U.S. patent application number 13/382834 was filed with the patent office on 2012-07-05 for permanently charged sodium and calcium channel blockers as anti- inflammatory agents.
Invention is credited to Bruce P. Bean, Clifford J. Woolf.
Application Number | 20120172429 13/382834 |
Document ID | / |
Family ID | 43429565 |
Filed Date | 2012-07-05 |
United States Patent
Application |
20120172429 |
Kind Code |
A1 |
Woolf; Clifford J. ; et
al. |
July 5, 2012 |
PERMANENTLY CHARGED SODIUM AND CALCIUM CHANNEL BLOCKERS AS ANTI-
INFLAMMATORY AGENTS
Abstract
The invention provides compounds, compositions, methods, and
kits for the treatment of neurogenic inflammation.
Inventors: |
Woolf; Clifford J.; (Newton,
MA) ; Bean; Bruce P.; (Waban, MA) |
Family ID: |
43429565 |
Appl. No.: |
13/382834 |
Filed: |
July 9, 2010 |
PCT Filed: |
July 9, 2010 |
PCT NO: |
PCT/US10/41537 |
371 Date: |
March 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61224512 |
Jul 10, 2009 |
|
|
|
Current U.S.
Class: |
514/523 ;
514/626; 558/408; 564/194 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
17/10 20180101; A61P 29/00 20180101; C07D 295/192 20130101; A61K
31/00 20130101; A61P 39/02 20180101; A61P 13/02 20180101; A61P
37/08 20180101; A61K 31/167 20130101; A61P 19/02 20180101; A61K
31/277 20130101; A61P 31/04 20180101; A61P 27/02 20180101; A61P
11/14 20180101; A61P 13/10 20180101; A61P 13/00 20180101; A61K
31/165 20130101; A61P 11/00 20180101; A61P 17/06 20180101; A61P
25/06 20180101; A61P 17/00 20180101; A61P 17/04 20180101; A61P
27/14 20180101; A61K 45/06 20130101; A61P 11/10 20180101; A61P
25/02 20180101; A61P 1/04 20180101; A61P 11/02 20180101; A61P 11/06
20180101; A61P 43/00 20180101; A61P 25/00 20180101; C07D 235/14
20130101; A61K 31/165 20130101; A61K 2300/00 20130101; A61K 31/167
20130101; A61K 2300/00 20130101; A61K 31/277 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/523 ;
514/626; 564/194; 558/408 |
International
Class: |
A61K 31/277 20060101
A61K031/277; C07C 237/14 20060101 C07C237/14; C07C 255/33 20060101
C07C255/33; A61P 25/00 20060101 A61P025/00; A61P 29/00 20060101
A61P029/00; A61P 11/06 20060101 A61P011/06; A61P 11/10 20060101
A61P011/10; A61P 19/02 20060101 A61P019/02; A61P 17/00 20060101
A61P017/00; A61P 1/00 20060101 A61P001/00; A61P 13/02 20060101
A61P013/02; A61P 25/06 20060101 A61P025/06; A61P 17/06 20060101
A61P017/06; A61P 11/02 20060101 A61P011/02; A61K 31/16 20060101
A61K031/16 |
Claims
1. A method for treating neurogenic inflammation in a patient, said
method comprising administering to said patient a therapeutically
effective amount of a compound that is capable of (i) entering a
nociceptor through a channel-forming receptor present in said
nociceptor when said receptor is activated and (ii) inhibiting a
voltage-gated ion channel present in said nociceptor, wherein said
compound does not substantially inhibit said channel when applied
to the extracellular face of said channel and when said receptor is
not activated.
2. The method of claim 1, wherein said compound inhibits
voltage-gated sodium channels, or wherein said compound inhibits
calcium channels.
3. The method of claim 2, wherein said compound is QX-314,
N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine,
pancuronium, or another low molecular weight, charged molecule that
inhibits voltage-gated sodium channels when present inside of said
nociceptor.
4. The method of claim 1, wherein said compound is a quarternary
amine derivative or other charged derivative of a compound selected
from the group consisting of riluzole, mexilitine, phenyloin,
carbamazepine, procaine, tocainide, prilocaine, articaine,
bupivicaine, mepivicine, diisopyramide, bencyclane, quinidine,
bretylium, lifarizine, lamotrigine, flunarizine, and fluspirilene;
or wherein said compound is a quarternary amine derivative or other
charged derivative of any of compounds (1)-(563).
5. (canceled)
6. The method of claim 2, wherein said compound is selected from
D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil,
N-methyl-devapamil, and dodecyltrimethylammonium; a quarternary
amine derivative of verapamil, gallopamil, devapamil, diltiazem,
fendiline, mibefradil, or farnesyl amine; a compound according to
any of Formulas (XI), (XII), (XIII-A), (XIII-B), (XIII-C), and
(XIV); and a quarternary amine derivative or other charged
derivative of any of compounds (45)-(563).
7. (canceled)
8. The method of claim 1, wherein said channel-forming receptor has
been activated prior to said administering of said compound.
9. The method of claim 1, further comprising administering a second
compound that activates said channel-forming receptor.
10. The method of claim 9, wherein said second compound activates a
channel-forming receptor selected from TRPV1, P2X(2/3), TRPA1, and
TRPM8.
11. The method of claim 10, wherein said second compound is an
activator of TRPV1 receptors, said activator selected from
capsaicin, a capsaicinoid, eugenol, arvanil
(N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl
borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate
13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA
(N-oleoyldopamine), N-arachidonyldopamine (NADA),
6'-iodoresiniferatoxin (6'-IRTX), C18 N-acylethanolamines,
lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic
acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins),
piperine, MSK195
(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3--
methoxyphenyl]acetamide), JYL79
(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-(4-hydroxy-3-methoxy-
benzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl
borate, 10-shogaol, oleylgingerol, oleylshogaol, SU200
(N-(4-tert-butylbenzyl)-N'-(4-hydroxy-3-methoxybenzyl)thiourea),
articaine, benzocaine, bupivacaine, carbocaine, carticaine,
chloroprocaine, cyclomethycaine, dibucaine (cinchocaine),
dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine,
lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine,
piperocaine, prilocaine, procaine (novacaine), proparacaine,
propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), or
trimecaine; or said second compound is an activator of TRPA1
receptors, said activator selected from cinnamaldehyde,
allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil,
wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool,
2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl
p-hydroxybenzoate, mustard oil, and 3'-carbamoylbiphenyl-3-yl
cyclohexylcarbamate (URB597), articaine, benzocaine, bupivacaine,
carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine
(cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine,
levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine),
metabutoxycaine, piperocaine, prilocaine, procaine (novacaine),
proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine
(amethocaine), or trimecaine; or said second compound is an
activator of P2X receptors, said activator selected from ATP,
2-methylthio-ATP, 2' and 3'-O-(4-benzoylbenzoyl)-ATP, and
ATP5'-O-(3-thiotriphosphate); or said second compound is an
activator of TRPM8 receptors, said activator selected from menthol,
iciclin, eucalyptol, linalool, geraniol, and
hydroxycitronellal.
12.-14. (canceled)
15. The method of claim 1, further comprising administering one or
more acetaminophens, NSAIDs, glucocorticoids, narcotics, tricyclic
antidepressants, amine transporter inhibitors, anticonvulsants,
antiproliferative agents, or immune modulators.
16. The method of claim 1, wherein said method is used to treat
asthma, conjunctivitis, sepsis, sinusisitis, cough, arthritis,
colitis, contact dermatitis, eczema, gastritis, cystitis,
urethritis, migraine headache, psoriasis, rhinitis, rosacea,
sunburn, traumatic brain injury, acute lung injury, chemical
warfare agents, inhaled tear gases, or inhaled pollutants.
17. The method of claim 1, wherein said administering comprises
intraarticular, surgical, intravenous, intramuscular, oral, rectal,
cutaneous, subcutaneous, topical, transdermal, sublingual, nasal,
vaginal, intraurethral, intravesicular, intrathecal, epidural,
mucosal, aural, or ocular administration by injection, inhalation,
or direct contact.
18. The method of claim 1, wherein said composition is formulated
for controlled or sustained release over time.
19. A kit comprising: a) a compound that is capable of (i) entering
a nociceptor through a channel-forming receptor present in said
nociceptor when said receptor is activated and (ii) inhibiting a
voltage-gated ion channel present in said nociceptor, wherein said
compound does not substantially inhibit said channel when applied
to the extracellular face of said channel and when said receptor is
not activated; and b) instructions for administering said compound
to a patient to treat neurogenic inflammation.
20.-31. (canceled)
32. A compound selected from the group consisting of: (a) a
compound according to Formula (XI): ##STR00100## wherein each
R.sup.11A, R.sup.11B, and R.sup.11C is selected, independently,
from H or C.sub.1-4 alkyl, and X.sup.- is any pharmaceutically
acceptable anion; (b) a compound according to Formula (XII),
##STR00101## wherein each of R.sup.12A, R.sup.12B, R.sup.12C, and
R.sup.12D is, independently, selected from C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl,
C.sub.7-14 alkaryl, C.sub.3-10 alkcycloalkyl, and C.sub.3-10
alkheterocyclyl; or R.sup.12A and R.sup.12B together complete a
heterocyclic ring having at least one nitrogen atom; n is an
integer between 1-5; each of R.sup.12E and R.sup.12F is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl,
C.sub.3-10 alkcycloalkyl, or C.sub.3-10 alkheterocyclyl; and X is
any pharmaceutically acceptable anion; ##STR00102## wherein each
R.sup.13A-R.sup.13J and R.sup.13O-R.sup.13T is selected,
independently, from H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl,
C.sub.3-10 alkcycloalkyl, and C.sub.3-10 alkheterocyclyl,
OR.sup.13AA, NR.sup.13ABR.sup.13AC, NR.sup.13ADC(O)R.sup.13AE,
S(O)R.sup.13AF, SO.sub.2R.sup.13AGR.sup.13AH,
SO.sub.2NR.sup.13AIR.sup.13AJ, SO.sub.3R.sup.13AK,
CO.sub.2R.sup.13AL, C(O)R.sup.13AM, and C(O)NR.sup.13ANR.sup.13AO;
each of R.sup.13AA-R.sup.13AO is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; each R.sup.13K, R.sup.13L, R.sup.13M, and
R.sup.13N is, independently, H or C.sub.1-4 alkyl, or R.sup.13K and
R.sup.13L, or R.sup.13M and R.sup.13N, combine to form C.dbd.O, or
R.sup.13K and R.sup.13M combine to form C.dbd.C; R.sup.13Y is H or
C.sub.1-4 alkyl; R.sup.13Z and R.sup.13Z' are, independently,
selected from H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl,
C.sub.3-10 alkcycloalkyl, and C.sub.3-10 alkheterocyclyl; and
X.sup.- is any pharmaceutically acceptable anion; and (d) a
compound having a structure according to ##STR00103## wherein n is
an integer between 0-5; R.sup.14A is heterocyclyl, each of
R.sup.14B, R.sup.14C, R.sup.14D, and R1.sup.4E is, independently,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.7-14 alkaryl, C.sub.3-10 alkcycloalkyl, and
C.sub.3-10 alkheterocyclyl; and R.sup.14F is selected from H,
halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl, C.sub.3-10
alkcycloalkyl, and C.sub.3-10 alkheterocyclyl, OR.sup.14G,
NR.sup.14HR.sup.14I, NR.sup.14JC(O)R.sup.14K, S(O)R.sup.14L,
S(O).sub.2R.sup.14MR.sup.14N, SO.sub.2NR.sup.14OR.sup.14P,
SO.sub.3R.sup.14Q, CO.sub.2R.sup.14R, C(O)R.sup.14S, and
C(O)NR.sup.14TR.sup.14V; and each of R.sup.14G-R.sup.13AO is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl.
33. The compound of claim 32, wherein said compound is:
##STR00104## wherein X is a pharmaceutically acceptable anion.
34.-39. (canceled)
40. A pharmaceutical composition, comprising the compound of claim
32 and a pharmaceutically acceptable excipient.
41. A pharmaceutical composition, comprising a quarternary amine
derivative or other charged derivative of any of compounds
(1)-(563).
42. The pharmaceutical composition of claim 40, wherein said
composition is formulated for oral, nasal, or inhalation
administration.
43. The pharmaceutical composition of claim 41, wherein said
composition is formulation for oral, nasal, or inhalation
administration.
44. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application No. 61/224,512, filed Jul. 10, 2009, which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention provides compounds, methods and kits for the
treatment of neurogenic inflammation.
BACKGROUND OF THE INVENTION
[0003] The invention features methods and kits for the treatment of
neurogenic inflammation by targeting nociceptors with drugs of low
molecular weight, while minimizing effects on non-pain-sensing
neurons or other types of cells. According to the method of the
invention, small, hydrophilic drug molecules gain access to the
intracellular compartment of pain-sensing neurons via entry through
receptor/channels that are present in pain-sensing neurons but to a
lesser extent or not at all in other types of neurons or in other
types of tissue. Neurogenic inflammation is a mode of inflammation
mediated by the efferent (motor) functions of sensory neurons, in
which pro-inflammatory mediator molecules released in the periphery
by pain-sensing neurons (nociceptors) both activate a variety of
inflammatory pathways and also act on the vascular system to alter
blood flow and capillary permeability.
[0004] Neurogenic inflammation contributes to the peripheral
inflammation elicited by tissue injury, autoimmune disease,
infection, exposure to irritants in a variety of tissues, and is
thought to play an important role in the pathogenesis of numerous
disorders (e.g. migraine, arthritis, rhinitis, gastritis, colitis,
cystitis, and sunburn).
[0005] One way to reduce neurogenic inflammation is to block
excitability in nociceptors, thereby preventing the activation of
nociceptor peripheral terminals and the release of pro-inflammatory
chemicals. Local anesthetics such as lidocaine and articaine act by
inhibiting voltage gated ion channels in neurons. Local anesthetics
are relatively hydrophobic molecules that gain access to their
blocking site on the sodium channel by diffusing into or through
the cell membrane. However, these anesthetics block sodium or
calcium channels and thereby the excitability of all neurons, not
just pain-sensing neurons. Thus, administration of local
anesthetics produces unwanted or deleterious effects such as
general numbness from block of low threshold pressure and touch
receptors, motor deficits from block of motor axons and other
complications from block of autonomic fibers. Local anesthetics
also act on sodium channels on smooth muscle in the cardiovascular
and respiratory systems producing deleterious effects.
[0006] Accordingly, there is a need for an approach to reducing
neurogenic inflammation that selectively targets nociceptors.
SUMMARY OF THE INVENTION
[0007] In a first aspect, the invention features a method for
treating neurogenic inflammation in a patient, such as a human, by
administering a therapeutically effective amount of a compound that
is capable of entering a nociceptor through a channel-forming
receptor present in the nociceptor when the receptor is activated
and inhibiting a voltage-gated ion channel present in the
nociceptor, wherein the compound does not substantially inhibit
said channel when applied to the extracellular face of the channel
and when the receptor is not activated. In certain embodiments, the
compound is an inhibitor of voltage-gated sodium channels.
Exemplary inhibitors of this class are QX-314, N-methyl-procaine,
QX-222, N-octyl-guanidine, 9-aminoacridine and pancuronium. In
other embodiments, the compound is a quarternary amine derivative
or other charged derivative of a compound selected from riluzole,
mexilitine, phenyloin, carbamazepine, procaine, articaine,
bupivicaine, mepivicaine, tocainide, prilocaine, diisopyramide,
bencyclane, quinidine, bretylium, lifarizine, lamotrigine,
flunarizine, and fluspirilene. In other embodiments, the compound
is an inhibitor of calcium channels. Inhibitors of this class
include D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil,
N-methyl-devapamil, dodecyltrimethylammonium, and terpene compounds
(e.g., sesquiterpenes), as well as charged derivatives (e.g., a
quarternary amine derivative or a guanylated derivative) of
verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil,
or farnesyl amine. Still other exemplary inhibitors of calcium
channels can be described by Formulas XI-XIV) and in Tables 1, 2,
and 3. In further embodiments, the ion channel inhibitor is a
charged derivative (e.g., a quarternary amine derivative or a
guanylated derivative) of any of compounds (1)-(563). Exemplary
derivatives are described herein.
[0008] The channel-forming receptor can be activated prior to
administering the compound by administration of a second compound
that opens the channel. Alternatively, the channel-forming receptor
can be activated by endogenous compounds present in the
patient.
[0009] The invention also features a kit that includes a
composition for treating neurogenic inflammation in a patient and
instructions for the administration of the composition to a patient
to treat neurogenic inflammation. The composition includes a
compound that is capable of entering a nociceptor through a
channel-forming receptor present in the nociceptor when the
receptor is activated and inhibiting a voltage-gated ion channel
present in the nociceptor, wherein the compound does not
substantially inhibit said channel when applied to the
extracellular face of the channel and when the receptor is not
activated. In certain embodiments, the compound is an inhibitor of
voltage-gated sodium channels or calcium channels, such as those
described herein. In some embodiments, the compound is QX-314,
N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine,
pancuronium, or another low molecular weight, charged molecule that
inhibits voltage-gated sodium channels when present inside of said
nociceptor. In other embodiments, the compound is D-890, CERM
11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil,
and dodecyltrimethylammonium; a quarternary amine derivative, of
verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil,
or farnesyl amine; a compound according to any of Formulas (XI),
(XII), (XIII-A), (XIII-B), (XIII-C), and (XIV); or a quarternary
amine derivative or other charged derivative of any of compounds
(1)-(563).
[0010] Any of the compositions, methods, and kits of the invention
may optionally feature a second compound that activates the
channel-forming receptor. In one embodiment, the second compound
activates a channel-forming receptor selected from TRPV1, P2X(2/3),
TRPA1, and TRPM8.
[0011] Activators of TRPV1 receptors include but are not limited to
capsaicin, eugenol, camphor, clotrimazole, arvanil
(N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl
borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate
13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA
(N-oleoyldopamine), N-arachidonyldopamine (NADA),
6'-iodoresiniferatoxin (6'-IRTX), C18 N-acylethanolamines,
lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic
acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins),
piperine, MSK195
(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3--
methoxyphenyl]acetamide), JYL79
(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-(4-hydroxy-3-methoxy-
benzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl
borate, 10-shogaol, oleylgingerol, oleylshogaol, SU200
(N-(4-tert-butylbenzyl)-N'-(4-hydroxy-3-methoxybenzypthiourea),
amylocaine, articaine, benzocaine, bupivacaine, carbocaine,
carticaine, chloroprocaine, cyclomethycaine, dibucaine
(cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine,
levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine),
metabutoxycaine, piperocaine, prilocaine, procaine (novacaine),
proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine
(amethocaine), and trimecaine. Other activators of TRPV1 receptors
are described in O'Dell et al., Bioorg Med Chem. (2007)
15:6164-6149, and Sexton et al., FASEB J (2007) 21:2695-2703. Still
other TRPV1 activators include black pepper compounds (e.g.,
Okumura et al., Biosci Biotechnol Biochem. 74(5):1068-72 (2010) and
Riera et al., Br J Pharmacol. 57(8):1398-409 (2009)), terpenoids
(Iwasaki et al., Life Sci. 85(1-2)60-69 (2009)), nickel (Luebbert
et al., Pflugers Arch. 459(5):737-50 (2010)), SA13353
([1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea];
see, e.g., Tsuji et al., Eur J Pharmacol. 627(1-3):332-9 (2010)),
oxidized linoleic metabolites (Patwardhan et al., Proc Natl Acad
Sci USA. 106(44):18820-4 (2009)), diallyl sulfides (Koizumi et al.,
Biochem Biophys Res Commun. 382(3):545-8 (2009)), and alkylamides
derived from sanshool (Menozzi-Smarrito et al., J Agric Food Chem.
57(5):1982-9 (2009)).
[0012] Still other activators of TRPV1 receptors include
capsaicinoids and capsaicinoid analogs as described herein (e.g.,
vanilloids (e.g., N-vanillyl-alkanedienamides,
N-vanillyl-alkanedienyls, and N-vanillyl-cis-monounsaturated
alkenamides), capsiate, dihydrocapsiate, nordihydrocapsiate and
other capsinoids, capsiconiate, dihydrocapsiconiate and other
coniferyl esters, capsiconinoid, resiniferatoxin, tinyatoxin,
civamide, N-phenylmethylalkenamide capsaicin derivatives, olvanil,
N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide,
N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral),
gingerols, piperines, shogaols, guaiacol, eugenol, zingerone,
nuvanil, NE-19550, NE-21610, and NE-28345). Additional
capsaicinoids, their structures, and methods of their manufacture
are described in U.S. Pat. Nos. 7,446,226 and 7,429,673, which are
hereby incorporated by reference.
[0013] Activators of TRPA1 receptors include but are not limited to
cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin,
cinnamon oil, wintergreen oil, clove oil, acrolein,
hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate,
4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil,
3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), amylocaine,
articaine, benzocaine, bupivacaine, carbocaine, carticaine,
chloroprocaine, cyclomethycaine, dibucaine (cinchocaine),
dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine,
lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine,
piperocaine, prilocaine, procaine (novacaine), proparacaine,
propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and
trimecaine. Other activators of TRPA1 receptors are described in
Taylor-Clark et al., Mol Pharmacol (2007) PMID: 18000030;
Macpherson et al., Nature (2007) 445:541-545; and Hill et al., J.
Biol. Chem. (2007) 282:7145-7153. Still other TRPA1 activators
include: fenamate NSAIDS (Hu et al., Pflugers Arch. 459(4):579-92
(2010)), congeners of AP18 (Defalco et al, Bioorg Med Chem Lett.
20(1):276-9 (2010)), tear gasses CN, CR, and CS (Brone et al.,
Toxicol Appl Pharmacol. 231(2):150-6 (2008)), nicotine (Talavera et
al, Nat Neurosci. 12(10):1293-9 (2009)), Sichuan and Melegueta
peppers (Riera et al., Br J Pharmacol. 157(8):1398-409 (2009)),
diallyl sulfides nifedipine, nimodipine, nicardipine, and
nitrendipine, L-type calcium channel agaonist BayK8644 (Fajardo et
al., Channels (Austin) 2(6):429-38 (2008)), and isovelleral and
polygodial (Escalera et al., J. Biol. Chem. 283(35):24136-44
(2008)).
[0014] Activators of P2X receptors include but are not limited to
ATP, 2-methylthio-ATP, 2' and 3'-O-(4-benzoylbenzoyl)-ATP, and
ATP5'-O-(3-thiotriphosphate).
[0015] Activators of TRPM8 receptors include but are not limited to
menthol, icilin, eucalyptol, linalool, geraniol, and
hydroxycitronellal.
[0016] In another aspect, the invention features compounds
according to Formula (XI),
##STR00001##
[0017] where each R.sup.11A, R.sup.11B, and R.sup.11C is selected,
independently, from H or C.sub.1-4 alkyl, and where 0, 1, 2, or 3
of the dashed bonds represents a carbon-carbon double bond (i.e.,
compounds of Formula (XI) can include 0, 1, 2, or 3 double bonds),
provided that when 2 or 3 carbon-carbon double bonds are present,
the double bonds are not adjacent to one another. In some
embodiments, compounds of Formula (XI) can be represented by the
following formula (XI-A),
##STR00002##
where each R.sup.11A, R.sup.11B, R.sup.11C, and X is according to
Formula (XI), and where each dashed bond represents an optional
carbon-carbon double bond, or by formula (XI-B),
##STR00003##
where each R.sup.11A, R.sup.11B, R.sup.11C, and X is according to
Formula (XI). In some embodiments, the compound of Formula (XI)
is
##STR00004##
[0018] In another aspect, the invention features compounds
according to Formula (XII),
##STR00005##
wherein
[0019] each of R.sup.12A, R.sup.12B, R.sup.12C, and R.sup.12D is,
independently, selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl,
C.sub.3-10 alkcycloalkyl, and C.sub.3-10 alkheterocyclyl; or
R.sup.12A and R.sup.12B together complete a heterocyclic ring
having at least one nitrogen atom; n is an integer between 1-5;
each of R.sup.12E and R.sup.12F is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.7-14 alkaryl, C.sub.3-10 alkcycloalkyl, or
C.sub.3-10 alkheterocyclyl; and X is any pharmaceutically
acceptable anion. In some embodiments, the compound has the
following structure,
##STR00006##
[0020] In another aspect, the invention features a compound having
a structure according to one of the following formulas:
##STR00007##
where each R.sup.13A-R.sup.13J and R.sup.13O-R.sup.13T is selected,
independently, from H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl,
C.sub.3-10 alkcycloalkyl, and C.sub.3-10 alkheterocyclyl,
OR.sup.13AA, NR.sup.13ABR.sup.13AC, NR.sup.13ADC(O)R.sup.13AE,
S(O)R.sup.13AF, SO.sub.2R.sup.13AGR.sup.13AH,
SO.sub.2NR.sup.13AIR.sup.13AJ, SO.sub.3R.sup.13AK,
CO.sub.2R.sup.13AL, C(O)R.sup.13AM, and C(O)NR.sup.13ANR.sup.13AO;
each of R.sup.13AA-R.sup.13AO is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; each R.sup.13K, R.sup.13L, R.sup.13M, and
R.sup.13N is, independently, H or C.sub.1-4 alkyl, or R.sup.13K
(and R.sup.13L, or R.sup.13M and R.sup.13N, combine to form
C.dbd.O, or R.sup.13K and R.sup.13M combine to form C.dbd.C;
R.sup.13Y is H or C.sub.1-4 alkyl; R.sup.13Z and R.sup.13Z and
R.sup.17Z' are, independently, selected from H, halogen, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl,
C.sub.7-14 alkaryl, C.sub.3-10 alkcycloalkyl, and C.sub.3-10
alkheterocyclyl; and X.sup.- is any pharmaceutically acceptable
anion. In some embodiments, the compound is selected from the group
consisting of:
##STR00008##
[0021] In another aspect, the invention features compounds
according to the following formula,
##STR00009##
[0022] where n is an integer between 0-5; R.sup.14A is
heterocyclyl, each of R.sup.14B, R.sup.14C, R.sup.14D, and
R1.sup.4E is, independently, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl,
C.sub.3-10 alkcycloalkyl, and C.sub.3-10 alkheterocyclyl; and
R.sup.14F is selected from H, halogen, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14
alkaryl, C.sub.3-10 alkcycloalkyl, and C.sub.3-10 alkheterocyclyl,
OR.sup.14G, NR.sup.14HR.sup.14I, NR.sup.14JC(O)R.sup.14K,
S(O)R.sup.14L, SO.sub.2R.sup.14MR.sup.14N,
SO.sub.2NR.sup.14OR.sup.14P, SO.sub.3R.sup.14Q, CO.sub.2R.sup.14R,
C(O)R.sup.14S, and C(O)NR.sup.14TR.sup.14V; and each of
R.sup.14G-R.sup.13AO is independently, selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4
heteroalkyl. In some embodiments, the compound is
##STR00010##
where X is a pharmaceutically acceptable anion.
[0023] The invention also features pharmaceutical compositions that
include a compound according to any of Formulas (XI)-(XIV), or any
of compounds (1)-(563), and a pharmaceutically acceptable
excipient. In some embodiments, the pharmaceutical composition is
formulated for oral, nasal, or inhalation administration.
[0024] In certain embodiments, the compounds, compositions,
methods, and kits of the invention may be used to treat any
disorder that is caused, wholly or in part, by neurogenic
inflammation. Non-limiting examples of such disorders include
asthma, rhinitis, conjunctivitis, arthritis, colitis, contact
dermatitis, pancreatitis, chronic cough, sinusisitis (e.g., chronic
rhinosinusistis), traumatic brain injury, sepsis (e.g.,
polymicrobial sepsis), tendinopathies chronic urticaria, rheumatic
disease, acute lung injury, exposure to irritants, inhalation of
irritants, pollutants or chemical warfare agents, eczema, cystitis,
gastritis, urethritis, migraine headache, psoriasis, rhinitis,
rosacea, sunburn, chemical warfare agents, inhaled tear gases, or
inhaled pollutants.
[0025] Some methods and kits of the invention also feature one or
more acetaminophens, NSAIDs, glucocorticoids, narcotics, tricyclic
antidepressants, amine transporter inhibitors, anticonvulsants,
antiproliferative agents, or immune modulators.
[0026] In another embodiment, the compositions are administered by
intraarticular, surgical, intravenous, intramuscular, oral, rectal,
cutaneous, subcutaneous, topical, transdermal, sublingual, nasal,
vaginal, intraurethral, intravesicular, intrathecal, epidural,
mucosal, aural, or ocular administration by injection, inhalation,
or direct contact. In yet another embodiment, the composition is
formulated for controlled or sustained release over time.
[0027] By "biologically active" is meant that a molecule, including
biological molecules, such as nucleic acids, peptides,
polypeptides, and proteins, exerts a physical or chemical activity
on itself or other molecule. For example, a "biologically active"
molecule may possess, e.g., enzymatic activity, protein binding
activity (e.g., antibody interactions), or cytotoxic activities
(e.g., anti-cancer properties). Biologically active agents that can
be used in the methods and kits described herein include, without
limitation, an antibody or antibody fragment, an antibiotic, a
polynucleotide, a polypeptide, a protein, an anti-cancer agent, a
growth factor, and a vaccine.
[0028] By "inflammation" is meant any types of inflammation, such
those caused by the immune system (immune-mediated inflammation)
and by the nervous system (neurogenic inflammation), and any
symptom of inflammation, including redness, heat, swelling, pain,
and/or loss of function.
[0029] By "neurogenic inflammation" is meant any type of
inflammation mediated by neurons (e.g. nociceptors) or any other
component of the central or peripheral nervous system.
[0030] By "patient" is meant any animal. In one embodiment, the
patient is a human. Other animals that can be treated using the
methods and kits of the invention include, but are not limited to,
non-human primates (e.g., monkeys, gorillas, chimpanzees),
domesticated animals (e.g., horses, pigs, goats, rabbits, sheep,
cattle, llamas), and companion animals (e.g., guinea pigs, rats,
mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).
[0031] Compounds useful in the invention include, but are not
limited to, those described herein in any of their pharmaceutically
acceptable forms, including isomers such as diastereomers and
enantiomers, salts, esters, amides, thioesters, solvates, and
polymorphs thereof, as well as racemic mixtures and pure isomers of
the compounds described herein.
[0032] By "low molecular weight" is meant less than about 650
Daltons.
[0033] The term "pharmaceutically acceptable salt" represents those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or separately by
reacting the free base function with a suitable organic acid.
Representative acid addition salts include, but are not limited to,
acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphersulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,
glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,
hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate,
nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,
pivalate, propionate, stearate, succinate, sulfate, tartrate,
thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the
like. These acid addition salts may also be referred to as
"pharmaceutically acceptable anions." Representative alkali or
alkaline earth metal salts include, but are not limited to, sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like.
[0034] In the generic descriptions of compounds of this invention,
the number of atoms of a particular type in a substituent group is
generally given as a range, e.g., an alkyl group containing from 1
to 4 carbon atoms or C.sub.1-4 alkyl. Reference to such a range is
intended to include specific references to groups having each of
the integer number of atoms within the specified range. For
example, an alkyl group from 1 to 4 carbon atoms includes each of
C.sub.1, C.sub.2, C.sub.3, and C.sub.4. A C.sub.1-12 heteroalkyl,
for example, includes from 1 to 12 carbon atoms in addition to one
or more heteroatoms. Other numbers of atoms and other types of
atoms may be indicated in a similar manner.
[0035] As used herein, the terms "alkyl" and the prefix "alk-" are
inclusive of both straight chain and branched chain groups and of
cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or
polycyclic and preferably have from 3 to 6 ring carbon atoms,
inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl groups.
[0036] By "C.sub.1-4 alkyl" is meant a branched or unbranched
hydrocarbon group having from 1 to 4 carbon atoms. A C.sub.1-4
alkyl group may be substituted or unsubstituted. Exemplary
substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,
arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino,
aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,
carboxyalkyl, and carboxyl groups. C.sub.1-4 alkyls include,
without limitation, methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, and cyclobutyl.
[0037] By "C.sub.2-4 alkenyl" is meant a branched or unbranched
hydrocarbon group containing one or more double bonds and having
from 2 to 4 carbon atoms. A C.sub.2-4 alkenyl may optionally
include monocyclic or polycyclic rings, in which each ring
desirably has from three to six members. The C.sub.2-4 alkenyl
group may be substituted or unsubstituted. Exemplary substituents
include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide,
hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,
disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl,
and carboxyl groups. C.sub.2-4 alkenyls include, without
limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and
2-methyl-2-propenyl.
[0038] By "C.sub.2-4 alkynyl" is meant a branched or unbranched
hydrocarbon group containing one or more triple bonds and having
from 2 to 4 carbon atoms. A C.sub.2-4 alkynyl may optionally
include monocyclic, bicyclic, or tricyclic rings, in which each
ring desirably has five or six members. The C.sub.2-4 alkynyl group
may be substituted or unsubstituted. Exemplary substituents include
alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy,
fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino,
quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
C.sub.2-4 alkynyls include, without limitation, ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
[0039] By "C.sub.2-6 heterocyclyl" is meant a stable 5- to
7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic
ring which is saturated partially unsaturated or unsaturated
(aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3
or 4 heteroatoms independently selected from N, O, and S and
including any bicyclic group in which any of the above-defined
heterocyclic rings is fused to a benzene ring. The heterocyclyl
group may be substituted or unsubstituted. Exemplary substituents
include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide,
hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,
disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl,
and carboxyl groups. The nitrogen and sulfur heteroatoms may
optionally be oxidized. The heterocyclic ring may be covalently
attached via any heteroatom or carbon atom which results in a
stable structure, e.g., an imidazolinyl ring may be linked at
either of the ring-carbon atom positions or at the nitrogen atom. A
nitrogen atom in the heterocycle may optionally be quaternized.
Preferably when the total number of S and O atoms in the
heterocycle exceeds 1, then these heteroatoms are not adjacent to
one another. Heterocycles include, without limitation, 1H-indazole,
2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,
4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,
b-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, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl,
phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
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. Preferred 5 to 10
membered heterocycles include, but are not limited to, pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl,
benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl,
1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl,
benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and
isoquinolinyl. Preferred 5 to 6 membered heterocycles include,
without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl,
thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
[0040] By "C.sub.6-12 aryl" is meant an aromatic group having a
ring system comprised of carbon atoms with conjugated .pi.
electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon
atoms. Aryl groups may optionally include monocyclic, bicyclic, or
tricyclic rings, in which each ring desirably has five or six
members. The aryl group may be substituted or unsubstituted.
Exemplary substituents include alkyl, hydroxy, alkoxy, aryloxy,
sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl,
hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted
amino, disubstituted amino, and quaternary amino groups.
[0041] By "C.sub.7-14 alkaryl" is meant an alkyl substituted by an
aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl)
having from 7 to 14 carbon atoms.
[0042] By "C.sub.3-10 alkcycloalkyl" is meant an alkyl substituted
by a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl) having from 3-10 carbon
atoms.
[0043] By "C.sub.3-10 alkheterocyclyl" is meant an alkyl
substituted heterocyclic group having from 3 to 10 carbon atoms in
addition to one or more heteroatoms (e.g., 3-furanylmethyl,
2-furanylmethyl, 3-tetrahydrofuranylmethyl, or
2-tetrahydrofuranylmethyl).
[0044] By "C.sub.1-7 heteroalkyl" is meant a branched or unbranched
alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in
addition to 1, 2, 3 or 4 heteroatoms independently selected from
the group consisting of N, O, S, and P. Heteroalkyls include,
without limitation, tertiary amines, secondary amines, ethers,
thioethers, amides, thioamides, carbamates, thiocarbamates,
hydrazones, imines, phosphodiesters, phosphoramidates,
sulfonamides, and disulfides. A heteroalkyl may optionally include
monocyclic, bicyclic, or tricyclic rings, in which each ring
desirably has three to six members. The heteroalkyl group may be
substituted or unsubstituted. Exemplary substituents include
alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl,
fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino,
quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and
carboxyl groups. Examples of C.sub.1-7 heteroalkyls include,
without limitation, methoxymethyl and ethoxyethyl.
[0045] By "halide" is meant bromine, chlorine, iodine, or
fluorine.
[0046] By "fluoroalkyl" is meant an alkyl group that is substituted
with a fluorine atom.
[0047] By "perfluoroalkyl" is meant an alkyl group consisting of
only carbon and fluorine atoms.
[0048] By "carboxyalkyl" is meant a chemical moiety with the
formula --(R)--COOH, wherein R is selected from C.sub.1-7 alkyl,
C.sub.2-7 alkenyl, C.sub.2-7 alkynyl, C.sub.2-6 heterocyclyl,
C.sub.6-12 aryl, C.sub.7-14 alkaryl, C.sub.3-10 alkheterocyclyl, or
C.sub.1-7 heteroalkyl.
[0049] By "hydroxyalkyl" is meant a chemical moiety with the
formula --(R)--OH, wherein R is selected from C.sub.1-7 alkyl,
C.sub.2-7 alkenyl, C.sub.2-7 alkynyl, C.sub.2-6 heterocyclyl,
C.sub.6-12 aryl, C.sub.7-14 alkaryl, C.sub.3-10 alkheterocyclyl, or
C.sub.1-7 heteroalkyl.
[0050] By "alkoxy" is meant a chemical substituent of the formula
--OR, wherein R is selected from C.sub.1-7 alkyl, C.sub.2-7
alkenyl, C.sub.2-7 alkynyl, C.sub.2-6 heterocyclyl, C.sub.6-12
aryl, C.sub.7-14 alkaryl, C.sub.3-10 alkheterocyclyl, or C.sub.1-7
heteroalkyl.
[0051] By "aryloxy" is meant a chemical substituent of the formula
--OR, wherein R is a C.sub.6-12 aryl group.
[0052] By "alkylthio" is meant a chemical substituent of the
formula --SR, wherein R is selected from C.sub.1-7 alkyl, C.sub.2-7
alkenyl, C.sub.2-7 alkynyl, C.sub.2-6 heterocyclyl, C.sub.6-12
aryl, C.sub.7-14 alkaryl, C.sub.3-10 alkheterocyclyl, or C.sub.1-7
heteroalkyl.
[0053] By "arylthio" is meant a chemical substituent of the formula
--SR, wherein R is a C.sub.6-12 aryl group.
[0054] By "quaternary amino" is meant a chemical substituent of the
formula --(R)--N(R')(R'')(R''').sup.+, wherein R, R', R'', and R'''
are each independently an optionally substituted alkyl,
heteroalkyl, alkaryl, alkcycloalkyl, alkheterocyclyl, alkenyl,
alkynyl, heteroaryl, or aryl group as described herein. R may be an
alkyl group linking the quaternary amino nitrogen atom, as a
substituent, to another moiety. The nitrogen atom, N, is covalently
attached to four carbon atoms of the alkyl, heteroalkyl, alkaryl,
alkcycloalkyl, alkheterocyclyl, alkenyl, alkynyl, heteroaryl,
and/or aryl groups, resulting in a positive charge at the nitrogen
atom.
[0055] By "charged moiety" is meant a moiety which gains a proton
at physiological pH thereby becoming positively charged (e.g.,
ammonium, guanidinium, or amidinium) or a moiety that includes a
net formal positive charge without protonation (e.g., quaternary
ammonium). The charged moiety may be either permanently charged or
transiently charged.
[0056] As used herein, the term "parent" refers to a channel
blocking compound which can be modified by quaternization or
guanylation of an amine nitrogen atom present in the parent
compound. The quaternized and guanylated compounds are derivatives
of the parent compound. The guanidyl derivatives described herein
are presented in their uncharged base form. These compounds can be
administered either as a salt (i.e., an acid addition salt) or in
their uncharged base form, which undergoes protonation in situ to
form a charged moiety.
[0057] By "therapeutically effective amount" means an amount
sufficient to produce a desired result, for example, the reduction
or elimination of neurogenic inflammation in a patient (e.g., a
human) suffering from a condition, disease, or illness that is
caused wholly or in part by neurogenic inflammation (e.g. asthma,
arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis,
gastritis, migraine headache, psoriasis, rhinitis, rosacea, or
sunburn).
[0058] Other features and advantages of the invention will be
apparent from the following detailed description, and from the
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0059] FIG. 1 is a graph showing the effect of intravenous QX-314
(0.4 mg/kg) on the edema elicited by injection of complete Freund's
adjuvant (CFA) in the rat hindpaw determined by measuring the total
volume of the hindpaw by plethysmography. The degree of swelling
produced by injection of CFA is reduced by administration of QX-314
reflecting reduction in neurogenic edema resulting from the
blockade of nociceptors by QX314. QX-314 by itself has no effect
different from administration of saline.
[0060] FIG. 2 shows the inhibition of voltage-dependent calcium
channel current in a dorsal root ganglion (DRG) neuron by
N-methyl-verapamil applied in the presence of capsaicin to open
TRPV1 channels. Entry of the drug into the cell, and its blocking
action, depends on applying the drug in the presence of capsaicin
to activate the TRPV1 channels present in the neuronal
membrane.
DETAILED DESCRIPTION OF THE INVENTION
[0061] The present invention features methods and kits for the
treatment of neurogenic inflammation by administering a
positively-charged, voltage-gated ion channel inhibitor. In
embodiments of the invention, the positively-charged, voltage-gated
ion channel inhibitor is administered alone or in combination with
a TRP channel agonist such as capsaicinoid (e.g. capsaicin),
mustard oil, or a "caine" drug (e.g., amylocaine, articaine,
benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine,
cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine),
etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine,
meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine,
procaine (novacaine), proparacaine, propoxycaine, risocaine,
ropivacaine, tetracaine (amethocaine), or trimecaine).
[0062] Voltage-gated ion channels in pain-sensing neurons are
currently of great interest in developing strategies to treat
neurogenic inflammation. Blocking voltage-dependent sodium channels
in nociceptors can reduce or eliminate neurogenic inflammation by
preventing activation of nociceptor peripheral terminals and the
release of pro-inflammatory chemicals. A limitation in designing
small organic molecules that inhibit sodium channels or calcium
channels is that they must be active when applied externally to the
target cell. The vast majority of such externally-applied molecules
are hydrophobic and can pass through cell membranes. Accordingly,
such molecules will enter all cells and thus exhibit no selectivity
for affecting only nociceptors.
[0063] Some inhibitors, such as the quarternary ammonium derivative
QX-314, are membrane-impermeant and are only effective when present
inside the nociceptor cell, and thus must pass through the cell
membrane via a channel or receptor, such as a transient receptor
potential ion channel (TRP channels, e.g., TRPAV1, TRPA1, TRPM8,
and P2X(2/3)), in order to produce an effect. Under normal
circumstances, most TRP channels in nociceptors are not active but
require a noxious thermal, mechanical, or chemical stimulus to
activate them. For example, TRP channels in nociceptors can be
activated by an exogenous TRP ligand (i.e. TRP agonist) such as
capsaicin, which opens the TRPV1 channel. Thus, one approach to
selectively targeting nociceptors is to co-administer the
membrane-impermeant ion channel inhibitor with an exogenous TRP
ligand that permits passage of the inhibitor through the TRP
channel into the cell. In addition to capsaicin, the exogenous TRP
ligand can also be another capsaicinoid, mustard oil, or lidocaine.
In another example, TRP channels may be active in response to
exogenous irritant activators such as inhaled acrolein from smoke
or chemical warfare agents such as tear gas.
[0064] Under certain circumstances, TRP channels can be activated
in the absence of exogenous TRP activators/ligands by endogenous
inflammatory activators that are generated by tissue damage,
infection, autoimmunity, atopy, ischemia, hypoxia, cellular stress,
immune cell activation, immune mediator production, and oxidative
stress. Under such conditions, endogenous molecules (e.g., protons,
lipids, and reactive oxygen species) can activate TRP channels
expressed on nociceptors, allowing membrane-impermeant,
voltage-gated ion channel blockers to gain access to the inside of
the nociceptor through the endogenously-activated TRP channels.
Endogenous inflammatory activators of TRP channels include, for
example, prostaglandins, nitric oxide (NO), peroxide
(H.sub.2O.sub.2), cysteine-reactive inflammatory mediators like
4-hydroxynonenal, endogenous alkenyl aldehydes, endocannabinoids,
and immune mediators (e.g., interleukin 1 (IL-1), nerve growth
factor (NGF), and bradykinin).
[0065] Thus, the inventors have discovered that
membrane-impermeant, positively-charged inhibitors of voltage-gated
ion channels (e.g., quarternary ammonium derivatives, such as
QX-314), alone or in combination with an exogenous TRP ligand, can
be used to selectively target nociceptors in order to effectively
treat (e.g., eliminate or alleviate) neurogenic inflammation in a
patient (e.g., a human).
[0066] The invention is described in more detail below.
Neurogenic Inflammation
[0067] Inflammation is a complex set of responses to harmful
stimuli that results in localized redness, swelling, and pain.
Inflammation has two components, one driven by antigens and
mediated by immune cells (immune-mediated inflammation) and one
mediated by the nervous system (neurogenic inflammation).
Neurogenic inflammation results from the efferent functions of
pain-sensing neurons (nociceptors), wherein neuropeptides and other
chemicals that are pro-inflammatory mediators are released from the
peripheral terminals of the nociceptors when they are activated.
This release process is mediated by calcium influx and exocytosis
of vesicles, and the pro-inflammatory mediators include substance
P, neurokinin A and B (collectively known as tachykinins), and
calcitonin gene-related peptide (CGRP).
[0068] The release of peripheral terminal chemicals stimulate a
variety of inflammatory responses. First, the release of substance
P can result in an increase in capillary permeability such that
plasma proteins leak from the intravascular compartment into the
extracellular space (plasma extravasation), causing edema. This can
be detected as a wheal (a firm, elevated swelling of the skin)
which is one component of a triad of inflammatory responses--wheal,
red spot, and flare--known as the Lewis triple response. Second,
the release of CGRP causes vasodilation, leading to increased blood
flow. This can be detected as a flare, which is another component
of the Lewis triple response.
[0069] Substance P also has a pro-inflammatory action on immune
cells (e.g. macrophages, T-cells, mast cells, and dendritic cells)
via their neurokinin-1 (NK1) receptor. This effect has been
documented in allergic rhinitis, gastitis, and colitis, and
represents an interface between the neurogenic and immune-mediated
components of inflammation. Substance P released from one
nociceptor may also act on NK1 receptors on neighboring nociceptors
to sensitize or activate them, causing a spread of activation and
afferent/efferent function.
[0070] These efferent functions of nociceptors can be triggered by:
1) Direct activation of a nociceptor terminal by a peripheral
adequate stimulus applied to the terminal (e.g. a pinch); 2)
Indirect antidromic activation of a non-stimulated nociceptor
terminal by the axon reflex, wherein action potential input from
one terminal of a nociceptor, upon reaching a converging axonal
branch point in the periphery, results in an action potential
traveling from the branch point down to the peripheral terminal of
a non-stimulated terminal; and 3) Activation as a result of
activity in nociceptor central terminals in the CNS traveling to
the periphery (e.g., primary afferent depolarization of central
terminals produced by GABA can be sufficient to initiate action
potentials traveling the "wrong way").
Neurogenic Inflammatory Disorders
[0071] In certain disorders, neurogenic inflammation contributes to
the peripheral inflammation elicited by tissue injury, autoimmune
disease, infection, and exposure to irritants in soft tissue, skin,
the respiratory system, joints, the urogenital and GI tract, the
liver, and the brain. Neurogenic inflammatory disorders include
asthma, rhinitis, conjunctivitis, arthritis, colitis, contact
dermatitis, diabetes, eczema, cystitis, gastritis, migraine
headache, psoriasis, rhinitis, rosacea, and sunburn, pancreatitis,
chronic cough, chronic rhinosinusistis, traumatic brain injury,
polymicrobial sepsis, tendinopathies chronic urticaria, rheumatic
disease, acute lung injury, exposure to irritants, inhalation of
irritants, pollutants, or chemical warfare agents, as described
herein.
[0072] Asthma
[0073] Asthma is a chronic respiratory disorder that is
characterized by airway obstruction, bronchial hyperresponsiveness,
and bronchial inflammation. Asthma can be induced by a variety of
stimuli, including natural inhaled allergens (e.g. dust mites,
pollen, and mold), household organic compounds (e.g. soap, perfume,
shampoo, creams, and lotions), medications, industrial chemicals,
food allergies, exercise, hormonal changes, and psychological
stress. Patients who chronically suffer from asthma experience
episodes of hypersensitivity to such stimuli where the bronchi
contract in spasms. During an asthma episode, inflammation of the
airways causes bronchoconstriction and excess mucus production,
making it difficult for the patient to breathe.
[0074] Cells responsible for airway hyperresponsiveness and
obstruction include sensory and motor neurons as well as epithelial
and smooth muscle cells. Asthma is the result of a complex set of
interactions between these cells and the immune system,
particularly the T-helper-2 cells which control the inflammatory
process. There is growing evidence that communication between
immune cells and neurons can be mediated by neurophilins, which are
produced in increased concentrations by immune cells that enter the
airways in an asthmatic episode. Neurophilins modify the functional
activity of neuronal function, leading to altered neuropeptide and
tachykinin production that results in neurogenic inflammation.
(Renz et al. Prog. Brain Res. 146:325, 2004.) TRPV1 and TRPA1
channels also contribute to the neurogenic component of allergic
asthma as well as cough and rhinitis.
[0075] Arthritis
[0076] Arthritis is a group of conditions involving inflammation
and damage to the joints of the body. Arthritis can have many
causes, including physical trauma and aging (osteoarthritis),
autoimmune disease (rheumatoid arthritis and psoriatic arthritis),
infection (septic arthritis), and gout (gouty arthritis).
[0077] Rheumatoid arthritis (RA) is a chronic, systemic
inflammatory disorder that principally affects the joints
(synovitis), characterized by destruction of articular cartilage
and bending/stiffness of the joints (ankylosis), and which leads to
pain and substantial loss of mobility. RA can also cause
inflammation in the skin, lungs, and kidneys. About 1% of the world
population develops rheumatoid arthritis, with women having a
three-fold higher risk than men.
[0078] The causes of autoimmunity in RA are not fully understood,
but evidence suggests the involvement of abnormal B- and T-cell
activation and the release of TNF and other cytokines. There has
also been a causal link between cigarette smoke and RA. Studies
have suggested that neurogenic inflammation makes an important
contribution to the pathogenesis of joint pain in RA. See, for
example, Levine et al. (J. Immunol. 135:843s, 1985), which showed
that the severity of joint injury in RA is correlated with a
greater local concentration of substance P.
[0079] Colitis
[0080] Colitis is a group of chronic autoimmune disorders
characterized by inflammation of the colon. Symptoms of colitis
include pain, tenderness of the abdomen, fatigue, rapid weight
loss, ulcers (ulcerative colitis), and gastrointestinal bleeding.
Colitis can also be triggered by many foods, including alcohol,
caffeine, dairy products, spicy foods, nuts, seeds, meats, refined
sugar, and raw vegetables. It is known that neurogenic mechanisms
are important to the inflammatory processes in colitis. For
example, studies have shown that induced colitis inflammation in
mice can be mitigated using NK-1 and CGRP receptor antagonists.
(Nguyen et al. Canadian J. Phys. Pharm. 81:920, 2003.)
[0081] Contact Dermatitis
[0082] Contact dermatitis is the local irritation of superficial
regions of the skin caused by contact with irritants or allergens.
In North America, the most common causes of allergic contact
dermatitis are plants such as poison ivy and poison oak. Common
causes of irritant contact dermatitis are chemicals such as harsh
soaps, detergents, and cleaning products. Symptoms of contact
dermatitis include rash, blisters, wheals, hives, and burning itch.
The role of neurogenic inflammation in contact dermatitis has been
discussed, for example, in Guy, AMA Arch. Derm. Syphilol. 66:1,
1952.
[0083] Gastritis
[0084] Gastritis refers to a collection of disorders which induce
inflammation of the stomach lining. Gastritis can be caused by
excessive alcohol consumption, prolonged use of NSAIDs such as
aspirin or ibuprofen, and chronic infection by bacteria (primarily
Helicobacter pylori). Certain autoimmune disorders can also cause
gastritis. Symptoms include internal bleeding, pain (especially in
the upper abdomen), vomiting, and bloating. Gastritis can also lead
to increased risk of stomach cancer.
[0085] Migraine
[0086] Migraine is a neurological disorder, more common in women
than in men, that is characterized by headache, nausea, and altered
perception. Migraine proceeds in several phases: 1) a prodrome
phase that includes fatigue, food craving, neck stiffness, altered
mood, and constipation or diarrhea; 2) an aura phase that includes
disturbances of vision consisting of white/multicolored flashes of
lights or dazzling lines, feelings of "pins-and-needles" in the
hand and arm, auditory/olfactory hallucinations, vertigo,
tingling/numbness of the face, and hypersensitivity to touch; 3) a
pain phase that includes a throbbing headache accompanied by
nausea, vomiting, blurred vision, nasal stuffiness, diarrhea, and
local edema; and 4) a postdrome phase including fatigue and
feelings of "hangover."
[0087] There are many theories about the cause of migraine. Among
these is the theory that certain nerves, when irritated, release
the pro-inflammatory mediators such as substance P that lead to
neurogenic inflammation and associated pain.
[0088] Rhinitis
[0089] Rhinitis, known commonly as the running nose, is a disorder
involving irritation and inflammation of internal nasal mucous
membranes. Rhinitis is characterized by the generation of large
amounts of mucus, producing running nose, nasal congestion, and
post-nasal drip. According to recent estimates, more than 50
million people in the U.S. alone suffer from rhinitis yearly.
Rhinitis is categoried into infective rhinitis (caused by bacterial
infection), nonallergic rhinitis (caused by hormones, drugs, and
foods), and allergic rhinitis (caused by immune reactions to
allergens, e.g. hayfever). The role of neurogenic inflammation in
the pathogenesis of rhinitis is similar to that of asthma, where
environmental substances enhance the immune response, leading to
downstream release of substance P from neurons.
[0090] Cystitis
[0091] Cystitis is inflammation of the urinary bladder. There are
several types of cystitis, including traumatic cystitis,
interstitial cystitis, eosinophilic cystitis, radiation cystitis,
and hemorrhagic cystitis. Interstitial cystitis, also known as
painful bladder syndrome, is a disorder characterized by urination
pain, urinary frequency, urgency, and pressure in the bladder.
Unlike traumatic cystitis, interstitial cystitis has not been shown
to be caused by bacterial infection. The cause of interstitial
cystitis is unknown but has been proposed to involve neurogenic
inflammation. For example, animal studies have shown that
interstitial cystitis is correlated with both central and
peripheral neural upregulation (Nazif et al., Urology 69:24-33
(2007)), and that acute bladder injury resulted in a significant
increase in the release of substance P and CGRP (Lucioni et al.,
BJU Int. 101:366-370, 2008).
[0092] Additional Neurogenic Inflammatory Disorders
[0093] Additional neurogenic inflammatory disorders will be known
to those skilled in the art, and include, but are not limited to
sunburn, inflammatory conditions with a neurogenic component such
as inflammation of blood vessels, eczema, rosacea, psoriasis,
gingivitis, pancreatitis, chronic cough, chronic rhinosinusistis,
traumatic brain injury, polymicrobial sepsis, tendinopathies
chronic urticaria, acute lung injury, exposure to irritants,
inhalation of irritants, pollutants, or chemical warfare
agents.
Inhibitors of Voltage-Gated Ion Channels
[0094] Inhibitors of voltage-gated ion channels that are suitable
for use in the methods and kits of the invention for the treatment
of neurogenic inflammation are desirably positively-charged,
hydrophilic compounds. In one embodiment, the compounds are
permanently charged (i.e., have a charge that is not transient). In
another embodiment, the compounds are transiently charged. Suitable
inhibitors of voltage-gated sodium channels include, but are not
limited to, QX-314, N-methyl-procaine (QX-222), N-octyl-guanidine,
9-aminoacridine, and pancuronium. Suitable inhibitors of
voltage-gated calcium channels include, but are not limited to,
D-890 (quaternary methoxyverapamil), CERM 11888 (quaternary
bepridil), N-methyl-verapamil, N-methylgallopamil,
N-methyl-devapamil, dodecyltrimethylammonium, and other compounds
as described herein (see, e.g., charged derivatives of the
compounds described in Tables 1 and 2).
[0095] Additionally, there are many known inhibitors of
voltage-gated ion channels that would be of a suitable size to be
useful in the methods of the invention (e.g., from about 100 to
4,000 Da, 100 to 3,000 Da, 100 to 2,000 Da, 150 to 1,500 Da, or
even 200 to 1,200 Da) and that have amine groups, or can be
modified to contain amine groups, that can be readily modified to
be charged (e.g., as positively-charged quarternary amines, or as
transiently charged, e.g., guanylated, compounds). Such inhibitors
include, but are not limited to, riluzole, mexilitine, phenyloin,
carbamazepine, procaine, tocainide, prilocaine, diisopyramide,
bencyclane, quinidine, bretylium, lifarizine, lamotrigine,
flunarizine, articaine, bupivicaine, mepivicaine, and
fluspirilene.
[0096] Compounds that can be used in the methods and kits of the
invention for the treatment of inflammation include compounds of
formulas I-X, below.
##STR00011##
[0097] In formula I, each of R.sup.1A, R.sup.1B, and R.sup.1C is,
independently, selected from H, halogen, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, OR.sup.1H, NR.sup.1IR.sup.1J,
NR.sup.1KC(O)R.sup.1L, S(O)R.sup.1M, SO.sub.2R.sup.1NR.sup.1O,
SO.sub.2NR.sup.1PR.sup.1Q, SO.sub.3R.sup.1R, CO.sub.2R.sup.1S,
C(O)R.sup.1T, and C(O)NR.sup.1UR.sup.1V; and each of R.sup.1H,
R.sup.1I, R.sup.1K, R.sup.1L, R.sup.1M, R.sup.1N, R.sup.1O,
R.sup.1P, R.sup.1Q, R.sup.1R, R.sup.1S, R.sup.1T, R.sup.1U, and
R.sup.1V is, independently, selected from H, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl
X.sup.1 is selected from --CR.sup.1WR.sup.1X--, --NR.sup.1YC(O)--,
--OC(O)--, --SC(O)--, --C(O)NR.sup.1Z--, --CO.sub.2--, and
--OC(S)--; and each of R.sup.1W, R.sup.1Y, and R.sup.1Z is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; R.sup.1D is selected
from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; and each of R.sup.1E, R.sup.1F, and R.sup.1G
is, independently, selected from C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; or R.sup.1D
and R.sup.1G together complete a heterocyclic ring having at least
one nitrogen atom. In a preferred embodiment, X.sup.1 is
--NHC(O)--. Exemplary compounds of formula I include methylated
quaternary ammonium derivatives of anesthetic drugs, such as
N-methyl lidocaine, N,N-dimethyl prilocaine, N,N,N-trimethyl
tocainide, N-methyl etidocaine, N-methyl ropivacaine, N-methyl
bupivacaine, N-methyl levobupivacaine, N-methyl mepivacaine. These
derivatives can be prepared using methods analogous to those
described in Scheme 1. Compounds of formula I include QX-314 (CAS
21306-56-9) and QX-222 (CAS 21236-55-5) (below).
##STR00012##
[0098] In formula II, each of R.sup.2A, R.sup.2B, and R.sup.2C is,
independently, selected from H, halogen, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, OR.sup.2I, NR.sup.2JR.sup.2K,
NR.sup.2LC(O)R.sup.2M, S(O)R.sup.2N, SO.sub.2R.sup.2OR.sup.2P,
SO.sub.2NR.sup.2QR.sup.2R, SO.sub.3R.sup.2S, CO.sub.2R.sup.2T,
C(O)R.sup.2U, and C(O)NR.sup.2VR.sup.2W; and each of R.sup.2I,
R.sup.2J, R.sup.2K, R.sup.2L, R.sup.2M, R.sup.2N, R.sup.2O,
R.sup.2P, R.sup.2Q, R.sup.2R, R.sup.2S, R.sup.2T, R.sup.2U,
R.sup.2V, R.sup.2W is, independently, selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4
heteroalkyl; X.sup.2 is selected from --CR.sup.2XR.sup.2Y--,
--NR.sup.2ZC(O)--, --OC(O)--, --SC(O)--, --C(O)NR.sup.2AA--,
--CO.sub.2--, and --OC(S)--; and each of R.sup.2X, R.sup.2Y,
R.sup.2Z, and R.sup.2AA is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; R.sup.2D is selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4
heteroalkyl; R.sup.2E is H or C.sub.1-4 alkyl; and each of
R.sup.2F, R.sup.2G, and R.sup.2H is, independently, selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; or R.sup.2F and R.sup.2G together complete a
heterocyclic ring having two nitrogen atoms. Where R.sup.2F and
R.sup.2G form a heterocyclic ring having two nitrogen atoms, the
resulting guanidine group is, desirably, selected from
##STR00013##
where R.sup.2H is H or CH.sub.3. Desirably, R.sup.2F and R.sup.2G
combine to form an alkylene or alkenylene of from 2 to 4 carbon
atoms, e.g., ring systems of 5, 6, and 7-membered rings. In a
preferred embodiment, X.sup.2 is --NHC(O)--. Exemplary compounds of
formula II include N-guanidyl derivatives (e.g., --C(NH)NH.sub.2
derivatives) of anesthetic drugs, such as desethyl-N-guanidyl
lidocaine, N-guanidyl prilocaine, N-guanidyl tocainide,
desethyl-N-guanidyl etidocaine, desbutyl-N-guanidyl ropivacaine,
desbutyl-N-guanidyl bupivacaine, desbutyl-N-guanidyl
levobupivacaine, desmethyl-N-guanidyl mepivacaine. These
derivatives can be prepared using methods analogous to those
described in Schemes 2-5.
[0099] The guanidyl derivatives described herein (e.g., the
compounds of formula II) are presented in their uncharged base
form. These compounds can be administered either as a salt (i.e.,
an acid addition salt) or in their uncharged base form, which
undergoes protonation in situ to form a charged moiety.
[0100] The synthesis of parent drugs of formulas I and II are
described in the literature. See, for example, U.S. Pat. No.
2,441,498 (synthesis of lidocaine), U.S. Pat. No. 3,160,662
(synthesis of prilocaine), DE Patent No. 2235745 (synthesis of
tocainide), DE Patent No. 2162744 (synthesis of etidocaine), PCT
Publication No. WO85/00599 (synthesis of ropivacaine), U.S. Pat.
No. 2,955,111 (synthesis of bupivacaine and levobupivacaine), and
U.S. Pat. No. 2,799,679 (synthesis of mepivacaine).
##STR00014##
[0101] In formula III, n=0-3 and m=0-3, with (n+m)=0-6; each of
R.sup.3A, R.sup.3B, and R.sup.3C is, independently, selected from
H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.2-4 heteroalkyl, OR.sup.3L, NR.sup.3MR.sup.3N,
NR.sup.3OC(O)R.sup.3P, S(O)R.sup.3Q, SO.sub.2R.sup.3RR.sup.3S,
SO.sub.2NR.sup.3TR.sup.3U, SO.sub.3R.sup.3V, CO.sub.2R.sup.3W,
C(O)R.sup.3X, and C(O)NR.sup.3YR.sup.3Z; and each of R.sup.3L,
R.sup.3M, R.sup.3N, R.sup.3O, R.sup.3P, R.sup.3Q, R.sup.3R,
R.sup.3S, R.sup.3T, R.sup.3U, R.sup.3V, R.sup.3W, R.sup.3X,
R.sup.3Y, R.sup.3Z is, independently, selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4
heteroalkyl; Y.sup.3 is selected from --CR.sup.3AAR.sup.3AB--,
--NR.sup.3ACC(O)--, --OC(O)--, --SC(O)--, --C(O)NR.sup.3AD--,
--CO.sub.2--, and --OC(S)--; and each of R.sup.3AA, R.sup.3AB,
R.sup.3AC, and R.sup.3AD is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; each of R.sup.3D, R.sup.3E, R.sup.3F, and
R.sup.3G is, independently, selected from H, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl,
C.sub.2-6 heterocyclyl, C.sub.6-12 aryl, C.sub.7-14 alkaryl, and
C.sub.3-10 alkheterocyclyl; each of R.sup.3H, R.sup.3J, and
R.sup.3K is, independently, selected from C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl.
The quaternary nitrogen in formula III is identified herein as N'.
Exemplary compounds of formula III include methylated quaternary
ammonium derivatives of anesthetic drugs, such as N'-methyl
procaine, N'-methyl proparacaine, N'-methyl allocain, N'-methyl
encainide, N'-methyl procainamide, N'-methyl metoclopramide,
N'-methyl stovaine, N'-methyl propoxycaine, N'-methyl
chloroprocaine, N',N'-dimethyl flecainide, and N'-methyl
tetracaine. These derivatives can be prepared using methods
analogous to those described in Scheme 1.
##STR00015##
[0102] In formula IV, n=0-3 and m=0-3, with (n+m)=0-6; each of
R.sup.4A and R.sup.4B is, independently, selected from H, halogen,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, OR.sup.4L, NR.sup.4MR.sup.4N, NR.sup.4OC(O)R.sup.4P,
S(O)R.sup.4Q, SO.sub.2R.sup.4RR.sup.4SSO.sub.2NR.sup.4TR.sup.4U,
SO.sub.3R.sup.4V, CO.sub.2R.sup.4W, C(O)R.sup.4X, and
C(O)NR.sup.4YR.sup.4Z; and each of R.sup.4L, R.sup.4MR.sup.4N,
R.sup.4O, R.sup.4P, R.sup.4Q, R.sup.4R, R.sup.4S, R.sup.4T,
R.sup.4U, R.sup.4V, R.sup.4W, R.sup.4X, R.sup.4Y, and R.sup.4Z is
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; Y.sup.4 is selected
from --CR.sup.4AAR.sup.4AB--, --NR.sup.4ACC(O)--, --OC(O)--,
--SC(O)--, --C(O)NR.sup.4AD--, --CO.sub.2--, and --OC(S)--; and
each of R.sup.4AA, R.sup.4AB, R.sup.4AC, and R.sup.4AD is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; each of R.sup.4C,
R.sup.4D, R.sup.4E, and R.sup.4F is, independently, selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.2-6 heterocyclyl, C.sub.6-12 aryl, C.sub.7-14
alkaryl, and C.sub.3-10 alkheterocyclyl; X.sup.4 is selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
NR.sup.4JR.sup.4K; each of R.sup.4J and R.sup.4K (is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; and each of R.sup.4G,
R.sup.4H, and R.sup.4I is, independently, selected from C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4
heteroalkyl. The quaternary nitrogen in formula IV is identified
herein as N''. Exemplary compounds of formula III include
methylated quaternary ammonium derivatives of anesthetic drugs,
such as N'',N'',N''-trimethyl procaine, N'',N'',N''-trimethyl
proparacaine, N'',N'',N''-trimethyl procainamide,
N'',N'',N''-trimethyl metoclopramide, N'',N'',N''-trimethyl
propoxycaine, N'',N'',N''-trimethyl chloroprocaine,
N'',N''-dimethyl tetracaine, N'',N'',N''-trimethyl benzocaine, and
N'',N'',N''-trimethyl butamben. These derivatives can be prepared
using methods analogous to those described in Scheme 1.
##STR00016##
[0103] In formula V, n=0-3 and m=0-3, with (n+m)=0-6; each of
R.sup.5A, R.sup.5B, and R.sup.5C is, independently, selected from
H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.2-4 heteroalkyl, OR.sup.5M, NR.sup.5NR.sup.5O,
NR.sup.5PC(O)R.sup.5Q, S(O)R.sup.5R, SO.sub.2R.sup.5SR.sup.5T,
SO.sub.2NR.sup.5UR.sup.5V, SO.sub.3R.sup.5W, CO.sub.2R.sup.5X,
C(O)R.sup.5Y, and C(O)NR.sup.5ZR.sup.5AA; and each of R.sup.5M,
R.sup.5N, R.sup.5O, R.sup.5P, R.sup.5Q, R.sup.5R, R.sup.5S,
R.sup.5T, R.sup.5U, R.sup.5V, R.sup.5W, R.sup.5X, R.sup.5Y,
R.sup.5Z, and R.sup.5AA is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; Y.sup.5 is selected from
--CR.sup.5ABR.sup.5AC--, --NR.sup.5ADC(O)--, --OC(O)--, --SC(O)--,
--C(O)NR.sup.5AE--, --CO.sub.2--, and --OC(S)--; and each of
R.sup.5AB, R.sup.5AC, R.sup.5AD, and R.sup.5AE is, independently,
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, and C.sub.2-4 heteroalkyl; each of R.sup.5D, R.sup.5E,
R.sup.5F, and R.sup.5G is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.2-6 heterocyclyl, C.sub.6-12 aryl, C.sub.7-14
alkaryl, and C.sub.3-10 alkheterocyclyl; R.sup.5H is H or C.sub.1-4
alkyl; and each of R.sup.5J, R.sup.5K, and R.sup.5L is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; or R.sup.5J and
R.sup.5K together complete a heterocyclic ring having two nitrogen
atoms. Where R.sup.5J and R.sup.5K form a heterocyclic ring having
two nitrogen atoms, the resulting guanidine group is, desirably,
selected from
##STR00017##
where R.sup.5L is H or CH.sub.3. Desirably, R.sup.5J and R.sup.5K
combine to form an alkylene or alkenylene of from 2 to 4 carbon
atoms, e.g., ring systems of 5, 6, and 7-membered rings. The
guanylated nitrogen in formula V is identified herein as N'.
Exemplary compounds of formula V include N-guanidyl derivatives
(e.g., --C(NH)NH.sub.2 derivatives) of anesthetic drugs, such as
such as desethyl-N'-guanidyl procaine, desethyl-N'-guanidyl
proparacaine, desethyl-N'-guanidyl allocain, desmethyl-N'-guanidyl
encainide, desethyl-N'-guanidyl procainamide, desethyl-N'-guanidyl
metoclopramide, desmethyl-N'-guanidyl stovaine,
desethyl-N'-guanidyl propoxycaine, desethyl-N'-guanidyl
chloroprocaine, N'-guanidyl flecainide, and desethyl-N'-guanidyl
tetracaine. These derivatives can be prepared using methods
analogous to those described in Schemes 2-5.
##STR00018##
[0104] In formula VI, n=0-3 and m=0-3, with (n+m)=0-6; each of
R.sup.6A and R.sup.6B is, independently, selected from H, halogen,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, OR.sup.6K, NR.sup.6LR.sup.6M, NR.sup.6NC(O)R.sup.6O,
S(O)R.sup.6P, SO.sub.2R.sup.6QR.sup.6R, SO.sub.2NR.sup.6SR.sup.6T,
SO.sub.3R.sup.6U, CO.sub.2R.sup.6V, C(O)R.sup.6W, and
C(O)NR.sup.6XR.sup.6Y; and each of R.sup.6K, R.sup.6L, R.sup.6M,
R.sup.6N, R.sup.6O, R.sup.6P, R.sup.6Q, R.sup.6R, R.sup.6S,
R.sup.6T, R.sup.6U, R.sup.6V, R.sup.6W, R.sup.6X, and R.sup.6Y is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; Y.sup.6 is selected
from --CR.sup.6ZR.sup.6AA--, --NR.sup.6ABC(O)--, --OC(O)--,
--SC(O)--, --C(O)NR.sup.6AC, --CO.sub.2--, and --OC(S)--; and each
of R.sup.6Z, R.sup.6AA, R.sup.6AB, and R.sup.6AC is, independently,
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, and C.sub.2-4 heteroalkyl; each of R.sup.6C, R.sup.6D,
R.sup.6E, and R.sup.6F is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.2-6 heterocyclyl, C.sub.6-12 aryl, C.sub.7-14
alkaryl, and C.sub.3-10 alkheterocyclyl; X.sup.6 is selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
NR.sup.6ADR.sup.6AE; each of R.sup.6AD and R.sup.6AE is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; R.sup.6G is H or
C.sub.1-4 alkyl; and each of R.sup.6H, R.sup.6I, and R.sup.6J is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; or R.sup.6H and
R.sup.6I together complete a heterocyclic ring having two nitrogen
atoms. Where R.sup.6H and R.sup.6I form a heterocyclic ring having
two nitrogen atoms, the resulting guanidine group is, desirably,
selected from
##STR00019##
where R.sup.6J is H or CH.sub.3. Desirably, R.sup.6H and R.sup.6I
combine to form an alkylene or alkenylene of from 2 to 4 carbon
atoms, e.g., ring systems of 5, 6, and 7-membered rings. The
guanylated nitrogen in formula V is identified herein as N''.
Exemplary compounds of formula VI include N-guanidyl derivatives
(e.g., --C(NH)NH.sub.2 derivatives) of anesthetic drugs, such as
such as N''-guanidyl procaine, N''-guanidyl proparacaine,
N''-guanidyl procainamide, N''-guanidyl metoclopramide,
N''-guanidyl propoxycaine, N''-guanidyl chloroprocaine,
N''-guanidyl tetracaine, N''-guanidyl benzocaine, and N''-guanidyl
butamben. These derivatives can be prepared using methods analogous
to those described in Schemes 2-5.
[0105] The synthesis of parent drugs of formulas III-VI are
described in the literature. See, for example, U.S. Pat. No.
812,554 (synthesis of procaine), Clinton et al., J. Am. Chem. Soc.
74:592 (1952) (synthesis of proparacaine), U.S. Pat. No. 2,689,248
(synthesis of propoxycaine), Hadicke et al., Pharm. Zentralh.
94:384 (1955) (synthesis of chloroprocaine), U.S. Pat. No.
1,889,645 (synthesis of tetracaine), Salkowski et al., Ber. 28:1921
(1895) (synthesis of benzocaine), Brill et al., J. Am. Chem. Soc.
43:1322 (1921) (synthesis of butamben), U.S. Pat. No. 3,931,195
(synthesis of encainide), Yamazaki et al., J. Pharm. Soc. Japan
73:294 (1953) (synthesis of procainamide), U.S. Pat. No. 3,177,252
(synthesis of metoclopramide), U.S. Pat. No. 3,900,481 (synthesis
of flecainide), and Fourneau et al., Bull. Sci. Pharmacol. 35:273
(1928) (synthesis of stovaine), each of which is hereby
incorporated by reference.
##STR00020##
[0106] In formula VII, n=0-3 and m=0-3, with (n+m)=0-6; each of
R.sup.7A, R.sup.7B, and R.sup.7C is, independently, selected from
H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.2-4 heteroalkyl, OR.sup.7L, NR.sup.7MR.sup.7N,
NR.sup.7OC(O)R.sup.7P, S(O)R.sup.7Q, SO.sub.2R.sup.7RR.sup.7S,
SO.sub.2NR.sup.7TR.sup.7U, SO.sub.3R.sup.7V, CO.sub.2R.sup.7W,
C(O)R.sup.7X, and C(O)NR.sup.7YR.sup.7Z; and each of R.sup.7L,
R.sup.7M, R.sup.7N, R.sup.7O, R.sup.7P, R.sup.7Q, R.sup.7R,
R.sup.7S, R.sup.7T, R.sup.7U, R.sup.7V, R.sup.7W, R.sup.7X,
R.sup.7Y, and R.sup.7Z is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; X.sup.7 is selected from
--CR.sup.7AAR.sup.7AB--, NR.sup.7AC(O)--, --OC(O)--, --SC(O)--,
--C(O)NR.sup.7AD--, --CO.sub.2--, and --OC(S)--; and each of
R.sup.7AA, R.sup.7AB, R.sup.7AC, and R.sup.7AD is, independently,
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, and C.sub.2-4 heteroalkyl; each of R.sup.7D, R.sup.7E,
R.sup.7F, and R.sup.7G is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.2-6 heterocyclyl, C.sub.6-12 aryl, C.sub.7-14
alkaryl, and C.sub.3-10 alkheterocyclyl; and each of R.sup.7H,
R.sup.7I, and R.sup.7K is, independently, selected from C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4
heteroalkyl. In a preferred embodiment, X.sup.7 is --C(O)NH--.
Exemplary compounds of formula VII include methylated quaternary
ammonium derivatives of anesthetic drugs, such as N'-methyl
dibucaine. These derivatives can be prepared using methods
analogous to those described in Scheme 1.
##STR00021##
[0107] In formula VIII, n=0-3 and m=0-3, with (n+m)=0-6; each of
R.sup.8A, R.sup.8B, and R.sup.8C is, independently, selected from
H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.2-4 heteroalkyl, OR.sup.8L, NR.sup.8MR.sup.8N,
NR.sup.8OC(O)R.sup.8P, S(O)R.sup.8Q, SO.sub.2R.sup.8RR.sup.8S,
SO.sub.2NR.sup.8TR.sup.8U, SO.sub.3R.sup.8V, CO.sub.2R.sup.8W,
C(O)R.sup.8X, and C(O)NR.sup.8YR.sup.8Z; and each of R.sup.8L,
R.sup.8M, R.sup.8N, R.sup.8O, R.sup.8P, R.sup.8Q, R.sup.8R,
R.sup.8S, R.sup.8T, R.sup.8U, R.sup.8V, R.sup.8W, R.sup.8X,
R.sup.8Y, and R.sup.8Z is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and
C.sub.2-4 heteroalkyl; X.sup.8 is selected
from --CR.sup.8AAR.sup.8AB--, --NR.sup.8ACC(O)--, --OC(O)--,
--SC(O)--, --C(O)NR.sup.8AD, --CO.sub.2--, and --OC(S)--; and each
of R.sup.8AA, R.sup.8AB, R.sup.8AC, and R.sup.8AD is independently,
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, and C.sub.2-4 heteroalkyl; each of R.sup.8D, R.sup.8E,
R.sup.8F, and R.sup.8G is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.2-6 heterocyclyl, C.sub.6-12 aryl, C.sub.7-14
alkaryl, and C.sub.3-10 alkheterocyclyl; R.sup.8H is H or C.sub.1-4
alkyl; and each of R.sup.8I, R.sup.8J, and R.sup.8K is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; or R.sup.8I and
R.sup.8J together complete a heterocyclic ring having two nitrogen
atoms. Where R.sup.8I and R.sup.8J form a heterocyclic ring having
two nitrogen atoms, the resulting guanidine group is, desirably,
selected from
##STR00022##
where R.sup.8K is H or CH.sub.3. Desirably, R.sup.8I and R.sup.8J
combine to form an alkylene or alkenylene of from 2 to 4 carbon
atoms, e.g., ring systems of 5, 6, and 7-membered rings. The
guanylated nitrogen in formula V is identified herein as N'. In a
preferred embodiment, X.sup.8 is --C(O)NH--. Exemplary compounds of
formula VIII include N-guanidyl derivatives (e.g., --C(NH)NH.sub.2
derivatives) of anesthetic drugs, such as such as
desethyl-N-guanidyl dibucaine. These derivatives can be prepared
using methods analogous to those described in Schemes 2-5.
##STR00023##
[0108] In formula IX, n=0-6; each of R.sup.9A, R.sup.9B, R.sup.9C,
R.sup.9D, and R.sup.9E is independently, selected from H, halogen,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, OR.sup.9I,
NR.sup.9JR.sup.9K, NR.sup.9LC(O)R.sup.9M, S(O)R.sup.9N,
SO.sub.2R.sup.9OR.sup.9P, SO.sub.2NR.sup.9QR.sup.9R,
SO.sub.3R.sup.9S, CO.sub.2R.sup.9T, C(O)R.sup.9U, and
C(O)NR.sup.9VR.sup.9W; and each of R.sup.9I, R.sup.9J, R.sup.9K,
R.sup.9L, R.sup.9M, R.sup.9N, R.sup.9O, R.sup.9P, R.sup.9Q,
R.sup.9R, R.sup.9S, R.sup.9T, R.sup.9U, R.sup.9V, and R.sup.9W is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl; X.sup.9 is selected
from --CR.sup.9XR.sup.9Y--, --O--, --S--, and --NR.sup.9Z--; and
each of R.sup.9X, R.sup.9Y, and R.sup.9Z is, independently,
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, and C.sub.2-4 heteroalkyl; Y.sup.9 is
NR.sup.9AANR.sup.9ABNR.sup.9AC or NR.sup.9ADZ.sup.9; each of
R.sup.9AA, R.sup.9AB, and R.sup.9AC is, independently, selected
from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl;
R.sup.9AD is H or C.sub.1-4 alkyl; Z.sup.9 is
##STR00024##
and each of R.sup.9F, R.sup.9G, and R.sup.9H is, independently,
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl, or R.sup.9F and R.sup.9G together complete a heterocyclic
ring having two nitrogen atoms. Where R.sup.9F and R.sup.9G form a
heterocyclic ring having two nitrogen atoms, the resulting
guanidine group is, desirably, selected from
##STR00025##
where R.sup.9H is H or CH.sub.3. Desirably, R.sup.9F and R.sup.9G
combine to form an alkylene or alkenylene of from 2 to 4 carbon
atoms, e.g., ring systems of 5, 6, and 7-membered rings. In a
preferred embodiment, X.sup.9.dbd.--O--. Exemplary compounds of
formula IX include N-guanidyl derivatives (e.g., --C(NH)NH.sub.2
derivatives), such as N-guanidyl fluoxetine, and methylated
quaternary ammonium derivatives, such as N,N-dimethyl fluoxetine.
These derivatives can be prepared using methods analogous to those
described in Schemes 1-5.
##STR00026##
[0109] In formula X, W.sub.3 is O, NH, NCH.sub.2R.sup.10J,
NC(O)CH.sub.2R.sup.10J, CHCH.sub.2R.sup.10J, C.dbd.CHR.sup.10J, or
C.dbd.CHR.sup.10K; W.sub.1-W.sub.2 is S, O, OCHR.sup.10K,
SCHR.sup.10K, N.dbd.CR.sup.10K, CHR.sup.10L--CHR.sup.10K, or
CR.sup.10L.dbd.CR.sup.10K; each of R.sup.10A, R.sup.10B, R.sup.10C,
R.sup.10D, R.sup.10E, R.sup.10F, R.sup.10G, and R.sup.10H is,
independently, selected from H, OH, halide, C.sub.1-4 alkyl, and
C.sub.2-4 heteroalkyl; R.sup.10J is CH.sub.2CH.sub.2X.sup.10A or
CH(CH.sub.3)CH.sub.2X.sup.10A; R.sup.10L is H or OH; R.sup.10K is
H, OH, or the group:
##STR00027##
X.sup.10A is NR.sup.10MR.sup.10NR.sup.10P, or NR.sup.10QX.sup.10C;
X.sup.10B is NR.sup.10RR.sup.10S, or NX.sup.10C; each of R.sup.10M,
R.sup.10N, R.sup.10P, R.sup.10R, and R.sup.10S is, independently,
selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, and C.sub.2-4 heteroalkyl, or R.sup.10R, and R.sup.10S
together complete a heterocyclic ring having at least one nitrogen
atom; R.sup.10Q is H or C.sub.1-4 alkyl; X.sup.10C is
##STR00028##
and each of R.sup.10T, R.sup.10U, and R.sup.10V is, independently,
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl, or R.sup.10T and R.sup.10V together complete a
heterocyclic ring having two nitrogen atoms. Where R.sup.10T and
R.sup.10V form a heterocyclic ring having two nitrogen atoms, the
resulting guanidine group is, desirably, selected from
##STR00029##
where R.sup.10U is H or CH.sub.3. Desirably, R.sup.10T and
R.sup.10V combine to form an alkylene or alkenylene of from 2 to 4
carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings.
Exemplary compounds of formula X include N-guanidyl derivatives
(e.g., --C(NH)NH.sub.2 derivatives) and methylated quaternary
ammonium derivatives. N-guanidyl derivatives of formula X include,
without limitation, N-guanidyl amoxapine, desmethyl-N-guanidyl
trimipramine, desmethyl-N-guanidyl dothiepin, desmethyl-N-guanidyl
doxepin, desmethyl-N-guanidyl amitriptyline, N-guanidyl
protriptyline, N-guanidyl desipramine, desmethyl-N-guanidyl
clomipramine, desmethyl-N-guanidyl clozapine, desmethyl-N-guanidyl
loxapine, N-guanidyl nortriptyline, desmethyl-N-guanidyl
cyclobenzaprine, desmethyl-N-guanidyl cyproheptadine,
desmethyl-N-guanidyl olopatadine, desmethyl-N-guanidyl
promethazine, desmethyl-N-guanidyl trimeprazine,
desmethyl-N-guanidyl chlorprothixene, desmethyl-N-guanidyl
chlorpromazine, desmethyl-N-guanidyl propiomazine,
desmethyl-N-guanidyl prochlorperazine, desmethyl-N-guanidyl
thiethylperazine, desmethyl-N-guanidyl trifluoperazine,
desethyl-N-guanidyl ethacizine, and desmethyl-N-guanidyl
imipramine. Methylated quaternary ammonium derivatives of formula X
include, without limitation, N,N-dimethyl amoxapine, N-methyl
trimipramine, N-methyl dothiepin, N-methyl doxepin, N-methyl
amitriptyline, N,N-dimethyl protriptyline, N,N-dimethyl
desipramine, N-methyl clomipramine, N-methyl clozapine, N-methyl
loxapine, N,N-dimethyl nortriptyline, N-methyl cyclobenzaprine,
N-methyl cyproheptadine, N-methyl olopatadine, N-methyl
promethazine, N-methyl trimeprazine, N-methyl chlorprothixene,
N-methyl chlorpromazine, N-methyl propiomazine, N-methyl
moricizine, N-methyl prochlorperazine, N-methyl thiethylperazine,
N-methyl fluphenazine, N-methyl perphenazine, N-methyl
flupenthixol, N-methyl acetophenazine, N-methyl trifluoperazine,
N-methyl ethacizine, and N-methyl imipramine. These derivatives can
be prepared using methods analogous to those described in Schemes
1-5.
[0110] Other ion channel blockers that can contain an amine
nitrogen which can be guanylated or quaternized as described herein
include, without limitation, orphenadrine, phenbenzamine, bepridil,
pimozide, penfluridol, flunarizine, fluspirilene, propiverine,
disopyramide, methadone, tolterodine, tridihexethyl salts,
tripelennamine, mepyramine, brompheniramine, chlorpheniramine,
dexchlorpheniramine, carbinoxamine, levomethadyl acetate,
gallopamil, verapamil, devapamil, tiapamil, emopamil, dyclonine,
pramoxine, lamotrigine, fendiline, mibefradil, gabapentin,
amiloride, diltiazem, nifedipine, nimodipine, nitrendipine,
cocaine, mexiletine, propafenone, quinidine, oxethazaine,
articaine, riluzole, bencyclane, lifarizine, and strychnine. Still
other ion channel blockers can be modified to incorporate a
nitrogen atom suitable for quaternization or guanylation. These ion
channel blockers include, without limitation, fosphenyloin,
ethotoin, phenyloin, carbamazepine, oxcarbazepine, topiramate,
zonisamide, and salts of valproic acid.
[0111] Examples of these channel blockers, including still other
derivatives that can be quaternized or guanylated according to the
methods described herein are provided in Table 1.
TABLE-US-00001 TABLE 1 No. Channel Blocker Exemplary References 1
orphenadrine U.S. Pat. No. 2,567,351 (see, e.g., the compounds of
Examples 1-6 and the formula described at col.1, lines 10-24). U.S.
Pat. No. 2,991,225 (see, e.g., the structure shown at col. 1, line
25). 2 phenbenzamine (RP- Passalacqua et al., "Structure and 2339;
Antergan .RTM.), Classification of H.sub.1-Antihistamines and
Overview of Their Activities," in Histamine and H1-antihistamines
in Allergic Disease, F.E.R. Simons, Ed., Informa Health Care
(2002). 3 bepridil U.S. Pat. No. 3,962,238 (see, e.g., Formulas I-V
and compounds 1-6 of Table 1). US RE30577 4 pimozide See, e.g.,
Janssen et al., Arzneimittel- Forsch. 18: 261, 279, 282 (1968), and
Journal of Neuroscience, 22(2): 396-403 (2002) 5 penfluridol U.S.
Pat. No. 3,575,990 (see, e.g., the compounds of Formula (I), claims
1-7, and Examples I-XXXIII). 6 flunarizine U.S. Pat. No. 3,773,939
(see, e.g., Formula (I) and the compound described at col. 5, line
40). 7 fluspirilene U.S. Pat. No. 3,238,216 (see, e.g., the
compounds recited in any of claims 1- 34). 8 propiverine DD 106643
9 disopyramide U.S. Pat. No. 3,225,054 (see, e.g., the compounds of
Examples 1-15 and claims 1-3) 10 methadone DE711069 U.S. Pat. No.
2,983,757 11 tolterodine U.S. Pat. No. 5,382,600 (see, e.g.,
Formula (I), the compounds described at col.3, lines 20-39, in
Table 1, and in claims 1-7) 12 tridihexethyl salts U.S. Pat. No.
2,913,494 (see, e.g., col. 1, lines 15-22) 13 tripelennamine U.S.
Pat. No. 2,502,151 (see, e.g., Formula (I) and the compounds
recited in claims 1-13) 14 mepyramine U.S. Pat. No. 2,502,151
(pyrilamine) 15 brompheniramine U.S. Pat. No. 2,567,245 (see, e.g.,
the formula described at col. 1, lines 30-45, the compounds of
Examples I-XXI, and the compounds recited in claims 1-15) U.S. Pat.
No. 2,676,964 (see, e.g., the formula described at col.1, lines
5-28, the compounds of Examples I-XLIV, and the compounds recited
in claims 1- 14) U.S. Pat. No. 3,061,517 (see, c.g., the formula at
col.1, lines 49-67, and the compounds described at col. 2, lines
17- 19, col. 2, lines 40-43, col. 4, lines 2-7, and claims 1-6) 16
chlorpheniramine U.S. Pat. No. 2,567,245 (see, e.g., the 17
dexchlorpheniramine formula described at col. 1, lines 30-45, the
compounds of Examples I-XXI, and the compounds recited in claims
1-15) U.S. Pat. No. 2,676,964 (see, e.g., the formula described at
col.1, lines 5-28, the compounds of Examples I-XLIV, and the
compounds recited in claims 1- 14) U.S. Pat. No. 3,061,517 (see,
e.g., the formula at col.1, lines 49-67, and the compounds
described at col. 2, lines 17- 19, col. 2, lines 40-43, col. 4,
lines 2-7, and claims 1-6)U.S. Pat. No. 2,766,174 (see, e.g., the
formula described at col. 1, lines 41-72) 18 carbinoxamine U.S.
Pat. No. 2,606,195 (see, e.g., the formula described at col. 1,
lines 7-24, Examples I-VIII, and in claims 1-3) U.S. Pat. No.
2,800,485 GB 905993 19 levomethadyl acetate Pohland et al., J. Am.
Chem. Soc. 71: 460 (1949) 20 gallopamil U.S. Pat. No. 3,261,859
(see, e.g., Formula (I), Examples 1-28, and claims 1-19) Theodore
et al., J. Org. Chem. 52: 1309 (1987) 21 verapamil U.S. Pat. No.
3,261,859 (see, e.g., Formulas (I) and (IV), Examples 1-28, and
claims 1-19) 22 devapamil Godfraind, Calcium Channel Blockers, 23
tiapamil Birkhauser Verlag (January 2004). 24 emopamil 25 dycloninc
Pofft, Chem. Tech. (Berlin) 4: 241 (1952) 26 pramoxine U.S. Pat.
No. 2,870,151 (see, e.g., the formula described at col.1, lines
18-25, and the compounds of Examples I-XII and claims 1-13). 27
lamotrigine EP21121 U.S. Pat. No. 4,602,017 (see, e.g., Formulas
(I)-(III) and the compounds described at col. 2, line 63-col. 3,
line 12, Examples 1-5, and claims 1-2) 28 mibefradil U.S. Pat. No.
4,808,605 (see, e.g., Formula I described at col.1, lines 10- 33
and the compounds described at col. 3, line 58-col. 7, line 6,
Examples 1-41, and claims 1-15). 29 gabapentin U.S. Pat. No.
4,024,175 (see, e.g., Formula (I) described at col.1, lines 5- 17,
Examples 1-12, and claims 1-11) 30 amiloride U.S. Pat. No.
3,313,813 (see, e.g., the compounds described at col. 1, line 13-
col.2, line 55, Examples 1-205, and claims 1-31) 31 diltiazem U.S.
Pat. No. 3,562,257 (see, e.g., Formula (I) described at col.1,
lines 39- 64, and the compounds described at col. 2, lines 15-30,
Tables 1-3, and claims 1- 43) U.S. Pat. No. 4,552,695 (see, e.g.,
the compound of Formula (I)) 32 nifedipine U.S. Pat. No. 3,485,847
(see, e.g., the Formula described at col. 1, line 40-col. 2, line
6, the compounds of Examples 1-6, and claims 1-27) 33 nimodipine
U.S. Pat. No. 3,799,934 (see, e.g., the Formula described at col.
1, lines 39- 69, the compounds described at col. 4, line 50-col. 5,
line 16, Examples 1-53, and claims 1-13) 34 nitrendipine 35
mexiletine U.S. Pat. No. 3,954,872 (see, e.g., Formula (I)
described at col.1, lines 14- 35, and the compounds of Examples 1-
6 and claims 1-4) 36 propafenone DE2001431 (see, e.g., claims 1-4)
37 quinidine Turner et al., The Alkaloids, Vol. 3, 1- 63 (1953)
Mason et al., Ann. N.Y. Acad. Sci. 432: 162-176 (1984) 38
oxethazaine U.S. Pat. No. 2,780,646 (see, e.g., the formula
described at col. 1, lines 18-42, and the compounds of Examples
1-14 and claims 1-8) 39 articaine Becker et al., Anesth Prog.
53(3): 98- 109 (Fall 2006) 40 riluzole U.S. Pat. No. 4,370,338
(see, e.g., the compound described at col. 1, line 15) 41
bencyclane HU 151865 42 lifarizine Grauert et al., J. Med. Chem.
45(17): 3755-3764 (2002) 43 strychnine Makarevich et al.,
"Quaternary salts of alkaloids,"Vol. 42, pages 473-476, Chemistry
of Natural Compounds, Springer New York: 2006. 44 fendiline U.S.
Pat. No. 3,262,977 (see, e.g., Formula (I), Examples 1-9, and the
compounds of claims 1-9)
Calcium-Channel Blockers
[0112] Exemplary cationic calcium channel blockers include D-890,
CERM 11888, N-methyl-verapamil, N-methylgallopamil,
N-methyl-devapamil, and dodecyltrimethylammonium. Other exemplary
compounds include any charged derivative, e.g., a quarternary amine
derivative, of verapamil, gallopamil, devapamil, diltiazem,
fendiline, mibefradil, terpene compounds (e.g., sesquiterpenes)
such as those described in Norman et al. Agricultural and
Biological Chemistry 49(10):2893-8 (1985), and other inhibitors of
calcium channels (see, for example, Triggle, European Journal of
Pharmacology, 375:311-325 (1999), Eller et al., British Journal of
Pharmacology, 130:669-677 (2000), and Yamamoto et al., Current
Topics in Medicinal Chemistry, 9:377-395 (2009), which can be
prepared according to the methods described herein.
[0113] For example, Yamamoto et al. provides the following N-type
calcium channel blockers (Table 2), which can be modified (e.g.,
quaternized or guanylated) according to the methods described
herein.
TABLE-US-00002 TABLE 2 No. Channel Blocker Exemplary References 45
##STR00030## Yamamoto et al., Bioorg. Med. Chem.14:5333-5339
(2006). 46 ##STR00031## Yamamoto et al., Bioorg. Med. Chem. Lett.
16:798-802 (2006). 47 ##STR00032## Yamamoto et al., Bioorg. Med.
Chem. Lett. 18:4813- 4815 (2008). 48 ##STR00033## See, e.g.,
WO08143263 and EP2149560 (e.g., Formula (I), the compounds of
Tables 6- 35, 43-110, 126-127, and the compounds of claims 1-6) 49
##STR00034## Miller et al., Soc. Neurosci. Abstr. 25(Part 2):896.3
(1999) 50 ##STR00035## WO0236567 (see, e.g., formulas I-IV, the
compounds of Table 2 (Examples 1-111), and claims 1-5) 51
##STR00036## Zhang et al., Eur. J. Pharmacol. 587:24-47 (2008) 52
##STR00037## Baell et al., Bioorg. Med. Chem. 12:4025-4037 (2004)
53 ##STR00038## Yamamoto et al., 22.sup.nd National Meeting of
American Chemical Society, American Chemical Scoiety: Washington,
DC: Chicago, IL 2001; Kaneda et al, Soc. Neurosci. Abstr. 27:332.15
(2001); Niidome et al., Soc. Neurosci. Abstr. 27:332.14 (2001); and
Suzuki et al., Bioorg. Med. Chem. Lett. 13:919-922 (2003). 54
E-2051 Kaneda, Soc. Neurosci. Abstr. 28:490.1 (2002) 55
##STR00039## WO07110449 (see, e.g., Formulas I-XIII, the compounds
described at Paragraphs [0181]-[0183] and Examples 1-14, and claims
1- 72) 56 ##STR00040## WO06040181 (see, e.g., Formulas I-X, the
compounds described at Paragraphs [0105]-[0109] and Examples 1-37,
and in claims 1-56) 57 ##STR00041## WO07118853 (see, e.g., Formulas
I-XIII, the compounds described at Paragraph [0320] and Examples
1-19, and the compounds of claims 1-165) 58 ##STR00042## WO07085357
(see, e.g., Formulas I-VII, the compounds described at Paragraphs
[0065]-[0067], Examples 1-6, and claims 1- 16) 59 ##STR00043##
WO07028638 (see, e.g., Formulas I-XXVI, the compounds described at
Paragraphs [0119]-[0123], Examples 1-24, and claims 1-20 60
##STR00044## WO07118854 (see, e.g., Formulas I-VII and the
compounds of Examples 1-11 and claims 1-36) 61 ##STR00045##
WO08008398 (see, e.g., Formulas I, I', I'', II, and II'; Examples
1-377, and claims 1-7) 62 ##STR00046## WO08150447 (see, e.g.,
Formulas I, I', I'', and the compounds of Examples 1- 135 and
claims 1-5 63 ##STR00047## Knutsen et al., Bioorg. Med. Chem. Lett.
17:662-667 (2007) 64 ##STR00048## O'Neill, Brain Res. 888:138- 149
(2001); Hicks et al., Eur. J. Pharmacol. 408:241-248 (2000) 65
##STR00049## WO07084394 (see, e.g., the compounds of Formulas I and
Ia-Ig, and the compounds of Examples 1-11 and claims 1 and 2) 66
##STR00050## WO08066803 (see, e.g., Formulas I and II, the compound
of Example 1, and claims 1-11) 67 ##STR00051## WO07075524 (see,
e.g., Formulas (I), (Ia)-(Ie), the compounds of Examples 1- 184,
and claims 1-16) 68 ##STR00052## WO08133867 (see, e.g., Formulas
(I) and (II), the compounds of Examples 1-163, and claims 1-16) 69
##STR00053## WO01045709 (see, e.g., Formula (1), the compounds of
Example 4, and claims 24- 38) WO06105670 (see, e.g., Formula (1),
the compounds described at Paragraphs [0065] and [0066], and claims
1-13) 70 ##STR00054## WO04089377 (see, e.g., Formula (1), Examples
1-5, original claims 1-13, and amended claims 1-17) 71 ##STR00055##
WO07071035 (see, e.g., Formula (1), the compounds of Examples 1-18,
and claims 20-35) 72 ##STR00056## WO08043183 (see, e.g., Formulas
(1) and (2), the compounds of Examples 1-16, and claims 16-28) 73
##STR00057## WO04089922 (see, e.g., Formulas (1)-(4), the compounds
of Examples 1-9, claims 1-17, and the compounds of Figure 1) 74
##STR00058## WO04105750 (see, e.g., Formulas (1)-(8), the compounds
of Examples 1-10, claims 1-23, and Figure 1) 75 ##STR00059##
WO08031227 (see, e.g., Formulas (1) and (2), the compounds of
Examples 1-20, and claims 21-37) 76 ##STR00060## Tatsumi et al.,
Jpn. J. Pharmacol. 73:193 (1997); Aoki et al., Brain Res.
890:162-169 (2001); Katsumata et al., Brain Res. 969:168-174
(2003); Tamura et al., Brain Res. 890:170-176 (2001); Shi et al.,
J. Thorac. Cardiovasc. Surg. 129:364- 371 (2005); Small, IDrugs,
3:460-465 (2000); Suma et al., Jpn. J. Pharmacol. 73:193 (1997);
Shimidzu et al., Naunyn Schmiedebergs Arch. Pharamcol. 355:601-608
(1997); and Suma et al., Eur. J. Pharmacol. 336:283-290 (1997). 77
##STR00061## Seko et al, Bioorg. Med. Chem. Lett. 11:2067-2070
(2001) 78 ##STR00062## Seko et al., Bioorg. Med. Chem. 11:1901-1913
(2003). Seko et al., Bioorg. Med. Chem. Lett. 12:915-918 (2002) 79
##STR00063## Seko et al., Bioorg. Med. Chem. Lett. 12:2267-2269
(2002) 80 ##STR00064## Menzler et al., Bioorg. Med. Chem. Lett.
10:345-347 (2000) 81 ##STR00065## Malone et al., 217.sup.th
National Meeting of the American Chemical Society, American
Chemical Society: Washington DC: Anaheim CA 1999; Hu et al., J.
Med. Chem. 42:4239-4249 (1999) 82 ##STR00066## Hu et al., Bioorg.
Med. Chem. Lett. 9:907-912 (1999) 83 ##STR00067## Hu et al.,
Bioorg. Med. Chem. Lett. 9:2151-2156 (1999) Ryder et al., Bioorg.
Med. Chem. Lett. 9:1813-1818 (1999) 84 ##STR00068## Hu et al.,
Bioorg. Med. Chem. Lett. 9:1121-1126 (1999) 85 ##STR00069## Bennett
et al., Pain 33:87-107 (1988) 86 ##STR00070## Hu et al., Bioorg.
Med. Chem. 8:1203-1212 (2000) 87 ##STR00071## Hu et al., Bioorg.
Med. Chem. 8:1203-1212 (2000) 88 ##STR00072## Hu et al., J. Med.
Chem. 42:4239-4249 (1999) 89 ##STR00073## Schelkun et al., Bioorg.
Med. Chem. Lett. 9:2447-2452 (1999). 90 ##STR00074## Yuen et al.,
Bioorg. Med. Chem. Lett. 8:2415-2418 (1998) 91 ##STR00075## Song et
al., J. Med. Chem. 43:3474-3477 (2000) 92 ##STR00076## WO07125398
(see, e.g., Formula (I), the compounds of Examples 1-29, and claims
1-9) 93 ##STR00077## WO08124118 (see, e.g., Formula I-VI, the
compounds of Paragraphs [0129] and Examples 1-5, and claims 1- 42)
94 ##STR00078## Campbell et al., Eur. J. Pharmacol. 401:419-428
(2000) 95 ##STR00079## Teodori et al., J. Med. Chem. 47:6070-6081
(2004) 96 ##STR00080## Teodori et al., J. Med. Chem. 47:6070-6081
(2004) 97 ##STR00081## Schroeder et al., Mol. Divers. 8:127-134
(2004). 98 ##STR00082## WO06030211 (see, e.g., Formula (I), the
compounds described at page 9, line 17- page 15, line 12, Examples
1- 99, and claims 1-12)
[0114] Farnesyl Amine Compounds
[0115] Compounds having a structure according to Formula (XI) can
also be used in the invention as calcium channel blockers.
##STR00083##
where each R.sup.11A, R.sup.11B, and R.sup.11C is selected,
independently, from H or C.sub.1-4 alkyl, and where 0, 1, 2, or 3
of the dashed bonds represents a carbon-carbon double bond (i.e.,
compounds of Formula (XI) can include 0, 1, 2, or 3 double bonds),
provided that when 2 or 3 carbon-carbon double bonds are present,
the double bonds are not adjacent to one another. Compounds that
include 0, 1, or 2 double bonds can be prepared according to
methods known in the literature, e.g., partial or total
hydrogenation of the parent triene.
[0116] In some embodiments, compounds of Formula (XI) can be
represented by the following formula (XI-A),
##STR00084##
where each R.sup.11A, R.sup.11B, R.sup.11C, and X is according to
Formula (XI), and where each dashed bond represents an optional
carbon-carbon double bond. Still other farnesyl amine compounds can
include those compounds that have a structure according to Formula
(XI-B),
##STR00085##
where each R.sup.11A, R.sup.11B, R.sup.11C, and X is according to
Formula (XI).
[0117] Exemplary compounds of Formula (XI) include
##STR00086##
[0118] Cysteine-Derived Compounds
[0119] Amino acid derivatives, e.g., those described in U.S. Pat.
No. 7,166,590 or in Seko et al., Bioorg. Med. Chem. Lett.
11(16):2067-2070 (2001), each of which is herein incorporated by
reference, can also be used in the invention. For example,
compounds having a structure according to Formula (XII) can be
N-type calcium channel blockers.
##STR00087##
wherein each of R.sup.12A, R.sup.12B, R.sup.12C, and R.sup.12D is
independently, selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl,
C.sub.3-40 alkcycloalkyl, and C.sub.3-10 alkheterocyclyl; or
R.sup.12A and R.sup.12B together complete a heterocyclic ring
having at least one nitrogen atom, n is an integer between 1-5,
each of R.sup.12E and R.sup.12F is, independently, selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4
heteroalkyl, C.sub.7-14 alkaryl, C.sub.3-10 alkcycloalkyl, or
C.sub.3-10 alkheterocyclyl, and X is any pharmaceutically
acceptable anion.
[0120] Exemplary compounds of Formula (XII) include
##STR00088##
[0121] Flunarizine and Related Compounds
[0122] Still other compounds that can be used in the invention are
charged derivatives of flunarizine and related compounds (see,
e.g., U.S. Pat. Nos. 2,883,271 and 3,773,939, as well as Zamponi et
al., Bioorg. Med. Chem. Lett. 19: 6467 (2009)), each of which is
hereby incorporated by reference. For example, compounds according
to Formulas (XIII-A), (XIII-B), and (XIII-C) can be prepared
according to, e.g., Zamponi et al., and used in the invention,
##STR00089##
[0123] where each R.sup.13A-R.sup.13J and R.sup.13O-R.sup.13T is
selected, independently, from H, halogen, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2A alkynyl, C.sub.2-4 heteroalkyl,
C.sub.7-14 alkaryl, C.sub.3-10 alkcycloalkyl, and C.sub.3-10
alkheterocyclyl, OR.sup.13AA, NR.sup.13ABR.sup.13AC,
NR.sup.13ADC(O)R.sup.13AE, S(O)R.sup.13AF,
SO.sub.2R.sup.13AGR.sup.13AH, SO.sub.2NR.sup.13AIR.sup.13AJ,
SO.sub.3R.sup.13AK, CO.sub.2R.sup.13AL, C(O)R.sup.13AM, and
C(O)NR.sup.13ANR.sup.13AO; and each of R.sup.13AA-R.sup.13AO is,
independently, selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.2-4 heteroalkyl;
[0124] each R.sup.13K, R.sup.13L, R.sup.13M, and R.sup.13N is,
independently, H or C.sub.1-4 alkyl, or R.sup.13K and R.sup.13L, or
R.sup.13M and R.sup.13N, combine to form C.dbd.O, or R.sup.13K and
R.sup.13M combine to form C.dbd.C;
[0125] R.sup.13Y is H or C.sub.1-4 alkyl;
[0126] R.sup.13Z and R.sup.13Z' are, independently, selected from
H, halogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl, C.sub.3-10
alkcycloalkyl, and C.sub.3-10 alkheterocyclyl; and
[0127] X.sup.- is any pharmaceutically acceptable anion.
[0128] Exemplary compounds according to Formulas (XIII-A)-(XIII-C)
include
##STR00090##
Mibefradil Derivatives
[0129] Derivatives of mibrefradil, such as those described in U.S.
Pat. No. 4,808,605, hereby incorporated by reference can also be
used. Exemplary mibrefadil derivatives include compounds of Formula
(XIV),
##STR00091##
where
[0130] n is an integer between 0-5;
[0131] R.sup.14A is heterocyclyl (e.g., a heteroaryl such as
benzimidazole),
[0132] each of R.sup.14B, R.sup.14C, R.sup.14D, and R1.sup.4E is,
independently, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.2-4 heteroalkyl, C.sub.7-14 alkaryl, C.sub.3-10
alkcycloalkyl, and C.sub.3-10 alkheterocyclyl; and
[0133] R.sup.14F is selected from H, halogen, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-4 heteroalkyl,
C.sub.7-14 alkaryl, C.sub.3-10 alkcycloalkyl, and C.sub.3-10
alkheterocyclyl, OR.sup.14G, NR.sup.14HR.sup.14I,
NR.sup.14JC(O)R.sup.14K, S(O)R.sup.14L, SO.sub.2R.sup.14MR.sup.14N,
SO.sub.2NR.sup.14OR.sup.14P, SO.sub.3R.sup.14Q, CO.sub.2R.sup.14R,
C(O)R.sup.14S, and C(O)NR.sup.14TR.sup.14V; and each of
R.sup.14G-R.sup.13AO is, independently, selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.2-4
heteroalkyl.
[0134] An exemplary compound of Formula (XIV) is
##STR00092##
[0135] 4-Piperidinylaniline Compounds
[0136] Charged derivatives of 4-piperidinylaniline compounds (e.g.,
Compounds (86)-(88) of Table 2) can be prepared according to
methods known in the literature and described herein. For example,
charged N-alkyl derivatives (e.g., N-methyl) of Compounds (86)-(88)
can be prepared and used in the compositions, methods, and kits
described herein.
[0137] Still other channel blockers that can be quaternized or
guanylated according to the methods described herein are described,
for example, in PCT Publication No. WO 2004/093813 (see, e.g.,
Tables 5, 6, and 8), which is herein incorporated by reference. For
example, the channel blockers shown in Table 3 can be quaternized
or guanylated as described herein.
TABLE-US-00003 TABLE 3 No. Channel Blocker Exemplary References 105
Isradipine 106 Nickel Chloride 107 A-53930A JP 08208690 108 AE-0047
Watanidipine EP 00424901 dihydrochloride 109 AGN-190604
Inflammation, 19(2): 261-275 (1995) 110 AGN-190744 EP372940 111
AH-1058 European Journal of Pharmacology, 398(1): 107-112 (2000)
112 AHR 5360C European Journal of Pharmacology 146(2-3): 215-22
(1988) 113 AHR 12234 Archives Internationales de Pharamcodynamie et
de Therapie 301: 131-50 (1989) 114 AHR-12742 ZA 08604522 115
AHR-16303B Journal of Cardiovascular Pharmacology 17(1): 134-44
(1991) 116 AHR-16462B Drug Development Research, 22(3): 259-271
(1991) 117 AIT 110 118 AIT 111 119 AJ 2615 WO 8601203 A1 120
AJ-3941 Arzneimittel Forschung 46(6): 567-71 (1996) 121 (+)-alismol
JP 04077420 A2 122 AM-336 (synthetic version of WO9954350 CVID
marine cone snail venom) 123 AM 543 124 amlodipine U.S. Pat. No.
4,572,902 125 S-(-)amlodipine GB 2233974 A1 126 AN 132 EP 196648
127 animpamil LU 42668 EP 64158 A1 128 antioquine (alkaloid from
stem Journal of natural Products bark) 55(9): 1281-6 (1992) 129
AP-1067 IDDB 268934 130 AQ-AH-208 CH 645628 A 131 AR 12456
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atosiban EP 00112809 134 azenidipine CS 905 EP 88266922 135 B 84439
EP 240828 136 barnidipine (derivative of U.S. Pat. No. 4,220,649
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EP 9206 139 BAY-T-7207 140 BBR-2160 EP 28204 A2 141 BDF 8784 EP
25111 142 belfosdil/BMY 21891/SR7037 EP 173041 A1 143
Bencylcalne/EGYT-201 FR 151193 144 benipidine/KW3049/Nakadipine
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CPU-86017 EP 00538844 199 CRE 202 WO 9323082 200 CRE 204 WO 9323082
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299 LAS Z077 300 LCB-2514 301 lemildipine P 59152373 A2 302
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McN 5691 (see RWJ 26240) 316 McN-6186 317 MCN 6497 318 MD 260792
319 MDL 143 320 MDL 12330A 321 MDL 16582A WO 9323082 322 MDL 72567
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OPC 13340 376 OPC 88117 EP 236140 A2 377 ORG 13020 378 Org-13061
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414421 A2 423 RGH 2970 424 riodipine 425 Ro-11-2933 EP 00523493 426
Ro 18-3981 427 Ro 40-5967 428 RO 445912 dithiane derivatives
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RJW-26902 439 RWJ-29009 EP 00493048 440 RWJ-37868 WO 0048584 441
ryanodine 442 S-(-)-amlodipine 443 S 11568 444 S 12967 ZA 9000231 A
445 S-12968 EP 00406502 446 S-2150 Ep 00615971 447 S-312-d JP
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460 SB-237376 WO 0209761 A2 461 SB 262470 WO 0183546 A1 462 SC
30552 463 SDZ-249482 464 selodipine 465 semotiadil (SD 3211) U.S.
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EP 400665 A2 490 SQ 32926 EP 400665 A2 491 SQ-33351 WO 09006118 492
SQ 33537 493 SQ 34399
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508 TH-1177 509 TH-9229 WO 09607415 510 thapsigargin British
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538 VUF-8929 EP 467435 A2 539 VULM 993 540 vantanipidine Ep 257616
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U.S. Pat. No. 4,172,896
Synthesis
[0138] The synthesis of charge-modified ion channel blockers may
involve the selective protection and deprotection of alcohols,
amines, ketones, sulfhydryls or carboxyl functional groups of the
parent ion channel blocker, the linker, the bulky group, and/or the
charged group. For example, commonly used protecting groups for
amines include carbamates, such as tert-butyl, benzyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl,
allyl, and m-nitrophenyl. Other commonly used protecting groups for
amines include amides, such as formamides, acetamides,
trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides,
trimethylsilylethanesulfonamides, and tert-butylsulfonyl amides.
Examples of commonly used protecting groups for carboxyls include
esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl,
2-(trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl,
O-nitrobenzyl, ortho-esters, and halo-esters. Examples of commonly
used protecting groups for alcohols include ethers, such as methyl,
methoxymethyl, methoxyethoxymethyl, methylthiomethyl,
benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl,
2-napthylmethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl,
9-phenylxanthyl, trityl (including methoxy-trityls), and silyl
ethers. Examples of commonly used protecting groups for sulfhydryls
include many of the same protecting groups used for hydroxyls. In
addition, sulfhydryls can be protected in a reduced form (e.g., as
disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic
esters, or sulfonic amides). Protecting groups can be chosen such
that selective conditions (e.g., acidic conditions, basic
conditions, catalysis by a nucleophile, catalysis by a Lewis acid,
or hydrogenation) are required to remove each, exclusive of other
protecting groups in a molecule. The conditions required for the
addition of protecting groups to amine, alcohol, sulfhydryl, and
carboxyl functionalities and the conditions required for their
removal are provided in detail in T. W. Green and P. G. M. Wuts,
Protective Groups in Organic Synthesis (2.sup.nd Ed.), John Wiley
& Sons, 1991 and P. J. Kocienski, Protecting Groups, Georg
Thieme Verlag, 1994.
[0139] Charge-modified ion channel blockers can be prepared using
techniques familiar to those skilled in the art. The modifications
can be made, for example, by alkylation of the parent ion channel
blocker using the techniques described by J. March, Advanced
Organic Chemistry: Reactions, Mechanisms and Structure, John Wiley
& Sons, Inc., 1992, page 617. The conversion of amino groups to
guanidine groups can be accomplished using standard synthetic
protocols. For example, Mosher has described a general method for
preparing mono-substituted guanidines by reaction of
aminoiminomethanesulfonic acid with amines (Kim et al., Tetrahedron
Lett. 29:3183 (1988)). A more convenient method for guanylation of
primary and secondary amines was developed by Bernatowicz employing
1H-pyrazole-1-carboxamidine hydrochloride;
1-H-pyrazole-1-(N,N'-his(tert-butoxycarbonyl)carboxamidine; or
1-II-pyrazole-1-(N,N'-bis(benzyloxycarbonyl)carboxamidine. These
reagents react with amines to give mono-substituted guanidines (see
Bernatowicz et al., J. Org. Chem. 57:2497 (1992); and Bernatowicz
et al., Tetrahedron Lett. 34:3389 (1993)). In addition, thioureas
and S-alkyl-isothioureas have been shown to be useful intermediates
in the syntheses of substituted guanidines (Poss et al.,
Tetrahedron Lett. 33:5933 (1992)). In certain embodiments, the
guanidine is part of a heterocyclic ring having two nitrogen atoms
(see, for example, the structures below).
The ring system can include an alkylene or
##STR00093##
alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6,
and 7-membered rings. Such ring systems can be prepared, for
example, using the methods disclosed by Schlama et al., J. Org.
Chem. 62:4200 (1997).
[0140] Charge-modified ion channel blockers can be prepared by
alkylation of an amine nitrogen in the parent compound as shown in
Scheme 1.
##STR00094##
[0141] Alternatively, charge-modified ion channel blockers can be
prepared by introduction of a guanidine group. The parent compound
can be reacted with a cynamide, e.g., methylcyanamide, as shown in
Scheme 2 or pyrazole-1-carboxamidine derivatives as shown in Scheme
3 where Z is H or a suitable protecting group. Alternatively, the
parent compound can be reacted with cyanogens bromide followed by
reaction with methylchloroaluminum amide as shown in Scheme 4.
Reagents such as 2-(methylthio)-2-imidazoline can also be used to
prepare suitably functionalized derivatives (Scheme 5).
##STR00095##
##STR00096##
##STR00097##
##STR00098##
[0142] Any ion channel blocker containing an amine nitrogen atom
(e.g., a compound selected from Compounds (1)-(563) or a compound
according to Formulas (I)-(XIV)) can be modified as shown in
Schemes 1-5.
TRPV1 Agonists
[0143] TRPV1 agonists that can be employed in the methods and kits
of the invention include but are not limited to any that activates
TRPV1 receptors on nociceptors and allows for entry of at least one
inhibitor of voltage-gated ion channels. A suitable TRPV1 agonist
is capsaicin or another capsaicinoids, which are members of the
vanilloid family of molecules. Naturally occurring capsaicinoids
are capsaicin itself, dihydrocapsaicin, nordihydrocapsaicin,
homodihydrocapsaicin, homocapsaicin, and nonivamide, whose
structures are provided below.
##STR00099##
[0144] Other suitable capsaicinoids and capsaicinoid analogs and
derivatives for use in the compositions and methods of the present
invention include naturally occurring and synthetic capsaicin
derivatives and analogs including, e.g., vanilloids (e.g.,
N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, and
N-vanillyl-cis-monounsaturated alkenamides), capsiate,
dihydrocapsiate, nordihydrocapsiate and other capsinoids,
capsiconiate, dihydrocapsiconiate and other coniferyl esters,
capsiconinoid, resiniferatoxin, tinyatoxin, civamide,
N-phenylmethylalkenamide capsaicin derivatives, olvanil,
N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide,
N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral),
gingerols, piperines, shogaols, guaiacol, eugenol, zingerone,
nuvanil, NE-19550, NE-21610, and NE-28345. Additional
capsaicinoids, their structures, and methods of their manufacture
are described in U.S. Pat. Nos. 7,446,226 and 7,429,673, which are
hereby incorporated by reference.
[0145] Additional suitable TRPV1 agonists include but are not
limited to eugenol, arvanil (N-arachidonoylvanillamine),
anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404,
resiniferatoxin, phorbol 12-phenylacetate 13-acetate
20-homovanillate (PPAHV), olvanil (NE 19550), OLDA
(N-oleoyldopamine), N-arachidonyldopamine (NADA),
6'-iodoresiniferatoxin (6'-IRTX), C18 N-acylethanolamines,
lipoxygenase derivatives such as 12-hydroperoxycicosatetraenoic
acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins),
piperine, MSK195
(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3--
methoxyphenyl]acetamide), JYL79
(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-(4-hydroxy-3-methoxy-
benzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl
borate, 10-shogaol, oleylgingerol, oleylshogaol, and SU200
(N-(4-tert-butylbenzyl)-N'-(4-hydroxy-3-methoxybenzyl)thiourea).
[0146] Still other TRPV1 agonists include amylocaine, articaine,
benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine,
cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine),
etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine,
meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine,
procaine (novacaine), proparacaine, propoxycaine, risocaine,
ropivacaine, tetracaine (amethocaine), and trimecaine.
TRP1A Agonists
[0147] TRP1A agonists that can be employed in the methods and kits
of the invention include any that activates TRP1A receptors on
nociceptors or pruriceptors and allows for entry of at least one
inhibitor of voltage-gated ion channels. Suitable TRP1A agonists
include but are not limited to cinnamaldehyde,
allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil,
wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool,
2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl
p-hydroxybenzoate, mustard oil, and 3'-carbamoylbiphenyl-3-yl
cyclohexylcarbamate (URB597). Still other agonists include
amylocaine, articaine, benzocaine, bupivacaine, carbocaine,
carticaine, chloroprocaine, cyclomethycaine, dibucaine
(cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine,
levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine),
metabutoxycaine, piperocaine, prilocaine, procaine (novacaine),
proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine
(amethocaine), and trimecaine.
P2X Agonists
[0148] P2X agonists that can be employed in the methods and kits of
the invention include any that activates P2X receptors on
nociceptors or pruriceptors and allows for entry of at least one
inhibitor of voltage-gated ion channels. Suitable P2X agonists
include but are not limited to 2-methylthio-ATP, 2' and
3'-O-(4-benzoylbenzoyl)-ATP, and ATP5'-O-(3-thiotriphosphate).
TRPM8 Agonists
[0149] TRPM8 agonists that can be employed in the methods and kits
of the invention include any that activates TRPM8 receptors on
nociceptors or pruriceptors and allows for entry of at least one
inhibitor of voltage-gated ion channels. Suitable TRPM8 agonists
include but are not limited to menthol, iciclin, eucalyptol,
linalool, geraniol, and hydroxycitronellal.
Additional Agents
[0150] If desired, one or more additional biologically active
agents typically used to treat neurogenic inflammation may be used
in combination with a composition of the invention described
herein. The biologically active agents include, but are not limited
to, acetaminophen, NSAIDs, glucocorticoids, narcotics (e.g.
opioids), tricyclic antidepressants, amine transporter inhibitors,
anticonvulsants, antiproliferative agents, and immune modulators.
The biologically active agents can be administered prior to,
concurrent with, or following administration of a composition of
the invention, using any formulation, dosing, or administration
known in the art that is therapeutically effective.
[0151] Non-steroidal anti-inflammatory drugs (NSAIDs) that can be
administered to a patient (e.g., a human) suffering from neurogenic
inflammation in combination with a composition of the invention
include, but are not limited to, acetylsalicylic acid, amoxiprin,
benorylate, benorilate, choline magnesium salicylate, diflunisal,
ethenzamide, faislamine, methyl salicylate, magnesium salicylate,
salicyl salicylate, salicylamide, diclofenac, aceclofenac,
acemethacin, alclofenac, bromfenac, etodolac, indometacin,
nabumetone, oxametacin, proglumetacin, sulindac, tolmetin,
ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen,
dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen,
ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen,
oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid,
flufenamic acid, meclofenamic acid, tolfenamic acid,
phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone,
metamizole, mofebutazone, oxyphenbutazone, phenazone,
sulfinpyrazone, piroxicam, droxicam, lornoxicam, meloxicam,
tenoxicam, and the COX-2 inhibitors celecoxib, etoricoxib,
lumiracoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically
acceptable salts thereof.
[0152] Glucocorticoids that can be administered to a patient (e.g.,
a human) suffering from neurogenic inflammation in combination with
a composition of the invention include, but are not limited to,
hydrocortisone, cortisone acetate, prednisone, prednisolone,
methylprednisolone, dexamethasone, betamethasone, triamcinolone,
beclometasone, fludrocortisones acetate, deoxycorticosterone
acetate, aldosterone, and pharmaceutically acceptable salts
thereof.
[0153] Narcotics that can be administered to a patient (e.g., a
human) suffering from neurogenic inflammation in combination with a
composition of the invention include, but are not limited, to
tramadol, hydrocodone, oxycodone, morphine, and pharmaceutically
acceptable salts thereof.
[0154] Antiproliferative and immune modulatory agents that can be
administered to a patient (e.g., a human) suffering from neurogenic
inflammation in combination with a composition of the invention
include, but are not limited to, alkylating agents, platinum
agents, antimetabolites, topoisomerase inhibitors, dihydrofolate
reductase inhibitors, antitumor antibiotics, antimitotic agents,
aromatase inhibitors, thymidylate synthase inhibitors, DNA
antagonists, farnesyltransferase inhibitors, pump inhibitors,
histone acetyltransferase inhibitors, metalloproteinase inhibitors,
ribonucleoside reductase inhibitors, TNF-alpha agonists, TNF-alpha
antagonists or scavengers, interleukin 1 (IL-1) antagonists or
scavengers, endothelin A receptor antagonists, retinoic acid
receptor agonists, hormonal agents, antihormonal agents,
photodynamic agents, and tyrosine kinase inhibitors.
Formulation of Compositions
[0155] The administration of a combination of the invention may be
by any suitable means that results in the reduction of inflammation
at the target region (e.g., any inflamed tissue or mucosal
surface). The inhibitor(s) of voltage-gated ion channels may be
contained in any appropriate amount in any suitable carrier
substance, and are generally present in amounts totaling 1-95% by
weight of the total weight of the composition. The composition may
be provided in a dosage form that is suitable for intraarticular,
oral, parenteral (e.g., intravenous, intramuscular), rectal,
cutaneous, subcutaneous, topical, transdermal, sublingual, nasal,
vaginal, intravesicular, intraurethral, intrathecal, epidural,
aural, or ocular administration, or by injection, inhalation, or
direct contact with the nasal, genitourinary, gastrointestinal,
reproductive or oral mucosa.
[0156] Thus, the composition may be in the form of, e.g., tablets,
capsules, pills, powders, granulates, suspensions, emulsions,
solutions, gels including hydrogels, pastes, ointments, creams,
plasters, drenches, osmotic delivery devices, suppositories,
enemas, injectables, implants, sprays, preparations suitable for
iontophoretic delivery, or aerosols. The compositions may be
formulated according to conventional pharmaceutical practice (see,
e.g., Remington: The Science and Practice of Pharmacy, 20th
edition, 2000, ed. A. R. Gennaro, Lippincott Williams &
Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical
Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel
Dekker, New York).
[0157] Each compound of a combination therapy, as described herein,
may be formulated in a variety of ways that are known in the art.
For example, the first and second agents of the combination therapy
may be formulated together or separately. Desirably, the first and
second agents are formulated together for the simultaneous or near
simultaneous administration of the agents.
[0158] The individually or separately formulated agents can be
packaged together as a kit. Non-limiting examples include, but are
not limited to, kits that contain, e.g., two pills, a pill and a
powder, a suppository and a liquid in a vial, two topical creams,
etc. The kit can include optional components that aid in the
administration of the unit dose to patients, such as vials for
reconstituting powder forms, syringes for injection, customized IV
delivery systems, inhalers, etc. Additionally, the unit dose kit
can contain instructions for preparation and administration of the
compositions.
[0159] The kit may be manufactured as a single use unit dose for
one patient, multiple uses for a particular patient (at a constant
dose or in which the individual compounds may vary in potency as
therapy progresses); or the kit may contain multiple doses suitable
for administration to multiple patients ("bulk packaging"). The kit
components may be assembled in cartons, blister packs, bottles,
tubes, and the like.
Controlled Release Formulations
[0160] Each compound of the invention, alone or in combination with
one or more of the biologically active agents as described herein,
can be formulated for controlled release (e.g., sustained or
measured) administration, as described in U.S. Patent Application
Publication Nos. 2003/0152637 and 2005/0025765, each incorporated
herein by reference. For example, a compound of the invention,
alone or in combination with one or more of the biologically active
agents as described herein, can be incorporated into a capsule or
tablet, that is administered to the site of inflammation.
[0161] Any pharmaceutically acceptable vehicle or formulation
suitable for local infiltration or injection into a site to be
treated (e.g., a painful surgical incision, wound, or joint), that
is able to provide a sustained release of compound of the
invention, alone or in combination with one or more of the
biologically active agents as described herein, may be employed to
provide for prolonged elimination or alleviation of inflammation,
as needed. Slow release formulations known in the art include
specially coated pellets, polymer formulations or matrices for
surgical insertion or as sustained release microparticles, e.g.,
microspheres or microcapsules, for implantation, insertion,
infusion or injection, wherein the slow release of the active
medicament is brought about through sustained or controlled
diffusion out of the matrix and/or selective breakdown of the
coating of the preparation or selective breakdown of a polymer
matrix. Other formulations or vehicles for sustained or immediate
delivery of an agent to a preferred localized site in a patient
include, e.g., suspensions, emulsions, gels, liposomes and any
other suitable art known delivery vehicle or formulation acceptable
for subcutaneous or intramuscular administration.
[0162] A wide variety of biocompatible materials may be utilized as
a controlled release carrier to provide the controlled release of a
compound of the invention, alone or in combination with one or more
biologically active agents, as described herein. Any
pharmaceutically acceptable biocompatible polymer known to those
skilled in the art may be utilized. It is preferred that the
biocompatible controlled release material degrade in vivo within
about one year, preferably within about 3 months, more preferably
within about two months. More preferably, the controlled release
material will degrade significantly within one to three months,
with at least 50% of the material degrading into non-toxic
residues, which are removed by the body, and 100% of the compound
of the invention being released within a time period within about
two weeks, preferably within about 2 days to about 7 days. A
degradable controlled release material should preferably degrade by
hydrolysis, either by surface erosion or bulk erosion, so that
release is not only sustained but also provides desirable release
rates. However, the pharmacokinetic release profile of these
formulations may be first order, zero order, bi- or multi-phasic,
to provide the desired reversible local anesthetic effect over the
desired time period.
[0163] Suitable biocompatible polymers can be utilized as the
controlled release material. The polymeric material may comprise
biocompatible, biodegradable polymers, and in certain preferred
embodiments is preferably a copolymer of lactic and glycolic acid.
Preferred controlled release materials which are useful in the
formulations of the invention include the polyanhydrides,
polyesters, co-polymers of lactic acid and glycolic acid
(preferably wherein the weight ratio of lactic acid to glycolic
acid is no more than 4:1 i.e., 80% or less lactic acid to 20% or
more glycolic acid by weight)) and polyorthoesters containing a
catalyst or degradation enhancing compound, for example, containing
at least 1% by weight anhydride catalyst such as maleic anhydride.
Examples of polyesters include polylactic acid, polyglycolic acid
and polylactic acid-polyglycolic acid copolymers. Other useful
polymers include protein polymers such as collagen, gelatin, fibrin
and fibrinogen and polysaccharides such as hyaluronic acid.
[0164] The polymeric material may be prepared by any method known
to those skilled in the art. For example, where the polymeric
material is comprised of a copolymer of lactic and glycolic acid,
this copolymer may be prepared by the procedure set forth in U.S.
Pat. No. 4,293,539, incorporated herein by reference.
Alternatively, copolymers of lactic and glycolic acid may be
prepared by any other procedure known to those skilled in the art.
Other useful polymers include polylactides, polyglycolides,
polyanhydrides, polyorthoesters, polycaprolactones,
polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceous
polymers, soluble derivatives of polysaccharides, soluble
derivatives of proteinaceous polymers, polypeptides, polyesters,
and polyorthoesters or mixtures or blends of any of these.
Pharmaceutically acceptable polyanhydrides which are useful in the
present invention have a water-labile anhydride linkage. The rate
of drug release can be controlled by the particular polyanhydride
polymer utilized and its molecular weight. The polysaccharides may
be poly-1,4-glucans, e.g., starch glycogen, amylose, amylopectin,
and mixtures thereof. The biodegradable hydrophilic or hydrophobic
polymer may be a water-soluble derivative of a poly-1,4-glucan,
including hydrolyzed amylopectin, hydroxyalkyl derivatives of
hydrolyzed amylopectin such as hydroxyethyl starch (HES),
hydroxyethyl amylose, dialdehyde starch, and the like. The
polyanhydride polymer may be branched or linear. Examples of
polymers which are useful in the present invention include (in
addition to homopolymers and copolymers of poly(lactic acid) and/or
poly(glycolic acid)) poly[bis(p-carboxyphenoxy)propane anhydride]
(PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM),
polyanhydrides of oligomerized unsaturated aliphatic acids,
polyanhydride polymers prepared from amino acids which are modified
to include an additional carboxylic acid, aromatic polyanhydride
compositions, and co-polymers of polyanhydrides with other
substances, such as fatty acid terminated polyanhydrides, e.g.,
polyanhydrides polymerized from monomers of dimers and/or trimers
of unsaturated fatty acids or unsaturated aliphatic acids.
Polyanhydrides may be prepared in accordance with the methods set
forth in U.S. Pat. No. 4,757,128, incorporated herein by reference.
Polyorthoester polymers may be prepared, e.g., as set forth in U.S.
Pat. No. 4,070,347, incorporated herein by reference.
Polyphosphoesters may be prepared and used as set forth in U.S.
Pat. Nos. 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255,
5,176,907 and 5,194,581, each of which is incorporated herein by
reference.
[0165] Proteinaceous polymers may also be used. Proteinaceous
polymers and their soluble derivatives include gelation
biodegradable synthetic polypeptides, elastin, alkylated collagen,
alkylated elastin, and the like. Biodegradable synthetic
polypeptides include poly-(N-hydroxyalkyl)-L-asparagine,
poly-(N-hydroxyalkyl)-L-glutamine, copolymers of
N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with
other amino acids. Suggested amino acids include L-alanine,
L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.
[0166] In additional embodiments, the controlled release material,
which in effect acts as a carrier for a compound of the invention,
alone or in combination with one or more biologically active agents
as described herein, can further include a bioadhesive polymer such
as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic
acid, mucin) or non-toxic lectins or the polymer itself may be
bioadhesive, e.g., polyanhydride or polysaccharides such as
chitosan.
[0167] In embodiments where the biodegradable polymer comprises a
gel, one such useful polymer is a thermally gelling polymer, e.g.,
polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer
such as Pluronic.TM. F127 from BASF Wyandotte. In such cases, the
local anesthetic formulation may be injected via syringe as a
free-flowing liquid, which gels rapidly above 30.degree. C. (e.g.,
when injected into a patient). The gel system then releases a
steady dose of a compound of the invention, alone or in combination
with one or more biologically active agents as described herein, at
the site of administration.
Solid Dosage Forms for Oral Use
[0168] Formulations for oral use include tablets containing the
active ingredient(s) in a mixture with non-toxic pharmaceutically
acceptable excipients. These excipients may be, for example, inert
diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol,
microcrystalline cellulose, starches including potato starch,
calcium carbonate, sodium chloride, lactose, calcium phosphate,
calcium sulfate, or sodium phosphate); granulating and
disintegrating agents (e.g., cellulose derivatives including
microcrystalline cellulose, starches including potato starch,
croscarmellose sodium, alginates, or alginic acid); binding agents
(e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium
alginate, gelatin, starch, pregelatinized starch, microcrystalline
cellulose, magnesium aluminum silicate, carboxymethylcellulose
sodium, methylcellulose, hydroxypropyl methylcellulose,
ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and
lubricating agents, glidants, and antiadhesives (e.g., magnesium
stearate, zinc stearate, stearic acid, silicas, hydrogenated
vegetable oils, or talc). Other pharmaceutically acceptable
excipients can be colorants, flavoring agents, plasticizers,
humectants, buffering agents, and the like.
[0169] Two or more compounds may be mixed together in a tablet,
capsule, or other vehicle, or may be partitioned. In one example,
the first compound is contained on the inside of the tablet, and
the second compound is on the outside, such that a substantial
portion of the second compound is released prior to the release of
the first compound.
[0170] Formulations for oral use may also be provided as chewable
tablets, or as hard gelatin capsules wherein the active ingredient
is mixed with an inert solid diluent (e.g., potato starch, lactose,
microcrystalline cellulose, calcium carbonate, calcium phosphate or
kaolin), or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, for example, peanut oil,
liquid paraffin, or olive oil. Powders, granulates, and pellets may
be prepared using the ingredients mentioned above under tablets and
capsules in a conventional manner using, e.g., a mixer, a fluid bed
apparatus or a spray drying equipment.
[0171] Dissolution or diffusion controlled release can be achieved
by appropriate coating of a tablet, capsule, pellet, or granulate
formulation of compounds, or by incorporating the compound into an
appropriate matrix. A controlled release coating may include one or
more of the coating substances mentioned above and/or, e.g.,
shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl
alcohol, glyceryl monostearate, glyceryl distearate, glycerol
palmitostearate, ethylcellulose, acrylic resins, dl-polylactic
acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl
acetate, vinyl pyrrolidone, polyethylene, polymethacrylate,
methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels,
1,3 butylene glycol, ethylene glycol methacrylate, and/or
polyethylene glycols. In a controlled release matrix formulation,
the matrix material may also include, e.g., hydrated
methylcellulose, carnauba wax and stearyl alcohol, carbopol 934,
silicone, glyceryl tristearate, methyl acrylate-methyl
methacrylate, polyvinyl chloride, polyethylene, and/or halogenated
fluorocarbon.
[0172] The liquid forms in which the compounds and compositions of
the present invention can be incorporated for administration orally
include aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions, and flavored emulsions with edible oils such as
cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as
elixirs and similar pharmaceutical vehicles.
[0173] Generally, when administered to a human, the oral dosage of
any of the compounds of the combination of the invention will
depend on the nature of the compound, and can readily be determined
by one skilled in the art. Typically, such dosage is normally about
0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per
day, and more desirably about 5 mg to 500 mg per day. Dosages up to
200 mg per day may be necessary.
[0174] Administration of each drug in a combination therapy, as
described herein, can, independently, be one to four times daily
for one day to one year, and may even be for the life of the
patient. Chronic, long-term administration will be indicated in
many cases.
Topical Formulations
[0175] A composition of the invention, alone or in combination with
one or more of the biologically active agents described herein, can
also be adapted for topical use with a topical vehicle containing
from between 0.0001% and 25% (w/w) or more of active
ingredient(s).
[0176] In a preferred combination, the active ingredients are
preferably each from between 0.0001% to 10% (w/w), more preferably
from between 0.0005% to 4% (w/w) active agent. The cream can be
applied one to four times daily, or as needed.
[0177] Performing the methods described herein, the topical vehicle
containing the composition of the invention, or a combination
therapy containing a composition of the invention is preferably
applied to the site of inflammation on the patient. For example, a
cream may be applied to the hands of a patient suffering from
arthritic fingers.
Formulations for Nasal and Inhalation Administration
[0178] The pharmaceutical compositions of the invention can be
formulated for nasal or intranasal administration. Formulations
suitable for nasal administration, when the carrier is a solid,
include a coarse powder having a particle size, for example, in the
range of approximately 20 to 500 microns which is administered by
rapid inhalation through the nasal passage. When the carrier is a
liquid, for example, a nasal spray or as nasal drops, one or more
of the formulations can be admixed in an aqueous or oily solution,
and inhaled or sprayed into the nasal passage.
[0179] For administration by inhalation, the active ingredient can
be conveniently delivered in the form of an aerosol spray
presentation from pressurized packs or a nebulizer, with the use of
a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol the
dosage unit can be determined by providing a valve to deliver a
metered amount, Capsules and cartridges of, for example, gelatin
for use in an inhaler or insufflator can be formulated containing a
powder mix of the compound and a suitable powder base such as
lactose or starch.
EXAMPLES
[0180] The following example is intended to illustrate the
invention, and is not intended to limit it.
Example 1
Treatment of Neurogenic Inflammation with Intravenous Injection of
QX-314
[0181] FIG. 1 is a graph showing the effect of intravenous QX-314
(0.4 mg/kg) on the edema elicited by injection of complete Freund's
adjuvant (CFA) in the rat hindpaw determined by measuring the total
volume of the hindpaw by plethysmography. The degree of swelling
produced by injection of CFA is reduced by administration of QX-314
reflecting reduction in neurogenic edema resulting from the
blockade of nociceptors by QX314. QX-314 by itself has no effect
different from administration of saline.
Example 2
Entry of N-Methyl-Verapamil into Dorsal Root Ganglion Neurons
Through Capsaicin-Activated TRPV1 Channels
[0182] N-methyl-verapamil, a charged derivative of the known
calcium channel blocker verapamil and structurally related to
D-890, can be loaded into dorsal root ganglion neurons through
activation of TRPV1 channels by capsaicin. The internally-loaded
N-methyl-verapamil then produces long-lasting inhibition of the
voltage-dependent calcium channels in the neurons. Entry of the
drug into the cell, and its blocking action, depends on applying
the drug in the presence of capsaicin to activate the TRPV1
channels present in the neuronal membrane.
[0183] As shown in FIG. 2, the inhibition of voltage-dependent
calcium channel current in a DRG neuron by N-methyl-verapamil
applied in the presence of capsaicin to open TRPV1 channels. The
traces show currents through voltage-activated calcium channels in
a dissociated rat dorsal root ganglion neuron, recorded in
whole-cell mode. Current was carried by 2 mM Ba.sup.2+ on a
background of 155 mM N-methyl-D-glucamine (to eliminate Na
current), with an internal CsCl-based solution. Calcium channels
were opened by a voltage step from -80 mV to -20 mV. When channels
are opened, inward-going current is carried by Ba.sup.2+ ions
flowing into the cell.
[0184] Each panel shows calcium channel currents before and 3
minutes after exposure of the cell to either 1 .mu.M capsaicin
alone (top panel), 300 .mu.M N-methyl-verapamil alone (middle
panel), or 300 .mu.M N-methyl-verapamil applied in the presence of
1 .mu.M capsaicin to open TRPV1 channels (bottom panel). Control
experiments using either capsaicin alone or N-methyl-verapamil
alone each produce weak, transient effects that are rapidly
reversed when the agents are washed away. The combination, however,
produces an inhibition of calcium channel currents that persists
after washout of the agents, consistent with N-methyl-verapamil
having entered through TRPV1 channels and remaining trapped inside
the cells, blocking the calcium channels from the inside.
OTHER EMBODIMENTS
[0185] Various modifications and variations of the described method
and system of the invention will be apparent to those skilled in
the art without departing from the scope and spirit of the
invention. Although the invention has been described in connection
with specific desired embodiments, it should be understood that the
invention as claimed should not be unduly limited to such specific
embodiments. Indeed, various modifications of the described modes
for carrying out the invention that are obvious to those skilled in
the fields of medicine, immunology, pharmacology, endocrinology, or
related fields are intended to be within the scope of the
invention.
[0186] All publications mentioned in this specification are herein
incorporated by reference to the same extent as if each independent
publication was specifically and individually incorporated by
reference.
* * * * *