U.S. patent application number 14/956653 was filed with the patent office on 2016-08-04 for amino acid derivatives for the treatment of neuropathic pain.
The applicant listed for this patent is Xianqi KONG. Invention is credited to Mohammed ATFANI, Stephane CIBLAT, Lucie JETTE, Xianqi KONG, Serge LAMOTHE, Nigel LEVENS.
Application Number | 20160220519 14/956653 |
Document ID | / |
Family ID | 43049873 |
Filed Date | 2016-08-04 |
United States Patent
Application |
20160220519 |
Kind Code |
A1 |
KONG; Xianqi ; et
al. |
August 4, 2016 |
AMINO ACID DERIVATIVES FOR THE TREATMENT OF NEUROPATHIC PAIN
Abstract
The invention relates to compounds, to compositions comprising
the same and uses thereof for the prevention or treatment of pain,
e.g. neuropathic pain while having neutral or beneficial effect on
metabolic parameters.
Inventors: |
KONG; Xianqi;
(Dollard-des-Ormeaux, CA) ; LEVENS; Nigel;
(Beaconsfiled, CA) ; LAMOTHE; Serge; (Boisbriand,
CA) ; ATFANI; Mohammed; (Laval, CA) ; CIBLAT;
Stephane; (Montreal, CA) ; JETTE; Lucie;
(Montreal, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KONG; Xianqi |
Dollard-des-Ormeaux |
|
CA |
|
|
Family ID: |
43049873 |
Appl. No.: |
14/956653 |
Filed: |
December 2, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14020284 |
Sep 6, 2013 |
9233913 |
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14956653 |
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13289897 |
Nov 4, 2011 |
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14020284 |
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PCT/CA2010/000670 |
Apr 30, 2010 |
|
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13289897 |
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61215490 |
May 6, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/198 20130101;
A61P 3/08 20180101; C07D 307/83 20130101; A61P 25/08 20180101; C07C
2601/14 20170501; A61P 29/02 20180101; C07C 2601/08 20170501; C07C
229/32 20130101; C07D 207/09 20130101; C07D 307/54 20130101; C07D
333/24 20130101; A61P 25/00 20180101; C07D 307/16 20130101; A61P
25/02 20180101; C07D 307/81 20130101; C07C 229/28 20130101; A61P
25/06 20180101; C07C 229/36 20130101; C07C 2601/16 20170501; A61P
29/00 20180101; C07C 2601/18 20170501 |
International
Class: |
A61K 31/198 20060101
A61K031/198 |
Claims
1.-19. (canceled)
20. A method for treating neuropathic pain in a subject in need
thereof, comprising administering a compound or a pharmaceutically
acceptable salt or ester thereof to the subject, the compound being
selected from a compound of Formula IV: ##STR00048## wherein, X is
O, NH, or S; R.sup.1 is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.3-6heterocycloalkyl,
C.sub.6aryl, or C.sub.5-9heteroaryl; R.sup.2 is hydrogen, or an
N-protecting group; R.sup.8 and R.sup.9 are each independently
hydrogen, C.sub.1-12alkyl, C.sub.6-10aryl, NH.sub.2, NHR.sup.6,
NR.sup.6R.sup.7, OR.sup.6, halide, cycloalkyl, alkylenyl,
arylalkyl, or R.sup.8 and R.sup.9 are taken together with their
adjacent atoms to form a spiro or fused heterocycloalkyl or
heteroaryl group, or R.sup.8 and R.sup.9 are attached to the same
carbon atom and together with the adjacent carbon atom form a
carbonyl; R.sup.4, R.sup.6 and R.sup.7 are each independently
hydrogen, C.sub.1-12alkyl, or C.sub.6-10aryl; and p is an integer
from 1 to 2; wherein when R.sup.1, R.sup.2, R.sup.4, R.sup.6,
R.sup.7, R.sup.8 or R.sup.9 is a group selected from alkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl, then said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group may be unsubstituted or
substituted with a group selected from the group consisting of
acyl, unsubstituted amino, alkylamino, dialkylamino, arylamino,
diarylamino, alkylarylamino, acylamino, carbamoyl, ureido,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and
dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro,
trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl,
thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy,
aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl,
alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide,
phosphate, phosphonato, phosphinato, oxo, guanidine, imino, and
formyl; such that neuropathic pain is treated in the subject;
wherein the neuropathic pain is associated with diabetic
neuropathy.
21. The method of claim 20, wherein pain is controlled in the
subject.
22. The method of claim 21, wherein said pain is nerve pain.
23. The method of claim 20, wherein X is an oxygen atom.
24. The method of claim 20, wherein X is NH.
25. The method of claim 20, wherein X is sulfur.
26. The method of claim 20, wherein p is 1.
27. The method of claim 20, wherein p is 2.
28. The method of claim 20, wherein R.sup.4 is hydrogen.
29. The method of claim 20, wherein R.sup.2 is hydrogen.
30. The method of claim 20, wherein R.sup.2 is an N-protecting
group selected from the group consisting of acyl, and
amino-substituted acyl.
31. The method of claim 30, wherein said amino-substituted acyl is
an amino acid residue linked through its carbonyl.
32. The method of claim 31, wherein said amino acid residue is
selected from valyl, leucyl, and isoleucyl.
33. The method of claim 20, wherein the compound is of
substantially pure S configuration.
34. The method of claim 20, wherein the compound is of
substantially pure R configuration.
35. The method of claim 20, wherein the compound is a mixture of
compounds where the chiral center C* is in the S or the R
configuration.
36. The method of claim 20, wherein the compound is selected from
the group consisting of: ##STR00049## and pharmaceutically
acceptable salts or esters thereof.
37. The method of claim 20, wherein the compound is ##STR00050## or
a pharmaceutically acceptable salt or ester thereof.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/020,284 filed Sep. 6, 2013, which is a continuation of U.S.
application Ser. No. 13/289,897 filed Nov. 4, 2011, which is a
continuation-in-part of PCT international application number
PCT/CA2010/000670 filed Apr. 30, 2010, which claims priority to
U.S. provisional application No. 61/215,490 filed on May 6,
2009.
FIELD OF THE INVENTION
[0002] The invention relates to .alpha.-amino acids, to
compositions comprising the same and uses thereof for the
prevention or treatment of pain, e.g neuropathic pain.
BACKGROUND OF THE INVENTION
[0003] Neuropathic pain (or neuralgia) is generally defined as
non-nociceptive pain. In fact, neuropathic pain is produced by a
change in neurological function or structure as opposed to
activation of pain receptor cells in the case of nociceptive
pain.
[0004] Diabetic neuropathy is a common complication of type II
diabetes that can affect virtually every tissue of the body and
induce significant morbidity and mortality. Pain affecting the feet
and ankles, which is often severe, is the most common symptom of
the condition. Duration of diabetes and poor glycemic control
appears to be responsible to some extent for nerve damage that
ultimately is perceived as painful impulses.
[0005] Treatment of diabetic neuropathy is challenging and is
currently far from optimal. In fact, neuropathic pain is recognized
as one of the most difficult pain syndromes to treat. Currently
available therapeutics are modestly to moderately effective in
relieving symptoms and are limited by side effects and drug-drug
interactions. At the present time, only two drugs are officially
approved for the symptomatic treatment of diabetic neuropathy:
pregabalin (structurally related to gabapentin) and duloxetine.
Both have troublesome side effects, including somnolence and
dizziness. More particularly, pregabalin, and also gabapentin, are
associated with body weight gain which can worsen the metabolic
control in patients with type II diabetes.
[0006] There is a need for a therapeutic having better or similar
analgesic properties as the currently available treatment but with
less adverse effects, and more particularly with beneficial or
neutral metabolic effect.
SUMMARY OF THE INVENTION
[0007] The invention relates to a-amino acid analogs, to
compositions comprising the same and their therapeutic uses.
According to one aspect, the compound of the invention is a
compound selected from the compounds of any one of Formulae 1 to
VI, including any specific embodiments thereof, a compound selected
from Compounds 1 to 30, or a compound of any one of sections a) to
e) herein defined, or a pharmaceutically acceptable salt, solvate,
prodrug, or ester thereof. In another aspect, the invention relates
to a compound of any one of Formulae I to VI, wherein the
configuration of the carbon a to the carboxyl is the same as the
L-configuration of natural amino acids. Aspects of the invention
provide compounds of Formulae H or IV. Another aspect of the
invention provides compounds of Formulae II or IV, wherein the
configuration of the carbon a to the carboxyl is the same as the
L-configuration of natural amino acids. Aspects of the invention
provide compounds of Formula II. Another aspect of the invention
provides compounds of Formula wherein the configuration of the
carbon a to the carboxyl is the same as the L-configuration of
natural amino acids. The invention also further relates to a
compound selected from the group consisting of Compounds 3-5, 11,
13, 15, 17, 19, 23, 24, 26, 27, 29 and the compounds of section d).
The invention also further relates to a compound selected from the
group consisting of Compounds 6-8, 10, 12, 14, 16, 18, 21, 22, 25,
28, 30, and the compounds of any one of sections a), b), c) or e)
herein described. The invention also further relates to a compound
selected from the group consisting of Compounds 6 to 8, or
Compounds 7 and 8. The invention also further relates to Compound
7. The invention also further relates to Compound 8.
[0008] According to another aspect, the invention pertains to
pharmaceutical compositions comprising at least one compound of the
invention as herein described.
[0009] According to other aspects, the invention relates to the use
of a compound as herein defined for the treatment of neuropathic
pain. The invention also further relates to the use of a compound
as herein defined for the treatment of diabetic neuropathy. The
invention also further relates to the use of a compound as herein
defined for the treatment of diabetic neuropathy while being
neutral of beneficial to metabolic symptoms, such as
glucose/insulin levels and body weight. The invention also further
relates to the use of a compound as herein defined for the
treatment of diabetic neuropathy while improving glucose control
and/or without body weight gain or reduced body weight. The
invention also relates to the use of a compound of the invention in
the manufacture of a medicament for the treatment of any of the
diseases and conditions herein described.
[0010] Another aspect of the invention also relates to methods of
treating neuropathic pain in a subject in need thereof comprising
the step of administering a therapeutically effective amount of a
compound of the invention. The invention also relates to methods of
treating diabetic neuropathy in a subject in need thereof
comprising the step of administering a therapeutically effective
amount of a compound of the invention. The invention also relates
to methods of treating diabetic neuropathy while having a neutral
of beneficial effect on metabolic symptoms, such as glucose/insulin
levels and body weight of a subject in need of such treatment, the
method comprising the step of administering a therapeutically
effective amount of a compound of the invention. The invention also
relates to methods of treating diabetic neuropathy, improving
glucose control and/or reducing body weight of a subject in need of
such treatment, the method comprising the step of administering a
therapeutically effective amount of a compound of the
invention.
[0011] Other aspects of the invention include the use of the
compounds of the invention in the treatment diseases and conditions
treatable by drugs with affinity to an .alpha..sub.2.delta. subunit
of voltage-gated N-type calcium ion channels. Examples of such
diseases and conditions include, without limitation, neuropathy,
neuropathic pain, diabetic neuropathy, post-herpetic neuralgia,
epilepsy, and fibriomyalgia.
[0012] In yet another aspect, the invention includes the use of the
compounds of the invention in the control of pain, and more
particularly nerve pain. Other aspects of the invention include the
use of the compounds of the invention in the treatment of a disease
or condition selected from neuropathy, neuropathic pain, diabetic
neuropathy, post-herpetic neuralgia, fibriomyalgia, migraine
headaches, post-operative chronic pain, nerve pain associated with
spinal cord injury, multiple sclerosis, and nystagmus.
[0013] Additional objects, advantages and features of the present
invention will become more apparent upon reading of the following
non-restrictive description of preferred embodiments which are
exemplary and should not be interpreted as limiting the scope of
the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1A shows fasted basal glycemia in DIO-mice treated with
Compounds 6A and 6B, (2S,3R,4S)-4-hydroxyisoleucine (4-OH-Ile), and
vehicle.
[0015] FIG. 1B shows fasted basal insulinamia in DIO-mice treated
with Compounds 6A and 6B, (2S,3R,4S)-4-hydroxyisoleucine (4-OH-Ile)
and vehicle.
[0016] FIG. 2A shows insulin secretion during OGTT in DIO-mice
treated with Compounds 6A and 6B, (2S,3R,4S)-4-hydroxyisoleucine
(4-OH-Ile) and vehicle
[0017] FIG. 2B shows insulin AUC following administration of
Compounds 6A and 6B, 4- OH-Ile and vehile in DIO-mice.
[0018] FIGS. 3A and 3B show pharmacokinetic profile (log scale) in
mice following administration of Compound 6B (50 mg/kg) and
Compound 18 (50 mg/kg) respectively i.v. and p.o.
[0019] FIG. 4 pharmacokinetic profile (log scale) in dogs following
administration of Compound 18 (25 mg/kg) p.o. and i.v.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0020] All technical and scientific terms used herein have the same
meaning as commonly understood by one ordinary skilled in the art
to which the invention pertains. For convenience, the meaning of
certain terms and phrases used herein are provided below.
[0021] To the extent the definitions of terms in the publications,
patents, and patent applications incorporated herein by reference
are contrary to the definitions set forth in this specification,
the definitions in this specification control. The section headings
used herein are for organizational purposes only, and are not to be
construed as limiting the subject matter disclosed.
[0022] It should be noted that, the singular forms "a", "an", and
"the" include plural referents unless the content clearly dictates
otherwise. Thus, for example, reference to a composition containing
"a compound" includes a mixture of two or more compounds. It should
also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates
otherwise.
[0023] The chemical structures herein are drawn according to the
conventional standards known in the art. Thus, where an atom, such
as a carbon atom, as drawn appears to have an unsatisfied valency,
then that valency is assumed to be satisfied by a hydrogen atom
even though that hydrogen atom is not necessarily explicitly drawn.
Hydrogen atoms should be inferred to be part of the compound.
[0024] The symbol "--" in general represents a bond between two
atoms in the chain. Thus CH.sub.3--OCH.sub.2--CH(R.sub.i)--CH.sub.3
represents a 2-substituted-1-methoxypropane compound. In addition,
the symbol "--" also represents the point of attachment of the
substituent to a compound. Thus for example
aryl(C.sub.1-C.sub.6)alkyl indicates an arylalkyl group, such as
benzyl, attached to the compound through the alkyl moiety.
[0025] Where multiple substituents are indicated as being attached
to a structure, it is to be understood that the substituent can be
the same or different. Thus for example "R.sub.m optionally
substituted with 1, 2 or 3 R.sub.q groups" indicates that R.sub.m
is substituted with 1, 2, or 3 R.sub.q groups where the R.sub.q
groups can be the same or different.
[0026] As used herein, the term "Compounds of the present
invention" and equivalent expressions refer to compounds mentioned
herein as being useful for at least one purpose of the invention,
e.g., those encompassed by structural Formulae such as Formulae I
to VI and their different aspects and embodiments, and includes
specific compounds disclosed herein such as encompassed by those
Formulae and to specifically mentioned compounds such as those
disclosed in Table 1 or the following sections a) to e), as well as
their pharmaceutically acceptable salts and solvates. Embodiments
herein may exclude one or more of the compounds of the invention.
Compounds 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 chemical structures disclosed 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 if applicable.
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,
e.g., chiral chromatography (such as chiral HPLC), immunoassay
techniques, or the use of covalently (such as Mosher's esters) and
non-covalently (such as chiral salts) bound chiral reagents to
respectively form a diastereomeric mixture which can be separated
by conventional methods, such as chromatography, distillation,
crystallization or sublimation, the chiral salt or ester is than
exchanged or cleaved by conventional means, to recover the desired
isomers. The compounds 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
disclosed compounds also include isotopically labeled compounds
where one or more atoms have an atomic mass different from the
atomic mass most abundantly found in nature, for example, without
limitation, .sup.2H (D), .sup.3H (T), .sup.11C, .sup.13C, .sup.14C,
.sup.15N, .sup.18O, .sup.17O, etc. Compounds may exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, compounds may be hydrated or solvated. Certain
compounds may exist in multiple crystalline or amorphous forms. In
general, all physical forms are equivalent for the uses
contemplated herein and are intended to be within the scope of the
present invention. Further, when partial structures of the
compounds are illustrated, brackets or equivalents indicate the
point of attachment of the partial structure to the rest of the
molecule.
[0027] The invention pertains to both salt forms and acid/base
forms of the compounds of the invention. For example, the invention
pertains not only to the particular salt forms of compounds shown
herein as salts, but also the invention includes other
pharmaceutically acceptable salts, and the acid and/or base form of
the compound. The invention also pertains to salt forms of
compounds shown herein.
[0028] The term "prodrug" and equivalent expressions refer to
agents which can be converted in vitro or vivo directly or
indirectly to an active form (see, e.g., R. B. Silverman, 1992,
"The Organic Chemistry of Drug Design and Drug Action," Academic
Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of
Prodrugs". 360 pp. Elsevier. Amsterdam; Stella, V.; Borchardt, R.;
Hageman, M.; Oliyai, R.; Maaa, H.; Tilley, J. (Eds.) (2007),
"Prodrugs: Challenges and Rewards, XVIII, 1470 p. Springer).
Prodrugs can be used to alter the biodistribution (e.g., to allow
agents which would not typically enter the reactive site of the
protease) or the pharmacokinetics for a particular agent. A wide
variety of groups have been used to modify compounds to form
prodrugs, for example, esters, ethers, phosphates, etc. When the
prodrug is administered to a subject, the group is cleaved,
enzymatically or non-enzymatically, reductively, oxidatively, or
hydrolytically, or otherwise to reveal the active form. As used
herein, "prodrug" includes pharmaceutically acceptable salts
thereof, or pharmaceutically acceptable solvates as well as
crystalline forms of any of the foregoing. Prodrugs can be
pharmaceutically active or inactive; and the latter will exert the
pharmaceutical activity when it is converted to the parent
drug(s).
[0029] The term "aliphatic group" includes organic moieties
characterized by straight or branched-chains, typically having
between 1 and 16 carbon atoms, or having between 1 to 12, 1 to 8, 1
to 5 or 1 to 3 carbon atoms. Aliphatic groups include acyclic alkyl
groups, alkenyl groups, and alkynyl groups.
[0030] As used herein, the term "acyclic" refers to an organic
moiety without ring system.
[0031] As used herein, the term "alkyl" refers to saturated
hydrocarbons having from one to sixteen carbon atoms, including
linear or branched alkyl groups. Examples of alkyl groups include,
without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl,
heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl,
isobutyl, and the like. The term "C.sub.1-C.sub.nalkyl" refers to
an alkyl group having from 1 to the indicated "n" number of carbon
atoms.
[0032] As used herein, the term "alkenyl" refers to unsaturated
hydrocarbons having from two to sixteen carbon atoms, including
linear or branched alkenyl groups, and comprising between one and
six carbon-carbon double bonds. Examples of alkenyl groups include,
without limitation, vinyl, allyl, 1-propen-2-yl, 1-buten-3-yl,
1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl, 1,3-pentadien-5-yl, and
the like. The term alkenyl includes both unsubstituted alkenyl
groups and substituted alkenyl groups. The term
"C.sub.2-C.sub.nalkenyl" refers to an alkenyl group having from 2
to the indicated "n" number of carbon atoms.
[0033] As used herein, the term "alkynyl" refers to unsaturated
hydrocarbons having from two to twelve carbon atoms, including
linear or branched alkynyl groups, and comprising between one to
six carbon-carbon triple bond. Examples of alkynyl groups include,
without limitation, ethynyl, 1-propyn-3-yl, 1-butyn-4-yl,
2-butyn-4-yl, 1-pentyn-5-yl, 1,3-pentadiyn-5-yl, and the like. The
term alkynyl includes both unsubstituted alkynyl groups and
substituted alkynyl groups. The term "C.sub.2-C.sub.nalkynyl"
refers to an alkynyl group having from 2 to the indicated "n"
number of carbon atoms.
[0034] Unless the number of carbons is otherwise specified, "lower"
as in "lower aliphatic," "lower alkyl," "lower alkenyl," and "lower
alkylnyl", as used herein means that the moiety has at least one
(two for alkenyl and alkynyl) and equal or less than 6 carbon
atoms.
[0035] The terms "cycloalkyl", "carbocyclic" and equivalent
expressions refer to a group comprising a saturated or partially
unsaturated (non aromatic) carbocyclic ring in a monocyclic or
polycyclic ring system, including spiro (sharing one atom) or fused
(sharing at least one bond) carbocyclic ring systems, having from
three to fifteen ring members. Examples of cycloalkyl groups
include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl,
cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl,
bicyclo[4,3,0]nonanyl, norbornyl, and the like. The term cycloalkyl
includes both unsubstituted cycloalkyl groups and substituted
cycloalkyl groups. The term "C.sub.3-C.sub.ncycloalkyl" refers to a
cycloalkyl group having from 3 to the indicated "n" number of
carbon atoms in the ring structure. Unless the number of carbons is
otherwise specified, "lower cycloalkyl" groups as herein used, have
at least 3 and equal or less than 8 carbon atoms in their ring
structure.
[0036] The term "heterocycloalkyl" and equivalent expressions refer
to a group comprising a saturated or partially unsaturated (non
aromatic) carbocyclic ring in a monocyclic or polycyclic ring
system, including spiro (sharing one atom) or fused (sharing at
least one bond) carbocyclic ring systems, having from three to
fifteen ring members, where one or more (up to six) ring members
are substituted or unsubstituted heteroatoms (e.g. N, O, S, P) or
groups containing such heteroatoms (e.g. NH, NR.sub.x (R.sub.x is
alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO.sub.2, SO,
SO.sub.2, and the like). Heterocycloalkyl groups may he C-attached
or heteroatom-attached (e.g. via a nitrogen atom) where such is
possible. Examples of heterocycloalkyl groups include, without
limitation, pyrrolidino, tetrahydrofuranyl, tetrahydrodithienyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,
thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl,
thietanyl, hompiperidinyl, oxepanyl, thiepanyl, oxazepinyl,
diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,
3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,
pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,
dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, 3-azabicyclo[3,1,0]hexanyl,
3-azabicyclo[4,1,0]heptanyl, quinolizinyl, and sugars, and the
like. The term heterocycloalkyl includes both unsubstituted
heterocycloalkyl groups and substituted heterocycloalkyl groups.
The term "C.sub.3-C.sub.nheterocycloalkyl" refers to a
heterocycloalkyl group having from 3 to the indicated "n" number of
atoms (carbon or heteroatom or group) in the ring structure,
including at least one hetero group or atom as defined above.
Unless the number of carbons is otherwise specified, "lower
heterocycloalkyl" groups as herein used, have at least 3 and equal
or less than 8 ring members in their ring structure.
[0037] The terms "aryl" and "aryl ring" refer to aromatic groups
having 4n+2 .pi.(pi) electrons, wherein n is an integer from 1 to
3, in a conjugated monocyclic or polycyclic system (fused or not)
and having six to fourteen ring atoms. A polycyclic ring system
includes at least one aromatic ring. Aryl may be directly attached,
or connected via a C.sub.1-C.sub.3alkyl group (also referred to as
arylalkyl or aralkyl). Examples of aryl groups include, without
limitation, phenyl, benzyl, phenetyl, 1-phenylethyl, tolyl,
naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl,
benzocycloheptenyl, azulenyl, acenaphthylenyl, fluorenyl,
phenanthernyl, anthracenyl, and the like. The term aryl includes
both unsubstituted aryl groups and substituted aryl groups. The
term "C.sub.6-C.sub.naryl" refers to an aryl group having from 6 to
the indicated "n" number of carbons in the ring structure.
[0038] The terms "heteroaryl" and "heteroaryl ring" refer to
aromatic groups having 4n+2 .pi.(pi) electrons, wherein n is an
integer from 1 to 3, in a conjugated monocyclic or polycyclic
system (fused or not) and having five to fourteen ring members,
including one to six substituted or unsubstituted heteroatoms (e.g.
N, O, S) or groups containing such heteroatoms (e.g. NH, NR.sub.x
(R.sub.x is alkyl, acyl, aryl, heteroaryl or cycloalkyl), SO, and
the like), A polycyclic ring system includes at least one
heteroaromatic ring. Heteroaryls may be directly attached, or
connected via a C.sub.1-C.sub.3alkyl group (also referred to as
heteroarylalkyl or heteroaralkyl). Heteroaryl groups may be
C-attached or heteroatom-attached (e.g. via a nitrogen atom), where
such is possible. Examples of heteroaryl groups include, without
limitation, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
tetrazolyl, furyl, thienyl; isooxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrollyl, quinolinyl, isoquinolinyl, indolyl,
3H-indolyl, indolinyl, isoindolyl, chromenyl, isochromenyl,
benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,
phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothienyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinolizinyl, quinolonyl,
isoquinolonyl, quinoxalinyl, naphthyridinyl, furopyridinyl,
carbazolyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
dibenzofurnayl, and the like. The term heteroaryl includes both
unsubstituted heteroaryl groups and substituted heteroaryl groups.
The term "C.sub.5-C.sub.nheteroaryl refers to an heteroaryl group
having from 5 to the indicated "n" number of atoms (carbon or
heteroatom or group) in the ring structure, including at least one
hetero group or atom as defined above.
[0039] The terms "heterocycle" or "heterocyclic" or "heterocyclyl"
include heterocycloalkyl and heteroaryl groups. Examples of
heterocycles include, without limitation, acridinyl, azocinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzexazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,
4.alpha.H-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,
isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl,
morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl piperonyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridomidazole,
pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyi, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, and the like. The term
heterocycle includes both unsubstituted heterocyclic groups and
substituted heterocyclic groups.
[0040] The term "amine" or "amino," as used herein, refers to an
unsubstituted or substituted moiety of the formula
--NR.sup.aR.sup.b, in which R.sup.a and R.sup.b are each
independently hydrogen, alkyl, aryl, or heterocyclyl, or R.sup.a
and R.sup.b, taken together with the nitrogen atom to which they
are attached, form a heterocyclic ring. The term "amide" or
"aminocarbonyl" includes compounds or moieties which contain a
nitrogen atom which is bound to the carbon of a carbonyl or a
thiocarbonyl group. The term acylamino refers to an amino group
directly attached to an acyl group as defined herein.
[0041] The term "nitro" means --NO.sub.2; the terms "halo" and
"halogen" refer to bromine, chlorine, fluorine or iodine
substituents: the term "thiol", "thio", or "mercapto" means SH; and
the term "hydroxyl" or "hydroxy" means --OH. The term "alkylthio"
refers to an alkyl group, having a sulfhydryl group attached
thereto. Suitable alkylthio groups include groups having 1 to about
12 carbon atoms, preferably from 1 to about 6 carbon atoms. The
term "alkylcarboxyl" as used herein means an alkyl group having a
carboxyl group attached thereto.
[0042] The term "alkoxy" or "lower alkoxy" as used herein means an
alkyl group having an oxygen atom attached thereto. Representative
alkoxy groups include groups having 1 to about 6 carbon atoms,
e.g., methoxy, ethoxy, propoxy, tert-butoxy and the like. Examples
of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy,
butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy, trichloromethoxy groups and the
like. The term alkoxy includes both unsubstituted or substituted
alkoxy groups, etc., as well as halogenated alkyloxy groups.
[0043] The term "carbonyl" or "carboxy" includes compounds and
moieties which contain a carbon connected with a double bond to an
oxygen atom. Examples of moieties which contain a carbonyl include
aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,
etc.
[0044] The term "acyl" refers to a carbonyl group that is attached
through its carbon atom to a hydrogen (i.e., forayl), an aliphatic
group (C.sub.1-C.sub.nalkyl, C.sub.1-C.sub.nalkenyl,
C.sub.1-C.sub.nalkynyl, wherein n is an integer from 2 to 10; e.g.
acetyl, a cycloalkyl group (e.g. C.sub.3-C.sub.8cycloalkyl), a
heterocyclic group (e.g. C.sub.3-C.sub.8heterocycloalkyl and
C.sub.5-C.sub.6heteroaryl), an aromatic group (e.g. C.sub.6aryl,
e.g., benzoyl), and the like. Acyl groups may be unsubstituted or
substituted acyl groups (e.g. salicyloyl).
[0045] The term "amino acid" generally refers to an organic
compound comprising both a carboxylic acid group and an amine
group. The term "amino acid" includes both "natural" and
"unnatural" or "non-natural" amino acids. Additionally, the term
amino acid includes O-alkylated or N-alkylated amino acids, as well
as amino acids having nitrogen or oxygen-containing side chains
(such as Lys, Orn, or Ser) in which the nitrogen or oxygen atom has
been acylated or alkylated. Amino acids may be pure L or D isomers
or mixtures of L and D isomers, including racemic mixtures. Amino
acid may be .alpha.-, or or .gamma.-, or .delta.-, or .omega.-amino
acid.
[0046] The term "natural amino acid" and equivalent expressions
refer to amino acids commonly found in naturally occurring
proteins. Examples of natural amino acids include, without
limitation, alanine (Ala), cystein (Cys), aspartic acid (Asp),
glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine
(His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine
(Met), asparagine (Asp), proline (Pro), glutamine (Gln), arginine
(Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan
(Trp), tyrosine (Tyr), .beta.-alanine (.beta.-ALA), and
.gamma.-aminobutyric acid (GABA).
[0047] The term "unnatural amino acid" refers loosely to any
compound which bears at least one amino group and at least one
carboxylic group in the same molecule; and the compound is nota
natural product or has not been found in nature at the time being
but rather a synthetic chemical entity. Examples of unnatural amino
acids include derivatives of natural amino acids including D forms,
and .alpha.- and .beta.-amino acid derivatives. The terms
"unnatural amino acid" and "non-natural amino acid" are used
interchangeably herein and are meant to include the same moieties.
It is noted that certain amino acids, e.g., hydroxyproline, that
are classified as a non-natural amino acid herein, may be found in
nature within a certain organism or a particular protein. Amino
acids with many different protecting groups appropriate for
immediate use in the solid phase synthesis of peptides are
commercially available. In addition to the twenty most common
naturally occurring amino acids, the following examples of
non-natural amino acids and amino acid derivatives may be used
according to the invention (common abbreviations in parentheses):
2-aminoadipic acid (Aad), 3-aminoadipic acid (.beta.-Aad),
2-aminobutyric acid (2-Abu), .alpha.,.beta.-dehydro-2-aminabutyric
acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC),
aminoisobutyric acid (Rib), 3-aminoisobutyric acid (.beta.-Aib),
2-amino-thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava),
6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe),
8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun),
12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz),
3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz),
4-amino-3-hydroxy-6-methylheptanoic acid (Statine. Sta),
aminooxyacetic acid (Aoa), 2-aminotetraline-2-carboxylic acid
(ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA),
para-aminophenylalanine (4-NH.sub.2-Phe), 2-aminopimelic acid
(Apm), biphenylalanine (Bip), para-bromophenylalanine (4-Br-Phe),
ortho-chlorophenylalanine (2-Cl-Phe), meta-chlorophenylalanine
(3-Cl-Phe), para-chlorophenylalanine (4-Cl-Phe),
meta-chlorotyrosine (3-Cl-Tyr), para-benzoylphenylalanine (Bpa),
tert-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine
(Chg), desmosine (Des), 2,2-diaminopimelic acid (Dpm),
2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu),
3,4-dichlorophenylalanine (3,4-C1.sub.2-Phe),
3,4-diflurorphenylalanine (3,4-F.sub.2-Phe), 3,5-diiodotyrosine
(3,5-I.sub.2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine
(EtAsn), ortho-fluorophenylalanine (2-F-Phe),
meta-fluorophenylalanine (3-F-Phe), para-fluorophenylaianine
(4-F-Phe), meta-fluorotyrosine (3-F-Tyr), homoserine (Hae),
homophenylalanine (Hfe), homotyrosine (Htyr), hydroxylysine (Hyl),
allo-hydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or
4-hydroxyproline (3- or 4-Hyp), para-iodophenylalanine (4-I-Phe),
3-iodotyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc),
isodesmosine (Ide), allo-isoleucine (a-Ile), isonipecotic acid
(Inp), N-methylisoleucine (MeIle), N-methyllysine (MeLys),
meta-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal),
1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal),
para-nitrophenylalanine (4-NO.sub.2-Phe). 3-nitrotyrosine
(3-NO.sub.2-Tyr), norleucine (Nle), norvaline (Nva), ornithine
(Om), ortho-phosphotyrosine (H.sub.2PO.sub.3-Tyr),
octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen),
pentafluorophenylalanine (F.sub.5-Phe), phenylglycine (Phg),
pipecolic acid (Pip), propargylglycine (Pra), pyroglutamic acid
(PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid
(Tic), thienylalanine, and thiazolidine-4-carboxylic acid
(thioproline, Th).
[0048] It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with the permitted valence of the substituted atom and
the substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc. As used
herein, the term `substituted" is meant to include all permissible
substituents of organic compounds. In a broad aspect, the
permissible substituents include acyclic and cyclic, branched and
unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic
substituents of organic compounds. The permissible substituents can
be one or more. The term "substituted", when in association with
any of the foregoing groups refers to a group substituted at one or
more position with substituents such as acyl, amino (including
simple amino, mono and dialkylamino, mono and diarylamino, and
alkylarylamino), acylamino (including carbamoyl, and ureido),
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and
dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro,
trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl,
thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy,
aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl,
alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide,
phosphate, phosphonato, phosphinato, oxo, guanidine, imino, formyl
and the like. Any of the above substituents can be further
substituted if permissible, e.g. if the group contains an alkyl
group, an aryl group, or other.
[0049] The term "solvate" refers to a physical association of a
compound of this invention with one or more solvent molecules,
whether organic or inorganic. This physical association includes
hydrogen bonding. In certain instances, the solvate will be capable
of isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid.
"Solvate" encompasses both solution-phase and isolable solvates.
Exemplary solvates include hydrates, ethanolates, methanolates,
hemiethanolates, and the like, preferably hydrates.
[0050] A "pharmaceutically acceptable salt" of a compound means a
salt of a compound that is pharmaceutically acceptable. Desirable
are salts of a compound that retain or improve the biological
effectiveness and properties of the free acids and bases of the
parent compound as defined herein or that takes advantage of an
intrinsically basic, acidic or charged functionality on the
molecule and that is not biologically or otherwise undesirable.
Example of pharmaceutically acceptable salts are also described,
for example, in Berge et al., "Pharmaceutical Salts", J. Pharm.
Sci. 66, 1-19 (1977). Such salts include:
[0051] (1) acid addition salts, formed on a basic or positively
charged functionality, by the addition of inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, sulfamic acid, nitric acid, phosphoric acid, carbonate
forming agents, and the like; or formed with organic acids such as
acetic acid, propionic acid, lactic acid, oxalic, glycolic acid,
pivalic acid, t-butylacetic acid, .beta.-hydroxybutyric acid,
valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic
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, cyclohexylaminosulfonic acid,
benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic
acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid,
camphorsulfonic acid, 3-phenyl propionic acid, lauryl sulphonic
acid, lauryl sulfuric acid, oleic acid, palmitic acid, stearic
acid, lauric acid, embonic (pamoic) acid, palmoic acid, pantothenic
acid, lactobionic acid, alginic acid, galactaric acid, galacturonic
acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic
acid, hydroxynapthoic acid, salicylic acid, ascorbic acid, stearic
acid, muconic acid, and the like;
[0052] (2) base addition salts, formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
including, an alkali metal ion (e.g. lithium, sodium, potassium),
an alkaline earth ion (e.g. magnesium, calcium, barium), or other
metal ions such as aluminum, zinc, iron and the like; or
coordinates with an organic base such as ammonia, ethylamine,
diethylamine, ethylenediamine, N,N'-dibenzylethylenediamine,
ethanolamine, diethanolamine, triethanolamine, tromethamine,
N-methylglucamine, piperazine, chloroprocain, procain, choline,
lysine and the like.
[0053] Pharmaceutically acceptable salts may be synthesized from
the parent agent that contains a basic or acidic moiety, by
conventional chemical methods. Generally, such salts are prepared
by reacting the free acid or base forms of these agents with a
stoichiometric amount of the appropriate base or acid in water or
in an organic solvent, or in a mixture of the two. Salts may be
prepared in situ, during the final isolation or purification of the
agent or by separately reacting a purified compound of the
invention in its free acid or base form with the desired
corresponding base or acid, and isolating the salt thus formed. The
term "pharmaceutically acceptable salts" also include zwitterionic
compounds containing a cationic group covalently bonded to an
anionic group, as they are "internal salts".
[0054] All acid, salt, base, and other ionic and non-ionic forms of
the compounds described are included as compounds of the invention.
For example, if a compound is shown as an acid herein, the salt
forms of the compound are also included. Likewise, if a compound is
shown as a salt, the acid and/or basic forms are also included.
[0055] "Bioavailability" refers to the rate and amount of a drug
that reaches the systemic circulation of a patient following
administration of the drug or prodrug thereof to the subject and
can be determined by evaluating, for example, the plasma or blood
concentration-versus-time profile for the drug. Parameters useful
in characterizing a plasma or blood concentration-versus-time curve
include the area under the curve (AUC), the time to peak
concentration (T.sub.max), and the maximum drug concentration
(C.sub.max). Bioavailability is often expressed as F(%) referring
to the ratio in percentage of the AUC of the compound fora specific
mode of administration (e.g. orally) over AUC of the compound after
an IV administration.
[0056] The term "reduction of side effects" of a compound (e.g. a
compound of the invention) refers to decreasing the amount of or
severity of one or more side effects of the compound by, e.g., 5%,
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9%, or
even 100%, which decrease is with respect to the side effects
observed when a patient is treated with gabapentin or
pregabalin.
[0057] More generally, the terms "lessening" etc., "increasing"
etc., refer in context herein to the percentage changes, e.g., by
5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 125%,
etc., or even more, e.g., 2, or 4 fold, or even more.
[0058] "Pharmaceutically acceptable" refers to drugs, medicaments,
inert ingredients etc., which the term describes, suitable for use
in contact with the tissues of humans and lower animals without
undue toxicity, incompatibility, instability, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio. It preferably refers to a compound or composition that is
approved or approvable by a regulatory agency of the Federal or
state government or listed in the U.S. Pharmacopoeia or other
generally recognized pharmacopoeia for use in animals and more
particularly in humans.
[0059] "Pharmaceutically acceptable vehicle" or "pharmaceutically
acceptable carrier" refers to a diluent, adjuvant, excipient, or
carrier with which a compound is administered.
[0060] "Pharmaceutical composition" refers to at least one compound
and at least one pharmaceutically acceptable vehicle or carrier,
with which the compound is administered to a patient.
[0061] Reference will now be made in detail to certain embodiments
of compounds and methods. The disclosed embodiments are not
intended to be limiting of the invention.
II. Compounds of the Invention
[0062] One aspect of the invention relates to new compounds,
cleamino acid derivatives, to compositions comprising the same and
uses thereof for the prevention or treatment of pain, e.g.
neuropathic pain.
[0063] Thus, in one aspect, the invention relates to a compound of
Formula I defined as follows:
##STR00001##
wherein,
[0064] R.sup.1 is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.3-6heterocycloalkyl,
C.sub.6aryl, or C.sub.5-9heteroaryl;
[0065] R.sup.2 is hydrogen, or an N-protecting group;
[0066] X is O, NH, or S;
[0067] R.sup.3 is hydrogen, C.sub.1-12alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.3-6heterocycloalkyl,
NH.sub.2, NHR.sup.6, NR.sup.6R.sup.7, OR.sup.6, halide, or R.sup.3
and R.sup.5 taken together with their adjacent carbon atoms form a
C.sub.3-12cycloalkyl, C.sub.3-12heterocycloalkyl, C.sub.6-10aryl,
or C.sub.5-10heteroaryl; and
[0068] R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each independently
hydrogen. C.sub.1-12alkyl, or C.sub.6-10aryl, or R.sup.4 and
R.sup.5 are taken together with their adjacent atoms to form a
heterocycloalkyl or heteroaryl group;
[0069] wherein when R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6 or R.sup.7 is a group selected from alkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then
said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
or heteroaryl group may be unsubstituted or substituted with a
group selected from the group consisting of acyl, unsubstituted
amino, alkylamino, dialkylamino, arylamino, diarylamino,
alkylarylannino, acylamino, carbamoyl, ureido, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxy,
carboxylate, aminocarbonyl, mono and dialkylaminocarbonyl, cyano,
azido, halogen, hydroxyl, nitro, trifluoromethyl, thio, alkylthio,
arylthio, alkylthiocarbonyl, thiocarboxylate, lower alkyl, lower
alkenyl, lower alkynyl, cycloalkyl, heterocycioalkyl, aryl,
heteroaryl, lower alkoxy, aryloxy, aryloxycarbonyloxy, benzyloxy,
benzyl, sulfinyl, alkyisulfinyl, sulfonyl, sulfate, sulfonate,
sulfonamide, phosphate, phosphonato, phosphinato, oxo, guanidine,
imino, and formyl; or a pharmaceutically acceptable salt, prodrug,
metabolite, or solvate thereof.
[0070] In one embodiment, the compound is a compound of Formula 1
and X is O. In an embodiment, the compound is a compound of Formula
I, provided that the compound is not a naturally occurring amino
acid. In a subclass of any of the above embodiments, the compound
is a compound of Formula I, provided that when R.sup.1, R.sup.2 and
W are all hydrogen atoms, R.sup.3 is hydrogen or a C.sub.1-10alkyl,
then R.sup.5 is nota C.sub.1-6alkyl. In another embodiment, R.sup.2
is a protecting group selected from the group selected from the
group consisting of acyl, and amino-substituted acyl, such as an
amino acid residue (e.g. valyl, leucyl and isoleucyl). In yet
another embodiment, R.sup.2 is hydrogen and all other groups are as
previously defined.
[0071] In another aspect, the invention relates to a compound of
Formula II defined as follows:
##STR00002##
wherein,
[0072] X is O, NH, or S;
[0073] R.sup.3 is hydrogen, C.sub.1-12alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.3-6heterocycloalkyl,
NH.sub.2, NHR.sup.6, NR.sup.6R.sup.7, OR.sup.6, or halide;
[0074] R.sup.8 and R.sup.9 are each independently hydrogen,
C.sub.1-12alkyl, C.sub.6-10aryl, NH.sub.2, NHR.sup.6,
NR.sup.6R.sup.7, OR.sup.6, halide, cycloalkyl, alkylenyl,
arylalkyl, or R.sup.8 and R.sup.9 are taken together with their
adjacent atoms to form a spiro or fused heterocycloalkyl or
heteroaryl group, or R.sup.8 and R.sup.9 are attached to the same
carbon atom and together with the adjacent carbon atom form a
carbonyl;
[0075] n is an integer selected from 0 to 3; and
[0076] R.sup.1, R.sup.2, R.sup.6, R.sup.7 and X are as previously
defined;
[0077] wherein when R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.7, R.sup.8 or R.sup.9 is a group selected from alkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl, then said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group may be unsubstituted or
substituted with a group selected from the group consisting of
acyl, unsubstituted amino, alkylamino, dialkylamino, arylamino,
diarylamino, alkylarylamino, acylamino, carbamoyl, ureido,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and
dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro,
trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl,
thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy,
aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl,
alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide,
phosphate, phosphonato, phosphinato, oxo, guanidine, imino, and
formyl;
or a pharmaceutically acceptable salt, prodrug, metabolite, or
solvate thereof.
[0078] In one embodiment, X is oxygen and all other groups are as
previously defined. In another embodiment, X is oxygen, n is 1,
R.sup.3 is a hydrogen and all other groups are as previously
defined. In another embodiment, X is oxygen, n is 1, R.sup.3 is a
hydrogen, the chiral center C* is in the S configuration and all
other groups are as previously defined. In another embodiment. X is
O, n is 1, R.sup.2 is a protecting group selected from the group
selected from the group consisting of acyl, and amino-substituted
acyl, such as an amino acid residue (e.g. valyl, leucyl and
isoleucyl) and all other groups are as previously defined. In yet
another embodiment, X is O, n is 1, R.sup.2 is hydrogen and all
other groups are as previously defined. In another embodiment, X is
oxygen, n is 0, and all other groups are as previously defined. In
another embodiment, X is oxygen, n is 2 and all other groups are as
previously defined. In another embodiment, X is oxygen, n is 3 and
all other groups are as previously defined. In a further
embodiment, the compound is a compound of Formula II, wherein X is
oxygen, n is 1 and R.sup.3 is hydrogen. I another embodiment, the
compound is a compound of Formula II, wherein X is oxygen, n is 1
and R.sup.3 is C.sub.1-6alkyl, or a C.sub.1-4alkyl, or a methyl,
ethyl, propyl, or i-propyl group. In yet another embodiment, X is
NH and all other groups are as previously defined. In further
embodiment, X is sulfur and all other groups are as previously
defined.
[0079] In another aspect, the invention relates to a compound of
Formula III defined as follows:
##STR00003##
wherein,
[0080] m is an integer from 1 to 3, wherein R.sup.8 is the same or
different in each instance;
[0081] R.sup.1, R.sup.2, R.sup.3, R.sup.8 and X are as previously
defined;
or a pharmaceutically acceptable salt, prodrug, metabolite, or
solvate thereof.
[0082] In an embodiment, R.sup.3 is a hydrogen, n is 1 or 2 and all
other groups are as previously defined. In one embodiment, X is
oxygen and all other groups are as previously defined. In yet
another embodiment, X is NH and all other groups are as previously
defined. In further embodiment, X is sulfur and all other groups
are as previously defined.
[0083] In yet another aspect, the invention relates to a compound
of Formula IV defined as follows:
##STR00004##
wherein,
[0084] p is an integer from 1 to 2; and
[0085] R.sup.1, R.sup.2, R.sup.4, R.sup.8, R.sup.9, and X are as
previously defined;
or a pharmaceutically acceptable salt, prodrug, metabolite, or
solvate thereof.
[0086] In one embodiment, X is oxygen and all other groups are as
previously defined. In another embodiment, X is oxygen, p is 1 and
all other groups are as previously defined. In another embodiment,
X is oxygen, p is 2 and all other groups are as previously defined.
In another embodiment, X is oxygen, p is 1, R.sup.4 is a hydrogen,
the chiral center C* is in the S configuration and ail other groups
are as previously defined. In another embodiment, X is O, p is 1,
R.sup.2 is a protecting group selected from the group selected from
the group consisting of acyl, and amino-substituted acyl, such as
an amino acid residue (e.g. valyl, leucyl and isoleucyl) and all
other groups are as previously defined. In yet another embodiment,
X is O, p is 1, R.sup.2 is hydrogen and all other groups are as
previously defined. In another embodiment, R.sup.2 is a protecting
group selected from the group selected from the group consisting of
acyl, and amino-substituted acyl, such as an amino acid residue
(e.g. valyl, leucyl and isoleucyl). In yet another embodiment,
R.sup.2 is hydrogen and all other groups are as previously defined.
In yet another embodiment, X is NH and all other groups are as
previously defined. In a further embodiment, X is sulfur and all
other groups are as previously defined.
[0087] In yet another aspect, the invention relates to a compound
of Formula V defined as follows:
##STR00005##
wherein,
[0088] R.sup.1, R.sup.2, R.sup.8, R.sup.9, X and p are as
previously defined;
or a pharmaceutically acceptable salt, prodrug, metabolite, or
solvate thereof.
[0089] In one embodiment, p is 1 and all other groups are as
previously defined. In another embodiment, p is 2 and all other
groups are as previously defined.
[0090] In yet another aspect, the invention relates to a compound
of Formula VI defined as follows:
##STR00006##
wherein,
[0091] R.sup.1, R.sup.2, R.sup.4, R.sub.8, R.sup.9, and X are as
previously defined;
or a pharmaceutically acceptable salt, prodrug, metabolite, or
solvate thereof.
[0092] In one embodiment, the invention relates to a compound of
any one of Formulae I to VI, wherein the compound is a mixture of
compounds where the chiral center C* is in the S or the R
configuration and all other groups are as previously defined, or
substantially pure S configuration, or substantially pure R
configuration, preferably in the S configuration. In another
embodiment, the invention relates to a compound of any one of
Formulae I to VI, wherein the compound is a mixture of compounds
where the chiral center C* is has the same configuration as D and L
amino acid and all other groups are as previously defined, or
substantially pure L configuration, or substantially pure D
configuration, preferably in the L configuration.
[0093] Exemplary compounds include, but are not limited to, the
compounds of Table 1:
TABLE-US-00001 TABLE 1 ID Structure 1 ##STR00007## 2 ##STR00008## 3
##STR00009## 4 ##STR00010## 5 ##STR00011## 6 ##STR00012## 7
##STR00013## 8 ##STR00014## 9 ##STR00015## 10 ##STR00016## 11
##STR00017## 12 ##STR00018## 13 ##STR00019## 14 ##STR00020## 15
##STR00021## 16 ##STR00022## 17 ##STR00023## 18 ##STR00024## 19
##STR00025## 20 ##STR00026## 21 ##STR00027## 22 ##STR00028## 23
##STR00029## 24 ##STR00030## 25 ##STR00031## 26 ##STR00032## 27
##STR00033## 28 ##STR00034## 29 ##STR00035## 30 ##STR00036##
or a pharmaceutically acceptable salt, solvate, prodrug or ester
thereof.
[0094] Other examples of exemplary compounds of the invention are
as follows, or a pharmaceutically acceptable salt, solvate, prodrug
or ester thereof:
[0095] a. Tetrahydrofuran-Based Compounds with L-Amino Acid
Configuration
##STR00037## ##STR00038##
[0096] b. Thiophen-Based:
##STR00039## ##STR00040##
[0097] c. Pyrrolidine-Based Examples
##STR00041##
[0098] d. Furan and Benzafuran-Based
##STR00042##
[0099] e. Cyclohexane-Based
##STR00043##
or a pharmaceutically acceptable salt, solvate, prodrug or ester of
any one of the above-referenced compound.
[0100] Although theory of operation is discussed herein, for
specific compound structures, including all generic structural
formulas and specific names and formulas of compounds, the
invention is not limited by any such theories unless specifically
stated otherwise. Thus, all uses of all novel compounds are
encompassed by the invention, irrespective of mechanism or theory
of operation.
[0101] The compounds according to the invention can be further
analyzed, tested or validated using a variety of methods,
techniques and assays known in the art. There is a substantial
amount of published scientific and patent literature concerning the
discussed diseases and conditions and the standard assays,
techniques and methods for assessing and measuring the safety,
biological activity, pharmacokinetics properties and efficacy of
the compounds. Therefore, one skilled in the art can readily
evaluate and test the compounds according to the invention by using
the information in the public domain. Nevertheless, the
Exemplification section provides examples of biological assays that
can be conducted to assess the instant compounds.
III. Synthesis of the Compounds of the Invention
[0102] In general, the compounds of the present invention may be
prepared by the methods illustrated in the Examples hereinafter
and/or other conventional methods, using readily available and/or
conventionally preparable starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants which are in themselves known, but
are not mentioned here. Certain novel and exemplary methods of
preparing the inventive compounds are described in the
Exemplification section. Such methods are within the scope of this
invention. Functional and structural equivalents of the compounds
described herein and which have the same general properties,
wherein one or more simple variations of substituents are made
which do not adversely affect the essential nature or the utility
of the compound are also included.
[0103] The compounds described herein can be prepared by any number
of methods known or obvious to those skilled in the art. The
synthetic approaches are chosen depending of the functional groups
present or introduced in the starting material used and the
compound to be produced.
IV. Pharmaceutical Compositions
[0104] Preferably, the compounds of the invention are formulated
prior to administration into pharmaceutical compositions using
techniques and procedures well known in the art. Accordingly, in
another embodiment, the present invention relates to pharmaceutical
compositions (e.g. solid or semi-solid mixtures, solutions,
suspensions or emulsions) comprising effective amounts of one or
more compounds according to any of the Formulae herein and a
pharmaceutically acceptable vehicle, as well as methods of using
and manufacturing such pharmaceutical compositions.
[0105] The pharmaceutical compositions are formulated into suitable
administration (orally, parenterally, (IV, IM, depo-IM, SC, and
depo-SC), sublingually, intranasally (inhalation), intrathecally,
topically, or rectally). Suitable pharmaceutically acceptable
vehicles include, without limitation, any non-immunogenic
pharmaceutical carrier or diluent suitable for oral, parenteral,
nasal, mucosal, transdermal, topical, intrathecal, rectal,
intravascular (IV), intraarterial (IA), intramuscular (IM), and
subcutaneous (SC) administration routes, such as phosphate buffer
saline (PBS). Also, the present invention includes such compounds
which have been lyophilized and which may be reconstituted to form
pharmaceutically acceptable formulations for administration, as by
intravenous, intramuscular, or subcutaneous injection.
Administration may also be intradermal or transdermal.
[0106] Preferably, the pharmaceutical composition of the invention
is suitable for oral administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. In general, the
formulations are prepared by uniformly and intimately bringing into
association a compound of the present invention with a
pharmaceutically acceptable vehicle (e.g. an inert diluent or an
assimilable edible, liquid or finely divided solid (or both),
carrier) and, optionally, one or more accessory ingredients and
then, if necessary, shaping the product. The amount of the
therapeutic agent in such therapeutically useful compositions is
such that a suitable dosage will be obtained.
[0107] Formulations of the invention suitable for oral
administration may be in the form of capsules (e.g. hard or soft
shell gelatin capsule), cachets, pills, tablets, lozenges, powders,
granules, pellets, dragees, e.g., coated (e.g., enteric coated) or
uncoated, or as a solution or a suspension in an aqueous or
non-aqueous liquid, or as an oil-in-water or water-in-oil liquid
emulsion, or as an elixir or syrup, or as pastilles (using an inert
base, such as gelatin and glycerin, or sucrose and acacia), and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste, or incorporated directly into the subject's diet. Moreover,
the compounds can be orally formulated to (a) provide for instant
or rapid drug release (i.e., have no coating on them); (b) be
coated, e.g., to provide for sustained drug release over time; or
(c) be enterically coated for better gastrointestinal tolerability
or protection from degradation in the stomach.
[0108] In solid dosage forms of the invention for oral
administration the active ingredient is typically mixed with one or
more pharmaceutically acceptable carriers, such as sodium citrate
or dicaicium phosphate, or any of the following: fillers or
extenders (e.g. starches, lactose, sucrose, glucose, mannitol, or
silicic acid); binders (e.g. carboxymethylcellulose, alginates,
gelatin, polyvinyl pyrrolidone, sucrose or acacia); humectants
(e.g. glycerol); disintegrating agents (e.g. agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate); solution retarding agents (e.g.,
as paraffin); absorption accelerators (e.g. quaternary ammonium
compounds); wetting agents (e.g., cetyl alcohol and glycerol
monostearate); absorbents (e.g., kaolin and bentonite clay);
lubricants (e.g. talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof);
and coloring agents. In the case of capsules, tablets and pills,
the pharmaceutical compositions may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
[0109] Peroral compositions typically also include liquid
solutions, emulsions, suspensions, and the like. The
pharmaceutically acceptable vehicles suitable for preparation of
such compositions are well known in the art. Typical components of
carriers for syrups, elixirs, emulsions and suspensions include
ethanol, glycerol, propylene glycol, polyethylene glycol, liquid
sucrose, sorbitol and water. For a suspension, typical suspending
agents include methyl cellulose, sodium carboxymethyl cellulose,
tragacanth, and sodium alginate; typical wetting agents include
lecithin and polysorbate 80; and typical preservatives include
methyl paraben and sodium benzoate. Peroral liquid compositions may
also contain one or more components such as sweeteners, flavoring
agents and colorants.
[0110] Pharmaceutical compositions suitable for injectable use
include sterile aqueous solutions (where water soluble) or
dispersions, and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersion. In all cases, the
composition must be sterile and must be fluid to the extent that
easy syringability exists. It must be stable under the conditions
of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi.
Sterile injectable solutions can be prepared by incorporating the
therapeutic agent in the required amount in an appropriate solvent
with one or a combination of ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the therapeutic agent
into a sterile vehicle which contains a basic dispersion medium and
the required other ingredients from those enumerated above. In the
case of sterile powders for the preparation of sterile injectable
solutions, the methods of preparation are vacuum drying and
freeze-drying which yields a powder of the active ingredient (i.e.,
the therapeutic agent) plus any additional desired ingredient from
a previously sterile-filtered solution thereof. Solvent or
dispersion medium suitable for injectable use are, for example,
water, ethanol, polyols (for example, glycerol, propylene glycol,
and liquid polyethylene glycol, and the like), suitable mixtures
thereof, and vegetable oils. Proper fluidity is maintained, for
example, by the maintenance of the required particle size in the
case of dispersion and by the use of surfactants. Prevention of the
action of microorganisms can be achieved by various antibacterial
and antifungal agents, for example, parabens, chlorobutanol,
phenol, ascorbic acid, thimerosal, and the like. In many cases,
isotonic agents are included, for example, sugars, sodium chloride,
or polyalcohols such as mannitol and sorbitol, in the composition.
Prolonged absorption of the injectable compositions can be brought
about by including in the composition an agent which delays
absorption, for example, aluminum monostearate or gelatin.
[0111] Pharmaceutical formulations are also provided which are
suitable for administration as an aerosol, by inhalation. These
formulations comprise a solution or suspension of the desired
compound of any Formula herein or a plurality of solid particles of
such compound(s). As a liquid, the formulation will comprise, for
example, a water-soluble compound of the invention, or a salt
thereof, in a carrier which comprises water. A surfactant may be
present which lowers the surface tension of the formulation
sufficiently to result in the formation of droplets within the
desired size range when subjected to nebulization. On the other
hand, solid particles can be obtained by processing the solid form
of a compound, or a salt thereof, in any appropriate manner known
in the art, such as by micronization. The liquid droplets or solid
particles should have a particle size in the range of about 0.5 to
about 5 microns. The size of the solid particles or droplets will
be, for example, from about 1 to about 2 microns. The desired
formulation may be placed in a small chamber and nebulized.
Nebulization may be accomplished by compressed air or by ultrasonic
energy to form a plurality of liquid droplets or solid particles
comprising the agents or salts. In this respect, commercial
nebulizers are available to achieve this purpose.
[0112] The compositions of this invention can also be administered
topically to a subject, e.g., by the direct lying on or spreading
of the composition on the epidermal or epithelial tissue of the
subject, or transdermally via a "patch". Such compositions include,
for example, lotions, creams, solutions, gels and solids. These
topical compositions may comprise an effective amount, usually at
least about 0.1%, or even from about 1% to about 5%, of an agent of
the invention. Suitable carriers for topical administration
typically remain in place on the skin as a continuous film, and
resist being removed by perspiration or immersion in water.
Generally, the carrier is organic in nature and capable of having
dispersed or dissolved therein the therapeutic agent. The carrier
may include pharmaceutically acceptable emollients, emulsifiers,
thickening agents, solvents and the like.
[0113] Other compositions useful for attaining systemic delivery of
the subject agents include sublingual, buccal and nasal dosage
forms. Such compositions typically comprise one or more of soluble
filler substances such as sucrose, sorbitol and mannitol; and
binders such as acacia, microcrystalline cellulose, carboxymethyl
cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants,
sweeteners, colorants, antioxidants and flavoring agents disclosed
above may also be included. The compound(s) of the invention may
also be administered parenterally, intraperitoneally,
intraspinally, or intracerebrally. For such compositions, the
compound(s) of the invention can be prepared in glycerol, liquid
polyethylene glycols, and mixtures thereof and in oils. Under
ordinary conditions of storage and use, these preparations may
contain a preservative to prevent the growth of microorganisms.
[0114] To administer the compound(s) of the invention by other than
parenteral administration, it may be useful to coat the compound(s)
with, or co-administer the compound(s) with a material to prevent
its inactivation. For example, the compound(s) of the invention may
be administered to a subject in an appropriate carrier, for
example, liposomes, or a diluent. Pharmaceutically acceptable
diluents include saline and aqueous buffer solutions. Liposomes
include water-in-oil-in-water CGF emulsions as well as conventional
liposomes.
[0115] Pharmaceutical compositions according to the invention may
also be coated by conventional methods, typically with pH or
time-dependent coatings, such that the compound(s) of the invention
is released in the vicinity of the desired location, or at various
times to extend the desired action. Such dosage forms typically
include, but are not limited to, one or more of cellulose acetate
phthalate, polyvinylacetate phthalate, hydroxypropyl methyl
cellulose phthalate, ethyl cellulose, waxes, and shellac.
[0116] Dosage forms provide the pharmaceutical compound upon in
vivo administration of a pharmaceutical composition of the
invention to a human patient. It is understood that appropriate
doses depend upon a number of factors within the knowledge of the
ordinarily skilled physician, veterinarian, or researcher (e.g. see
Wells et al. eds., Pharmacotherapy Handbook, 2.sup.nd Edition,
Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia,
Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon
Publishing, Loma Linda, Calif. (2000)). The dose(s) of the
compound(s) of the invention will vary, for example, depending upon
a variety of factors including, but not limited to: the activity,
biological and pharmacokinetic properties and/or side effects of
the compound being used; the age, body weight, general health,
gender, and diet of the subject; the time of administration, the
route of administration, the rate of excretion, and any drug
combination, if applicable; the effect which the practitioner
desires the compound to have upon the subject; and the properties
of the compound being administered (e.g. bioavailability,
stability, potency, toxicity, etc). Such appropriate doses may be
determined using the assays described herein or known in the art.
When one or more of the compounds of the invention is to be
administered to humans, a physician may for example, prescribe a
relatively low dose at first, subsequently increasing the dose
until an appropriate response is obtained.
[0117] There are no particular limitations on the dose of each of
the compounds for use in the composition of the present invention.
Exemplary doses include milligram or microgram amounts of the
compound per kilogram of subject or sample weight (e.g., about 50
micrograms per kilogram to about 500 milligrams per kilogram, about
1 milligram per kilogram to about 100 milligrams per kilogram,
about 1 milligram per kilogram to about 50 milligram per kilogram,
about 1 milligram per kilogram to about 10 milligrams per kilogram,
or about 3 milligrams per kilogram to about 5 milligrams per
kilogram). Additional exemplary doses include doses of about 5 to
about 500 mg, about 25 to about 300 mg, about 25 to about 200 mg,
about 50 to about 150 mg, or about 50, about 100, about 150 mg,
about 200 mg or about 250 mg, and, preferably, daily or twice
daily, or lower or higher amounts.
[0118] It is generally advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. The term "unit dosage form" refers to a
physically discrete unit suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical
vehicle. The specification for the dosage unit forms of the
invention may vary and are dictated by and directly dependent on
(a) the unique characteristics of the therapeutic agent and the
particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding such a therapeutic
agent for the prevention of treatment of neuropathic pain.
[0119] Administration of the compounds and compositions of the
present invention to a subject to be treated can be carried out
using known procedures, at dosages and for periods of time
effective to achieved a desired purposes. Dosage regimens can be
adjusted to provide the optimum therapeutic response. For example,
several divided doses may be administered daily or the dose may be
proportionally reduced as indicated by the exigencies of the
therapeutic situation. Preferably, the compound(s) of the invention
is administered at a therapeutically effective dosage sufficient to
reduce neuropathic pain symptoms in a subject, preferably a human
subject while being neutral or beneficial to a metabolic disorder,
such as diabetes.
[0120] The compound(s) of the invention may be packaged as part of
a kit, optionally including a container (e.g. packaging, a box, a
vial, etc). The kit may be commercially used according to the
methods described herein and may include instructions for use in a
method of the invention. Additional kit components may include
acids, bases, buffering agents, inorganic salts, solvents,
antioxidants, preservatives, or metal chelators. The additional kit
components are present as pure compositions, or as aqueous or
organic solutions that incorporate one or more additional kit
components. Any or all of the kit components optionally further
comprise buffers.
[0121] V. Methods of use of the Compounds and Compositions of the
Invention
[0122] Another aspect of the invention pertains to a method for
treating neuropathic pain in a subject by administering an
effective amount of a compound of the present invention. The term
"subject" includes living organisms with neuropathic pain, or which
are susceptible to neuropathic pain (or neuralgia), e.g. diabetic
neuropathy. Examples of subjects include humans, monkeys, cows,
rabbits, sheep, goats, pigs, dogs, cats, rats, mice, and transgenic
species thereof. The term "subject" preferably includes animals
susceptible to states characterized by metabolic diseases and/or
neuropathic pain, e.g., mammals, e.g. primates, e.g. humans. The
animal can also be an animal model for a disorder, e.g., a pain
mouse model, or an obese or diabetic mouse or rat model.
[0123] In certain embodiments of the invention, the human subject
is in need of treatment by the methods of the invention, and is
selected for treatment based on this need. A subject in need of
treatment is art-recognized, and includes subjects that have been
identified as having neuropathic pain, has a symptom of such a
disease or disorder, or is at risk of such a disease or disorder,
and would be expected, based on diagnosis, e.g., medical diagnosis,
to benefit from treatment (e.g., curing, healing, preventing,
alleviating, relieving, altering, remedying, ameliorating,
improving, or affecting the disease or disorder, the symptom of the
disease or disorder, or the risk of the disease or disorder).
[0124] For example, the human subject may be a human over 30 years
old, human over 40 years old, a human over 50 years old, a human
over 60 years old, a human over 70 years old, a human over 80 years
old. The subject may be a female human, including a postmenopausal
female human, who may be on hormone (estrogen) replacement therapy.
The subject may also be a male human. In another embodiment, the
subject is under 40 years old.
[0125] In some embodiments, the subject may have symptoms of a
metabolic disease or condition, such as diabetes (e.g. type II
diabetes), metabolic syndrome, obesity, etc. In another embodiment,
the subject may have symptoms of type II diabetes and be
overweight. In one embodiment, the subject has a body mass index
(BMI) of 25 or more, a BMI between 25 and 30, or a BMI of 30 or
more. The Body Mass Index, or BMI is a measure of a person's weight
taking into account their height. It is given by the formula: BMI
equals a person's weight (mass) in kilograms divided by the square
of the person's height in metres.
[0126] "Preventing" or "prevention" is intended to refer at least
the reduction of likelihood or the risk of (or susceptibility t))
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). The term
"prevention" or "preventing" is also used to describe the
administration of a compound or composition of the invention to a
subject who is at risk of (or susceptible to) such a disease or
condition. Patients amenable to treatment for prevention of the
disease or condition include individuals at risk of the disease or
condition but not showing symptoms, as well as patients presently
showing symptoms. Predisposing factors identified or proposed in
the scientific literature include, among others, environmental
factors predisposing a subject to neuropathic pain; past history of
infection by viral and bacterial agents predisposing a subject to
neuropathic pain (e.g. shingles); and metabolic disorders
predisposing a subject to neuropathic pain (e.g. type II
diabetes).
[0127] "Treating" or "treatment" of any disease or disorder refers,
in some embodiments, to ameliorating at least one disease or
disorder (i.e., arresting or reducing the development of the
disease or at least one of the clinical symptoms thereof). In
certain embodiments "treating" or "treatment" refers to
ameliorating at least one physical parameter. In certain
embodiments, "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 certain embodiments, "treating" or
"treatment" refers to delaying the onset of the disease or
disorder. The term "treating" refers to any indicia of success in
the treatment or amelioration of an injury, pathology or condition,
including any objective or subjective parameter such as abatement;
remission; diminishing of symptoms or making the injury, pathology
or condition more tolerable to the subject; improving a subject's
physical or mental well-being, reducing or pain experienced by the
patient; and, in some situations additionally improving at least
one parameter of a metabolic disorder (e.g. glucose tolerance,
insulin secretion, reducing weight gain, etc). The treatment or
amelioration of symptoms can be based on objective or subjective
parameters; including the results of a physical examination or the
subject's evaluation of symptoms, or of a test known in the art
(e.g. glucose level, etc).
[0128] As used herein the term "therapeutically effective amount"
refers to the amount or dose of the compound, upon single or
multiple dose administration to the patient, which provides the
desired effect in the patient under diagnosis or treatment. An
effective amount can be readily determined by the attending
diagnostician, as one skilled in the art, by the use of known
techniques and by observing results obtained under analogous
circumstances. In determining the effective amount or dose of
compound administered, a number of factors are considered by the
attending diagnostician, including, but not limited to: the size,
age, and general health of the subject; the specific disease(s)
involved; the degree of or involvement or the severity of the
disease; the response of the individual subject; the particular
compound administered; the mode of administration; the
bioavailability characteristics of the preparation administered;
the dose regimen selected; the use of concomitant medication; and
other relevant circumstances.
[0129] Improvement in condition is present within the context of
the present invention if there is a measurable difference between
the performances of subjects treated using the methods of the
invention as compared to members of a placebo group, historical
control, or between subsequent tests given to the same subject. The
invention also pertains to a method for treating, including slowing
or stopping neuropathic pain in a disease or condition associated
with metabolism, by administering to a subject an effective amount
of a therapeutic compound of the invention, wherein the compound is
neutral to or improves any metabolic symptom.
[0130] It is to be understood that wherever values and ranges are
provided herein, e.g., in ages of subject populations, dosages, and
blood levels, all values and ranges encompassed by these values and
ranges, are meant to be encompassed within the scope of the present
invention. Moreover, all values in these values and ranges may also
be the upper or lower limits of a range.
[0131] In certain embodiments, the compounds and composition
according to the invention can be used in combination therapy with
at least one other therapeutic or nutraceutic agent. The compounds
of the invention when administered in association with at least one
other (same or different) therapeutic agent(s), can act additively
or, in certain embodiments, synergistically.
[0132] The compounds of the invention can be administered prior,
subsequent to or concomitantly with the other therapeutic or
nutraceutic agent. The compositions of the present invention can be
administered with the other therapeutic agent as part of the same
pharmaceutical composition as, or in a different composition from,
that containing the compounds of the present invention. The at
least one other agent can be effective for treating the same or
different disease, disorder, or condition. Preferably, the other
agent is suitable for the treatment of symptoms of neuropathy,
neuropathic pain, or a metabolic disorder, e.g. diabetes, metabolic
syndrome, obesity, and the like.
[0133] Methods of the present invention include administration of
one or more compounds or pharmaceutical compositions of the present
invention and one or more other therapeutic agents provided that
the combined administration does not inhibit the therapeutic
efficacy of the one or more compounds of the present invention
and/or does not produce adverse combination effects.
[0134] In some aspects, the combination therapy comprises
alternating between administering a composition of the present
invention and a composition comprising another therapeutic agent,
e.g., to minimize adverse side effects associated with a particular
drug. When a compound of the present invention is administered
concurrently with another therapeutic agent that potentially can
produce adverse side effects including, but not limited to,
toxicity, the therapeutic agent can advantageously be administered
at a dose that falls below the threshold at which the adverse side
effect is elicited. A pharmaceutical composition can also further
comprise substances to enhance, modulate and/or control release,
bioavailability, therapeutic efficacy, therapeutic potency,
stability, and the like.
[0135] The compounds or pharmaceutical compositions of the present
invention include, or can be administered to a patient together
with, another therapeutic drug that may be available
over-the-counter or by prescription. Therapeutic drugs as well as
nutraceuticals useful in a combination with a therapeutic compound
of the present invention are known to the skilled artisan.
Preferred therapeutic drugs to be used with the compounds or
pharmaceutical compositions of the present invention are
therapeutic drugs useful in the prevention or treatment of, but not
limited to, neuropathic pain, diabetes and other metabolism
disorders, or anti-obesity agents.
[0136] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures, embodiments, claims, and
examples described herein. Such equivalents are considered to be
within the scope of this invention and covered by the claims
appended hereto. The contents of all references, issued patents,
and published patent applications cited throughout this application
are hereby incorporated by reference. The invention is further
illustrated by the following examples, which should not be
construed as further limiting.
EXAMPLES
[0137] The Examples set forth herein below provide exemplary
syntheses of certain representative compounds of the invention.
Also provided are exemplary methods for assaying the compounds of
the invention for in vitro stability, microsomes metabolism and
mouse bioavailability.
[0138] Unless otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, concentrations,
properties, and so forth used in the specification and claims are
to be understood as being modified in all instances by the term
"about." At the very least, each numerical parameter should at
least be construed in light of the number of reported significant
digits and by applying ordinary rounding techniques. Accordingly,
unless indicated to the contrary, the numerical parameters set
forth in the present specification and attached claims are
approximations that may vary depending upon the properties sought
to be obtained. Notwithstanding that the numerical ranges and
parameters setting forth the broad scope of the embodiments are
approximations, the numerical values set forth in the specific
examples are reported as precisely as possible. Any numerical
value, however, inherently contain certain errors resulting from
variations in experiments, testing measurements, statistical
analyses and such.
[0139] The present invention also relates to novel compounds and
the synthesis thereof. The following detailed examples describe how
to prepare the various compounds and/or perform the various
processes of the invention and are to be construed as merely
illustrative, and not limitations of the preceding disclosure in
any way whatsoever. Those skilled in the art will promptly
recognize appropriate variations from the procedures both as to
reactants and as to reaction conditions and techniques. In some
cases, the compounds may be commercially available.
Example 1
Chemical Synthesis of Selected Compounds
[0140] Accordingly, the following examples are presented to
illustrate how selected compounds according to the invention may be
prepared.
Preparation of Compounds 6, 7 and 8
Method 1: Preparation and Separation of a Mixture of
Diastereoisomers
##STR00044##
[0141] To a degassed (with N.sub.2) solution of
(2S)-3-(2-furyl)alanine (1.5 g, 10 mmol) in a 10:1 mixture of
H.sub.2O:MeOH (100 mL) was added palladium hydroxide (Pd(OH).sub.2,
100 mg). The mixture was stirred for 24 h under hydrogen (40 psi).
The mixture was filtered through Celite (with methanol) and the
filtrate was evaporated under vacuum. A mixture of the two
diasteromers was obtained (Compound 6). The two diastereomers were
separated by HPLC (Polar column, 2% isocratic acetonitrile in water
(0.05% trifluoroacefic acid)) to afford Compound 6A (400 mg) and
Compound 6B (530 mg). Compound 6A is of the same chemical structure
as Compound 7 while Compound 6B is of the same chemical structure
as Compound 8. The structure of each was confirmed by
diastereoselective synthesis.
Method 2: Diastereoselective Synthesis of Both Diastereoisomers
[0142] This method allows the diastereoselective synthesis of both
diastereoiomers and the determination of the stereochemistry of the
stereocenters.
Step 1: Preparation of (2S)- and
(2R)-2-(iodomethyl)tetrahydrofuran
##STR00045##
[0144] 1--Method a: A solution of tetrahydrofuran-2-carboxylic acid
(5 g, 43 mmol) in THF (30 mL) was added dropwise to a -20.degree.
C. solution of LAH (1M in diethylether, 65 mL, 65 mmol). The
mixture was gradually warmed up to room temperature and stirred
overnight. After being cooled to 0.degree. C., ethyl acetate (20
mL) was added, followed by addition of H.sub.2O (20 mL). The
mixture was stirred at room temperature for 1 h, and filtered
through Celite (using ethyl acetate). The filtrate was concentrated
on a rotary evaporator; and the residual alcohol was used in the
next step without further purification.
[0145] Method b: A 1M solution of lithium aluminum hydride in
tetrahydrofuran (75 mL, 75 mmol) was cooled to -78.degree. C.
Tetrahydrofuran-2-carboxylic acid (5.4 mL, 50.0 mmol) was slowly
added dropwise (H.sub.2 released). The solution was stirred at
-78.degree. C., slowly warmed over several hours and stirred at
room temperature overnight. Water (2.9 mL) was added slowly while
the mixture was cooled to 0.degree. C. At room temperature, a 5N
aqueous sodium hydroxide solution (2.3 mL) was added to the
reaction mixture followed by water (8.7 mL). The mixture was
diluted with THF (100 mL), stirred for 4 hour, and filtered on a
buchner funnel (rinsed with THF (150 mL)). The resulting solution
was concentrated under reduced pressure, co-evaporated with
toluene, re-dissolved in dichloromethane and concentrated under
reduced pressure, giving the corresponding alcohol (4.9 g, 96%) as
a colorless, slightly volatile, oil.
[0146] 2--The residual alcohol from method (a) was dissolved in a
mixture of triethylamine (30 mL, 215 mmol) and dichloromethane (300
mL). To the solution was added p-toluenesulfonyl chloride (8.2 g,
43 mmol). The mixture was stirred at room temperature for 24 h, and
a 1N HCl solution was added to adjust pH until 3. The organic layer
was separated and the aqueous layer was extracted with
dichloromethane (2.times.100 mL). The combined organic layers were
dried over magnesium sulfate and filtered. The filtrate was
evaporated under reduced pressure. The residual material was
purified by chromatography on silica gel (Hexane/ethyl acetate,
99/1 to 70/30 linear gradient), providing the corresponding
tosylate (5.3 g) as a colorless liquid.
[0147] 3--To a solution of the tosylate (7.4 g, 28.9 mmol) in
acetone (290 mL) was added sodium iodide (43.4 g, 289 mmol) and the
reaction was stirred overnight at 70.degree. C. in an oil bath. The
reaction mixture was cooled to room temperature, filtered on a
buchner funnel, and rinsed with acetone. The filtrate was
concentrated under reduced pressure without heating to give a wet
orange solid. This residual solid was stirred in diethyl ether (250
mL), filtered through a plug of silica gel, and rinsed with diethyl
ether. The filtrate was concentrated to dryness (without heating)
and the residual material was submitted to purification by silica
gel chromatography (hexanes/diethyl ether, 2:1) to give
2-(iodomethyl)tetrahydrofuran (5.42 g, 89%).
Step 2: Synthesis of Compounds 7 and 8.
##STR00046##
[0149] LHMDS (1.63 mL, 1.63 mmol) was added to a -78.degree. C.
solution of dihydropyrazine (300 mg, 1.63 mmol) in THF (10 mL). The
mixture was kept at -78.degree. C. for 30 minutes, followed by
dropwise addition of a solution of 2-(iodomethyl)tetrahydrofuran
(346 mg, 1.63 mmol; R or S-isomer) in THF (5 mL). The mixture was
gradually warmed up to 0.degree. C. and stirred at this temperature
overnight, followed by addition of aqueous HCl (1M, 5 mL). The
mixture was kept at room temperature for 2 h and concentrated under
reduced pressure. The residual material was purified by
reverse-phase chromatography (HPLC, C18 column, water:methanol
(0.05% TFA), 100:0 to 0:100), giving the corresponding methyl
ester.
[0150] Lithium hydroxide (250 mg) was added to a solution of the
methyl ester of Compound 7 or 8 (360 mg) in water (10 mL) and THF
(10 mL) and stirred for 2 hours at room temperature. The solution
was then adjusted to pH 6 with 1N hydrochloric acid and
concentrated to dryness. The crude mixture was purified by
reverse-phase chromatography (gradient of water:methanol (0.01%
TFA), 100:0 to 90:10 over 30 minutes) to give the desired Compound
7 or 8 respectively.
Method 3: Alternate Method for Diastereoselective Synthesis of both
Diastereoisomers
##STR00047##
[0151] 1--To a stirred -78.degree. C. suspension of finely ground
cesium hydroxide hydrate (10 g) were added
N-(diphenylmethylene)glycine t-butyl ester (3.5 g), Reagent A
(O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide, 712 mg),
and R-2-(iodomethyl)tetrahydrofuran (3.73 g) in dichloromethane (10
mL). The mixture was allowed to slowly warm up to -20.degree. C.
and stirred at constant temperature overnight. The reaction mixture
was worked up using ethyl acetate and water. The crude product was
purified by silica gel chromatography (hexanes:ethyl acetate, 95:5
to 80:20 to afford 2.1 g of the diprotected amino acid.
[0152] 2--A solution of the diprotected amino acid (2.1 g) from 1
in tetrahydrofuran (50 mL) and aqueous hydrochloric acid (5N, 25
mL) was heated under reflux for 3 hours. The resulting reaction
solution was concentrated in vacuo. The residual material was
dissolved in water and the solution was freeze dried. The solid was
dissolved in water (containing 0.01% TFA) and purified by
preparative HPLC (Gemini, water (0.01% TFA): acetonitrile, linear
gradient 100:0 to 90:10 over 20 minutes) to afford Compound 7 (555
mg). .sup.1H NMR (D.sub.2O, 500 MHz) 1.59-1.66 (m, 1H), 1.87-1.98
(m, 2H), 2.09-2.14 (m, 2H), 2.15-2.21 (m, 1H), 378 (q, J=8.0 Hz,
1H), 3.88 (q, J=7.5 Hz, 1H), 4.08 (m, 1H), 4.16 (dd, J=6.0, 4.0 Ha,
1H).
[0153] Compound 8 was synthesized from
S-2-(iodomethyl)tetrahydrofuran following the same procedure as
described for Compound 7: .sup.1H NMR (D.sub.2O, 500 MHz) 1.58-1.65
(m, 1H), 1.87-2.00 (m, 3H), 2.12 (m, 1H), 2.23 (dt, J=15.5, 8.0,
4.5 Hz, 1H), 37.9 (q, J=7.5 Hz, 1H), 3.85 (q, J=7.5 Hz, 1H), 4.11
(dd, J=8.0, 5.0 Hz, 1H), 4.18 (m, 1H).
Example 2
In Vitro Affinity, .sup.3H-Gabapentin Binding Site
[0154] a) Method 1:
[0155] Materials: Gabapentin is from TRC, [.sup.3H]-Gabapentin is
from GE Healthcare, and Meltilex A sheets (melt-on scintillator
sheets) are from Perkin Elmer. Rat brain membranes are prepared
in-house by conventional methods.
[0156] All solutions are prepared for the assay just before use,
except for the membrane dilution. In each plate of vial a
triplicate (3.times. each concentration for each compound tested),
the following is added in this order: 1) 50 .mu.l of diluted
compound plate (500, 50 and 5 .mu.M in water or DMS, 3 vials for
each); 2) 50 .mu.l of diluted Gabapentin/.sup.3H-Gabapentin (200 nM
in 0.5M Hepes/KOH (pH: 7.4), including 70 .mu.Ci of
.sup.3H-Gabapentin); and 3) 150 .mu.l of rat brain membrane diluted
to 500 .mu.g/mL in 0.5M Hepes/KOH (pH: 7.4). The final compound
concentration in the assay is 1, 10 and 100 .mu.M. The same is done
with a solution not containing the test articles as control. The
test plate is then incubated for 30 minutes at room temperature
with agitation. The binding reaction is terminated using a Tomtec
cell harvester machine (Mach III M-FP-1). A meltilex sheet is
placed on the filtermat (harvest from the assay) and is allowed to
melt in the oven at 65.degree. C. for 1 to 4 min. The filter is
inserted in the plastic pouch, which is sealed and allowed to cool
for 1 h before counting with a Microbeta Trilux counter (Perkin
Elmer).
[0157] Results are calculated using the count per minutes (CPM)
obtained for each sample with the Trilux. The CPM obtained for the
control diluent represents the 100% binding of .sup.3H-Gabapentin
to membrane. The CPM obtained for the control gabapentin 100 .mu.M
represents the 0% binding. The % of binding for each compound is
calculated by the formula:
% of binding = CPM of tested compound - CPM of gabapentin CPM of
diluent - CPM of gabapentin .times. 100 ##EQU00001##
[0158] A compound is considered positive if its % of binding is
lower then 50%. Results in Table 2 are shown in % inhibition, as
well as by their IC50 (concentration for 50% inhibition) and Ki
(inhibitory constant) values, which are both calculated by standard
methods from the results obtained.
TABLE-US-00002 TABLE 2 Binding affinity to the Gabapentin binding
site % inhibition ID 1 .mu.M 10 .mu.M IC50 (.mu.M) Ki (.mu.M)
Gabapentin 80% 90% 0.07 0.05 4-HO-IIe* 13% 51% 9.6 6.32 Compound 6
82% 92% <1 N/A Compound 6A N/A N/A 0.53 0.345 Compound 6B N/A
N/A 0.32 0.207 Compound 18 87% 90% 0.15 0.097 *(26,3R,4S)
4-hydroxyisoleucine N/A: not available
[0159] b) Method 2:
[0160] Membrane preparation: cortices from 5 rats were homogenized
in a 0.32 M sucrose solution containing 10 mM HEPES/KOH.
Suspensions were centrifuged for 10 minutes at 2500.times.g and the
supernatants were centrifuged at 48000.times.g for 20 minutes.
Pellets were washed twice in 10 mM HEPES containing 1.25 mM EDTA
and 1.25 mM EGTA and centrifuged at 48000.times.g. The final
pellets were re-suspended in 10 mM HEPES/KOH. Protein concentration
was determined using a BCA kit from Pierce (Rockford, Ill.). The
quality of the preparation was assessed in a binding assay to
gabapentin.
[0161] Binding assay: In 96-well plates, the selected compounds
were incubated in 10 mM HEPES/KOH pH 7.4 at concentrations of 10
and 1 .mu.M for 30 minutes at room temperature in the presence of
20 nM [.sup.3H]-gabapentin and rat brain membranes (300 .mu.g/mL of
proteins). Radioactivity was assessed after filtration with the
Tomtec cell harvester using a glass fiber filter A. Counts were
obtained using the Microbeat Trilux counter.
[0162] Binding results: Effect of the tested compounds on the
binding of [.sup.3H]-gabapentin was determined by calculating the
specific binding of [.sup.3H]-gabapentin in the presence of the
compound divided by the specific binding of [.sup.3H]-gabapentin
alone:
% of binding = ( [ total binding ] c - [ non - specific binding ] c
) ( [ total binding ] c - [ non - specific binding ] c ) .times.
100 ##EQU00002##
wherein: [0163] [total binding], is the total binding of
[.sup.3H]-gabapentin in the presence of the compound; [0164]
[non-specific binding], is the non specific binding of
[.sup.3H]-gabapentin in the presence of 100 .mu.M cold gabapentin
(c=control); and [0165] [total binding], is the total binding of
[.sup.3H]-gabapentin alone.
[0166] IC50 determination: IC50 was determined following incubation
of crude rat brain membranes with varying concentrations of the
tested compound (0.1 nM to 100 .mu.M) in the presence of 20 nM
rHFgabapentin for 30 minutes at room temperature, as described in
for the binding assay above. Table 3 shows % inhibition and IC50
results obtained using this method.
TABLE-US-00003 TABLE 3 Binding affinity to the Gabapentin binding
site % inhibition ID 1 .mu.M 10 .mu.M IC50 (.mu.M) Gabapentin N/A
N/A 0.25 (2S)-Compound* 61% (.+-.8) 16% (.+-.3) N/A Compound 7 19%
(.+-.4) 1% (.+-.1) 0.56 Compound 8 11% (.+-.1) 0% (.+-.2) 0.48
Compound 18 21% (.+-.3) 6% (.+-.1) N/A *(2S)-3-(2-furyl)alanine
(see Example 1, method 1) N/A: not available
Example 3
In Vivo Activity in Neuropathic Pain Rat Models
[0167] Neuropathic pain is a condition resulting from nerve injury
or inflammation. The pain may persist for years even though the
damaged tissues may have appeared to heal. Various experimental
paradigms have been developed to mimic this human condition. The
Chronic Constructive Model (CCI), Partial sciatic Nerve Ligation
(PNL), Tibial Nerve Transection (TNT) and Spinal Nerve Ligation
(SNL) models are recognized as stable and consistent models for
neuropathic pain. To induce CCI, loose ligatures are tied around
the proximal part of the sciatic nerve. PNL is induced by tight
ligation of 1/2 of the sciatic nerve trunk. TNT is induced by
ligation and transaction of the tibial nerve, one of the three
major terminal branches of the sciatic nerve. To perform an SNL,
the L5 spinal nerve is ligated and transected. The procedures are
undertaken on one side of the animal and the contra-lateral side
serves as an internal control. Enhanced pain responses to thermal
and/or mechanical stimulation are assessed by the Hargreaves' test
and/or the von Frey fiber assay. In the Hargreaves' test, a radiant
heat beam is projected on the plantar skin of each hind paw. The
latency to paw withdrawal is recorded as a measure of the thermal
pain threshold. Mechanical allodynia is determined by determining
the 50% mechanical threshold with von Frey fibers using Dixon's
up-and-down method. Using an SNL rat model (n=5) as described above
and in Imamura Y et al (1995), J. Pharmacol. Exp. Ther, 275(10),
177-82, results are obtained as in Table 4 below. Percentage
inhibition of allodynia in rats with nerve ligation is calculated
and upaired Stdent's t test is applied for comparison between
vehicle control and treated group.
TABLE-US-00004 TABLE 4 Inhibition of neuropathic pain in rats ID
Dose (mg/kg) % inhibition Control (vehicle) -- -5.0 .+-. 3.4
Gabapentin 200 61.0* .+-. 14.3 Compound 18 200 55.7* .+-. 15.7
*Statistically significant from control values
Example 4
In Vivo Activity in a Metrazole-Induced Convulsions Model
[0168] A compound is tested in a model for convulsions (see Chen G
et at (1954), Proc. Soc. Exp. Biol. Med., 87, 334. This model uses
metrazole to induce convulsions. Prevention of .gtoreq.50% of
metrazole (100 mg/kg)-induced clonic convulsions (2 points per
mouse) and mortality (1 point per mouse) for a maximum score of 9.
Results expressed in percentage (100%=9) for Compound 18 (200
mg/kg) as compared to gabapentin (100 mg/kg) or diazepam (1 mg/kg)
are sown in Table 5.
TABLE-US-00005 TABLE 5 Prevention of convulsions in mice. ID Dose
(mg/kg) % Prevention Control (vehicle) -- 0 Diazepam 1 67
Gabapentin 100 67 Compound 18 200 67
Example 5
In Vivo Activity in a Diabetes/Obesity Model
[0169] The objective of this study is to determine the effect of
the compounds of the invention, namely Compounds 6A, 6B and 18,
glycemia, insulin and body weight gain in a Diet-Induced Obesity
(DIO) mouse model. Results are compared with
(2S,3R,4S)-4-hydroisoleucine (positive control) and vehicle
(negative control).
[0170] C57BL/6 mice are tested at 17-18 weeks of age and fed a high
fat diet (60% of calories from fat) for 8 weeks. Fasted glycemia
and body weight values are used to randomize the mice into control
and treatment groups (n=8). The animals are treated twice daily
(BID) (once on 7.sup.th day) by oral gavage with
4-hydroxyisoleucine. Compounds 6A, 6B and 18 (100 mg per kg of body
weight), and the control group receive vehicle (water) alone. The
animals are treated for 7 days.
[0171] Oral glucose Tolerance Test (OGTT) is performed at 5 hours
.+-.30 minutes Post starvation (day 0 only) or Post AM test article
administration (for day 7). Blood samples are collected via tail
vein for glucose determination prior to glucose challenge
(Pre-OGTT) and at 5, 10, 20, 30, 60, 90 and 120 minutes
post-glucose administration. Glucose determination is performed
using a hand held glucometer (Model OneTouch Ultra, LifeScan).
[0172] A second blood sample is also collected Pre-OGTT and at 5,
10, 60 and 120 minutes Post-OGTT for insulin determination. Insulin
determination is done using an enzyme immunoassay kit (Mecodia
Ultrasensitive Mouse Insulin ELISA, ALPCO Diagnostics, Wndham,
N.H.).
[0173] Body weight of the mice is measured at arrival,
randomization, and on days 0, 3 and 7 of treatment. At the end of
the study, the epididymal fat pads were isolated and weighed. Data
are expressed as mean .+-.SEM of body weight and mean .+-.SEM of
fat pad weight.
[0174] Results show that Compounds 6A and 6B exhibited neutral or
beneficial effect on glycemia (FIG. 1A) and on insulin (FIGS. 1B,
2A and 2B) when compared to control. Compound 18 showed no effect
on glycemia.
[0175] The compounds tested did not show any significant effect on
body weight as compared to vehicle treated mice. These results show
that the compounds tested all have neutral or beneficial effect on
metabolic parameters.
Example 6
Pharmacokinetic Profiles
a) Pharmacokinetic Profiles in Mice
[0176] Compounds are tested for pharmacokinetic profile, including
oral bioavailability in mice using the following procedure.
Bioavailability estimates are performed after administration of 100
mg/kg of Compound 6B and 50 mg/kg of Compound 18 either
intravenously (IV) or orally (PO). Four animals per time point, per
mode of administration are used. At each specific time point
following drug administration, a blood sample is collected
terminally (under isoflurane anesthesia) via cardiac puncture from
each the 4 animals. Samples are collected at pre-dose and at 5, 15,
30, and 60 minutes and at 2, 4, 6, 8, 14 and 24 hours post oral
administration and at pre-dose and 2, 5, 15, 30, and 60 minutes and
2, 4, 8, 14 and 24 hours post intravenous administration. Blood
samples are collected into tubes containing K.sub.3-EDTA as
anticoagulant, kept on ice until centrifugation at 4.degree. C. at
a minimum speed of 3000 rpm (1620G) for 10 min. Plasma samples are
harvested into polypropylene tubes, immediately placed on dry ice
and stored at -80.degree. C.
[0177] Compounds in mouse plasma are extracted using protein
precipitation. Quantitation of the compounds in mouse plasma matrix
is achieved using LC-MS detection. Sample concentration is
calculated using a calibration curve. FIGS. 3A and 3B show mouse PK
curves in log scale for Compounds 6B and 18 respectively.
Bioavailability (%F) was about 100% for Compound 6B, and 88.4% for
Compound 18.
b) Pharmacokinetic Profile in Dogs
[0178] The pharmacokinetic profile of Compound 18 is evaluated in
one female Beagle dog. One single oral and one single IV dose of 25
mg/kg separated by a wash-out period are administered to the dog to
get key preliminary information about the pharmacokinetics and oral
bioavailability of Compound 18. The results are presented in FIG.
4. Compound 18 showed a classical first order type of
pharmacokinetic profile at the dose administered with a terminal
half live of around 7 hours. The compound is rapidly and very well
absorbed following oral administration and does not demonstrate any
significant first pass effect (oral bioavailability of 97%).
[0179] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and puNiew of this application and scope of the appended
claims.
[0180] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The preceding preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0181] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0182] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *