication No. WO 02/28883; Gallop et
al, International Publication No. WO 02/28411; Gallop et al,
International Publication No. WO 02/32376; Gallop et al,
International Publication No. WO 02/42414). Typically, in a
prodrug, a polar functional group (e.g., a carboxylic acid, an
amino group, a hydroxyl group, etc.) is masked by a promoiety,
which is labile under physiological conditions. Accordingly,
prodrugs are usually transported through hydrophobic biological
barriers such as membranes and typically possess superior
physicochemical properties in comparison to the parent drug.
[0007] Pharmacologically effective prodrugs are ideally non-toxic
and are preferably selectively cleaved at the locus of drug action.
Ideally, cleavage of the promoiety occurs rapidly and
quantitatively with the formation of non-toxic by-products (i.e.,
the hydrolyzed promoiety).
[0008] Many GABA analog prodrugs exhibit unacceptable toxicity when
administered orally in conventional dosage forms. In part this is
due to the high doses required for many GABA analog therapy and in
part because most of the therapeutic indications for GABA analogs
require long-term chronic administration (i.e., administration for
periods of months, years or even for the remaining lifetime of the
patient). Additional problems may be caused by the chemical
structure of the promoiety, which may hydrolyze to toxic
metabolites (e.g., aldehydes or acids). Accordingly, what is needed
is a method for reducing toxicity when administering prodrugs of
GABA analogs. Ideally, the above method is particularly effective
when the promoiety hydrolyzes to provide toxic metabolites.
SUMMARY OF THE INVENTION
[0009] The present invention addresses these and other needs by
providing oral dosage forms for prodrugs of GABA analogs which
exhibits lower toxicity than conventional oral dosage forms of
these same prodrugs. The oral dosage form of the present invention
has particular utility in administering prodrugs of GABA analogs
which are metabolized to form an aldehyde. In addition, the dosage
forms of the present invention may be used to administer prodrugs
of GABA analogs which are metabolized to form acids which deplete
the body's carnitine reserves. The present invention also provides
methods for treating patients using these dosage forms. In one
aspect, the current invention comprises an oral sustained release
dosage form for administering a prodrug of a GABA analog. In
another aspect, the invention comprises a method of reducing
toxicity of orally administered GABA analogs. The above method
includes formulating the GABA analog as a prodrug, comprised of the
GABA analog covalently bound to a cleavable promoiety. The GABA
analog prodrug is placed in a sustained release oral dosage form
and the dosage form is introduced into an intestinal lumen of a
patient by having the patient swallow the dosage form. The method
further includes releasing the prodrug gradually from the swallowed
dosage form into the intestinal lumen of the patient over a period
of hours and allowing the GABA analog to be cleaved from the
promoiety after swallowing to provide a therapeutic concentration
of the GABA analog in the blood plasma of the patient. When
following this method, the toxicity of the prodrug of the GABA
analog is less than a toxicity of an equivalent dose of the prodrug
administered from an immediate release oral dosage form. In one
preferred embodiment, the prodrug is metabolized to form an
aldehyde (e.g., formaldehyde). In another embodiment, the prodrug
is metabolized to form an acid which depletes the body's carnitine
reserves, (e.g., pivalic acid).
[0010] Preferably, the prodrug is released from the dosage form
over a period of at least about 6 hours, more preferably, over a
period of at least about 8 hours, and most preferably, over a
period of at least about 12 hours. Further, the dosage form
preferably releases from 0 to 20% of the prodrug in 0 to 2 hours,
from 20 to 50% of the prodrug in 2 to 12 hours, from 50 to 85% of
the prodrug in 3 to 20 hours and greater than 75% of the prodrug in
5 to 18 hours.
[0011] In a preferred embodiment, the current invention provides an
oral dosage form of a prodrug of a GABA analog, wherein the dosage
form, upon swallowing, provides a curve of concentration of the
GABA analog in the plasma over time, the curve having an area under
the curve (AUC) which is proportional to the dose of GABA analog
administered, and preferably, also has a maximum concentration
C.sub.max that is proportional to the dose of GABA analog
administered. In one embodiment, the C.sub.max is less than 75%,
and is preferably less than 60%, of the C.sub.max obtained from
administering an equivalent dose of the prodrug from an immediate
release oral dosage form. Preferably, the AUC is at least 50% of
the AUC obtained from administering an equivalent dose of the
prodrug from an immediate release oral dosage forn((more
preferably, at least 75% of the AUC obtained from administering an
equivalent dose of the prodrug from an immediate release oral
dosage form) and most preferably, substantially the same as, the
AUC obtained from administering an equivalent dose of the prodrug
from an immediate release oral dosage form).
[0012] The oral sustained release dosage forms of the present
invention can take any form as long as the release characteristics
and pharmacokinetic profiles above are satisfied. For example, the
dosage form can be in the form of an osmotic dosage form, a
prodrug-releasing polymer, prodrug-releasing tiny timed-release
pills, prodrug-releasing lipids, prodrug-releasing waxes and/or
prodrug releasing beads.
[0013] The dosage forms and administration methods of the present
invention may be useful for treating or preventing epilepsy,
depression,.anxiety, psychosis, faintness attacks, hypokinesia,
cranial disorders, neurodegenerative disorders, panic, pain
(especially, neuropathic pain and muscular and skeletal pain),
inflammatory disease (i.e., arthritis), insomnia, gastrointestinal
disorders or ethanol withdrawal syndrome.
DISCLOSURE OF THE INVENTION
[0014] Definitions
[0015] "Active transport or active transport process" refers to the
movement of molecules across cellular membranes that:
[0016] a) is directly or indirectly dependent on an energy mediated
process (i.e., driven by ATP hydrolysis, ion gradient, etc.);
or
[0017] b) occurs by facilitated diffusion mediated by interaction
with specific transporter proteins.
[0018] "Alkyl" refers to a saturated or unsaturated, branched,
straight-chain or cyclic monovalent hydrocarbon radical derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene or alkyne. Typical alkyl groups include, but
are not limited to, methyl; ethyls such as ethanyl, ethenyl,
ethynyl; propyls such as propan-1-yl, propan-2-yl,
cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl
(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl ,
prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl , but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl,
but-3-yn-1-yl, etc.; and the like.
[0019] The term "alkyl" is specifically intended to include groups
having any degree or level of saturation, i.e., groups having
exclusively single carbon-carbon bonds, groups having one or more
double carbon-carbon bonds, groups having one or more triple
carbon-carbon bonds and groups having mixtures of single, double
and triple carbon-carbon bonds. Where a specific level of
saturation is intended, the expressions "alkanyl," "alkenyl," and
"alkynyl" are used. Preferably, an alkyl group comprises from 1 to
20 carbon atoms, more preferably, from 1 to 10 carbon atoms.
[0020] "Alkanyl" refers to a saturated branched, straight-chain or
cyclic alkyl radical derived by the removal of one hydrogen atom
from a single carbon atom of a parent alkane. Typical alkanyl
groups include, but are not limited to, methanyl; ethanyl;
propanyls such as propan-1-yl, propan-2-yl (isopropyl),
cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,
butan-.sup.2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),
2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the
like.
[0021] "Alkenyl" refers to an unsaturated branched, straight-chain
or cyclic alkyl radical having at least. one carbon-carbon double
bond derived by the removal of one hydrogen atom from a single
carbon atom of a parent alkene. The group may be in either the cis
or trans conformation about the double bond(s). Typical alkenyl
groups include, but are not limited to, ethenyl; propenyls such as
prop-1-en-1-yl , prop-1-en-2-yl, prop-2-en-1-yl (allyl),
prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl ; butenyls
such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl , but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, etc.; and the like.
[0022] "Alkynyl" refers to an unsaturated branched, straight-chain
or cyclic alkyl radical having at least one carbon-carbon triple
bond derived by the removal of one hydrogen atom from a single
carbon atom of a parent alkyne. Typical alkynyl groups include, but
are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl,
prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,
but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
[0023] "Acyl" refers to a radical --C(O)R, where R is hydrogen,
alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl as defined herein. Representative
examples include, but are not limited to formyl, acetyl,
cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,
benzylcarbonyl and the like.
[0024] "Acylamino" (or alternatively "acylamido") refers to a
radical --NR'C(O)R, where R' and R are each independently hydrogen,
alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl, as defined herein. Representative
examples include, but are not limited to, formylamino, acetylamino
(i.e., acetamido), cyclohexylcarbonylamino,
cyclohexylmethyl-carbonylamino, benzoylamino (i.e., benzamido),
benzylcarbonylamino and the like.
[0025] "Acyloxy" refers to a radical --OC(O)R, where R is hydrogen,
alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl or heteroarylalkyl, as defined herein. Representative
examples include, but are not limited to, acetyloxy (or acetoxy),
butyloxy (or butoxy), benzoyloxy and the like.
[0026] "Alkylamino" means a radical --NHR where R represents an
alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methylamino, ethylamino,
1-methylethylamino, cyclohexyl amino and the like.
[0027] "Alkoxy" refers to a radical --OR where R represents an
alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methoxy, ethoxy, propoxy,
butoxy, cyclohexyloxy and the like.
[0028] "Alkoxycarbonyl" refers to a radical --C(O)-alkoxy where
alkoxy is as defined herein.
[0029] "Alkylsulfonyl" refers to a radical --S(O).sub.2R where R is
an alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methylsulfonyl,
ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
[0030] "Alkylsulfinyl" refers to a radical --S(O)R where R is an
alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methylsulfinyl,
ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.
[0031] "Alkylthio" refers to a radical --SR where R is an alkyl or
cycloalkyl group as defined herein that may be optionally
substituted as defined herein. Representative examples include, but
are not limited to methylthio, ethylthio, propylthio, butylthio and
the like.
[0032] "Amino" refers to the radical --NH.sub.2.
[0033] "Aryl" refers to a monovalent aromatic hydrocarbon group
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include,
but are not limited to, groups derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene and the like. Preferably, an aryl group comprises
from 6 to 20 carbon atoms, more preferably between 6 to 12 carbon
atoms.
[0034] "Arylalkyl" refers to an acyclic alkyl group in which one of
the hydrogen atoms bonded to a carbon atom, typically a terminal or
sp.sup.3 carbon atom, is replaced with an aryl group. Typical
arylalkyl groups include, but are not limited to, benzyl,
2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,
2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,
2-naphthophenylethan-1-yl and the like. Where specific alkyl
moieties are intended, the nomenclature arylalkanyl, arylalkenyl
and/or arylalkynyl is used. Preferably, an arylalkyl group is
(C.sub.6-C.sub.30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl
moiety of the arylalkyl group is (C.sub.1-C.sub.10) and the aryl
moiety is (C.sub.6-C.sub.20), more preferably, an arylalkyl group
is (C.sub.6-C.sub.20) arylalkyl, e.g., the alkanyl, alkenyl or
alkynyl moiety of the arylalkyl group is (C.sub.1-C.sub.8) and the
aryl moiety is (C.sub.6-C.sub.12).
[0035] "Arylalkyloxy" refers to an --O---arylalkyl group where
arylalkyl is as defined herein.
[0036] "Aryloxycarbonyl" refers to a radical --C(O)--O-aryl where
aryl is as defined herein.
[0037] "AUC" is the area under the plasma drug
concentration-versus-time curve extrapolated from zero time to
infinity.
[0038] "Bridged cycloalkyl" refers to a radical selected from the
group consisting of 1
[0039] wherein:
[0040] A is (CR.sup.35R.sup.36).sub.b;
[0041] R.sup.35 and R.sup.36 are independently selected from the
group consisting of hydrogen and methyl;
[0042] R.sup.33 and R.sup.34 are independently selected from the
group consisting of hydrogen and methyl;
[0043] b is an integer from 1 to 4; and
[0044] c is an integer from 0 to 2.
[0045] "Carbamoyl" refers to the radical --C(O)N(R).sub.2 where
each R group is independently hydrogen, alkyl, cycloalkyl or aryl
as defined herein, which may be optionally substituted, as defined
herein.
[0046] "Carboxy" means the radical --C(O)OH.
[0047] "Carcinogenic potency (TD o)" (see Peto et al.,
Environmental Health Perspectives 1984, 58, 1-8) is defined for-a
particular compound in a given animal species as that chronic
dose-rate in mg/kg body wt/day which would induce tumors in half
the test animals at the end of a standard lifespan for the species.
Since the tumor(s) of interest often does occur in control animals,
TDso is more precisely defined as: that dose-rate in mg/kg body
wt/day which, if administered chronically for the standard lifespan
of the species, will halve the probability of remaining tumorless
throughout that period. A TD.sub.50 can be computed for any
particular type of neoplasm, for any particular tissue, or for any
combination of these.
[0048] "C.sub.max" is the highest drug concentration observed in
plasma following an extravascular dose of drug.
[0049] "Compounds used in the invention" refers to GABA analog
prodrug compounds encompassed by generic formulae disclosed herein
and includes any specific compounds within that formula whose
structure is disclosed herein. The compounds used in the invention
may be identified either by their chemical structure and/or
chemical name. When the chemical structure and chemical name
conflict, the chemical structure is determinative of the identity
of the compound. The compounds used in the invention may contain
one or more chiral centers and/or double bonds and therefore, may
exist as stereoisomers, such as double-bond isomers (i.e.,
geometric isomers), enantiomers or diastereomers. Accordingly, the
chemical structures depicted herein encompass all possible
enantiomers and stereoisomers of the illustrated compounds
including the stereoisomerically pure form (e.g., geometrically
pure, enantiomerically pure or diastereomerically pure) and
enantiomeric and stereoisomeric mixtures. Enantiomeric and
stereoisomeric mixtures can be resolved into their component
enantiomers or stereoisomers using separation techniques or chiral
synthesis techniques well known to the skilled artisan. The
compounds used in the invention may also exist in several
tautomeric forms including the enol form, the keto form and
mixtures thereof. Accordingly, the chemical structures depicted
herein encompass all possible tautomeric forms of the illustrated
compounds. The compounds used in the invention also include
isotopically labeled compounds where one or more atoms have an
atomic mass different from the atomic mass conventionally found in
nature. Examples of isotopes that may be incorporated into the
compounds of the invention include, but are not limited to,
.sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F and .sup.36Cl. Further, it
should be understood, when partial structures of the compounds used
in the invention are illustrated, that brackets indicate the point
of attachment of the partial structure to the rest of the
molecule.
[0050] "Composition used in the invention" refers to at least one
GABA analog prodrug used in the invention and a pharmaceutically
acceptable vehicle, with which the prodrug is administered to a
patient. When administered to a patient, the prodrugs are
administered in isolated form, which means separated from a
synthetic organic reaction mixture.
[0051] "Cyano" means the radical --CN.
[0052] "Cycloalkyl" refers to a saturated or unsaturated cyclic
alkyl radical. Where a specific level of saturation is intended,
the nomenclature "cycloalkanyl" or "cycloalkenyl" is used. Typical
cycloalkyl groups include, but are not limited to, groups derived
from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the
like. Preferably, the cycloalkyl group is (C.sub.3-CIO) cycloalkyl,
more preferably (C.sub.3-C.sub.7) cycloalkyl.
[0053] "Cycloheteroalkl" refers to a saturated or unsaturated
cyclic alkyl radical in which one or more carbon atoms (and any
associated hydrogen atoms) are independently replaced with the same
or different heteroatom. Typical heteroatoms to replace the carbon
atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where
a specific level of saturation is intended, the nomenclature
"cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Typical
cycloheteroalkyl groups include, but are not limited to, groups
derived from epoxides, imidazolidine, morpholine, piperazine,
piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the
like.
[0054] "Cycloheteroalkyloxycarbonyl" refers to a radical --C(O)--OR
where R is cycloheteroalkyl is as defined herein.
[0055] "Derived from a bile acid" refers to a moiety that is
structurally related to a compound of Formulae (V) or (VI): 2
[0056] wherein each of D, E and F are independently H or OH.
[0057] The structure of the moiety is identical to the compound
except at 1 or 2 positions. At these positions, a hydrogen atom
attached to a hydroxyl group and/or the hydroxyl moiety of the
carboxylic acid group has been replaced with a covalent bond that
serves as a point of attachment to another moiety, which is
preferably a GABA analog.
[0058] "Derived from a GABA analog" refers to a moiety that is
structurally related to a GABA analog. The structure of the moiety
is identical to the compound except at 1 or 2 positions. At these
positions, a hydrogen atom attached to the amino group and
(optionally) the hydroxyl moiety of the carboxylic acid group has
been replaced with a covalent bond that serves as a point of
attachment to another moiety.
[0059] "Dialkylamino" means a radical --NRR' where R and R'
independently represent an alkyl or cycloalkyl group as defined
herein. Representative examples include, but are not limited to,
dimethylamino, methylethylamino, di-(1-methylethyl)amino,
(cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino,
(cyclohexyl)(propyl)amino and the like.
[0060] "GABA analog" refers to a compound, unless specified
otherwise, as having the following structure: 3
[0061] wherein:
[0062] R is hydrogen, or R and R.sup.6 together with the atoms to
which they are attached form an azetidine, substituted azetidine,
pyrrolidine or substituted pyrrolidine ring;
[0063] R.sup.3 and R.sup.6 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl and substituted heteroarylalkyl; and
[0064] R.sup.4 and R.sup.5 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, acyl,
substituted acyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl and substituted heteroarylalkyl or optionally,
R.sup.4 and R.sup.5 together with the carbon atom to which they are
attached form a cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl or bridged
cycloalkyl ring.
[0065] "Halo" means fluoro, chloro, bromo, or iodo.
[0066] "Heteroalkyloxy" means an --O---heteroalkyl group where
heteroalkyl is as defined herein.
[0067] "Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl"
refer to alkyl, alkanyl, alkenyl and alkynyl radical, respectively,
in which one or more of the carbon atoms (and any associated
hydrogen atoms) are each independently replaced with the same or
different heteroatomic groups. Typical heteroatomic groups include,
but are not limited to, --O--, --S--, --O--O--, --S--S--, --O--S--,
--NR'--, .dbd.N--N.dbd., --N.dbd.N--, --N.dbd.N--NR'--, --PH--,
--P(O).sub.2--, --O--P(O).sub.2--, --S(O)--, --S(O).sub.2--,
--SnH.sub.2-- and the like, where R' is hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or
substituted aryl.
[0068] "Heteroarvl" refers to a monovalent heteroaromatic radical
derived by the removal of one hydrogen atom from a single atom of a
parent heteroaromatic ring system. Typical heteroaryl groups
include, but are not limited to, groups derived from acridine,
arsindole, carbazole, .beta.-carboline, chromane, chromene,
cinnoline, furan, imidazole, indazole, indole, indoline,
indolizine, isobenzofuran, isochromene, isoindole, isoindoline,
isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,
oxazole, perimidine, phenanthridine, phenanthroline, phenazine,
phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine,
quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,
thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
Preferably, the heteroaryl group is between 5-20 membered
heteroaryl, more preferably between 5-10 membered heteroaryl.
Preferred heteroaryl groups are those derived from thiophene,
pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline,
imidazole, oxazole and pyrazine.
[0069] "Heteroaryloxycarbonyl" refers to a radical --C(O)--OR where
R is heteroaryl as defined herein.
[0070] "Heteroarylalkyl" refers to an acyclic alkyl group in which
one of the hydrogen atoms bonded to a carbon atom, typically a
terminal or sp.sup.3 carbon atom, is replaced with a heteroaryl
group. Where specific alkyl moieties are intended, the nomenclature
heteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is
used. In preferred embodiments, the heteroarylalkyl group is a 6-30
membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl
moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl
moiety is a 5-20-membered heteroaryl, more preferably, 6-20
membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl
moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl
moiety is a 5-12-membered heteroaryl.
[0071] "Passive diffusion" refers to uptake of an agent that is not
mediated by a specific transporter protein. An agent that is
substantially incapable of passive diffusion has a permeabilty
across a standard cell monolayer (e.g., Caco-2) in vitro of less
than 5.times.10.sup.-6 cm/sec, and usually less than
1.times.10.sup.-6 cm/sec (in the absence of an efflux
mechanism).
[0072] "Patient" includes humans. The terms "human" and "patient"
are used interchangeably herein.
[0073] "Pharmaceutically acceptable" means approved or approvable
by a regulatory agency of the Federal or a state government or
listed in the U.S. Pharmacopoeia or other generally recognized
pharmacopeias for use in animals, and more particularly in
humans.
[0074] "Pharmaceutically acceptable salt" refers to a salt of a
compound of the invention that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. Such salts include: (1) acid addition salts, formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-- 2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the
like.
[0075] "Pharmaceutically acceptable vehicle" refers to a diluent,
adjuvant, excipient or carrier with which a compound of the
invention is administered.
[0076] "Preventing" or "prevention" refers to a reduction in risk
of acquiring a disease or disorder (i.e., causing at least one of
the clinical symptoms of the disease not to develop in a patient
that may be exposed to or predisposed to the disease but does not
yet experience or display symptoms of the disease).
[0077] "Prodrug" refers to a derivative of a drug molecule that
requires a transformation within the body to release the active
drug. Prodrugs are frequently (though not necessarily)
pharmacologically inactive until converted to the parent drug.
[0078] "Promoiety" refers to a form of protecting group that when
used to mask a functional group within a drug molecule converts the
drug into a prodrug. Typically, the promoiety will be attached to
the drug via bond(s) that are cleaved by enzymatic or non-enzymatic
means in vivo.
[0079] "Protecting group" refers.to a grouping of atoms that when
attached to a reactive functional group in a molecule masks,
reduces or prevents reactivity of the flnctional group. Examples of
protecting groups can be found in Green et al., "Protective Groups
in Organic Chemistry", (Wiley, 2.sup.nd ed. 1991) and Harrison et
al., "Compendium of Synthetic Organic Methods", Vols. 1-8 (John
Wiley and Sons, 1971-1996). Representative amino protecting groups
include, but are not limited to, formyl, acetyl, trifluoroacetyl,
benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"),
trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"),
trityl and substituted trityl groups, allyloxycarbonyl,
9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl
("NVOC") and the like. Representative hydroxy protecting groups
include, but are not limited to, those where the hydroxy group is
either acylated or alkylated such as benzyl, and trityl ethers as
well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl
ethers and allyl ethers.
[0080] "Substituted" refers to a group in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s). Typical substituents include, but are not
limited to, --X, --R.sup.29, --O.sup.-, .dbd.O, --OR.sup.29,
--SR.sup.29, --S.sup.-, .dbd.S, --NR.sup.29R.sup.30,
.dbd.NR.sup.29, --CX.sub.3, --CF.sub.3, --CN, --OCN, --SCN, --NO,
--NO.sub.2, .dbd.N.sub.2, --N.sub.3, --S(O).sub.2O, --S(O).sub.2OH,
--S(O).sub.2R.sup.29, --OS(O.sub.2)O--, --OS(O).sub.2R.sup.29,
--P(O)(O.sup.-).sub.2, --P(O)(OR.sup.29) (O.sup.-), --OP(O)
(OR.sup.29) (OR.sup.30), --C(O)R.sup.29, --C(S)R.sup.29,
--C(O)OR.sup.29, --C(O)NR.sup.29R.sup.30,--C(O)O.sup.-,
--C(S)OR.sup.29, --NR.sup.31C(O)NR.sup.29R.sup.30,
--NR.sup.31C(S)NR.sup.29R.sup.30, --NR.sup.31
C(NR.sup.29)NR.sup.29R.sup.- 30 and
--C(NR.sup.29)NR.sup.29R.sup.30, where each X is independently a
halogen; each R.sup.29 and R.sup.30 are independently hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl, substituted heteroarylalkyl, --NR.sup.3lR.sup.32,
--C(O)R.sup.31 or --S(O).sub.2R.sup.31 or optionally R.sup.29 and
R.sup.30 together with the atom to which they are both attached
form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R.sup.31 and R.sup.32 are independently hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,
heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl.
[0081] "Transporter protein" refers to a protein that has a direct
or indirect role in transporting a molecule into and/or through a
cell. For example, a transporter protein may be, but is not limited
to, solute carrier transporters, co-transporters, counter
transporters, uniporters, symporters, antiporters, pumps,
equilibrative transporters, concentrative transporters and other
proteins, which mediate active transport, energy-dependent
transport, facilitated diffusion, exchange mechanisms and specific
absorption mechanisms. Transporter proteins, may also be, but are
not limited to, membrane-bound proteins that recognize a substrate
and effect its entry into or exit from a cell by a carrier-mediated
transporter or by receptor-mediated transport. A transporter
protein, may also be, but is not limited to, an intracellularly
expressed protein that participates in trafficking of substrates
through or out of a cell. Transporter proteins, may also be, but
are not limited to, proteins or glycoproteins exposed on the
surface of a cell that do not directly transport a substrate but
bind to the substrate holding it in proximity to a receptor or
transporter protein that effects entry of the substrate into or
through the cell. Examples of carrier proteins include: the
intestinal and liver bile acid transporters, dipeptide
transporters, oligopeptide transporters, simple sugar transporters
(e.g., SGLT1), phosphate transporters, monocarboxcylic acid
transporters, P-glycoprotein transporters, organic anion
transporters (OAT), and organic cation transporters. Examples of
receptor-mediated transport proteins include: viral receptors,
immunoglobulin receptors, bacterial toxin receptors, plant lectin
receptors, bacterial adhesion receptors, vitamin transporters and
cytokine growth factor receptors.
[0082] "Toxic" and "toxicity" refers to a medically measurable
undesirable effect in a patient to which a particular drug has been
orally administered. In the case of a prodrug with an
aldehyde-producing promoiety, the terms "toxic" and "toxicity"
refer to effects such as carcinogenicity, irritation, mucosal
damage, gastritis, hyperkeratosis, elevation of liver enzymes
(e.g., transaminases) and fertility impairment. In the case of a
prodrug that releases gabapentin or other GABA analogs upon
cleavage, the terms "toxic" and "toxicity" mean an undesirable
side-effects, such as somnolence, dizziness, ataxia,
choreoathetosis, nystagmus or dyspepsia, caused by an undesirably
high concentration of the parent compound in the systemic
circulation of the patient.
[0083] "Treating" or "treatment" of any disease or disorder refers,
in one embodiment, to ameliorating the disease or disorder (i.e.,
arresting or reducing the development of the disease or at least
one of the clinical symptoms thereof). In another embodiment
"treating" or "treatment" refers to ameliorating at least one
physical parameter, which may not be discernible by the patient. In
yet another embodiment, "treating" or "treatment" refers to
inhibiting the disease or disorder, either physically, (e.g.,
stabilization of a discernible symptom), physiologically, (e.g.,
stabilization of a physical parameter), or both. In yet another
embodiment, "treating" or "treatment" refers to delaying the onset
of the disease or disorder.
[0084] "Therapeutically effective amount" means the amount of a
compound that, when administered to a patient for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the patient to be treated.
[0085] Reference will now be made in detail to preferred
embodiments of the invention. While the invention will be described
in conjunction with the preferred embodiments, it will be
understood that it is not intended to limit the invention to those
preferred embodiments. To the contrary, it is intended to cover
alternatives, modifications, and equivalents as may be included
within the spirit and scope of the invention as defined by the
appended claims.
SUSTAINED RELEASE ORAL DOSAGE FORMS OF THE INVENTION
[0086] The present invention can be practiced with a number of
different dosage forms, which may be adapted to provide sustained
release of the prodrug upon oral administration.
[0087] In one embodiment of the invention, the dosage form
comprises beads that on dissolution or diffusion release the
prodrug over an extended period of hours, preferably, over a period
of at least 6 hours, more preferably, over a period of at least 8
hours and most preferably, over a period of at least 12 hours. The
prodrug-releasing beads may have a central composition or core
comprising a prodrug and pharmaceutically acceptable vehicles,
including an optional lubricant, antioxidant and buffer. The beads
may be medical preparations with a diameter of about 1 to 2 mm.
Individual beads may comprise doses of the prodrug, for example,
doses of up to about 40 mg of prodrug. The beads, in one
embodiment, are formed of non-cross-linked materials to enhance
their discharge from the gastrointestinal tract. The beads may be
coated with a release rate-controlling polymer that gives a timed
release profile.
[0088] The time release beads may be manufactured into a tablet for
therapeutically effective prodrug administration. The beads can be
made into matrix tablets by the direct compression of a plurality
of beads coated with, for example, an acrylic resin and blended
with.excipients such as hydroxypropylmethyl cellulose. The
manufacture of beads has been disclosed in the art (Lu, Int. J
Pharm., 1994, 112, 117-124; Pharmaceutical Sciences by Remington,
14.sup.th ed, pp1626-1628 (1970); Fincher, J. Pharm. Sci. 1968, 57,
1825-1835 ( ); and U.S. Pat. No. 4,083,949) as has the manufacture
of tablets (Pharmaceutical Sciences, by Remington, 17.sup.th Ed,
Ch. 90, pp1603-1625 (1985).
[0089] In another embodiment, an oral sustained release pump may be
used (see Langer, supra; Sefton, 1987, CRC Crit RefBiomed Eng.
14:201; Saudek et al., 1989, N. Engl. J Med. 321:574).
[0090] In another embodiment, polymeric materials can be used (see
"Medical Applications of Controlled Release," Langer and Wise
(eds.), CRC Press., Boca Raton, Florida (1974); "Controlled Drug
Bioavailability," Drug Product Design and Performance, Smolen and
Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J.
Macromol. Sci. Rev. Macromol Chem. 23:61; see also Levy et al.,
1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351;
Howard et al, 1989, J. Neurosurg. 71:105). In a preferred
embodiment, polymeric materials are used for oral sustained release
delivery. Preferred polymers include sodium carboxymethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellul- ose and
hydroxyethylcellulose (most preferred, hydroxypropylmethylcellulos-
e). Other preferred cellulose ethers have been described (Alderman,
Int. J Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1-9). Factors
affecting drug release are well known to the skilled artisan and
have been described in the art (Bamba et al., Int. J. Pharm., 1979,
2, 307).
[0091] In another embodiment, enteric-coated preparations can be
used for oral sustained release administration. Preferred coating
materials include polymers with a pH-dependent solubility (i.e.,
pH-controlled release), polymers with a slow or pH-dependent rate
of swelling, dissolution or erosion (i.e., time-controlled
release), polymers that are degraded by enzymes (i.e.,
enzyme-controlled release) and polymers that form firm layers that
are destroyed by an increase in pressure (i.e., pressure-controlled
release).
[0092] In yet another embodiment, drug-releasing lipid matrices can
be used for oral sustained release administration. One particularly
preferred example is when solid microparticles of the prodrug are
coated with a thin controlled release layer of a lipid (e.g.,
glyceryl behenate and/or glyceryl palmitostearate) as disclosed in
Farah et al., U.S. Pat. No. 6,375,987 and Joachim et al., U.S. Pat.
No. 6,379,700. The lipid-coated particles can optionally be
compressed to form a tablet. Another controlled release lipid-based
matrix material which is suitable for sustained release oral
administration comprises polyglycolized glycerides as disclosed in
Roussin et al., U.S. Pat. No. 6,171,615.
[0093] In yet another embodiment, prodrug-releasing waxes can be
used for oral sustained release administration. Examples of
suitable sustained prodrug-releasing waxes are disclosed in Cain et
al., U.S. Pat. No. 3,402,240 (carnauba wax, candedilla wax, esparto
wax and ouricury wax); Shtohryn et al. U.S. Pat. No. 4,820,523
(hydrogenated vegetable oil, bees wax, caranuba wax, paraffin,
candelillia, ozokerite and mixtures thereof); and Walters, U.S.
Pat. No. 4,421,736 (mixture of paraffin and castor wax).
[0094] In still another embodiment, osmotic delivery systems are
used for oral sustained release administration (Verma et al., Drug
Dev. Ind. Pharm., 2000, 26:695-708). In a preferred embodiment,
OROS.RTM. systems made by Alza Corporation, Mountain View, Calif.
are used for oral sustained release delivery devices (Theeuwes et
al., U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No.
3,916,899).
[0095] In yet another embodiment, a controlled-release system can
be placed in proximity of the target of the prodrug of the GABA
analog, thus requiring only a fraction of the systemic dose (see,
e.g., Goodson, in "Medical Applications of Controlled Release,"
supra, vol. 2, pp. 115-138 (1984)). Other controlled-release
systems discussed in Langer, 1990, Science 249:1527-1533 may also
be used.
[0096] In another embodiment of the invention, the dosage form
comprises a prodrug of a GABA analog coated on a polymer substrate.
The polymer can be an erodible, or a nonerodible polymer. The
coated substrate may be folded onto itself to provide a bilayer
polymer drug dosage form. For example prodrug of a GABA analog can
be coated onto a polymer such as a polypeptide, collagen, gelatin,
polyvinyl alcohol, polyorthoester, polyacetyl, or a
polyorthocarbonate and the coated polymer folded onto itself to
provide a bilaminated dosage form. In operation, the bioerodible
dosage form erodes at a controlled rate to dispense the prodrug
over a sustained release period. Representative biodegradable
polymer comprise a member selected from the group consisting of
biodegradable poly(amides), poly (amino acids), poly(esters),
poly(lactic acid), poly(glycolic acid), poly(carbohydrate),
poly(orthoester), poly (orthocarbonate), poly(acetyl),
poly(anhydrides), biodegradable poly(dehydropyrans), and
poly(dioxinones) which are known in the art (Rosoff, Controlled
Release ofDrugs, Chap. 2, pp. 53-95 (1989); and in U.S. Pat. Nos.
3,811,444; 3,962,414; 4,066,747, 4,070,347; 4,079,03.8; and
4,093,709).
[0097] In another embodiment of the invention, the dosage form
comprises a prodrug loaded into a polymer that releases the prodrug
by diffusion through a polymer, or by flux through pores or by
rupture of a polymer matrix. The drug delivery polymeric dosage
form comprises a concentration of 10 mg to 2500 mg homogenously
contained in or on a polymer. The dosage form comprises at least
one exposed surface at the beginning of dose delivery. The
non-exposed surface, when present, is coated with a
pharmaceutically acceptable material impermeable to the passage of
a prodrug. The dosage form may be manufactured by procedures known
in the art. An example of providing a dosage form comprises
blending a pharmaceutically acceptable carrier like polyethylene
glycol, with a known dose of prodrug at an elevated temperature,
like 37.degree. C., and adding it to a silastic medical grade
elastomer with a cross-linking agent, for example, octanoate,
followed by casting in a mold. The step is repeated for each
optional successive layer. The system is allowed to set for 1 hour,
to provide the dosage form. Representative polymers for
manufacturing the dosage form comprise a member selected from the
group consisting of olefin, and vinyl polymers, addition polymers,
condensation polymers, carbohydrate polymers, and silicon polymers
as represented by polyethylene, polypropylene, polyvinyl acetate,
polymethylacrylate, polyisobutylmethacrylate, poly alginate,
polyamide and polysilicon. The polymers and procedures for
manufacturing them have been described in the art (Coleman et al.,
Polymers 1990, 31, 1187-1231; Roerdink et al., Drug Carrier Systems
1989, 9, 57-10.; Leong et al., Adv. Drug Delivery Rev. 1987, 1,
199-233; Roffet al., Handbook of Common Polymers 1971, CRC Press;
U.S. Pat. No. 3,992,518).
[0098] In another embodiment of the invention, the dosage from
comprises a plurality of tiny pills. The tiny time-released pills
provide a number of individual doses for providing various time
doses for achieving a sustained-release prodrug delivery profile
over an extended period of time up to 24 hours. The matrix
comprises a hydrophilic polymer selected from the group consisting
of a polysaccharide, agar, agarose, natural gum, alkali alginate
including sodium alginate, carrageenan, fucoidan, furcellaran,
laminaran, hypnea, gum arabic, gum ghatti, gum karaya, grum
tragacanth, locust bean gum, pectin, amylopectin, gelatin, and a
hydrophilic colloid. The hydrophilic matric comprises a plurality
of 4 to 50 tiny pills, each tiny pill comprise a dose population of
from 10 ng, 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg etc. The
tiny pills comprise a release rate-controlling wall of 0.001 up to
10. mm thickness to provide for the timed release of prodrug.
Representative wall forming materials include a triglyceryl ester
selected from the group consisting of glyceryl tristearate,
glyceryl monostearate, glyceryl dipalmitate, glyceryl laureate,
glyceryl didecenoate and glyceryl tridenoate. Other wall forming
materials comprise polyvinyl acetate, phthalate, methylcellulose
phthalate and microporous olefins. Procedures for manufacturing
tiny pills are disclosed in U.S. Pat. Nos. 4,434,153; 4,721,613;
4,853,229; 2,996,431; 3,139,383 and 4,752,470.
[0099] In another embodiment of the invention, the dosage form
comprises an osmotic dosage form, which comprises a semipermeable
wall that surrounds a therapeutic composition comprising the
prodrug. In use within a patient, the osmotic dosage form
comprising a homogenous composition imbibes fluid through the
semipermeable wall into the dosage form in response to the
concentration gradient across the semipermeable wall. The
therapeutic composition in the dosage form develops osmotic energy
that causes the therapeutic composition to be administered through
an exit from the dosage form over a prolonged period of time up to
24 hours (or even in some cases up to 30 hours) to provide
controlled and sustained prodrug release. These delivery platforms
can provide an essentially zero order delivery profile as opposed
to the spiked profiles of immediate release formulations.
[0100] In another embodiment of the invention, the dosage form
comprises another osmotic dosage form comprising a wall surrounding
a compartment, the wall comprising a semipermeable polymeric
composition permeable to the passage of fluid and substantially
impermeable to the passage of prodrug present in the compartment, a
prodrug-containing layer composition in the compartment, a hydrogel
push layer composition in the compartment comprising an osmotic
formulation for imbibing and absorbing fluid for expanding in size
for pushing the prodrug composition layer from the dosage form, and
at least one passageway in the wall for releasing the prodrug
composition. The method delivers the prodrug by imbibing fluid
through the semipermeable wall at a fluid imbibing rate determined
by the permeability of the semipermeable wall and the osmotic
pressure across the semipermeable wall causing the push layer to
expand, thereby delivering the prodrug from the dosage form through
the exit passageway to a patient over a prolonged period of time
(up to 24 or even 30 hours). The hydrogel layer composition may
comprise 10 mg to 1000 mg of a hydrogel such as a member selected
from the group consisting of a polyalkylene oxide of 1,000,000 to
8,000,000 which are selected from the group consisting of a
polyethylene oxide of 1,000,000 weight-average molecular weight, a
polyethylene oxide of 2,000,000 molecular weight, a polyethylene
oxide of 4,000,000 molecular weight, a polyethylene oxide of
5,000,000 molecular weight, a polyethylene oxide of 7,000,000
molecular weight and a polypropylene oxide of the 1,000,000 to
8,000,000 weight-average molecular weight; or 10 mg to 1000 mg of
an alkali carboxymethylcellulose of 10,000 to 6,000,000 weight
average molecular weight, such as sodium carboxymethylcellulose or
potassium carboxymethylcellulose. The hydrogel expansion layer
comprises 0.0 mg to 350 mg, in present manufacture; 0.1 mg to 250
mg of a hydroxyalkylcellulose of 7,500 to 4,500,00 weight-average
molecular weight (e.g., hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxybutylcellulose or hydroxypentylcellulose) in present
manufacture; 1 mg to 50 mg of an osmagent selected from the group
consisting of sodium chloride, potassium chloride, potassium acid
phosphate, tartaric acid, citric acid, raffinose, magnesium
sulfate, magnesium chloride, urea, inositol, sucrose, glucose and
sorbitol; 0 to 5 mg of a colorant, such as ferric oxide; 0 mg to 30
mg, in a present manufacture, 0.1 mg to 30 mg of a
hydroxypropylalkylcellulose of 9,000 to 225,000 average-number
molecular weight, selected from the group consisting of
hydroxypropylethylcellulose, hydroxypropypentylcellulose,
hydroxypropylmethylcellulose, and hydropropylbutylcellulose; 0.00
to 1.5 mg of an antioxidant selected from the group consisting of
ascorbic acid, butylated hydroxyanisole, butylatedhydroxyquinone,
butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene,
cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl
gallate, propyl-hydroxybenzoate, trihydroxybutylrophenone,
dimethylphenol, dibutylphenol, vitamin E, lecithin and
ethanolamine; and 0.0 mg to 7 mg of a lubricant selected from the
group consisting of calcium stearate, magnesium stearate, zinc
stearate, magnesium oleate, calcium palmitate, sodium suberate,
potassium laureate, salts of fatty acids, salts of alicyclic acids,
salts of aromatic acids, stearic acid, oleic acid, palmitic acid, a
mixture of a salt of a fatty, alicyclic or aromatic acid, and a
fatty, alicyclic, or aromatic acid.
[0101] In the osmotic dosage forms, the semipermeable wall
comprises a composition that is permeable to the passage of fluid
and impermeable to the passage of prodrug. The wall is nontoxic and
comprises a polymer selected from the group consisting of a
cellulose acylate, cellulose diacylate, cellulose triacylate,
cellulose acetate, cellulose diacetate and cellulose triacetate.
The wall comprises 75 wt % (weight percent) to 100 wt % of the
cellulosic wall-forming polymer; or, the wall can comprise
additionally 0.01 wt % to 80 wt % of polyethylene glycol, or 1 wt %
to 25 wt % of a cellulose ether selected from the group consisting
of hydroxypropylcellulose or a hydroxypropylalkycellulose such as
hydroxypropylmethylcellulose. The total weight percent of all
components comprising the wall is equal to 100 wt %. The internal
compartment comprises the prodrug-containing composition alone or
in layered position with an expandable hydrogel composition. The
expandable hydrogel composition in the compartment increases in
dimension by imbibing the fluid through the semipermeable wall,
causing the hydrogel to expand and occupy space in the compartment,
whereby the drug composition is pushed from the dosage form. The
therapeutic layer and the expandable layer act together during the
operation of the dosage form for the release of prodrug to a
patient over time. The dosage form comprises a passageway in the
wall that connects the exterior of the dosage form with the
internal compartment. The osmotic powered dosage form provided by
the invention delivers prodrug from the dosage form to the patient
at a zero order rate of release over a period of up to about 24
hours.
[0102] The expression "passageway" as used herein comprises means
and methods suitable for the metered release of the prodrug from
the compartment of the dosage form. The exit means comprises at
least one passageway, including orifice, bore, aperture, pore,
porous element, hollow fiber, capillary tube, channel, porous
overlay, or porous element that provides for the osmotic controlled
release of prodrug. The passageway includes a material that erodes
or is leached from the wall in a fluid environment of use to
produce at least one controlled-release dimensioned passageway.
Representative materials suitable for forming a passageway, or a
multiplicity of passageways comprise a leachable poly(glycolic)
acid or poly(lactic) acid polymer in the wall, a gelatinous
filament, poly(vinyl alcohol), leach-able polysaccharides, salts,
and oxides. A pore passageway, or more than one pore passageway,
can be formed by leaching a leachable compound, such as sorbitol,
from the wall. The passageway possesses controlled-release
dimensions, such as round, triangular, square and elliptical, for
the metered release of prodrug from the dosage form. The dosage
form can be constructed with one or more passageways in spaced
apart relationship on a single surface or on more than one surface
of the wall. The expression "fluid environment" denotes an aqueous
or biological fluid as in a human patient, including the
gastrointestinal tract. Passageways and equipment for forming
passageways are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899;
4,063,064; 4,088,864 and 4,816,263. Passageways formed by leaching
are disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.
[0103] Regardless of the specific form of sustained release oral
dosage form used, the prodrug is preferably released from the
dosage form over a period of at least about 6 hours, more
preferably, over a period of at least about 8 hours, and most
preferably, over a period of at least about 12 hours. Further, the
dosage form preferably releases from 0 to 20% of the prodrug in 0
to 2 hours, from 20 to 50% of the prodrug in 2 to 12 hours, from 50
to 85% of the prodrug in 3 to 20 hours and greater than 75% of the
prodrug in 5 to 18 hours. The sustained release oral dosage form
further provides a concentration of the GABA analog in the blood
plasma of the patient over time, which curve has an area under the
curve (AUC) that is proportional to the dose of the prodrug of GABA
analog administered, and a maximum concentration C.sub.max. The
C.sub.max is less than 75%, and is preferably, less than 60%, of
the C.sub.max obtained from administering an equivalent dose of the
prodrug from an immediate release oral dosage form, and the AUC is
substantially the same as the AUC obtained from administering an
equivalent dose of the prodrug from an immediate release oral
dosage form.
[0104] Preferably, the dosage forms of the invention are
administered twice per day (more preferably, once per day).
PRODRUGS USEFUL IN THE INVENTION
[0105] It should be understood that the present invention is not
restricted to particular prodrugs of GABA analogs. Accordingly, the
present invention may be practiced with any GABA analog
prodrug.
[0106] One preferred class of GABA analog prodrugs particularly
useful in the present invention has the structure of Formula (I):
4
[0107] or a pharmaceutically acceptable salt, hydrate or solvate
thereof, wherein:
[0108] n is 0 or 1;
[0109] Y is O or S;
[0110] R.sup.16 is hydrogen, alkyl or substituted alkyl;
[0111] R.sup.2 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
substituted acyl, acylamino, substituted acylamino, alkylamino,
substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl,
alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted
alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, aryloxy,
substituted aryloxy, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino,
substituted dialkylamino, halo, heteroalkyl, substituted
heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted heteroarylalkyl, heteroalkyloxy, substituted
heteroalkyloxy, heteroaryloxy and substituted heteroaryloxy, or
optionally, R.sup.2 and R.sup.16 together with the atoms to which
they are attached form a cycloheteroalkyl or substituted
cycloheteroalkyl ring;
[0112] R.sup.3 and R.sup.6 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl and substituted heteroarylalkyl;
[0113] R.sup.4 and R.sup.5 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, acyl,
substituted acyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl and substituted heteroarylalkyl or optionally,
R.sup.4 and R.sup.5 together with the carbon atom to which they are
attached form a cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl or bridged
cycloalkyl ring;
[0114] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl and substituted heteroarylalkyl;
[0115] R.sup.13 and R.sup.14 are each independently hydrogen,
alkyl, substituted alkyl, alkoxycarbonyl, substituted
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl or optionally, R.sup.13 and R.sup.14 together with
the carbon atom to which they are attached form a cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring; and
[0116] R.sup.25 is selected from the group consisting of acyl,
substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,
heteroalkyl, substituted heteroalkyl, heteroaryl, substituted
heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.
[0117] Preferably, R.sup.13 and R.sup.14 are independently
hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl,
arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloalkoxycarbonyl or heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl). More preferably, R.sup.13 and R.sup.14 are independently
hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,
tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl,
phenethyl or 3-pyridyl.
[0118] In one embodiment, R.sup.13 and R.sup.14 are independently
hydrogen, alkanyl, substituted alkanyl, cycloalkanyl or substituted
cycloalkanyl. Preferably, R.sup.13 and R.sup.14 are hydrogen,
alkanyl or cycloalkanyl. More preferably, R.sup.13 and R.sup.14 are
independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. Even
more preferably, R.sup.13 is methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl
and R.sup.14 is hydrogen, or R.sup.13 is methyl and R.sup.14 is
methyl.
[0119] In another embodiment, R.sup.13 and R.sup.14 are
independently hydrogen, aryl, arylalkyl or heteroaryl. More
preferably, R.sup.13 and R.sup.14 are independently hydrogen,
phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferably, R
.sup.3is phenyl, benzyl, phenethyl or 3-pyridyl and R.sup.14 is
hydrogen.
[0120] In still another embodiment, R.sup.13 and R.sup.14 are
independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,
carbamoyl, or cycloalkoxycarbonyl. Preferably, when R.sup.13 is
alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl. More preferably, R.sup.13 is methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or
cyclohexyloxycarbonyl and R.sup.14 is methyl.
[0121] In still another embodiment, R.sup.13 and R.sup.14 together
with the carbon atom to which they are attached form a cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring. Preferably, R.sup.13 and R.sup.14 together
with the carbon atom to which they are attached form a cycloalkyl
ring. More preferably, R.sup.13 and R.sup.14 together with the
carbon atom to which they are attached form a cyclobutyl,
cyclopentyl or cyclohexyl ring.
[0122] In still another preferred embodiment of compounds of
Formula (I),
[0123] R.sup.25 is acyl, substituted acyl, alkyl, substituted
alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl;
[0124] R.sup.13 and R.sup.14 are independently hydrogen, alkyl,
substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl,
carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl,
substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl
or R.sup.13 and R.sup.14 together with the carbon atom to which
they are attached form a cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably,
R.sup.25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl or heteroaryl. More preferably, R.sup.25 is
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.
[0125] In still another embodiment, R.sup.25 is acyl or substituted
acyl. More preferably, R.sup.25 is acetyl, propionyl, butyryl,
benzoyl or phenacetyl.
[0126] In still another embodiment, R.sup.25 is alkanyl or
substituted alkanyl. Preferably, R.sup.25 is methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,
sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,
1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,
1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl or
1-(1,3-dioxan-2-yl)-2-phenethyl. More preferably, R.sup.25 is
methyl, ethyl, propyl, isopropyl, butyl, 1,1-dimethoxyethyl or
1,1-diethoxyethyl.
[0127] In still another embodiment, R.sup.25 is aryl, arylalkyl or
heteroaryl. Preferably, R.sup.25 is phenyl, 4-methoxyphenyl,
benzyl, phenethyl, styryl or 3-pyridyl.
[0128] In still another embodiment, R.sup.25 is cycloalkyl or
substituted cycloalkyl. More preferably R.sup.25 is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
[0129] In still another embodiment of compounds of Formula (I),
R.sup.25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, and R.sup.13 and R.sup.14 are independently
hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or
substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl,
substituted cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl). Preferably, R.sup.25 is acyl, substituted acyl, alkyl,
substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and
R.sup.13 and R.sup.14 are independently hydrogen, alkyl,
substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl,
cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably, when
R.sup.13 is alkoxycarbonyl, substituted alkoxycarbonyl,
cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl
then R.sup.14 is methyl). More preferably, R.sup.25 is methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,
isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-e- thyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R.sup.13 and
R.sup.14 are independently hydrogen, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl,
cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl,
phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferably,
R.sup.25 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,
1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1,1-dimethoxy-2-phenethyl,
1,1-diethoxy-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,
phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, cyclohexyl
or 3-pyridyl, and R.sup.13 and R.sup.14 are independently hydrogen,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl,
benzyl, phenethyl or 3-pyridyl.
[0130] In still another embodiment, R.sup.25 is acyl, substituted
acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl, and R.sup.13 and
R.sup.14 together with the atom to which they are attached form a
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted
cycloheteroalkyl ring. Preferably, R.sup.25 is acyl, substituted
acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or
heteroaryl and R.sup.13 and R.sup.14 together with the atom to
which they are attached form a cycloalkyl or substituted cycloalkyl
ring. More preferably, R.sup.25 is methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,
sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,
1-(1,3-dioxolan-2-yl)-e- thyl, 1-(1,3-dioxan-2-yl)-ethyl,
1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R.sup.13 and
R.sup.14 together with the atom to which they are attached form a
cyclobutyl, cyclopentyl or a cyclohexyl ring.
[0131] In still another embodiment, R.sup.25 is acyl or substituted
acyl and R.sup.13 and R.sup.14 are independently hydrogen, alkyl,
substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl,
carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl,
substituted cycloalkoxycarbonyl, heteroaryl or substituted
heteroaryl (preferably, when R.sup.13 is alkoxycarbonyl,
substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted
cycloalkoxycarbonyl or carbamoyl then R.sup.14 is methyl).
Preferably, R.sup.25 is acetyl, propionyl, butyryl, benzoyl or
phenacetyl, and R.sup.13 and R.sup.14 are independently hydrogen,
alkyl, substituted alkyl, alkoxycarbonyl, substituted
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or
substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl).
[0132] In still another preferred embodiment, R.sup.25 is alkanyl
or substituted alkanyl and R.sup.13 and R.sup.14 are independently
hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or
substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl,
substituted cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl). Preferably, R.sup.25 is methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,
neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,
1-(1,3-dioxolan-2-yl)-e- thyl, 1-(1,3-dioxan-2-yl)-ethyl,
1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl or
1-(1,3-dioxan-2-yl)-2-phenethyl, and R.sup.13 and R.sup.14 are
independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,
substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,
heteroaryl or substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl).
[0133] In still another embodiment, R.sup.25 is aryl, substituted
aryl, arylalkyl, substituted arylalkyl, heteroaryl or substituted
heteroaryl, and R.sup.13 and R.sup.14 are independently hydrogen,
alkyl, substituted alkyl, alkoxycarbonyl, substituted
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or
substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl,
substituted cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl). Preferably R.sup.25 is phenyl, 4-methoxyphenyl, benzyl,
phenethyl, styryl or 3-pyridyl and R.sup.13 and R.sup.14 are
independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,
substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,
heteroaryl or substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl).
[0134] In still another embodiment, R.sup.25 is cycloalkyl or
substituted cycloalkyl, and R.sup.13 and R.sup.14 are independently
hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,
cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or
substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl,
substituted cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl). Preferably, R.sup.25 is. cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl and R.sup.13 and R.sup.14 are
independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,
substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,
heteroaryl or substituted heteroaryl (preferably, when R.sup.13 is
alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R.sup.14 is
methyl).
[0135] In still another embodiment, R.sup.25 is acyl, substituted
acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl or substituted heteroarylalkyl, and R.sup.13 and
R.sup.14 are independently hydrogen, alkyl, substituted alkyl,
aryl, arylalkyl, cycloalkyl or heteroaryl. Preferably, R.sup.25 is
acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl,
cycloalkyl or heteroaryl and R.sup.13 and R.sup.14 are
independently hydrogen, alkanyl, substituted alkanyl, cycloalkanyl
or substituted cycloalkanyl. More preferably, R.sup.25 is acyl,
substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl,
cycloalkyl or heteroaryl and R.sup.13 and R.sup.14 are
independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In the
above embodiments, R.sup.25 is preferably methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,
sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,
1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,
1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.
[0136] In still another embodiment, R.sup.25 is acyl, substituted
acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or
heteroaryl and R.sup.13 and R.sup.14 are independently hydrogen,
alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or
heteroaryl. Preferably, R.sup.25 is acyl, substituted acyl, alkyl,
substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and
R.sup.13 and R.sup.14 are independently hydrogen, aryl, arylalkyl
or heteroaryl. More preferably, R.sup.25 is acyl, substituted acyl,
alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl
and R.sup.13 and R.sup.14 are independently hydrogen, phenyl,
benzyl, phenethyl or 3-pyridyl. In the above embodiments, R.sup.25
is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.
[0137] In still another embodiment, R.sup.25 is acyl, substituted
acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or
heteroaryl and R.sup.13 and R.sup.14 are independently hydrogen,
alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or
heteroaryl. Preferably, R.sup.25 is acyl, substituted acyl, alkyl,
substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and
R.sup.13 and R.sup.14 are independently hydrogen, alkyl,
substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,
carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl
(preferably, when R.sup.13 is alkoxycarbonyl, substituted
alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted
cycloalkoxycarbonyl then R.sup.14 is methyl, more preferably,
R.sup.13 is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl,
and R.sup.14 is methyl). In the above embodiments, R.sup.25 is
preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-e-
thyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl,
1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,
1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,
1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,
1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.
[0138] In still another preferred embodiment, R.sup.25 is acyl,
substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl,
cycloalkyl or heteroaryl and R.sup.13 and R.sup.14 together with
the atom to which they are attached form a cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.
Preferably, R.sup.25 is acyl, substituted acyl, alkyl, substituted
alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R.sup.13 and
R.sup.14 together with the atom to which they are attached form a
cycloalkyl or substituted cycloalkyl ring. More preferably R.sup.25
is acyl, substituted acyl, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl or heteroaryl, and R.sup.13 and R.sup.14
together with the atom to which they are attached form a
cyclobutyl, cyclopentyl or cyclohexyl ring. In the above
embodiments, R.sup.25 is preferably methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,
sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,
1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,
1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.
[0139] In still another preferred embodiment of compounds of
Formula (I), R.sup.4 and R.sup.5 together with the carbon atom to
which they are attached form a cyclobutyl or substituted cyclobutyl
ring. Preferably, the substituted cyclobutyl ring is substituted
with one or more substituents selected from the group consisting of
alkanyl, substituted alkanyl, halo, hydroxy, carboxy and
alkoxycarbonyl.
[0140] In still another preferred embodiment of compounds of
Formula (I), R.sup.4 and R.sup.5 together with the carbon atom to
which they are attached form a cyclopentyl or substituted
cyclopentyl ring. Preferably, the cyclopentyl ring is substituted
with alkanyl, substituted alkanyl, halo, hydroxy, carboxy or
alkoxycarbonyl. More preferably, the cyclopentyl ring is
substituted with alkanyl. Even more preferably, the cyclopentyl
ring is selected from the group consisting of 5
[0141] Preferably, in a more specific version of this embodiment,
R.sup.7 is hydrogen.
[0142] In still another preferred embodiment of compounds of
formula (IV), R.sup.4 and R.sup.5 together with the carbon atom to
which they are attached form a cyclohexyl or substituted cyclohexyl
ring. Preferably, the cyclohexyl ring is substituted with alkanyl,
substituted alkanyl, halo, hydroxy, carboxy or alkoxycarbonyl. More
preferably, the cyclohexyl ring is substituted with alkanyl. Even
more preferably, the cyclohexyl ring is selected from the group
consisting of 6
[0143] Preferably, in a more specific version of this embodiment,
R.sup.7 is hydrogen.
[0144] In still another preferred embodiment of compounds of
Formula (I), R.sup.4 and R.sup.5 together with the carbon atom to
which they are attached form a cycloheteroalkyl or substituted
cycloheteroalkyl ring. In one embodiment, n is 0. In another
embodiment, n is 1, and R.sup.2 is hydrogen, methyl, 2-propyl,
2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl,
benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl, --CH.sub.20H,
--CH(OH)CH.sub.3, --CH.sub.2CO.sub.2H, --CH.sub.2CH.sub.2CO.sub.2H,
--CH.sub.2CONH.sub.2, --CH.sub.2CH.sub.2CONH.sub.2,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2SH,
--CH.sub.2(CH.sub.2).sub.3NH.sub.2 or
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH- .sub.2. In another embodiment,
n is 1 and R.sup.2 and R.sup.16 together with the atoms to which
they are attached form a pyrrolidine ring. Preferably, R.sup.4 and
R.sup.5 together with the carbon atom to which they are attached
form a cycloheteroalkanyl ring. More preferably, the
cycloheteroalkanyl ring is selected from the group consisting of
7
[0145] wherein Z is O, S(O).sub.p or NR.sup.18;
[0146] p is 0, 1 or 2; and
[0147] R.sup.18 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, acyl and alkoxycarbonyl. More preferably,
the cycloheteroalkanyl ring is selected from the group consisting
of 8
[0148] Preferably, in a more specific version of this embodiment,
R.sup.7 is hydrogen.
[0149] In still another embodiment of compounds of Formula (I),
R.sup.4 and R.sup.5 together with the carbon atom to which they are
attached form a bridged cycloalkyl ring. In one embodiment, n is 0.
In another embodiment, n is 1 and R.sup.2 is hydrogen, methyl,
2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl,
phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl, 2-indolyl,
--CH.sub.2OH, --CH(OH)CH.sub.3, --CH.sub.2CO.sub.2H,
--CH.sub.2CH.sub.2CO.sub.2H, --CH.sub.2CONH.sub.2,
--CH.sub.2CH.sub.2CONH.sub.2, --CH.sub.2CH.sub.2SCH.sub.3,
CH.sub.2SH, --CH.sub.2(CH.sub.2).sub.3NH.sub.2 or
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH- .sub.2. In another embodiment,
n is 1 and R.sup.2 and R.sup.16 together with the atoms to which
they are attached form a pyrrolidine ring. Preferably, the bridged
cycloalkyl group is 9
[0150] Preferably, in a more specific version of this embodiment,
R.sup.7is hydrogen.
[0151] In still another embodiment of compounds of Formula (I), Y
is O, R.sup.6 and R.sup.7 are hydrogen, R.sup.4 is alkyl or
cycloalkyl, R.sup.5 is hydrogen or alkyl and R.sup.3 is hydrogen or
alkyl. In one embodiment, n is 0. In another embodiment, n is 1 and
R.sup.2 is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,
cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl,
2-imidazolyl, 2-indolyl, --CH.sub.2OH, --CH(OH)CH.sub.3,
--CH.sub.2CO.sub.2H, --CH.sub.2CH.sub.2CO.sub.2H,
--CH.sub.2CONH.sub.2, --CH.sub.2CH.sub.2CONH.sub.2,
--CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2SH,
--CH.sub.2(CH.sub.2).sub.3NH.sub- .2 or
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2. In another embodiment, n
is 1 and R.sup.2 and R.sup.16 together with the atoms to which they
are attached form a pyrrolidine ring. Preferably, R.sup.4 is
cycloalkyl, R.sup.5is hydrogen or methyl, and R.sup.3is hydrogen or
methyl. Preferably, R.sup.3 is hydrogen, R.sup.4 is isobutyl and
R.sup.5is hydrogen.
[0152] In still another embodiment of compounds of Formula (I), Y
is O, R.sup.5 and R.sup.7 are hydrogen or alkanyl, R.sup.3 and
R.sup.6 are hydrogen and R.sup.4 is substituted heteroalkyl.
Preferably, R.sup.4 is 10
[0153] A is NR.sup.19, O or S;
[0154] B is alkyl, substituted alkyl, alkoxy, halogen, hydroxy,
carboxy, alkoxycarbonyl or amino;
[0155] R.sup.19 is hydrogen, alkyl, cycloalkyl or aryl;
[0156] j is an integer from 0 to 4;
[0157] k is an integer from 1 to 4; and
[0158] 1 is an integer from 0 to 3.
[0159] More preferably, k is 1.
[0160] In still another embodiment of compounds of Formula (I), Y
is O, R.sup.5 and R.sup.7 are hydrogen or alkanyl, R.sup.3 and
R.sup.6 are hydrogen and R.sup.4 is substituted alkanyl,
cycloalkanyl or substituted cycloalkanyl. Preferably, R.sup.4 is
selected from the group consisting of 11
[0161] Preferably, R.sup.4 is 12
[0162] h is an integer from 1 to 6; and
[0163] i is an integer from 0 to 6.
[0164] More preferably, h is 1,2, 3 or 4 and i is 0 or 1. Even more
preferably, R.sup.4 is selected from the group consisting of 13
[0165] Preferably, compounds of Formula (I) are derived from a GABA
analog of Formula (IV): 14
[0166] wherein the GABA analog of Formula (IV) is selected from the
group consisting of:
[0167] 1-Aminomethyl-1-cyclohexane acetic acid;
[0168] 1-Aminomethyl-1-(3-methylcyclohexane) acetic acid;
[0169] 1-Aminomethyl-1-(4-methylcyclohexane) acetic acid;
[0170] 1-Aminomethyl-1-(4-isopropylcyclohexane) acetic acid;
[0171] 1-Aminomethyl-1-(4-tert-butylcyclohexane) acetic acid;
[0172] 1-Aminomethyl-1-(3,3-dimethylcyclohexane) acetic acid;
[0173] 1-Aminomethyl-1-(3,3,5,5-tetramethylcyclohexane) acetic
acid;
[0174] 1-Aminomethyl-1-cyclopentane acetic acid;
[0175] 1-Aminomethyl-1-(3-methylcyclopentane) acetic acid;
[0176] 1-Aminomethyl-1-(3,4-dimethylcyclopentane) acetic acid;
[0177] 7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid;
[0178] 9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid;
[0179] 4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid;
[0180] 3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid;
[0181] 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid;
[0182] 3-Aminomethyl-3-(tetrahydrothiopyran-3-yl) acetic acid;
[0183] 3-Aminomethyl-5-methyl-hexanoic acid;
[0184] 3-Aminomethyl-5-methyl-heptanoic acid;
[0185] 3-Aminomethyl-5-methyl-octanoic acid;
[0186] 3-Aminomethyl-5-methyl-nonanoic acid;
[0187] 3-Aminomethyl-5-methyl-decanoic acid;
[0188] 3-Aminomethyl-5-cyclopropyl-hexanoic acid;
[0189] 3-Aminomethyl-5-cyclobutyl-hexanoic acid;
[0190] 3-Aminomethyl-5-cyclopentyl-hexanoic acid;
[0191] 3-Aminomethyl-5-cyclohexyl-hexanoic acid;
[0192] 3-Aminomethyl-5-phenyl-hexanoic acid;
[0193] 3-Aminomethyl-5-phenyl-pentanoic acid;
[0194] 3-Aminomethyl4-cyclobutyl-butyric acid;
[0195] 3-Aminomethyl-4-cyclopentyl-butyric acid;
[0196] 3-Aminomethyl-4-cyclohexyl-butyric acid;
[0197] 3-Aminomethyl-4-phenoxy-butyric acid;
[0198] 3-Aminomethyl-5-phenoxy-hexanoic acid; and
[0199] 3-Aminomethyl-5-benzylsulfanyl-pentanoic acid.
[0200] In a preferred embodiment, compounds of Formula (I) have the
structure of Formulae (II) and (III): 15
[0201] and a pharmaceutically acceptable salt, hydrate or solvate
thereof, wherein:
[0202] n, R.sup.2, R.sup.7, R.sup.13, R.sup.14, R.sup.16 and
R.sup.25 are as previously defined.
[0203] In one preferred embodiment of compounds of Formulae (II)
and (III), n is 0. In another embodiment, n is 1. When n is 1,
preferably the .alpha.-amino acid is of the L-stereochemical
configuration.
[0204] In one embodiment of compounds of Formulae (II) and (III),
R.sup.7 is hydrogen, alkanyl, substituted alkanyl, alkenyl,
substituted alkenyl, aryl or substituted aryl. More preferably,
R.sup.7 is H, --C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2C(O)N(CH.sub.3).sub.2, 16
[0205] where V is O or CH.sub.2.
[0206] Most preferably, R.sup.7is hydrogen.
[0207] In one embodiment of compounds of Formulae (II) and (III), n
is 0. In another embodiment of compounds of Formulae (II) and
(III), n is 1, R.sup.16 is hydrogen and R.sup.2 is hydrogen,
methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl,
cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 2-imidazolyl,
2-indolyl, --CH.sub.2OH, --CH(OH)CH.sub.3, --CH.sub.2CO.sub.2H,
--CH.sub.2CH.sub.2.sub.CO.sub.2H, --CH.sub.2CONH.sub.2,
--CH.sub.2CH.sub.2CONH.sub.2, --CH.sub.2CH.sub.2SCH.sub.3,
--CH.sub.2SH, --CH.sub.2(CH.sub.2).sub.3NH.s- ub.2 or
--CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2. More preferably R.sup.16
is hydrogen and R.sup.2 is hydrogen, methyl, 2-propyl, 2-butyl,
isobutyl, tert-butyl, cyclohexyl, phenyl or benzyl. In another
embodiment, n is 1 and R.sup.2 and R.sup.16 together with the atoms
to which they are attached form a pyrrolidine ring.
[0208] In still another embodiment, of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(I,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
hydrogen and R.sup.14 is hydrogen.
[0209] In still another embodiment, of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,i-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
methyl and R.sup.14 is hydrogen.
[0210] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
ethyl and R.sup.14 is hydrogen.
[0211] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
propyl and R.sup.14 is hydrogen.
[0212] In still another preferred embodiment of compounds of
Formulae (II) and (III), R.sup.25 is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
isopropyl and R.sup.14 is hydrogen.
[0213] In still another preferred embodiment of compounds of
Formulae (II) and (III), R.sup.25 is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
butyl and R.sup.14 is hydrogen.
[0214] In still another preferred embodiment of compounds of
Formulae (II) and (III), R.sup.25 is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
isobutyl and R.sup.14 is hydrogen.
[0215] In still another preferred embodiment of compounds of
Formulae (II) and (III), R.sup.25 is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
sec-butyl and R.sup.14 is hydrogen.
[0216] In still another preferred embodiment of compounds of
Formulae (II) and (III), R.sup.25 is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
tert-butyl and R.sup.14 is hydrogen.
[0217] In still another embodiment, of compounds of Formulae (11)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
cyclopentyl and R.sup.14 is hydrogen.
[0218] In still another embodiment, of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, , 1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
cyclohexyl and R.sup.14 is hydrogen.
[0219] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
methyl and R.sup.14 is methyl.
[0220] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
methoxycarbonyl and R.sup.14 is methyl.
[0221] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
ethoxycarbonyl and R.sup.14 is methyl.
[0222] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
propoxycarbonyl and R.sup.14 is methyl.
[0223] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
isopropoxycarbonyl and R.sup.14 is methyl.
[0224] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,
1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,
1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,
1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,
1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
butoxycarbonyl and R.sup.14 is methyl.
[0225] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
isobutoxycarbonyl and R.sup.14 is methyl.
[0226] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
sec-butoxycarbonyl and R.sup.14 is methyl.
[0227] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
tert-butoxycarbonyl and R.sup.14 is methyl.
[0228] In still another embodiment of compounds of Formulae (II)
and (III), is selected from the group consisting of methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,
1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
cyclohexyloxycarbonyl and R.sup.14 is methyl.
[0229] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
phenyl and R.sup.14 is hydrogen.
[0230] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
benzyl and R.sup.14 is hydrogen.
[0231] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
phenethyl and R.sup.14 is hydrogen.
[0232] In still another embodiment of compounds of Formulae (II)
and (III), R.sup.25 is selected from the group consisting of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,
1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,
1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,
1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,
1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,
1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,
1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,
1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,
1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,
acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,
4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R.sup.13 is
3-pyridyl and R.sup.14 is hydrogen.
[0233] In a preferred embodiment, prodrugs of GABA analogs that are
useful in practicing the current invention are those disclosed in
the art (Bryans et al., International Publication No. WO 01/90052;
U.K. Application GB 2,362,646; European Applications EP 1,201,240
and 1,178,034; Yatvin et al., U.S. Pat. No. 6,024,977; Mulvihill et
al., International Publication No. WO 01/544881; Gallop et al,
International Publication No. WO 02/42414). In a particularly
preferred embodiment, prodrugs of GABA analogs that are useful in
practicing the current invention are those disclosed by Bryans et
al., International Publication No. WO 01/90052. In one embodiment,
preferred prodrugs of GABA analogs include, but are not limited to,
[1-(acetoxymethoxycarbonylaminomethyl)-c- yclohexyl]-acetic acid;
[1-(acetoxymethoxycarbonylaminomethyl)-cyclohexyl]- -acetic acid
ethyl ester; 2,2-dimethylpropionic acid
1-carboxymethylcyclohexylmethyl-carbamoyloxymethyl ester;
2,2-dimethylpropionic acid
1-ethoxycarbonylmethylcyclohexylmethyl-carbamo- yloxymethyl ester;
benzoic acid 1-carboxymethyl-cyclohexylmethylcarbamoylo- xymethyl
ester; and benzoic acid 1-ethoxycarbonlymethyl-cyclohexylnethylca-
rbamoyloxymethyl ester. In another embodiment, preferred prodrugs
of GABA analogs include, but are not limited to, gabapentin and
pregabalin peptide derivatives wherein the amino group of the GABA
analog is acylated with particular .alpha.-aminoacyl or dipeptide
moieties. More specifically, the .alpha.-amino acids comprising
these peptide prodrug derivatives are the 20 naturally encoded
.alpha.-amino acids, plus phenylglycine.
SYNTHESIS OF THE PRODRUGS USED IN THE INVENTION
[0234] The prodrugs useful in the invention may be obtained via the
synthetic methods illustrated in Schemes 1-5. Those of skill in the
art will appreciate that a preferred synthetic route to the
compounds of the invention will consist of attaching promoieties to
GABA analogs. Numerous methods have been described in the art for
the synthesis of GABA analogs (See, e.g., Satzinger et al., U.S.
Pat. No. 4,024,175; Silverman et al., U.S. Pat. No. 5,563,175;
Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S.
Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;
Silverman et al., U.S. Pat. No. 6,117,906; Silverman, International
Publication No. WO 92/09560; Silverman et al., International
Publication No. WO 93/23383; Horwell et al., International
Publication No. WO 97/29101, Horwell et al., International
Publication No. WO 97/33858; Horwell et al., International
Publication No. WO 97/33859; Bryans et al., International
Publication No. WO 98/17627; Guglietta et al., International
Publication No. WO 99/08671; Bryans et al., International
Publication No. WO 99/21824; Bryans et al., International
Publication No. WO 99/31057; Belliotti et al., International
Publication No. WO 99/31074; Bryans et al., International
Publication No. WO 99/31075; Bryans et al., International
Publication No. WO 99/61424; Bryans et al., International
Publication No. WO 00/15611; Bryans, International Publication No.
WO 00/31020; and Bryans et al., International Publication No. WO
00/50027). Other methods are known in the art for synthesizing GABA
analogs, which are readily accessible to the skilled artisan. The
promoieties described herein, are known in the art and may be
prepared and attached to GABA analogs by established procedures
(See e.g., Green et al., "Protective Groups in Organic Chemistry",
(Wiley, 2.sup.nd ed. 1991); Harrison et al., "Compendium of
Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons,
1971-1996); "Beilstein Handbook of Organic Chemistry," Beilstein
Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al.,
"Reagents for Organic Synthesis," Volumes 1-17, Wiley Interscience;
Trost et al., "Comprehensive Organic Synthesis," Pergamon Press,
1991; "Theilheimer's Synthetic Methods of Organic Chemistry,"
Volumes 1-45, Karger, 1991; March, "Advanced Organic Chemistry,"
Wiley Interscience, 1991; Larock "Comprehensive Organic
Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of
Reagents for Organic Synthesis," John Wiley & Sons, 1995,
Bodanzsky, "Principles of Peptide Synthesis," Springer Verlag,
1984; Bodanzsky, "Practice of Peptide Synthesis," Springer Verlag,
1984).
[0235] Accordingly, starting materials useful for preparing
compounds used in the invention and intermediates thereof are
commercially available or can be prepared by well-known synthetic
methods. Other methods for synthesis of the prodrugs described
herein are either described in the art or will be readily apparent
to the skilled artisan in view of the references provided above and
may be used to synthesize the compounds of the invention.
Accordingly, the methods presented in the Schemes herein are
illustrative rather than comprehensive.
[0236] In any of the Schemes below, after the amino group of a GABA
analog has been functionalized with a promoiety or other protecting
group, the carboxylic acid group may be converted to an ester or
thioester by many synthetic methods, which are well-known to the
skilled artisan. In one preferred embodiment, GABA analogs may be
reacted with an alcohol or thiol in the presence of a coupling
reagent (e.g., carbodiimide and dimethylamino pyridine) to provide
the ester. In another preferred embodiment, GABA analogs may be
reacted with an alkyl halide in the presence of base to yield the
ester. Other methods for converting GABA analogs to esters or
thioesters are well within the purview of the skilled artisan in
view of the references provided herein.
[0237] One method for synthesis of compounds of Formula (I) is
illustrated in Scheme 1. 17
[0238] Chloroformate (1) is treated with an aromatic leaving group
such as p-nitrophenol in the presence of base to provide
p-nitrophenylcarbonate (2). Halide interchange provides iodide (3),
which is reacted with a metal or tetraalkylammonium salt of a
carboxylic acid to afford compound (4). Treatment of (4) with GABA
derivative (5), optionally in the presence of trimethylsilyl
chloride, affords a compound of Formula (I). Methods for making
related acyloxyalkyl carbamate compounds have been described in the
art (Alexander, U.S. Pat. No. 4,760,057; Alexander, U.S. Pat. No.
4,916,230; Alexander, U.S. Pat. No. 5,466,811; Alexander, U.S. Pat.
No. 5,684,018).
[0239] Alternatively compounds of Formula (I) can be prepared from
carbonate (4) in a stepwise fashion as illustrated in Scheme 2.
Here reaction of (4) with an .alpha.-amino acid (6), optionally
protected as a carboxylate ester, affords intermediate (7) which
upon deprotection (if necessary) provides compound (8), which is
then coupled to GABA analog (9) using standard peptide coupling
reagents well known in the art. 18
[0240] Another method for synthesis of compounds of Formula (I)
proceeds via carbonylation of GABA analog derivative (5) to an
intermediate carbamic acid species, which is captured by an in situ
alkylation reaction in an adaptation of the methods disclosed in
the art (Butcher, Synlett, 1994, 825-6; and Ferres et al., U.S.
Pat. No. 4,036,829). Carbon dioxide gas is bubbled into a solution
containing (5) and a base (e.g., Cs.sub.2CO.sub.3, Ag.sub.2CO.sub.3
or AgO) in a solvent such as DMF or NMP. The activated halide is
added, optionally in the presence of iodide ion as a catalyst, and
the carbonylation continued until the reaction is completed. This
method is illustrated in Scheme 3 for the preparation of compounds
of Formula (I) from halide (10). 19
[0241] Alternatively compounds of Formula (I) can be prepared in a
stepwise fashion as illustrated in Scheme 4. Carbonylation and
alkylation of carboxyl protected .alpha.-amino acid (6) provides
intermediate (7), which upon deprotection is coupled to GABA analog
(9) as previously described in Scheme 2. 20
[0242] Yet another method for synthesis of compounds of Formula (I)
relies upon oxidation of ketocarbamate derivatives of GABA analogs
(Gallop et al., U.S. patent application Ser. No. ______ entitled
"Methods for Synthesis of Prodrugs from 1-Acyl-Alkyl Derivatives
and Compositions Thereof"). As illustrated in Scheme 5, oxidation
of ketocarbamate (11) affords compounds of Formula (I). Preferred
solvents include, but are not limited to, t-butanol, diethylether,
acetic acid, hexane, dichloroethane, dichloromethane, ethyl
acetate, acetonitrile, methanol, chloroform and water. Generally,
the oxidant may be an organism (e.g., yeast or bacteria), or a
chemical reagent (e.g., an enzyme or peroxide).Preferred oxidants
include those, which have been successfully used in Baeyer-Villager
oxidations of ketones to esters or lactones (Strukul, Angnew. Chem.
Int. Ed., 1998, 37, 1198; Renz et al., Eur. J. Org. Chem. 1999,
737; Beller et al., in "Transition Metals in Organic Synthesis"
Chapter 2, Wiley VCH; Stewart, Current Organic Chemistry, 1998,2,
195; Kayser et al., Synlett, 1999, 1, 153). 21
THERAPEUTIC USES OF THE DOSAGE OF THE INVENTION
[0243] In accordance with the invention, an extended release oral
dosage form of the invention is administered to a patient,
preferably a human, suffering from epilepsy, depression, anxiety,
psychosis, faintness attacks, hypokinesia, cranial disorders,
neurodegenerative disorders, panic, pain (especially, neuropathic
pain and muscular and skeletal pain), inflammatory disease (i.e.,
arthritis), insomnia, gastrointestinal disorders or ethanol
withdrawal syndrome. Further, in certain embodiments, the dosage
forms of the invention are administered to a patient, preferably a
human, as a preventative measure against various diseases or
disorders. Thus, the dosage forms of the invention may be
administered as a preventative measure to a patient having a
predisposition for epilepsy, depression, anxiety, psychosis,
faintness attacks, hypokinesia, cranial disorders,
neurodegenerative disorders, panic, pain (especially, neuropathic
pain and muscular and skeletal pain), inflammatory disease (i.e.,
arthritis), insomnia, gastrointestinal disorders and ethanol
withdrawal syndrome. Accordingly, the dosage forms of the invention
may be used for the prevention of one disease or disorder and
concurrently treating another (e.g., prevention of psychosis while
treating gastrointestinal disorders; prevention of neuropathic pain
while treating ethanol withdrawal syndrome).
[0244] The suitability of the dosage forms of the invention in
treating epilepsy, depression, anxiety, psychosis, faintness
attacks, hypokinesia, cranial disorders, neurodegenerative
disorders, panic, pain (especially neuropathic pain and muscular
and skeletal pain), inflammatory disease (i.e., arthritis),
insomnia, gastrointestinal disorders and ethanol withdrawal
syndrome may be determined by methods described in the art (See,
e.g., Satzinger et al., U.S. Pat. No. 4,024,175; Satzinger et al.,
U.S. Pat. No. 4,087,544; Woodruff, U.S. Pat. No. 5,084,169;
Silverman et al., U.S. Pat. No. 5,563,175; Singh, U.S. Pat. No.
6,001,876; Horwell et al., U.S. Pat. No. 6,020,370; Silverman et
al., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No.
6,103,932; Silverman et al., U.S. Pat. No. 6,117,906; Silverman,
International Publication No. WO 92/09560; Silverman et al.,
International Publication No. WO 93/23383; Horwell et al.,
International Publication No. WO 97/29101, Horwell et al.,
International Publication No. WO 97/33858; Horwell et al.,
International Publication No. WO 97/33859; Bryans et al.,
International Publication No. WO 98/17627; Guglietta et al.,
International Publication No. WO 99/08671; Bryans et al.,
International Publication No. WO 99/21824; Bryans et al.,
International Publication No. WO 99/31057; Magnus-Miller et al.,
International Publication No. WO 99/37296; Bryans et al.,
International Publication No. WO 99/31075; Bryans et al.,
International Publication No. WO 99/61424; Pande, International
Publication No. WO 00/23067; Bryans, International Publication No.
WO 00/31020; Bryans et al., International Publication No. WO
00/50027; and Bryans et al, International Publication No. WO
02/00209). The dosage forms of the invention may be used to treat
or prevent epilepsy, depression, anxiety, psychosis, faintness
attacks, hypokinesia, cranial disorders, neurodegenerative
disorders, panic, pain (especially neuropathic pain and muscular
and skeletal pain), inflammatory disease (i.e., arthritis),
insomnia, gastrointestinal disorders and ethanol withdrawal
syndrome by procedures described in the art (see references above).
Thus, it is well with the capability of those of skill in the art
to assay and use the dosage forms of the invention to treat or
prevent epilepsy, depression, anxiety, psychosis, faintness
attacks, hypokinesia, cranial disorders, neurodegenerative
disorders, panic, pain (especially, neuropathic pain and muscular
and skeletal pain), inflammatory disease (i.e., arthritis),
insomnia, gastrointestinal disorders and ethanol withdrawal
syndrome.
[0245] Therapeutic/Prophvlactic Administration
[0246] The dosage forms of the invention may be advantageously used
in human medicine. As previously described, the dosage forms of the
invention are useful for the treatment or prevention of epilepsy,
depression, anxiety, psychosis, faintness attacks, hypokinesia,
cranial disorders, neurodegenerative disorders, panic, pain
(especially, neuropathic pain and muscular and skeletal pain),
inflammatory disease (i.e., arthritis), insomnia, gastrointestinal
disorders or ethanol withdrawal syndrome.
[0247] When used to treat or prevent the above disease or disorders
the dosage forms of the invention may be administered or applied
singly, or in combination with other agents. The dosage forms of
the invention may also deliver a GABA analog prodrug in combination
with another pharmaceutically active agent, including another GABA
analog prodrug.
[0248] The current invention provides methods of treatment and
prophylaxis by administration to a patient a GABA analog prodrug
dosage form of the present invention. The patient may be an animal,
is more preferably a mammal, and most preferably a. human.
[0249] The dosage forms of the invention, upon releasing the GABA
analog prodrug, preferably provide GABA analogs (e.g., gabapentin
and pregablin) upon in vivo administration to a patient. While not
wishing to bound by theory, the promoiety or promoieties of the
prodrug may be cleaved either chemically and/or enzymatically. One
or more enzymes present in the stomach, intestinal lumen,
intestinal tissue, blood, liver, brain or any other suitable tissue
of a mammal may enzymatically cleave the promoiety or promoieties
of the prodrug. The mechanism of cleavage is not important to the
current invention. Preferably, GABA analogs formed by cleavage of
prodrugs from the compounds used in the invention do not contain
substantial quantities of lactam contaminant (preferably, less than
0.5% by weight, more preferably, less than 0.2% by weight, most
preferably less than 0.1% by weight) (See Augart et al., U.S. Pat.
No. 6,054,482). The extent of release of lactam contaminant from
the prodrugs of this invention may be assessed using the standard
in vitro analytical methods.
[0250] While not wishing to bound by theory, the promoiety or
promoieties may be cleaved prior to absorption by the
gastrointestinal tract (e.g., within the stomach or intestinal
lumen) and/or after absorption by the gastrointestinal tract (e.g.,
in intestinal tissue, blood, liver or other suitable tissue of a
mammal). If the promoiety or promoieties are cleaved prior to
absorption by the gastrointestinal tract, the resulting GABA
analogs may be absorbed into the systemic circulation
conventionally (e.g. via the large neutral amino acid transporter
located in the small intestine). If the promoiety or promoieties
are cleaved after absorption by the gastrointestinal tract, these
GABA analog prodrugs may have the opportunity to be absorbed into
the systemic circulation either by passive diffusion, active
transport or by both passive and active processes.
[0251] If the promoiety or promoieties are cleaved after absorption
by the gastrointestinal tract, these GABA analog prodrugs may have
the opportunity to be absorbed into the systemic circulation from
the large intestine. It is preferred that the promoiety or
promoieties are cleaved after absorption by the gastrointestinal
tract.
COMPOSITIONS USEFUL IN THE INVENTION
[0252] The present compositions contain a therapeutically effective
amount of one or more GABA analog prodrugs, preferably in purified
form, together with a suitable amount of a pharmaceutically
acceptable vehicle, as to provide the form for proper
administration to a patient. When administered to a patient, the
prodrug and pharmaceutically acceptable vehicles are preferably
sterile. Suitable pharmaceutical vehicles also include excipients
such as starch, glucose, lactose, sucrose, gelatin, malt, rice,
flour, chalk, silica gel, sodium stearate, glycerol monostearate,
talc, sodium chloride, dried skim milk, glycerol, propylene,
glycol, water, ethanol and the like. The present compositions, if
desired, can also contain minor amounts of wetting or emulsifying
agents, or pH buffering agents. In addition, auxiliary,
stabilizing, thickening, lubricating and coloring agents may be
used.
[0253] In one embodiment, the compositions used in the invention
are free of lactam side products formed by intramolecular
cyclization. In a preferred embodiment, the compositions used in
the invention are stable to extended storage (preferably, greater
than one year) without substantial lactam formation (preferably,
less than 0.5% lactam by weight, more preferably, less than 0.2%
lactam by weight, most preferably, less than 0. 1% lactam by
weight).
[0254] Methods of Use And Doses
[0255] The extended release oral dosage forms of GABA analog
prodrugs are administered to treat or prevent diseases or disorders
such as epilepsy, depression, anxiety, psychosis, faintness
attacks, hypokinesia, cranial disorders, neurodegenerative
disorders, panic, pain (especially neuropathic pain and muscular
and skeletal pain), inflammatory disease (i.e., arthritis),
insomnia, gastrointestinal disorders and/or ethanol withdrawal
syndrome.
[0256] The amount of GABA analog prodrug that will be effective in
the treatment of a particular disorder or condition disclosed
herein will depend on the nature of the disorder or condition, and
can be determined by standard clinical techniques known in the art
as previously described. In addition, in vitro or in vivo assays
may optionally be employed to help identify optimal dosage ranges.
The amount of a prodrug administered will, of course, be dependent
on, among other factors, the subject being treated, the weight of
the subject, the severity of the affliction, the manner of
administration and the judgment of the prescribing physician.
[0257] Preferably, the dosage forms of the invention are adapted to
be administered to a patient no more than twice per day, more
preferably, only once per day. Dosing may be provided alone or in
combination with other drugs and may continue as long as required
for effective treatment of the disease state or disorder.
[0258] Suitable dosage ranges for oral administration are dependent
on the potency of the particular GABA analog drug (once cleaved
from the promoiety), but are generally about 0.001 mg to about 200
mg of drug per kilogram body weight. When the GABA analog is
gabapentin, typical daily doses of the drug in adult patients are
900 mg/day to 3600 mg/day and the dose of gabapentin prodrug may be
adjusted to provide an equivalent molar quantity of gabapentin.
Other GABA analogs may be more potent than gabapentin (e.g.,
pregabalin), and lower doses may be appropriate for both the
cleaved drug and any prodrug (measured on an equivalent molar
basis). Dosage ranges may be readily determined by methods known to
the skilled artisan.
[0259] The prodrugs used in the invention are preferably assayed in
vitro and in vivo, for the desired therapeutic or prophylactic
activity, prior to use in humans. For example, in vitro assays can
be used to determine whether administration of a specific prodrug
or a combination of prodrugs is preferred for reducing convulsion.
The prodrugs may also be demonstrated to be effective and safe
using animal model systems.
[0260] It will be apparent to those skilled in the art that many
modifications, both to materials and methods, may be practiced
without departing from the scope of the invention.
[0261] Finally, it should be noted that there are alternative ways
of implementing both the present invention. Accordingly, the
present embodiments are to be considered as illustrative and not
restrictive, and the invention is not to be limited to the details
given herein, but may be modified within the scope and equivalents
of the appended claims.
[0262] All publications and patents cited herein are incorporated
by reference in their entirety.
* * * * *