U.S. patent application number 13/027901 was filed with the patent office on 2011-06-09 for 2-propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity.
This patent application is currently assigned to University of Virginia Patent Foundation. Invention is credited to Robert Alan Figler, Joel M. Linden, Timothy L. Macdonald, Lauren J. Murphree, Jayson M. Rieger, Gail W. Sullivan.
Application Number | 20110136755 13/027901 |
Document ID | / |
Family ID | 35787921 |
Filed Date | 2011-06-09 |
United States Patent
Application |
20110136755 |
Kind Code |
A1 |
Rieger; Jayson M. ; et
al. |
June 9, 2011 |
2-PROPYNYL ADENOSINE ANALOGS WITH MODIFIED 5'-RIBOSE GROUPS HAVING
A2A AGONIST ACTIVITY
Abstract
The invention provides compounds having the following general
formula (I): ##STR00001## wherein X, R.sup.1, R.sup.2, R.sup.7 and
Z are as described herein.
Inventors: |
Rieger; Jayson M.;
(Charlottesville, VA) ; Linden; Joel M.; (La
Jolla, CA) ; Macdonald; Timothy L.; (Charlottesville,
VA) ; Sullivan; Gail W.; (Charlottesville, VA)
; Murphree; Lauren J.; (Rockville, MD) ; Figler;
Robert Alan; (Earlysville, VA) |
Assignee: |
University of Virginia Patent
Foundation
Charlottesville
VA
|
Family ID: |
35787921 |
Appl. No.: |
13/027901 |
Filed: |
February 15, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12487235 |
Jun 18, 2009 |
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13027901 |
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11196529 |
Aug 2, 2005 |
7605143 |
|
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12487235 |
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60598018 |
Aug 2, 2004 |
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Current U.S.
Class: |
514/46 |
Current CPC
Class: |
A61P 31/10 20180101;
A61P 31/00 20180101; A61P 35/00 20180101; A61P 29/00 20180101; A61P
31/12 20180101; A61P 37/08 20180101; A61P 17/02 20180101; A61P 9/00
20180101; A61P 19/06 20180101; C07H 19/16 20130101; C07H 19/167
20130101; A61P 43/00 20180101; A61K 31/7076 20130101; A61P 17/00
20180101; A61P 9/10 20180101; A61K 45/06 20130101; A61K 31/7076
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/46 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076 |
Goverment Interests
GOVERNMENT FUNDING
[0002] This invention was made with government support under Grant
No. (RO1-HL37942) awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A composition comprising a compound of formula ##STR00105## or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable diluent or carrier.
2. A composition comprising a compound of formula ##STR00106## or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable diluent or carrier.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of and claims the benefit
of priority under 35 U.S.C. .sctn.120 to U.S. patent application
Ser. No. 12/487,235, filed on Jun. 18, 2009, entitled: "2-PROPYNYL
ADENOSINE ANALOGS WITH MODIFIED 5'-RIBOSE GROUPS HAVING A.sub.2A
AGONIST ACTIVITY," which is a continuation of and claims the
benefit of priority under 35 U.S.C. .sctn.120 to U.S. patent
application Ser. No. 11/196,529, filed on Aug. 2, 2005, entitled:
"2-PROPYNYL ADENOSINE ANALOGS WITH MODIFIED 5'-RIBOSE GROUPS HAVING
A.sub.2A AGONIST ACTIVITY", which claims the benefit of priority
under 35 U.S.C. .sctn.119(e) to U.S. Provisional Patent Application
Ser. No. 60/598,018, filed on Aug. 2, 2004, entitled: "2-PROPYNYL
ADENOSINE ANALOGS and COMPOSITIONS WITH MODIFIED 5'-RIBOSE GROUPS
HAVING A.sub.2A AGONIST ACTIVITY," the benefit of priority of each
of which is claimed hereby, and each of which are incorporated by
reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0003] The inflammatory response serves the purpose of eliminating
harmful agents from the body. There is a wide range of pathogenic
insults that can initiate an inflammatory response including
infection, allergens, autoimmune stimuli, immune response to
transplanted tissue, noxious chemicals, and toxins,
ischemia/reperfusion, hypoxia, mechanical and thermal trauma.
Inflammation normally is a very localized action, which serves in
expulsion, attenuation by dilution, and isolation of the damaging
agent and injured tissue. The body's response becomes an agent of
disease when it results in inappropriate injury to host tissues in
the process of eliminating the targeted agent, or responding to a
traumatic insult.
[0004] As examples, inflammation is a component of pathogenesis in
several vascular diseases or injuries. Examples include:
ischemia/reperfusion injury (N. G. Frangogiannis et al., in
Myocardial Ischemia: Mechanisms, Reperfusion, Protection, M.
Karmazyn, ed., Birkhuser Verlag (1996) at 236-284; H. S. Sharma et
al., Med. of Inflamm., 6, 175 (1987)), atherosclerosis (R. Ross,
Nature, 362, 801 (1993)), inflammatory aortic aneurysms (N. Girardi
et al., Ann Thor. Surg., 64, 251 (1997); D. I. Walker et al., Brit.
J. Surg., 59, 609 (1972); R. L. Pennell et al., J. Vasc. Surg., 2,
859 (1985)), and restenosis following balloon angioplasty (see, R.
Ross cited above). The cells involved with inflammation include
leukocytes (i.e., the immune system cells--neutrophils,
eosinophils, lymphocytes, monocytes, basophils, macrophages,
dendritic cells, and mast cells), the vascular endothelium,
vascular smooth muscle cells, fibroblasts, and myocytes.
[0005] The release of inflammatory cytokines such as tumor necrosis
factor-alpha (TNF.alpha.) by leukocytes is a means by which the
immune system combats pathogenic invasions, including infections.
TNF.alpha. stimulates the expression and activation of adherence
factors on leukocytes and endothelial cells, primes neutrophils for
an enhanced inflammatory response to secondary stimuli and enhances
adherent neutrophil oxidative activity. See, Sharma et al., cited
herein. In addition, macrophages/dendritic cells act as accessory
cells processing antigen for presentation to lymphocytes. The
lymphocytes, in turn, become stimulated to act as pro-inflammatory
cytotoxic cells.
[0006] Generally, cytokines stimulate neutrophils to enhance
oxidative (e.g., superoxide and secondary products) and
non-oxidative (e.g., myeloperoxidase and other enzymes)
inflammatory activity. Inappropriate and over-release of cytokines
can produce counterproductive exaggerated pathogenic effects
through the release of tissue-damaging oxidative and non-oxidative
products (K. G. Tracey et al., J. Exp. Med., 167, 1211 (1988); and
D. N. Mannel et al., Rev. Infect. Dis., 9 (suppl. 5), S602-S606
(1987)). For example, TNF.alpha. can induce neutrophils to adhere
to the blood vessel wall and then to migrate through the vessel to
the site of injury and release their oxidative and non-oxidative
inflammatory products.
[0007] Although monocytes collect slowly at inflammatory foci,
given favorable conditions, the monocytes develop into long-term
resident accessory cells and macrophages. Upon stimulation with an
inflammation trigger, monocytes/macrophages also produce and
secrete an array of cytokines (including TNF.alpha.), complement,
lipids, reactive oxygen species, proteases and growth factors that
remodel tissue and regulate surrounding tissue functions.
[0008] For example, inflammatory cytokines have been shown to be
pathogenic in: arthritis (C. A. Dinarello, Semin. Immunol., 4, 133
(1992)); ischemia (A. Seekamp et al., Agents-Actions-Supp., 41, 137
(1993)); septic shock (D. N. Mannel et al., Rev. Infect. Dis., 9
(suppl. 5), S602-S606 (1987)); asthma (N. M. Cembrzynska et al.,
Am. Rev. Respir. Dis., 147, 291 (1993)); organ transplant rejection
(D. K. Imagawa et al., Transplantation, 51, 57 (1991); multiple
sclerosis (H. P. Hartung, Ann Neurol., 33, 591 (1993)); AIDS (T.
Matsuyama et al., AIDS, 5, 1405 (1991)); and in alkali-burned eyes
(F. Miyamoto et al., Opthalmic Res., 30, 168 (1997)). In addition,
superoxide formation in leukocytes has been implicated in promoting
replication of the human immunodeficiency virus (HIV) (S.
Legrand-Poels et al., AIDS Res. Hum. Retroviruses, 6, 1389
(1990)).
[0009] It is well known that adenosine and some analogs of
adenosine that non-selectively activate adenosine receptor subtypes
decrease neutrophil production of inflammatory oxidative products
(B. N. Cronstein et al., Ann N.Y. Acad. Sci., 451, 291 (1985); P.
A. Roberts et al., Biochem. J., 227, 669 (1985); D. J. Schrier et
al., J. Immunol., 137, 3284 (1986); B. N. Cronstein et al.,
Clinical Immunol. and Immunopath., 42, 76 (1987); M. A Iannone et
al., in Topics and Perspective in Adenosine Research, E. Gerlach et
al., eds., Springer-Verlag, Berlin, p. 286 (1987); S. T. McGarrity
et al., J. Leukocyte Biol., 44, 411421 (1988); J. De La Harpe et
al., J. Immunol., 143, 596 (1989); S. T. McGarrity et al., J.
Immunol., 142, 1986 (1989); and C. P. Nielson et al., Br. J.
Pharmacol., 97, 882 (1989)). For example, adenosine has been shown
to inhibit superoxide release from neutrophils stimulated by
chemoattractants such as the synthetic mimic of bacterial peptides,
f-met-leu-phe (fMLP), and the complement component C.sub.5a (B. N.
Cronstein et al., J. Immunol., 135, 1366 (1985)). Adenosine can
decrease the greatly enhanced oxidative burst of PMN (neutrophil)
first primed with TNF-.alpha. and then stimulated by a second
stimulus such as f-met-leu-phe (G. W. Sullivan et al., Clin. Res.,
41, 172A (1993)). Additionally, it has been reported that adenosine
can decrease the rate of HIV replication in a T-cell line (S. Sipka
et al., Acta. Biochim. Biopys. Hung., 23, 75 (1988)). However,
there is no evidence that in vivo adenosine has anti-inflammatory
activity (G. S. Firestein et al., Clin. Res., 41, 170A (1993); and
B. N. Cronstein et al., Clin. Res., 41, 244A (1993)).
[0010] It has been suggested that there is more than one subtype of
adenosine receptor on neutrophils that can have opposite effects on
superoxide release (B. N. Cronstein et al., J. Clin. Invest., 85,
1150 (1990)). The existence of A.sub.2A receptor on neutrophils was
originally demonstrated by Van Calker et al. (D. Van Calker et al.,
Eur. J. Pharmacology, 206, 285 (1991)).
[0011] There has been progressive development of compounds that are
more and more potent and/or selective as agonists of A.sub.2A
adenosine receptors (AR) based on radioligand binding assays and
physiological responses. Initially, compounds with little or no
selectivity for A.sub.2A receptors were developed, such as
adenosine itself or 5'-carboxamides of adenosine, such as
5'-N-ethylcarboxamidoadenosine (NECA) (B. N. Cronstein et al., J.
Immunol., 135, 1366 (1985)). Later, it was shown that addition of
2-alkylamino substituents increased potency and selectivity, e.g.,
CV1808 and CGS21680 (M. F. Jarvis et al., J. Pharmacol. Exp. Ther.,
251, 888 (1989)). 2-Alkoxy-substituted adenosine derivatives such
as WRC-0090 are even more potent and selective as agonists at the
coronary artery A.sub.2A receptor (M. Ueeda et al., J. Med. Chem.,
34, 1334 (1991)). The 2-alklylhydrazino adenosine derivatives,
e.g., SHA 211 (also called WRC-0474) have also been evaluated as
agonists at the coronary artery A.sub.2A receptor (K. Niiya et al.,
J. Med. Chem., 35, 4557 (1992)).
[0012] There is one report of the combination of relatively
nonspecific adenosine analogs, R-phenylisopropyladenosine (R-PIA)
and 2-chloroadenosine (Cl-Ado) with a phosphodiesterase (PDE)
inhibitor resulting in a lowering of neutrophil oxidative activity
(M. A Iannone et al., Topics and Perspectives in Adenosine
Research, E. Garlach et al., eds., Springer-Verlag, Berlin, pp.
286-298 (1987)). However, R-PIA and Cl-Ado analogs are actually
more potent activators of A.sub.1 adenosine receptors than of
A.sub.2A adenosine receptors and, thus, are likely to cause side
effects due to activation of A.sub.1 receptors on cardiac muscle
and other tissues causing effects such as "heart block."
[0013] R. A. Olsson et al. (U.S. Pat. No. 5,278,150) disclose
selective adenosine A.sub.2 receptor agonists of the formula:
##STR00002##
wherein Rib is ribosyl, R.sub.1 can be H and R.sub.2 can be
cycloalkyl. The compounds are disclosed to be useful for treating
hypertension, atherosclerosis and as vasodilators.
[0014] Olsson et al. (U.S. Pat. No. 5,140,015) disclose certain
adenosine A.sub.2 receptor agonists of formula:
##STR00003##
wherein C(X)BR.sub.2 can be CH.sub.2OH and R.sub.1 can be alkyl- or
alkoxyalkyl. The compounds are disclosed to be useful as
vasodilators or an antihypertensives.
[0015] Linden et al. (U.S. Pat. No. 5,877,180) is based on the
discovery that certain inflammatory diseases, such as arthritis and
asthma, may be effectively treated by the administration of
compounds which are selective agonists of A.sub.2A adenosine
receptors, preferably in combination with a Type IV
phosphodiesterase inhibitor. An embodiment of the Linden et al.
invention provides a method for treating inflammatory diseases by
administering an effective amount of an A.sub.2A adenosine receptor
of the following formula:
##STR00004##
wherein R and X are as described in the patent.
[0016] In one embodiment, the Linden et al. invention involves the
administration of a Type IV phosphodiesterase (PDE) inhibitor in
combination with the A.sub.2A adenosine receptor agonist. The Type
IV phosphodiesterase (PDE) inhibitor includes racemic and optically
active 4-(polyalkoxyphenyl)-2-pyrrolidones of the following
formula:
##STR00005##
wherein RN, R.sup.18, R.sup.19 and X are as disclosed and described
in U.S. Pat. No. 4,193,926. Rolipram is an example of a suitable
Type IV PDE inhibitor included within the above formula.
[0017] G. Cristalli (U.S. Pat. No. 5,593,975) discloses
2-arylethynyl, 2-cycloalkylethynyl or 2-hydroxyalkylethynyl
derivatives, wherein the riboside residue is substituted by carboxy
amino, or substituted carboxy amino (R.sub.3HNC(O)--).
2-Alkynylpurine derivatives have been disclosed in Miyasaka et al.
(U.S. Pat. No. 4,956,345), wherein the 2-alkynyl group is
substituted with (C.sub.3-C.sub.16)alkyl. The '975 compounds are
disclosed to be vasodilators and to inhibit platelet aggregation,
and thus to be useful as anti-ischemic, anti-atherosclerosis and
anti-hypertensive agents.
[0018] Recently, U.S. Pat. No. 6,232,297 to Linden, et al.
disclosed compounds having the general formula:
##STR00006##
[0019] wherein each R is H, X is ethylaminocarbonyl and R.sup.1 is
4-carboxycyclo-hexylmethyl (DWH-146a), R.sup.1 is
4-methoxycarbonylcyclohexylmethyl (DWH-146e) or R.sup.1 is
4-acetoxymethyl-cyclohexylmethyl (JMR-193). These compounds are
reported to be A.sub.2A agonists.
[0020] However, a continuing need exists for selective A.sub.2
adenosine receptor agonists useful for therapeutic applications,
which have reduced side effects. In addition, a continuing need
exists for selective A2 adenosine receptor agonists useful for use
as pharmacological stressors in stress imaging or in other
ventricular function imaging techniques, that preferably have
reduced side effects, while being chemically stable and
short-acting.
SUMMARY OF THE INVENTION
[0021] The present invention comprises compounds and methods of
their use for the treatment of inflammatory activity in mammalian
tissue. The inflammatory tissue activity can be due to pathological
agents or can be due to physical, chemical or thermal trauma, or
the trauma of medical procedures, such as organ, tissue or cell
transplantation, angioplasty (PCTA), inflammation following
ischemia/reperfusion, or grafting. The present compounds comprise a
novel class of 2-alkynyladenosine derivatives, substituted at the
ethyn-2-yl position by substituted cycloalkyl and heterocycle
(heterocyclic) moieties. Preferably, the riboside residue is
modified at the 5'-position by substituting an
N-(cycloalkyl)carboxyamino ("aminocarbonyl") moiety ("X") or a 5-
or 6-membered heterocyclic ring. Thus, the present invention
provides a method for inhibiting the inflammatory response in a
mammal, such as a human subject, and protecting the tissue subject
to the response, by administering an effective amount of one or
more compounds of the invention.
[0022] The compounds of the invention have general formula (I):
##STR00007##
[0023] wherein
[0024] Z is CR.sup.3R.sup.4R.sup.5 or NR.sup.4R.sup.5;
[0025] each R.sup.1 is independently hydrogen, halo, --OR.sup.a,
--SR.sup.a, (C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.3-8cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkylene-, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --N.dbd.NR.sup.a, or
--OPO.sub.21V;
[0026] each R.sup.2 is independently hydrogen, halo,
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene-; or
[0027] R.sup.1 and R.sup.2 and the atom to which they are attached
is C.dbd.O, C.dbd.S or C.dbd.NR.sup.c.
[0028] R.sup.4 and R.sup.5 together with the atoms to which they
are attached form a saturated or partially unsaturated, or aromatic
ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms optionally
comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy
(--O--), thio (--S--), sulfinyl (--SO--), sulfonyl (--S(O).sub.2--)
or amine (--NR.sup.a--) in the ring;
[0029] wherein any ring comprising R.sup.4 and R.sup.5 is
substituted with from 1 to 14 R.sup.6 groups;
[0030] wherein each R.sup.6 is independently hydrogen, halo,
--OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)cycloalkyl(C.sub.1-C.sub.8)alkylene-,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle or heterocycle
(C.sub.1-C.sub.8)alkylene-, aryl, aryl (C.sub.1-C.sub.8)alkylene-,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-,
--CO.sub.2R.sup.a, R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--,
--OCO.sub.2R.sup.a, R.sup.aR.sup.bNC(.dbd.O)O--,
R.sup.bOC(.dbd.O)N(R.sup.a)--, R.sup.aR.sup.bN--,
R.sup.aR.sup.bNC(.dbd.O)--, R.sup.aC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, --NNR.sup.a, --OPO.sub.2R.sup.a, or two R.sup.6
groups and the atom to which they are attached is C.dbd.O, or
C.dbd.S; or two R.sup.6 groups together with the atom or atoms to
which they are attached can form a carbocyclic or a heterocyclic
ring comprising from 1 to 6 carbon atoms and 1, 2, 3, or 4
heteroatoms selected from non-peroxide oxy (--O--), thio (--S--),
sulfinyl sulfonyl (--S(O).sub.2--), phosphine (--OP(O).sub.2--, or
amine (--NR.sup.a--) in the ring;
[0031] R.sup.3 is hydrogen, halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)cycloalkyl-(C.sub.1-C.sub.8)alkylene-,
heterocycle, heterocycle(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkylene-, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --NNR.sup.a,
--OPO.sub.2R.sup.a; or if the ring formed from CR.sup.4R.sup.5 is
aryl or heteroaryl or partially unsaturated then R.sup.3 can be
absent;
[0032] each R.sup.7 is independently hydrogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)cycloalkyl(C.sub.1-C.sub.8)alkylene-, heterocycle,
heterocycle (C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene-;
[0033] X is --CH.sub.2OR.sup.e, --CO.sub.2R.sup.e,
--CH.sub.2OC(O)R.sup.e, --C(O)NR.sup.eR.sup.f, --CH.sub.2SR.sup.e,
--C(S)OR.sup.e, --CH.sub.2OC(S)R.sup.e or
C(S)NR.sup.eR.sup.f--CH.sub.2N(R.sup.e)(R.sup.f), or a group having
the formula
##STR00008##
[0034] wherein each Z.sup.1 is non-peroxide --O--, --S(O).sub.p--,
--C(R.sup.8).sub.j--, or --N(R.sup.8)--; provided that at least one
Z.sup.1 is non-peroxide --O--, --S(O).sub.p--, or
--N(R.sup.8)--;
[0035] each R.sup.8 is independently hydrogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkenyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkenyl,
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkenyl, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene-; wherein any of the alkyl or
alkenyl groups of R.sup.8 are optionally interrupted by --O--,
--S--, or --N(R.sup.a)--;
[0036] R.sup.e is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl;
[0037] R.sup.f is hydrogen, (C.sub.1-C.sub.8)alkyl, or
(C.sub.1-C.sub.8)alkyl substituted with 1-3
(C.sub.1-C.sub.8)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)alkylthio, amino acid, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene; and
[0038] wherein any of the alkyl, alkenyl, cycloalkyl, cycloalkenyl,
heterocycle, aryl, or heteroaryl, groups of R.sup.1, R.sup.2,
R.sup.3, R.sup.6, R.sup.7 and R.sup.8 is optionally substituted on
carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected
from the group consisting of halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle or
heterocycle(C.sub.1-C.sub.8)alkylene-, aryl, aryloxy, aryl
(C.sub.1-C.sub.8)alkylene-, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkylene-, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O).sub.p--, R.sup.aR.sup.bNS(O).sub.p--,
N.dbd.NR.sup.a, and --OPO.sub.2R.sup.a;
[0039] wherein any (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
(C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)alkanoyl,
(C.sub.1-C.sub.8)alkylene, or heterocycle, is optionally partially
unsaturated;
[0040] R.sup.a and R.sup.b are each independently hydrogen,
(C.sub.1-C.sub.18)alkyl, or (C.sub.1-C.sub.18)alkyl substituted
with 1-3 (C.sub.1-C.sub.18)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.18)alkylthio, amino acid, aryl,
aryl(C.sub.1-C.sub.18)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.18)alkylene; or R.sup.a and R.sup.b,
together with the nitrogen to which they are attached, form a
pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
and
[0041] R.sup.c is hydrogen or (C.sub.1-C.sub.6)alkyl;
[0042] m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; i is 1, or 2; each j is
independently 1, or 2; and each p is independently 0, 1, or 2;
[0043] or a pharmaceutically acceptable salt thereof.
[0044] In another embodiment, the compounds of the invention have
general formula (I):
##STR00009##
wherein
[0045] Z is CR.sup.3R.sup.4R.sup.5 or NR.sup.4R.sup.5;
[0046] each R.sup.1 is independently hydrogen, halo, --OR.sup.a,
--SR.sup.a, (C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, C.sub.3-8cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkylene-, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --N.dbd.NR.sup.a, or
--OPO.sub.2R.sup.a;
[0047] each R.sup.2 is independently hydrogen, halo,
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl, heterocycle,
heterocycle(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene-; or
[0048] R.sup.1 and R.sup.2 and the atom to which they are attached
is C.dbd.O, C.dbd.S or C.dbd.NR.sup.c.
[0049] R.sup.4 and R.sup.5 together with the atoms to which they
are attached form a saturated or partially unsaturated, or aromatic
ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms optionally
comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy
(--O--), thio (--S--), sulfinyl (--SO--), sulfonyl (--S(O).sub.2--)
or amine (--NR.sup.a) in the ring;
[0050] wherein any ring comprising R.sup.4 and R.sup.5 is
substituted with from 1 to 14 R.sup.6 groups;
[0051] wherein each R.sup.6 is independently hydrogen, halo,
--OR.sup.a, --SR.sup.a, (C.sub.1-C.sub.8)alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)cycloalkyl(C.sub.1-C.sub.8)alkylene-,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle or heterocycle
(C.sub.1-C.sub.8)alkylene-, aryl, aryl (C.sub.1-C.sub.8)alkylene-,
heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkylene-,
--CO.sub.2R.sup.a, R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--,
--OCO.sub.2R.sup.a, R.sup.aR.sup.bNC(.dbd.O)O--,
R.sup.bOC(.dbd.O)N(R.sup.a)--, R.sup.aR.sup.bN--,
R.sup.aR.sup.bNC(.dbd.O)--, R.sup.aC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, --NR.sup.a, --OPO.sub.2R.sup.a, or two R.sup.6
groups and the atom to which they are attached is C.dbd.O, or
C.dbd.S; or two R.sup.6 groups together with the atom or atoms to
which they are attached can form a carbocyclic or a heterocyclic
ring comprising from 1 to 6 carbon atoms and 1, 2, 3, or 4
heteroatoms selected from non-peroxide oxy (--O--), thio (--S--),
sulfinyl (--SO--), sulfonyl (--S(O).sub.2--), phosphine
(--OP(O).sub.2--, or amine (--NR.sup.a--) in the ring;
[0052] R.sup.3 is hydrogen, halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)cycloalkyl-(C.sub.1-C.sub.8)alkylene-,
heterocycle, heterocycle(C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene-, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkylene-, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O)--, R.sup.aS(.dbd.O).sub.2--, --NNR.sup.a,
--OPO.sub.2R.sup.a; or if the ring formed from CR.sup.4R.sup.5 is
aryl or heteroaryl or partially unsaturated then R.sup.3 can be
absent;
[0053] each R.sup.7 is independently hydrogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)cycloalkyl(C.sub.1-C.sub.8)alkylene-, heterocycle,
heterocycle (C.sub.1-C.sub.8)alkylene-, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene-;
[0054] X is --CH.sub.2OR.sup.e, --CO.sub.2R.sup.e,
--CH.sub.2OC(O)R.sup.e, --C(O)NR.sup.eR.sup.f, --CH.sub.2SR.sup.e,
--C(S)OR.sup.e, --CH.sub.2OC(S)R.sup.e or
C(S)NR.sup.eR.sup.f--CH.sub.2N(R.sup.e)(R.sup.f), or a group having
the formula
##STR00010##
[0055] wherein each Z.sup.1 is non-peroxide --O--, --S(O).sub.p--,
--C(R.sup.8).sub.j--, or --N(R.sup.8)--; provided that at least one
Z.sup.1 is non-peroxide --O--, --S(O).sub.p--, or
--N(R.sup.8)--;
[0056] each R.sup.8 is independently hydrogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkenyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkenyl,
(C.sub.1-C.sub.8)alkyl(C.sub.3-C.sub.8)cycloalkenyl, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene-; wherein any of the alkyl or
alkenyl groups of R.sup.8 are optionally interrupted by --O--,
--S--, or --N(R.sup.a)--;
[0057] R.sup.e is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl;
[0058] R.sup.f is hydrogen, (C.sub.1-C.sub.8)alkyl, or
(C.sub.1-C.sub.8)alkyl substituted with 1-3
(C.sub.1-C.sub.8)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)alkylthio, amino acid, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene; and
[0059] wherein any of the alkyl, alkenyl, cycloalkyl, cycloalkenyl,
heterocycle, aryl, or heteroaryl, groups of R.sup.1, R.sup.2,
R.sup.3, R.sup.6, R.sup.7 and R.sup.8 is optionally substituted on
carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected
from the group consisting of halo, --OR.sup.a, --SR.sup.a,
(C.sub.1-C.sub.8)alkyl, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.6-C.sub.12)bicycloalkyl, heterocycle or
heterocycle(C.sub.1-C.sub.8)alkylene-, aryl, aryloxy, aryl
(C.sub.1-C.sub.8)alkylene-, heteroaryl,
heteroaryl(C.sub.1-C.sub.8)alkylene-, --CO.sub.2R.sup.a,
R.sup.aC(.dbd.O)O--, R.sup.aC(.dbd.O)--, --OCO.sub.2R.sup.a,
R.sup.aR.sup.bNC(.dbd.O)O--, R.sup.bOC(.dbd.O)N(R.sup.a)--,
R.sup.aR.sup.bN--, R.sup.aR.sup.bNC(.dbd.O)--,
R.sup.aC(.dbd.O)N(R.sup.b)--, R.sup.aR.sup.bNC(.dbd.O)N(R.sup.b)--,
R.sup.aR.sup.bNC(.dbd.S)N(R.sup.b)--, --OPO.sub.3R.sup.a,
R.sup.aOC(.dbd.S)--, R.sup.aC(.dbd.S)--, --SSR.sup.a,
R.sup.aS(.dbd.O).sub.p--, R.sup.aR.sup.bNS(O).sub.p--,
N.dbd.NR.sup.a, and --OPO.sub.2R.sup.a;
[0060] wherein any (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.12)bicycloalkyl,
(C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)alkanoyl,
(C.sub.1-C.sub.8)alkylene, or heterocycle, is optionally partially
unsaturated;
[0061] R.sup.a and R.sup.b are each independently hydrogen,
(C.sub.1-C.sub.8)alkyl, or (C.sub.1-C.sub.8)alkyl substituted with
1-3 (C.sub.1-C.sub.8)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.8)alkylthio, amino acid, aryl,
aryl(C.sub.1-C.sub.8)alkylene, heteroaryl, or
heteroaryl(C.sub.1-C.sub.8)alkylene; or R.sup.a and R.sup.b,
together with the nitrogen to which they are attached, form a
pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
and
[0062] R.sup.c is hydrogen or (C.sub.1-C.sub.6)alkyl;
[0063] m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; i is 1, or 2; each j is
independently 1, or 2; and each p is independently 0, 1, or 2;
[0064] or a pharmaceutically acceptable salt thereof.
[0065] The invention provides a compound of formula I for use in
medical therapy, preferably for use in treating inflammation or
protecting mammalian tissue from inflammation such as an
inflammatory response, e.g., resulting from allergy, trauma or
ischemia/reperfusion injury, as well as the use of a compound of
formula I for the manufacture of a medicament for the treatment of
an inflammatory response due to a pathological condition or symptom
in a mammal, such as a human, which is associated with
inflammation.
[0066] The invention also includes the use of a combination of
these compounds with type IV phosphodiesterase inhibitors to
preferably cause synergistic decreases in the inflammatory response
mediated by leukocytes.
[0067] The invention also provides a pharmaceutical composition
comprising an effective amount of the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable diluent or carrier, and optionally, in
combination with a Type IV phosphodiesterase (PDE) inhibitor.
Preferably, the composition is presented as a unit dosage form.
[0068] Additionally, the invention provides a therapeutic method
for preventing or treating a pathological condition or symptom in a
mammal, such as a human, wherein the activity of A.sub.2A adenosine
receptors is implicated and agonism of said receptors is desired,
comprising administering to a mammal in need of such therapy, an
effective amount of a compound of formula I, or a pharmaceutically
acceptable salt thereof. It is believed that activation of A.sub.2A
adenosine receptors inhibits inflammation by affecting neutrophils,
mast cells, monocytes/macrophages, platelets T-cells and/or
eosinophils. Inhibition of these inflammatory cells results in
tissue protection following tissue insults.
[0069] In addition, the present invention provides a therapeutic
method for treating biological diseases that includes the
administration of an effective amount of a suitable antibiotic
agent, antifungal agent or antiviral agent in conjunction with an
A.sub.2A adenosine receptor agonist. If no anti-pathogenic agent is
known the A.sub.2A agonist can be used alone to reduce
inflammation, as may occur during infection with antibiotic
resistant bacteria, or certain viruses such as those that cause
SARS or Ebola. Optionally, the method includes administration of a
type IV PDE inhibitor. The A.sub.2A adenosine receptor agonist can
provide adjunctive therapy for treatment conditions such as, the
inflammation, caused by sepsis, for example, human uremic syndrome
when administered with antibiotics in the treatment of
bio-terrorism weapons, such as anthrax, tularemia, Escherichia
coli, plague and the like. The present invention also provides
adjunctive therapy for treatment of lethal bacterial, fungal and
viral infections such as anthrax, tularemia, escherichia and plague
comprising administration of an antibacterial agent, an antifungal
agent or an antiviral agent in conjunction with selective, A.sub.2A
adenosine receptor agonists.
[0070] The present invention provides a therapeutic method for
treating biological diseases that provoke inflammation either alone
or in combination with a disease killing medicine. These include
bacteria in combination with antibiotics, including but not limited
to bacteria that cause anthrax, tularemia, plague, lyme disease and
anthrax. Also included are viruses including but not limited to
those that cause RSV, severe acute respiratory syndrome (SARS),
influenza and Ebola with or without anti-viral therapy. Also
included are yeast and fungal infections with or without anti-yeast
or anti-fungal agents.
[0071] The antibacterial agent, antifungal agent or antiviral agent
can be co-administered (e.g., simultaneously) with the A.sub.2A
adenosine receptor agonist or they can be can be administered
either simultaneously or as a mixture or they can be administered
subsequently. The subsequent administration of the A.sub.2A
adenosine receptor agonists can be prior to the agent, within
minutes or up to about 48 hours after the administration of the
agent. Preferably the administration of the A.sub.2A adenosine
receptor agonists will be within about 24 hours and more preferably
within about 12 hours.
[0072] The method of the invention will also be useful for treating
patients with sepsis, severe sepsis, and potentially, the systemic
inflammatory response syndrome, in addition to septic shock. The
A.sub.2AAR agonists exert multiple anti-inflammatory effects early
in the inflammatory cascade, and thus a short course of an
A.sub.2AAR agonists could produce profound benefit in serious,
life-threatening infectious and inflammatory disorders of humans,
including inhalational anthrax, tularemia, escherichia and
plague.
[0073] The anti-inflammatory effect of A.sub.2AAR agonists has been
documented in vivo, in experimental models of meningitis,
peritonitis and arthritis. The potentially fatal syndrome of
bacterial sepsis is an increasingly common problem in acute care
units. Sepsis and septic shock, now the eleventh leading cause of
death in the United States, are increasing in frequency. Current
estimates indicate that about 900,000 new cases of sepsis
(approximately 60% Gram negative) occur in the United States
annually with an estimated crude mortality rate of 35%.
Furthermore, the mortality rate, as assessed in recent clinical
trials, is approximately 25%, while approximately 10% of patients
die from their underlying disease. Shock develops in approximately
200,000 cases annually with an attributable mortality rate of 46%
(92,000 deaths). Sepsis accounts for an estimated $ 5-10 billion
annually in health care expenditures. It is now widely appreciated
that among hospitalized patients in non-coronary intensive care
units, sepsis is the most common cause of death. Sepsis syndrome is
a public health problem of major importance. A.sub.2AAR agonists
are anticipated to have use as a new and unique adjunctive
therapeutic approach to reduce morbidity and mortality. It is
believed that this treatment will improve the outcome in systemic
anthrax, tularemia, escherichia and plague.
[0074] The agonists of A.sub.2A adenosine receptors of the
invention can inhibit neutrophil, macrophage and T cell activation
and thereby reduce inflammation caused by bacterial and viral
infections. The compounds, in conjunction with antibiotics or
antiviral agents can prevent or reduce mortality caused by sepsis
or hemolytic uremic syndrome or other inflammatory conditions. The
effects of adenosine A.sub.2A agonists are enhanced by type IV
phosphodiesterase inhibitors such as rolipram.
[0075] The invention also provides a pharmaceutical composition
comprising an effective amount of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable diluent or carrier. Preferably, the
composition is presented as a unit dosage form, and can be adapted
for parenteral, e.g., intravenous infusion.
[0076] The invention also provides a compound of formula I for use
in medical therapy (e.g., for use as an adjunct in the treatment of
potentially lethal bacterial infections, such as, anthrax,
tularemia, Escherichia, plague, or other bacterial or viral
infections, and treatment of systemic intoxification caused by
bacterial and/or viral infections, as well as the use of a compound
of formula I for the manufacture of a medicament for reducing
inflammation caused by the bacteria or virus or the treatment
thereof in a mammal, such as a human. The compounds of the
invention are also useful for treatment of treating systemic
intoxification wherein the bacterial or viral agents cause
inflammation either directly or as a result of treatment, e.g.,
with an antibiotic or antiviral agent.
[0077] Sepsis is a severe illness caused by overwhelming infection
of the bloodstream by toxin-producing bacteria or viruses. The
infection, which can manifest as inflammation, can be caused by the
bacteria or virus pathogens directly or from the treatment thereof,
i.e., the death of the pathogens due to treatment with
antibacterial or antiviral agents. Sepsis can be also be viewed as
the body's response to an infection. The infection can be caused by
microorganisms or "germs" (usually bacteria) invade the body, can
be limited to a particular body region (e.g., a tooth abscess) or
can be widespread in the bloodstream (often referred to as
"septicemia" or "blood poisoning")
[0078] The systemic intoxification or inflammatory shock is often
referred to as Septic shock; Bacteremic shock; Endotoxic shock;
Septicemic shock; or Warm shock.
[0079] Septic shock is a serious, abnormal condition that occurs
when an overwhelming infection leads to low blood pressure and low
blood flow. Vital organs, such as the brain, heart, kidneys, and
liver may not function properly or may fail. Septic shock occurs
most often in the very old and the very young. It also occurs in
people with underlying illnesses. Any bacterial organism can cause
septic shock. Fungi and viruses may also cause this condition.
Toxins released by the bacteria, fungi or viruses may cause direct
tissue damage, and may lead to low blood pressure and/or poor organ
function. These toxins can also produce a vigorous inflammatory
response from the body, which contributes to septic shock.
[0080] In another aspect, the present invention also provides a
method to treat severe acute respiratory syndrome (SARS),
comprising administering to a mammal in need of said therapy, an
effective anti-inflammatory amount of an agonists of A.sub.2A
adenosine receptor, optionally with a PDE-IV inhibitor, such as,
rolipram.
[0081] The present invention provides compounds and methods of
their use for detecting the presence of, and assessing the severity
of, coronary artery stenoses in a mammal, such as a human or
domestic animal. Preferably, the compounds of the invention are
used as pharmacological stress-inducing agents or stressors that
are useful in pharmacological stress imaging for the detection and
assessment of coronary artery disease. The specific compounds of
the invention useful as stress-inducing agents are potent and
selective at A.sub.2A adenosine receptors, but are also
short-acting, so that they are rapidly cleared by the body
following the imaging process.
[0082] Thus, the present invention provides a method for detecting
the presence and severity of coronary artery stenoses in a mammal,
such as a human subject, comprising (1) administering an amount of
one or more compounds of the general formula (I) and (2) performing
a technique on said mammal to detect and/or determine the severity
of said coronary artery stenoses.
[0083] The invention provides a compound of formula (I) for use in
medical diagnostic procedures, preferably for use in detecting the
presence of, and assessing the severity of, coronary artery
stenoses in a human subject. The present invention provides the use
of a compound of formula (I) for the manufacture of a pharmacologic
vasodilator agent which could be used with clinical perfusion
imaging techniques for diagnosing and assessing the extent of
coronary artery disease. Preferred perfusion imaging techniques are
planar or single photon emission computed tomography (SPECT) gamma
camera scintigraphy, positron emission tomography (PET), nuclear
magnetic resonance (NMR) imaging, magnetic resonance inaging (MRI)
imaging, perfusion contrast echocardiography, digital subtraction
angiography (DSA) and ultrafast X-ray computed tomography (CINE
CT).
[0084] The invention also provides a pharmaceutical composition
comprising an effective amount of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable diluent or carrier. Preferably, the
composition is presented as a unit dosage form, and can be adapted
for parenteral, e.g., intravenous infusion.
BRIEF DESCRIPTION OF THE FIGURES
[0085] FIG. 1 is an illustration of the duration of action of
A.sub.2A agonists by monitoring the reduction of blood pressure in
rats after administration of compounds of the present invention
compared with other A.sub.2A agonists.
[0086] FIG. 2 is an illustration of the duration of action of
A.sub.2A agonists by monitoring the reduction of blood pressure in
rats after administration of compounds of the present invention
orally compared with other A.sub.2A agonists.
DETAILED DESCRIPTION OF THE INVENTION
[0087] The following definitions are used, unless otherwise
described. Halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy,
aralkyl, alkylaryl, etc. denote both straight and branched alkyl
groups; but reference to an individual radical such as "propyl"
embraces only the straight chain radical, a branched chain isomer
such as "isopropyl" being specifically referred to. Aryl includes a
phenyl radical or an ortho-fused bicyclic carbocyclic radical
having about nine to ten ring atoms in which at least one ring is
aromatic. Heteroaryl encompasses a radical attached via a ring
carbon of a monocyclic aromatic ring containing five or six ring
atoms consisting of carbon and one to four heteroatoms each
selected from the group consisting of non-peroxide oxygen, sulfur,
and N(X) wherein X is absent or is H, O, (C.sub.1-C.sub.4)alkyl,
phenyl or benzyl, as well as a radical of an ortho-fused bicyclic
heterocycle of about eight to ten ring atoms derived therefrom,
particularly a benz-derivative or one derived by fusing a
propylene, trimethylene, or tetramethylene diradical thereto.
[0088] It will be appreciated by those skilled in the art that the
compounds of formula (I) have more than one chiral center and may
be isolated in optically active and racemic forms. Preferably, the
riboside moiety of formula (I) is derived from D-ribose. Some
compounds may exhibit polymorphism. It is to be understood that the
present invention encompasses any racemic, optically-active,
polymorphic, or stereoisomeric form, or mixtures thereof, of a
compound of the invention, which possess the useful properties
described herein, it being well known in the art how to prepare
optically active forms (for example, by resolution of the racemic
form by recrystallization techniques, or enzymatic techniques, by
synthesis from optically-active starting materials, by chiral
synthesis, or by chromatographic separation using a chiral
stationary phase) and how to determine adenosine agonist activity
using the tests described herein, or using other similar tests
which are well known in the art.
[0089] Among the inflammatory responses that can be treated
(including treated prophylactically) with a compound of formula I,
optionally with a Type IV PDE inhibitor, are inflammation due to:
[0090] (a) autoimmune stimulation (autoimmune diseases), such as
lupus erythematosus, multiple sclerosis, infertility from
endometriosis, type I diabetes mellitus including the destruction
of pancreatic islets leading to diabetes and the inflammatory
consequences of diabetes, including leg ulcers, Crohn's disease,
ulcerative colitis, inflammatory bowel disease, osteoporosis and
rheumatoid arthritis; [0091] (b) allergic diseases such as asthma,
hay fever, rhinitis, poison ivy, vernal conjunctivitis and other
eosinophil-mediated conditions; [0092] (c) skin diseases such as
psoriasis, contact dermatitis, eczema, infectious skin ulcers,
healing of open wounds, cellulitis; [0093] (d) infectious diseases
including sepsis, septic shock, encephalitis, infectious arthritis,
endotoxic shock, gram negative shock, Jarisch-Herxheimer reaction,
anthrax, plague, tularemia, ebola, shingles, toxic shock, cerebral
malaria, bacterial meningitis, acute respiratory distress syndrome
(ARDS), chronic obstructive pulmonary disease (COPD), lyme disease,
HIV infection, (TNF.alpha.-enhanced HIV replication, TNF.alpha.
inhibition of reverse transcriptase inhibitor activity); [0094] (e)
wasting diseases: cachexia secondary to cancer and HIV; [0095] (f)
organ, tissue or cell transplantation (e.g., bone marrow, cornea,
kidney, lung, liver, heart, skin, pancreatic islets) including
transplant rejection, and graft versus host disease; [0096] (g)
adverse effects from drug therapy, including adverse effects from
amphotericin B treatment, adverse effects from immunosuppressive
therapy, e.g., interleukin-2 treatment, adverse effects from OKT3
treatment, contrast dyes, antibiotics, adverse effects from GM-CSF
treatment, adverse effects of cyclosporine treatment, and adverse
effects of aminoglycoside treatment, stomatitis and mucositis due
to immunosuppression; [0097] (h) cardiovascular conditions
including circulatory diseases induced or exasperated by an
inflammatory response, such as ischemia, atherosclerosis,
peripheral vascular disease, restenosis following angioplasty,
inflammatory aortic aneurysm, vasculitis, stroke, spinal cord
injury, congestive heart failure, hemorrhagic shock,
ischemia/reperfusion injury, vasospasm following subarachnoid
hemorrhage, vasospasm following cerebrovascular accident,
pleuritis, pericarditis, and the cardiovascular complications of
diabetes; [0098] (i) dialysis, including pericarditis, due to
peritoneal dialysis; [0099] (j) gout; and [0100] (k) chemical or
thermal trauma due to burns, acid, alkali and the like.
[0101] Of particular interest and efficacy is the use of the
present compounds to limit inflammatory responses where the
ischemia/reperfusion injury is caused by angioplasty or
throbolysis. Also of particular interest and efficacy is the use of
the present compounds to limit inflammatory responses due to organ,
tissue or cell transplantation, i.e., the transplantation of
allogeneic or xenogeneic tissue into a mammalian recipient,
autoimmune diseases and inflammatory conditions due to circulatory
pathologies and the treatment thereof, including angioplasty, stent
placement, shunt placement or grafting. Unexpectedly, it was found
that administration of one or more compounds of formula (I) was
effective after the onset of the inflammatory response, e.g., after
the subject was afflicted with the pathology or trauma that
initiates the inflammatory response.
[0102] Tissue or cells comprising ligand bound receptor sites can
be used to measure the selectively of test compounds for specific
receptor subtypes, the amount of bioactive compound in blood or
other physiological fluids, or can be used as a tool to identify
potential therapeutic agents for the treatment of diseases or
conditions associated with receptor site activation, by contacting
said agents with said ligand-receptor complexes, and measuring the
extent of displacement of the ligand and/or binding of the agent,
or the cellular response to said agent (e.g., cAMP
accumulation).
[0103] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0104] Specifically, (C.sub.1-C.sub.8)alkyl can be methyl, ethyl,
propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl,
hexyl, heptyl, octyl and the like. As used herein, the term
"(C.sub.1-C.sub.8)alkoxy" can be methoxy, ethoxy, propoxy,
isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy,
hexyloxy, 1-methylhexyloxy, heptyloxy and the like.
[0105] As used herein, the term "cycloalkyl" can be bicycloalkyl
(norbornyl, 2.2.2-bicyclooctyl, etc.) and tricycloalkyl (adamantyl,
etc.), optionally including 1-2 N, O or S. Cycloalkyl also
encompasses (cycloalkyl)alkyl. Thus, (C.sub.3-C.sub.6)cycloalkyl
can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the
like. Specifically, (C.sub.6-C.sub.12)bicycloalkyl includes
norbornyl, 2.2.2-bicyclooctyl and the like.
[0106] As used herein, the term "(C.sub.1-C.sub.8)alkoxy" can be
methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy,
sec-butoxy, pentoxy, 3-pentoxy, hexyloxy; and the like.
[0107] As used herein, the term "(C.sub.2-C.sub.6)alkenyl" can be
vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the
like
[0108] As used herein, the term "(C.sub.2-C.sub.6)alkynyl" can be
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,
2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.
[0109] As used herein, the term "(C.sub.1-C.sub.8)alkanoyl" can be
acetyl, propanoyl, butanoyl, and the like.
[0110] As used herein, the term "halo(C.sub.1-C.sub.8)alkyl" can be
iodomethyl, bromomethyl, chloromethyl, fluoromethyl,
trifluoromethyl, 2-chloroethyl, 2-fluoroethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
[0111] As used herein, the term "hydroxy(C.sub.1-C.sub.6)alkyl" can
be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl,
2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl,
1-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, 6-hydroxyhexyl,
and the like.
[0112] As used herein, the term "(C.sub.1-C.sub.8)alkylthio" can be
methylthio, ethylthio, propylthio, isopropylthio, butylthio,
isobutylthio, pentylthio, hexylthio, and the like.
[0113] As used herein, the term "aryl includes phenyl, indenyl,
indanyl, naphthyl, and the like. In addition, aryl includes
ortho-fused bicyclic carbocyclic radicals having about nine to ten
ring atoms in which at least one ring is aromatic. The term "aryl"
can include radicals of an ortho-fused bicyclic heterocycle of
about eight to ten ring atoms derived therefrom, particularly a
benz-derivative or one derived by fusing a propylene, trimethylene,
or tetramethylene diradical thereto.
[0114] As used herein, the term "heteroaryl" can be a monocyclic
aromatic ring containing five or six ring atoms consisting of
carbon and 1, 2, 3, or 4 heteroatoms each selected from the group
consisting of non-peroxide oxygen, sulfur, and N(Y) where Y is
absent or is H, O, (C.sub.1-C.sub.8)alkyl, phenyl or benzyl.
Non-limiting examples of heteroaryl groups include furyl,
imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl,
isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl,
(or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl,
isoquinolyl (or its N-oxide), quinolyl (or its N-oxide) and the
like. The term "heteroaryl" can include radicals of an ortho-fused
bicyclic heterocycle of about eight to ten ring atoms derived
therefrom, particularly a benz-derivative or one derived by fusing
a propylene, trimethylene, or tetramethylene diradical thereto.
Examples of heteroaryl can be furyl, imidazolyl, triazolyl,
triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyraxolyl,
pyrrolyl, pyrazinyl, tetrazolyl, pyridyl (or its N-oxide),
thientyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or
its N-oxide), quinolyl (or its N-oxide), and the like.
[0115] As used herein, the
##STR00011##
symbol in the heterocyclic X ring denotes that the ring can have
one or two double bonds and may be aromatic. Non-limiting examples
of X rings include:
##STR00012##
and the like.
[0116] The term "heterocycle" generally represents a non aromatic
heterocyclic group, having from 3 to about 10 ring atoms, which can
be saturated or partially unsaturated, containing at least one
heteroatom (e.g., 1, 2, or 3) selected from the group consisting of
oxygen, nitrogen, and sulfur. Specific, "heterocycle" groups
include monocyclic, bicyclic, or tricyclic groups containing one or
more heteroatoms selected from the group consisting of oxygen,
nitrogen, and sulfur. A "heterocycle" group also can include one or
more oxo groups (.dbd.O) attached to a ring atom. Non-limiting
examples of heterocycle groups include 1,3-dioxolane, 1,4-dioxane,
1,4-dithiane, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl,
imidazolidinyl, imidazolinyl, indolinyl, isochromanyl,
isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl,
pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline,
quinuelidine, thiomorpholine, and the like.
[0117] The term "alkylene" refers to a divalent straight or
branched hydrocarbon chain (e.g. ethylene
--CH.sub.2--CH.sub.2-).
[0118] The term "aryl(C.sub.1-C.sub.8)alkylene" for example
includes benzyl, phenethyl, naphthylmethyl and the like.
[0119] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and
maximum number of carbon atoms in the moiety, i.e., the prefix
C.sub.i-C.sub.j indicates a moiety of the integer "i" to the
integer "j" carbon atoms, inclusive. Thus, for example,
(C.sub.1-C.sub.8)alkyl refers to alkyl of one to eight carbon
atoms, inclusive.
[0120] The compounds of the present invention are generally named
according to the IUPAC or CAS nomenclature system. Abbreviations
which are well known to one of ordinary skill in the art may be
used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h"
for hour or hours and "rt" for room temperature).
[0121] A specific value for R.sup.1 is hydrogen, --OH, halo,
--CH.sub.2OH, --OMe, --OAc, --NH.sub.2, --NHMe, --NMe.sub.2 or
--NHAc.
[0122] Another specific value for R.sup.1 is hydrogen, --OH, --F,
--OMe, --OAc, --NH.sub.2, --NHMe, --NMe.sub.2 or --NHAc.
[0123] Another specific value for R.sup.1 is hydrogen, --OH, --F,
--OMe, or --NH.sub.2.
[0124] Another specific value for R.sup.1 is hydrogen, --OH, --F,
or --NH.sub.2.
[0125] A more specific value for R.sup.1 is hydrogen or --OH.
[0126] A specific value for R.sup.2 is hydrogen, halo, or
(C.sub.1-C.sub.8)alkyl, cyclopropyl, cyclohexyl or benzyl.
[0127] Another specific value for R.sup.2 is hydrogen, --F, methyl,
ethyl or propyl.
[0128] Another specific value for R.sup.2 is hydrogen or
methyl.
[0129] A more specific value for R.sup.2 is hydrogen.
[0130] A specific value for R', R.sup.2 and the carbon atom to
which they are attached is carbonyl (C.dbd.O).
[0131] A specific value for R.sup.3 is hydrogen, OH, OMe, OAc,
NH.sub.2, NHMe, NMe.sub.2 or NHAc.
[0132] Another specific value for R.sup.3 is hydrogen, OH, OMe, or
NH.sub.2.
[0133] Another specific value for R.sup.3 is hydrogen, OH, or
NH.sub.2.
[0134] A more specific value for R.sup.3 is hydrogen or OH.
[0135] A specific value for the ring comprising R.sup.4, R.sup.5
and the atom to which they are connected is cyclopentane,
cyclohexane, piperidine, dihydro-pyridine, tetrahydro-pyridine,
pyridine, piperazine, decaline, tetrahydro-pyrazine,
dihydro-pyrazine, pyrazine, dihydro-pyrimidine,
tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, imidazole,
dihydro-imidazole, imidazolidine, pyrazole, dihydro-pyrazole, and
pyrazolidine.
[0136] A more specific value for the ring comprising R.sup.4 and
R.sup.5 and the atom to which they are connected is, cyclohexane,
piperidine or piperazine.
[0137] A specific value for R.sup.6 is (C.sub.1-C.sub.8)alkyl,
substituted (C.sub.1-C.sub.8)alkyl, halo, --OR.sup.a,
--CO.sub.2R.sup.a, --OCO.sub.2R.sup.a, --C(.dbd.O)R.sup.a,
--OC(.dbd.O)R.sup.a, --NR.sup.aR.sup.b, --C(.dbd.O)NR.sup.aR.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.b, or aryl.
[0138] Another specific value for R.sup.6 is
(C.sub.1-C.sub.4)alkyl, chloro, fluoro, phenyl, --OR.sup.a,
--CH.sub.2OR.sup.a, --CO.sub.2R.sup.a, --CH.sub.2CO.sub.2R.sup.a,
--OCO.sub.2R.sup.a, --CH.sub.2OCO.sub.2R.sup.a, --C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --OC(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --NR.sup.aR.sup.b,
--CH.sub.2NR.sup.aR.sup.b, --C(.dbd.O)NR.sup.aR.sup.b,
--CH.sub.2C(.dbd.O)NR.sup.aR.sup.b, --OC(.dbd.O)NR.sup.aR.sup.b, or
--CH.sub.2C(.dbd.O)NR.sup.aR.sup.b.
[0139] Another specific value for R.sup.6 is OH, OMe, methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,
--CH.sub.2OH, phenyl, --OAc, --CH.sub.2OAc, --CO.sub.2H,
--CO.sub.2Me, --CO.sub.2Et, --CO.sub.2i-Pr, --CO.sub.2i-Bu,
--CO.sub.2t-Bu, --OCO.sub.2Me, --OCO.sub.2Et, --C(.dbd.O)CH.sub.3,
--CONH.sub.2, --CONHMe, --CONMe.sub.2, --CONMeEt, --NH.sub.2,
--NHMe, --NMe.sub.2, --NHEt, --N(Et).sub.2, or
--CH.sub.2N(CH.sub.3).sub.2.
[0140] Another specific value for R.sup.6 is OH, OMe, methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,
--CH.sub.2OH, phenyl, --OAc, --CH.sub.2OAc, --CO.sub.2Me,
--CO.sub.2Et, --CO.sub.2i-Pr, --CO.sub.2i-Bu, --CO.sub.2t-Bu,
--OCO.sub.2Me, --OCO.sub.2Et, --CONMe.sub.2, --CONMeEt.
[0141] A specific number of R.sup.6 groups substituted on the Z
ring is an integer from 1 to about 4.
[0142] A specific value for R.sup.a is hydrogen, methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl
or benzyl.
[0143] A specific value for R.sup.b is hydrogen, methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl
or benzyl.
[0144] Another specific value for R.sup.a is hydrogen, methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or
tert-butyl and R.sup.b is hydrogen, or methyl.
[0145] Another specific value for R.sup.a and R.sup.b together with
the nitrogen to which they are attached, form a pyrrolidino,
piperidino, morpholino, or thiomorpholino ring.
[0146] Another specific value for R.sup.a and R.sup.b together with
the nitrogen to which they are attached, form a pyrrolidino,
piperidino, or morpholino, ring.
[0147] A specific value for R.sup.7 is hydrogen,
(C.sub.1-C.sub.4)alkyl, aryl, aryl(C.sub.1-C.sub.8)alkylene,
diaryl(C.sub.1-C.sub.8)alkylene,
heteroaryl(C.sub.1-C.sub.8)alkylene, or
diheteroaryl(C.sub.1-C.sub.8)alkylene.
[0148] Another specific value for R.sup.7 is hydrogen, methyl,
ethyl, 3-pentyl, phenylCH.sub.2CH.sub.2--,
(phenyl).sub.2CHCH.sub.2--, pyridylCH.sub.2--, benzyl, or
##STR00013##
[0149] Another specific value for R.sup.7 is hydrogen, 3-pentyl,
pyridylmethyl, or benzyl.
[0150] A specific value for --N(R.sup.7).sub.2 is amino,
methylamino, dimethylamino, ethylamino, diethylamino, pentylamino,
diphenylethylamino, benzylamino, or
##STR00014##
(pyridylmethylamino).
[0151] A specific pyridylmethylamino Group is
##STR00015##
[0152] A more specific value for R.sup.7 is H.
[0153] Another specific value for N(R.sup.7).sub.2 is amino
(NH.sub.2), 3-pentylamino, diphenylethylamino, pyridylmethylamino,
benzylamino, or a group having the formula:
##STR00016##
[0154] Another specific value for --N(R.sup.7).sub.2 is amino,
diphenylethylamino, pentylamino or benzylamino.
[0155] A more specific value for N(R.sup.7).sub.2 is amino.
[0156] A specific value for X is --CH.sub.2OR.sup.e,
--CO.sub.2R.sup.e, --CH.sub.2OC(O)R.sup.e, --C(O)NR.sup.eR.sup.f,
or --CH.sub.2N(R.sup.e)(R.sup.f).
[0157] Another specific value for X is --CH.sub.2OR.sup.e or
--C(O)NR.sup.eR.sup.f.
[0158] Another specific value for X is
##STR00017##
[0159] Another specific value for X is
##STR00018##
[0160] Another specific value for X is
##STR00019##
[0161] A specific value for R.sup.8 is methyl, ethyl, isopropyl,
isopropenyl, --CH.dbd.CH.sub.2, CH.sub.2OH, propyl,
--CH.sub.2--CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3, cyclopropyl,
cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, cyclobutyl,
cyclobutenyl, --(CH.sub.2)Y(CH.sub.2).sub.nH,
--(CH.sub.2).sub.nCOOCH.sub.3,
--(CH.sub.2).sub.nCO(CH.sub.2).sub.nH, where Y is O, S,
N(CH.sub.2).sub.n.
[0162] Another specific value for R.sup.8 is
(C.sub.1-C.sub.3)alkyl, CH.sub.2OH, cyclopropyl, cyclobutyl,
cyclopropylmethyl, --(CH.sub.2).sub.2CO.sub.2CH.sub.3,
--(CH.sub.2).sub.2-3OH, --(CH.sub.2).sub.2halogen.
[0163] A more specific value for R.sup.8 is methyl, ethyl, propyl,
2-propenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl,
--(CH.sub.2).sub.2CO.sub.2CH.sub.3, --(CH.sub.2).sub.2-30H
[0164] A more specific value for R.sup.8 is methyl, ethyl,
cyclopropyl.
[0165] A specific value for R.sup.e is cyclopropyl, or
cyclobutyl.
[0166] A specific value for R.sup.e is cyclopropyl.
[0167] A specific value for R.sup.e is cyclobutyl.
[0168] A specific value for R.sup.f is hydrogen, or
(C.sub.1-C.sub.8)alkyl.
[0169] Another specific value for R.sup.f is hydrogen, methyl,
ethyl, or propyl.
[0170] Another specific value for R.sup.f is hydrogen, or
methyl.
[0171] Another specific value for R.sup.f is hydrogen.
[0172] A specific value for i is 1.
[0173] Another specific value for i is 2.
[0174] A specific value for j is 1.
[0175] Another specific value for j is 2.
[0176] A specific value for m is 0, 1, or 2.
[0177] A more specific value for m is 0, or 1.
[0178] Specific examples of rings comprising R.sup.4, R.sup.5 and
the atom to which they are connected include:
##STR00020##
where q is from 1 to 14 and R.sup.d is hydrogen, provided that when
q is zero then R.sup.d is not hydrogen.
[0179] More specific examples of rings comprising R.sup.4, R.sup.5
and the atom to which they are connected include:
##STR00021##
[0180] A specific value for the ring comprising
--C(R.sup.3)R.sup.4R.sup.5 is 2-methyl cyclohexane,
2,2-dimethylcyclohexane, 2-phenylcyclohexane, 2-ethylcyclohexane,
2,2-diethylcyclohexane, 2-tert-butyl cyclohexane, 3-methyl
cyclohexane, 3,3-dimethylcyclohexane, 4-methyl cyclohexane,
4-ethylcyclohexane, 4-phenyl cyclohexane, 4-tert-butyl cyclohexane,
4-carboxymethyl cyclohexane, 4-carboxyethyl cyclohexane,
3,3,5,5-tetramethyl cyclohexane, 2,4-dimethyl cyclopentane.
4-cyclohexanecarboxylic acid, 4-cyclohexanecarboxylic acid esters,
or 4-methyloxyalkanoyl-cyclohexane.
[0181] A specific value for the ring comprising
--C(R.sup.3)R.sup.4R.sup.5 is 4-piperidine,
4-piperidene-1-carboxylic acid, 4-piperidine-1-carboxylic acid
methyl ester, 4-piperidine-1-carboxylic acid ethyl ester,
4-piperidine-1-carboxylic acid propyl ester,
4-piperidine-1-carboxylic acid tert-butyl ester, 1-piperidine,
1-piperidine-4-carboxylic acid methyl ester,
1-piperidine-4-carboxylic acid ethyl ester,
1-piperidine-4-carboxylic acid propyl ester,
1-piperidine-4-carboxylic acid tert-butyl ester,
1-piperidine-4-carboxylic acid methyl ester, 3-piperidine,
3-piperidene-1-carboxylic acid, 3-piperidine-1-carboxylic acid
methyl ester, 3-piperidine-1-carboxylic acid tert-butyl ester,
1,4-piperazine, 4-piperazine-1-carboxylic acid,
4-piperazine-1-carboxylic acid methyl ester,
4-piperazine-1-carboxylic acid ethyl ester,
4-piperazine-1-carboxylic acid propyl ester,
4-piperazine-1-carboxylic acid tert-butylester, 1,3-piperazine,
3-piperazine-1-carboxylic acid, 3-piperazine-1-carboxylic acid
methyl ester, 3-piperazine-1-carboxylic acid ethyl ester,
3-piperazine-1-carboxylic acid propyl ester,
3-piperidine-1-carboxylic acid tert-butylester,
1-piperidine-3-carboxylic acid methyl ester,
1-piperidine-3-carboxylic acid ethyl ester,
1-piperidine-3-carboxylic acid propyl ester or
1-piperidine-3-carboxylic acid tert-butyl ester.
[0182] A specific value for the ring comprising R.sup.4 and R.sup.5
is 2-methyl cyclohexane, 2,2-dimethylcyclohexane, 2-phenyl
cyclohexane, 2-ethylcyclohexane, 2,2-diethylcyclohexane,
2-tert-butyl cyclohexane, 3-methyl cyclohexane,
3,3-dimethylcyclohexane, 4-methyl cyclohexane, 4-ethylcyclohexane,
4-phenyl cyclohexane, 4-tert-butyl cyclohexane, 4-carboxymethyl
cyclohexane, 4-carboxyethyl cyclohexane, 3,3,5,5-tetramethyl
cyclohexane, 2,4-dimethyl cyclopentane, 4-piperidine-1-carboxylic
acid methyl ester, 4-piperidine-1-carboxylic acid tert-butyl ester
4-piperidine, 4-piperazine-1-carboxylic acid methyl ester,
4-piperidine-1-carboxylic acid tert-butylester,
1-piperidine-4-carboxylic acid methyl ester,
1-piperidine-4-carboxylic acid tert-butyl ester, tert-butylester,
1-piperidine-4-carboxylic acid methyl ester, or
1-piperidine-4-carboxylic acid tert-butyl ester,
3-piperidine-1-carboxylic acid methyl ester,
3-piperidine-1-carboxylic acid tert-butyl ester, 3-piperidine,
3-piperazine-1-carboxylic acid methyl ester,
3-piperidine-1-carboxylic acid tert-butylester,
1-piperidine-3-carboxylic acid methyl ester,
1-piperidine-3-carboxylic acid tert-butyl ester.
[0183] Specific compounds of the invention include formula (IA)
##STR00022##
[0184] In formula (IA) n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, or 18. In another group of specific
compounds n is, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or
18.
[0185] Specific compounds of the invention include formula (IB)
##STR00023##
[0186] In formula (IB) k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, or 18.
[0187] Specific compounds of the invention include formula (IC)
##STR00024##
[0188] In formula (IC) 1 is 0, 1, 2, 3, or 4.
[0189] Other specific compounds of the invention include
##STR00025##
[0190] Additional compounds of the invention are depicted in Table
1, below:
TABLE-US-00001 TABLE 1 ##STR00026## Compound R.sup.1 R.sup.2 Y R6
101 H H CH CO.sub.2Me 102 H H CH CO.sub.2Et 103 H H CH CO.sub.2iPr
104 H H CH CO.sub.2tBu 105 H H CH CO.sub.2iBu 106 H H CH CH.sub.2OH
107 H H CH CH.sub.2OAc 108 H H N CO.sub.2Me 109 H H N CO.sub.2Et
110 H H N CO.sub.2iPr 111 H H N CO.sub.2tBu 112 H H N
CO.sub.2iBu
TABLE-US-00002 TABLE 2 ##STR00027## Compound # R.sup.6 201
2-CH.sub.3 202 3-CH.sub.3 (R) 203 3-CH.sub.3 (S) 204 3-Et (R) 205
3-Et (S) 206 4-Me 207 4-Et 208 4-Pr 209 4-tBu 210 4-Phenyl
TABLE-US-00003 TABLE 3 ##STR00028## ##STR00029## ##STR00030##
##STR00031## ##STR00032## ##STR00033## R.sup.1 = R.sup.2 = H,
R.sup.7 = NH.sub.2 Compound R8 Z Y R6 301 Methyl Z1 CH CO.sub.2Me
302 Methyl Z1 CH CO.sub.2Et 303 Methyl Z1 CH CO.sub.2iPr 304 Methyl
Z1 CH CO.sub.2tBu 305 Methyl Z1 CH CO.sub.2iBu 306 Methyl Z1 CH
CH.sub.2OH 307 Methyl Z1 CH CH.sub.2OAc 308 Methyl Z1 N CO.sub.2Me
309 Methyl Z1 N CO.sub.2Et 310 Methyl Z1 N CO.sub.2iPr 311 Methyl
Z1 N CO.sub.2tBu 312 Methyl Z1 N CO.sub.2iBu 313 Ethyl Z1 CH
CO.sub.2Me 314 Ethyl Z1 CH CO.sub.2Et 315 Ethyl Z1 CH CO.sub.2iPr
316 Ethyl Z1 CH CO.sub.2tBu 317 Ethyl Z1 CH CO.sub.2iBu 318 Ethyl
Z1 CH CH.sub.2OH 319 Ethyl Z1 CH CH.sub.2OAc 320 Ethyl Z1 N
CO.sub.2Me 321 Ethyl Z1 N CO.sub.2Et 322 Ethyl Z1 N CO.sub.2iPr 323
Ethyl Z1 N CO.sub.2tBu 324 Ethyl Z1 N CO.sub.2iBu 325 Cyclopropyl
Z1 CH CO.sub.2Me 326 Cyclopropyl Z1 CH CO.sub.2Et 327 Cyclopropyl
Z1 CH CO.sub.2iPr 328 Cyclopropyl Z1 CH CO.sub.2tBu 329 Cyclopropyl
Z1 CH CO.sub.2iBu 330 Cyclopropyl Z1 CH CH.sub.2OH 331 Cyclopropyl
Z1 CH CH.sub.2OAc 332 Cyclopropyl Z1 N CO.sub.2Me 333 Cyclopropyl
Z1 N CO.sub.2Et 334 Cyclopropyl Z1 N CO.sub.2iPr 335 Cyclopropyl Z1
N CO.sub.2tBu 336 Cyclopropyl Z1 N CO.sub.2iBu 337 Methyl Z2 CH
CO.sub.2Me 338 Methyl Z2 CH CO.sub.2Et 339 Methyl Z2 CH CO.sub.2iPr
340 Methyl Z2 CH CO.sub.2tBu 341 Methyl Z2 CH CO.sub.2iBu 342
Methyl Z2 CH CH.sub.2OH 343 Methyl Z2 CH CH.sub.2OAc 344 Methyl Z2
N CO.sub.2Me 345 Methyl Z2 N CO.sub.2Et 346 Methyl Z2 N CO.sub.2iPr
347 Methyl Z2 N CO.sub.2tBu 348 Methyl Z2 N CO.sub.2iBu 349 Ethyl
Z2 CH CO.sub.2Me 350 Ethyl Z2 CH CO.sub.2Et 351 Ethyl Z2 CH
CO.sub.2iPr 352 Ethyl Z2 CH CO.sub.2tBu 353 Ethyl Z2 CH CO.sub.2iBu
354 Ethyl Z2 CH CH.sub.2OH 355 Ethyl Z2 CH CH.sub.2OAc 356 Ethyl Z2
N CO.sub.2Me 357 Ethyl Z2 N CO.sub.2Et 358 Ethyl Z2 N CO.sub.2iPr
359 Ethyl Z2 N CO.sub.2tBu 360 Ethyl Z2 N CO.sub.2iBu 361
Cyclopropyl Z2 CH CO.sub.2Me 362 Cyclopropyl Z2 CH CO.sub.2Et 363
Cyclopropyl Z2 CH CO.sub.2iPr 364 Cyclopropyl Z2 CH CO.sub.2tBu 365
Cyclopropyl Z2 CH CO.sub.2iBu 366 Cyclopropyl Z2 CH CH.sub.2OH 367
Cyclopropyl Z2 CH CH.sub.2OAc 368 Cyclopropyl Z2 N CO.sub.2Me 369
Cyclopropyl Z2 N CO.sub.2Et 370 Cyclopropyl Z2 N CO.sub.2iPr 371
Cyclopropyl Z2 N CO.sub.2tBu 372 Methyl Z3 CH CO.sub.2Me 373 Methyl
Z3 CH CO.sub.2Et 374 Methyl Z3 CH CO.sub.2iPr 375 Methyl Z3 CH
CO.sub.2tBu 376 Methyl Z3 CH CO.sub.2iBu 377 Methyl Z3 CH
CH.sub.2OH 378 Methyl Z3 CH CH.sub.2OAc 379 Methyl Z3 N CO.sub.2Me
380 Methyl Z3 N CO.sub.2Et 381 Methyl Z3 N CO.sub.2iPr 382 Methyl
Z3 N CO.sub.2tBu 383 Methyl Z3 N CO.sub.2iBu 384 Ethyl Z3 CH
CO.sub.2Me 385 Ethyl Z3 CH CO.sub.2Et 386 Ethyl Z3 CH CO.sub.2iPr
387 Ethyl Z3 CH CO.sub.2tBu 388 Ethyl Z3 CH CO.sub.2iBu 389 Ethyl
Z3 CH CH.sub.2OH 390 Ethyl Z3 CH CH.sub.2OAc 391 Ethyl Z3 N
CO.sub.2Me 392 Ethyl Z3 N CO.sub.2Et 393 Ethyl Z3 N CO.sub.2iPr 394
Ethyl Z3 N CO.sub.2tBu 395 Ethyl Z3 N CO.sub.2iBu 396 Cyclopropyl
Z3 CH CO.sub.2Me 397 Cyclopropyl Z3 CH CO.sub.2Et 398 Cyclopropyl
Z3 CH CO.sub.2iPr 399 Cyclopropyl Z3 CH CO.sub.2tBu 400 Cyclopropyl
Z3 CH CO.sub.2iBu 401 Cyclopropyl Z3 CH CH.sub.2OH 402 Cyclopropyl
Z3 CH CH.sub.2OAc 403 Cyclopropyl Z3 N CO.sub.2Me 404 Cyclopropyl
Z3 N CO.sub.2Et 405 Cyclopropyl Z3 N CO.sub.2iPr 406 Cyclopropyl Z3
N CO.sub.2tBu 407 Cyclopropyl Z3 N CO.sub.2iBu 408 Methyl Z4 CH
CO.sub.2Me 409 Methyl Z4 CH CO.sub.2Et 410 Methyl Z4 CH CO.sub.2iPr
411 Methyl Z4 CH CO.sub.2tBu 412 Methyl Z4 CH CO.sub.2iBu 413
Methyl Z4 CH CH.sub.2OH 414 Methyl Z4 CH CH.sub.2OAc 415 Methyl Z4
N CO.sub.2Me 416 Methyl Z4 N CO.sub.2Et 417 Methyl Z4 N CO.sub.2iPr
418 Methyl Z4 N CO.sub.2tBu 419 Methyl Z4 N CO.sub.2iBu 420 Ethyl
Z4 CH CO.sub.2Me 421 Ethyl Z4 CH CO.sub.2Et 422 Ethyl Z4 CH
CO.sub.2iPr 423 Ethyl Z4 CH CO.sub.2tBu 424 Ethyl Z4 CH CO.sub.2iBu
425 Ethyl Z4 CH CH.sub.2OH 426 Ethyl Z4 CH CH.sub.2OAc 427 Ethyl Z4
N CO.sub.2Me 428 Ethyl Z4 N CO.sub.2Et 429 Ethyl Z4 N CO.sub.2iPr
430 Ethyl Z4 N CO.sub.2tBu 431 Ethyl Z4 N CO.sub.2iBu 432
Cyclopropyl Z4 CH CO.sub.2Me 433 Cyclopropyl Z4 CH CO.sub.2Et 434
Cyclopropyl Z4 CH CO.sub.2iPr 435 Cyclopropyl Z4 CH CO.sub.2tBu 436
Cyclopropyl Z4 CH CO.sub.2iBu 437 Cyclopropyl Z4 CH CH.sub.2OH 438
Cyclopropyl Z4 CH CH.sub.2OAc 439 Cyclopropyl Z4 N CO.sub.2Me 440
Cyclopropyl Z4 N CO.sub.2Et 441 Cyclopropyl Z4 N CO.sub.2iPr 442
Cyclopropyl Z4 N CO.sub.2tBu 443 Methyl Z5 CH CO.sub.2Me 444 Methyl
Z5 CH CO.sub.2Et 445 Methyl Z5 CH CO.sub.2iPr 446 Methyl Z5 CH
CO.sub.2tBu 447 Methyl Z5 CH CO.sub.2iBu 448 Methyl Z5 CH
CH.sub.2OH 449 Methyl Z5 CH CH.sub.2OAc 450 Methyl Z5 N CO.sub.2Me
451 Methyl Z5 N CO.sub.2Et 452 Methyl Z5 N CO.sub.2iPr 453 Methyl
Z5 N CO.sub.2tBu 454 Methyl Z5 N CO.sub.2iBu 455 Ethyl Z5 CH
CO.sub.2Me 456 Ethyl Z5 CH CO.sub.2Et 457 Ethyl Z5 CH CO.sub.2iPr
458 Ethyl Z5 CH CO.sub.2tBu 459 Ethyl Z5 CH CO.sub.2iBu 460 Ethyl
Z5 CH CH.sub.2OH 461 Ethyl Z5 CH CH.sub.2OAc 462 Ethyl Z5 N
CO.sub.2Me 463 Ethyl Z5 N CO.sub.2Et 464 Ethyl Z5 N CO.sub.2iPr 465
Ethyl Z5 N CO.sub.2tBu 466 Ethyl Z5 N CO.sub.2iBu 467 Cyclopropyl
Z5 CH CO.sub.2Me 468 Cyclopropyl Z5 CH CO.sub.2Et 469 Cyclopropyl
Z5 CH CO.sub.2iPr 470 Cyclopropyl Z5 CH CO.sub.2tBu 471 Cyclopropyl
Z5 CH CO.sub.2iBu 472 Cyclopropyl Z5 CH CH.sub.2OH 473 Cyclopropyl
Z5 CH CH.sub.2OAc 474 Cyclopropyl Z5 N CO.sub.2Me 475 Cyclopropyl
Z5 N CO.sub.2Et 476 Cyclopropyl Z5 N CO.sub.2iPr 477 Cyclopropyl Z5
N CO.sub.2tBu 478 Cyclopropyl Z5 N CO.sub.2iBu
TABLE-US-00004 TABLE 4 ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039## Compound R.sup.8 Z R.sup.6
501 Methyl Z1 2-CH.sub.3 502 Methyl Z1 3-CH.sub.3 (R) 503 Methyl Z1
3-CH.sub.3 (S) 504 Methyl Z1 3-Et (R) 505 Methyl Z1 3-Et (S) 506
Methyl Z1 4-Me 507 Methyl Z1 4-Et 508 Methyl Z1 4-Pr 509 Methyl Z1
4-tBu 510 Methyl Z1 4-Phenyl 511 Ethyl Z1 2-CH.sub.3 512 Ethyl Z1
3-CH.sub.3 (R) 513 Ethyl Z1 3-CH.sub.3 (S) 514 Ethyl Z1 3-Et (R)
515 Ethyl Z1 3-Et (S) 516 Ethyl Z1 4-Me 517 Ethyl Z1 4-Et 518 Ethyl
Z1 4-Pr 519 Ethyl Z1 4-tBu 520 Ethyl Z1 4-Phenyl 521 Cyclopropyl Z1
2-CH.sub.3 522 Cyclopropyl Z1 3-CH.sub.3 (R) 523 Cyclopropyl Z1
3-CH.sub.3 (S) 524 Cyclopropyl Z1 3-Et (R) 525 Cyclopropyl Z1 3-Et
(S) 526 Cyclopropyl Z1 4-Me 527 Cyclopropyl Z1 4-Et 528 Cyclopropyl
Z1 4-Pr 529 Cyclopropyl Z1 4-tBu 530 Cyclopropyl Z1 4-Phenyl 531
Methyl Z2 2-CH.sub.3 532 Methyl Z2 3-CH.sub.3 (R) 533 Methyl Z2
3-CH.sub.3 (S) 534 Methyl Z2 3-Et (R) 535 Methyl Z2 3-Et (S) 536
Methyl Z2 4-Me 537 Methyl Z2 4-Et 538 Methyl Z2 4-Pr 539 Methyl Z2
4-tBu 540 Methyl Z2 4-Phenyl 541 Ethyl Z2 2-CH.sub.3 542 Ethyl Z2
3-CH.sub.3 (R) 543 Ethyl Z2 3-CH.sub.3 (S) 544 Ethyl Z2 3-Et (R)
545 Ethyl Z2 3-Et (S) 546 Ethyl Z2 4-Me 547 Ethyl Z2 4-Et 548 Ethyl
Z2 4-Pr 549 Ethyl Z2 4-tBu 550 Ethyl Z2 4-Phenyl 551 Cyclopropyl Z2
2-CH3 552 Cyclopropyl Z2 3-CH3 (R) 553 Cyclopropyl Z2 3-CH3 (S) 554
Cyclopropyl Z2 3-Et (R) 555 Cyclopropyl Z2 3-Et (S) 556 Cyclopropyl
Z2 4-Me 557 Cyclopropyl Z2 4-Et 558 Cyclopropyl Z2 4-Pr 559
Cyclopropyl Z2 4-tBu 560 Cyclopropyl Z2 4-Phenyl 561 Methyl Z3
2-CH.sub.3 562 Methyl Z3 3-CH.sub.3 (R) 563 Methyl Z3 3-CH.sub.3
(S) 564 Methyl Z3 3-Et (R) 565 Methyl Z3 3-Et (S) 566 Methyl Z3
4-Me 567 Methyl Z3 4-Et 568 Methyl Z3 4-Pr 569 Methyl Z3 4-tBu 570
Methyl Z3 4-Phenyl 571 Ethyl Z3 2-CH.sub.3 572 Ethyl Z3 3-CH.sub.3
(R) 573 Ethyl Z3 3-CH.sub.3 (S) 574 Ethyl Z3 3-Et (R) 575 Ethyl Z3
3-Et (S) 576 Ethyl Z3 4-Me 577 Ethyl Z3 4-Et 578 Ethyl Z3 4-Pr 579
Ethyl Z3 4-tBu 580 Ethyl Z3 4-Phenyl 581 Cyclopropyl Z3 2-CH.sub.3
582 Cyclopropyl Z3 3-CH.sub.3 (R) 583 Cyclopropyl Z3 3-CH.sub.3 (S)
584 Cyclopropyl Z3 3-Et (R) 585 Cyclopropyl Z3 3-Et (S) 586
Cyclopropyl Z3 4-Me 587 Cyclopropyl Z3 4-Et 588 Cyclopropyl Z3 4-Pr
589 Cyclopropyl Z3 4-tBu 590 Cyclopropyl Z3 4-Phenyl 591 Methyl Z4
2-CH.sub.3 592 Methyl Z4 3-CH.sub.3 (R) 593 Methyl Z4 3-CH.sub.3
(S) 594 Methyl Z4 3-Et (R) 595 Methyl Z4 3-Et (S) 596 Methyl Z4
4-Me 597 Methyl Z4 4-Et 598 Methyl Z4 4-Pr 599 Methyl Z4 4-tBu 600
Methyl Z4 4-Phenyl 601 Ethyl Z4 2-CH.sub.3 602 Ethyl Z4 3-CH.sub.3
(R) 603 Ethyl Z4 3-CH.sub.3 (S) 604 Ethyl Z4 3-Et (R) 605 Ethyl Z4
3-Et (S) 606 Ethyl Z4 4-Me 607 Ethyl Z4 4-Et 608 Ethyl Z4 4-Pr 609
Ethyl Z4 4-tBu 610 Ethyl Z4 4-Phenyl 611 Cyclopropyl Z4 2-CH.sub.3
612 Cyclopropyl Z4 3-CH.sub.3 (R) 613 Cyclopropyl Z4 3-CH.sub.3 (S)
614 Cyclopropyl Z4 3-Et (R) 615 Cyclopropyl Z4 3-Et (S) 616
Cyclopropyl Z4 4-Me 617 Cyclopropyl Z4 4-Et 618 Cyclopropyl Z4 4-Pr
619 Cyclopropyl Z4 4-tBu 620 Cyclopropyl Z4 4-Phenyl 621 Methyl Z5
2-CH.sub.3 622 Methyl Z5 3-CH.sub.3 (R) 623 Methyl Z5 3-CH.sub.3
(S) 624 Methyl Z5 3-Et (R) 625 Methyl Z5 3-Et (S) 626 Methyl Z5
4-Me 627 Methyl Z5 4-Et 628 Methyl Z5 4-Pr 629 Methyl Z5 4-tBu 630
Methyl Z5 4-Phenyl 631 Ethyl Z5 2-CH.sub.3 632 Ethyl Z5 3-CH.sub.3
(R) 633 Ethyl Z5 3-CH.sub.3 (S) 634 Ethyl Z5 3-Et (R) 635 Ethyl Z5
3-Et (S) 636 Ethyl Z5 4-Me 637 Ethyl Z5 4-Et 638 Ethyl Z5 4-Pr 639
Ethyl Z5 4-tBu 640 Ethyl Z5 4-Phenyl 641 Cyclopropyl Z5 2-CH.sub.3
642 Cyclopropyl Z5 3-CH.sub.3 (R) 643 Cyclopropyl Z5 3-CH.sub.3 (S)
644 Cyclopropyl Z5 3-Et (R) 645 Cyclopropyl Z5 3-Et (S) 646
Cyclopropyl Z5 4-Me 647 Cyclopropyl Z5 4-Et 648 Cyclopropyl Z5 4-Pr
649 Cyclopropyl Z5 4-tBu 650 Cyclopropyl Z5 4-Phenyl
[0191] The following abbreviations have been used herein: [0192]
2-Aas 2-alkynyladenosines; [0193] .sup.125I-ABA
N.sup.6-(4-amino-3-.sup.125iodo-benzyl)adenosine [0194] APCI
Atmospheric pressure chemical ionization [0195] ATL146e
4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxytetrahydro-furan-2-yl)-9H--
purin-2-yl]-prop-2-ynyl}cyclohexanecarboxylic acid methyl ester;
[0196] CCPA 2-chloro-N.sup.6-cyclopentyladenosine; [0197] CGS21680
2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamidoadenosine;
[0198] Cl-IB-MECA
116-3-iodo-2-chlorobenzyladenosine-5'-N-methyluronamide; [0199] CPA
N.sup.6-cyclopentyladenosine [0200] DMF dimethylformamide [0201]
DMSO dimethylsulfoxide [0202] DMSO-d.sub.6 deuterated
dimethylsulfoxide [0203] EtOAc ethyl acetate [0204] eq equivalent
[0205] GPCR G protein coupled receptor; hA.sub.2AAR, Recombinant
human A.sub.2A adenosine receptor; [0206] IADO 2-Iodoadenosine
[0207] .sup.125I-APE,
2-[2-(4-amino-3-[.sup.125I]iodophenyl)ethylamino]adenosine; NECA,
5'-N-ethylcarboxamidoadenosine; [0208] IB-MECA
N.sup.6-3-iodobenzyladenosine-5'-N-methyluronamide; [0209]
2-Iodoadenosine
5-(6-amino-2-iodo-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-carboxylic
acid ethylamide [0210] HPLC high-performance liquid
chromatography
[0211] HRMS high-resolution mass spectrometry [0212]
.sup.125I-ZM241385,
.sup.125I-4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]-triazin--
5-yl-amino]ethyl)phenol; [0213] INECA
2-iodo-N-ethylcarboxamidoadenosine [0214] LC/MS liquid
chromatography/mass spectrometry [0215] m.p. melting point [0216]
MHz megahertz [0217] MRS 1220,
N-(9-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]-quinazolin-5-yl)-2-phenyl-
acetamide; [0218] MS mass spectrometry [0219] NECA
N-ethylcarboxamidoadenosine [0220] NMR nuclear magnetic resonance
[0221] RP-HPLC reverse phase high-performance liquid chromatography
[0222] TBAF tetrabutylammonium fluoride [0223] TBS
tert-butyldimethylsilyl [0224] TBDMSCl
tert-butyldimethylsilylchloride [0225] TEA triethylamine [0226] TFA
trifluoroacetic acid [0227] THF tetrahydrofuan [0228] TLC thin
layer chromatography [0229] p-TSOH para-toluenesulfonic acid [0230]
XAC
8-(4-((2-a-minoethyl)aminocarbonyl-methyloxy)-phenyl)-1-3-dipropylxanthin-
e;
[0231] Specific Type IV phosphodiesterase (PDE) inhibitors useful
in practicing the instant invention include racemic and optically
active 4-(polyalkoxyphenyl)-2-pyrrolidones of the following
formula:
##STR00040##
wherein RN, R.sup.18, R.sup.19 and X are as disclosed and described
in U.S. Pat. No. 4,193,926. Rolipram is an example of a suitable
Type IV PDE inhibitor included within the above formula.
[0232] Additional non-limiting examples of PDE IV inhibitors useful
in practicing the instant invention include but are not limited to
compounds having the following formulas and variations thereof.
##STR00041## ##STR00042## ##STR00043##
[0233] The present invention further provides pharmaceutical
compositions that include a compound of Formula (I) in combination
with one of more members selected from the group consisting of the
following: (a) Leukotriene biosynthesis inhibitors, 5-lipoxygenase
(5-LO) inhibitors, and 5-lipoxygenase activating protein (FLAP)
antagonists selected from the group consisting of zileuton;
ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761;
N-(5-substituted)-thiophene-2-alkylsulfonamides of Formula (5.2.8);
2,6-di-tert-butylphenol hydrazones of Formula (5.2.10); Zeneca
ZD-2138 of Formula (5.2.11); SB-210661 of Formula (5.2.12);
pyridinyl-substituted 2-cyanonaphthalene compound L-739,010;
2-cyanoquinoline compound L-746,530; indole and quinoline compounds
MK-591, MK-886, and BAY x 1005; (b) Receptor antagonists for
leukotrienes LTB4, LTC4, LTD4, and LTE4 selected from the group
consisting of phenothiazin-3-one compound L-651,392; amidino
compound CGS-25019c; benzoxazolamine compound ontazolast;
benzenecarboximidamide compound BIIL 284/260; compounds
zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),
RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195; (d)
5-Lipoxygenase (5-LO) inhibitors; and 5-lipoxygenase activating
protein (FLAP) antagonists; (e) Dual inhibitors of 5-lipoxygenase
(5-LO) and antagonists of platelet activating factor (PAF); (f)
Theophylline and aminophylline; (g) COX-1 inhibitors (NSAIDs); and
nitric oxide NSAIDs; (h) COX-2 selective inhibitor rofecoxib; (i)
Inhaled glucocorticoids with reduced systemic side effects selected
from the group consisting of prednisone, prednisolone, flunisolide,
triamcinolone acetonide, beclomethasone dipropionate, budesonide,
fluticasone propionate, and mometasone furoate; (j) Platelet
activating factor (PAF) antagonists; (k) Monoclonal antibodies
active against endogenous inflammatory entities; (1) Anti-tumor
necrosis factor (TNF.alpha.) agents selected from the group
consisting of etanercept, infliximab, and D2E7; (m) Adhesion
molecule inhibitors including VLA-4 antagonists; (n)
Immunosuppressive agents selected from the group consisting of
cyclosporine, azathioprine, and methotrexate; or (O) anti-gout
agents selected from the group consisting of colchicines.
[0234] Compounds of the invention can generally be prepared as
illustrated in Schemes 1A and 1B below. Starting materials can be
prepared by procedures described in these schemes, procedures
described in the General methods below or by procedures that would
be well known to one of ordinary skill in organic chemistry. The
variables used in Schemes 1A and Scheme 1B are as defined herein or
as in the claims.
[0235] The preparation of alkynyl cycloalkanols is illustrated in
Scheme 1A. A solution of an appropriate cycloalkanone (where j is
from 0-5) is prepared in a solvent such as THF. A solution of a
suitable ethynylmagnesium halide compound in a solvent is added to
the cycloalkanone. After addition, the solution is allowed to stir
at about 20.degree. C. for about 20 hours. The reaction is
monitored via TLC until the starting material is consumed. The
reaction is quenched with water, filtered over a plug of sand and
silica, washed with a solvent, such as EtOAc, and evaporated to
provide the product. Typically, two products are formed, the
isomers formed by the axial/equatorial addition of the alkyne
(where m is as defined above, and the sum of m1 and m2 is from 0 to
about 7) to the ketone. The compounds are purified via flash
chromatography using EtOAc/Hexanes to provide the product.
##STR00044##
[0236] The preparation of 2-alkynyladenosines is illustrated in
Scheme 1B. A flame-dried round bottom under nitrogen is charged
with
5-(6-Amino-2-iodo-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-carboxylic
acid ethylamide (NECA 2-Iodoadenosine) and a solvent such as DMF.
The appropriate alkyne, wherein R is a --(CR.sup.1R.sup.2).sub.m Z
group, is dissolved in acetonitrile followed by TEA, 5 mole %
Pd(PPh.sub.3).sub.4, and CuI. All solvents are thoroughly
degassed.
[0237] The solution is allowed to stir for about 24 hours at room
temperature, and monitored until complete by HPLC. If the reaction
is not complete after this time, additional catalyst, CuI, and TEA
are added. After the reaction is complete, the solvents are removed
under high-vacuum and the residue taken up in a small amount of
DMF. This product is isolated using preparative silica TLC. The
product is purified by RP-HPLC.
##STR00045##
[0238] Examples of pharmaceutically acceptable salts are organic
acid addition salts formed with acids that form a physiological
acceptable anion, for example, tosylate, methanesulfonate, malate,
acetate, citrate, malonate, tart rate, succinate, benzoate,
ascorbate, .alpha.-ketoglutarate, and .alpha.-glycerophosphate.
Suitable inorganic salts may also be formed, including
hydrochloride, sulfate, nitrate, bicarbonate, and carbonate
salts.
[0239] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made.
[0240] The compounds of formula I can be formulated as
pharmaceutical compositions and administered to a mammalian host,
such as a human patient in a variety of forms adapted to the chosen
route of administration, i.e., orally or parenterally, by
intravenous, intramuscular, topical or subcutaneous routes.
[0241] Thus, the present compounds may be systemically
administered, e.g., orally, in combination with a pharmaceutically
acceptable vehicle such as an inert diluent or an assimilable
edible carrier. They may be enclosed in hard or soft shell gelatin
capsules, may be compressed into tablets, or may be incorporated
directly with the food of the patient's diet. For oral therapeutic
administration, the active compound may be combined with one or
more excipients and used in the form of ingestible tablets, buccal
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such compositions and preparations should contain at
least 0.1% of active compound. The percentage of the compositions
and preparations may, of course, be varied and may conveniently be
between about 2 to about 60% of the weight of a given unit dosage
form. The amount of active compound in such therapeutically useful
compositions is such that an effective dosage level will be
obtained.
[0242] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices.
[0243] The active compound may also be administered intravenously
or intraperitoneally by infusion or injection. Solutions of the
active compound or its salts can be prepared in water, optionally
mixed with a nontoxic surfactant. Dispersions can also be prepared
in glycerol, liquid polyethylene glycols, triacetin, and mixtures
thereof and in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to prevent the growth of
microorganisms.
[0244] The pharmaceutical dosage forms suitable for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions, optionally encapsulated in
liposomes. In all cases, the ultimate dosage form must be sterile,
fluid and stable under the conditions of manufacture and storage.
The liquid carrier or vehicle can be a solvent or liquid dispersion
medium comprising, for example, water, ethanol, a polyol (for
example, glycerol, propylene glycol, liquid polyethylene glycols,
and the like), vegetable oils, nontoxic glyceryl esters, and
suitable mixtures thereof. The proper fluidity can be maintained,
for example, by the formation of liposomes, by the maintenance of
the required particle size in the case of dispersions or by the use
of surfactants. The prevention of the action of microorganisms can
be brought about by various antibacterial and antifungal agents,
for example, parabens, chlorobutanol, phenol, sorbic acid,
thimerosal, and the like. In many cases, it will be preferable to
include isotonic agents, for example, sugars, buffers or sodium
chloride. Prolonged absorption of the injectable compositions can
be brought about by the use in the compositions of agents delaying
absorption, for example, aluminum monostearate and gelatin.
[0245] Sterile injectable solutions are prepared by incorporating
the active compound in the required amount in the appropriate
solvent with various of the other ingredients enumerated above, as
required, followed by filter sterilization. In the case of sterile
powders for the preparation of sterile injectable solutions, the
preferred methods of preparation are vacuum drying and the freeze
drying techniques, which yield a powder of the active ingredient
plus any additional desired ingredient present in the previously
sterile-filtered solutions.
[0246] For topical administration, the present compounds may be
applied in pure form, i.e., when they are liquids. However, it will
generally be desirable to administer them to the skin as
compositions or formulations, in combination with a
dermatologically acceptable carrier, which may be a solid, a liquid
or in a dermatological patch.
[0247] Useful solid carriers include finely divided solids such as
talc, clay, microcrystalline cellulose, silica, alumina and the
like. Useful liquid carriers include water, alcohols or glycols or
water-alcohol/glycol blends, in which the present compounds can be
dissolved or dispersed at effective levels, optionally with the aid
of non-toxic surfactants. Adjuvants such as fragrances and
additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers.
[0248] Thickeners such as synthetic polymers, fatty acids, fatty
acid salts and esters, fatty alcohols, modified celluloses or
modified mineral materials can also be employed with liquid
carriers to form spreadable pastes, gels, ointments, soaps, and the
like, for application directly to the skin of the user.
[0249] Examples of useful dermatological compositions, which can be
used to deliver the compounds of formula Ito the skin are disclosed
in Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No.
4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman
(U.S. Pat. No. 4,820,508).
[0250] Useful dosages of the compounds of formula I can be
determined by comparing their in vitro activity, and in vivo
activity in animal models. Methods for the extrapolation of
effective dosages in mice, and other animals, to humans are known
to the art; for example, see U.S. Pat. No. 4,938,949. Useful
dosages of Type IV PDE inhibitors are known to the art. For
example, see, U.S. Pat. No. 5,877,180, Col. 12.
[0251] Generally, the concentration of the compound(s) of formula
(I) in a liquid composition, such as a lotion, will be from about
0.1-25% wt-%, preferably from about 0.5-10 wt-%. The concentration
in a semi-solid or solid composition such as a gel or a powder will
be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
[0252] The amount of the compound, or an active salt or derivative
thereof, required for use in treatment will vary not only with the
particular salt selected but also with the route of administration,
the nature of the condition being treated and the age and condition
of the patient and will be ultimately at the discretion of the
attendant physician or clinician.
[0253] In general, however, a suitable dose will be in the range of
from about 0.5 to about 100 .mu.g/kg, e.g., from about 10 to about
75 .mu.g/kg of body weight per day, such as 3 to about 50 .mu.g per
kilogram body weight of the recipient per day, preferably in the
range of 6 to 90 .mu.g/kg/day, most preferably in the range of 15
to 60 .mu.g/kg/day.
[0254] The compound is conveniently administered in unit dosage
form; for example, containing 5 to 1000 .mu.g, conveniently 10 to
750 .mu.g, most conveniently, 50 to 500 .mu.g of active ingredient
per unit dosage form.
[0255] Ideally, the active ingredient should be administered to
achieve peak plasma concentrations of the active compound of from
about 0.1 to about 10 nM, preferably, about 0.2 to 10 nM, most
preferably, about 0.5 to about 5 nM. This may be achieved, for
example, by the intravenous injection of a 0.05 to 5% solution of
the active ingredient, optionally in saline, or orally administered
as a bolus containing about 1-100 .mu.g of the active ingredient.
Desirable blood levels may be maintained by continuous infusion to
provide about 0.01-5.0 .mu.g/kg/hr or by intermittent infusions
containing about 0.4-15 .mu.g/kg of the active ingredient(s).
[0256] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye. For example, it is desirable to administer the
present compositions intravenously over an extended period of time
following the insult that gives rise to inflammation.
[0257] The ability of a given compound of the invention to act as
an A.sub.2A adenosine receptor agonist (or antagonist) may be
determined using pharmacological models which are well known to the
art, or using tests described below.
[0258] The present compounds and compositions containing them are
administered as pharmacological stressors and used in conjunction
with any one of several noninvasive diagnostic procedures to
measure aspects of myocardial perfusion. For example, intravenous
adenosine may be used in conjunction with thallium-201 myocardial
perfusion imaging to assess the severity of myocardial ischemia. In
this case, any one of several different radiopharmaceuticals may be
substituted for thallium-201 (e.g., technetium-99m-labeled
radiopharmaceuticals (i.e.: Tc-99m-sestamibi, Tc-99m-teboroxime),
iodine-123-labeled radiopharmaceuticals such as I-123-IPPA or
BMIPP, rubidium-82, nitrogen-13, etc. . . . ). Similarly, one of
the present compounds may be administered as a pharmacological
stressor in conjunction with radionuclide ventriculography to
assess the severity of myocardial contractile dysfunction. In this
case, radionuclide ventriculographic studies may be first pass or
gated equilibrium studies of the right and/or left ventricle.
Similarly, a compound of formula (I) may be administered as a
pharmacological stressor in conjunction with echocardiography to
assess the presence of regional wall motion abnormalities.
Similarly, the active compound may be administered as a
pharmacological stressor in conjunction with invasive measurements
of coronary blood flow such as by intracardiac catheter to assess
the functional significance of stenotic coronary vessels.
[0259] The method typically involves the administration of one or
more compounds of formula (I) by intravenous infusion in doses
which are effective to provide coronary artery dilation
(approximately 0.25-500, preferably 1-250 mcg/kg/min). However, its
use in the invasive setting may involve the intracoronary
administration of the drug in bolus doses of 0.5-50 mcg.
[0260] Preferred methods comprise the use of a compound of formula
(I) as a substitute for exercise in conjunction with myocardial
perfusion imaging to detect the presence and/or assess the severity
of coronary artery disease in humans wherein myocardial perfusion
imaging is performed by any one of several techniques including
radiopharmaceutical myocardial perfusion imaging using planar
scintigraphy or single photon emission computed tomography (SPECT),
positron emission tomograph (PET), nuclear magnetic resonance (NMR)
imaging, perfusion contrast echocardiography, digital subtraction
angiography (DSA), or ultrafast X-ray computed tomography (CINE
CT).
[0261] A method is also provided comprising the use of a compound
of formula (I) as a substitute for exercise in conjunction with
imaging to detect the presence and/or assess the severity of
ischemic ventricular dysfunction in humans wherein ischemic
ventricular dysfunction is measured by any one of several imaging
techniques including echocardiography, contrast ventriculography,
or radionuclide ventriculography. The myocardial dysfunction can be
coronary artery disease, ventricular dysfunction, differences in
blood flow through disease-free coronary vessels and stenotic
coronary vessels and the like
[0262] A method is also provided comprising the use of a compound
of formula (I) as a coronary hyperemic agent in conjunction with
means for measuring coronary blood flow velocity to assess the
vasodilatory capacity (reserve capacity) of coronary arteries in
humans wherein coronary blood flow velocity is measured by any one
of several techniques including Doppler flow catheter or digital
subtraction angiography.
[0263] The invention will be further described by reference to the
following detailed examples, which are given for illustration of
the invention, and are not intended to be limiting thereof.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0264] All melting points were determined with a Thomas Hoover
capillary melting point apparatus and are uncorrected. Nuclear
magnetic resonance spectra for proton (.sup.1H NMR) were recorded
on a 300 MHz GE spectrophotometer. The chemical shift values are
expressed in ppm (parts per million) relative to tetramethylsilane.
For data reporting, s=singlet, d=doublet, t=triplet, q=quartet, and
m=multiplet. Mass spectra were measured on a Finnigan LcQ Classic.
High resolution mass spectrometry (HRMS) data was provided by the
Nebraska Center for Mass Spectrometry. Analytical HPLC was done on
a Waters 2690 Separation Module with a Waters Symmetry C8
(2.1.times.150 mm) column operated at room temperature. Compounds
were eluted at 200 .mu.L/min with 70:30 acetonitrile:water,
containing 0.5% acetic acid, with UV detection at 214 nm using a
Waters 486 Tunable Detector. Preparative HPLC was performed on a
Shimadzu Discovery HPLC with a Shim-pack VP-ODS C.sub.18
(20.times.100 mm) column operated at room temperature. Compounds
were eluted at 30 mL/min with a gradient 20-80% of water
(containing 0.1% TFA) to methanol over 15 minutes with UV detection
at 214 nm using a SPD10A VP Tunable detector. All final compounds
presented here were determined to be greater than 98% pure by HPLC.
Flash chromatography was performed on Silicyle 60A gel (230-400
mesh) or using reusable chromatography columns and system from RT
Scientific, Manchester N.H. Analytical thin-layer chromatography
was done on Merck Kieselgel 60 F254 aluminum sheets. Preparative
thin-layer chromatography was done using 1000 micron Analtech
Uniplate with silica gel. All reactions were done under a nitrogen
atmosphere in flame-dried glassware unless otherwise stated.
General Method 1: Preparation of Alkynyl Cyclohexanols
##STR00046##
[0266] To a solution of 10 mmol of the appropriate cyclohexanone in
50 mL of THF was added 60 mL (30 mmol) of 0.5 M ethynylmagnesium
bromide in THF. The solution was allowed to stir at 20.degree. C.
for 20 h, at which time TLC indicated that all the starting
material had been consumed. The reaction was quenched with 5 mL of
water, filtered over a plug of sand and silica, washed with EtOAc,
and evaporated to yield a yellow oil usually containing two spots
on TLC w/20% EtOAc/Hexanes which were visualized with Vanillin.
These two products were usually the different isomers formed by the
axial/equatorial addition of the alkyne to the ketone. The
compounds were purified via flash chromatography using 10%
EtOAc/Hexanes to yield clear oils or white solids in 50-80%
yields.
General Method 2: Preparation of Propargyl Piperadines and
Piperazines.
##STR00047##
[0268] To a solution of 10.0 mmol of the appropriate piperazine or
piperadine in 20 mL acetonitrile were added 12.0 mmol of propargyl
bromide (80% stabilized in toluene) and 50.0 mmol of anhydrous
potassium carbonate. The reaction mixture was filtered, and
evaporated to dryness. The residue was taken up in 50 mL of
dichloromethane/water and the organic removed. The aqueous was
washed with an additional 3.times.25 mL dichloromethane. The
organic was then dried using anhydrous sodium sulfate, filtered,
and concentrated to yield crude product which was purified using
column chromatography.
General Method 3: Preparation of Modified Piperadines and
Piperazines.
##STR00048##
[0270] To 100 mg of the appropriate Boc-protected piperazine or
piperadine, JR3275/JR3255 respectively, was added 2-4 mL of neat
TFA. The solution was allowed to stir for 6 hours, after which time
the TFA was removed under reduced pressure to yield a yellow oil.
This oil was taken up in 10 mL of dichloromethane to which was
added 10-fold excess of TEA and 3 equivalents of the appropriate
electrophile. The yellow solution was allowed to stir at r.t. for
12 hours, after which time the solvents were removed and the
product purified using a 1.1.times.30 cm 14 g RTSI column with a
5%-30% gradient of ethyl acetate/hexanes.
General Method 4: Preparation of 2-AAs (2-alkynyladenosines).
##STR00049##
[0271] A flame dried 25 mL round bottom under nitrogen was charged
with 2-Iodo adenosine analog (40 mg) and dissolved in 2 mL of DMF.
The appropriate alkyne (approx 0.1 mL) was then added followed by 4
mL of acetonitrile and 0.1 mL of TEA. All three solvents had been
degassed with nitrogen for at least 24 hours. To this solution was
added 5 mole percent Pd(PPh.sub.3).sub.4 and 6 mole % copper
iodide. The yellowish solution was allowed to stir for 24 hours at
room temperature, or until complete by HPLC. If the reaction was
not complete at this time, additional catalyst, CuI, and TEA were
added. After the reaction was complete, the solvents were removed
under high-vacuum and the red/black residue taken back up in a
small amount of DMF. This solution was added to a preparative
silica TLC plate (Analtech 1000 microns, 20 cm.times.20 cm) and
eluted first with 120 mL of 40% Hexanes/CH.sub.2Cl.sub.2, and then
again after addition of 40 mL of MeOH. The UV active band (usually
yellow in color) in the middle of the plate is collected, slowly
washed with 4.times.25 mL 20% MeOH/CH.sub.2Cl.sub.2, and
concentrated. This product is then purified by RP-HPLC to yield
solids after trituration with anhydrous ethyl ether.
##STR00050##
[0272] To a cooled solution of compound 1.1 in alcohol is added
about 5 equivalents of ice-cooled thionyl chloride. This solution
is allowed to stir, gradually coming to room temperature for about
12 hours. The solvent is then removed en vacuo to yield 1.2 as a
white solid. This solid is then treated according to general method
4 to yield compound 1.3.
##STR00051##
[0273] To a cooled solution of compound 1.1 in methanol is added
about 5 equivalents of ice-cooled thionyl chloride. This solution
is allowed to stir, gradually coming to r.t for about 12 hours. The
solvent is then removed en vacuo to yield compound 1.2, which is
dissolved in the appropriate amine (NHR.sub.aR.sub.b) at 0 C and
allowed to stir for several hours or until complete. The solvent is
then removed under vacuum and the product purified via
crystallization or chromatography using a gradient of methanol and
dichloromethane to afford 2.2 as a white solid. This solid is then
treated according to general method 4 to yield compound 2.3.
##STR00052##
[0274] Hydrazine hydrate (1 equiv) is added to a stirred solution
of 1.1 (1 equiv) in dry DMF, HBTU (1 equiv) and DIEA (2.5 equiv)
and the solution is allowed to stir for about 24 hours. After
extractive work-up, 3.2 can be isolated. 3.2 can be treated
according to general method 4 to afford 3.3 which can then be
dissolved in EtOH and treated with ethylacetimidate hydrochloride
and TEA and refluxed for about 16 h to yield 3.4 after
chromatography and deprotection using 50% formic acid for 6 h.
##STR00053##
[0275] Pivaloyl chloride is added to a cooled solution of 1.1 in
DCM and TEA and allowed to stir for several hours. Ammonia gas is
the bubbled through the solution to afford 4.2 after isolation and
purification. 4.2 can be treated according to general method 4 to
afford 4.3 which is then taken up in anhydrous acetonitrile and TEA
and DMAP are added. To the ice-cooled solution is cautiously added
POCl.sub.3. After stirring for about 30 minutes, DMF is added to
the solution and the mixture heated to 95 C for about 24 h.
Purification affords 4.4, to which is added potassium carbonate and
hydroxylamine hydrochloride after dissolution in EtOH. This
solution is refluxed for about 24 h to yield 4.5 after
purification. Treatment of 4.5 with the appropriate carboxylic
acid/anhydride pair affords 4.6 after reflux and deprotection using
50% formic acid.
##STR00054##
[0276] Pivaloyl chloride is added to a solution of 1.1 in THF and
DIEA at 0 C. After stirring for several hours the appropriate
hydrazide is added and the mixture allowed to stir for about 3 days
to yield 5.2. This product can be treated according to general
method 4 to afford 5.3 which is dissolved in DMF and treated with
POCl.sub.3 at 0 C for several hours to yield 5.4 after purification
and deprotection with 50% formic acid.
##STR00055##
[0277] Pivaloyl chloride is added to a solution of 1.1 in DCM and
DIEA at 0 C. After stirring for several hours the appropriate
1,2-hydroxylamine is added and the mixture allowed to stir for
about 24 h to yield 6.2. This product can be treated according to
general method 4 to afford 6.3. This product is dissolved in DCM
and treated with PDC, 4 .ANG. molecular sieves, and AcOH to convert
the alcohol to the ketone. This intermediate is then converted to
6.4 by reflux in toluene after treatment with POCl.sub.3 and
subsequent heating in 50% formic acid for 6 h
##STR00056##
[0278] Pivaloyl chloride is added to a solution of 1.1 in THF and
DIEA at 0 C. After stirring for several hours the appropriate
hydrazide is added and the mixture is allowed to stir for several
additional hours to yield 7.2. This product can be treated
according to general method 4 to afford 7.3 which is dissolved in
acetonitrile and treated with Lawessons reagent at 50 C for about 1
day to yield 7.4 after purification and deprotection with 50%
formic acid for 6 hours.
##STR00057##
[0279] Pivaloyl chloride is added to a cooled solution of 1.1 in
DCM and TEA and allowed to stir for several hours. Ammonia gas is
the bubbled through the solution to afford 4.2 after isolation and
purification. 4.2 is then taken up in anhydrous acetonitrile and
TEA and DMAP are added. To the ice-cooled solution is cautiously
added POCl.sub.3. After stirring for about 30 minutes, DMF is added
to the solution and the mixture heated to 95 C for about 24 h.
Purification affords 4.4, to which is added toluene,
azidotrimethylsilane, and dibutyltin oxide and the mixture is
heated to 60 C for about 15 hours to afford 8.5. Treatment of 8.5
with the appropriate alkyl halide and potassium carbonate affords
8.6 after reflux and deprotection with 50% formic acid for 6 h.
Preparation 1:
[4-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol
(83)
##STR00058##
[0281] To a 100 mL-flask containing 79 (4.0 g, 27.8 mmol) in DMF
(40 mL) was added TBDMSCl (3.56 g, 23.6 mmol) and imidazole (3.79
g, 55.6 mmol). The reaction was allowed to stir at 25.degree. C.
for 16 hoursafter which time saturated aqueous LiBr (50 mL) was
added and the reaction extracted with ether (2.times.50 mL). The
ether layers were pooled and extracted again with LiBr (2.times.35
mL). The ether layer became clear. The ether layer was then
concentrated in vacuo and the product purified by flash
chromatography, on a silica gel column, eluting with 1:2
ether/petroleum ether to yield 83 (3.80 g, 62%) as a homogenous
oil. .sup.1H NMR (CDCl.sub.3) .delta. 3.46 (d, J=6.2 Hz, 2H), 3.39
(d, J=6.2 Hz, 2H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H),
1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); .sup.13C NMR
(CDCl.sub.3) .delta. 69.2, 69.1, 41.2, 41.1, 29.5, 26.5, 18.9,
-4.8; APCI m/z (rel intensity) 259 (MH.sup.+, 100).
Preparation 2: Toluene-4-sulfonic acid
4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexylmethyl ester
(84)
##STR00059##
[0283] To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in
CHCl.sub.3 (30 mL) was added tosyl chloride (3.26 g, 17.1 mmol) and
pyridine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at
25.degree. C. for 14 hours after which time the reaction was
concentrated in vacuo to yield a wet white solid. To this solid was
added ether (50 mL) and the solid was filtered and subsequently
washed with additional ether (2.times.50 mL). The ether layers were
pooled, concentrated in vacuo to yield a clear oil which was
purified by flash chromatography, on a silica gel column, eluting
with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83%) as a white
solid. .sup.1H NMR (CDCl.sub.3) .delta. 7.78 (d, J=7.7, 2H), 7.33
(d, J=7.7 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.37 (d, J=6.2, 2H),
2.44 (s, 3H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H),
1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); .sup.13C NMR
(CDCl.sub.3) .delta. 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7,
38.0, 29.1, 26.5, 22.1, 18.9, -4.9; APCI m/z (rel intensity) 413
(MH.sup.+, 100).
Preparation 3: (4-Prop-2-ynyl-cyclohexyl)-methanol (86)
##STR00060##
[0285] A 3-neck 250 mL-flask equipped with a gas inlet tube and
dry-ice condenser was cooled to -78.degree. C. and charged with
liquid ammonia (40 mL). To the reaction mixture was added lithium
wire (600 mg, 86.4 mmol) generating a deep blue solution. The
mixture was allowed to stir for 1 hour. Acetylene, passed through a
charcoal drying tube, was added to the ammonia until all the
lithium had reacted and the solution turned colorless, at which
time the flow of acetylene was stopped, the acetylene-inlet tube
and condenser removed and the flask outfitted with a thermometer.
DMSO (20 mL) was added and the ammonia evaporated with a warm water
bath until the mixture reached a temperature of 30.degree. C. The
solution was stirred at this temperature for 2 hours until the
solution stopped bubbling. The mixture was cooled to 5.degree. C.
and compound 84 (11.25 g, 27.3 mmol), in DMSO (10 mL), was added.
The temperature was maintained at 5.degree. C. The mixture was
allowed to stir at 5.degree. C. for 0.5 hours. Then the solution
was gradually warmed to room temperature and stirred for an
additional 18 hours. The brown/black reaction mixture was poured
slowly over ice (300 g) and extracted with ether (4.times.100 mL),
dried with anhydrous sodium sulfate, and concentrated in vacuo to
yield a yellow oil. The oil was subsequently dissolved in THF (200
mL) and changed to a brownish color upon addition of TBAF hydrate
(11.20 g, 35.5 mmol). The solution was allowed to stir for 24 hours
2 under N.sub.2 atmosphere. After stirring, the reaction was
quenched with water (200 mL) and extracted with ether (3.times.100
mL). The ether extracts were combined and concentrated in vacuo.
The crude product was purified by chromatography, on a silica gel
column, eluting with 1:1 ether/petroleum ether to yield 86 (3.91 g,
93%) as a yellow oil. .sup.1H NMR (CDCl.sub.3) .delta. 3.45 (d,
J=6.2, 2H), 2.10 (d, J=6.2, 2H), 1.9 (s, 1H), 1.94-1.69 (m, 4H),
1.52-1.34 (m, 2H), 1.16-0.83 (m, 4H); .sup.13C NMR (CDCl.sub.3)
.delta. 83.8, 69.5, 69.0, 40.8, 37.7, 32.3, 29.7, 26.5.
Preparation 4: (4-prop-2-ynylcyclohexyl)methyl acetate (87)
##STR00061##
[0287] To a solution of 960 mg (6.31 mmol) of 86 in 6 mL DMF was
added 0.62 mL (7.57 mmol) pyridine and 0.78 mL (8.27 mmol) acetic
anhydride. The reaction was allowed to stir overnight at room
temperature. After 16 hours, starting material still remained. The
reaction mixture was heated at 75.degree. C. for 3 hours. The
solvent was removed under reduced pressure to yield a yellow oil
which was purified by flash chromatography, on silica gel, eluting
with 1:3 ether/petroleum ether to yield 1.12 g (91%) of 87 as an
oil. .sup.1H NMR (CDCl.sub.3) .delta.3.87 (d, J=6.2 Hz, 2H), 2.06
(d, J=4.3 Hz, 2H), 2.03 (s, 3H), 1.98-1.93 (m, 1H), 1.92-1.83 (m,
2H), 1.83-1.74 (m, 2H), 1.63-1.36 (m, 2H), 1.12-0.90 (m, 4H);
.sup.13C NMR (CDCl.sub.3) .delta. 171.7, 83.7, 69.9, 69.6, 37.4,
37.3, 32.1, 29.7, 26.5, 21.4; APCI m/z (rel intensity) 195
(M.sup.+, 30), 153 (M.sup.+, 70), 135 (M.sup.+, 100).
Preparation 5: 4-prop-2-ynyl-cyclohexanecarboxylic acid (88)
##STR00062##
[0289] A solution of chromium trioxide (600 mg, 6.0 mmol) in 1.5 M
H.sub.2SO.sub.4 (2.6 mL, 150 mmol) was cooled to 5.degree. C. and
added to a solution of 86 (280 mg, 1.84 mmol) in acetone (15 mL).
The mixture was allowed to warm to room temperature and allowed to
stir overnight. Isopropanol (4 mL) was added to the green/black
solution, which turned light blue after 1 hr. After adding water
(15 mL), the solution was extracted with CHCl.sub.3 (6.times.25
mL). The organic layers were pooled and concentrated in vacuo to
yield a white solid. The solid was dissolved in ether (50 mL) and
extracted with 1 M NaOH (2.times.30 mL). The basic extracts were
pooled, acidified w/10% HCl, and re-extracted with ether
(3.times.30 mL). The ether layers were combined, dried with sodium
sulfate and concentrated in vacuo to yield a white solid. The
product was recrystallized from acetone/water to yield 88 (222 mg,
73%) as white needles: mp 84-85.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 2.30-2.23 (m, 1H), 2.17-2.11 (m, 2H),
2.07-2.03 (m, 2H), 1.97-1.91 (m, 3H), 1.51-1.39 (m, 3H), 1.13-1.01
(m, 2H); .sup.13C NMR (CDCl.sub.3) .delta. 182.5, 83.8, 69.6, 40.7,
37.7, 32.3, 29.6, 26.5; APCI m/z (rel intensity) 165 (M.sup.+,
100).
Preparation 6: Methyl 4-prop-2-ynylcyclohexanecarboxylate (89)
##STR00063##
[0291] To a solution of 88 (240 mg, 1.45 mmol) in 7:3
CH.sub.2Cl.sub.2:MeOH (10 mL) was added TMS Diazomethane (2.0 M in
hexanes) (0.9 mL, 1.8 mmol) in 0.2 ml aliquots until the color
remained yellow. The reaction was allowed to stir for an additional
0.25 hours at room temperature. After stirring, glacial acetic acid
was added dropwise until the solution became colorless. The
reaction was concentrated in vacuo to an oil which was purified by
flash chromatography on silica gel using ether:petroleum ether
(1:9) to yield 89 (210 mg, 80%) as a clear oil. .sup.1H NMR
(CDCl.sub.3) .delta. 3.60 (s, 3H), 2.25-2.13 (m, 1H), 2.08-1.94 (m,
3H), 1.95-1.90 (m, 2H), 1.49-1.31 (m, 3H), 1.10-0.93 (m, 2H);
.sup.13C NMR (CDCl.sub.3) .delta. 176.7, 83.3, 69.8, 51.9, 43.4,
36.7, 31.9, 29.2, 26.3; APCI m/z (rel intensity) 181 (MH.sup.+,
100).
Preparation 7: Trans[4-(1-Propargyl)cyclohexylmethyl]methyl
carbonate (90)
##STR00064##
[0293] Yield: 345 mg, 81%. .sup.1H NMR (CDCl.sub.3) .delta.
0.98-1.07, 1.40-1.52, 1.57-1.70, 1.78-1.93 (4.times.m, 10H,
cyclohexyl), 1.96 (t, 1H, acetylene), 2.10 (dd, 2H,
--C.sub.6H.sub.10CH.sub.2CCH), 3.78 (s, 3H, --OCH.sub.3), 3.96 (d,
--C.sub.6H.sub.10CH.sub.2O--).
Preparation 8: Trans[4-(1-Propargyl)cyclohexylmethyl]iso-butyl
carbonate (91)
##STR00065##
[0295] Yield: 433 mg, 83%. .sup.1H NMR (CDCl.sub.3) .delta. 0.95
(d, 4H, --OCH.sub.2CH(CH.sub.3).sub.2), 0.98-1.09, 1.40-1.51,
1.57-1.70, 1.78-1.93 (4.times.m, 10H, cyclohexyl), 1.94-2.04 (m,
1H, --OCH.sub.2CH(CH.sub.3).sub.2), 1.96 (t, 1H, acetylene), 2.10
(dd, 2H, --C.sub.6H.sub.10CH.sub.2CCH), 3.91, 3.95 (2.times.d, 4H,
--OCH.sub.2CH(CH.sub.3).sub.2, --C.sub.6H.sub.10CH.sub.2O--).
Preparation 9: Trans[4-(1-Propargyl)cyclohexylmethyl]benzyl
carbonate (92)
##STR00066##
[0297] Yield: 340 mg, 69%. .sup.1H NMR (CDCl.sub.3) .delta.
0.97-1.08, 1.40-1.49, 1.55-1.69, 1.77-1.93 (4.times.m, 10H,
cyclohexyl), 1.96 (t, 1H, acetylene), 2.10 (dd, 2H,
--C.sub.6H.sub.10CH.sub.2CCH), 3.98 (d,
--C.sub.6H.sub.10CH.sub.2O--), 5.15 (s, 2H, --OCH.sub.2Ph),
7.33-7.40 (m, 5H, Ar).
Preparation 10:
4-(Toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid
tert-butyl ester (JR3215)
##STR00067##
[0299] A solution of N-Boc-4-piperidinemethanol, 5.0 g (23.2 mmol)
in chloroform, 50 mL, was prepared. Toluene sulfonyl chloride, 5.75
g (30.2 mmol), in 5.6 mL of pyridine (69.6 mmol) was added. The
solution was stirred under nitrogen allowed to stir for 24 hours.
Standard workup and chromatographic purification provided the title
compound. Yield 6.0 g
Preparation 11: (R)-1-Ethynyl-(R)-3-methyl-cyclohexanol (JR3217A),
(S)-1-Ethynyl-(R)-3-methyl-cyclohexanol (JR3217B)
##STR00068##
[0301] To a solution of 1.0 g (8.9 mmol)
(R)-(+)-3-methyl-cyclohexanone in 50 mL of THF was added 54 mL
(26.7 mmol) of 0.5 M ethynylmagnesium bromide in THF. The solution
was allowed to stir at 20.degree. C. for 20 hours. Analysis by TLC
indicated that the starting material had been consumed. The
reaction was quenched with 5 mL of water, filtered over a plug of
sand and silica, washed with EtOAc, and evaporated to yield 1.15 g
of a yellow oil containing two spots (r.f.'s 0.33 (minor, JR3217A)
and 0.25 (major, JR3217B), 20% EtOAc/Hexanes) which were visualized
with Vanillin. The compound was purified via flash chromatography
using 10% EtOAc/Hexanes (225 mL silica) to provide JR3217A and
JR3217B.
Preparation 12: 1-Prop-2-ynyl-piperidine-2-carboxylic acid methyl
ester (JR3249)
##STR00069##
[0303] The title compound was prepared starting with 4.0 g (22.3
mmol) of methylpipecolinate hydrochloride according to general
method 2.
Preparation 13: 1-Prop-2-ynyl-piperidine-4-carboxylic acid methyl
ester (JR3245)
##STR00070##
[0305] To a solution of methyl isonipecotate 3.5 g (24.4 mmol, 3.30
mL) in 100 mL dichloromethane was added TEA (1.5 eq, 36.6 mmol, 5.1
mL), propargyl bromide (3.0 eq, 73.2 mmol, 6.5 ml), at room
temperature for 36 hrs. The reaction was quenched with 35 mL water
to yield to provide a clear solution. The solution was extracted
with dichloromethane 2.times.25 mL, dried with Na2SO4, and the
solvent evaporated to provide a yellow oil. r.f. (40%
EtOAc/Hexanes) 0.26 stains faint white with Vanillin, starting
material r.f. 0.05 stains yellow with Vanillin. The product
appeared pure after extraction.
Preparation 14: 1-Prop-2-ynyl-piperidine-4-carboxylic acid ethyl
ester (JR3271)
##STR00071##
[0307] The title compound was prepared starting with 2.0 g (12.7
mmol) of ethyl isonipecotate according to general method 2.
Preparation 15: 4-Prop-2-ynyl-piperazine-1-carboxylic acid
tert-butyl ester (JR3275)
##STR00072##
[0309] To a solution of 10.0 g (54.8 mmol) of
tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added
5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol)
anhydrous potassium carbonate. Additional propargyl bromide, 1.5
mL, was added after stirring for 36 hours at room temperature. The
residue was evaporated to dryness. Dichloromethane, 50 mL, and
water, 50 mL, were added. The reaction mixture was extracted with
CH.sub.2Cl.sub.2, 4.times.40 mL, dried over magnesium sulfate, and
evaporate to provide a brown oil. The oil was dissolved in
dichloromethane and purify with a RT Scientific system using
hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil,
which ultimately crystallized upon standing.
Preparation 16: 4-Cyanomethyl-piperazine-1-carboxylic acid ethyl
ester (JR3287)
##STR00073##
[0311] To a solution of 3 g (19.0 mmol) of ethyl
N-piperazinecarboxylate in 25 mL of CH.sub.3CN was added 1.57 g
(1.32 mL 20.1 mmol) of 2-chloroacetonitrile and 15.6 g (95 mmol)
K.sub.2CO.sub.3.11/2H.sub.2O. The suspension was stirred at room
temperature for 16 hours. The reaction was analyzed using TLC (35%
Ethyl acetate/Hexanes, product r.f. 0.38 vs. s.m. r.f. of 0.02).
The analysis indicated the reaction was complete. The golden yellow
solution was evaporated to dryness. The residue was extracted with
CH.sub.2Cl.sub.2/H.sub.2O, dried with MgSO.sub.4, and
concentrated.
Preparation 17: 1-Cyclohexyl-4-prop-2-ynyl-piperazine (JR4019)
##STR00074##
[0313] The title compound was prepared starting with 3 g (17.9
mmol) of 1-cyclohexylpiperazine according to general method 2
Preparation 18: 1-Prop-2-ynyl-piperazine (JR4029)
##STR00075##
[0315] To a flame-dried 25 mL round bottom flask under nitrogen was
added 2.1 g of 4-Prop-2-ynyl-piperazine-1-carboxylic acid
tert-butyl ester. To this solid was added 5 mL of 98% TFA in 1 mL
portions. The solution turned wine red, bubbled and smoked. The
additional portions of TFA were added when this activity subsided.
After the third portion of TFA had been added only minimal bubbling
occurred. The solution was allowed to stir under nitrogen at room
temperature for an additional hour and evaporated under reduced
pressure to yield the product as a thick red syrup. Assumed
quantitative yield of 1.16 g. The residue was suspended in 20 mL
dichloromethane and used immediately without further purification
for the preparation of compounds JR4031, JR4033, and JR4035.
Preparation 19: 4-Prop-2-ynyl-piperazine-1-carboxylic acid methyl
ester (JR4031)
##STR00076##
[0317] The title compound was prepared starting with 385 mg (3.1
mmol) of JR4029 and using methylchloroformate according to general
method 3.
Preparation 20: 4-Prop-2-ynyl-piperazine-1-carboxylic acid isobutyl
ester (JR4035)
##STR00077##
[0319] The title compound was prepared starting with 385 mg (3.1
mmol) of JR4029 and using isobutylchloroformate according to
general method 3.
Preparation 21:
3,3-Dimethyl-1-(4-prop-2-ynyl-piperidin-1-yl)-butan-1-one
(JR4041)
##STR00078##
[0321] The title compound was prepared starting with tert-butyl
ester (JR3257) and using tert-butylacetylchloride according to
general method 3.
Preparation 22: 1-(4-Prop-2-ynyl-piperazin-1-yl)-ethanone
(JR4043)
##STR00079##
[0323] The title compound was prepared starting with 385 mg (3.1
mmol) of JR4029 and using acetyl chloride according to general
method 3.
[0324] The following intermediate compounds are prepared using the
general method 1 described herein and the appropriate starting
materials.
(R)-1-Ethynyl-3-tent-butyl-cyclohexanol (JR3255A),
(S)-1-Ethynyl-3-tert-butyl-cyclohexanol (JR3255B)
##STR00080##
[0325] Toluene-4-sulfonic acid 4-prop-2-ynyl-cyclohexylmethyl ester
(JR3077)
##STR00081##
[0326] 1-Ethyl-4-prop-2-ynyl-cyclohexane (JR3083)
##STR00082##
[0327] 1-(4-Prop-2-ynyl-cyclohexyl)-ethanone (JR3115)
##STR00083##
[0328] 1,1-Dicyclohexyl-prop-2-yn-1-ol (JR3127)
##STR00084##
[0329] 1-Cyclohexyl-prop-2-yn-1-ol (JR3129)
##STR00085##
[0330] 4-Ethyl-1-ethynyl-cyclohexanol (JR3143)
##STR00086##
[0331] 1-Ethynyl-3-methyl-cyclohexanol
##STR00087##
[0332] 1-Ethynyl-3,3,5,5-tetramethyl-cyclohexanol (JR3151)
##STR00088##
[0333] 1-Ethynyl-4-phenyl-cyclohexanol (JR3153)
##STR00089##
[0334] 1-Ethynyl-2-methyl-cyclohexanol (JR3167B)
##STR00090##
[0335] 4-tert-Butyl-1-ethynyl-cyclohexanol (JR3191)
##STR00091##
[0336] 1-Ethynyl-3,3-dimethyl-cyclohexanol (JR3193)
##STR00092##
[0337] 4-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl
ester (JR3199)
##STR00093##
[0338] 4-Prop-2-ynyl-piperazine-1-carboxylic acid ethyl ester
(JR3211)
##STR00094##
[0339] 4-Prop-2-ynyl-piperidine-1-carboxylic acid tert-butyl ester
(JR3257)
##STR00095##
[0340] 4-Prop-2-ynyl-piperidine-1-carboxylic acid ethyl ester
(JR3267B)
##STR00096##
[0341] 2-(4-Prop-2-ynyl-piperazin-1-yl)-pyrimidine (JR3277)
##STR00097##
[0342] 1-(4-Prop-2-ynyl-piperidin-1-yl)-ethanone (JR4037)
##STR00098##
[0343] 2,2-Dimethyl-1-(4-prop-2-ynyl-piperidin-1-yl)-propan-1-one
(JR4039)
##STR00099##
[0344] Example 1
4-{3-[6-Amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-y-
l)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl
ester
##STR00100##
[0346] MS: m/z 499.3 (M+H).sup.+.
Example 2
4-{3-[6-Amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-y-
l)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl
ester
##STR00101##
[0348] MS: m/z 500.4 (M+H).sup.+.
Example 3
5-[6-Amino-2-(1-hydroxy-3-methyl-cyclohexylethynyl)-purin-9-yl]-3,4-dihydr-
oxy-tetrahydro-furan-2-carboxylic acid cyclopropylamide
##STR00102##
[0350] MS: m/z 457.4 (M+H).sup.+.
Example 4
5-(6-Amino-2-iodo-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-carboxylic
acid cyclopropylamide
##STR00103##
[0351] Example 5
Cell Culture and Membrane Preparation
[0352] Sf9 cells were cultured in Grace's medium supplemented with
10% fetal bovine serum, 2.5 .mu.g/ml amphotericin B and 50 .mu.g/ml
gentamycin in an atmosphere of 50% N.sub.2/50% O.sub.2. Viral
infection was performed at a density of 2.5.times.10.sup.6 cells/mL
with a multiplicity of infection of two for each virus used.
Infected cells were harvested 3 days post-infection and washed
twice in insect PBS (PBS pH 6.3). Cells were then resuspended in
lysis buffer (20 mM HEPES pH 7.5, 150 mM NaCl, 3 mM MgCl.sub.2, 1
mM .beta.-mercaptoethanol (BME), 5 .mu.g/mL leupeptin, 5 .mu.g/mL
pepstatin A, 1 .mu.g/mL aprotinin, and 0.1 mM PMSF) and snap frozen
for storage at -80.degree. C. Cells were thawed on ice, brought to
30 mL total volume in lysis buffer, and burst by N.sub.2 cavitation
(600 psi for 20 minutes). A low-speed centrifugation was performed
to remove any unlysed cells (1000.times.g for 10 minutes), followed
by a high-speed centrifugation (17,000.times.g for 30 minutes). The
pellet from the final centrifugation was homogenized in buffer
containing 20 mM HEPES pH 8, 100 mM NaCl, 1% glycerol, 2 .mu.g/mL
leupeptin, 2 .mu.g/mL pepstatin A, 2 .mu.g/mL Aprotinin, 0.1 mM
PMSF, and 10 .mu.M GDP using a small glass homogenizer followed by
passage through a 26 gauge needle. Membranes were aliquoted, snap
frozen in liquid N.sub.2, and stored at -80.degree. C. Membranes
from cells stably expressing the human A.sub.1 AR (CHO K1 cells) or
A.sub.3 AR (HEK 293 cells) were prepared as described (Robeva et
al., 1996).
Example 6
Radioligand Binding Assays
[0353] Radioligand binding to recombinant human A.sub.2A receptors
in Sf9 cell membranes was performed using either the radio labeled
agonist, .sup.125I-APE (Luthin et al., 1995) or the radio labeled
antagonist, .sup.125I-ZM241385 (.sup.125I-ZM). To detect the high
affinity, GTP.gamma.S-sensitive state of A.sub.1 and A.sub.3AR, we
used the agonist, .sup.125I-ABA (Linden et al., 1985; Linden et
al., 1993). Binding experiments were performed in triplicate with 5
.mu.g (A.sub.2A) or 25 .mu.g (A.sub.1 and A.sub.3) membrane protein
in a total volume of 0.1 mL HE buffer (20 mM HEPES and 1 mM EDTA)
with 1 U/mL adenosine deaminase and 5 mM MgCl.sub.2 with or without
50 .mu.M GTP.gamma.S. Membranes were incubated with radioligands at
room temperature for three hours (for agonists) or two hours (for
antagonists) in Millipore Multiscreen.RTM. 96-well GF/C filter
plates and assays were terminated by rapid filtration on a cell
harvester (Brandel, Gaithersburg, Md.) followed by 4.times.150
.mu.l washes over 30 seconds with ice cold 10 mM Tris-HCl, pH 7.4,
10 mM MgCl.sub.2. Nonspecific binding was measured in the presence
of 50 .mu.M NECA. Competition binding assays were performed as
described (Robeva et al., 1996) using 0.5-1 nM .sup.125I-APE,
.sup.125I-ZM241385, or .sup.125I-ABA. We found that it was
sometimes important to change pipette tips following each serial
dilution to prevent transfer on tips of potent hydrophobic
compounds. The Ki values for competing compound binding to a single
site were derived from IC.sub.so values with correction for
radioligand and competing compound depletion as described
previously (Linden, 1982).
[0354] Linden J (1982) Calculating the Dissociation Constant of an
Unlabeled Compound From the Concentration Required to Displace
Radiolabel Binding by 50%. J Cycl Nucl Res 8: 163-172.
[0355] Linden J, Patel A and Sadek S (1985)
[.sup.125I]Aminobenzyladenosine, a New Radioligand With Improved
Specific Binding to Adenosine Receptors in Heart. Circ Res 56:
279-284.
[0356] Linden J, Taylor H E, Robeva A S, Tucker A L, Stehle J H,
Rivkees S A, Fink J S and Reppert S M (1993) Molecular Cloning and
Functional Expression of a Sheep A.sub.3 Adenosine Receptor With
Widespread Tissue Distribution. Mol Pharmacol 44: 524-532.
[0357] Luthin D R, Olsson R A, Thompson R D, Sawmiller D R and
Linden J (1995) Characterization of Two Affinity States of
Adenosine A.sub.2A Receptors With a New Radioligand,
2-[2-(4-Amino-3-[.sup.125I]Iodophenyl)Ethylamino]Adenosine. Mol
Pharmacol 47: 307-313.
[0358] Robeva A S, Woodard R, Luthin D R, Taylor H E and Linden J
(1996) Double Tagging Recombinant A.sub.1- and A.sub.2A-Adenosine
Receptors With Hexahistidine and the FLAG Epitope. Development of
an Efficient Generic Protein Purification Procedure. Biochem
Pharmacol 51: 545-555.
[0359] Chemiluminescence Methods: Luminol enhanced
chemiluminescence, a measure of neutrophil oxidative activity, is
dependent upon both superoxide production and mobilization of the
granule enzyme myeloperoxidase. The light is emitted from unstable
high-energy oxygen species such as hypochlorous acid and singlet
oxygen generated by activated neutrophils.
[0360] Purified human neutrophils (2.times.106/ml) suspended in
Hanks balanced salt solution containing 0.1% human serum albumin
(HA), adenosine deaminase (1 U/mL) and rolipram (100 nM) were
incubated (37.degree. C.) in a water bath for 15 min with or
without rhTNF (10 U/ml). Following incubation 100 L aliquots of the
PMN were transferred to wells (White walled clear bottom 96 well
tissue culture plates Costar #3670; 2 wells/condition) containing
501 HA and luminol (final concentration 100 M) with or without
adenosine agonist (final agonist concentrations 0.01-1000 nM). The
plate was incubated 5 min (37.degree. C.) and then fMLP (50 l in
HA; final concentration 1M) was added to all wells.
[0361] Peak chemiluminescence was determined with a Victor 1420
Multilabel Counter in the chemiluminescence mode using the Wallace
Workstation software.
[0362] Data are presented as peak chemiluminescence as percent of
activity in the absence of an adenosine agonist. The EC.sub.50 was
determined using PRISM software. All compounds were tested with
PMNs from three separate donors. The results are summarized in
Table 5.
TABLE-US-00005 TABLE 5 Binding Affinity And Selectivity For
A.sub.2A Agonists Functional Functional + Compound A.sub.1 (nM)
A.sub.2A (nM) A.sub.3 (nM) (nM).sup.1 Roli (nM).sup.2 Example 1 32
.58 34 2.0 0.20 Example 2 57 .7 247 2.0 0.20 Example 3 1.5 .5 3 0.3
0.04 Example 4 33 0.6 45 2.0 0.20 .sup.1Human neutrophil experiment
as described in Example 7 without Rolipram. .sup.2Human neutrophil
experiment as described in Example 7 with Rolipram.
Example 7
Effect of A.sub.2A Agonists on Neutrophil Oxidative Activity
A. Materials.
[0363] f-met-leu-phe (fMLP), luminol, superoxide dismutase,
cytochrome C, fibrinogen, adenosine deaminase, and trypan blue were
obtained from Sigma Chemical. Ficoll-hypaque was purchased from ICN
(Aurora, Ohio), and Cardinal Scientific (Santa Fe, N. Mex.) and
Accurate Chemicals and Scientific (Westerbury, N.Y.). Endotoxin
(lipopolysaccharide; E. coli K235) was from List Biologicals
(Campbell, Calif.). Hanks balanced salt solution (HBSS), and
limulus amebocyte lysate assay kit were from BioWittaker
(Walkersville, Md.). Human serum albumin (HSA) was from Cutter
Biological (Elkhart, Ind.). Recombinant human tumor necrosis
factor-alpha was supplied by Dianippon Pharmaceutical Co. Ltd.
(Osaka, Japan). ZM241385
(4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl
amino]ethyl)phenol) was a gift from Simon Poucher, Zeneca
Pharmaceuticals, Cheshire, UK. Stock solutions (1 mM and 10 mM in
DMSO) were made and stored at -20.degree. C.
B. Human Neutrophil Preparation
[0364] Purified neutrophils (-98% neutrophils and >95% viable by
trypan blue exclusion) containing<1 platelet per 5 neutrophils
and <50 pg/ml endotoxin (limulus amebocyte lysate assay) were
obtained from normal heparinized (10 U/ml) venous blood by a one
step Ficoll-hypaque separation procedure (A. Ferrante et al., J.
Immunol. Meth., 36, 109 (1980)).
C. Release of Inflammatory Reactive Oxygen Species from Primed and
Stimulated Human Neutrophils Chemiluminescence
[0365] Luminol-enhanced chemiluminescence, a measure of neutrophil
oxidative activity, is dependent upon both superoxide production
and mobilization of the lysosomal granule enzyme myeloperoxidase.
The light is emitted from unstable high-energy oxygen species
generated by activated neutrophils. Purified neutrophils
(5-10.times.10.sup.5/ml) were incubated in Hanks balanced salt
solution containing 0.1% human serum albumin (1 ml) with the tested
A.sub.2A agonist with or without rolipram and with or without tumor
necrosis factor-alpha (1 U/ml) for 30 minutes at 37.degree. C. in a
shaking water bath. Then luminol (1.times.10.sup.-4 M) enhanced
f-met-leu-phe (1 mcM) stimulated chemiluminescence was read with a
Chronolog.RTM. Photometer (Crono-log Corp., Havertown, Pa.) at
37.degree. C. for 2-4 minutes. Chemiluminescence is reported as
relative peak light emitted (=height of the curve) compared to
samples with tumor necrosis factor-alpha and without agonist or
rolipram.
Example 8
In Vivo Rat Blood Pressure Experiments
[0366] Sprague-Dawley rats (mean weights, 250-300 grams) were
anthesthetized and jugular and carotid catheters are implanted
ipsilaterally and the animals are allowed to recover 24-48 hours.
Prior to each experiment a baseline blood pressure reading is
established for 30 minutes with each drug injection being preceded
by a vehicle control. Drugs are injected bolus I.V. through a
jugular catheter in a 200 microliter volume of saline and the
catheter is flushed with an additional 300 microliters of saline.
To measure blood pressure, a central line from the carotid catheter
is attached to the pressure transducer of a Digi-Med Blood Pressure
Analyzer. Systolic pressure, diastolic pressure, mean pressure, and
heart rate are all recorded in real time at 30-60 second intervals.
Data is recorded until mean blood pressure has returned to baseline
and remained constant for 20 minutes. The data is presented as a
fraction of the mean blood pressure averaged over the 10 minutes
immediately prior to drug injection. The blood pressures are
recorded and plotted over time as a means of determining potency of
the compounds as well as biological half-life.
[0367] The compounds of examples 1 and 2 were tested against a
control compound, illustrated below:
##STR00104##
The results are illustrated in FIGS. 1-2.
[0368] All publications, patents, and patent documents are
incorporated by reference herein, as though individually
incorporated by reference. The invention has been described with
reference to various specific and preferred embodiments and
techniques. However, it should be understood that many variations
and modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *