U.S. patent application number 14/003762 was filed with the patent office on 2013-12-26 for small molecule modulators of the cold and menthol receptor trpm8.
This patent application is currently assigned to B.R.A.I.N. Biotechnology Research and Information Network AG. The applicant listed for this patent is Michael Krohn, Holger Zinke. Invention is credited to Michael Krohn, Holger Zinke.
Application Number | 20130345300 14/003762 |
Document ID | / |
Family ID | 44910347 |
Filed Date | 2013-12-26 |
United States Patent
Application |
20130345300 |
Kind Code |
A1 |
Krohn; Michael ; et
al. |
December 26, 2013 |
SMALL MOLECULE MODULATORS OF THE COLD AND MENTHOL RECEPTOR
TRPM8
Abstract
The present invention relates to the use of compounds which are
capable of producing a cooling sensation when they are brought into
contact with the human body. In particular, the present invention
relates to the use of compounds modulating TRPM8, and optionally to
the use of compounds selectively exhibiting agonist activity at the
TRPM8 channel. Such compounds have applications in many fields,
particularly in oral and personal hygiene products and foodstuffs,
but also in pharmaceutical composition products, cosmetics, textile
products and packaging products. The present invention further
relates to products containing such compounds and to the medical
use of such compounds.
Inventors: |
Krohn; Michael; (Lorsch,
DE) ; Zinke; Holger; (Heppenheim, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Krohn; Michael
Zinke; Holger |
Lorsch
Heppenheim |
|
DE
DE |
|
|
Assignee: |
B.R.A.I.N. Biotechnology Research
and Information Network AG
Zwingenberg
DE
|
Family ID: |
44910347 |
Appl. No.: |
14/003762 |
Filed: |
March 8, 2012 |
PCT Filed: |
March 8, 2012 |
PCT NO: |
PCT/EP12/54046 |
371 Date: |
September 6, 2013 |
Current U.S.
Class: |
514/456 ;
428/221; 435/375; 549/403 |
Current CPC
Class: |
A61K 8/411 20130101;
A61K 8/49 20130101; A23L 27/2056 20160801; A61K 31/136 20130101;
A61K 31/00 20130101; A61K 8/4933 20130101; A61K 8/41 20130101; A61K
31/352 20130101; A61Q 5/00 20130101; A61K 8/498 20130101; A23L
27/2054 20160801; A23V 2002/00 20130101; A61Q 11/00 20130101; A61K
31/513 20130101; A61Q 19/00 20130101; A61K 31/137 20130101; A61K
31/351 20130101; A23L 27/88 20160801; C07D 311/36 20130101; A61K
31/35 20130101; A61K 31/353 20130101; Y10T 428/249921 20150401;
A61Q 17/02 20130101; A23L 27/2052 20160801; A23L 27/204 20160801;
A61K 2800/782 20130101; A61K 31/496 20130101; A61K 2800/244
20130101; A61K 31/4439 20130101 |
Class at
Publication: |
514/456 ;
549/403; 435/375; 428/221 |
International
Class: |
A61K 31/353 20060101
A61K031/353 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 8, 2011 |
EP |
11157329.1 |
Claims
1. A product comprising a Compound I.2 having the following general
formula: ##STR00098## or a pharmaceutically acceptable derivative
thereof; wherein: R.sub.1 is selected from --H; --OT.sub.3,
--ST.sub.3, or --(C.sub.1-C.sub.3)alkyl, wherein T.sub.3 is
selected from --H or --(C.sub.1-C.sub.2)alkyl; R.sub.3 is selected
from -phenyl or -heteroaryl selected from the group consisting of
pyridine, pyrazine, pyridazine and pyrimidine, each of which is
unsubstituted or substituted with 1 or 2 independently selected
R.sub.6 groups; R.sub.4 is selected from --(C.sub.1-C.sub.3)alkyl,
--(C.sub.2-C.sub.3)alkenyl, --(C.sub.2-C.sub.3)alkynyl, or
--(C.sub.1-C.sub.3)alkoxy; and R.sub.6 is selected from --H,
--(C.sub.1-C.sub.2)alkyl, --(C.sub.2)alkenyl, --(C.sub.2)alkynyl,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, -halo, --N.sub.3, --NO.sub.2,
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, or --CH.sub.3; and each halo is independently selected
from --F, --Cl, --Br, or --I; and wherein the product is selected
from the group consisting of a cosmetic product composition, a food
product composition, a textile product, a pharmaceutical product
composition and a packaging product.
2. The product of claim 1, wherein the compound exhibits selective
agonist activity at TRPM8.
3. The product of claim 1, wherein the compound exhibits activity
at TRPM8, which activity is at least three times, or even at least
four times, greater than the activity of the compound at TRPA1.
4. The product of claim 3, wherein in a functional cell based assay
the compound modulates the intracellular calcium level of human
cells recombinantly expressing human TRPM8 at least four times more
efficient than that of human cells recombinantly expressing human
TRPA1.
5. (canceled)
6. The product of claim 1, wherein the compound is Compound I.3
having the following chemical structure: ##STR00099##
7. (canceled)
8. The product of claim 1, wherein the cosmetic product composition
is selected from the group consisting of an insect repellent
composition, an oral hygiene composition, a skin care composition,
and a hair care composition or the food product composition is
selected from the group consisting of ice cream, mousse, creme,
beverages and confectionery or the textile product is selected from
the group consisting of shirts, trousers, socks, towels, headgear,
underwear and shoes or the pharmaceutical product composition is
selected from the group consisting of anticancer medicaments,
bladder disease medicaments and medicaments for the treatment of
pain.
9-11. (canceled)
12. A method of treating a patient comprising administering a
compound as defined in claim 1 to a patient in need thereof.
13. A method of treating pain comprising administering a compound
as defined in claim 1 to a patient in need thereof.
14. A method of producing a cooling sensation, the method
comprising contacting skin and/or a mucosal membrane of a human or
animal with an effective amount of a compound as defined in claim 1
to produce the cooling sensation.
15. In vitro method of modulating the cold and menthol receptor
TRPM8, wherein TRPM8 is contacted with a compound as defined in
claim 1.
16. The product of claim 5, wherein the cosmetic product
composition is selected from the group consisting of an insect
repellent composition, an oral hygiene composition, a skin care
composition, and a hair care composition or the food product
composition is selected from the group consisting of ice cream,
mousse, creme, beverages and confectionery or the textile product
is selected from the group consisting of shirts, trousers, socks,
towels, headgear, underwear and shoes or the pharmaceutical product
composition is selected from the group consisting of anticancer
medicaments, bladder disease medicaments and medicaments for the
treatment of pain.
17. A method of treating a patient comprising administering a
compound as defined in claim 5 to a patient in need thereof.
18. A method of treating pain comprising administering a compound
as defined in claim 5 to a patient in need thereof.
19. A method of producing a cooling sensation, the method
comprising contacting skin and/or a mucosal membrane of a human or
animal with an effective amount of a compound as defined in claim 5
to produce the cooling sensation.
20. In vitro method of modulating the cold and menthol receptor
TRPM8, wherein TRPM8 is contacted with a compound as defined in
claim 5.
Description
SUBJECT OF THE INVENTION
[0001] The present invention relates to the use of compounds which
are capable of producing a cooling sensation when they are brought
into contact with the human body. In particular, the present
invention relates to the use of compounds modulating TRPM8, and
optionally to the use of compounds selectively exhibiting agonist
activity at the TRPM8 channel. Such compounds have applications in
many fields, particularly in oral and personal hygiene products and
foodstuffs, but also in pharmaceutical composition products,
cosmetics, textile products and packaging products. The present
invention further relates to products containing such compounds and
to the medical use of such compounds.
BACKGROUND OF THE INVENTION
[0002] The transient receptor potential (TRP) ion channel family is
a group of ion channels located mostly in the plasma membrane of
numerous human and animal cell types. There are about 28 TRP
channels that share some structural similarity to each other. Many
of these channels mediate a variety of sensations like the
sensations of pain, hotness, warmth or coldness, different kinds of
tastes, pressure and vision. In the body, some TRP channels are
thought to be involved in thermosensation and to be used in animals
to sense hot or cold. Some TRP channels are activated by the
pungent ingredients of spices like garlic, chilli pepper, wasabi;
others are activated by menthol, camphor, peppermint, and cooling
agents; yet others are activated by drugs like cannabinoids, e.g.
marijuana. Some act as sensors of cellular stress such as osmotic
pressure, volume, stretch, and vibration.
[0003] Six protein families are comprised by the mammalian TRP
superfamily: the classic TRPs (TRPCs), the vanilloid receptor TRPs
(TRPVs), the melastatin or long TRPs (TRPMs), the mucolipins
(TRPMLs), the polycystins (TRPPs), and ankyrin transmembrane
protein 1 (ANKTM1, TRPA1). With the exception of some polycystins,
TRPs are generally assumed to have six transmembrane domains. The
TRP channels are a family of ion channel proteins that mediate ion
influx of Na.sup.+ and Ca.sup.2+ and, in several cases, Mg.sup.2+
and other divalent cations. Since TRPs are intimately linked with
intracellular Ca.sup.2+ signaling, they are implicated in the
control of cell cycle progression, cell migration, and programmed
cell death.
[0004] The TRPM subfamily comprises eight members, including the
cold and menthol receptor TRPM8, also designated as TRP melastatin
8, cold and menthol receptor 1 (CMR1) or transient receptor
potential cation channel subfamily M member 8. In 2002, using
divergent approaches, two scientific groups simultaneously
identified and described TRPM8 (McKemy D D et al., Nature 2002,
416(6876):52-58; Peier A M et al., Cell 2002, 108(5):705-15). The
channel is expressed, e.g., in small-diameter primary sensory
neurones, where it presumably functions as a thermosensor. TRPM8
consists of six putative transmembrane spanning segments, a
pore-forming loop and intracellularly located NH.sub.2 and COOH
termini. Assembly of channel subunits as tetramers results in the
formation of cation-selective channels that permeate calcium ions.
TRPM8 is involved in the detection of sensations such as coolness
triggered, inter alia, by cooling agents and/or by cold (i.e.
temperatures ranging from about 8.degree. C. to about 28.degree.
C.).
[0005] Cooling agents are used extensively by flavor and fragrance
suppliers in order to evoke associations with freshness and
cleanliness. Hence, over the last 30 years a considerable number of
compounds have been synthesized and evaluated for the physiological
sensation of "cooling". For instance, the international patent
application WO 2010/017609 discloses the use of the ingredients of
Mentha and Eucalyptus oil as antiperspirants, the ingredients
presumably acting as TRPM8 agonists. Furthermore, menthol, a cyclic
terpene alcohol found in leaves of the genus Mentha, is used in a
wide range of products, such as confectionary, candy, toothpastes,
vaporubs, and aromatherapy inhalations. When applied at low
concentrations to the skin or the oral mucosa, menthol elicits a
pleasant cool sensation, while higher doses can cause burning,
irritation, and pain.
[0006] It is known in the art that menthol can act as natural
modulator of TRPM8 (McKemy D D et al., Nature 2002,
416(6876):52-58; Peier A M et al., Cell 2002, 108(5):705-15; McKemy
D D, Molecular Pain 2005, 1:16). Upon activation, a signal
transduction cascade is mediated by TRPM8, producing the perception
of cold in the nervous system. For instance, activation of TRPM8
can induce an increase of intracellular calcium ions in
cold-sensitive neurones. This calcium influx subsequently produces
an inward current that provokes cold sensing.
[0007] In addition to menthol, a number of further cooling agents,
including icilin (also designated as AG-3-5), Cool-actP, Cooling
Agent 10, FrescolatMGA, FrescolatML, geraniol, hydroxycitronellal,
linalool, PMD38, WS-3, and WS-23 are known in the art to activate
TRPM8 in vitro (McKemy D D et al., Nature 2002, 416(6876):52-58;
Weil A et al., Mol. Pharmacol. 2005, 68(2):518-27; Behrendt H J et
al., Br. J. Pharmacol. 2004, 141(4):737-45). Of these icilin, was
first identified as a super-cooling agent in the early 1980s and
bears little resemblance to menthol structurally (WO
2004/026840).
[0008] A number of methanol derivatives or other cooling agents
which may exhibit a similar action at TRPM8 are known in the art.
For instance, the international patent application WO 2010/026094
relates to modulators of TRPM8, to a method of modulating the TRPM8
channel, to the use of the modulators for induction of cold
sensation and to the objects and means produced using said
modulators. High concentrations of menthol can trigger other ion
channels (e.g. TRPA1), presumably leading to these unpleasant
sensations through activation of nociceptive sensory neurons (see
e.g. review by McKemy D D, Mol. Pain. 2005, 1:16). In addition
menthol has a typical flavour and aroma which sometimes is
disadvantageous for industrial applications in the food and
cosmetic industry. Hence, there is a need for compounds which
selectively modulate TRPM8, e.g. compounds which exhibit distinct
activation concentrations at TRPM8 and TRPA1.
[0009] TRPA1 is a member of the TRPA branch of the TRP ion channel
gene family. TRPA1 was identified as a potential mediator of
noxious cold stimuli in nociceptive sensory neurons. Moreover,
recent studies found evidence that TRPA1 is involved in sensory
neural responses to mustard oil, allicin, and other chemical
irritants (Jordt S E et al., Nature 2004, 427(6971):260-65; Bandell
M et al., Neuron. 2004, 41(6):849-57). Hence, TRPA1 channels
respond to a multitude of irritants with diverse origins and
chemical structures, leading to, amongst others, sensations of
pain, coughing, apnea, and lachrymation.
[0010] Some of the above-mentioned cooling agents have cooling
effects at least to some extents, but may be insufficient and
unsatisfactory in the retainability of the cooling effect. Hence,
there is a strong demand in the art for providing cooling agents
that have an improved sensory stimulating effect. Furthermore, some
of the cooling agents known in the art may be insufficient with
regard to their efficacy, their period of action, their scent,
their taste, their solubility, and/or their volatility, and/or may
cause irritation of the mucous membranes, itching of skin, tearing
and/or the urge to cough. Accordingly, there is a need for
alternative cooling agents that may overcome one or more of these
drawbacks.
OBJECT AND SUMMARY OF THE INVENTION
[0011] It is an object of the invention to provide compounds that
modulate the TRPM8 channel activity. In certain embodiments of the
invention, such compounds exhibit agonist activity at the TRPM8
channel. In certain embodiments of the invention, such compounds
exhibit partial agonist activity at the TRPM8 channel. In certain
embodiments of the invention, such compounds exhibit selective
agonist activity at the TRPM8 channel. In certain embodiments of
the invention, such compounds exhibit antagonistic activity at the
TRPM8 channel. In certain embodiments of the invention, such
compounds exhibit partial antagonistic activity at the TRPM8
channel. In certain embodiments of the invention, such compounds
exhibit selective antagonistic activity at the TRPM8 channel.
[0012] In certain embodiments of the invention, such compounds
exhibit activity for activating TRPM8 in a lower concentration
range than needed for activating TRPA1. In another embodiment, a
compound of the invention acts as a TRPM8 agonist, but not as a
TRPA1 agonist. In another embodiment, a compound of the invention
acts as a TRPM8 partial agonist, but not as a TRPA1 agonist.
[0013] It is a further object of the invention to provide compounds
which are excellent in evocation of cool and/or refreshing feeling
or chilly and refreshing feeling without giving undesirable
stimulation, peculiar odor, stinging, pungent or burning sensations
and/or bitter taste, and which are usable as cooling agents and/or
sensory stimulation agents. It is a further object of the invention
to provide compounds which selectively modulate the cold and
menthol receptor TRPM8. It is also an object of the invention to
provide selective agonists of the cold and menthol receptor TRPM8.
It is a further object of the invention to provide compounds which
modulate the cold and menthol receptor TRPM8, but do not
substantially trigger TRPA1, or at least to a lesser extent.
[0014] Also, the object of the invention is to provide cooling
agent compositions comprising one or more of said compounds.
Further, the object of the invention is to provide fragrance
compositions, beverage or food products, cosmetic products,
toiletry products, bathing agents, textile products, packaging
products or pharmaceutical products comprising one or more of said
compounds.
[0015] These objectives as well as others which will become
apparent from the ensuing description are attained by the subject
matter of the independent claims. Some of the embodiments of the
present invention are defined by the subject matter of the
dependent claims.
[0016] In one embodiment, the present invention relates to a
product comprising a compound that selectively modulates TRPM8, and
wherein the product is selected from the group consisting of a
cosmetic product composition, a food product composition, a textile
product, a pharmaceutical product composition and a packaging
product.
[0017] According to an optional embodiment, the compound exhibits
selective agonist activity at TRPM8.
[0018] According to a further optional embodiment, the compound
exhibits activity at TRPM8, which activity is at least three times
or even at least four times, greater than the activity of the
compound at TRPA 1.
[0019] According to a further optional embodiment, in a functional
cell based assay the compound modulates the intracellular calcium
level of human cells recombinantly expressing human TRPM8 at least
four times more efficient than that of human cells recombinantly
expressing human TRPA1.
[0020] Optionally, the compound is selected from the group
consisting of Compounds I.1, II.1, III.1, IV.1, V.1, VI.1, and
VII.1, the Compounds having the chemical structures as described
hereinafter.
[0021] Optionally, the compound is selected from the group
consisting of Compounds I.2, II.2, III.2, IV.2, V.2, VI.2, and
VII.2, the Compounds having the chemical structures as described
hereinafter.
[0022] Optionally, the compound is selected from the group
consisting of Compounds I.3, II.3, III.3, IV.3, V.3, VI.3, and
VII.3, the Compounds having the following chemical structures:
TABLE-US-00001 Com- pound Chemical structure I.3 ##STR00001## II.3
##STR00002## III.3 ##STR00003## IV.3 ##STR00004## V.3 ##STR00005##
VI.3 ##STR00006## VII.3 ##STR00007##
[0023] In one further embodiment, the present invention relates to
the use of a compound as defined in any of claims 1 to 6 and/or as
described hereinafter in a product selected from the group
consisting of a cosmetic product composition, a food product
composition, a textile product, a pharmaceutical product
composition, and a packaging product.
[0024] According to an optional embodiment, the cosmetic product
composition is selected from the group consisting of an insect
repellent composition, an oral hygiene composition, a skin care
composition, and a hair care composition.
[0025] According to an optional embodiment, the food product
composition is selected from the group consisting of ice cream,
mousse, creme, beverages and confectionery.
[0026] According to an optional embodiment, the textile product is
selected from the group consisting of shirts, trousers, socks,
towels, headgear, underwear and shoes.
[0027] According to an optional embodiment, the pharmaceutical
product composition is selected from the group consisting of
anticancer medicaments, medicaments for the treatment of bladder
diseases, and medicaments for the treatment of pain.
[0028] In one further embodiment, the present invention relates to
a compound as defined in any of claims 1 to 6 and/or as described
hereinafter for use in therapy.
[0029] In one further embodiment, the present invention relates to
a compound as defined in any of claims 1 to 6 and/or as described
hereinafter for use in the treatment of pain.
[0030] In one further embodiment, the present invention relates to
a cosmetic use of a compound as defined in any of claims 1 to 6
and/or as described hereinafter as cooling agent.
[0031] In one further embodiment, the present invention relates to
an in vitro method of modulating the cold and menthol receptor
TRPM8, wherein TRPM8 is contacted with a compound as defined in any
of claims 1 to 6 and/or as described hereinafter.
FIGURE LEGENDS
[0032] The accompanying drawings, which are incorporated and form
part of the specification, merely illustrate certain embodiments of
the present invention. They are meant to serve to explain specific
modes of the present invention to those of skilled in the art. In
the drawings:
[0033] FIG. 1 depicts a comparison of the EC.sub.50 value of
Compound I.3 acting as activator of TRPM8 with the EC.sub.50 value
of Compound I.3 acting as activator of TRPA1, as well as the
chemical structure of Compound I.3. EC.sub.50 of Compound I.3
acting as activator of TRPM8 is about 2.01 .mu.M. EC.sub.50 of
Compound I.3 acting as activator of TRPA1 is about 72.42 .mu.M.
Hence, EC.sub.50 of Compound I.3 acting as activator of TRPM8 is
about 36 times lower than EC.sub.50 of Compound I.3 acting as
activator of TRPA1. The efficacy of Compound I.3 with respect to
activation of TRPM8 has been evaluated to be about 110.06%
(compared to 20 .mu.M menthol).
[0034] FIG. 2 depicts a comparison of the EC.sub.50 value of
Compound II.3 acting as activator of TRPM8 with the EC.sub.50 value
of Compound II.3 acting as activator of TRPA1, as well as the
chemical structure of Compound II.3. EC.sub.50 of Compound II.3
acting as activator of TRPM8 is about 8.01 .mu.M. EC.sub.50 of
Compound II.3 acting as activator of TRPA1 is about 123.22 .mu.M.
Hence, EC.sub.50 of Compound II.3 acting as activator of TRPM8 is
about 15.4 times lower than EC.sub.50 of Compound II.3 acting as
activator of TRPA1. The efficacy of Compound II.3 with respect to
activation of TRPM8 has been evaluated to be about 46.59% (compared
to 20 .mu.M menthol).
[0035] FIG. 3 depicts a comparison of the EC.sub.50 value of
Compound III.3 acting as activator of TRPM8 with the EC.sub.50
value of Compound III.3 acting as activator of TRPA1, as well as
the chemical structure of Compound III.3. EC.sub.50 of Compound
III.3 acting as activator of TRPM8 is about 5.27 .mu.M. EC.sub.50
of Compound III.3 acting as activator of TRPA1 is about 113.40
.mu.M. Hence, EC.sub.50 of Compound III.3 acting as activator of
TRPM8 is about 21.5 times lower than EC.sub.50 of Compound III.3
acting as activator of TRPA1. The efficacy of Compound III.3 with
respect to activation of TRPM8 has been evaluated to be about
97.65% (compared to 20 .mu.M menthol).
[0036] FIG. 4 depicts a comparison of the EC.sub.50 value of
Compound IV.3 acting as activator of TRPM8 with the EC.sub.50 value
of Compound IV.3 acting as activator of TRPA1, as well as the
chemical structure of Compound IV.3. EC.sub.50 of Compound IV.3
acting as activator of TRPM8 is about 4.12 .mu.M. EC.sub.50 of
Compound IV.3 acting as activator of TRPA1 is about 117.89 .mu.M.
Hence, EC.sub.50 of Compound IV.3 acting as activator of TRPM8 is
about 28.6 times lower than EC.sub.50 of Compound IV.3 acting as
activator of TRPA1. The efficacy of Compound IV.3 with respect to
activation of TRPM8 has been evaluated to be about 34.14% (compared
to 20 .mu.M menthol).
[0037] FIG. 5 depicts a comparison of the EC.sub.50 value of
Compound V.3 acting as activator of TRPM8 with the EC.sub.50 value
of Compound V.3 acting as activator of TRPA1, as well as the
chemical structure of Compound V.3. EC.sub.50 of Compound V.3
acting as activator of TRPM8 is about 7.53 .mu.M. EC.sub.50 of
Compound V.3 acting as activator of TRPA1 is about 138.37 .mu.M.
Hence, EC.sub.50 of Compound V.3 acting as activator of TRPM8 is
about 18.4 times lower than EC.sub.50 of Compound V.3 acting as
activator of TRPA1. The efficacy of Compound V.3 with respect to
activation of TRPM8 has been evaluated to be about 70.90% (compared
to 20 .mu.M menthol).
[0038] FIG. 6 depicts a comparison of the EC.sub.50 value of
Compound VI.3 acting as activator of TRPM8 with the EC.sub.50 value
of Compound VI.3 acting as activator of TRPA1, as well as the
chemical structure of Compound VI.3. EC.sub.50 of Compound VI.3
acting as activator of TRPM8 is about 8.15 .mu.M. EC.sub.50 of
Compound VI.3 acting as activator of TRPA1 is about 107.64 .mu.M.
Hence, EC.sub.50 of Compound VI.3 acting as activator of TRPM8 is
about 13.2 times lower than EC.sub.50 of Compound VI.3 acting as
activator of TRPA1. The efficacy of Compound VI.3 with respect to
activation of TRPM8 has been evaluated to be about 95.36% (compared
to 20 .mu.M menthol).
[0039] FIG. 7 depicts a comparison of the EC.sub.50 value of
Compound VII.3 acting as activator of TRPM8 with the EC.sub.50
value of Compound VII.3 acting as activator of TRPA1, as well as
the chemical structure of Compound VII.3. EC.sub.50 of Compound
VII.3 acting as activator of TRPM8 is about 10.94 .mu.M. EC.sub.50
of Compound VII.3 acting as activator of TRPA1 is about 56.62
.mu.M. Hence, EC.sub.50 of Compound VII.3 acting as activator of
TRPM8 is about 5.2 times lower than EC.sub.50 of Compound VII.3
acting as activator of TRPA1. The efficacy of Compound VII.3 with
respect to activation of TRPM8 has been evaluated to be about
45.12% (compared to 20 .mu.M menthol).
DETAILED DESCRIPTION OF THE INVENTION
[0040] The present invention illustratively described in the
following may suitably be practiced in the absence of any element
or elements, limitation or limitations, not specifically disclosed
herein.
[0041] The present invention will be described with respect to
particular embodiments and with reference to certain drawings but
the invention is not limited thereto but only by the claims. The
drawings described are only schematic and are non-limiting. In the
drawings, the size of some of the elements may be exaggerated and
not drawn on scale for illustrative purposes.
[0042] Where the term "comprising" is used in the present
description and claims, it does not exclude other elements or
steps. For the purposes of the present invention, the term
"consisting of" is considered to be a preferred embodiment of the
term "comprising of". If hereinafter a group is defined to comprise
at least a certain number of embodiments, this is also to be
understood to disclose a group which optionally consists only of
these embodiments.
[0043] Where an indefinite or definite article is used when
referring to a singular noun e.g. "a" or "an", "the", this includes
a plural of that noun unless something else is specifically
stated.
[0044] The term "about" in the context of the present invention
denotes an interval of accuracy that the person skilled in the art
will understand to still ensure the technical effect of the feature
in question. The term typically indicates deviation from the
indicated numerical value of +10%, and optionally .+-.5%.
[0045] Furthermore, the terms first, second, third and the like in
the description and in the claims, are used for distinguishing
between similar elements and not necessarily for describing a
sequential or chronological order. It is to be understood that the
terms so used are interchangeable under appropriate circumstances
and that the embodiments of the invention described herein are
capable of operation in other sequences than described or
illustrated herein.
[0046] Further definitions of term will be given in the following
in the context of which the terms are used.
Compounds
[0047] In one embodiment, the present invention relates to a
compound having the following general formula (I):
##STR00008##
or a pharmaceutically acceptable derivative thereof wherein: Q is
selected from fused benzo or (5- or 6-membered)heteroaryl; each
R.sub.1 is independently selected from: [0048] (a) -halo, --CN,
--NO.sub.2; or [0049] (b) --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3; or [0050]
(c) --C(.dbd.O)T.sub.3, --C(.dbd.O)OT.sub.3,
--C(.dbd.O)N(T.sub.1)(T.sub.2); or [0051] (d) --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0052] (e)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0053] (f)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicycloalkyl,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0054] (g) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups; a
is an integer selected from 0, 1, 2 or 3; R.sub.2 is selected from
.dbd.O, .dbd.NT.sub.3, .dbd.S, --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3, --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3, or
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); R.sub.3 and R.sub.4 are
each independently selected from: [0055] (a) --H; or [0056] (b)
-halo, --CN, --NO.sub.2; or [0057] (c) --OT.sub.3,
--OC(.dbd.O)T.sub.3, --OC(.dbd.O)N(T.sub.1)(T.sub.2),
--OC(.dbd.O)OT.sub.3; or [0058] (d) --C(.dbd.O)T.sub.3,
--C(.dbd.O)OT.sub.3, --C(.dbd.O)N(T.sub.1)(T.sub.2); or [0059] (e)
--ST.sub.3, --S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0060] (f)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0061] (g)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0062] (h) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups; E
is selected from C(T.sub.1)(T.sub.2), O, S or NT.sub.3; each
R.sub.5 is independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, -(5- or
6-membered)heteroaryl, -phenyl, --(C.sub.1-C.sub.6)alkylCOOR.sub.7,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, .dbd.O, .dbd.S, -halo, --N.sub.3,
--NO.sub.2, --CH.dbd.N(R.sub.7),
--NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.3, --C(.dbd.O)R.sub.7,
--C(.dbd.O)--C(.dbd.O)OR.sub.7, --C(.dbd.O)N(R.sub.7).sub.2,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--OC(.dbd.O)N(R.sub.7).sub.2, --OC(.dbd.O)OR.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.6 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, --OR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)N(R.sub.7).sub.2, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --OC(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, --(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.5-C.sub.8)cycloalkenyl,
-phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to
10-membered)heteroaryl, --C(halo).sub.3, --CH(halo).sub.2, or
--CH.sub.2(halo); each R.sub.8 is independently selected from --H
or --(C.sub.1-C.sub.4)alkyl; each T.sub.1, T.sub.2, and T.sub.3 is
independently --H or --(C.sub.1-C.sub.10)alkyl which is
unsubstituted or substituted with 1, 2 or 3 independently selected
R.sub.5 groups; the dashed line in the 6-membered ring denotes the
presence or absence of a bond; and each halo is independently
selected from --F, --Cl, --Br, or --I.
[0063] In a further embodiment, the present invention relates to a
compound having the following general formula (I.1):
##STR00009##
or a pharmaceutically acceptable derivative thereof wherein: Q is
selected from fused benzo or 6-membered heteroaryl; each R.sub.1 is
independently selected from: [0064] (a) -halo, --CN, --NO.sub.2; or
[0065] (b) --OT.sub.3, --OC(.dbd.O)T.sub.3; or [0066] (c)
--C(.dbd.O)T.sub.3; or [0067] (d) --ST.sub.3, --S(.dbd.O)T.sub.3,
--S(.dbd.O).sub.2T.sub.3, --S(.dbd.O).sub.2OT.sub.3; or [0068] (e)
--(C.sub.1-C.sub.4)alkyl, --(C.sub.2-C.sub.4)alkenyl,
--(C.sub.2-C.sub.4)alkynyl, --(C.sub.1-C.sub.4)alkoxy, each of
which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.5 groups; a is an integer selected from 0, 1, or 2;
Y and E are each independently selected from O, S, or NT.sub.3;
R.sub.3 and R.sub.4 are each independently selected from: [0069]
(a) --H; or [0070] (b) --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.4)alkenyl, --(C.sub.2-C.sub.4)alkynyl,
--(C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups;
[0071] (c) -phenyl or -(5- or 6-membered)heteroaryl containing 1 or
2 atoms selected from the group consisting of O, N and S, each of
which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.6 groups; the dashed line in the 6-membered ring
denotes the presence or absence of a bond; each R.sub.5 is
independently selected from --(C.sub.1-C.sub.3)alkyl,
--(C.sub.2-C.sub.3)alkenyl, --(C.sub.2-C.sub.3)alkynyl,
--(C.sub.1-C.sub.3)alkylCOOR.sub.7, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, .dbd.O,
.dbd.S, -halo, --N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.7 is
independently selected from --H, --CH.sub.3, or --CH.sub.2CH.sub.3;
each T.sub.3 is independently --H or --(C.sub.1-C.sub.5)alkyl which
is unsubstituted or substituted with 1 or 2 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0072] In a further embodiment, the present invention relates to a
compound having the following general formula (I.2):
##STR00010##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from --H; --OT.sub.3, --ST.sub.3, or
--(C.sub.1-C.sub.3)alkyl, wherein T.sub.3 is selected from --H or
--(C.sub.1-C.sub.2)alkyl; R.sub.3 is selected from -phenyl or
-heteroaryl selected from the group consisting of pyridine,
pyrazine, pyridazine and pyrimidine, each of which is unsubstituted
or substituted with 1 or 2 independently selected R.sub.6 groups;
R.sub.4 is selected from --(C.sub.1-C.sub.3)alkyl,
--(C.sub.2-C.sub.3)alkenyl, --(C.sub.2-C.sub.3)alkynyl, or
--(C.sub.1-C.sub.3)alkoxy; and R.sub.6 is selected from --H,
--(C.sub.1-C.sub.2)alkyl, --(C.sub.2)alkenyl, --(C.sub.2)alkynyl,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, -halo, --N.sub.3, --NO.sub.2,
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, or --CH.sub.3; and each halo is independently selected
from --F, --Cl, --Br, or --I.
[0073] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein the fused benzo is
substituted as follows:
##STR00011##
wherein R.sub.1 is defined as above.
[0074] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein the fused benzo is
substituted as follows:
##STR00012##
wherein R.sub.1 is defined as above.
[0075] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein the fused benzo is
substituted as follows:
##STR00013##
wherein R.sub.1 is defined as above.
[0076] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein the fused benzo is
substituted as follows:
##STR00014##
wherein R.sub.1 is defined as above.
[0077] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is selected from
--H; --Cl, --OH, --OCH.sub.3, --SH, --SCH.sub.3 or --CH.sub.3.
[0078] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein the fused benzo is
substituted as follows:
##STR00015##
wherein R.sub.1 is selected from --H; --OH, --OCH.sub.3, or
--CH.sub.3.
[0079] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.3 is -phenyl, which is
unsubstituted or substituted with 1 or 2 independently selected
groups selected from --H, --CH.sub.3, --OH, --SH, --OCH.sub.3, and
--Cl.
[0080] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.3 is -phenyl, which is
unsubstituted.
[0081] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.4 is selected from
--H, --CH.sub.3, and --CH.sub.2CH.sub.3.
[0082] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, wherein halo is Cl.
[0083] In a further embodiment, the present invention relates to a
compound having the following general formula (II):
##STR00016##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl or -(5- or 6-membered)heteroaryl,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.6 groups; R.sub.2, each R.sub.3 and
each R.sub.4 are each independently selected from: [0084] (a) --H;
or [0085] (b) -halo, --CN, --NO.sub.2; or [0086] (c) .dbd.O,
--OT.sub.3, --OC(.dbd.O)T.sub.3, --OC(.dbd.O)N(T.sub.1)(T.sub.2),
--OC(.dbd.O)OT.sub.3; or [0087] (d) --C(.dbd.O)T.sub.3,
--C(.dbd.O)OT.sub.3, --C(.dbd.O)N(T.sub.1)(T.sub.2); or [0088] (e)
.dbd.S, --ST.sub.3, --S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0089] (f)
.dbd.NT.sub.3, --N(T.sub.1)(T.sub.2),
--N(T.sub.3)N(T.sub.1)(T.sub.2), --N(T.sub.3)C(.dbd.O)T.sub.3,
--N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0090] (g)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0091] (h) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
[0092] wherein both R.sub.4 can together form a
(C.sub.2-C.sub.6)bridge, which is unsubstituted or substituted with
1, 2 or 3 independently selected R.sub.5 groups; E is selected from
C(T.sub.1)(T.sub.2), O, S or NT.sub.3; each R.sub.5 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, -(5- or
6-membered)heteroaryl, -phenyl, --(C.sub.1-C.sub.6)alkylCOOR.sub.7,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, .dbd.O, .dbd.S, -halo, --N.sub.3,
--NO.sub.2, --CH.dbd.N(R.sub.7),
--NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)--C(.dbd.O)OR.sub.7, --C(.dbd.O)N(R.sub.7).sub.2,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--OC(.dbd.O)N(R.sub.7).sub.2, --OC(.dbd.O)OR.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.6 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, --OR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)N(R.sub.7).sub.2, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --OC(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, --(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.5-C.sub.8)cycloalkenyl,
-phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to
10-membered)heteroaryl, --C(halo).sub.3, --CH(halo).sub.2, or
--CH.sub.2(halo); each R.sub.8 is independently selected from --H
or --(C.sub.1-C.sub.4)alkyl; each T.sub.1, T.sub.2, and T.sub.3 is
independently is independently --H or --(C.sub.1-C.sub.10)alkyl
which is unsubstituted or substituted with 1, 2 or 3 independently
selected R.sub.5 groups; the dashed line denotes the presence or
absence of a bond; and each halo is independently selected from
--F, --Cl, --Br, or --I.
[0093] In a further embodiment, the present invention relates to a
compound having the following general formula (II.1):
##STR00017##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl or -(6-membered)heteroaryl, each
of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.6 groups; R.sub.2 and each R.sub.4 are
each independently selected from: [0094] (a) --H; or [0095] (b)
-halo, --CN, --NO.sub.2; or [0096] (c) --OT.sub.3,
--OC(.dbd.O)T.sub.3; or [0097] (d) --C(.dbd.O)T.sub.3; or [0098]
(e) --ST.sub.3, --S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3; or [0099] (f) --(C.sub.1-C.sub.5)alkyl,
--(C.sub.2-C.sub.5)alkenyl, --(C.sub.2-C.sub.5)alkynyl,
--(C.sub.1-C.sub.5)alkoxy, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl, or -(5- or
6-membered)heterocycle, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups;
wherein both R.sub.4 can together form a (C.sub.2-C.sub.6)bridge,
which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.5 groups; or E is selected from O, S or NT.sub.3;
each Y is independently selected from O, S or NT.sub.3; each
R.sub.5 is independently selected from --(C.sub.1-C.sub.3)alkyl,
--(C.sub.2-C.sub.3)alkenyl, --(C.sub.2-C.sub.3)alkynyl,
--(C.sub.1-C.sub.3)alkylCOOR.sub.7, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, .dbd.O,
.dbd.S, -halo, --N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.7 is
independently selected from --H, --CH.sub.3, or --CH.sub.2CH.sub.3;
each T.sub.3 is independently --H or --(C.sub.1-C.sub.5)alkyl which
is unsubstituted or substituted with 1 or 2 independently selected
R.sub.5 groups; the dashed line denotes the presence or absence of
a bond; and each halo is independently selected from --F, --Cl,
--Br, or --I.
[0100] In a further embodiment, the present invention relates to a
compound having the following general formula (II.2):
##STR00018##
or a pharmaceutically acceptable derivative thereof wherein: each
R.sub.1 is independently selected from --(C.sub.1-C.sub.2)alkyl,
--(C.sub.2)alkenyl, --(C.sub.2)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, or --CH.sub.3; each halo is independently selected from
--F, --Cl, --Br, or --I; a is an integer selected from 1 or 2; each
T.sub.3 is independently selected from --H or
--(C.sub.1-C.sub.2)alkyl; the dashed line denotes the presence or
absence of a bond; and each Y is independently selected from O, S
or NT.sub.3.
[0101] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein a is 2 and the phenyl group
comprising --(R.sub.1).sub.a is substituted as follows:
##STR00019##
wherein R.sub.1 is defined as above.
[0102] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein a is 2 and the phenyl group
comprising --(R.sub.1).sub.a is substituted as follows:
##STR00020##
wherein R.sub.1 is defined as above.
[0103] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein a=2 and each R.sub.1 is
independently selected from --H; --OH, --Cl, --OCH.sub.3, --SH,
--SCH.sub.3 or --CH.sub.3.
[0104] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein a=1 and R.sub.1 is selected
from --H; --OH, Cl, --OCH.sub.3, --SH, --SCH.sub.3 or
--CH.sub.3.
[0105] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein a is 2 and the phenyl group
comprising --(R.sub.1).sub.a is substituted as follows:
##STR00021##
wherein each R.sub.1 is independently selected from --H; --OH,
--OCH.sub.3, --SH, --SCH.sub.3, --Cl or --CH.sub.3.
[0106] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein each T.sub.3 is
independently selected from --H or --CH.sub.3.
[0107] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein the dashed line denotes the
presence of a bond.
[0108] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, wherein each Y is O.
[0109] In a further embodiment, the present invention relates to a
compound having the following general formula (III):
##STR00022##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: [0110] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0111] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, or -(5- or 6-membered)heteroaryl,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.6 groups; R.sub.2 is selected from
.dbd.O, .dbd.NT.sub.3, .dbd.S, --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3, --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3, or
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); R.sub.3 is selected from:
[0112] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is substituted with 1 or 2 independently selected
R.sub.4 groups; or [0113] (b) -phenyl, -naphthalenyl,
--(C.sub.14)aryl, or -(5- or 6-membered)heteroaryl, each of which
is substituted with 1 or 2 independently selected R.sub.4 groups;
each R.sub.4 is independently selected from: [0114] (a)
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.5-C.sub.10)cycloalkenyl, or
-(5- or 6-membered)heterocycle, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups; or
[0115] (b) -phenyl, or -(5- or 6-membered)heteroaryl, each of which
is unsubstituted or substituted with 1 or 2 independently selected
R.sub.6 groups; each R.sub.5 is independently selected from
--(C.sub.1-C.sub.4)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl,
--(C.sub.1-C.sub.6)alkylCOOR.sub.7, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, .dbd.O,
.dbd.S, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)--C(.dbd.O)OR.sub.7, --C(.dbd.O)N(R.sub.7).sub.2,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--OC(.dbd.O)N(R.sub.7).sub.2, --OC(.dbd.O)OR.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.6 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, --OR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)N(R.sub.7).sub.2, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --OC(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, --(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.5-C.sub.8)cycloalkenyl,
-phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to
10-membered)heteroaryl, --C(halo).sub.3, --CH(halo).sub.2, or
--CH.sub.2(halo); each R.sub.8 is independently selected from --H
or --(C.sub.1-C.sub.4)alkyl; the dashed line denotes the presence
or absence of a bond, wherein E.sub.1 is selected from
C(T.sub.3).sub.2, O, S or NT.sub.3 if the bond is absent, and
E.sub.1 is selected from CT.sub.3, or N if the bond is present;
E.sub.2 is selected from C(T.sub.3).sub.2, O, S or NT.sub.3; each
T.sub.1, T.sub.2, and T.sub.3 is independently is independently --H
or --(C.sub.1-C.sub.10)alkyl which is unsubstituted or substituted
with 1, 2 or 3 independently selected R.sub.5 groups; and each halo
is independently selected from --F, --Cl, --Br, or --I.
[0116] In a further embodiment, the present invention relates to a
compound having the following general formula (III.1):
##STR00023##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl, or -(5- or 6-membered)heteroaryl,
each of which is unsubstituted or substituted with 1 or 2
independently selected R.sub.6 groups; Y is selected from O, S, or
NT.sub.3; R.sub.4 is selected from: [0117] (a)
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.5-C.sub.10)cycloalkenyl, or
-(5- or 6-membered)heterocycle, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups; or
[0118] (b) -phenyl, or -(5- or 6-membered)heteroaryl, each of which
is unsubstituted or substituted with 1 or 2 independently selected
R.sub.6 groups; E.sub.1 is selected from CT.sub.3, or N; E.sub.2 is
selected from C(T.sub.3).sub.2, O, S or NT.sub.3; E.sub.3 is
selected from C(T.sub.3).sub.2, O, S or NT.sub.3; E.sub.4 is
selected from CT.sub.3, or N; each R.sub.5 is independently
selected from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --(C.sub.1-C.sub.3)alkylCOOR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, .dbd.O, .dbd.S, -halo, --N.sub.3, --NO.sub.2,
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.7 is
independently selected from --H, --CH.sub.3, or --CH.sub.2CH.sub.3;
each T.sub.3 is independently --H or --(C.sub.1-C.sub.5)alkyl which
is unsubstituted or substituted with 1 or 2 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0119] In a further embodiment, the present invention relates to a
compound having the following general formula (III.2):
##STR00024##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: -phenyl, or -heteroaryl selected from the
group consisting of pyridine, pyrazine, pyridazine and pyrimidine,
each of which is unsubstituted or substituted with 1 or 2
independently selected R.sub.6 groups; F.sub.3 is selected from
C(T.sub.3).sub.2, O, S or NT.sub.3; E.sub.4 is selected from
CT.sub.3, or N; E.sub.5 is selected from C(T.sub.3).sub.2, O, or S;
R.sub.6 is selected from --H, --(C.sub.1-C.sub.2)alkyl,
--(C.sub.2)alkenyl, --(C.sub.2)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, or --CH.sub.3; each T.sub.3 is independently selected
from --H or --CH.sub.3; and each halo is independently selected
from --F, --Cl, --Br, or --I.
[0120] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is:
##STR00025##
wherein R.sub.6 is defined as above.
[0121] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is:
##STR00026##
wherein R.sub.6 is defined as above.
[0122] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is:
##STR00027##
wherein R.sub.6 is defined as above.
[0123] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is:
##STR00028##
wherein R.sub.6 is selected from --H, --CH.sub.3, --OH, --SH,
--OCH.sub.3, or --Cl.
[0124] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is:
##STR00029##
[0125] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein E.sub.3 is NT.sub.3 and
T.sub.3 is as defined above.
[0126] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein E.sub.4 is N.
[0127] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein E.sub.5 is S.
[0128] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein E.sub.3 is NT.sub.3, E.sub.4
is N and E.sub.5 is S, and T.sub.3 is as defined above.
[0129] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.6 is selected from
--H, --CH.sub.3, --OH, --SH, --OCH.sub.3, or --Cl.
[0130] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is -phenyl, which is
unsubstituted or substituted with 1 or 2 independently selected
groups selected from --H, --CH.sub.3, --OH, --SH, --OCH.sub.3,
--NH.sub.2, --N(CH.sub.3).sub.2 and --Cl.
[0131] In one embodiment, the present invention relates to a
compound having the following general formula (IV):
##STR00030##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: [0132] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.4 groups; or [0133] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, or -(5- or 6-membered)heteroaryl,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.4 groups; R.sub.2 is selected from
.dbd.O, .dbd.NT.sub.3, .dbd.S, --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3, --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3, or
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); R.sub.3 is selected from:
[0134] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0135] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, or -(5- or 6-membered)heteroaryl,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.6 groups; each R.sub.4 is
independently selected from: [0136] (a) -halo, --CN, --NO.sub.2; or
[0137] (b) --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3; or [0138]
(c) --C(.dbd.O)T.sub.3, --C(.dbd.O)OT.sub.3,
--C(.dbd.O)N(T.sub.1)(T.sub.2); or [0139] (d) --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0140] (e)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0141] (f)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicycloalkyl,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0142] (g) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
E.sub.1 and E.sub.2 are each independently selected from
C(T.sub.3).sub.2, O, S or NT.sub.3; the dashed line denotes the
presence or absence of a bond; each R.sub.5 is independently
selected from --(C.sub.1-C.sub.4)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl,
--(C.sub.1-C.sub.6)alkylCOOR.sub.7, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, .dbd.O,
.dbd.S, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)--C(.dbd.O)OR.sub.7, --C(.dbd.O)N(R.sub.7).sub.2,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--OC(.dbd.O)N(R.sub.7).sub.2, --OC(.dbd.O)OR.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.6 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, --OR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)N(R.sub.7).sub.2, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --OC(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, --(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.5-C.sub.8)cycloalkenyl,
-phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to
10-membered)heteroaryl, --C(halo).sub.3, --CH(halo).sub.2, or
--CH.sub.2(halo); each R.sub.8 is independently selected from --H
or --(C.sub.1-C.sub.4)alkyl; each T.sub.1, T.sub.2, and T.sub.3 is
independently --H or --(C.sub.1-C.sub.10)alkyl which is
unsubstituted or substituted with 1, 2 or 3 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0143] In one embodiment, the present invention relates to a
compound having the following general formula (IV.1):
##STR00031##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.3 is selected from -phenyl, or -(6-membered)heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.6 groups; each R.sub.4 is independently selected
from: [0144] (a) --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.4)alkenyl, --(C.sub.2-C.sub.4)alkynyl,
--(C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups; or
[0145] (b) --OR.sub.7, --SR.sub.7, --C(halo).sub.3,
--CH(halo).sub.2, --CH.sub.2(halo), --CN, .dbd.O, .dbd.S, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)N(T.sub.1)(T.sub.2),
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; Y is selected from O, S, or NT.sub.3;
E.sub.1 and E.sub.2 are each independently selected from
C(T.sub.3).sub.2, O, S or NT.sub.3; each dashed line in the
6-membered ring independently denotes the presence or absence of a
bond, wherein E.sub.3 is selected from C(T.sub.3).sub.2, or
NT.sub.3 if the adjacent bond is absent, and E.sub.3 is selected
from CT.sub.3, or N if the adjacent bond is present; E.sub.4 is
selected from C(T.sub.3).sub.2, or NT.sub.3; a is an integer
selected from 1, 2 or 3; each R.sub.5 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --(C.sub.1-C.sub.3)alkylCOOR.sub.7,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, .dbd.O, .dbd.S, -halo, --N.sub.3,
--NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.7 is
independently selected from --H, --CH.sub.3, or --CH.sub.2CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently --H or
--(C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with
1 or 2 independently selected R.sub.5 groups; and each halo is
independently selected from --F, --Cl, --Br, or --I.
[0146] In one embodiment, the present invention relates to a
compound having the following general formula (IV.2):
##STR00032##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.3 is selected from: -phenyl, or -heteroaryl selected from the
group consisting of pyridine, pyrazine, pyridazine and pyrimidine,
each of which is unsubstituted or substituted with 1 or 2
independently selected R.sub.6 groups; R.sub.4 is selected from:
--(C.sub.1-C.sub.4)alkyl, --(C.sub.2-C.sub.4)alkenyl,
--(C.sub.2-C.sub.4)alkynyl, --(C.sub.1-C.sub.4)alkoxy; E.sub.1 is
selected from O or S; Y is selected from O or S; each R.sub.6 is
independently selected from --H, --(C.sub.1-C.sub.2)alkyl,
--(C.sub.2)alkenyl, --(C.sub.2)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, or --CH.sub.3; each T.sub.3 is independently selected
from --H or --CH.sub.3; and each halo is independently selected
from --F, --Cl, --Br, or --I.
[0147] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.3 is:
##STR00033##
wherein R.sub.6 is defined as above and a is an integer selected
from 1 or 2.
[0148] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.3 is:
##STR00034##
wherein R.sub.6 is defined as above.
[0149] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.3 is:
##STR00035##
wherein R.sub.6 is defined as above.
[0150] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.3 is:
##STR00036##
wherein R.sub.6 is selected from --C(Cl).sub.3, --CH(Cl).sub.2,
--CH.sub.2(Cl), --Cl.
[0151] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.4 is
--(C.sub.1-C.sub.4)alkyl.
[0152] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein E.sub.1 is S.
[0153] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein Y is O.
[0154] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.6 is -halo.
[0155] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, wherein halo is Cl.
[0156] In one embodiment, the present invention relates to a
compound having the following general formula (V):
##STR00037##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: [0157] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.3 groups; or [0158] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, -(5- or 6-membered)heteroaryl or
-(7- or 10-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.3 groups;
R.sub.2 is selected from: [0159] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0160] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, -(5- or 6-membered)heteroaryl or
-(7- or 10-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
each R.sub.3 is independently selected from: [0161] (a) -halo,
--CN, --NO.sub.2; or [0162] (b) --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3; or [0163]
(c) --C(.dbd.O)T.sub.3, --C(.dbd.O)OT.sub.3,
--C(.dbd.O)N(T.sub.1)(T.sub.2); or [0164] (d) --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0165] (e)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0166] (f)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicycloalkyl,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0167] (g) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups; a
is an integer selected from 1, 2 or 3; Y is selected from O, S, or
NT.sub.3; the 6-membered ring denoted as Q.sub.1 is selected from
--(C.sub.6)cycloalkyl, --(C.sub.6)cycloalkenyl,
-(6-membered)heterocycle, -phenyl, or -(6-membered)heteroaryl; n is
an integer selected from 0, 1, 2 or 3; each R.sub.5 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, -(5- or
6-membered)heteroaryl, -phenyl, --(C.sub.1-C.sub.6)alkylCOOR.sub.7,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, .dbd.O, .dbd.S, -halo, --N.sub.3,
--NO.sub.2, --CH.dbd.N(R.sub.7),
--NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)--C(.dbd.O)OR.sub.7, --C(.dbd.O)N(R.sub.7).sub.2,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--OC(.dbd.O)N(R.sub.7).sub.2, --OC(.dbd.O)OR.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.6 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, --OR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)N(R.sub.7).sub.2, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --OC(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, --(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.5-C.sub.8)cycloalkenyl,
-phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to
10-membered)heteroaryl, --C(halo).sub.3, --CH(halo).sub.2, or
--CH.sub.2(halo); each R.sub.8 is independently selected from --H
or --(C.sub.1-C.sub.4)alkyl; each T.sub.1, T.sub.2, and T.sub.3 is
independently --H or --(C.sub.1-C.sub.10)alkyl which is
unsubstituted or substituted with 1, 2 or 3 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0168] In one embodiment, the present invention relates to a
compound having the following general formula (V.1):
##STR00038##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: [0169] (a) --H; or [0170] (b) -halo,
--CN, --NO.sub.2; or [0171] (c) --OT.sub.3, --OC(.dbd.O)T.sub.3; or
[0172] (d) --C(.dbd.O)T.sub.3; or [0173] (e) --N(T.sub.1)(T.sub.2),
--N(T.sub.3)N(T.sub.1)(T.sub.2), --N(T.sub.3)C(.dbd.O)T.sub.3,
--N(T.sub.3)C(.dbd.O)OT.sub.3; or [0174] (f) --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3; or [0175] (g) --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.4)alkenyl, --(C.sub.2-C.sub.4)alkynyl,
--(C.sub.1-C.sub.4)alkoxy, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups; each
R.sub.2 is independently selected from: [0176] (a) --H; or [0177]
(b) -halo, --CN, --NO.sub.2; or [0178] (c) --OT.sub.3,
--OC(.dbd.O)T.sub.3; or [0179] (d) --C(.dbd.O)T.sub.3; or [0180]
(e) --N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3; or
[0181] (f) --ST.sub.3, --S(.dbd.O)T.sub.3,
--S(.dbd.O).sub.2T.sub.3, --S(.dbd.O).sub.2OT.sub.3; or [0182] (g)
--(C.sub.1-C.sub.5)alkyl, --(C.sub.2-C.sub.5)alkenyl,
--(C.sub.2-C.sub.5)alkynyl, --(C.sub.1-C.sub.5)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.5-C.sub.10)cycloalkenyl, or
-(5- or 6-membered)heterocycle, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups;
[0183] wherein both R.sub.2 can together form a (2- to
6-membered)bridge, which is unsubstituted or substituted with 1 or
2 independently selected R.sub.5 groups; the 6-membered ring
denoted as Q.sub.1 is selected from -(6-membered)heterocycle, or
-(6-membered)heteroaryl, each of each at least containing one
nitrogen atom at the position as depicted in formula (V.1); Q.sub.2
is selected from fused benzo or 6-membered heteroaryl, each of
which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.6 groups; E.sub.1 is selected from C(T.sub.3).sub.2,
or NT.sub.3; the dashed line in the 5-membered ring denotes the
presence or absence of a bond, wherein E.sub.2 is selected from
C(T.sub.3).sub.2, NT.sub.3 if the bond is absent, and E.sub.2 is
selected from CT.sub.3, or N if the bond is present; Y is selected
from O, S, or NT.sub.3; a is an integer selected from 1, 2 or 3;
each R.sub.5 is independently selected from
--(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --(C.sub.1-C.sub.3)alkylCOOR.sub.7,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, .dbd.O, .dbd.S, -halo, --N.sub.3,
--NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.7 is
independently selected from --H, --CH.sub.3, or --CH.sub.2CH.sub.3;
each T.sub.1, T.sub.2, and T.sub.3 is independently is
independently --H or --(C.sub.1-C.sub.5)alkyl which is
unsubstituted or substituted with 1 or 2 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0184] In one embodiment, the present invention relates to a
compound having the following general formula (V.2):
##STR00039##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from --H; --OT.sub.3, --N(T.sub.3).sub.2,
--ST.sub.3, --(C.sub.1-C.sub.3)alkoxy or --(C.sub.1-C.sub.3)alkyl,
wherein T.sub.3 is selected from --H or --(C.sub.1-C.sub.2)alkyl; a
is an integer selected from 1, 2 or 3; each E.sub.3 is
independently selected from O or S; each R.sub.6 is independently
selected from --H, --(C.sub.1-C.sub.2)alkyl, --(C.sub.2)alkenyl,
--(C.sub.2)alkynyl, --OR.sub.7, --SR.sub.7, --C(halo).sub.3,
--CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo, --N.sub.3,
--NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, or --CH.sub.3; and each halo is independently selected
from --F, --Cl, --Br, or --I.
[0185] In an optional embodiment, the present invention relates to
a compound having the general formula (V.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is
--(O--C.sub.3)alkyl.
[0186] In an optional embodiment, the present invention relates to
a compound having the general formula (V.2) or a pharmaceutically
acceptable derivative thereof, wherein a=2.
[0187] In an optional embodiment, the present invention relates to
a compound having the general formula (V.2) or a pharmaceutically
acceptable derivative thereof, wherein E.sub.3 is O.
[0188] In an optional embodiment, the present invention relates to
a compound having the general formula (V.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.6 is --H; --OH, --Cl,
--OCH.sub.3, --SH, --SCH.sub.3 or --CH.sub.3.
[0189] In one embodiment, the present invention relates to a
compound having the following general formula (VI):
##STR00040##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: [0190] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0191] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, -(5- or 6-membered)heteroaryl or
-(7- or 10-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
each R.sub.2 is independently selected from: [0192] (a) --H; or
[0193] (b) -halo, --CN, --NO.sub.2; or [0194] (c) --OT.sub.3,
--OC(.dbd.O)T.sub.3, --OC(.dbd.O)N(T.sub.1)(T.sub.2),
--OC(.dbd.O)OT.sub.3; or [0195] (d) --C(.dbd.O)T.sub.3,
--C(.dbd.O)OT.sub.3, --C(.dbd.O)N(T.sub.1)(T.sub.2); or [0196] (e)
--ST.sub.3, --S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0197] (f)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0198] (g)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0199] (h) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
[0200] wherein both R.sub.2 can together form a (2- to
6-membered)bridge, which is unsubstituted or substituted with 1 or
2 independently selected R.sub.5 groups; R.sub.3 is selected from
.dbd.O, .dbd.NT.sub.3, --S, --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3, --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3, or
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); R.sub.4 is selected from:
[0201] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0202] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, -(5- or 6-membered)heteroaryl or
-(7- or 10-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
E.sub.1 is selected from C(T.sub.3).sub.2, O, S or NT.sub.3; a is
an integer selected from 0, 1, 2, or 3; each R.sub.5 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, -(5- or
6-membered)heteroaryl, -phenyl, --(C.sub.1-C.sub.6)alkylCOOR.sub.7,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, .dbd.O, --S, -halo, --N.sub.3, --NO.sub.2,
--CH.dbd.N(R.sub.7), --NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7,
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)--C(.dbd.O)OR.sub.7, --C(.dbd.O)N(R.sub.7).sub.2,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--OC(.dbd.O)N(R.sub.7).sub.2, --OC(.dbd.O)OR.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.6 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, --OR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)N(R.sub.7).sub.2, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --OC(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, --(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.5-C.sub.8)cycloalkenyl,
-phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to
10-membered)heteroaryl, --C(halo).sub.3, --CH(halo).sub.2, or
--CH.sub.2(halo); each R.sub.8 is independently selected from --H
or --(C.sub.1-C.sub.4)alkyl; each T.sub.1, T.sub.2, and T.sub.3 is
independently --H or --(C.sub.1-C.sub.10)alkyl which is
unsubstituted or substituted with 1, 2 or 3 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0203] In a further embodiment, the present invention relates to a
compound having the following general formula (VI.1):
##STR00041##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl, or -(6-membered)heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.6 groups; Y is selected from O or S; each R.sub.2 is
independently selected from: [0204] (a) --H; or [0205] (b) -halo,
--CN, --NO.sub.2; or [0206] (c) --OT.sub.3, --OC(.dbd.O)T.sub.3; or
[0207] (d) --C(.dbd.O)T.sub.3; or [0208] (e) --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3; or [0209] (f) --(C.sub.1-C.sub.5)alkyl,
--(C.sub.2-C.sub.5)alkenyl, --(C.sub.2-C.sub.5)alkynyl,
--(C.sub.1-C.sub.5)alkoxy, --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl, or -(5- or
6-membered)heterocycle, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups;
[0210] wherein both R.sub.2 can together form a (2- to
6-membered)bridge, which is unsubstituted or substituted with 1 or
2 independently selected R.sub.5 groups; R.sub.4 is selected from
-phenyl, or -(6-membered)heteroaryl, each of which is unsubstituted
or substituted with 1 or 2 independently selected R.sub.6 groups;
E.sub.1 is selected from CT.sub.3, or N; each R.sub.5 is
independently selected from --(C.sub.1-C.sub.3)alkyl,
--(C.sub.2-C.sub.3)alkenyl, --(C.sub.2-C.sub.3)alkynyl,
--(C.sub.1-C.sub.3)alkylCOOR.sub.7, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, .dbd.O,
.dbd.S, -halo, --N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.7 is
independently selected from --H, --CH.sub.3, or --CH.sub.2CH.sub.3;
each T.sub.3 is independently --H or --(C.sub.1-C.sub.5)alkyl which
is unsubstituted or substituted with 1 or 2 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0211] In a further embodiment, the present invention relates to a
compound having the following general formula (VI.2):
##STR00042##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl or -heteroaryl selected from the
group consisting of pyridine, pyrazine, pyridazine and pyrimidine,
each of which is unsubstituted or substituted with 1 or 2
independently selected R.sub.6 groups; a is an integer selected
from 0, 1 or 2;
E.sub.2 is O or S;
[0212] T.sub.3 is selected from --H or --CH.sub.3; each R.sub.6 is
independently selected from --H, --(C.sub.1-C.sub.2)alkyl,
--(C.sub.2)alkenyl, --(C.sub.2)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, or --CH.sub.3; and each halo is independently selected
from --F, --Cl, --Br, or --I.
[0213] In an optional embodiment, the present invention relates to
a compound having the general formula (VI.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is:
##STR00043##
wherein R.sub.6 is selected from --H; --OH, --OCH.sub.3, --SH,
--SCH.sub.3, --Cl or --CH.sub.3.
[0214] In an optional embodiment, the present invention relates to
a compound having the general formula (VI.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is:
##STR00044##
wherein R.sub.6 is defined as above.
[0215] In an optional embodiment, the present invention relates to
a compound having the general formula (VI.2) or a pharmaceutically
acceptable derivative thereof, wherein a=1.
[0216] In an optional embodiment, the present invention relates to
a compound having the general formula (VI.2) or a pharmaceutically
acceptable derivative thereof, wherein E.sub.2 is O.
[0217] In an optional embodiment, the present invention relates to
a compound having the general formula (VI.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.6 is selected from
--H; --OH, --OCH.sub.3, --SH, --SCH.sub.3, --Cl or --CH.sub.3.
[0218] In one embodiment, the present invention relates to a
compound having the following general formula (VII):
##STR00045##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from: [0219] (a) --(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0220] (b) -phenyl,
-naphthalenyl, --(C.sub.14)aryl, -(5- or 6-membered)heteroaryl or
-(7- or 10-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
R.sub.2 is selected from: [0221] (a) --H; or [0222] (b) -halo,
--CN, --NO.sub.2; or [0223] (c) --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3; or [0224]
(d) --C(.dbd.O)T.sub.3, --C(.dbd.O)OT.sub.3,
--C(.dbd.O)N(T.sub.1)(T.sub.2); or [0225] (e) --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0226] (f)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0227] (g)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicyclo alkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0228] (h) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
each R.sub.3 is independently selected from --H, .dbd.O,
.dbd.NT.sub.3, .dbd.S, --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3, --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3, or
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); R.sub.4 is selected from:
[0229] (a) --H; or [0230] (b) -halo, --CN, --NO.sub.2; or [0231]
(c) --OT.sub.3, --OC(.dbd.O)T.sub.3,
--OC(.dbd.O)N(T.sub.1)(T.sub.2), --OC(.dbd.O)OT.sub.3; or [0232]
(d) --C(.dbd.O)T.sub.3, --C(.dbd.O)OT.sub.3,
--C(.dbd.O)N(T.sub.1)(T.sub.2); or [0233] (e) --ST.sub.3,
--S(.dbd.O)T.sub.3, --S(.dbd.O).sub.2T.sub.3,
--S(.dbd.O).sub.2OT.sub.3, --S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--S(.dbd.O)OT.sub.3, --S(.dbd.O)N(T.sub.1)(T.sub.2); or [0234] (f)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O).sub.2T.sub.3,
--N(T.sub.3)S(.dbd.O).sub.2N(T.sub.1)(T.sub.2),
--N(T.sub.3)S(.dbd.O)T.sub.3,
--N(T.sub.3)S(.dbd.O)N(T.sub.1)(T.sub.2); or [0235] (g)
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.6-C.sub.14)bicycloalkyl,
--(C.sub.8-C.sub.20)tricycloalkyl,
--(C.sub.5-C.sub.10)cycloalkenyl,
--(C.sub.7-C.sub.14)bicycloalkenyl,
--(C.sub.8-C.sub.20)tricycloalkenyl, -(5- or
6-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle,
each of which is unsubstituted or substituted with 1, 2 or 3
independently selected R.sub.5 groups; or [0236] (h) -phenyl or
-(5- or 6-membered)heteroaryl, each of which is unsubstituted or
substituted with 1, 2 or 3 independently selected R.sub.6 groups;
E.sub.1 is selected from C(T.sub.3).sub.2, O, S or NT.sub.3; a is
an integer selected from 0, 1, 2, or 3; b is an integer selected
from 0, 1, 2, or 3; each R.sub.5 is independently selected from
--(C.sub.1-C.sub.4)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, -(5- or 6-membered)heteroaryl, -phenyl,
--(C.sub.1-C.sub.6)alkylCOOR.sub.7, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, .dbd.O,
.dbd.S, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--NR.sub.7(C.sub.1-C.sub.6)alkylCOOR.sub.7, --N(R.sub.7).sub.2,
--N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)--C(.dbd.O)OR.sub.7, --C(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)N(R.sub.7).sub.2, --OC(.dbd.O)OR.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.6 is
independently selected from --(C.sub.1-C.sub.4)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl, --OR.sub.7,
--SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo),
--CN, -halo, --N.sub.3, --NO.sub.2, --CH.dbd.N(R.sub.7),
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --N(R.sub.7)S(.dbd.O)R.sub.8,
--N(R.sub.7)S(.dbd.O).sub.2R.sub.8, --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.7)C(.dbd.O)N(R.sub.7).sub.2,
--N(R.sub.7)C(.dbd.O)OR.sub.8, --C(.dbd.O)R.sub.7,
--C(.dbd.O)N(R.sub.7).sub.2, --C(.dbd.O)OR.sub.7,
--OC(.dbd.O)R.sub.7, --OC(.dbd.O)N(R.sub.7).sub.2,
--OC(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.7 is independently selected
from --H, --(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)alkoxy,
--(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.5-C.sub.8)cycloalkenyl,
-phenyl, -benzyl, -(3- to 6-membered)heterocycle, -(5- to
10-membered)heteroaryl, --C(halo).sub.3, --CH(halo).sub.2, or
--CH.sub.2(halo); each R.sub.8 is independently selected from --H
or --(C.sub.1-C.sub.4)alkyl; each T.sub.1, T.sub.2, and T.sub.3 is
independently --H or --(C.sub.1-C.sub.10)alkyl which is
unsubstituted or substituted with 1, 2 or 3 independently selected
R.sub.5 groups; and each halo is independently selected from --F,
--Cl, --Br, or --I.
[0237] In a further embodiment, the present invention relates to a
compound having the following general formula (VII.1):
##STR00046##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl, or -(6-membered)heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.6 groups; R.sub.2 is selected from: [0238] (a) --H;
or [0239] (b) --(C.sub.1-C.sub.5)alkyl, --(C.sub.2-C.sub.5)alkenyl,
--(C.sub.2-C.sub.5)alkynyl, --(C.sub.1-C.sub.5)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.5-C.sub.10)cycloalkenyl, or
-(5- or 6-membered)heterocycle, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups; each
R.sub.3 is independently selected from --H, .dbd.O, .dbd.NT.sub.3,
or .dbd.S; R.sub.4 is selected from: [0240] (a) --H; or [0241] (b)
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, --N(T.sub.3)C(.dbd.O)OT.sub.3,
--N(T.sub.3)C(.dbd.O)N(T.sub.1)(T.sub.2); or [0242] (c) --OT.sub.3,
--OC(.dbd.O)T.sub.3; or [0243] (d) --C(.dbd.O)T.sub.3; or [0244]
(e) --(C.sub.1-C.sub.5)alkyl, --(C.sub.2-C.sub.5)alkenyl,
--(C.sub.2-C.sub.5)alkynyl, --(C.sub.1-C.sub.5)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --(C.sub.5-C.sub.10)cycloalkenyl, or
-(5- or 6-membered)heterocycle, each of which is unsubstituted or
substituted with 1 or 2 independently selected R.sub.5 groups; a is
an integer selected from 1, 2, or 3; b is an integer selected from
1, 2, or 3; each R.sub.5 is independently selected from
--(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --(C.sub.1-C.sub.3)alkylCOOR.sub.7,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, .dbd.O, .dbd.S, -halo, --N.sub.3,
--NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --(C.sub.1-C.sub.3)alkyl, --(C.sub.2-C.sub.3)alkenyl,
--(C.sub.2-C.sub.3)alkynyl, --OR.sub.7, --SR.sub.7,
--C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), --CN, -halo,
--N.sub.3, --NO.sub.2, --N(R.sub.7).sub.2, --N(R.sub.7)OH,
--C(.dbd.O)R.sub.7, --C(.dbd.O)OR.sub.7, --OC(.dbd.O)R.sub.7,
--S(.dbd.O)R.sub.7, or --S(.dbd.O).sub.2R.sub.7; each R.sub.7 is
independently selected from --H, --CH.sub.3, or --CH.sub.2CH.sub.3,
each T.sub.1, T.sub.2, and T.sub.3 is independently --H or
--(C.sub.1-C.sub.5)alkyl which is unsubstituted or substituted with
1 or 2 independently selected R.sub.5 groups; and each halo is
independently selected from --F, --Cl, --Br, or --I.
[0245] In a further embodiment, the present invention relates to a
compound having the following general formula (VII.2):
##STR00047##
or a pharmaceutically acceptable derivative thereof wherein:
R.sub.1 is selected from -phenyl or -heteroaryl selected from the
group consisting of pyridine, pyrazine, pyridazine and pyrimidine,
each of which is unsubstituted or substituted with 1 or 2
independently selected R.sub.6 groups; R.sub.2 is selected from
--(C.sub.1-C.sub.4)alkyl, --(C.sub.2-C.sub.4)alkenyl,
--(C.sub.2-C.sub.4)alkynyl, --(C.sub.1-C.sub.4)alkoxy, each of
which is unsubstituted or substituted with 1 or 2 independently
selected R.sub.5 groups; R.sub.4 is selected from
--N(T.sub.1)(T.sub.2), --N(T.sub.3)N(T.sub.1)(T.sub.2),
--N(T.sub.3)C(.dbd.O)T.sub.3, or --N(T.sub.3)C(.dbd.O)OT.sub.3; a
is an integer selected from 1 or 2; b is an integer selected from 1
or 2; each R.sub.5 is independently selected from --H,
--(C.sub.1-C.sub.2)alkyl, --(C.sub.2)alkenyl, --(C.sub.2)alkynyl,
--OR.sub.7, --SR.sub.7, --C(halo).sub.3, --CH(halo).sub.2,
--CH.sub.2(halo), --CN, -halo, --N.sub.3, --NO.sub.2,
--N(R.sub.7).sub.2, --N(R.sub.7)OH, --C(.dbd.O)R.sub.7,
--C(.dbd.O)OR.sub.7, --S(.dbd.O)R.sub.7, or
--S(.dbd.O).sub.2R.sub.7; each R.sub.6 is independently selected
from --C(halo).sub.3, --CH(halo).sub.2, --CH.sub.2(halo), or -halo;
each R.sub.7 is independently selected from --H, or --CH.sub.3; and
each T.sub.1, T.sub.2, and T.sub.3 is independently selected from
--H or --CH.sub.3; and each halo is independently selected from
--F, --Cl, --Br, or --I.
[0246] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is -phenyl, which is
unsubstituted or substituted with 1 or 2 independently selected
R.sub.6 groups.
[0247] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.1 is -phenyl, which is
unsubstituted or substituted with 1 or 2 independently selected
groups selected from --C(Cl).sub.3, --CH(Cl).sub.2, --CH.sub.2(Cl),
or --Cl.
[0248] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, wherein
##STR00048##
wherein R.sub.6 is selected from --H, --C(Cl).sub.3,
--CH(Cl).sub.2, --CH.sub.2(Cl), or --Cl.
[0249] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.2 is
--(C.sub.1-C.sub.4)alkyl.
[0250] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, wherein R.sub.4 is
--N(T.sub.1)(T.sub.2), wherein each T.sub.1, and T.sub.2 is
independently selected from --H or --CH.sub.3
[0251] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, wherein a=1 and b=1.
[0252] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, wherein halo is Cl.
Exemplified Compounds
[0253] In an optional embodiment, the present invention relates to
the compounds depicted in Table 1 or a pharmaceutically acceptable
derivative thereof.
TABLE-US-00002 TABLE 1 Com- pound Chemical structure I.3
##STR00049## II.3 ##STR00050## III.3 ##STR00051## IV.3 ##STR00052##
V.3 ##STR00053## VI.3 ##STR00054## VII.3 ##STR00055##
[0254] In an optional embodiment, the present invention relates to
a compound having the general formula (I.2) or a pharmaceutically
acceptable derivative thereof, where Compound (I.3) is
excluded.
[0255] In an optional embodiment, the present invention relates to
a compound having the general formula (II.2) or a pharmaceutically
acceptable derivative thereof, where Compound (II.3) is
excluded.
[0256] In an optional embodiment, the present invention relates to
a compound having the general formula (III.2) or a pharmaceutically
acceptable derivative thereof, where Compound (III.3) is
excluded.
[0257] In an optional embodiment, the present invention relates to
a compound having the general formula (IV.2) or a pharmaceutically
acceptable derivative thereof, where Compound (IV.3) is
excluded.
[0258] In an optional embodiment, the present invention relates to
a compound having the general formula (V.2) or a pharmaceutically
acceptable derivative thereof, where Compound (V.3) is
excluded.
[0259] In an optional embodiment, the present invention relates to
a compound having the general formula (VI.2) or a pharmaceutically
acceptable derivative thereof, where Compound (VI.3) is
excluded.
[0260] In an optional embodiment, the present invention relates to
a compound having the general formula (VII.2) or a pharmaceutically
acceptable derivative thereof, where Compound (VII.3) is
excluded.
DEFINITIONS
[0261] As used in connection with the Compounds herein, the terms
used herein having following meaning:
[0262] When a first group is "substituted with one or more" second
groups, one or more hydrogen atoms of the first group is replaced
with a corresponding number of second groups. When the number of
second groups is two or greater, each second group can be the same
or different. In one embodiment, a first group is substituted with
up to three second groups. In another embodiment, a first group is
substituted with one or two second groups. In another embodiment, a
first group is substituted with only one second group.
[0263] "--(C.sub.1-C.sub.10)alkyl" means a straight chain or
branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
Representative straight chain --(C.sub.1-C.sub.10)alkyls include
-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl,
-n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. A branched alkyl means
that one or more straight chain --(C.sub.1-C.sub.8)alkyl groups,
such as methyl, ethyl or propyl, replace one or both hydrogens in a
--CH.sub.2-- group of a straight chain alkyl. A branched non-cyclic
hydrocarbon means that one or more straight chain
--(C.sub.1-C.sub.10)alkyl groups, such as methyl, ethyl or propyl,
replace one or both hydrogens in a --CH.sub.2-- group of a straight
chain non-cyclic hydrocarbon. Representative branched
--(C.sub.1-C.sub.10)alkyls include -iso-propyl, -sec-butyl,
-iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl,
2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,
1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,
5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,
1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl,
1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.
[0264] "--(C.sub.1-C.sub.6)alkyl" means a straight chain or
branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
Representative straight chain --(C.sub.1-C.sub.6)alkyls include
-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl.
Representative branched --(C.sub.1-C.sub.6)alkyls include
-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,
-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,
2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and
3,3-dimethylbutyl.
[0265] "--(C.sub.1-C.sub.4)alkyl" means a straight chain or
branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms.
Representative straight chain --(C.sub.1-C.sub.4)alkyls include
-methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched
--(C.sub.1-C.sub.4)alkyls include -iso-propyl, -sec-butyl,
-iso-butyl, and -tert-butyl.
[0266] "--(C.sub.1-C.sub.3)alkyl" means a straight chain or
branched non-cyclic hydrocarbon having from 1 to 3 carbon atoms.
Representative straight chain --(C.sub.1-C.sub.3)alkyls include
-methyl, -ethyl, and -n-propyl. Representative branched
--(C.sub.1-C.sub.3)alkyls include -iso-propyl.
[0267] "--(C.sub.1-C.sub.2)alkyl" means a straight chain non-cyclic
hydrocarbon having 1 or 2 carbon atoms. Representative straight
chain --(C.sub.1-C.sub.2)alkyls include -methyl and -ethyl.
[0268] "--(C.sub.2-C.sub.10)alkenyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms
and including at least one carbon-carbon double bond. A branched
alkenyl means that one or more straight chain
--(C.sub.1-C.sub.8)alkyl groups, such as methyl, ethyl or propyl,
replace one or both hydrogens in a --CH.sub.2-- or --CH.dbd. group
of a straight chain alkenyl. Representative straight chain and
branched (C.sub.2-C.sub.10)alkenyls include -vinyl, -allyl,
-1-butenyl, -2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl,
-3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,
-1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl,
-3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl,
-2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl, and the
like.
[0269] "--(C.sub.2-C.sub.6)alkenyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and
including at least one carbon-carbon double bond. Representative
straight chain and branched (C.sub.2-C.sub.6)alkenyls include
-vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl,
-1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,
-2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl, and the
like.
[0270] "--(C.sub.2-C.sub.4)alkenyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 4 carbon atoms and
including at least one carbon-carbon double bond. Representative
(C.sub.2-C.sub.4)alkenyls include -vinyl, -allyl, -1-butenyl,
-2-butenyl, -iso-butylenyl, and the like.
[0271] "--(C.sub.2-C.sub.3)alkenyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 3 carbon atoms and
including at least one carbon-carbon double bond. Representative
(C.sub.2-C.sub.3)alkenyls include -vinyl, -allyl, and the like.
[0272] "--(C.sub.2)alkenyl" means a straight chain non-cyclic
hydrocarbon having 2 carbon atoms and including one carbon-carbon
double bond.
[0273] "--(C.sub.2-C.sub.10)alkynyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms
and including at least one carbon-carbon triple bond. A branched
alkynyl means that one or more straight chain
--(C.sub.1-C.sub.8)alkyl groups, such as methyl, ethyl or propyl,
replace one or both hydrogens in a --CH.sub.2-- group of a straight
chain alkynyl. Representative straight chain and branched
--(C.sub.2-C.sub.10)alkynyls include -acetylenyl, -propynyl,
-1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl,
-3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl,
-5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl,
-2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl,
-1-decynyl, -2-decynyl, -9-decynyl, and the like.
[0274] "--(C.sub.2-C.sub.6)alkynyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and
including at least one carbon-carbon triple bond. Representative
straight chain and branched (C.sub.2-C.sub.6)alkynyls include
-acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl,
-2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,
-2-hexynyl, -5-hexynyl, and the like.
[0275] "--(C.sub.2-C.sub.4)alkynyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 4 carbon atoms and
including at least one carbon-carbon triple bond. Representative
(C.sub.2-C.sub.4)alkynyls include -acetylenyl, -propynyl,
-1-butynyl, -2-butynyl, and the like.
[0276] "--(C.sub.2-C.sub.3)alkynyl" means a straight chain or
branched non-cyclic hydrocarbon having from 2 to 3 carbon atoms and
including at least one carbon-carbon triple bond. Representative
(C.sub.2-C.sub.3)alkynyls include -acetylenyl, -propynyl, and the
like.
[0277] "--(C.sub.2)alkynyl" means a straight chain non-cyclic
hydrocarbon having 2 carbon atoms and including one carbon-carbon
triple bond.
[0278] "--(C.sub.1-C.sub.6)alkoxy" means a straight chain or
branched non-cyclic hydrocarbon having one or more ether groups and
from 1 to 6 carbon atoms. Representative straight chain and
branched (C.sub.1-C.sub.6)alkoxys include -methoxy, -ethoxy,
methoxymethyl, 2-methoxyethyl, -5-methoxypentyl, 3-ethoxybutyl and
the like.
[0279] "--(C.sub.1-C.sub.4)alkoxy" means a straight chain or
branched non-cyclic hydrocarbon having one or more ether groups and
from 1 to 4 carbon atoms. Representative (C.sub.1-C.sub.4)alkoxys
include -methoxy, -ethoxy, methoxymethyl, 2-methoxyethyl, and the
like.
[0280] "--(C.sub.1-C.sub.3)alkoxy" means a straight chain or
branched non-cyclic hydrocarbon having one or more ether groups and
from 1 to 3 carbon atoms. Representative (C.sub.1-C.sub.3)alkoxys
include -methoxy, -ethoxy, methoxymethyl, 2-methoxyethyl, and the
like.
[0281] "--(C.sub.3-C.sub.14)cycloalkyl" means a saturated
monocyclic hydrocarbon having from 3 to 14 carbon atoms.
Representative (C.sub.3-C.sub.14)cycloalkyls are -cyclopropyl,
-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,
-cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl, and
-cyclotetradecyl.
[0282] "--(C.sub.3-C.sub.12)cycloalkyl" means a saturated
monocyclic hydrocarbon having from 3 to 12 carbon atoms.
Representative (C.sub.3-C.sub.12)cycloalkyls are -cyclopropyl,
-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,
-cyclononyl, -cyclodecyl, cycloundecyl, and -cyclododecyl.
[0283] "--(C.sub.6-C.sub.12)cycloalkyl" means a saturated
monocyclic hydrocarbon having from 6 to 12 carbon atoms.
Representative (C.sub.6-C.sub.12)cycloalkyls are -cyclohexyl,
-cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl, cycloundecyl,
and -cyclododecyl.
[0284] "--(C.sub.4-C.sub.8)cycloalkyl" or "4- to 8-member
cycloalkyl ring" means a saturated monocyclic hydrocarbon having
from 4 to 8 carbon atoms. Representative
--(C.sub.4-C.sub.8)cycloalkyls are -cyclobutyl, -cyclopentyl,
-cyclohexyl, -cycloheptyl, and -cyclooctyl.
[0285] "--(C.sub.3-C.sub.8)cycloalkyl" means a saturated monocyclic
hydrocarbon having from 3 to 8 carbon atoms. Representative
(C.sub.3-C.sub.8)cycloalkyls include -cyclopropyl, -cyclobutyl,
-cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl.
[0286] "--(C.sub.3-C.sub.7)cycloalkyl" means a saturated monocyclic
hydrocarbon having from 3 to 7 carbon atoms. Representative
(C.sub.3-C.sub.7)cycloalkyls include cyclopropyl, -cyclobutyl,
-cyclopentyl, -cyclohexyl, and -cycloheptyl.
[0287] "--(C.sub.6-C.sub.14)bicycloalkyl" means a bi-cyclic
hydrocarbon ring system having from 6 to 14 carbon atoms and at
least one saturated cyclic alkyl ring. Representative
--(C.sub.6-C.sub.14)bicycloalkyls include -indanyl, -norbornyl,
-1,2,3,4-tetrahydronaphthalenyl, -5,6,7,8-tetrahydronaphthalenyl,
-perhydronaphthalenyl, bicyclo[2.2.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, bicyclo[3.3.1]heptyl, bicyclo[3.2.1]octyl,
bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl,
bicyclo[4.2.2]decyl, bicyclo[4.3.2]undecyl, bicyclo[4.3.1]decyl,
and the like.
[0288] "--(C.sub.8-C.sub.20)tricycloalkyl" means a tri-cyclic
hydrocarbon ring system having from 8 to 20 carbon atoms and at
least one saturated cyclic alkyl ring. Representative
--(C.sub.8-C.sub.20)tricycloalkyls include -pyrenyl, -adamantyl,
noradamantyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl
-aceanthrenyl, -1,2,3,4-tetrahydropenanthrenyl,
-5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl,
tetradecahydro-1H-cyclohepta[a]naphthalenyl,
tetradecahydro-1H-cycloocta[e]indenyl,
tetradecahydro-1H-cyclohepta[e]azulenyl,
hexadecahydrocycloocta[b]naphthalenyl,
hexadecahydrocyclohepta[a]heptalenyl, tricyclo-pentadecanyl,
tricyclo-octadecanyl, tricyclo-nonadecanyl, tricyclo-icosanyl, and
the like.
[0289] "--(C.sub.3-C.sub.14)cycloalkenyl" means a cyclic
non-aromatic hydrocarbon having at least one carbon-carbon double
bond in the cyclic system and from 3 to 14 carbon atoms.
Representative (C.sub.3-C.sub.14)cycloalkenyls include
-cyclopropenyl, -cyclobutenyl, -cyclopentenyl, -cyclopentadienyl,
-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,
-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl,
-cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,
-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl,
-cyclotetradecenyl, -cyclododecadienyl, and the like.
[0290] "--(C.sub.5-C.sub.14)cycloalkenyl" means a cyclic
non-aromatic hydrocarbon having at least one carbon-carbon double
bond in the cyclic system and from 5 to 14 carbon atoms.
Representative (C.sub.5-C.sub.14)cycloalkenyls include
-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,
-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl,
-cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,
-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl,
-cyclodecenyl, -cyclodecadienyl, -cyclotetradecenyl,
-cyclododecadienyl, and the like.
[0291] "--(C.sub.6-C.sub.12)cycloalkenyl" means a cyclic
non-aromatic hydrocarbon having at least one carbon-carbon double
bond in the cyclic system and from 6 to 12 carbon atoms.
Representative (C.sub.6-C.sub.12)cycloalkenyls include
-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,
-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl,
-cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,
-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl,
-cyclododecadienyl, and the like.
[0292] "--(C.sub.5-C.sub.10)cycloalkenyl" means a cyclic
non-aromatic hydrocarbon having at least one carbon-carbon double
bond in the cyclic system and from 5 to 10 carbon atoms.
Representative (C.sub.5-C.sub.10)cycloalkenyls include
-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,
-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl,
-cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,
-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl,
-cyclodecenyl, -cyclodecadienyl, and the like.
[0293] "--(C.sub.5-C.sub.8)cycloalkenyl" means a cyclic
non-aromatic hydrocarbon having at least one carbon-carbon double
bond in the cyclic system and from 5 to 8 carbon atoms.
Representative (C.sub.5-C.sub.8)cycloalkenyls include
-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,
-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl,
-cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,
-cyclooctatetraenyl, and the like.
[0294] "--(C.sub.7-C.sub.14)bicycloalkenyl" means a bi-cyclic
hydrocarbon ring system having at least one carbon-carbon double
bond in each ring and from 7 to 14 carbon atoms. Representative
--(C.sub.7-C.sub.14)bicycloalkenyls include
-bicyclo[3.2.0]hept-2-enyl, -indenyl, -pentalenyl, -naphthalenyl,
-azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl,
norbornenyl, and the like.
[0295] "--(C.sub.8-C.sub.20)tricycloalkenyl" means a tri-cyclic
hydrocarbon ring system having at least one carbon-carbon double
bond in each ring and from 8 to 20 carbon atoms. Representative
--(C.sub.8-C.sub.20)tricycloalkenyls include -anthracenyl,
-phenanthrenyl, -phenalenyl, -acenaphthalenyl, as-indacenyl,
s-indacenyl, 2,3,6,7,8,9,10,11-octahydro-1H-cycloocta[e]indenyl,
2,3,4,7,8,9,10,11-octahydro-1H-cyclohepta[a]naphthalenyl,
8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalenyl,
2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-cyclohepta[a]heptalenyl,
1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-dicyclohepta[a,c]cyclooct-
enyl,
2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-dibenzo[a,c]cyclononenyl,
and the like.
[0296] "-(3- to 7-membered)heterocycle" or "-(3- to
7-membered)heterocyclo" means a 3-to 7-membered monocyclic
heterocyclic ring which is either saturated, unsaturated
non-aromatic, or aromatic. A 3-membered heterocycle can contain up
to 1 heteroatom, a 4-membered heterocycle can contain up to 2
heteroatoms, a 5-membered heterocycle can contain up to 4
heteroatoms, a 6-membered heterocycle can contain up to 4
heteroatoms, and a 7-membered heterocycle can contain up to 5
heteroatoms. Each heteroatom is independently selected from
nitrogen, which can be quaternized; oxygen; and sulfur, including
sulfoxide and sulfone. The -(3- to 7-membered)heterocycle can be
attached via a nitrogen or carbon atom. Representative -(3- to
7-membered)heterocycles include pyridyl, furyl, thiophenyl,
pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl,
thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,
pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl,
piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl,
hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl,
tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,
and the like.
[0297] "-(5- or 6-membered)heterocycle" or "-(5- or
6-membered)heterocyclo" means a 5- or 6-membered monocyclic
heterocyclic ring which is either saturated, unsaturated
non-aromatic, or aromatic. A 5-membered heterocycle can contain up
to 4 heteroatoms and a 6-membered heterocycle can contain up to 4
heteroatoms. Each heteroatom is independently selected from
nitrogen, which can be quaternized; oxygen; and sulfur, including
sulfoxide and sulfone. The -(5- or 6-membered)heterocycle can be
attached via a nitrogen or carbon atom. Representative -(5- or
6-membered)heterocycles include pyridyl, furyl, thiophenyl,
pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl,
thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,
pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl,
piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl,
hydantoinyl, valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl,
dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrazolyl, and the
like.
[0298] "-(3- to 5-membered)heterocycle" or "-(3- to
5-membered)heterocyclo" means a 3-to 5-membered monocyclic
heterocyclic ring which is either saturated, unsaturated
non-aromatic, or aromatic. A 3-membered heterocycle can contain up
to 1 heteroatom, a 4-membered heterocycle can contain up to 2
heteroatoms, and a 5-membered heterocycle can contain up to 4
heteroatoms. Each heteroatom is independently selected from
nitrogen, which can be quaternized; oxygen; and sulfur, including
sulfoxide and sulfone. The -(3- to 5-membered)heterocycle can be
attached via a nitrogen or carbon atom. Representative -(3- to
5-membered)heterocycles include furyl, thiophenyl, pyrrolyl,
oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl,
isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl,
pyrrolidinyl, 2,3-dihydrofuranyl, hydantoinyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl and the
like.
[0299] "-(7- to 10-membered)bicycloheterocycle" or "-(7- to
10-membered)bicycloheterocyclo" means a 7- to 10-membered bicyclic,
heterocyclic ring which is either saturated, unsaturated
non-aromatic, or aromatic. A -(7- to 10-membered)bicycloheterocycle
contains from 1 to 4 heteroatoms independently selected from
nitrogen, which can be quaternized; oxygen; and sulfur, including
sulfoxide and sulfone. The -(7- to 10-membered)bicycloheterocycle
can be attached via a nitrogen or carbon atom. Representative -(7-
to 10-membered)bicycloheterocycles include -quinolinyl,
-isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl,
-benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl,
-4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,
-naphthyridinyl, -carbazolyl, -.beta.-carbolinyl, -indolinyl,
-isoindolinyl, -1,2,3,4-tetrahydroquinolinyl,
-1,2,3,4-tetrahydroisoquinolinyl, pyrrolopyrrolyl and the like.
[0300] "--(C.sub.3-C.sub.12)cycloalkoxy" means a saturated
monocyclic hydrocarbon having from 3 to 12 carbon atoms where at
least one of the carbon atoms is replaced by an oxygen atom.
Representative (C.sub.3-C.sub.12)cycloalkoxy are -oxiranyl,
-oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,
-1,4-dioxanyl, -oxepanyl, -1,4-dioxepanyl, -oxocanyl,
-1,5-dioxocanyl, -1,3,5-trioxocanyl, -oxonanyl, -1,5-dioxonanyl,
-1,4,7-trioxonanyl, -oxacyclododecanyl, -1,7-dioxacyclododecanyl,
and -1,5,9-trioxacyclododecanyl.
[0301] "--(C.sub.3-C.sub.7)cycloalkoxy" means a saturated
monocyclic hydrocarbon having from 3 to 7 carbon atoms where at
least one of the carbon atoms is replaced by an oxygen atom.
Representative (C.sub.3-C.sub.7)cycloalkoxy are -oxiranyl,
-oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,
-1,4-dioxanyl, -oxepanyl, and -1,4-dioxepanyl.
[0302] "--(C.sub.14)aryl" means a 14-membered aromatic carbocyclic
moiety such as -anthryl or -phenanthryl.
[0303] "-(5- to 10-membered)heteroaryl" means an aromatic
heterocycle ring of 5 to 10 members, including both mono- and
bicyclic ring systems, where at least one carbon atom of one or
both of the rings is replaced with a heteroatom independently
selected from nitrogen, oxygen, and sulfur, or at least two carbon
atoms of one or both of the rings are replaced with a heteroatom
independently selected from nitrogen, oxygen, and sulfur. In one
embodiment, one of the -(5- to 10-membered)heteroaryl's rings
contain at least one carbon atom. In another embodiment, both of
the -(5- to 10-membered)heteroaryl's rings contain at least one
carbon atom. Representative -(5- to 10-membered)heteroaryls include
pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl,
quinolinyl, isoquinolinyl, pyrrolyl, indolyl, oxazolyl,
benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,
benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl, isothiazolyl,
pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl, thiadiazolyl,
triazinyl, thienyl, cinnolinyl, phthalazinyl, and quinazolinyl.
[0304] "-(5- or 6-membered)heteroaryl" means a monocyclic aromatic
heterocycle ring of 5 or 6 members where at least one carbon atom
is replaced with a heteroatom independently selected from nitrogen,
oxygen, and sulfur. In one embodiment, one of the -(5- or
6-membered)heteroaryl's ring contains at least one carbon atom.
Representative -(5- or 6-membered)heteroaryls include pyridyl,
furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,
pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.
[0305] "--CH.sub.2(halo)" means a methyl group where one of the
hydrogens of the methyl group has been replaced with a halogen.
Representative --CH.sub.2(halo) groups include --CH.sub.2F,
--CH.sub.2Cl, --CH.sub.2Br, and --CH.sub.2I.
[0306] "--CH(halo).sub.2" means a methyl group where two of the
hydrogens of the methyl group have been replaced with a halogen.
Representative --CH(halo).sub.2 groups include --CHF.sub.2,
--CHCl.sub.2, --CHBr.sub.2, --CHBrCl, --CHClI, and --CHI.
[0307] "--C(halo).sub.3" means a methyl group where each of the
hydrogens of the methyl group has been replaced with a halogen.
Representative --C(halo).sub.3 groups include --CF.sub.3,
--CCl.sub.3, --CBr.sub.3, and --Cl.sub.3.
[0308] "-Halogen" or "-halo" means --F, --Cl, --Br, or --I.
[0309] "Oxo", ".dbd.O", and the like as used herein mean an oxygen
atom doubly bonded to carbon or another element.
[0310] "Thiooxo", "thioxo", ".dbd.S", and the like as used herein
mean a sulfur atom doubly bonded to carbon or another element.
[0311] "Imino", ".dbd.NT.sub.3", and the like as used herein mean a
nitrogen atom doubly bonded to carbon or another element.
[0312] As used herein in connection with Formula (I), when the
dashed line in the 6-membered ring that is fused to the Q group is
absent, then Formula (I) is understood to appear as follows
##STR00056##
i.e., the 6-membered ring that is fused to the Q group contains no
double bond between the ring-carbon to which the R.sub.3 group is
attached and the adjacent carbon atom to which the R.sub.4 is
attached.
[0313] As used herein in connection with Formula (I), when the
dashed line in the 6-membered, nitrogen-containing ring that is
fused to the Q group indicates the presence of a bond, then Formula
(I) is understood to appear as follows
##STR00057##
i.e., the 6-membered ring that is fused to the Q group contains a
double bond between the ring-carbon to which the R.sub.3 group is
attached and the adjacent carbon atom to which the R.sub.4 is
attached.
[0314] As used herein in connection with Formula (I.1), when the
dashed line in the 6-membered ring that is fused to the Q group is
absent, then Formula (I.1) is understood to appear as follows
##STR00058##
i.e., the 6-membered ring that is fused to the Q group contains no
double bond between the ring-carbon to which the R.sub.3 group is
attached and the adjacent carbon atom to which the R.sub.4 is
attached.
[0315] As used herein in connection with Formula (I.1), when the
dashed line in the 6-membered, nitrogen-containing ring that is
fused to the Q group indicates the presence of a bond, then Formula
(I.1) is understood to appear as follows
##STR00059##
i.e., the 6-membered ring that is fused to the Q group contains a
double bond between the ring-carbon to which the R.sub.3 group is
attached and the adjacent carbon atom to which the R.sub.4 is
attached.
[0316] As used herein in connection with Formula (II), when the
dashed line is absent, then Formula (II) is understood to appear as
follows
##STR00060##
i.e., the Formula contains no double bond between the carbon atom
to which the R.sub.2 group and E are attached and the adjacent
carbon atom.
[0317] As used herein in connection with Formula (II), when the
dashed line is absent, then Formula (II) is understood to appear as
follows
##STR00061##
i.e., the Formula contains a double bond between the carbon atom to
which the R.sub.2 group and E are attached and the adjacent carbon
atom.
[0318] "(C.sub.2-C.sub.6)bridge" as used in connection with
Formulas (II) and (II.1) means a hydrocarbon chain containing 2 to
6 carbon atoms joining the two carbon atoms connected to R.sub.4
according to Formulas (II) and (II.1) to form a cyclic ring system.
Exemplary compounds of the invention include those with a
(C.sub.2)bridge, --CH.sub.2--CH.sub.2--, joining the two carbon
atoms connected to R.sub.4; a (C.sub.3)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--, joining the two carbon atoms
connected to R.sub.4; a (C.sub.4)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, joining the two carbon
atoms connected to R.sub.4; a (C.sub.5)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, joining the
two carbon atoms connected to R.sub.4; or a (C.sub.6)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
joining the two carbon atoms connected to R.sub.4. Examples of a
(C.sub.2-C.sub.6)bridge which optionally contains --HC.dbd.CH--
within the (C.sub.2-C.sub.6)bridge include --HC.dbd.CH--,
--CH.sub.2--HC.dbd.CH--, --HC.dbd.CH--CH.sub.2--,
--CH.sub.2--HC.dbd.CH--CH.sub.2--, and the like. Examples of a
(C.sub.2-C.sub.6)bridge which optionally contains --O-- within the
(C.sub.2-C.sub.6)bridge include --CH.sub.2--O--CH.sub.2--
(containing 2 carbon atoms), --CH.sub.2--O--CH.sub.2--CH.sub.2--
and --CH.sub.2--CH.sub.2--O--CH.sub.2-- (each containing 3 carbon
atoms), --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.2-- (each containing 4
carbon atoms), and the like.
[0319] As used herein in connection with Formula (III), when the
dashed line is absent, then Formula (II.1) is understood to appear
as follows
##STR00062##
i.e., the Formula contains no double bond between the carbon atom
to which the R.sub.2 group and E are attached and the adjacent
carbon atom.
[0320] As used herein in connection with Formula (II.1), when the
dashed line is absent, then Formula (II.1) is understood to appear
as follows
##STR00063##
i.e., the Formula contains a double bond between the carbon atom to
which the R.sub.2 group and E are attached and the adjacent carbon
atom.
[0321] As used herein in connection with Formula (II.2), when the
dashed line is absent, then Formula (II.2) is understood to appear
as follows
##STR00064##
i.e., the Formula contains no double bond between the carbon atom
to which the nitrogen is attached and the adjacent carbon atom
comprised by the 6-membered ring.
[0322] As used herein in connection with Formula (II.2), when the
dashed line is absent, then Formula (II.2) is understood to appear
as follows
##STR00065##
i.e., the Formula contains a double bond between the carbon atom to
which the nitrogen is attached and the adjacent carbon atom
comprised by the 6-membered ring.
[0323] As used herein in connection with Formula (III), when the
dashed line is absent, then Formula (III) is understood to appear
as follows
##STR00066##
i.e., the Formula contains no double bond between the carbon atom
to which R.sub.1 is attached and the adjacent E.sub.1 group.
[0324] As used herein in connection with Formula (III), when the
dashed line is absent, then Formula (III) is understood to appear
as follows
##STR00067##
i.e., the Formula contains a double bond between the carbon atom to
which R.sub.1 is attached and the adjacent E.sub.1 group.
[0325] As used herein in connection with Formula (IV), when the
dashed line is absent, then Formula (IV) is understood to appear as
follows
##STR00068##
i.e., the Formula contains no double bond between the carbon atom
to which E.sub.1 is attached and the adjacent carbon atom to which
R.sub.2 and E.sub.2 are attached.
[0326] As used herein in connection with Formula (IV), when the
dashed line is absent, then Formula (IV) is understood to appear as
follows
##STR00069##
i.e., the Formula contains a double bond between the carbon atom to
which E.sub.1 is attached and the adjacent carbon atom to which
R.sub.2 and E.sub.2 are attached.
[0327] As used herein in connection with Formula (IV.1), when both
dashed lines are absent, then Formula (IV.1) is understood to
appear as follows
##STR00070##
i.e., the Formula contains no double bond in the 6-membered ring
containing E.sub.3 and E.sub.4.
[0328] As used herein in connection with Formula (IV.1), when one
dashed line is absent, then Formula (IV.1) is understood to appear
as follows
##STR00071##
i.e., the Formula contains one double bond in the 6-membered ring
containing E.sub.3 and E.sub.4.
[0329] As used herein in connection with Formula (IV.1), when both
dashed lines are present, then Formula (IV.1) is understood to
appear as follows
##STR00072##
i.e., the Formula contains two double bonds in the 6-membered ring
containing E.sub.3 and E.sub.4.
[0330] As used herein in connection with Formula (V.1), when the
dashed line is absent, then Formula (V.1) is understood to appear
as follows
##STR00073##
i.e., the Formula contains no double bond in the 5-membered ring
containing E.sub.1 and E.sub.2.
[0331] As used herein in connection with Formula (V.1), when the
dashed line is present, then Formula (V.1) is understood to appear
as follows
##STR00074##
i.e., the Formula contains a double bond in the 5-membered ring
containing E.sub.1 and E.sub.2.
[0332] The phrase "benzo", "benzo group" and the like, when used in
connection with the optionally-substituted Q group in Formulas (I)
and (I.1), means
##STR00075##
where R.sub.1 and a are defined above for the compounds of Formulas
(I) and (IA).
[0333] The phrase "(5- or 6-membered)heteroaryl" when used in
connection with the optionally-substituted Q group in Formula (I),
means
##STR00076##
where at least one carbon atom is replaced with a heteroatom
independently selected from nitrogen, oxygen, and sulfur and
R.sub.1 and a are defined above for the compounds of Formula (I).
Representative -(5- or 6-membered)heteroaryls include pyridyl,
furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,
pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.
[0334] The phrase "6-membered heteroaryl" when used in connection
with the optionally-substituted Q group in Formula (I.1), means
##STR00077##
where at least one carbon atom is replaced with a nitrogen, and
R.sub.1 and a are defined above for the compounds of Formula (I.1).
Representative 6-membered heteroaryls include pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, and the like.
[0335] The phrase "pyridine", "pyridino group" and the like, when
used in connection with the optionally-substituted Q group in
Formulas (I) and (IA), means
##STR00078##
where R.sub.1 and a are defined above for the Compounds of Formulas
(I) and (I.1).
[0336] The phrase "pyrimidino", "pyrimidino group" and the like,
when used in connection with the optionally-substituted Q group in
Formulas (I) and (I.1), means
##STR00079##
where R.sub.1 and a are defined above for the Compounds of Formulas
(I) and (I.1).
[0337] The phrase "pyrazino", "pyrazino group" and the like, when
used in connection with the optionally-substituted Q group in
Formulas (I) and (I.1), means
##STR00080##
where R.sub.1 and a are defined above for the Compounds of Formulas
(I) and (I.1).
[0338] The phrase "pyridazino", "pyridazino group" and the like,
when used in connection with the optionally-substituted Q group in
Formulas (I) and (I.1), means
##STR00081##
where R.sub.1 and a are defined above for the Compounds of Formulas
(I) and (IA).
[0339] The phrase "pyridine", "pyridino group" and the like, when
used in connection with the optionally-substituted R.sub.3 group in
Formula (I.2) or with the optionally-substituted R.sub.1 group in
Formula (III.2) or with the optionally-substituted R.sub.3 group in
Formula (IV.2) or with the optionally-substituted R.sub.1 group in
Formula (VI.2) or with the optionally-substituted R.sub.1 group in
Formula (VII.2), means
##STR00082##
where R.sub.6 is defined above for the compounds of Formulas (I.2)
or (III.2) or (IV.2) or (VI.2) or (VII.2), respectively, and a is
an integer selected from 1 or 2.
[0340] The phrase "pyrimidine", "pyrimidino group" and the like,
when used in connection with the optionally-substituted R.sub.3
group in Formula (I.2) or with the optionally-substituted R.sub.1
group in Formula (III.2) or with the optionally-substituted R.sub.3
group in Formula (IV.2) or with the optionally-substituted R.sub.1
group in Formula (VI.2) or with the optionally-substituted R.sub.1
group in Formula (VII.2), means
##STR00083##
where R.sub.6 is defined above for the compounds of Formula (I.2)
or (III.2) or (IV.2) or (VI.2) or (VII.2), respectively, and a is
an integer selected from 1 or 2.
[0341] The phrase "pyrazine", "pyrazino group" and the like, when
used in connection with the optionally-substituted R.sub.3 group in
Formula (I.2) or with the optionally-substituted R.sub.1 group in
Formula (III.2) or with the optionally-substituted R.sub.3 group in
Formula (IV.2) or with the optionally-substituted R.sub.1 group in
Formula (VI.2) or with the optionally-substituted R.sub.1 group in
Formula (VII.2), means
##STR00084##
where R.sub.6 is defined above for the compounds of Formula (I.2)
or (III.2) or (IV.2) or (VI.2) or (VII.2), respectively, and a is
an integer selected from 1 or 2.
[0342] The phrase "pyridazine", "pyridazino group" and the like,
when used in connection with the optionally-substituted R.sub.3
group in Formula (I.2) or with the optionally-substituted R.sub.1
group in Formula (III.2) or with the optionally-substituted R.sub.3
group in Formula (IV.2) or with the optionally-substituted R.sub.1
group in Formula (VI.2) or with the optionally-substituted R.sub.1
group in Formula (VII.2), means
##STR00085##
where R.sub.6 is defined above for the compounds of Formula (I.2)
or (III.2) or (IV.2) or (VI.2) or (VII.2), respectively, and a is
an integer selected from 1 or 2.
[0343] The phrase "(C.sub.6)cycloalkyl" when used in connection
with the optionally-substituted Q.sub.1 group in Formula (V),
means
##STR00086##
where R.sub.2 is defined above for the compounds of Formula
(V).
[0344] The phrase "(C.sub.6)cycloalkenyl" when used in connection
with the optionally-substituted Q.sub.1 group in Formula (V),
means
##STR00087##
where the cyclic non-aromatic hydrocarbon has at least one
carbon-carbon double bond in the cyclic system and where R.sub.2 is
defined above for the compounds of Formula (V).
[0345] The phrase "(6-membered)heterocycle" when used in connection
with the optionally-substituted Q.sub.1 group in Formula (V),
means
##STR00088##
where at least one carbon atom in the ring is replaced with a
heteroatom independently selected from nitrogen, oxygen, and
sulfur, and where R.sub.2 is defined above for the compounds of
Formula (V).
[0346] The phrase "(6-membered)heteroaryl" when used in connection
with the optionally-substituted Q.sub.1 group in Formula (V),
means
##STR00089##
where at least one carbon atom in the ring is replaced with a
nitrogen, and where R.sub.2 is defined above for the compounds of
Formula (V).
[0347] The phrase "(6-membered)heterocycle" when used in connection
with the optionally-substituted Q.sub.1 group in Formula (V.1),
means
##STR00090##
where at least one further carbon atom in the ring can be replaced
with a heteroatom independently selected from nitrogen, oxygen, and
sulfur, and where R.sub.2 is defined above for the compounds of
Formula (V.1).
[0348] The phrase "(6-membered)heteroaryl" when used in connection
with the optionally-substituted Q.sub.1 group in Formula (V.1),
means
##STR00091##
where at least one further carbon atom in the ring can be replaced
with a nitrogen, and where R.sub.2 is defined above for the
compounds of Formula (V.1).
[0349] The phrase "benzo", "benzo group" and the like, when used in
connection with the optionally-substituted Q.sub.2 group in Formula
(V.1), means
##STR00092##
where R.sub.6 and a are defined above for the compounds of Formula
(V.1).
[0350] The phrase "(6-membered)heteroaryl" when used in connection
with the optionally-substituted Q.sub.2 group in Formula (V.1),
means
##STR00093##
where at least one carbon atom is replaced with a nitrogen, and
R.sub.6 and a are defined above for the compounds of Formula (V.1).
Representative (6-membered)heteroaryls include pyridyl,
pyridazinyl, pyrimidyl, and pyrazinyl.
[0351] The phrase "pyridine", "pyridino group" and the like, when
used in connection with the optionally-substituted Q.sub.2 group in
Formula (V.1), means
##STR00094##
where R.sub.6 and a are defined above for the Compounds of Formula
(V.1).
[0352] The phrase "pyrimidino", "pyrimidino group" and the like,
when used in connection with the optionally-substituted Q.sub.2
group in Formula (V.1), means
##STR00095##
where R.sub.6 and a are defined above for the Compounds of Formula
(V.1).
[0353] The phrase "pyrazino", "pyrazino group" and the like, when
used in connection with the optionally-substituted Q.sub.2 group in
Formula (V.1), means
##STR00096##
where R.sub.6 and a are defined above for the Compounds of Formula
(V.1).
[0354] The phrase "pyridazino", "pyridazino group" and the like,
when used in connection with the optionally-substituted Q.sub.2
group in Formula (V.1), means
##STR00097##
where R.sub.6 and a are defined above for the Compounds of Formula
(V.1).
[0355] "(2- to 6-membered)bridge" as used in connection with
Formula (V.1) means a hydrocarbon chain containing 1 to 6 carbon
atoms joining the two atoms of the phenyl ring of Formula (V.1)
connected to R.sub.2 to form a fused bicyclic ring system. For
example, compounds of the invention can comprise a
(C.sub.2-C.sub.6)bridge joining the two positions of the ring.
Exemplary compounds of the invention include those with a
(C.sub.2)bridge, --CH.sub.2--CH.sub.2--; a (C.sub.3)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--; a (C.sub.4)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--; a (C.sub.5)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--; or a
(C.sub.6)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--.
Examples of a (2- to 6-membered)bridge which optionally contains
--O-- within the bridge include --O--CH.sub.2--O-- (containing 1
carbon atom), --CH.sub.2--O--CH.sub.2-- (containing 2 carbon
atoms), --CH.sub.2--O--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--O--CH.sub.2-(each containing 3 carbon atoms),
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.2-- (each containing 4
carbon atoms), and the like.
[0356] "(2- to 6-membered)bridge" as used in connection with
Formulas (VI) and (VI.1) means a hydrocarbon chain containing 1 to
6 carbon atoms to form a cyclic ring system connected through just
one atom, i.e. the carbon atom connected to R.sub.1 is comprised by
the cyclic ring system. For example, compounds of the invention can
comprise a (C.sub.2-C.sub.6)bridge joining the two positions of the
ring. Exemplary compounds of the invention include those with a
(C.sub.2)bridge, --CH.sub.2--CH.sub.2--; a (C.sub.3)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--; a (C.sub.4)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--; a (C.sub.5)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--; or a
(C.sub.6)bridge,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--.
Examples of a (2- to 6-membered)bridge which optionally contains a
heteroatom selected from nitrogen, oxygen and sulfur within the
bridge include --CH.sub.2--O--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2-- (each containing 3 carbon
atoms), --CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2--,
--CH.sub.2--O--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.2-- (each containing 4
carbon atoms), and the like.
[0357] The term "animal" includes, but is not limited to, a human
or a non-human animal, such as a companion animal or livestock,
e.g., a cow, monkey, baboon, chimpanzee, horse, sheep, pig,
chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea
pig.
[0358] Preferably, the compounds of the present invention
selectively modulate vertebrate TRPM8, more preferably they
selectively modulate mammalian TRPM8 and most preferably they
selectively modulate human TRPM8.
[0359] The phrase "pharmaceutically acceptable derivative", as used
herein, includes any pharmaceutically acceptable salt, solvate,
prodrug, radiolabeled, stereoisomer, enantiomer, diastereomer,
other stereoisomeric form, racemic mixture, geometric isomer,
and/or tautomer, e.g., of a compound disclosed herein. In one
embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, solvate, radiolabeled,
stereoisomer, enantiomer, diastereomer, other stereoisomeric form,
racemic mixture, geometric isomer, and/or tautomer, e.g., of a
compound disclosed herein. In another embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, e.g., of a compound disclosed herein.
[0360] The phrase "pharmaceutically acceptable salt", as used
herein, is any pharmaceutically acceptable salt that can be
prepared from a compound disclosed herein including a salt formed
from an acid and a basic functional group, such as a nitrogen
group, of a compound disclosed herein. Illustrative salts include,
but are not limited, to sulfate, citrate, acetate,
trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,
bisulfate, phosphate, acid phosphate, isonicotinate, lactate,
salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucoronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term
"pharmaceutically acceptable salt" also includes a salt prepared
from a compound disclosed herein having an acidic functional group,
such as a carboxylic acid functional group, and a pharmaceutically
acceptable inorganic or organic base. Suitable bases include, but
are not limited to, hydroxides of alkali metals such as sodium,
potassium, cesium, and lithium; hydroxides of alkaline earth metal
such as calcium and magnesium; hydroxides of other metals, such as
aluminum and zinc; ammonia and organic amines, such as
unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;
dicyclohexylamine; tributyl amine; pyridine; picoline;
N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or
tris-(2-hydroxy-(C.sub.1-C.sub.3)alkyl amines), such as mono-,
bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine,
N,N-di-[(C.sub.1-C.sub.3)alkyl]-N-(hydroxy-(C.sub.1-C.sub.3)alkyl)-amines-
, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or
tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like. One skilled in the art will
recognize that, e.g., acid addition salts of a compound disclosed
herein can be prepared by reaction of the compounds with the
appropriate acid via a variety of known methods.
[0361] A compound disclosed herein can contain one or more
asymmetric centers and can thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The invention is
also meant to encompass all such possible forms as well as their
racemic and resolved forms or any mixture thereof. When a compound
disclosed herein contains an olefinic double bond or other center
of geometric asymmetry, and unless specified otherwise, it is
intended to include all "geometric isomers", e.g., both E and Z
geometric isomers. All "tautomers", e.g., ketone-enol, amide-imidic
acid, lactam-lactim, enamine-imine, amine-imine, and
enamine-enimine tautomers, are intended to be encompassed by the
invention as well.
[0362] As used herein, the terms "stereoisomer", "stereoisomeric
form", and the like are general terms for all isomers of individual
molecules that differ only in the orientation of their atoms in
space. It includes enantiomers and isomers of compounds with more
than one chiral center that are not mirror images of one another
("diastereomers").
[0363] The term "chiral center" refers to a carbon atom to which
four different groups are attached.
[0364] The term "enantiomer" or "enantiomeric" refers to a molecule
that is nonsuperimposeable on its mirror image and hence optically
active where the enantiomer rotates the plane of polarized light in
one direction and its mirror image rotates the plane of polarized
light in the opposite direction.
[0365] The term "racemic" refers to a mixture of equal parts of
enantiomers which is optically inactive.
[0366] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule.
[0367] Optical isomers of a compound disclosed herein can be
obtained by known techniques such as chiral chromatography or
formation of diastereomeric salts from an optically active acid or
base.
[0368] The phrases "treatment of", "treating", and the like include
the amelioration or cessation of a condition or a symptom thereof.
In one embodiment, treating includes inhibiting, for example,
decreasing the overall frequency of episodes of a condition or a
symptom thereof. The phrases "prevention of", "preventing", and the
like include the avoidance of the onset of a condition or a symptom
thereof. A "disorder" includes, but is not limited to, the
conditions defined above.
[0369] The term "half maximal effective concentration" or
"EC.sub.50" refers to the concentration of a compound disclosed
herein which induces a response on a channel halfway between the
baseline and maximum after some specified exposure time. The
EC.sub.50 of a graded dose response curve therefore represents the
concentration of a compound where 50% of its maximal effect (which
may be either agonistic or antagonistic) on the respective channel
is observed.
Preparation of the Compounds
[0370] The compounds disclosed herein are either commercially
available or can be made using conventional organic synthesis which
are known to the person skilled in the art.
Screening Method
[0371] As part of the invention, compound libraries can be employed
comprising compounds to be tested for having modulating activity
for one or more members of the transient receptor potential cation
channel families. The methods of the invention can employ such
compound libraries e.g. for identifying suitable modulators of
TRPM8 and/or any further member of the transient receptor potential
cation channel families.
[0372] In the context of the present invention, the term "chemical
library" means a collection of chemical compounds. A "chemical
library" employed in the present invention will comprise at least 2
different compounds, rarely less than about 5 compounds, usually at
least about 10 compounds, frequently will have about 50 compounds
or more, usually more than about 500 compounds such as about 15,000
compounds or more.
[0373] The activity of the compounds comprised by such compound
libraries on TRPM8 or TRPA 1 (or any further member of the
transient receptor potential cation channel families) can be
evaluated in a functional cell based assay. In such "functional
cell based assays" a compound-channel interaction can lead to a
functional response of the cell. The physiological response of the
cell, initiated by a screening compound can be quantified by using
recombinant reporter technology. It is known in the art that the
TRP channels are a family of ion channel proteins that mediate ion
influx of Na.sup.+ and Ca.sup.2+ and, in several cases, Mg.sup.2+.
In the case of TRPM8, assembly of the channel subunits as tetramers
results in the formation of cation-selective channels that permeate
calcium ions. Upon activation, a signal transduction cascade is
mediated by TRPM8, producing the perception of cold in the nervous
system. For instance, the action of menthol on TRPM8 provides the
"cool" sensation via activation of the channel and subsequent
increase of intracellular calcium ions in cells expressing the
channel. This calcium influx can be used as read-out in functional
cell based assays.
[0374] The sequences that encode the members of the transient
receptor potential cation channel families are available to the
person skilled in the art (cf. National Center for Biotechnology
Information website: http://www.ncbi.nlm.nih.gov). The methods of
amplifying and cloning such sequences (e.g., by PCR) are also
commonly known in the art. According to an optional embodiment,
TRPM8 (human) has the nucleic acid or amino acid sequence as
disclosed in GenBank Accession Number NM.sub.--024080 or
NP.sub.--076985.4 and TRPA1 (human) has the nucleic acid or amino
acid sequence as disclosed in GenBank Accession Number
NM.sub.--007332 or NP.sub.--015628.2.
[0375] Methods of providing suitable test systems are known to the
person skilled in the art. For example, a cell based test system
can be based on stably transfected cell lines expressing human
TRPM8 or TRPA1. Methods of producing suitable test systems are
disclosed, inter alia, in Behrendt H J et al., Br. J. Pharmacol.
2004, 141:737-745, which is enclosed herein by reference. According
to an optional embodiment, the functional cell based assay utilizes
human HEK293 cells recombinantly expressing human TRPM8 or TRPA1.
Agonistic or antagonistic action of a compound can be quantified
via a Ca.sup.2+-sensitive dye (such as FURA, Fluo-4, etc.), wherein
agonists produce an increase of intracellular calcium ions and
antagonists inhibit an increase of intracellular calcium ions
(e.g., triggered by endogenous ligands). Such assays are routine
and well known to the person skilled in the art.
[0376] According to an optional embodiment of the present
invention, a compound library comprising suitable compounds is
tested in a screening for agonistic and/or antagonistic activity
towards TRPM8 and/or other channels. Optionally, compounds can be
selected as development candidates, which compounds are agonists or
partial agonists of TRPM8 in cells expressing the channel, but do
substantially not exhibit agonist activity at another channel, such
as TRPA1, or at least to a lesser extend. Optionally, the compounds
can further be analyzed with regard to their EC.sub.50 values as
well as their efficacy values and/or can be analyzed in a
structure-action relationship. Such screening methods are routine
and well known to the person skilled in the art.
[0377] According to an embodiment, the present invention further
encompasses compounds which are identified in such a screening as
development candidates.
EMBODIMENTS OF THE INVENTION
[0378] The present invention relates to compounds which are capable
of producing a cooling sensation when they are brought into contact
with the human body. Such compounds have applications in many
fields, for example in oral and personal hygiene products and
foodstuffs, but also in cosmetics, pharmaceutical composition
products, textile products and packaging products.
[0379] As discussed above, a known compound for producing a
sensation of cold is menthol (2-isopropyl-5-methyl-cyclohexanol),
which has been extensively applied as an additive in, for example,
foodstuffs and oral hygiene products (see e.g.
http://www.leffingwell.com/menthol1/menthinfo.htm; Furrer S M et
al., Chem. Percept. 2008, 1(2):119-126). It is used primarily
because it elicits a sensation of coolness in the mouth, and
because it has a pleasing mint flavour and odour. The cooling
effect of menthol is due to the action of menthol as activating the
TRPM8 ligand on sensory/free nerve endings which detect thermal
stimuli. Without wishing to be bound by any theory, menthol is
believed to activate cold receptors on nerve endings. However, the
use of menthol is limited by its strong minty smell which is
undesirable for some applications and its relative volatility and
burning sensations at high concentrations through unintentional
activation of other TRPs/ion channels.
[0380] It was found that icilin was capable of producing the same
cooling effect as menthol. Icilin has a number of advantages over
menthol, for example it is more potent, and has a lower acute
toxicity, due to its lack of anaesthetic properties. Icilin was
considered to be a particularly useful compound for pharmacological
applications because it lacks the flavour and odour of menthol and
is not readily absorbed through the skin (see e.g. US 2006/0280697
A1 and WO 03/092697 A1).
[0381] The compounds and compositions disclosed in the present
invention have the ability to produce a cooling sensation when in
contact with the skin and/or mucosal membrane of a human or animal
body. The term "cooling sensation", as used herein, is thus
intended to mean any sensation of coolness which is perceived by
human or animal body. Such a cooling sensation is analogous to the
sensation produced by compounds such as menthol, and/or the
sensation elicited when cold-sensitive receptors, in particular
TRPM8, are stimulated.
[0382] A cooling sensation is desirable in many different
applications. For example, the compounds and compositions of the
invention have applications in a number of products, such as
cosmetic product compositions, food product compositions, textile
products, pharmaceutical product compositions and packaging
products.
[0383] In an embodiment, the present invention relates to a product
comprising a compound that, optionally selectively, modulates the
TRPM8 channel (e.g. as evaluated in a functional cell based assay
under standard conditions as described herein), and wherein the
product is selected from the group consisting of a cosmetic product
composition, a food product composition, a textile product, a
pharmaceutical product composition and a packaging product. It is
understood that such products can comprise any combination of
compounds as described herein above, and optionally can also
comprise further cooling agents.
[0384] In a further embodiment, the present invention relates to a
product comprising a compound that exhibits selective agonist
activity at the TRPM8 channel (e.g. as evaluated in a functional
cell based assay under standard conditions as described herein),
and wherein the product is selected from the group consisting of a
cosmetic product composition, a food product composition, a textile
product, a pharmaceutical product composition and a packaging
product.
[0385] In a further embodiment, the present invention relates to a
product comprising a compound that acts as a selective TRPM8
agonist or partial agonist (e.g. as evaluated in a functional cell
based assay under standard conditions as described herein), and
wherein the product is selected from the group consisting of a
cosmetic product composition, a food product composition, a textile
product, a pharmaceutical product composition and a packaging
product.
[0386] In a further embodiment, the present invention relates to a
product comprising an effective amount of a compound that acts as a
selective TRPM8 agonist or partial agonist (e.g. as evaluated in a
functional cell based assay under standard conditions as described
herein), and wherein the product is selected from the group
consisting of a cosmetic product composition, a food product
composition, a textile product, a pharmaceutical product
composition and a packaging product.
[0387] In a further embodiment, the present invention relates to a
product comprising a compound that exhibits an activity at TRPM8,
which activity is at least three times or even at least four times,
greater than the activity of the compound at TRPA1 (e.g. as
evaluated in a functional cell based assay under standard
conditions as described herein), and wherein the product is
selected from the group consisting of a cosmetic product
composition, a food product composition, a textile product, a
pharmaceutical product composition and a packaging product.
[0388] In a further embodiment, the present invention relates to a
product selected from the group consisting of a cosmetic product
composition, a food product composition, a textile product, a
pharmaceutical product composition and a packaging product, which
product comprises a compound selected from the group consisting of
Compounds I, II, III, IV, V, VI, VII, I.1, II.1, III.1, IV.1, V.1,
VI.1, VII.1, I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3,
III.3, IV.3, V.3, VI.3, and VII.3, wherein the Compounds have the
chemical structures as defined herein above.
[0389] In a further embodiment, the present invention relates to a
product selected from the group consisting of a cosmetic product
composition, a food product composition, a textile product, a
pharmaceutical product composition and a packaging product, which
product comprises a compound selected from the group consisting of
Compounds I.1, II.1, III.1, IV.1, V.1, VI.1, VII.1, I.2, II.2,
III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3,
and VII.3, wherein the Compounds have the chemical structures as
defined herein above.
[0390] In a further embodiment, the present invention relates to a
product selected from the group consisting of a cosmetic product
composition, a food product composition, a textile product, a
pharmaceutical product composition and a packaging product, which
product comprises a compound selected from the group consisting of
Compounds I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3,
III.3, IV.3, V.3, VI.3, and VII.3, wherein the Compounds have the
chemical structures as defined herein above.
[0391] In a further embodiment, the present invention relates to a
product selected from the group consisting of a cosmetic product
composition, a food product composition, a textile product, a
pharmaceutical product composition and a packaging product, which
product comprises a compound selected from the group consisting of
Compounds I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, wherein the
Compounds have the chemical structures as defined herein above.
[0392] In a further embodiment, the present invention relates to a
compound selected from the group consisting of Compounds I, II,
III, IV, V, VI, VII, I.1, II.1, III.1, IV.1, V.1, VI.1, VII.1, I.2,
II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3,
VI.3, and VII.3, wherein the Compounds have the chemical structures
as defined herein above. In a further embodiment, the present
invention relates to a compound selected from the group consisting
of Compounds I.1, II.1, III.1, IV.1, V.1, VI.1, VII.1, I.2, II.2,
III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3,
and VII.3, wherein the Compounds have the chemical structures as
defined herein above. In a further embodiment, the present
invention relates to a compound selected from the group consisting
of Compounds I.2, II.2, III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3,
III.3, IV.3, V.3, VI.3, and VII.3, wherein the Compounds have the
chemical structures as defined herein above. In a further
embodiment, the present invention relates to a compound selected
from the group consisting of Compounds I.2, II.2, III.2, IV.2, V.2,
VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, wherein
the Compounds have the chemical structures as defined herein above.
In a further embodiment, the present invention relates to a
compound selected from the group consisting of Compounds I.3, II.3,
III.3, IV.3, V.3, VI.3, and VII.3, wherein the Compounds have the
chemical structures as defined herein above.
[0393] Optionally, the compound exhibits an activity at TRPM8,
which activity is at least three times, optionally at least four
times, five times, seven times, ten times, 12 times, 15 times or 20
times, greater than the activity of the compound at TRPA1 (e.g. as
evaluated in a functional cell based assay under standard
conditions as described herein).
[0394] According to an optional embodiment, the compound acts as a
TRPM8 partial agonist or agonist (e.g. as evaluated in a functional
cell based assay under standard conditions as described herein).
According to an optional embodiment, the compound acts as a
selective TRPM8 partial agonist or agonist (e.g. as evaluated in a
functional cell based assay under standard conditions as described
herein).
[0395] According to an optional embodiment, the compound acts as a
selective TRPM8 partial antagonist or antagonist (e.g. as evaluated
in a functional cell based assay under standard conditions as
described herein).
[0396] According to a further optional embodiment, in a functional
cell based assay the compound modulates the intracellular calcium
level of human cells recombinantly expressing human TRPM8 at least
four times, five times, seven times, ten times, 12 times, 15 times
or 20 times more efficient than that of human cells recombinantly
expressing human TRPA1 (e.g. as evaluated in a functional cell
based assay under standard conditions as described herein).
[0397] According to an optional embodiment of the present
invention, the efficacy value of the compound with regard to TRPM8
(compared to 20 .mu.M menthol) is greater than 30%, 40%, 50%, 60%,
70%, 80%, 90%, 100% or 110% (as evaluated in a functional cell
based assay under standard conditions as described herein).
According to an optional embodiment of the present invention, the
EC.sub.50 value of the compound with regard to TRPM8 (agonistic
activity) is less than 20 .mu.M, 15 .mu.M, 12 .mu.M, 10 .mu.M, 8
.mu.M, 6 .mu.M or 4 .mu.M (as evaluated in a functional cell based
assay under standard conditions as described herein). According to
an optional embodiment of the present invention, the EC.sub.50
value of the compound with regard to TRPA1 (agonistic activity) is
greater than 50 .mu.M, 70 .mu.M, 90 .mu.M, 100 .mu.M, 110 .mu.M,
120 .mu.M or 130 .mu.M (as evaluated in a functional cell based
assay under standard conditions as described herein). According to
an optional embodiment of the present invention, the EC.sub.50
value of the compound with regard to TRPM8 (agonistic activity) is
about 4 times, 5 times, 7 times, 10 times, 15 times, 20 times, 25
times or 30 times lower than the EC.sub.50 value of a compound with
regard to TRPA1 (agonistic activity) as evaluated in a functional
cell based assay under standard conditions as described herein.
[0398] Optionally, the compound is selected from the group
consisting of Compounds I, II, III, IV, V, VI, VII, I.1, II.1,
III.1, IV.1, V.1, VI.1, VII.1, I.2, II.2, III.2, IV.2, V.2, VI.2,
VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, wherein the
Compounds have the chemical structures as defined herein above.
Optionally, the compound is selected from the group consisting of
Compounds I.1, II.1, III.1, IV.1, V.1, VI.1, VII.1, I.2, II.2,
III.2, IV.2, V.2, VI.2, VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3,
and VII.3, wherein the Compounds have the chemical structures as
defined herein above. Optionally, the compound is selected from the
group consisting of Compounds I.2, II.2, III.2, IV.2, V.2, VI.2,
VII.2, I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, wherein the
Compounds have the chemical structures as defined herein above.
Optionally, the compound is selected from the group consisting of
Compounds I.3, II.3, III.3, IV.3, V.3, VI.3, and VII.3, wherein the
Compounds have the chemical structures as defined herein above.
[0399] In one further embodiment, the present invention relates to
the use of a compound as defined herein above in a product selected
from the group consisting of a cosmetic product composition, a food
product composition, a textile product, a pharmaceutical product
composition, and a packaging product. In one further embodiment,
the present invention relates to a compound as defined herein above
for use in therapy. In one further embodiment, the present
invention relates to a compound as defined herein above for use in
the treatment of pain. In one further embodiment, the present
invention relates to an in vitro use of a compound as defined
herein above as cooling agent. In one further embodiment, the
present invention relates to a cosmetic use of a compound as
defined herein above as cooling agent. In one further embodiment,
the present invention relates to an in vitro method of modulating
the cold and menthol receptor TRPM8, wherein TRPM8 is contacted
with a compound as defined herein above.
[0400] In the context of the present invention, the phrase
"effective amount", when used in connection with a compound of the
invention, means an amount effective for: (a) treating or
preventing a condition; or (b) detectably activating TRPM8 function
in a cell (as evaluated in a functional cell based assay under
standard conditions as described herein). The terms "modulate",
"modulating", and the like as used herein with respect to TRPM8 or
TRPA1 mean the mediation of a pharmacodynamic response in a cell
from (i) inhibiting or activating the respective channel, or (ii)
directly or indirectly affecting the normal regulation of the
channel activity (e.g., as evaluated in a functional cell based
assay under standard conditions as described herein). Compounds
that modulate the channel activity include agonists, partial
agonists, antagonists, mixed agonists/antagonists, mixed partial
agonists/antagonists and compounds which directly or indirectly
affect regulation of the channel activity (as evaluated in a
functional cell based assay under standard conditions as described
herein).
[0401] The terms "selective modulation", "selectively modulate",
and the like as used herein with respect to TRPM8 or TRPA1 mean the
mediation of a pharmacodynamic response in a cell from (i)
inhibiting or activating the respective channel (in particular,
TRPM8) without substantially triggering another channel (in
particular, TRPA1), or (ii) directly or indirectly affecting the
normal regulation of the activity of the respective channel (in
particular, TRPM8) without substantially affecting the normal
regulation of the activity of another channel (in particular,
TRPA1) (e.g., as evaluated in a functional cell based assay under
standard conditions as described herein).
[0402] The terms "selective modulation of TRPM8", "selectively
modulate TRPM8", and the like as used herein with respect to TRPM8
mean the mediation of a pharmacodynamic response in a cell from (i)
inhibiting or activating TRPM8 without substantially triggering
TRPA1 (or at least to a lesser extend), or (ii) directly or
indirectly affecting the normal regulation of the activity of TRPM8
without substantially affecting the normal regulation of the
activity of TRPA1 (e.g., as evaluated in a functional cell based
assay under standard conditions as described herein).
[0403] As used herein, a compound disclosed herein that binds to a
channel and mimics the regulatory effect(s) of an endogenous ligand
is defined as an "agonist" (e.g., as evaluated in a functional cell
based assay under standard conditions as described herein). As used
herein, a compound that binds to a channel and is only partly
effective as an agonist is defined as a "partial agonist" (e.g., as
evaluated in a functional cell based assay under standard
conditions as described herein). As used herein, a compound that
binds to a channel but produces no regulatory effect, but rather
blocks binding of another agent to the channel or blocks the
functional modulation of the channel by another agent is defined as
an "antagonist" or "silent agonist" (i.e. a compound with no
efficacy but binding capacity). For an overview of drug binding
mechanisms see: Ross and Kenakin, Pharmacodynamics: Mechanisms of
Drug Action and the Relationship Between Drug Concentration and
Effect, Chapter 2 in Goodman & Gilman's The Pharmacological
Basis of Therapeutics 31-32 (J. G. Hardman, L. E. Limbird and A.
Goodman-Gilman eds., 10.sup.th ed 2001).
[0404] In the context of the present invention, the phrases
"selective agonist" or "exhibit selective agonist activity" and the
like, when used in connection with a compound of the invention,
mean a compound disclosed herein that binds to a channel (in
particular, TRPM8) and mimics the regulatory effect(s) of an
endogenous ligand (e.g., as evaluated in a functional cell based
assay under standard conditions as described herein), but does not
substantially activate further channels (in particular, TRPA1), or
at least to a lesser extend.
[0405] In the context of the present invention, the phrases
"selective TRPM8 partial agonist or agonist" or "exhibit selective
agonist activity at TRPM8" and the like, when used in connection
with a compound of the invention, means a compound that binds to
TRPM8 and mimics the regulatory effect(s) of an endogenous ligand
(e.g., as evaluated in a functional cell based assay under standard
conditions as described herein), but does not substantially
activate TRPA1, or at least to a lesser extend.
[0406] In the context of the present invention, the phrase
"antagonist" or "silent agonist", when used in connection with a
compound of the invention, means a compound according to the
invention that binds to a channel (in particular, TRPM8) and
produces no regulatory effect, but rather blocks binding of another
agent to the channel or blocks the functional modulation of the
channel by another agent such as an endogenous ligand, e.g., as
evaluated in a functional cell based assay under standard
conditions as described herein.
[0407] The term "exhibit activity on TRPM8" and the like as used
herein with respect to TRPM8 mean the agonist activity (if the
compound acts as agonist) or inhibitory activity (if the compound
acts as antagonist) at TRPM8, as can be evaluated in a functional
cell based assay under standard conditions as described herein.
Optionally, the term "exhibit activity at TRPM8" and the like as
used herein with respect to TRPM8 mean the agonist activity at
TRPM8, as can be evaluated in a functional cell based assay under
standard conditions as described herein.
[0408] As used herein, a functional cell based assay under standard
conditions means evaluating the cellular activity of compounds with
regard to the modulation of the intracellular calcium level using
cells recombinantly expressing human TRPM8 or human TRPA1. In
particular, in this context the term "standard conditions" means an
activity test using HEK293 cells recombinantly expressing either
human TRPM8 or human TRPA1, which cells have been contacted with a
calcium-sensitive dye (such as Fluo-4AM, i.e.
Fluo-4-acetoxymethylester), wherein the cells are incubated with
the compound to be tested, and receptor modulation is
quantitatively detected by calcium-dependent changes is
fluorescence intensity. Such a test system is disclosed, inter
alia, in Behrendt H J et al., Br. J. Pharmacol. 2004, 141:737-745,
which is enclosed herein by reference.
[0409] According to an optional embodiment, the cosmetic product
composition is selected from the group consisting of an insect
repellent composition, an oral hygiene composition, a skin care
composition, and a hair care composition. Personal hygiene
applications such as skin care compositions and hair care
compositions include lotions, shaving cream, post shaving
preparations, shampoos, conditioners, facial cleansers, soaps, bath
oils and foams, antiperspirants, deodorants. Oral hygiene
applications include toothpastes, mouthwashes, dental floss,
chewing gum and breath fresheners.
[0410] According to an optional embodiment, the food product
composition is selected from the group consisting of ice cream,
mousse, creme, beverages and confectionery. According to an
optional embodiment, the textile product is selected from the group
consisting of shirts, trousers, socks, towels, headgear, underwear
and shoes. According to an optional embodiment, the pharmaceutical
product composition is selected from the group consisting of
anticancer medicaments, bladder disease medicaments and medicaments
for the treatment of pain.
[0411] It is known in the art that modulators of TRPM8 (including
its insect analoga) can act as insect repellent, can have an
activity in the treatment of tumor (e.g., prostate tumors), can
have an activity in the treatment of inflammatory
pain/hyperalgesia, and can act as TRPM8 antagonists in the
treatment of bladder syndrome or an hyperactive bladder (cf. WO
2010/026094).
[0412] Accordingly, the present invention further relates to a
compound as defined herein above for use as insect repellent. The
present invention further relates to a compound as defined herein
above for use in the treatment of cancer, in particular prostate
cancer. The present invention further relates to a compound as
defined herein above for use in the treatment of inflammatory pain
or hyperalgesia. The present invention further relates to a
compound as defined herein above for use in the treatment of
bladder syndrome or hyperactive bladder.
[0413] A cooling sensation can be desirable in packaging products,
wherein such cooling sensation is particularly detected upon
contact with the content of such packaging products (which can
comprise different materials such as paper or plastics). Compounds
according to the present invention may be associated with the
packaging product material in various ways, e.g., by spin coating,
printing, micro capsules, direct incorporation into the material
(e.g. extrusion), covalent binding to molecules of the packaging
material etc. Suitable methods are known to the person skilled in
the art.
[0414] A cooling sensation can also be desirable in textile
products, wherein such cooling sensation is particularly detected
by wearing such products. Compounds according to the present
invention may be associated with the textile product material in
various ways, e.g., by spin coating, printing, micro capsules,
direct incorporation into the material (e.g. extrusion), covalent
binding to molecules of the packaging material etc. Suitable
methods are known to the person skilled in the art.
[0415] The specific nature of the products and compositions of the
present invention (e.g. the nature of the additional components,
the relative proportions of the components and the physical nature
of the composition) will depend on the particular application and
are known to the skilled person.
[0416] While the above invention has been described with respect to
some of its preferred embodiments, this is in no way to limit the
scope of the invention. The person skilled in the art is clearly
aware of further embodiments and alterations to the previously
described embodiments that are still within the scope of the
present invention.
EXAMPLES
[0417] A screening for novel modulators of TRPM8 was conducted. For
the screening, a routine screening setup was used. In particular,
the compounds comprised by a compound library were tested for
agonistic activity towards TRPM8 and a dose response analysis of
the most promising candidates was conducted (TRPM8 versus TRPA1).
In particular, promising candidates were analyzed with regard to
their EC.sub.50 values as well as their efficacy values, and 7
development candidates were selected (i.e. Compounds I.3, II.3,
III.3, IV.3, V.3, VI.3, and VII.3, as described herein above).
[0418] The IUPAC names of the compounds are as follows:
I.3=7-methoxy-2-methyl-3-phenyl-4H-chromen-4-one
II.3=2-{[(2,5-dimethoxyphenyl)amino]methylidene}-5,5-dimethylcyclohexane--
1,3-dione
III.3=3-(5-methylthiophen-2-yl)-N'-[(1E)-pyridin-4-ylmethylidene-
]-1H-pyrazole-5-carbohydrazide
IV.3=N-(2,5-dichlorophenyl)-2-[(6-oxo-4-propyl-1,6-dihydropyrimidin-2-yl)-
sulfanyl]acetamide
V.3=1-[4-(2H-1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-(2-methyl-1H-1,-
3-benzodiazol-1-yl)propan-1-one
VI.3=4-methyl-N-[(4-phenyloxan-4-yl)methyl]benzamide
VII.3=[3-(4-chlorophenyl)-4-methylpentyl][3-(dimethylamino)propyl]amine
[0419] These compounds are commercially available at, e.g.,
InterBioScreen Ltd.(Moscow, Russia), Vitas-M Laboratory Ltd.
(Moskow, Russia) or Princeton BioMolecular Research. Inc.
(Princeton, N.J., USA).
[0420] For the above analysis, a functional cell based assay under
standard conditions as described herein was used, i.e. the cellular
activity of the compounds with regard to the modulation of the
intracellular calcium level was evaluated using cells recombinantly
expressing human TRPM8 or human TRPA1. In particular, human cells
recombinantly expressing either human TRPM8 or human TRPA1 were
used, which cells have been contacted with a calcium-sensitive dye,
wherein the cells were incubated with the compound to be tested,
and receptor modulation was quantitatively detected by
calcium-dependent changes in fluorescence intensity. Such a test
system is disclosed, inter alia, in Behrendt H J et al., Br. J.
Pharmacol. 2004, 141:737-745, which is enclosed herein by
reference. Such a test system is also disclosed, inter alia, in WO
2010/026094, which is also enclosed herein by reference. However,
it should be understood that any screening method and method
suitable for evaluating the agonistic activity of compounds towards
a channel (such as TRPM8) can be used. Suitable methods are routine
and known to the skilled person.
[0421] The dose response analysis of the 7 development candidates
are depicted in FIGS. 1-7 and summarized in Table 2.
TABLE-US-00003 TABLE 2 EC.sub.50 EC.sub.50 Efficacy for TRPM8
(TRPM8) (TRPA1) activation (in %) Compound (in .mu.M) (in .mu.M)
(compared to 20 .mu.M menthol) I.3 2.01 72.42 110.06 II.3 8.01
123.22 46.59 III.3 5.27 113.40 97.65 IV.3 4.12 117.89 34.14 V.3
7.53 138.37 70.90 VI.3 8.15 107.64 95.36 VII.3 10.94 56.62
45.12
* * * * *
References