HK1115386B

HK1115386B - 2-propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity

Info

Publication number: HK1115386B
Application number: HK08105033.0A
Authority: HK
Inventors: Jayson M. Rieger; Joel M. Linden; Timothy L. Macdonald; Gail W. Sullivan; Lauren J. Murphree; Robert Alan Figler
Original assignee: University Of Virginia Patent Foundation; Adenosine Therapeutics Llc
Priority date: 2004-08-02
Filing date: 2005-08-02
Publication date: 2014-02-14

Description

Having a2A2-propynyl adenosine analogs with modified 5' -ribose groups for agonist activity

RELATED APPLICATIONS

The application claims the name: priority of the provisional application for "2-propynyl adenosine analogs with modified 5' -ribose groups and compositions having A2A agonist activity" was filed on 8/2 2004, serial No. 60/598,018, the entire contents of which are incorporated herein by reference.

Government fund

The invention described herein was made with government support under the grant of national science fund (RO1-HL 37942). The united states government has certain rights in this invention.

Background

The inflammatory response is used to destroy harmful factors of the body. The range of pathogenic damage that can trigger an inflammatory response is broad, including infection, allergens, autoimmune stimuli, immune responses to transplanted tissue, harmful chemicals and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal injury. Inflammation is often a very localized effect used to expel, dilute, attenuate and isolate damaging factors from damaged tissue. When the body responds by causing inappropriate damage to host tissues during the process of destroying the targeted agent or in response to traumatic injury, it becomes the causative agent of the disease.

As an example, inflammation is an integral part of pathogenesis in a variety of vascular diseases or injuries. Examples include: Ischemia/Reperfusion injury (N.G. Frangogannis et al, inMyocardial Ischemia: Mechanisms, Reperfusion, Protection, M.Karmazyn, eds., 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 aneurysm (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.Vase.Surg., 2, 859(1985)), and post-balloon angioplasty restenosis (R.Ross, cited above). Cells associated with inflammation include leukocytes (i.e., immune system cells-neutrophils, eosinophils, lymphocytes, monocytes, basophils, macrophages, dendritic cells, and mast cells), vascular endothelium, vascular smooth muscle cells, fibroblasts, and muscle cells.

The release of inflammatory cytokines such as tumor necrosis factor-alpha by leukocytes is a means by which the immune system resists pathogenic invasion, including infectious agents. TNF α stimulates the expression and activation of adhesion factors on leukocytes and endothelial cells, triggers an enhanced inflammatory response of neutrophils to secondary stimuli, and enhances the oxidative activity of adherent neutrophils. See, Sharma et al, cited herein. In addition, macrophages/dendritic cells also serve as accessory cells for processing antigen presentation to lymphocytes. Lymphocytes themselves function as pro-inflammatory cytotoxic cells upon stimulation.

In general, cytokines stimulate neutrophils to enhance oxidative (e.g., hyper-oxidative and secondary products) and non-oxidative (e.g., myeloperoxidase and other enzymes) inflammatory activity. Inappropriate and excessive release of cytokines may produce a very pathogenic effect by oxidation of tissue damage as opposed to release of non-oxidized products (k.g. tracey et al, j.exp.med., 167, 1211(1988) and d.n. mannel et al, rev.infect.dis., 9 (supplement 5), S602-S606 (1987)). For example, TNF α can induce neutrophils to adhere to the walls of blood vessels and then travel through the blood vessels to the site of injury, releasing their oxidative and non-oxidative inflammatory products.

Although monocytes slowly accumulate at the site of the inflammatory foci, monocytes develop into resident accessory cells and macrophages if conditions are appropriate. Monocytes/macrophages are also capable of producing and secreting a range of cytokines (including TNF α), complement, lipids, reactive oxygen species, proteases and growth factors that remodel tissues and regulate peripheral tissue function when stimulated with inflammatory triggers.

For example, inflammatory cytokines have been shown to be causative agents of the following diseases: 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 (supplement 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 alkali burned eyes (F.Miyamoto et al, OpthalmicRes., 30, 168(1997)), furthermore, the formation of peroxides in leukocytes is associated with the promotion of replication of Human Immunodeficiency Virus (HIV) (S.Legrand-Poels et al, SRAIDs.hum. Retroviruses, 6, 1389 (1990)).

It is well known that adenosine and certain adenosine analogues that non-selectively activate adenosine receptor subtypes reduce neutrophil production of inflammatory oxidation 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 Adenos Research, E.Gerlach et al, eds., Springer-Verlag, Berlin, P.286 (1987); S.T.gamma.J.Mcbelieved et al, Leyce E.44, E.J.1988, 1989, and Br); B.A.A.Ianno N.Iannone et al, 1986). For example, adenosine has been shown to inhibit chemoattractants such as the synthetic mimetic of bacterial peptides, f-met-leu-phe (fMLP), and complement component C₅a stimulation of neutrophils releases peroxide (b.n. cronstein et al, j. immunol., 135, 1366 (1985)). Adenosine can reduce the oxidative burst of a significant increase in PMNs (neutrophils) first sensitized by 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)). In addition, adenosine has been reported to decrease the rate of HIV replication in T-cell lines (S.Sipka et al, acta.Biochim.Biopys.Hung., 23, 75 (1988)). There is no evidence of anti-inflammatory activity of adenosine in vivo (G.S. Firestein et al, Clin.Res., 41, 170a (1993); and B.N.Cronstein et al, Clin.Res., 41, 244a (1993)).

It has been suggested that on neutrophils which may have an adverse effect on peroxide releaseThere is more than one adenosine receptor subtype (b.n. cronstein et al, j.clin.invest., 85, 1150 (1990)). Van Calker et al originally demonstrated A on neutrophils_2AThe presence of receptors (d.van Calker et al, eur.j. pharmacology, 206, 285 (1991)).

Many have been developed as A in step-by-step based on radioligand binding assays and physiological responses_2ACompounds with increased potency and/or increased selectivity for agonists of Adenosine Receptors (ARs). Initially developed Compound Pair A_2AReceptors are very selective or even non-selective, for example adenosine itself or 5 '-carboxamides of adenosine, such as 5' -N-ethylcarboxamidoadenosine (NECA) (B.N.Cronstein et al, J.Immunol., 135, 1366 (1985)). Subsequently, it was found that the addition of 2-alkylamino substituents can enhance potency and selectivity, for example CVl808 and CGS21680(M.F. Jarvis et al, J.Pharmacol. exp. Ther., 251, 888 (1989)). 2-alkoxy-substituted adenosine derivatives such as WRC-0090 as agonists in coronary artery A_2AHigher potency and selectivity at the receptor (m.ueda et al, j.med.chem., 34, 1334 (1991)). In the coronary artery A_2A2-alkylhydrazinoadenosine derivatives such as SHA 211 (also known as WRC-0474) have also been evaluated at the receptor as agonists (K.Niiya et al, J.Med.chem., 35, 4557 (1992)).

One document reports that the combined use of relatively nonspecific Adenosine analogues, R-phenylisopropyladenosine (R-PIA) and 2-chloroadenosine (Cl-Ado) with Phosphodiesterase (PDE) inhibitors results in a decrease in 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)). But actually is compared with A_2AAdenosine receptors, R-PIA and Cl-Ado being A₁Stronger activators of adenosine receptors, and thus, due to A on cardiac muscle and other tissues₁Receptor activation can cause side effects such as "cardiac block".

R.A. Olsson et al (U.S. Pat. No.5,278,150) disclose selective adenosine A of the formula₂Receptor agonists:

wherein Rib is ribosyl, R₁Is H and R₂Is a cycloalkyl group. The disclosed compounds are useful for the treatment of hypertension, atherosclerosis and as vasodilators.

Olsson et al (U.S. Pat. No.5,140,015) disclose certain adenosines A of the formula₂Receptor agonists:

wherein C (X) BR₂Is CH₂OH and R₁Is alkyl or alkoxyalkyl. The disclosed compounds are useful as vasodilators or anti-hypertensive agents.

The invention of Linden et al (U.S. Pat. No.5,877,180) is based on the following findings: by applying as A_2AAdministration of a compound that is a selective agonist of the adenosine receptor, preferably in combination with a phosphodiesterase type IV inhibitor, is effective in the treatment of certain inflammatory diseases, such as arthritis and asthma. In the invention of Linden et al, embodiments thereof provide a method of treating a condition or disorder by administering an effective amount of a compound of formula a_2AA method of treating inflammatory diseases with adenosine receptors:

wherein R and X are as defined in the patent.

In one embodiment, the invention of Linden et al comprises administering a Phosphodiesterase (PDE) type IV inhibitor in combination with A_2AAdenosine receptor antagonists. Phosphodiesterase type IV (PDE) inhibitors include racemic and optically active 4- (polyalkoxyphenyl) -2-pyrrolidinones of the following formula:

wherein R', R¹⁸，R¹⁹And X is as disclosed and described in U.S. patent No.4,193,926. Rolipram is an example of a suitable type IV PDE inhibitor included within the scope of the above formula.

Cristalli (U.S. Pat. No.5,593,975) discloses 2-arylethynyl, 2-cycloalkylethynyl or 2-hydroxyalkylethynyl derivatives in which the nucleoside residue is substituted with a carboxyamino group, or a substituted carboxyamino group (R)₃HNC (O) -. Miyasaka et al (U.S. Pat. No.4,956,345) have disclosed 2-alkynylpurine derivatives in which the 2-alkynyl group is replaced by (C)₃ -C₁₆) Alkyl substitution. The disclosed' 975 compounds are believed to be vasodilators, inhibit platelet aggregation, and are therefore useful as anti-ischemic agents, anti-atherosclerotic agents, and anti-hypertensive agents.

More recently, U.S. patent 6,232,297 to Linden et al discloses compounds having the general formula:

wherein each R is H, X is ethylaminocarbonyl and R¹Is 4-carboxycyclohexylmethyl (DWH-146a), R¹Is 4-methoxycarbonylcyclohexylmethyl (DWH-146e) or R¹Is 4-acetoxymethyl-cyclohexylmethyl (JMR-193). These compounds are reported to be A_2AAn antagonist.

However, there is still a continuing need for selective a useful for therapeutic applications and having reduced side effects₂Adenosine receptor agonismAnd (3) preparing. Furthermore, there is a continuing need for selective a2 adenosine receptor agonists for use as pharmacological stressors in stress imaging or other ventricular function imaging techniques, which preferably have reduced side effects, while being chemically stable and short-acting.

Summary of The Invention

The present invention includes compounds and methods of use thereof for treating inflammatory activity in mammalian tissue. Inflammatory tissue activity may be due to pathological factors, or may be due to physical, chemical or thermal trauma, or medical procedures such as organ, tissue or cell transplantation, angioplasty (PCTA), inflammation following ischemia/reperfusion, or trauma during transplantation. The compounds of the present invention include a novel class of 2-alkynyl adenosine derivatives, substituted with cycloalkyl and heterocyclic (heterocyclic) moieties at the ethynyl-2-yl position. Nucleoside residues are preferably modified at the 5' -position by substitution of an N- (cycloalkyl) carboxy amino ("aminocarbonyl") moiety ("X") or a 5-or 6-membered heterocyclic ring. Accordingly, the present invention provides methods for inhibiting an inflammatory response in a mammal, such as a human, by administering an effective amount of one or more compounds of the present invention, and protecting tissues susceptible to such an inflammatory response.

The compounds of the invention have the general formula (I):

wherein

Z is CR³R⁴R⁵Or NR⁴R⁵；

Each R¹Independently hydrogen, halogen, -OR^a，-SR^a，(C₁-C₈) Alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,C_3-8cycloalkyl, heterocycle (C)₁-C₈) Alkylene-, aryl (C)₁-C₈) Alkylene-, heteroaryl (C)₁-C₈) Alkylene-, -CO₂R^a，R^aC(＝O)O-，R^aC(＝O)-，-OCO₂R^a，R^aR^bNC(＝O)O-，R^bOC(＝O)N(R^a)-，R^aR^bN-，R^aR^bNC(＝O)-，R^aC(＝O)N(R^b)-，R^aR^bNC(＝O)N(R^b)-，R^aR^bNC(＝S)N(R^b)-，-OPO₃R^a，R^aOC(＝S)-，R^aC(＝S)-，-SSR^a，R^aS(＝O)-，R^aS(＝O)₂-，-N＝NR^aor-OPO₂R^a；

Each R²Independently hydrogen, halogen, (C)₁-C₈) Alkyl radical (C)₃-C₈) Cycloalkyl, heterocycle (C)₁-C₈) Alkylene-, aryl (C)₁-C₈) Alkylene-, heteroaryl, or heteroaryl (C)₁-C₈) An alkylene group; or

R¹And R²And the atom to which they are attached is C ═ O, C ═ S or C ═ NR^C。

R⁴And R⁵Together 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 containing 1, 2, 3, or 4 atoms in the ring selected from the group consisting of nonperoxy form of oxygen (-O-), sulfur (-S-), sulfinyl (-SO-), sulfonyl (-S (O))₂-) or an amine (-NR)^a-) is a heteroatom;

any of which contains R⁴And R⁵Is substituted by 1 to 14R⁶Substituted by groups;

wherein each R⁶Independently hydrogen, halogen, -OR^a，-SR^a，(C₁-C₈) Alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C)₁-C₈) Cycloalkyl group, (C)₁-C₈) Cycloalkyl (C)₁-C₈) Alkylene-, (C)₆-C₁₂) Bicycloalkyl, heterocyclic or heterocyclic (C)₁-C₈) Alkylene-, aryl (C)₁-C₈) Alkylene-, heteroaryl (C)₁-C₈) -alkylene, -CO₂R^a，R^aC(＝O)O-，R^aC(＝O)-，-OCO₂R^a，R^aR^bNC(＝O)O-，R^bOC(＝O)N(R^a)-，R^aR^bN-，R^aR^bNC(＝O)-，R^aC(＝O)N(R^b)-，R^aR^bNC(＝O)N(R^b)-，R^aR^bNC(＝S)N(R^b)-，-OPO₃R^a，R^aOC(＝S)-，R^aC(＝S)-，-SSR^a，R^aS(＝O)-，-NNR^a，-OPO₂R^a(ii) a Or two R⁶The radicals and the atoms to which they are attached are C ═ O or C ═ S; or two R⁶The radicals together with the atoms to which they are attached form a ring containing from 1 to 6 carbon atoms and 1, 2, 3, or 4 atoms selected from nonperoxyoxy (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-, phosphine (-OP (O))₂-, or amines (-NR)^a-) carbocyclic or heterocyclic ring of a heteroatom;

R³is hydrogen, halogen, -OR^a，-SR^a，(C₁-C₈) Alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C)₃-C₈) Cycloalkyl group, (C)₁-C₈) Cycloalkyl (C)₁-C₈) Alkylene-, heterocycle (C)₁-C₈) Alkylene-, aryl (C)₁-C₈) Alkylene-, heteroaryl (C)₁-C₈) Alkylene-, -CO₂R^a，R^aC(＝O)O-，R^aC(＝O)-，-OCO₂R^a，R^aR^bNC(＝O)O-，R^bOC(＝O)N(R^a)-，R^aR^bN-，R^aR^bNC(＝O)-，R^aC(＝O)N(R^b)-，R^aR^bNC(＝O)N(R^b)-，R^aR^bNC(＝S)N(R^b)-，-OPO₃R^a，R^aOC(＝S)-，R^aC(＝S)-，-SSR^a，R^aS(＝O)-，R^aS(＝O)₂-，-NNR^a，-OPO₂R^a(ii) a Or if from CR⁴R⁵The ring formed being aryl or heteroaryl or partially saturated, then R³May be absent;

each R⁷Independently is hydrogen, (C)₁-C₈) Alkyl radical (C)₃-C₈) Cycloalkyl group, (C)₁-C₈) Cycloalkyl (C)₁-C₈) Alkylene-, heterocycle (C)₁-C₈) Alkylene-, aryl (C)₁-C₈) Alkylene, heteroaryl, or heteroaryl (C)₁-C₈) Alkylene-;

x is-CH₂OR^e，-CO₂R^e，-CH₂OC(O)R^e，-C(O)NR^eR^f，-CH₂SR^e，-C(S)OR^e，-CH₂OC(S)R^eOr C (S)

NR^eR^f-CH₂N(R^e)(R^f) Or a group of the formula

Wherein each Z¹Is non-peroxy-O-, -S (O)_p-，-C(R⁸)_j-, or-N (R)⁸) -; provided that at least one Z¹Is non-peroxy-O-, -S (O)_p-, or-N (R)⁸)-；

Each R⁸Independently is hydrogen, (C)₁-C₈) Alkyl radical (C)₁-C₈) Alkenyl, (C)₃-C₈) Cycloalkyl group, (C)₁-C₈) Alkyl radical (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Cycloalkenyl radical, (C)₁-C₈) Alkyl radical (C)₃ -C₈) Cycloalkenyl, aryl (C)₁-C₈) Alkylene-, heteroaryl, or heteroaryl (C)₁-C₈) Alkylene-in which R is⁸Any alkyl or alkenyl of (A) is optionally substituted by-O-, -S-, or-N (R)^a) -a discontinuity;

R^eis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

R^fis hydrogen, (C)₁-C₈) Alkyl, or substituted by 1-3 of the following groups (C)₁-C₈) Alkyl groups: (C)₁-C₈) Alkoxy group, (C)₃-C₈) Cycloalkyl group, (C)₁-C₈) Alkylthio, amino acid, aryl (C)₁-C₈) Alkylene, heteroaryl, or heteroaryl (C)₁-C₈) An alkylene group; and

wherein R is¹，R²，R³，R⁶，R⁷And R⁸Any alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, OR heteroaryl of (a) is optionally substituted on carbon with one OR more (e.g., 1, 2, 3, OR 4) substituents selected from halogen, -OR^a，-SR^a，(C₁-C₈) Alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C)₃-C₈) Cycloalkyl group, (C)₆-C₁₂) Bicycloalkyl, heterocyclic or heterocyclic (C)₁-C₈) Alkylene-, aryl, aryloxy, aryl (C)₁-C₈) Alkylene-, heteroaryl (C)₁-C₈) Alkylene-, -CO₂R^a，R^aC(＝O)O-，R^aC(＝O)-，-OCO₂R^a，R^aR^bNC(＝O)O-，R^bOC(＝O)N(R^a)-，R^aR^bN-，R^aR^bNC(＝O)-，R^aC(＝O)N(R^b)-，R^aR^bNC(＝O)N(R^b)-，R^aR^bNC(＝S)N(R^b)-，-OPO₃R^a，R^aOC(＝S)-，R^aC(＝S)-，-SSR^a，R^aS(＝O)_P-，R^aR^bNS(O)_P-，N＝NR^aand-OPO₃R^a；

Any of them (C)₁-C₈) Alkyl radical (C)₃-C₈) Cycloalkyl group, (C)₆-C₁₂) Bicycloalkyl (C)₁-C₈) Alkoxy group, (C)₁-C₈) Alkanoyl radical, (C)₁-C₈) Alkylene, or heterocycle is optionally partially unsaturated;

R^aand R^bEach independently is hydrogen, (C)₁-C₁₈) Alkyl, or substituted by 1-3 of the following groups (C)₁-C₁₈) Alkyl groups: (C)₁-C₁₈) Alkoxy group, (C)₃-C₈) Cycloalkyl group, (C)₁-C₁₈) Alkylthio, amino acid, aryl (C)₁-C₁₈) Alkylene, heteroaryl, or heteroaryl (C)₁-C₁₈) An alkylene group; or R^aAnd R^bTogether with the nitrogen to which they are attached form a pyrrolidino (pyrrolidino), piperidino (piperidino), morpholino, or thiomorpholino ring; and

R^cis hydrogen or (C)₁-C₆) An alkyl group;

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;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compounds of the invention have the general formula (I):

wherein

Z is CR³R⁴R⁵Or NR⁴R⁵；

Each R¹Independently hydrogen, halogen, -OR^a，-SR^a，(C₁-C₈) Alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C_3-8Cycloalkyl, heterocycle (C)₁-C₈) Alkylene-, aryl (C)₁-C₈) Alkylene-, heteroaryl (C)₁-C₈) Alkylene-, -CO₂R^a，R^aC(＝O)O-，R^aC(＝O)-，-OCO₂R^a，R^aR^bNC(＝O)O-，R^bOC(＝O)N(R^a)-，R^aR^bN-，R^aR^bNC(＝O)-，R^aC(＝O)N(R^b)-，R^aR^bNC(＝O)N(R^b)-，R^aR^bNC(＝S)N(R^b)-，-OPO₃R^a，R^aOC(＝S)-，R^aC(＝S)-，-SSR^a，R^aS(＝O)-，R^aS(＝O)₂-，-N＝NR^aor-OPO₂R^a；

wherein each R⁶Independently hydrogen, halogen, -OR^a，-SR^a，(C₁-C₈) Alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C)₁-C₈) Cycloalkyl group, (C)₁-C₈) Cycloalkyl (C)₁-C₈) Alkylene-, (C)₆-C₁₂) Bicycloalkyl, heterocyclic or heterocyclic (C)₁-C₈) Alkylene-, aryl (C)₁-C₈) Alkylene-, heteroaryl (C)₁-C₈) -alkylene, -CO₂R^a，R^aC(＝O)O-，R^aC(＝O)-，-OCO₂R^a，R^aR^bNC(＝O)O-，R^bOC(＝O)N(R^a)-，R^aR^bN-，R^aR^bNC(＝O)-，R^aC(＝O)N(R^b)-，R^aR^bNC(＝O)N(R^b)-，R^aR^bNC(＝S)N(R^b)-，-OPO₃R^a，R^aOC(＝S)-，R^aC(＝S)-，-SSR^a，R^aS(＝O)-，-NNR^a，-OPO₂R^a(ii) a Or two R⁶The radicals and the atoms to which they are attached are C ═ O or C ═ S; or two R⁶The radicals together with the atoms to which they are attached form a ring containing from 1 to 6 carbon atoms and 1, 2, 3, or 4 atoms selected from the group consisting of nonperoxy forms of oxygen (-O-), sulfur (-S-), sulfinyl (-SO-), sulfonyl (-S (O)₂-, phosphine (-OP (O))₂-, or amines (-NR)^a-) carbocyclic or heterocyclic ring of a heteroatom;

NR^eR^f-CH₂N(R^e)(R^f) Or a group of the formula

Wherein each Z¹Is a nonperoxy form-O-, -S (O)_p-，-C(R⁸)_j-, or-N (R)⁸) -; provided that at least one Z¹Is a nonperoxy form-O-, -S (O)_p-, or-N (R)⁸)-；

R^eis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

wherein R is¹，R²，R³，R⁶，R⁷And R⁸Any alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl of (a) is optionally substituted on carbon by one or more(e.g., 1, 2, 3, OR 4) substituents selected from halogen, -OR^a，-SR^a，(C₁-C₈) Alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C)₃-C₈) Cycloalkyl group, (C)₆-C₁₂) Bicycloalkyl, heterocyclic or heterocyclic (C)₁-C₈) Alkylene-, aryl, aryloxy, aryl (C)₁-C₈) Alkylene-, heteroaryl (C)₁-C₈) Alkylene-, -CO₂R^a，R^aC(＝O)O-，R^aC(＝O)-，-OCO₂R^a，R^aR^bNC(＝O)O-，R^bOC(＝O)N(R^a)-，R^aR^bN-，R^aR^bNC(＝O)-，R^aC(＝O)N(R^b)-，R^aR^bNC(＝O)N(R^b)-，R^aR^bNC(＝S)N(R^b)-，-OPO₃R^a，R^aOC(＝S)-，R^aC(＝S)-，-SSR^a，R^aS(＝O)_P-，R^aR^bNS(O)_P-，N＝NR^aand-OPO₃R^a；

R^aand R^bEach independently is hydrogen, (C)₁-C₈) Alkyl, or substituted by 1-3 of the following groups (C)₁-C₈) Alkyl groups: (C)₁-C₈) Alkoxy group, (C)₃-C₈) Cycloalkyl group, (C)₁-C₈) Alkylthio, amino acid, aryl (C)₁-C₈) Alkylene, heteroaryl, or heteroaryl (C)₁-C₈) An alkylene group; or R^aAnd R^bTogether with the nitrogen to which they are attached form pyrrolidino, piperidinoMorpholino, or thiomorpholino ring; and

R^cis hydrogen or (C)₁-C₆) An alkyl group;

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound of formula I for use in medical therapy, preferably for use in the treatment of inflammation or protection of mammalian tissue from inflammatory responses such as those caused by allergic reactions, trauma or ischemia/reperfusion injury, and the use of a compound of formula I for the manufacture of a medicament for the treatment of inflammatory responses due to a pathological condition or symptom associated with inflammation in a mammal, such as a human.

The invention also includes the use of these compounds in combination with a phosphodiesterase type IV inhibitor to preferably synergistically reduce leukocyte-mediated inflammatory responses.

The invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, optionally a phosphodiesterase type IV (PDE) inhibitor. Preferably, the composition is in unit dosage form.

In addition, the invention provides therapeutic methods for preventing or treating pathological conditions or symptoms in a mammal, such as a human, wherein A is involved_2AAdenosine receptor activity and requires agonistic activity at said receptor, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. Is believed to activate A_2AAdenosine receptors can inhibit inflammation by affecting neutrophils, mast cells, monocytes/macrophages, T-cells and/or eosinophils. Inhibition of these inflammatory cells can result in tissue damage.

In addition, the present invention provides therapeutic methods for treating biological diseases comprising administering an effective amount of an antibiotic, antifungal or antiviral agent in combination with an A2a adenosine receptor mediator. If the anti-pathogenic agent is not known, an A2a antagonist alone can be used to reduce inflammation, which can occur, for example, during infection by antibiotic-resistant bacteria, or some viruses, such as those causing SARS or Ebola. Optionally, the method comprises administering a type IV PDE inhibitor. A2a adenosine receptor antagonists can provide adjunctive therapy for the treatment of conditions such as inflammation caused by sepsis, for example, human uremic syndrome when antibiotics are administered for the treatment of bioterrorism weapons such as anthrax, tularemia, E.coli, plague, and the like. The invention also provides adjunctive therapy for the treatment of lethal bacterial, fungal and viral infections such as anthrax, tularemia, escherichia and plague comprising the administration of an antibacterial, antifungal or antiviral agent in combination with a selective A2a adenosine receptor agonist.

The present invention provides methods for treating biological diseases that cause inflammation, either alone or in combination with agents that eliminate the disease. These include bacteria associated with antibiotics, but are not limited to bacteria causing anthrax, tularemia, plague, lyme disease and anthrax. Viruses that cause, but are not limited to, RSV, Severe Acute Respiratory Syndrome (SARS), influenza and Ebola, with or without antiviral therapy are also included. Also included are yeast and fungal infections with or without the use of anti-yeast or anti-fungal agents.

The antibacterial, antifungal or antiviral agent may be administered { e.g., simultaneously } with the A2A adenosine receptor agonist or they may be administered simultaneously or as a mixture or subsequently. Subsequent administration of the A2A adenosine receptor agonist may be administered prior to drug administration, or within minutes or up to about 48 hours after drug administration. Preferably, A is administered within about 24 hours, more preferably within about 12 hours_2AAn adenosine receptor agonist.

The methods of the invention can treat patients with sepsis, severe sepsis, and potentially systemic inflammatory response syndrome in addition to septic shockA patient. A. the_2AAR agonists exert multiple anti-inflammatory effects in the early stages of the inflammatory cascade, and thus A_2AShort courses of AR agonists can produce great benefit in serious, life-threatening infectious and inflammatory diseases, including inhaled anthrax, tularemia, escherichia and plague.

A has been proved_2AAnti-inflammatory effects of AR agonists in experimental models of meningitis, peritonitis and arthritis in vivo. The potentially fatal syndrome of bacterial sepsis is becoming an increasingly common problem in acute care units. Sepsis and septic shock, which are the eleventh leading cause of death in the united states, occur in ever increasing numbers. Current estimates show that there are approximately 900,000 new cases of sepsis (nearly 60% gram-negative) annually in the united states with a roughly estimated mortality rate of 35%. Moreover, as assessed in recent clinical trials, mortality rates approach 25%, while nearly 10% of patients die from their primary morbidity. The mortality rate from shock is 46% (92,000 deaths) in nearly 200,000 cases per year. The annual health care expenditure for sepsis is estimated to be $ 50-100 billion. It is now generally recognized that sepsis is a common cause of death in patients hospitalized in non-cardiac intensive care units (non-cardiac care units). Sepsis syndrome is a crucial public health problem. Expectation of A_2AAR agonists can be used as a new and unique adjunctive therapeutic approach to reduce morbidity and mortality. It is believed that this treatment will improve the outcome of systemic anthrax, tularemia, escherichia and plague.

A of the invention_2AAdenosine receptor agonists inhibit neutrophil, macrophage and T cell activation and thus reduce inflammation caused by bacterial and viral infections. The compounds in combination with antibiotics or antiviral agents can prevent or reduce death caused by sepsis or hemolytic uremic syndrome or other inflammatory conditions. Enhancement of A by phosphodiesterase type IV inhibitors such as rolipram_2AAdenosine agonists.

The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. Preferably, the composition is in the form of a dosage unit and may be suitable for parenteral, e.g., intravenous, injection.

The invention also provides compounds of formula I for use in medical therapy (e.g., as adjuvants in the treatment of potentially lethal bacterial infections, such as anthrax, tularemia, Escherichia, plague, or other bacterial or viral infections, and systemic poisoning (oxygenation) caused by bacterial and/or viral infections), and the use of compounds of formula I for the manufacture of medicaments for reducing inflammation caused by bacteria or viruses or for treating inflammation in mammals, such as humans.

Sepsis is a serious disease caused by fulminant infection of the bloodstream with toxin-producing bacteria or viruses. Infection, which may manifest as inflammation, may be caused directly by a bacterial or viral pathogen or as a result of treatment thereof, i.e. as a result of death of the pathogen as a result of treatment with an antibacterial or antiviral agent. Sepsis can also be seen as the body's response to infection. Infection may result from the invasion of the body by microorganisms or "germs" (usually bacteria), may be limited to a particular body area (e.g., dental abscesses) or may be widely distributed in the blood (commonly referred to as "sepsis" or "blood poisoning")

Systemic poisoning or inflammatory shock is commonly referred to as septic shock; shock due to bacteremia; endotoxic shock; septic shock; or warm shock.

Septic shock is a serious abnormal condition when a fulminant infection leads to hypotension and low blood flow. Vital organs, such as the brain, heart, kidney, and liver, do not function or may fail. Septic shock most commonly occurs in very old and very young people. It also occurs in people with primary disease. Any bacterial organism may cause septic shock. Fungi and viruses can also cause this condition. Toxins released by bacteria, fungi or viruses can cause direct tissue damage and can lead to hypotension and/or organ dysfunction. These toxins may also cause the body to mount a severe inflammatory response that causes septic shock.

In another aspect, the invention also provides a method of treating Severe Acute Respiratory Syndrome (SARS) comprising administering to a mammal in need of such treatment an effective anti-inflammatory amount of A_2AAn adenosine receptor agonist, optionally administered with a PDE-IV inhibitor, e.g., rolipram.

The present invention provides compounds and methods of using them to detect the presence and assess the severity of coronary artery stenosis in a mammal, such as a human or livestock. Preferably, the compounds of the invention are used as pharmacological emergency inducers or responders for use in pharmacological stress imaging for the detection and assessment of coronary artery disease. The particular compounds of the present invention used as emergency inducers are potent and selective A2a adenosine receptors, but are also short acting, such that they are rapidly cleared by the body after the imaging procedure.

Accordingly, the present invention provides a method for detecting the presence and severity of a coronary stenosis in a mammal, such as a human subject, comprising (1) administering a substantial amount of one or more compounds of formula (I) and (2) performing a technique in said mammal to detect and/or determine the severity of said coronary stenosis.

The present invention provides compounds of formula (I) for use in medical diagnostic procedures, preferably for detecting the presence of, and assessing the severity of, coronary artery stenosis in a human subject. The present invention provides the use of a compound of formula (I) for the preparation of a pharmacological vasodilator useful in conjunction with clinical perfusion imaging techniques for the diagnosis and assessment of the extent of coronary artery disease. Preferred perfusion imaging techniques are two-dimensional or Single Photon Emission Computed Tomography (SPECT) gamma camera scintigraphy, Positron Emission Tomography (PET), Nuclear Magnetic Resonance (NMR) imaging, Magnetic Resonance Imaging (MRI), perfusion contrast echocardiography, Digital Subtraction Angiography (DSA) and hyperkinetic X-ray computed tomography (CINE CT).

The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. Preferably, the composition is in unit dosage form and may be adapted for parenteral, e.g., intravenous, injection.

Brief Description of Drawings

FIG. 1 illustrates the reduction of blood pressure in rats following administration of the compounds of the invention by monitoring_2AAgonist compared to A_2ADuration of action of the agonist.

FIG. 2 illustrates the reduction of blood pressure in rats following oral administration of the compounds of the invention by monitoring_2AAgonist compared to A_2ADuration of action of the agonist.

Detailed Description

The following definitions apply, unless otherwise indicated. Halogen is fluorine, chlorine, bromine, or iodine. Alkyl, alkoxy, aralkyl, alkylaryl, and the like represent straight and branched alkyl groups; however, the term "propyl" as used herein includes only straight chain groups and branched chain isomers such as "isopropyl" are specifically indicated. Aryl groups include phenyl or ortho-fused bicyclic carbocyclic groups having about 9 to 10 ring atoms, wherein at least one ring is aromatic. Heteroaryl includes groups attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1 to 4 members independently selected from the nonperoxy forms of oxygen, sulfur and N (X), wherein X is absent or is H, O, (C)₁-C₄) Alkyl radicalPhenyl or benzyl, and groups derived from ortho-fused diheterocycles containing about 8 to 10 ring atoms, in particular benzo derivatives or derivatives obtained by fusing a propylene, trimethylene or tetramethylene diradical thereto.

One skilled in the art will recognize that the compounds of formula (I) have more than one chiral center and can thus be separated into optically active and racemic forms. Preferably the nucleoside moiety of formula (I) is derived from D-ribose. Certain compounds may exhibit polymorphism. It is therefore to be understood that the present invention includes any racemate, optically active, polymorphic or stereoisomeric form, or mixtures thereof, of a compound of the present invention, all of which possess the beneficial properties described herein. It is well known to those skilled in the art how to prepare optically active forms (e.g., by resolution of racemic forms using recrystallization techniques or enzymatic techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase) and how to determine adenosine agonist activity using the assays described herein or using other similar assays well known in the art.

The inflammatory response that can be treated (including prophylactic treatment) using a compound of formula I, optionally in combination with a type IV PDE inhibitor, refers to inflammation that results from:

(a) autoimmune stimuli (autoimmune diseases), such as lupus erythematosus, multiple sclerosis, infertility due to endometriosis, type I diabetes including islet destruction leading to diabetes and inflammatory consequences of diabetes, including leg ulcers, Crohn's disease, ulcerative colitis, inflammatory bowel disease, osteoporosis and rheumatoid arthritis;

(b) allergic diseases such as asthma, hay fever, rhinitis, poison ivy, vernal conjunctivitis and other eosinophil-mediated disorders;

(c) skin diseases such as psoriasis, contact dermatitis, eczema, infectious skin ulcer, healing of open wound, cellulitis;

(d) infectious diseases such as sepsis, septic shock, encephalitis, infectious arthritis, endotoxic shock, gram-negative bacterial shock, Jarisch-Herxheimer reaction, anthrax, plague, tularemia, ebola, herpes zoster, toxic shock, cerebral malaria, bacterial meningitis, Acute Respiratory Distress Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), Lyme disease, HIV infection, (TNF α -enhanced HIV replication, TNF α inhibition of reverse transcriptase inhibitor activity);

(e) wasting disease, cachexia secondary to cancer and HIV;

(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;

(g) side effects of drug therapy, including side effects of amphotericin B therapy, side effects of immunosuppressive therapy such as interleukin-2 therapy, side effects of OKT3 therapy, contrast dyes, antibiotics, side effects of GM-CSF therapy, side effects of cyclosporin therapy, and side effects of aminoglycoside therapy, stomatitis and mucositis due to immunosuppression;

(h) cardiovascular disorders including circulatory disorders induced or exacerbated by inflammatory responses, 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, subarachnoid post-hemorrhage vasospasm, post-cerebrovascular accident vasospasm, pleurisy, pericarditis, and diabetic cardiovascular complications;

(i) dialysis, including pericarditis due to peritoneal dialysis;

(j) gout; and

(k) chemical or thermal trauma due to burns, acids, bases, etc.

Of particular value and efficacy is the use of the compounds of the present invention to limit the inflammatory response to ischemia/reperfusion injury due to angioplasty or thrombolytic. Also of particular value and efficacy is the use of the compounds of the present invention to limit inflammatory responses due to organ, tissue or cell transplantation, i.e., transplantation of allogeneic or xenogeneic tissues into a mammalian recipient, autoimmune diseases and inflammatory conditions due to circulatory diseases and treatments thereof, including angioplasty, stent placement, shunt placement (crush) or transplantation. Surprisingly, it has been found that administration of one or more compounds of formula (I) after the onset of an inflammatory response, for example after a subject is afflicted with a lesion or wound capable of eliciting an inflammatory response, is effective.

Tissues or cells containing a ligand-binding receptor site can be used to determine the selectivity of a test compound for a particular receptor subtype, the amount of biologically active compound in blood or other physiological fluids, or can be used as a means for identifying an effective therapeutic agent by contacting the ligand-receptor complex with a therapeutic agent for treating a disease or condition associated with receptor site activation, and can determine the degree of ligand displacement and/or binding of the therapeutic agent, or the cellular response (e.g., cAMP accumulation) to the therapeutic agent.

Tissues or cells containing a ligand-associated receptor site can be used to measure the selectivity of a test compound for a particular receptor subtype, the amount of a biologically active compound in blood or other physiological fluids, or can be used as a means for identifying potential therapeutic agents for treating diseases or conditions associated with activation of the receptor site by contacting such agents with the ligand-receptor complexes described above and measuring the extent of metastasis of the ligand and/or bound agent, or the cellular response (e.g., cAMP accumulation) of such agents.

The specific and preferred meanings given below for the groups, substituents and ranges are illustrative only; they do not exclude other defined meanings or other meanings within the definition of the group and the substituent.

In particular, (C)₁-C₈) The alkyl radical maySo as to be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl and the like. As used herein, the term "(C)₁-C₈) The alkoxy group "may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-butoxy, s-butoxy, pentyloxy, 3-pentyloxy, hexyloxy, 1-methylhexyloxy, heptyloxy, or the like.

As used herein, the term "cycloalkyl" may be bicycloalkyl (norbornyl, 2.2.2-bicyclooctyl, etc.) and tricycloalkyl (adamantyl, etc.), optionally including 1-2N, O or S. Cycloalkyl also includes (cycloalkyl) alkyl. Thus, (C)₃-C₆) Cycloalkyl groups may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. In particular, (C)₆-C₁₂) The bicycloalkyl group includes norbornyl, 2.2.2-bicyclooctyl and the like.

As used herein, the term "(C)₁-C₈) Alkoxy "may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, 3-pentyloxy, hexyloxy; and the like.

As used herein, the term "(C)₂-C₆) Alkenyl "may be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-n-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like.

As used herein, the term "(C)₂-C₆) Alkynyl "may 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.

As used herein, the term "(C)₁-C₈) Alkanoyl "can be acetyl, propionyl, butyryl, etc.

As used herein, the term "halogen (C)₁-C₈) Alkyl "may be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2, 2-trifluoroethyl, pentylfluoroethyl, and the like.

As used herein, the term "hydroxy (C)₁-C₆) Alkyl "may + 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.

As used herein, the term "(C)₁-C₈) Alkylthio "can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, hexylthio, and the like.

As used herein, the term "aryl" includes phenyl, indenyl, indanyl, naphthyl, and the like. Additionally, aryl includes an ortho-fused bicyclic carbocyclic group having about nine to ten ring atoms, wherein at least one ring is aromatic. The term "aryl" may include groups derived from ortho-fused bis-heterocycles containing about 8 to 10 ring atoms, in particular benzo derivatives or derivatives obtained by fusing a divalent radical of propylene, trimethylene or tetramethylene thereto.

The term "heteroaryl" as used herein may be a compound consisting of carbon and 1, 2, 3, or 4 members selected from the non-peroxy forms oxygen, sulfur and N (Y), respectively, wherein Y is absent or is H, O, (C)₁-C₈) A single aromatic ring consisting of five or six ring atoms consisting of heteroatoms of alkyl, phenyl or benzyl. Non-limiting examples of heteroaryl groups include furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or N-oxide thereof), thienyl, pyrimidinyl (or N-oxide thereof), indolyl, isoquinolyl (or N-oxide thereof), quinolyl (or N-oxide thereof), and the like. The term "heteroaryl" may include aryl groups consisting of groups containing from about 8 to about 10 ring atomsOrtho-fused diheterocycle derived groups, in particular benzo derivatives or derivatives obtained by fusing a propylene, trimethylene or tetramethylene diradical thereto. Examples of heteroaryl groups may be furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyraxolyl, 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.

As herein, on the heterocyclic X ringDenotes a ring having one or two double bonds and may be an aromatic ring. Non-limiting examples of the X ring include:

and the like.

The term "heterocycle" generally refers to a non-aromatic heterocyclic group having from 3 to about 10 ring atoms, which may be saturated or partially unsaturated, containing at least one (e.g., 1, 2, or 3) heteroatom(s) selected from oxygen, nitrogen, and sulfur. In particular, "heterocyclic" groups include monocyclic, bicyclic, or tricyclic groups containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur. A "heterocyclic" group may also include one or more oxo groups (═ O) attached to ring atoms. Non-limiting examples of heterocyclic 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 (piperazinyl), piperidine, piperidinyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine (quinuelidine), thiomorpholine, and the like.

The term "alkylene" refers to a divalent straight or branched hydrocarbon chain (e.g., ethylene-CH)₂-CH₂ -)。

The term "aryl (C)₁-C₈) Alkylene "includes, for example, benzyl, phenethyl, naphthylmethyl and the like.

The content of carbon atoms for various hydrocarbon-containing moieties is expressed in terms of the prefixes specifying the minimum and maximum number of carbon atoms in the moiety, i.e., prefix C_i-C_jDenotes the portion of carbon atoms that includes the integer "i" through the integer "j". Thus, for example, (C)₁-C₈) Alkyl refers to alkyl groups comprising one to eight carbon atoms.

The compounds of the invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations well known to those of ordinary skill in the art may be used. (e.g., "Ph" refers to phenyl, "Me" refers to methyl, "Et" refers to ethyl, "h" refers to hours or hours and "rt" refers to room temperature).

R¹A particular meaning is hydrogen, -OH, halogen, -CH₂OH，-OMe，-OAc，-NH₂，-NHMe，-NMe₂or-NHAc.

R¹Another specific meaning is hydrogen, -OH, -F, -OMe, -OAc, -NH₂，-NHMe，-NMe₂or-NHAc.

R¹Another specific meaning is hydrogen, -OH, -F, -OMe, or-NH₂。

R¹Another specific meaning is hydrogen, -OH, -F, or-NH₂。

R¹A more specific meaning is hydrogen or-OH.

R²A particular meaning is hydrogen, halogen, or (C)₁-C₈) Alkyl, cyclopropyl, cyclohexyl or benzyl.

R²Another specific meaning is hydrogen, -F, methyl, ethyl or propyl.

R²Another specific meaning is hydrogen or methyl.

R²A more specific meaning is hydrogen.

R¹，R²And the carbon atom to which they are attached a particular meaning is carbonyl (C ═ O).

R³A particular meaning is hydrogen, OH, OMe, OAc, NH₂，NHMe，NMe₂Or NHAc.

R³Another specific meaning is hydrogen, OH, OMe, or NH₂。

R³Another specific meaning is hydrogen, OH, or NH₂。

R³A more specific meaning is hydrogen or OH.

Comprising R⁴，R⁵And the ring to which they are attached have one particular meaning of cyclopentane, cyclohexane, piperidine, dihydropyridine, tetrahydropyridine, pyridine, piperazine, decalin (decalin), tetrahydropyrazine, dihydropyrazine, pyrazine, dihydropyrimidine, tetrahydropyrimidine, hexahydropyrimidine, pyrazine, imidazole, dihydroimidazole, imidazolidine (imidazolidine), pyrazole, dihydropyrazole, and pyrazolidine.

Comprising R⁴，R⁵And the ring to which they are attached are cyclohexane, piperidine or piperazine.

R⁶A specific meaning is (C)₁-C₈) Alkyl, substituted (C)₁-C₈) Alkyl, halogen, -OR^a，-CO₂R^a，-OCO₂R^a，-C(＝O)R^a，-OC(＝O)R^a，-NR^aR^b， -C(＝O)NR^aR^b，-OC(＝O)NR^aR^bOr an aryl group.

R⁶Another specific meaning is (C)₁-C₄) Alkyl, chloro, fluoro, phenyl, -OR^a，-CH₂OR^a，-CO₂R^a，-CH₂CO₂R^a，-OCO₂R^a，-CH₂OCO₂R^a，-C(＝O)R^a，-CH₂C(＝O)R^a，-OC(＝O)R^a，-CH₂OC(＝O)R^a，-NR^aR^b，-CH₂NR^aR^b，-C(＝O)NR^aR^b，-CH₂C(＝O)NR^aR^b，-OC(＝O)NR^aR^bor-CH₂OC(＝O)NR^aR^b。

R⁶Another specific meaning is OH, OMe, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -CH₂OH, phenyl, -OAc, -CH₂OAc，-CO₂H，-CO₂Me，-CO₂Et，-CO₂i-Pr，-CO₂i-Bu，-CO₂t-Bu，-OCO₂Me，-OCO₂Et，-C(＝O)CH₃，-CONH₂，-CONHMe，-CONMe₂，-CONMeEt，-NH₂，-NHMe，-NMe₂，-NHEt，-N(Et)₂or-CH₂N(CH₃)₂。

R⁶Another specific meaning is OH, OMe, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -CH₂OH, phenyl, -OAc, -CH₂OAc，-CO₂Me，-CO₂Et，-CO₂i-Pr，-CO₂i-Bu，-CO₂t-Bu，-OCO₂Me，-OCO₂Et，-CONMe₂，-CONMeEt。

R substituted on the Z ring⁶Specific values of the groups are integers from 1 to about 4.

R^aA particular meaning is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl or benzyl.

R^bA particular meaning is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl or benzyl.

R^aAnother specific meaning is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and R^bIs hydrogen, or methyl.

R^aAnd R^bAnother specific meaning of the nitrogen to which they are attached is the formation of a pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

R^aAnd R^bAnother specific meaning of the nitrogen to which they are attached is the formation of a pyrrolidino, piperidino, or morpholino ring.

R⁷A particular meaning is hydrogen, (C)₁-C₄) Alkyl, aryl (C)₁-C₈) Alkylene, diaryl (C)₁-C₈) Alkylene, heteroaryl (C)₁-C₈) Alkylene, or diheteroaryl (C)₁ -C₈) An alkylene group.

R⁷Another specific meaning is hydrogen, methyl, ethyl, 3-pentyl, benzene CH₂CH₂-, (benzene)₂CHCH₂-, pyridine CH₂-, benzyl, or

R⁷Another specific meaning is hydrogen, 3-pentyl, picolyl, or benzyl. -N (R)⁷)₂A particular meaning is amino, methylamino, dimethylamino, ethylamino, diethylamino, pentylamino, diphenylamino, benzylamino, or(pyridylmethyl amino).

Particular pyridylmethyl amino group is

R⁷A more specific meaning is H.

-N(R⁷)₂Another specific meaning is amino (NH)₂) 3-pentylamino, diphenylethylamino, pyridylmethylamino, benzylamino, or a group having the formula:

-N(R⁷)₂another particular meaning is amino, diphenylethylamino, pentylamino or benzylamino.

-N(R⁷)₂A more specific meaning is amino.

X has the meaning of-CH₂OR^e，-CO₂R^e，-CH₂OC(O)R^e，-C(O)NR^eR^for-CH₂N(R^e)(R^f)。

Another specific meaning of X is-CH₂OR^eor-C (O) NR^eR^f。

X has another specific meaning

R⁸A particular meaning is methyl, ethyl, isopropyl, isopropenyl, -CH ═ CH₂，CH₂OH, propyl, -CH₂-CH＝CH₂，-CH＝CH-CH₃Cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, cyclobutyl, cyclobutenyl, - (CH)₂)Y(CH₂)_nH，-(CH₂)_nCOOCH₃，-(CH₂)_nCO(CH₂)_nH, wherein Y is O, S, N (CH)₂)_n。

R⁸Another specific meaning is (C)₁-C₃) Alkyl radical, CH₂OH, cyclopropyl, cyclobutyl, cyclopropylmethyl, - (CH)₂)₂CO₂CH₃，-(CH₂)_2-3OH，-(CH₂)₂A halogen.

R⁸More particularly one of the meanings is methyl, ethyl, propyl, 2-propenyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, - (CH)₂)₂CO₂CH₃，-(CH₂)_2-3OH

R⁸Furniture setOne meaning of the body is methyl, ethyl, cyclopropyl.

R^eA particular meaning is cyclopropyl, or cyclobutyl.

R^eOne particular meaning is cyclopropyl.

R^eA specific meaning is cyclobutyl.

R^fA particular meaning is hydrogen, or (C)₁-C₈) An alkyl group.

R^fAnother specific meaning is hydrogen, methyl, ethyl, or propyl.

R^fAnother specific meaning is hydrogen, or methyl.

R^fAnother specific meaning is hydrogen.

i has a specific meaning of 1.

i another specific meaning is 2.

j has a specific meaning of 1.

Another specific meaning of j is 2.

m has a specific meaning of 0, 1, or 2.

m more specifically has a meaning of 0, or 1.

Comprising R⁴，R⁵And the specific examples of the ring to which they are attached include:

wherein q is 1 to 14 and R^dIs hydrogen, with the proviso that when q is zero and R is^dIs not hydrogen.

Comprising R⁴，R⁵More specific examples of rings and their linking atoms include:

comprising-C (R)³)R⁴R⁵A specific meaning of the ring of (A) is 2-methylcyclohexane, 2, 2-dimethylcyclohexane, 2-phenylcyclohexane, 2-ethylcyclohexane, 2, 2-diethylcyclohexane, 2-tert-butylcyclohexane, 3-methylcyclohexane, 3, 3-dimethylcyclohexane, 4-methylcyclohexane, 4-ethylcyclohexane, 4-phenylcyclohexane, 4-tert-butylcyclohexane, 4-carboxymethylcyclohexane, 4-carboxyethylcyclohexane, 3, 3, 5, 5-tetramethylcyclohexane, 2, 4-dimethylcyclopentane. 4-cyclohexanecarboxylic acid, 4-cyclohexanecarboxylate, or 4-methoxyalkanoyl-cyclohexane.

comprising-C (R)³)R⁴R⁵The ring of (A) is specifically defined as 4-piperidine, 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-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-1-carboxylic acid methyl ester, 3-piperidine-1-carboxylic acid tert-butyl ester, 1, 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-butyl ester, 1, 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-butyl ester, 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.

Comprising R⁴And R⁵The ring of (a) is specifically 2-methylcyclohexane, 2, 2-dimethylcyclohexane, 2-phenylcyclohexane, 2-ethylcyclohexane, 2, 2-diethylcyclohexane, 2-tert-butylcyclohexane,3-methylcyclohexane, 3, 3-dimethylcyclohexane, 4-methylcyclohexane, 4-ethylcyclohexane, 4-phenylcyclohexane, 4-tert-butylcyclohexane, 4-carboxymethylcyclohexane, 4-carboxyethylcyclohexane, 3, 3, 5, 5-tetramethylcyclohexane, 2, 4-dimethylcyclopentane, 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-butyl ester, 1-piperidine-4-carboxylic acid methyl ester, 1-piperidine-4-carboxylic acid tert-butyl ester, 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-butyl ester, 1-piperidine-3-carboxylic acid methyl ester, 1-piperidine-3-carboxylic acid tert-butyl ester.

Specific compounds of the invention include formula (IA)

Formula (IA) wherein n is 0, 1, 2, 3, 4,5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In another specific group of compounds n is, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

Specific compounds of the invention include those of formula (IB)

Formula (IB) wherein k is 1, 2, 3, 4,5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

Specific compounds of the invention include those of formula (IC)

In formula (IC), l is 0, 1, 2, 3, or 4.

Other specific compounds of the invention include

Additional compounds of the invention are described in table 1 below:

TABLE 1

Compound (I)	R¹	R²	Y	R⁶
					101	H	H	CH	CO₂Me
102	H	H	CH	CO₂Et
					103	H	H	CH	CO₂iPr
104	H	H	CH	CO₂tBu
					105	H	H	CH	CO₂iBu
106	H	H	CH	CH₂OH
					107	H	H	CH	CH₂OAc
108	H	H	N	CO₂Me
					109	H	H	N	CO₂Et
110	H	H	N	CO₂iPr
					111	H	H	N	CO₂tBu
112	H	H	N	CO₂iBu

[0231] TABLE 2

Compound #	R⁶
		201	2-CH₃
202	3-CH₃(R)
		203	3-CH₃(S)
204	3-Et(R)
		205	3-Et(S)
206	4-Me
		207	4-Et
208	4-Pr
		209	4-tBu
210	4-phenyl radical

[0234] TABLE 3

Compound (I)	R⁸	Z	Y	R⁶
					301	Methyl radical	Z1	CH	CO₂Me
302	Methyl radical	Z1	CH	CO₂Et
					303	Methyl radical	Z1	CH	CO₂iPr
304	Methyl radical	Z1	CH	CO₂tBu
					305	Methyl radical	Z1	CH	CO₂iBu
306	Methyl radical	Z1	CH	CH₂OH
					307	Methyl radical	Z1	CH	CH₂OAc
308	Methyl radical	Z1	N	CO₂Me
					309	Methyl radical	Z1	N	CO₂Et
310	Methyl radical	Z1	N	CO₂iPr
					311	Methyl radical	Z1	N	CO₂tBu
312	Methyl radical	Z1	N	CO₂iBu
					313	Ethyl radical	Z1	CH	CO₂Me
314	Ethyl radical	Z1	CH	CO₂Et
					315	Ethyl radical	Z1	CH	CO₂iPr
316	Ethyl radical	Z1	CH	CO₂tBu
					317	Ethyl radical	Z1	CH	CO₂iBu
318	Ethyl radical	Z1	CH	CH₂OH
					319	Ethyl radical	Z1	CH	CH₂OAc
320	Ethyl radical	Z1	N	CO₂Me
					321	Ethyl radical	Z1	N	CO₂Et
322	Ethyl radical	Z1	N	CO₂iPr

[0237]

323	Ethyl radical	Z1	N	CO₂tBu
					324	Ethyl radical	Z1	N	CO₂iBu
325	Cyclopropyl group	Z1	CH	CO₂Me
					326	Cyclopropyl group	Z1	CH	CO₂Et
327	Cyclopropyl group	Z1	CH	CO₂iPr
					328	Cyclopropyl group	Z1	CH	CO₂tBu
329	Cyclopropyl group	Z1	CH	CO₂iBu
					330	Cyclopropyl group	Z1	CH	CH₂OH
331	Cyclopropyl group	Z1	CH	CH₂OAc
					332	Cyclopropyl group	Z1	N	CO₂Me
333	Cyclopropyl group	Z1	N	CO₂Et
					334	Cyclopropyl group	Z1	N	CO₂iPr
335	Cyclopropyl group	Z1	N	CO₂tBu
					336	Cyclopropyl group	Z1	N	CO₂iBu
337	Methyl radical	Z2	CH	CO₂Me
					338	Methyl radical	Z2	CH	CO₂Et
339	Methyl radical	Z2	CH	CO₂iPr
					340	Methyl radical	Z2	CH	CO₂tBu
341	Methyl radical	Z2	CH	CO₂iBu
					342	Methyl radical	Z2	CH	CH₂OH
343	Methyl radical	Z2	CH	CH₂OAc
					344	Methyl radical	Z2	N	CO₂Me
345	Methyl radical	Z2	N	CO₂Et
					346	Methyl radical	Z2	N	CO₂iPr
347	Methyl radical	Z2	N	CO₂tBu
					348	Methyl radical	Z2	N	CO₂iBu
349	Ethyl radical	Z2	CH	CO₂Me
					350	Ethyl radical	Z2	CH	CO₂Et
351	Ethyl radical	Z2	CH	CO₂iPr
					352	Ethyl radical	Z2	CH	CO₂tBu
353	Ethyl radical	Z2	CH	CO₂iBu

[0238]

354	Ethyl radical	Z2	CH	CH₂OH
					355	Ethyl radical	Z2	CH	CH₂OAc
356	Ethyl radical	Z2	N	CO₂Me
					357	Ethyl radical	Z2	N	CO₂Et
358	Ethyl radical	Z2	N	CO₂iPr
					359	Ethyl radical	Z2	N	CO₂tBu
360	Ethyl radical	Z2	N	CO₂iBu
					361	Cyclopropyl group	Z2	CH	CO₂Me
362	Cyclopropyl group	Z2	CH	CO₂Et
					363	Cyclopropyl group	Z2	CH	CO₂iPr
364	Cyclopropyl group	Z2	CH	CO₂tBu
					365	Cyclopropyl group	Z2	CH	CO₂iBu
366	Cyclopropyl group	Z2	CH	CH₂OH
					367	Cyclopropyl group	Z2	CH	CH₂OAc
368	Cyclopropyl group	Z2	N	CO₂Me
					369	Cyclopropyl group	Z2	N	CO₂Et
370	Cyclopropyl group	Z2	N	CO₂iPr
					371	Cyclopropyl group	Z2	N	CO₂tBu
372	Methyl radical	Z3	CH	CO₂Me
					373	Methyl radical	Z3	CH	CO₂Et
374	Methyl radical	Z3	CH	CO₂iPr
					375	Methyl radical	Z3	CH	CO₂tBu
376	Methyl radical	Z3	CH	CO₂iBu
					377	Methyl radical	Z3	CH	CH₂OH
378	Methyl radical	Z3	CH	CH₂OAc
					379	Methyl radical	Z3	N	CO₂Me
380	Methyl radical	Z3	N	CO₂Et
					381	Methyl radical	Z3	N	CO₂iPr
382	Methyl radical	Z3	N	CO₂tBu
					383	Methyl radical	Z3	N	CO₂iBu
384	Ethyl radical	Z3	CH	CO₂Me

[0239]

385	Ethyl radical	Z3	CH	CO₂Et
					386	Ethyl radical	Z3	CH	CO₂iPr
387	Ethyl radical	Z3	CH	CO₂tBu
					388	Ethyl radical	Z3	CH	CO₂iBu
389	Ethyl radical	Z3	CH	CH₂OH
					390	Ethyl radical	Z3	CH	CH₂OAc
391	Ethyl radical	Z3	N	CO₂Me
					392	Ethyl radical	Z3	N	CO₂Et
393	Ethyl radical	Z3	N	CO₂iPr
					394	Ethyl radical	Z3	N	CO₂tBu
395	Ethyl radical	Z3	N	CO₂iBu
					396	Cyclopropyl group	Z3	CH	CO₂Me
397	Cyclopropyl group	Z3	CH	CO₂Et
					398	Cyclopropyl group	Z3	CH	CO₂iPr
399	Cyclopropyl group	Z3	CH	CO₂tBu
					400	Cyclopropyl group	Z3	CH	CO₂iBu
401	Cyclopropyl group	Z3	CH	CH₂OH
					402	Cyclopropyl group	Z3	CH	CH₂OAc
403	Cyclopropyl group	Z3	N	CO₂Me
					404	Cyclopropyl group	Z3	N	CO₂Et
405	Cyclopropyl group	Z3	N	CO₂iPr
					406	Cyclopropyl group	Z3	N	CO₂tBu
407	Cyclopropyl group	Z3	N	CO₂iBu
					408	Methyl radical	Z4	CH	CO₂Me
409	Methyl radical	Z4	CH	CO₂Et
					410	Methyl radical	Z4	CH	CO₂iPr
411	Methyl radical	Z4	CH	CO₂tBu
					412	Methyl radical	Z4	CH	CO₂iBu
413	Methyl radical	Z4	CH	CH₂OH
					414	Methyl radical	Z4	CH	CH₂OAc
415	Methyl radical	Z4	N	CO₂Me

[0240]

416	Methyl radical	Z4	N	CO₂Et
					417	Methyl radical	Z4	N	CO₂iPr
418	Methyl radical	Z4	N	CO₂tBu
					419	Methyl radical	Z4	N	CO₂iBu
420	Ethyl radical	Z4	CH	CO₂Me
					421	Ethyl radical	Z4	CH	CO₂Et
422	Ethyl radical	Z4	CH	CO₂iPr
					423	Ethyl radical	Z4	CH	CO₂tBu
424	Ethyl radical	Z4	CH	CO₂iBu
					425	Ethyl radical	Z4	CH	CH₂OH
426	Ethyl radical	Z4	CH	CH₂OAc
					427	Ethyl radical	Z4	N	CO₂Me
428	Ethyl radical	Z4	N	CO₂Et
					429	Ethyl radical	Z4	N	CO₂iPr
430	Ethyl radical	Z4	N	CO₂tBu
					431	Ethyl radical	Z4	N	CO₂iBu
432	Cyclopropyl group	Z4	CH	CO₂Me
					433	Cyclopropyl group	Z4	CH	CO₂Et
434	Cyclopropyl group	Z4	CH	CO₂iPr
					435	Cyclopropyl group	Z4	CH	CO₂tBu
436	Cyclopropyl group	Z4	CH	CO₂iBu
					437	Cyclopropyl group	Z4	CH	CH₂OH
438	Cyclopropyl group	Z4	CH	CH₂OAc
					439	Cyclopropyl group	Z4	N	CO₂Me
440	Cyclopropyl group	Z4	N	CO₂Et
					441	Cyclopropyl group	Z4	N	CO₂iPr
442	Cyclopropyl group	Z4	N	CO₂tBu
					443	Methyl radical	Z5	CH	CO₂Me
444	Methyl radical	Z5	CH	CO₂Et
					445	Methyl radical	Z5	CH	CO₂iPr
446	Methyl radical	Z5	CH	CO₂tBu

[0241]

447	Methyl radical	Z5	CH	CO₂iBu
					448	Methyl radical	Z5	CH	CH₂OH
449	Methyl radical	Z5	CH	CH₂OAc
					450	Methyl radical	Z5	N	CO₂Me
451	Methyl radical	Z5	N	CO₂Et
					452	Methyl radical	Z5	N	CO₂iPr
453	Methyl radical	Z5	N	CO₂tBu
					454	Methyl radical	Z5	N	CO₂iBu
455	Ethyl radical	Z5	CH	CO₂Me
					456	Ethyl radical	Z5	CH	CO₂Et
457	Ethyl radical	Z5	CH	CO₂iPr
					458	Ethyl radical	Z5	CH	CO₂tBu
459	Ethyl radical	Z5	CH	CO₂iBu
					460	Ethyl radical	Z5	CH	CH₂OH
461	Ethyl radical	Z5	CH	CH₂OAc
					462	Ethyl radical	Z5	N	CO₂Me
463	Ethyl radical	Z5	N	CO₂Et
					464	Ethyl radical	Z5	N	CO₂iPr
465	Ethyl radical	Z5	N	CO₂tBu
					466	Ethyl radical	Z5	N	CO₂iBu
467	Cyclopropyl group	Z5	CH	CO₂Me
					468	Cyclopropyl group	Z5	CH	CO₂Et
469	Cyclopropyl group	Z5	CH	CO₂iPr
					470	Cyclopropyl group	Z5	CH	CO₂tBu
471	Cyclopropyl group	Z5	CH	CO₂iBu
					472	Cyclopropyl group	Z5	CH	CH₂OH
473	Cyclopropyl group	Z5	CH	CH₂OAc
					474	Cyclopropyl group	Z5	N	CO₂Me
475	Cyclopropyl group	Z5	N	CO₂Et
					476	Cyclopropyl group	Z5	N	CO₂iPr
477	Cyclopropyl group	Z5	N	CO₂tBu
					478	Cyclopropyl group	Z5	N	CO₂iBu

[0242] TABLE 4

Compound (I)	R⁸	Z	R⁶
				501	Methyl radical	Z1	2-CH₃
502	Methyl radical	Z1	3-CH₃(R)
				503	Methyl radical	Z1	3-CH₃(S)
504	Methyl radical	Z1	3-Et(R)
				505	Methyl radical	Z1	3-Et(S)
506	Methyl radical	Z1	4-Me
				507	Methyl radical	Z1	4-Et
508	Methyl radical	Z1	4-Pr
				509	Methyl radical	Z1	4-tBu
510	Methyl radical	Z1	4-phenyl radical
				511	Ethyl radical	Z1	2-CH₃
512	Ethyl radical	Z1	3-CH₃(R)
				513	Ethyl radical	Z1	3-CH₃(S)
514	Ethyl radical	Z1	3-Et(R)
				515	Ethyl radical	Z1	3-Et(S)
516	Ethyl radical	Z1	4-Me
				517	Ethyl radical	Z1	4-Et
518	Ethyl radical	Z1	4-Pr
				519	Ethyl radical	Z1	4-tBu
520	Ethyl radical	Z1	4-phenyl radical
				521	Cyclopropyl group	Z1	2-CH₃

[0245]

522	Cyclopropyl group	Z1	3-CH₃(R)
				523	Cyclopropyl group	Z1	3-CH₃(S)
524	Cyclopropyl group	Z1	3-Et(R)
				525	Cyclopropyl group	Z1	3-Et(S)
526	Cyclopropyl group	Z1	4-Me
				527	Cyclopropyl group	Z1	4-Et
528	Cyclopropyl group	Z1	4-Pr
				529	Cyclopropyl group	Z1	4-tBu
530	Cyclopropyl group	Z1	4-phenyl radical
				531	Methyl radical	Z2	2-CH₃
532	Methyl radical	Z2	3-CH₃(R)
				533	Methyl radical	Z2	3-CH₃(S)
534	Methyl radical	Z2	3-Et(R)
				535	Methyl radical	Z2	3-Et(S)
536	Methyl radical	Z2	4-Me
				537	Methyl radical	Z2	4-Et
538	Methyl radical	Z2	4-Pr
				539	Methyl radical	Z2	4-tBu
540	Methyl radical	Z2	4-phenyl radical
				541	Ethyl radical	Z2	2-CH₃
542	Ethyl radical	Z2	3-CH₃(R)
				543	Ethyl radical	Z2	3-CH₃(S)
544	Ethyl radical	Z2	3-Et(R)
				545	Ethyl radical	Z2	3-Et(S)
546	Ethyl radical	Z2	4-Me
				547	Ethyl radical	Z2	4-Et
548	Ethyl radical	Z2	4-Pr
				549	Ethyl radical	Z2	4-tBu
550	Ethyl radical	Z2	4-phenyl radical
				551	Cyclopropyl group	Z2	2-CH₃
552	Cyclopropyl group	Z2	3-CH₃(R)

[0246]

553	Cyclopropyl group	Z2	3-CH₃(S)
				554	Cyclopropyl group	Z2	3-Et(R)
555	Cyclopropyl group	Z2	3-Et(S)
				556	Cyclopropyl group	Z2	4-Me
557	Cyclopropyl group	Z2	4-Et
				558	Cyclopropyl group	Z2	4-Pr
559	Cyclopropyl group	Z2	4-tBu
				560	Cyclopropyl group	Z2	4-phenyl radical
561	Methyl radical	Z3	2-CH₃
				562	Methyl radical	Z3	3-CH₃(R)
563	Methyl radical	Z3	3-CH₃(S)
				564	Methyl radical	Z3	3-Et(R)
565	Methyl radical	Z3	3-Et(S)
				566	Methyl radical	Z3	4-Me
567	Methyl radical	Z3	4-Et
				568	Methyl radical	Z3	4-Pr
569	Methyl radical	Z3	4-tBu
				570	Methyl radical	Z3	4-phenyl radical
571	Ethyl radical	Z3	2-CH₃
				572	Ethyl radical	Z3	3-CH₃(R)
573	Ethyl radical	Z3	3-CH₃(S)
				574	Ethyl radical	Z3	3-Et(R)
575	Ethyl radical	Z3	3-Et(S)
				576	Ethyl radical	Z3	4-Me
577	Ethyl radical	Z3	4-Et
				578	Ethyl radical	Z3	4-Pr
579	Ethyl radical	Z3	4-tBu
				580	Ethyl radical	Z3	4-phenyl radical
581	Cyclopropyl group	Z3	2-CH₃
				582	Cyclopropyl group	Z3	3-CH₃(R)
583	Cyclopropyl group	Z3	3-CH₃(S)

[0247]

584	Cyclopropyl group	Z3	3-Et(R)
				585	Cyclopropyl group	Z3	3-Et(S)
586	Cyclopropyl group	Z3	4-Me
				587	Cyclopropyl group	Z3	4-Et
588	Cyclopropyl group	Z3	4-Pr
				589	Cyclopropyl group	Z3	4-tBu
590	Cyclopropyl group	Z3	4-phenyl radical
				591	Methyl radical	Z4	2-CH₃
592	Methyl radical	Z4	3-CH₃(R)
				593	Methyl radical	Z4	3-CH₃(S)
594	Methyl radical	Z4	3-Et(R)
				595	Methyl radical	Z4	3-Et(S)
596	Methyl radical	Z4	4-Me
				597	Methyl radical	Z4	4-Et
598	Methyl radical	Z4	4-Pr
				599	Methyl radical	Z4	4-tBu
600	Methyl radical	Z4	4-phenyl radical
				601	Ethyl radical	Z4	2-CH₃
602	Ethyl radical	Z4	3-CH₃(R)
				603	Ethyl radical	Z4	3-CH₃(S)
604	Ethyl radical	Z4	3-Et(R)
				605	Ethyl radical	Z4	3-Et(S)
606	Ethyl radical	Z4	4-Me
				607	Ethyl radical	Z4	4-Et
608	Ethyl radical	Z4	4-Pr
				609	Ethyl radical	Z4	4-tBu
610	Ethyl radical	Z4	4-phenyl radical
				611	Cyclopropyl group	Z4	2-CH₃
612	Cyclopropyl group	Z4	3-CH₃(R)
				613	Cyclopropyl group	Z4	3-CH₃(S)
614	Cyclopropyl group	Z4	3-Et(R)

[0248]

615	Cyclopropyl group	Z4	3-Et(S)
				616	Cyclopropyl group	Z4	4-Me
617	Cyclopropyl group	Z4	4-Et
				618	Cyclopropyl group	Z4	4-Pr
619	Cyclopropyl group	Z4	4-tBu
				620	Cyclopropyl group	Z4	4-phenyl radical
621	Methyl radical	Z5	2-CH₃
				622	Methyl radical	Z5	3-CH₃(R)
623	Methyl radical	Z5	3-CH₃(S)
				624	Methyl radical	Z5	3-Et(R)
625	Methyl radical	Z5	3-Et(S)
				626	Methyl radical	Z5	4-Me
627	Methyl radical	Z5	4-Et
				628	Methyl radical	Z5	4-Pr
629	Methyl radical	Z5	4-tBu
				630	Methyl radical	Z5	4-phenyl radical
631	Ethyl radical	Z5	2-CH₃
				632	Ethyl radical	Z5	3-CH₃(R)
633	Ethyl radical	Z5	3-CH₃(S)
				634	Ethyl radical	Z5	3-Et(R)
635	Ethyl radical	Z5	3-Et(S)
				636	Ethyl radical	Z5	4-Me
637	Ethyl radical	Z5	4-Et
				638	Ethyl radical	Z5	4-Pr
639	Ethyl radical	Z5	4-tBu
				640	Ethyl radical	Z5	4-phenyl radical
641	Cyclopropyl group	Z5	2-CH₃
				642	Cyclopropyl group	Z5	3-CH₃(R)
643	Cyclopropyl group	Z5	3-CH₃(S)
				644	Cyclopropyl group	Z5	3-Et(R)
645	Cyclopropyl group	Z5	3-Et(S)

[0249]

646	Cyclopropyl group	Z5	4-Me
				647	Cyclopropyl group	Z5	4-Et
648	Cyclopropyl group	Z5	4-Pr
				649	Cyclopropyl group	Z5	4-tBu
650	Cyclopropyl group	Z5	4-phenyl radical

The following abbreviations are used herein:

2-Aas 2-alkynyladenosine;

¹²⁵I-ABA N⁶- (4-amino-3-)¹²⁵Iodo-benzyl) adenosine

APCI atmospheric pressure chemical ionization

ATL146e 4- {3- [ 6-amino-9- (5-ethylcarbamoyl-)

3, 4-dihydroxy-tetrahydro-furan-2-yl) -9H-

Purin-2-yl-prop (prop) -2-yne (ynyl) } cyclohexane

Alkyl carboxylic acid methyl ester;

CCPA 2-chloro-N⁶-cyclopentyladenosine;

CGS 216802- [4- (2-carboxyethyl) phenethylamino ] -5' -N-

Ethyl-carboxamido adenosine;

Cl-IB-MECA N⁶-3-iodo-2-chlorophenylmethyladenosine-5' -N-methyl

Aldosylamide (methylgluconamide);

CPA N⁶-cyclopentyladenosine

DMF dimethyl formamide

DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide

EtOAc ethyl acetate

eq equivalent weight

GPCR G protein-coupled receptors; hA_2AAR, recombinant human A_2AAdenosine (I)

A receptor;

IADO 2-iodoadenosine

¹²⁵I-APE, 2- [2- (4-amino-3- ], a¹²⁵I]Iodophenyl) ethylammoniums

Alkyl ] adenosine;

NECA, 5' -N-ethylcarboxamidoadenosine;

IB-MECA N⁶-3-iodobenzyladenosine-5' -N-methylglycoaldehyde

An amide;

2-iodoadenosine 5- (6-amino-2-iodo-purin-9-yl) -3, 4-

Dihydroxy tetrahydro-furan-2 carboxylic acid acetamide

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

^I25I-ZM241385， ^I25I-4- (2- [ 7-amino-2- [ 2-furan)][1，2，4]

Triazolo [2, 3-alpha ] [1, 3, 5] -triazin-5 yl-amino ] ethanes

Phenyl) phenol;

INECA 2-iodo-N-ethylcarboxamide adenosine

LC/MS liquid chromatography/Mass Spectrometry

m.p. melting Point

MHz megahertz

MRS 1220, N- (9-chloro-2-furan-2-yl- [1, 2, 4] triazole

[1, 5-c ] -quinazolin-5-yl) -2-phenylacetyl

An amine;

MS Mass Spectrometry

NECA N-ethylcarboxamide adenosine

NMR nuclear magnetic resonance

RP-HPLC reversed-phase high performance liquid chromatography

TBAF tert-butylammonium fluoride

TBS Tert-butyldimethylsilane

TBDMSCl tert-butyldimethylsilyl chloride

TEA Triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

p-TSOH p-toluenesulfonic acid

XAC 8- (4- ((2-aminoethyl) aminocarbonyl-methyloxy)

-phenyl) -1-3-dipropylxanthine;

specific Phosphodiesterase (PDE) type IV inhibitors useful in the practice of the present invention include specifically racemic and optically active 4- (polyalkoxyphenyl) -2-pyrrolidinone of the following formula:

wherein R', R¹⁸，R¹⁹And X is as disclosed and described in U.S. patent No.4,193,926. Rolipram is an example of a suitable type IV PDE inhibitor included within the above formula.

Non-limiting examples of additional PDE IV inhibitors useful in practicing the present invention include, but are not limited to, compounds having the formula and variants thereof.

The present invention still further provides a pharmaceutical composition comprising a compound of formula (I) in combination with one or more members selected from the group consisting of: (a) an inhibitor of leukotriene biosynthesis, a 5-lipoxygenase (5-LO) inhibitor, and a 5-lipoxygenase activating protein (FLAP) antagonist selected from zileuton; ABT-761; fenton; teposalin; abbott-79175; abbott-85761; an N- (5-substituted) -thiophen-2-alkylsulfonamide of formula (5.2.8); 2, 6-di-tert-butylphenol hydrazone of formula (5.2.10); ZD-2138 of formula (5.2.11); SB-210661 of formula (5.2.12); pyrimidine-substituted 2-cyanonaphthalene compounds L-739,010; 2-cyanoquinoline compound L-746,530; indole and quinoline compounds MK-591, MK-886, and BAY x 1005; (b) leukotriene LTB4, LTC4, LTD4, and LTE4 receptor antagonists selected from the group consisting of L-651,392 of phenothiazin-3-one compounds; amidino compound CGS-25019 c; the benzoxazole compound, ondansilast; the benzene carbodiimide (benzacarboximidamide) compound BIIL 284/260; the compounds zafirlukast, arlukast, montelukast, pranlukast, vilukast (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) a dual inhibitor of 5-lipoxygenase (5-LO) and a platelet activating factor antagonist (PAF); (f) theophylline and aminophylline; (g) COX-I inhibitors (NSAIDs); and nitroxide NSAIDs; (h) a COX-2 selective inhibitor rofecoxib; (I) inhaled glucocorticoids with reduced systemic side effects selected from prednisone, prednisolone, flunisolide, prednisolone acetonide; beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate; (j) platelet Activating Factor (PAF) antagonists; (k) a monoclonal active antibody against an endogenous inflammatory entity; (l) An anti-tumor necrosis factor (TNF α) drug selected from the group consisting of etanercept, infliximab, and D2E 7; (m) the adhesion molecule inhibitor comprises a VLA-4 antagonist; (n) the immunosuppressant is selected from the group consisting of cyclosporine, azathioprine, and methotrexate; or (o) the anti-gout agent is selected from colchicine.

The compounds of the present invention can generally be prepared as illustrated in schemes IA and IB below. The starting materials can be prepared by the procedures described in these schemes, and the procedures described in the general methods below and the preparations by these procedures are well known to those of ordinary skill in the art of organic chemistry. The variables used in flowchart IA and flowchart IB are as defined herein and in the claims.

Scheme IA illustrates the preparation of alkynylcycloalkanols. Solutions of the appropriate cycloalkanone (where j is 0-5) are prepared in a solvent such as THF. A solution of the appropriate acetylenic magnesium halide in a solvent is added to the cycloalkanone. After the addition, the solution was stirred at about 20 ℃ for about 20 hours. The reaction was monitored by TLC until the starting material was consumed. The reaction was quenched with water, filtered through a plug of sand and silica, washed with a solvent, e.g., EtOAc, and evaporated to give the product. Typically, the secondary product, the isomer, is formed by addition of an alkyne (where m is as defined above and the sum of m1 and m2 is from 0 to about 7) to a ketone in the axial/equatorial direction. The compound was purified by flash chromatography using EtOAc/hexanes to afford the product.

Flow chart IA

General route to alkyne precursor Synthesis

Scheme IB illustrates the preparation of alkynyladenosines. Filling the flame-dried mixture with 5- (6-amino-2-iodo-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-carboxylic acid ethylamine (NECA 2-iodoadenosine) and a solvent such as DMF under nitrogenA round bottom flask. Wherein R is- (CR)¹R²)_mThe appropriate alkyne for the Z group is dissolved in acetonitrile followed by TEA, 5 mol% Pd (PPh)₃)₄And CuI. All solvents were completely degassed.

The solution was stirred at room temperature for about 24 hours and monitored by HPLC until completion. If the reaction is not complete after this time, additional catalyst, CuI and TEA, is added. After the reaction was complete, the solvent was removed under high vacuum and the residue was dissolved in a small amount of DMF. The product was isolated using preparative silica TLC. The product was purified by RP-HPLC.

Flow chart IB

Examples of pharmaceutically acceptable salts are organic acid addition salts with acids capable of forming physiologically acceptable anions, such as tosylate, mesylate, maleate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α -ketoglutarate and α -glycerophosphate. Suitable inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates and carbonates.

Pharmaceutically acceptable salts can be obtained by conventional methods well known in the art, for example by reacting a compound having a sufficiently strong basicity, such as an amine, with a suitable acid to provide a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids may also be produced.

The compounds of formula I may be formulated in pharmaceutical compositions and administered to a mammalian host, e.g., a human patient, in a variety of different forms suitable for the chosen route of administration, i.e., oral or parenteral, intravenous, intramuscular, topical, or subcutaneous.

Thus, the compounds of the present invention may be administered systemically, e.g., orally, with a pharmaceutically acceptable excipient such as an inert diluent or a carrier acceptable for ingestion. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly into the patient's food. 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% active compound. The above percentages in the compositions and formulations can, of course, vary and are preferably from about 2 to about 60% by weight for a given unit dosage form. The active compound is present in these therapeutic compositions in an amount effective to achieve the desired dosage level.

The preparation such as tablet, lozenge, pill, capsule, etc. can also contain the following components: binding agents such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweetening agents such as sucrose, fructose, lactose or aspartame or flavoring agents 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 kind, a liquid carrier such as a vegetable oil or polyethylene glycol. Various other materials may be present in the form of coatings or to modify the physical form of the solid unit dosage form. For example, 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 or propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any materials used in preparing the various unit dosage forms should be pharmaceutically acceptable and substantially non-toxic in the dosages employed. In addition, the active compounds may also be incorporated into sustained release formulations and devices.

The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salt may be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof, as well as in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent microbial growth.

Pharmaceutical dosage forms suitable for injection or infusion may comprise sterile aqueous solutions or dispersions or sterile powders containing the active ingredient which are suitable for extemporaneous formulation into injection or infusion solutions or dispersions, and which are optionally encapsulated in liposomes. For all such dosage forms, the final dosage form must be sterile, liquid and stable under the conditions of manufacture and storage. The liquid carrier or excipient may be a solvent or liquid dispersion medium comprising, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil, nontoxic glyceryl esters, and suitable mixtures thereof. 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 use of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like, can produce a microbe-inhibiting effect. In many cases, these dosage forms preferably contain 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.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by sterile filtration. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the technique of lyophilization to produce a powder containing the active ingredient plus any additional desired ingredient present in the sterile-filtered solution.

For topical administration, the compounds of the invention may be used in pure form, i.e. in the case where they are liquids. It is generally preferred to apply them to the skin in the form of compositions or formulations which may be in the form of solid, liquid or skin patches, formulated with a dermatologically acceptable carrier.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica gel, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which an effective amount of a compound of the invention is dissolved or dispersed, optionally with the aid of a non-toxic surfactant. Adjuvants such as fragrances and other antibacterial agents may be added to optimize their properties for a given use. The liquid compositions produced can be applied by means of absorbent pads, for impregnating bandages and other dressings, or sprayed onto the affected area with pump-type or aerosol sprayers.

For direct application to the skin of the user, thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified inorganic materials may also be used in combination with the liquid carrier to form spreadable pastes, gels, ointments, soaps, and the like.

Examples of beneficial dermatological compositions that may be used to deliver a compound of formula I to 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).

Effective doses of the compounds of formula I can be determined by comparing their in vitro and in vivo activity in animal models. Methods for extrapolating effective dosages suitable for humans from those in mice and other animals are known in the art, see U.S. Pat. No.4,938,949. Effective dosages of type IV PDE inhibitors are also known in the art, see, e.g., u.s.pat. No.5,877,180, CoL 12.

Generally, the concentration of the compound of formula (I) in a liquid composition such as a lotion is about 0.1-25% wt-%, preferably about 0.5-10% wt-%. The concentration in a semi-solid or solid composition such as a gel or powder is about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.

The therapeutically required amount of the compound, or an active salt or derivative thereof, will vary not only with the particular salt selected, but also with the route of administration, the severity of the condition being treated and the age and health of the patient and will ultimately be at the discretion of the attendant physician or clinician.

Generally, however, suitable dosages will be in the range of from about 0.5 to about 100 μ g per kg body weight per day, for example from about 10 to about 75 μ g (such as from 3 to about 50 μ g), preferably from 6 to 90 μ g, most preferably from 15 to 60 μ g/kg/day.

The compounds of the present invention can be conveniently administered in unit dosage form; for example, each unit dosage form contains from 5 to 1000. mu.g, suitably from 10 to 750. mu.g, most suitably from 50 to 500. mu.g, of active ingredient.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of about 0.1 to about 10nM, preferably about 0.2 to 10nM, and most preferably about 0.5 to about 5 nM. This can be achieved, for example, by intravenous injection of a 0.05-5% solution of the active ingredient, optionally dissolved in physiological saline, or by oral administration of a bolus containing about 1-100. mu.g of the active ingredient. The desired blood level may be maintained by continuous infusion at a rate of about 0.01-5.0 μ g/kg/hr or by intermittent infusion with about 0.4-15 μ g/kg of active ingredient.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example two, three, four or more small doses per day. The small dose itself may be further subdivided into a plurality of loosely spaced discrete administration forms, such as multiple inhalations from an insufflator or drops of multiple drops into the eye. For example, it may be desirable to administer the compositions of the present invention intravenously for a period of time following an injury that can cause inflammation.

Compounds given in the invention as A_2AThe ability of an adenosine receptor agonist (or antagonist) can be determined using pharmacological models well known in the art or using the assays described below.

The compounds of the invention and compositions containing them can be administered as pharmacological stressors and can be used in conjunction with any of the non-invasive diagnostic methods for determining the status of myocardial perfusion. For example, intravenous adenosine can be used in conjunction with thallium-201 myocardial perfusion imaging to assess the severity of myocardial ischemia. In this case, any of a variety of radiopharmaceuticals may be used in place of thallium-201 (e.g., technetium-99 m-labeled radiopharmaceuticals (i.e., Tc-99 m-sesami, Tc-99m-teboroxime), iodine-123-labeled radiopharmaceuticals such as I-123-IPPA or BMIPP, rubidium-82, nitrogen-13, etc.). Similarly, the compounds of the present invention may be administered as pharmacological stressors in conjunction with radionuclide ventricular angiography to assess the severity of myocardial contractile dysfunction. In this case, the radionuclide ventriculography study may be a first pass (first pass) or gated equilibrium study of the right and/or left ventricles. Similarly, the compounds of formula (I) may be administered as pharmacological stressors in conjunction with echocardiography to assess the presence of abnormalities in ventricular wall activity. Similarly, the active compounds can be administered as pharmacological stressors in combination with invasive measurements of coronary blood flow, for example by intracardiac catheter, to assess the functional importance of stenotic coronary vessels.

The method typically comprises administering one or more compounds of formula (I) by intravenous infusion in a dose (about 0.25-500, preferably 1-250mcg/kg/min) effective to provide coronary artery dilation. However, in invasive setting (invasive setting) involves intracoronary administration of the drug at a bolus dose of 0.5-50 mcg.

Preferred methods include the use of a compound of formula (I) as an exercise surrogate in conjunction with myocardial perfusion imaging to detect the presence and/or assess the severity of human coronary artery disease, wherein myocardial perfusion imaging is carried out by radiopharmaceutical myocardial perfusion imaging using either technique, including planar scintigraphy or Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), magnetic resonance (NMR) imaging, perfusion contrast echocardiography, Digital Subtraction Angiography (DSA), or overspeed X-ray computed tomography (CINE CT).

Also provided are methods comprising the use of exercise-surrogate compounds of formula (I) in combination with imaging to detect the presence and/or assess the severity of ischemic ventricular dysfunction in humans, wherein the ischemic ventricular dysfunction is determined by any one of imaging techniques including echocardiography, contrast agent ventricular angiography, or radionuclide ventricular angiography. Myocardial dysfunction may be coronary artery disease, ventricular dysfunction, differences in blood flow through disease-free coronary vessels and abnormally stenotic coronary vessels, and the like.

Also provided are methods comprising using a compound of formula (I) as a coronary blood-filling agent in combination with a method of determining coronary blood flow rate to assess vasodialator ability of a human coronary artery, wherein coronary blood flow rate is determined by any one of a number of techniques including doppler flow catheter (doppler flow catheter) or digital subtraction angiography.

The invention will be further described with reference to the following detailed examples, which are intended to illustrate the invention without limiting it.

Description of the preferred embodiments

All melting points were determined using a Thomas Hoover capillary method melting point apparatus and were not corrected. Recording proton NMR spectra in 300MHz GE Spectrophotometer ((¹HNMR). Chemical shift values relative to tetramethylsilane are expressed in ppm (parts per million). For the data report, s is singlet, d is doublet, t is triplet, q is quartet, and m is multiplet. Mass spectrometry was performed on a Finnigan LcQ Classic. High Resolution Mass Spectrometry (HRMS) data was provided by mass spectrometry Nebraska centre. Analytical HPLC was performed at room temperature by operating a Waters 2690 separationModule equipped with a Waters Symmetry C8 (2.1X 150mm) column. The compound was eluted using 70: 30 acetonitrile: water containing 0.5% acetic acid at 200. mu.L/minUV measurements were performed at 214nm using a Waters 486 Tunable Detector. By working with Shim-pack VP-ODS C at room temperature₁₈Preparative HPLC was performed on Shimadzu Discovery HPLC (20X 100mm) columns. The compounds were eluted with a gradient of 30mL/min over 15 min using 20-80% water (containing 0.1% TFA) to methanol, and UV measurements were performed at 214nm using a SPD10A VP Tunable detector. All final compounds provided herein were greater than 98% pure as determined by HPLC. Flash chromatography was performed on silica 60A gel (230- & 400 mesh) columns or using reusable chromatography columns and systems available from RT Scientific, Manchester NH. Analytical thin layer chromatography was performed on a Merck Kieselgel 60F254 aluminum plate. Preparative thin layer chromatography was performed using 1000 micron Analtech Uniplate and silica gel. All reactions were carried out under a nitrogen atmosphere in a flame-dried glass vessel unless otherwise indicated.

General procedure 1: preparation of alkynylcyclohexanols

To a 10mmol solution of the appropriate cyclohexanone in 50mL THF was added 60mL (30mmol) of 0.5M acetylenic magnesium bromide in THF. The solution was stirred at 20 ℃ for 20 hours, at which time TLC indicated that all starting material was consumed. The reaction was quenched with 5ml water, filtered through a plug of sand and silica, washed with EtOAc, evaporated to a yellow oil containing two spots on TLC w/20% EtOAc/hexane, the spots were developed with vanillin. These two products are usually different isomers formed by the axial/planar addition of an alkyne to a ketone. The compound was purified by flash chromatography using 10% EtOAc/hexanes to give a clear oil or white solid in 50-80% yield.

General procedure 2: preparation of propargylpiperidine (piperadine) and piperazine

To a 10.0mmol solution of the appropriate piperazine or piperidine (piperadine) in 20ml acetonitrile was added 12.0mmol propargyl bromide (80% stable in toluene) and 50.0mmol anhydrous potassium carbonate. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in 50mL dichloromethane/water and the organic layer was removed. The aqueous layer was washed with another 3X 25mL of dichloromethane. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified using column chromatography.

General procedure 3: preparation of modified piperidines (piperadine) and piperazines

To 100mg of the appropriate Boc-protected piperazine or piperidine (piperadine), JR3275/JR3255, respectively, was added 2-4mL of neat TFA. The solution was stirred for 6 hours and TFA was removed under reduced pressure to give a yellow oil. The oil was dissolved in 10ml of dichloromethane, to which was added a 10-fold excess of TEA and 3 equivalents of the appropriate electrophile. The yellow solution was stirred at room temperature for 12 hours and after removal of the solvent, the product was purified using a 1.1X 30cm 14g RTSI column eluting with a gradient of 5% to 30% ethyl acetate in hexane.

General procedure 4: preparation of 2-AAs (2-alkynyladenosine)

A flame dried (flame dried) 25mL round bottom flask was charged with 2-iodoadenosine analog (40mg) and dissolved in 2mL DMF under nitrogen. The appropriate alkyne (approximately 0.1mL) was then added followed by4mL acetonitrile and 0.1mL TEA. All three solvents were degassed using nitrogen for at least 24 hours. To this solution was added 5 mole% Pd (PPh3)4 and 6 mole% copper iodide (copper iodide). The light yellow solution was stirred at room temperature for 24 hours or checked by HPLC for reaction completion. If the reaction is not complete at this point, additional catalysts CuI and TEA are added. After completion of the reaction, the solvent was removed under high vacuum and the red/black residue was recovered and dissolved using a small amount of DMF. The solution was applied to a preparative silica TLC plate (Analtech 1000. mu.m, 20 cm. times.20 cm) and initially washed with 120mL of 40% hexane/CH₂Cl₂Elution was performed and then 40mL MeOH was added again. The UV active band (usually yellow) in the middle of the plate was collected using 4X 25mL of 20% MeOH/CH₂Cl₂The mixture was washed slowly and concentrated. The product was then purified by RP-HPLC after trituration with anhydrous ether to give a solid.

The flow chart is as follows: preparation of 5' ester analogs:

to the cooled solution of compound 1.1 in alcohol was added about 5 equivalents of ice-cooled thionyl chloride. The solution was stirred and gradually returned to room temperature over about 12 hours. The solvent was then removed by vacuum trap (en vacuo) to give 1.2 as a white solid. The solid was then treated according to general procedure 4 to give compound 1.3.

The flow chart is as follows: preparation of 5' amide analogues:

to the cooled solution of compound 1.1 in methanol was added about 5 equivalents of ice-cooled thionyl chloride. The solution was stirred and gradually returned to room temperature over about 12 hours. The solvent was then removed in vacuo (en vacuo) to give compound 1.2, which was dissolved in the appropriate amine (NHR) at 0 deg.C₃R_b) Stirring for several hours or until the reaction is complete. The solvent was then removed in vacuo and the product was purified by crystallization or chromatography using a gradient of methanol and dichloromethane to give 2.2 as a white solid. The solid was then treated according to general procedure 4 to obtain compound 2.3.

The flow chart is as follows: preparation of 4' triazole:

hydrazine hydrate (1 eq) was added to a 1.1(1 eq) solution stirred in anhydrous DMF, HBTU (1 eq) and DIEA (2.5 eq) and the solution was stirred for about 24 hours. After extraction, 3.2 was isolated. Treatment of 3.2 according to general procedure 4 can give 3.3, then 3.3 can be dissolved in EtOH and treated with ethyl imino monoacetate hydrochloride and TEA. Reflux for about 16h gave 3.4 after chromatography and deprotection with 50% formic acid for 6 h.

The flow chart is as follows: preparation of 4' -1, 2, 4-oxadiazoles

Pivaloyl chloride was added to a cooled 1.1 solution of DCM and TEA and stirred for several hours. Ammonia gas was bubbled into the solution after separation and purification to give 4.2. Treatment of 4.2 according to general procedure 4 gave 4.3, which was dissolved in anhydrous acetonitrile and TEA and DMAP added. Carefully add POCl to the ice-cooled solution₃. After stirring for about 30 minutes, DMF was added to the solution and the mixture was heated for about 24 hours to 95 ℃. Purification gave 4.4, which was dissolved in EtOH and to which potassium carbonate and hydroxylamine hydrochloride were added. The solution was refluxed for about 24 hours and after purification was obtainedTo 4.5. Treatment 4.5 with the appropriate carboxylic acid/anhydride gave 4.6 after refluxing and deprotection with 50% formic acid.

The flow chart is as follows: preparation of 4' -1, 3, 4-oxadiazoles

Pivaloyl chloride was added to a 1.1 solution of THF and DIEA at 0 deg.C. After stirring for several hours, the appropriate hydrazide is added and the mixture is stirred for about 3 days to give 5.2. The product was worked up according to general method 4 to give 5.3, which was dissolved in DMF and taken up with POCl at 0 deg.C₃Treatment for several hours gives, after purification and deprotection with 50% formic acid, 5.4

The flow chart is as follows: preparation of 4' -1, 3-oxazoles

Pivaloyl chloride was added to a 1.1 solution of THF and DIEA at 0 deg.C. After stirring for several hours, the appropriate 1, 2-hydroxylamine was added and the mixture was stirred for about 24 hours to give 6.2. The product was worked up according to general procedure 4 to give 6.3. The product was dissolved in DCM, using PDC,molecular sieve and AcOH treatment convert alcohols to ketones. Then using POCl₃This intermediate was converted to 6.4 by refluxing after work-up and subsequent heating in 50% formic acid for 6 hours.

The flow chart is as follows: preparation of 4' -1, 3, 4-thiadiazo

Pivaloyl chloride was added to a 1.1 solution of THF and DIEA at 0 deg.C. After stirring for several hours, the appropriate hydrazide is added and the mixture is stirred for an additional few hours to give 7.2. This product was treated according to general procedure 4 to give 7.3, which was dissolved in acetonitrile, treated with Lawessons reagent at 50 ℃ for about 1 day to give 7.4 after purification and deprotection with 50% formic acid for 6 hours.

The flow chart is as follows: preparation of 4' -tetrazoles

Pivaloyl chloride was added to a cooled 1.1 solution of DCM and TEA and stirred for several hours. Ammonia gas was bubbled into the solution after separation and purification to give 4.2. 4.2 was then dissolved in anhydrous acetonitrile and TEA and DMAP were added. Carefully add POCl to the ice-cooled solution₃. After stirring for about 30 minutes, DMF was added to the solution and the mixture was heated for about 24 hours to 95 ℃. Purification gave 4.4 to which were added toluene, azidotrimethylsilane and dibutyltin oxide. The mixture was heated to 60 ℃ for about 15 hours to give 8.5. Treatment of 8.5 with the appropriate alkyl halide and potassium carbonate gave 8.6 after 6 hours of reflux and deprotection with 50% formic acid.

Preparation 1: [4- (tert-butyl-dimethyl-silanyloxymethyl) -cyclohexyl ] -methanol (83).

To a 100mL flask containing 79(4.0g, 27.8mmol) in DMF (40mL) was added TBDMSCl (3.56g, 23.6mmol) and imidazole (3.79g, 55.6 mmol). The reaction was stirred at 25 ℃ for 16h, after which time saturated LiBr solution (50mL) was added and the reaction was extracted with ether (2X 50 mL). The ether layer was collected and reusedExtraction was performed with LiBr (2X 35 mL). The ether layer became transparent. The ether layer was then concentrated in vacuo and the product was purified by flash chromatography on a silica gel column eluting with 1: 2 ether/petroleum ether to give 83(3.80g, 62%) as a homogeneous oil.¹H NMR(CDCl₃)δ3.46(d，J＝6.2Hz，2H)，3.39(d，J＝6.2Hz，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)；¹³C NMR(CDCl₃)δ69.2，69.1，41.2，41.1，29.5，26.5，18.9，-4.8；.APCI m/z(rel intensity)259(MH⁺，100)。

Preparation 2: toluene-4-sulfonic acid 4- (tert-butyl-dimethyl-silanyloxymethyl) -cyclohexylmethyl ester (84).

To a mixture containing in CHCl₃A100 mL flask of 83(3.4g, 13.2mmol) in 30mL was charged with tosyl chloride (3.26g, 17.1mmol) and pyridine (3.2mL, 39.6 mmol). The reaction was stirred at 25 ℃ for 14 hours, after which the reaction was concentrated in vacuo to give a wet white solid. To the solid was added ether (50mL), the solid was filtered and then washed with additional ether (2X 50 mL). The ether layers were pooled and concentrated in vacuo to give a clear oil. The product was purified by flash chromatography on a silica gel column eluting with 1: 4 ether/petroleum ether to give 84 as a white solid (4.5g, 83%).¹H NMR(CDCl₃)δ7.78(d，J＝7.7，2H)，7.33(d，J＝7.7Hz，2H)，3.81(d，J＝6.2Hz，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)；¹³C NMR(CDCl₃)δ145.1，133.7，130.3，128.4，75.8，68.9，40.7，38.0，29.1，26.5，22.1，18.9，-4.9；APCI m/z(rel intensity)413(MH⁺，100)。

Preparation 3: (4-prop-2-ynyl-cyclohexyl) -methanol (86).

A250 mL three-necked flask equipped with an air inlet tube and a dry ice condenser was cooled to-78 ℃ and charged with liquid ammonia (40 mL). Lithium wire (600mg, 86.4mmol) was added to the reaction mixture to give a dark blue solution. The mixture was stirred for 1 hour, acetylene was added to the ammonia through a carbon drying tube until all the lithium reacted and the solution became colorless, at which point the flow of acetylene was stopped, the acetylene inlet tube and condenser were removed and the flask was fitted with a thermometer. DMSO (20mL) was added and ammonia was evaporated using a warm water bath until the temperature of the mixture reached 30 ℃. The solution was stirred at this temperature for 2 hours until the solution stopped bubbling. The mixture was cooled to 5 ℃ and Compound 84(11.25g, 27.3mmol) in DMSO (10mL) was added. The temperature was maintained at 5 ℃. The mixture was stirred at 5 ℃ for 0.5 hour. The solution was then gradually warmed to room temperature and stirred for an additional 18 hours. The brown/black mixture was slowly poured onto ice (300g) and extracted with ether, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow oil. The oil was then dissolved in THF (200mL) and turned brown when TBAF hydrate (11.20g, 35.5mmol) was added. The solution is placed in N₂Stirred under atmosphere for 24 hours. After stirring, the reaction was quenched with water (200mL) and extracted with ether (3X 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 give 86 as a yellow oil (3.91g, 93%).¹H NMR(CDCl₃)δ3.45(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)；¹³C NMR(CDCl₃)δ83.8，69.5，69.0，40.8，37.7，32.3，29.7，26.5。

Preparation 4: (4-prop-2-ynyl cyclohexyl) acetic acid methyl ester (87).

To a solution of 960mg (6.31mmol)86 in 6mL DMF was added 0.62mL (7.57mmol) pyridine and 0.78mL (8.27mmol) acetic anhydride. The reaction was stirred at rt overnight. After 16 hours, starting material remained. The reaction mixture was heated at 75 ℃ for 3 hours. The solvent was removed under reduced pressure to give a yellow oil which was purified by flash chromatography on a silica gel column eluting with 1: 3 ether/petroleum ether to give 1.12g (91%) of 87 as an oil.¹HNMR(CDCl₃)δ3.87(d，J＝6.2Hz，2H)，2.06(d，J＝4.3Hz，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)；¹³C NMR(CDCl₃)δ171.7，83.7，69.9，69.6，37.4，37.3，32.1，29.7，26.5，21.4；APCI m/z(rel intensity)195(M⁺，30)，153(M⁺，70)，135(M⁺，100)。

Preparation 5: 4-prop-2-ynyl-cyclohexanecarboxylic acid (88).

Will be at 1.5M H₂SO₄A solution of chromium trioxide (600mg, 6.0mmol) in (2.6mL, 150mmol) was cooled to 5 deg.C and a solution of 86(280mg, 1.84mmol) in acetone (15mL) was added. The mixture was warmed to room temperature and stirred overnight. Isopropanol (4mL) was added to the green/black solution and after 1 hour the solution turned pale blue. After addition of water (15mL), the solution was taken up in CHCl₃(6X 25 mL.) the solution was extracted. The organic layer was concentrated and concentrated in vacuo to give a white solid. The solid was dissolved in ether (50mL) and extracted with 1M NaOH (2X 30 mL). The alkaline extracts were pooled, acidified with w/10% HCl and re-extracted with ether (3X 30 mL). The ether layers were combined, dried over sodium sulfate and concentrated in vacuo to give a white colorAnd (3) a solid. The product was recrystallized from acetone/water to give 88 as white needles (222mg, 73%): mp 84-85 ℃;¹H NMR(CDCl₃)δ2.30-2.23(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)；¹³C NMR(CDCl₃)δ182.5，83.8，69.6，40.7，37.7，32.3，29.6，26.5；APCI m/z(rel intensity)165(MH⁺，100)。

preparation 6: methyl-4-prop-2-ynyl cyclohexanecarboxylate (89).

In the direction of 7: 3CH₂Cl₂To a solution of 88(240mg, 1.45mmol) in MeOH (10mL) was added a 0.2mL aliquot of TMS diazomethane (2.0M in hexanes) (0.9mL, 1.8mmol) until the color remained yellow. The reaction was stirred at room temperature for an additional 0.25 hours. 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 a silica gel column using ether: purification by eluting with petroleum ether (1: 9) gave 89(210mg, 80%) as a clear oil.¹H NMR(CDCl₃)δ3.60(s，3H)32.25-2.13(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)；¹³C NMR(CDCl₃)δ176.7，83.3，69.8，51.9，43.4，36.7，31.9，29.2，26.3；APCI m/z(rel intensity)181(MH⁺，100)。

Preparation 7: trans [4- (1-propargyl) cyclohexylmethyl ] carbonate methyl ester (90).

Yield: 345mg, 81%.¹H NMR(CDCl₃) Delta 0.98-1.07, 1.40-1.52, 1.57-1.70, 1.78-1.93(4x m, 10H, cyclohexyl), 1.96(t, 1H, acetylene), 2.10(dd, 2H, -C)₆H₁₀CH₂CCH)，3.78(s，3H，-OCH₃)，3.96(d，-C₆H₁₀CH₂O-)。

Preparation 8: trans [4- (1-propargyl) cyclohexylmethyl ] isobutyl carbonate (91).

Yield: 433mg, 83%.¹H NMR(CDCl₃)δ0.95(d，4H，-OCH₂CH(CH₃)₂) 0.98-1.09, 1.40-1.51, 1.57-1.70, 1.78-1.93(4xm, 10H, cyclohexyl), 1.94-2.04(m, 1H, -OCH)₂CH(CH₃)₂) 1.96(t, IH, acetylene), 2.10(dd, 2H, -C)₆H₁₀CH₂CCH)，3.91，3.95(2x d，4H，-OCH₂CH(CH₃)₂，-C₆H₁₀CH₂O-)。

Preparation 9: trans [4- (1-propargyl) cyclohexylmethyl ] carbonate benzyl ester (92).

Yield: 340mg, 69%.¹H NMR(CDCl₃) Delta 0.97-1.08, 1.40-1.49, 1.55-1.69, 1.77-1.93(4x m, 1OH, cyclohexyl), 1.96(t, 1H, acetylene), 2.10(dd, 2H, -C)₆H₁₀CH₂CCH)，3.98(d，-C₆H₁₀CH₂O-)，5.15(s，2H，-OCH₂Ph)，7.33-7.40(m，5H，Ar)。

Preparation 10: 4- (toluene-4-sulfonyloxymethyl) -piperidine-1-carboxylic acid tert-butyl ester (JR 3215).

A solution of 5.0g (23.2mmol) of N-Boc-4-piperidinemethanol in 50ml of chloroform was prepared. 5.75g (30.2mmol) of tosyl chloride in 5.6ml of pyridine (69.6mmol) are added. The solution was stirred under nitrogen for 24 hours. Routine examination and chromatographic purification gave the title compound. Yield 6.0 g.

Preparation 11: (R) -1-ethynyl- (R) -3-methyl-cyclohexanol (JR3217A), (S) -1-ethynyl- (R) -3-methyl-cyclohexanol (JR 3217B).

To a solution of 1.0g (8.9mmol) of (R) - (+) -3-methyl-cyclohexanone in 50mL of THF was added 54mL (26.7mmol) of 0.5M acetylenic magnesium bromide in THF. The solution was stirred at 20 ℃ for 20 hours. Analysis by TLC indicated that the starting material had been consumed. The reaction was quenched with 5ml water, filtered through sand and silica stopcock, washed with EtOAc, evaporated to give 1.15g of an oil containing two spots (r.f.'s 0.33 (small, JR3217A) and 0.25 (mainly, JR3217B), 20% EtOAc/hexanes) which were developed with vanillin. The compound was purified by flash chromatography using 10% EtOAc/hexanes (225mL silica) to afford JR3217A and JR 3217B.

Preparation 12: 1-prop-2-ynyl-piperidine-2-carboxylic acid methyl ester (JR 3249).

The title compound was prepared according to general method 2 starting from 4.0g (22.3mmol) of methyl pipecolinate hydrochloride.

Preparation 13: 1-prop-2-ynyl-piperidine-4-carboxylic acid methyl ester (JR 3245).

To a solution of 3.5g (24.4mmol, 3.30mL) of methylpiperidate in 100mL of dichloromethane was added TEA (1.5 equiv., 36.6mmol, 5.1mL), propargyl bromide (3.0 equiv., 73.2mmol, 6.5mL) and reacted at room temperature for 36 hours. The reaction was quenched with 35ml of water to give a clear solution. The solution was extracted with 2X 25mL of dichloromethane over Na₂SO₄Drying and evaporation of the solvent gave a yellow oil. r.f. (40% EtOAc/hexanes) 0.26, developed as light white spots using vanillin, starting material r.f.0.05, developed as yellow spots using vanillin. After extraction, the product appeared to be free of impurities.

Preparation 14: 1-prop-2-ynyl-piperidine-4-carboxylic acid ethyl ester (JR 3271).

The title compound was prepared according to general method 2 starting from 2.0g (12.7mmol) of ethyl isopiperidinecarboxylate.

Preparation 15: 4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester (JR 3275).

To a solution of 10.0g (54.8minol) of tert-butyl-1-piperazine carboxylate in 60mL of acetonitrile was added 5.20mL (60.4mmol) of propargyl bromide and 37.9g (274mmol) of anhydrous potassium carbonate. After stirring at room temperature for a further 36 hoursAn additional 1.5ml of propargyl bromide was added. The residue was evaporated to dryness. 50mL of methylene chloride and 50mL of water were added. Using CH₂Cl₂The reaction mixture was extracted 4X 40mL, dried over magnesium sulfate and evaporated to a brown oil. The oil was dissolved in dichloromethane and purified by RT Scientific system using a hexane/ethyl acetate gradient to give 5.5g (46%) of a yellow oil which finally crystallized on standing. Preparation 16: 4-cyanomethyl-piperazine-1-carboxylic acid ethyl ester (JR 3287).

To 25mL CH₃To a solution of 3g (19.0mmol) of ethyl N-piperazine carboxylate in CN were added 1.57g (1.32mL of 20.1mmol) of 2-chloroacetonitrile and 15.6g (95mmol) of K₂CO₃·1_1/2H₂And O. The suspension was stirred at room temperature for 16 hours. The reaction was analyzed using TLC (35% ethyl acetate/hexane, product r.f.0.38vs.s.m.r.f.of 0.02). Analysis indicated the reaction was complete. The golden yellow solution was evaporated to dryness. Using CH₂Cl₂/H₂O extraction of the residue with MgSO₄Dried and concentrated.

Preparation 17: 1-cyclohexyl-4-prop-2-ynyl-piperazine (JR 4019).

The title compound was prepared according to general method 2 starting from 3g (17.9mmol) of 1-cyclohexylpiperazine.

Preparation 18: 1-prop-2-ynyl-piperazine (JR 4029).

To a flame-dried 25mL round bottom flask was added under nitrogen 2.1g of 4-prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester. To the solid was added 5mL 98% TFA in 1mL portions. The solution turned wine-red, creating air bubbles and smoking. When this activity decreased, an additional portion of TFA was added. After addition of a third portion of TFA, only a small amount of bubbles were generated. The solution was stirred under nitrogen at room temperature for an additional hour and evaporated under reduced pressure to give the product as a thick red syrup. The calculated quantitative yield was 1.16 g. The residue was suspended in 20mL of dichloromethane and used without further purification to prepare the compound: JR4031, JR4033, and JR 4035.

Preparation 19: 4-prop-2-ynyl-piperazine-1-carboxylic acid methyl ester (JR 4031).

The title compound was prepared according to general method 3 starting from 385mg (3.1mmol) of JR4029 and using methyl chloroformate.

Preparation 20: 4-prop-2-ynyl-piperazine-1-carboxylic acid isobutyl ester (JR 4035).

The title compound is prepared according to general method 3 starting from 385mg (3.1mmol) of JR4029 and using isobutyl chloroformate.

Preparation 21: 3, 3-dimethyl-1- (4-prop-2-ynyl-piperidin-1-yl) -butan (butan) -1-one (JR 4041).

The title compound was prepared according to general method 3 starting from tert-butyl ester and using tert-butyl acetyl chloride.

Preparation 22: 1- (4-prop-2-ynyl-piperazin-1-yl) -ethanone (JR 4043).

The title compound is prepared according to general method 3 starting from 385mg (3.1mmol) JR4029 and using acetyl chloride

The following intermediate compounds were prepared using general procedure 1 and the appropriate starting materials described herein.

(R) -1-alkynyl-3-tert-butyl-cyclohexanol (JR3255A), (S) -1-alkynyl-3-tert-butyl-cyclohexanol (JR 3255B).

Toluene-4-sulfonic acid 4-prop-2-ynyl-cyclohexylmethyl ester (JR 3077).

1-ethyl-4-prop-2-ynyl-cyclohexane (JR 3083).

1- (4-prop-2-ynyl-cyclohexyl) -ethanone (JR 3115).

1, 1-dicyclohexyl-prop-2-ynyl-1-ol (JR 3127).

1-cyclohexyl-prop-2-ynyl-1-ol (JR 3129).

4-ethyl-1-ethynyl-cyclohexanol (JR 3143).

1-ethynyl-3-methyl-cyclohexanol.

1-ethynyl-3, 3, 5, 5-tetramethyl-cyclohexanol (JR 3151).

1-ethynyl-4-phenyl-cyclohexanol (JR 3153).

1-ethynyl-2-methyl-cyclohexanol (JR 3167B).

4-tert-butyl-1-ethynyl-cyclohexanol (JR 3191).

1-ethynyl-3, 3-dimethyl-cyclohexanol (JR 3193).

4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (JR 3199).

4-prop-2-ynyl-piperazine-1-carboxylic acid ethyl ester (JR 3211).

4-prop-2-ynyl-piperidine-1-carboxylic acid tert-butyl ester (JR 3257).

4-prop-2-ynyl-piperidine-1-carboxylic acid ethyl ester (JR 3267B).

2- (4-prop-2-ynyl-piperazin-1-yl) -pyrimidine (JR 3277).

1- (4-prop-2-ynyl-piperidin-1-yl) -ethanone (JR 4037).

2, 2-dimethyl-1- (4-prop-2-ynyl-piperidin-1-yl) -propan-1-one (JR 4039).

Example 1: 4- {3- [ 6-amino-9- (5-cyclopropylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl) -9H-purin-2-yl ] -prop-2-ynyl } -cyclohexanecarboxylic acid methyl ester

MS：m/z 499.3(M+H)⁺。

Example 2: 4- {3- [ 6-amino-9- (5-cyclopropylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl) -9H-purin-2-yl ] -prop-2-ynyl } -piperidine-1-carboxylic acid methyl ester

MS：m/z 500.4(M+H)⁺。

Example 3: 5- [ 6-amino-2- (1-hydroxy-3-methyl-cyclohexylacetylene) -purin-9-yl ] -3, 4-dihydroxy-tetrahydro-furan-2-carboxylic acid cyclopropylamide

MS：m/z 457.4(M+H)⁺。

Example 4: 5- (6-amino-2-iodo-purin-9-yl) -3, 4-dihydroxy-tetrahydro-furan-2-carboxylic acid cyclopropylamide

Example 5: cell culture and membrane preparation

At 50% N₂/50％O₂In Grace's medium supplemented with 10% fetal bovine serum, 2.5. mu.g/ml amphotericin B and 50. mu.g/ml gentamicin. 2.5X 10 for each virus used⁶Concentration of cells/mL by a multiple of twoAnd re-infecting to carry out virus infection. Infected cells were collected on day 3 post-infection and washed twice with insect PBS (instect PBS) (PBS pH 6.3). The cells were then lysed in lysis buffer (20mM HEPES pH 7.5, 150mM NaCl, 3mM MgCl)₂1mM beta-mercaptoethanol (BME), 5. mu.g/ml leupeptin, 5. mu.g/ml aprotinin A, 1. mu.g/ml aprotinin, 0.1mM PMSF) were resuspended and immediately frozen and stored at-80 ℃. Cells were thawed on ice, total volume was brought to 30mL using lysis buffer, and passed N₂Cavitation (600psi, 20 min) causes the cells to burst. Low speed centrifugation to remove any undissolved cells (1000Xg, 10 min), followed by high speed centrifugation (17,000Xg, 30 min). The pellet from the final centrifugation was homogenized in a buffer containing 20mM HEPES pH 8, 100mM NaCl, 1% glycerol, 2. mu.g/ml leupeptin, 2. mu.g/ml pepstatin A, 2. mu.g/ml aprotinin, 0.1mM PMSF and 10. mu.M GDP using a small glass homogenizer followed by a 26-gauge needle. The membrane was aliquoted in liquid N₂Immediately frozen and stored at-80 ℃. Human A was stably expressed as described (Robeva et al, 1996)₁AR (CHO Kl cells) or A₃AR (HEK 293 cells) cells prepared membranes.

Example 6: radioligand binding assays

Using radiolabeled agonists¹²⁵I-APE (Luthin et al, 1995) or radiolabeled antagonists¹²⁵I-ZM241385(¹²⁵I-ZM) recombinant human A binding radioligand to Sf9 cell membrane_2AA receptor. To determine high affinity, A₁And A₃GTP γ S-sensitive state of AR, we used agonists¹²⁵I-ABA (Linden et al, 1985; Linden et al, 1993). Mu.g (A) in a total volume of 0.1ml HE buffer (20mM HEPES and 1mM EDTA) was used_2A) Or 25. mu.g (A)₁And A₃) Membrane protein with 1U/mL adenosine deaminase and 5mM MgCl₂Binding assays were repeated three times with or without 50 μ M GTP γ S. Room temperature in Millipore MultiscreenThe membrane was incubated with radioligand for 3 hours (agonist) or 2 hours (antagonist) in 96-well GF/C filter plates, and the assay was terminated by rapid filtration on a cell harvester (Brandel, Gaithersburg, Md.), followed by ice-cold 10mM Tris-HCl, pH 7.4, 10mM MgCl₂A4X 150. mu.l wash was carried out in 30 seconds. Nonspecific binding was determined in the presence of 50 μ M NECA. 0.5-1nM as described in the literature (Robeva et al, 1996)¹²⁵I-APE，¹²⁵I-ZM241385 or¹²⁵I-ABA was subjected to competitive binding assays. We have found that it is sometimes important to replace pipette tips after each serial dilution in order to prevent transfer of an effective hydrophobic compound from the pipette tip. As described in the literature (Linden, 1982), Ki values for binding of competitive compounds to a single site are derived from IC corrected for radioligand and competitive compound consumption₅₀The value is obtained.

Linden J(1982)Calculating the Dissociation Constant of an Unlabeled Compound From the Concentration Required to DisplaceRadiolabel Binding by 50％.J Cycl Nucl Res 8：163-172。

Linden J，Patel A and Sadek S(1985)[¹²⁵I]Aminobenzyladenosine，aNew Radioligand With Improved Specific Binding to Adenosine Receptorsin Heart.Circ Res 56：279-284。

Linden J，Taylor HE，Robeva AS，Tucker AL，Stehle JH，RivkeesSA，Fink JS and Reppert SM(1993)Molecular Cloning and FunctionalExpression of a Sheep A₃Adenosine Receptor With Widespread TissueDistribution.MoI Pharmacol 44：524-532。

Luthin DR，Olsson RA，Thompson RD，Sawmiller DR and LindenJ(1995)Characterization of Two Affinity States of Adenosine A_2A Receptors With a New Radioligand，2-[2-(4-Amino-3-[¹²⁵I]Iodophenyl)Ethylamino]Adenosine.Mol Pharmacol 47：307-313。

Robeva AS，Woodard R，Luthin DR，Taylor HE and Linden J(1996)Dou ble Tagging Recombinant A₁-and A_2A-Adenosine Receptors WithHexahistidine and the FLAG Epitope.Development of an EfficientGeneric Protein Purification Procedure.Biochem Pharmacol 51：545-555。

The chemiluminescence method comprises the following steps: luminol-enhanced chemiluminescence, which can measure the oxidative activity of neutrophils, is dependent on the production of peroxide and the activation of the granzyme myeloperoxidase. Light is released by unstable energetic oxygen species such as hypochlorous acid and singlet oxygen produced by activated neutrophils.

Purified human neutrophils (2X 106/mL) r suspended in Hanks' balanced salt solution containing 0.1% human serum albumin (HA), adenosine deaminase (1U/mL) and rolipram (100nM) were incubated in a water bath (37 ℃) for 15 minutes with or without rhTNF (10U/mL). After incubation, 100L aliquots of PMN were transferred to wells (white wall clean bottom 96-well tissue culture plate Costar # 3670; 2 wells/condition) containing 501HA and luminol (final concentration 100M), with or without adenosine agonist (final agonist concentration 0.01-1000 nM). The plate was incubated for 5 min (37 ℃) and then fMLP (501 in HA; final concentration 1M) was added to all wells.

Chemiluminescence peaks were determined by Victor 1420 Multilabel Counter using Wallace workshop software. Data for peak chemiluminescence in the absence of adenosine agonist is provided as a percentage of activity. Determination of EC Using PRISM software₅₀. All compounds were tested using PMNs obtained from three different donors. The results are summarized in table 5.

TABLE 5

A_2AAgonist bindingAssay and Selectivity

Compound (I)	A₁(nM)	A_2A(nM)	A₃(nM)	Function (nM)¹	Function + Roli (nM)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

1-human neutrophil assay as described in example 7, without rolipram

2-human neutrophil assay as described in example 7, containing rolipram

Example 7: a. the_2AEffect of agonists on neutrophil oxidative Activity

A. Material

f-met-leu-phe (fMLP), luminol, superoxide dismutase, cytochrome C, fibrinogen, adenosine deaminase and Trypan blue were all obtained from Sigma Chemical. Polysucrose-diatrizoate is available from ICN (Aurora, OH), and Cardinal Scientific (Santa Fe, NM) and Accurate Chemicals and Scientific (Westerbury, NY). Coli K235 from List Biologicals (Campbell, CA). Hanks Balanced Salt Solution (HBSS), and limulus amebocyte lysate assay kit were from biowittkaker (walker, MD). Human Serum Albumin (HSA) was derived from Cutter Biological (Elkhart, IN). Recombinant human tumor necrosis factor- α is supplied by Dianippon Pharmaceutical co. ZM241385(4- (2- [ 7-amino-2- (2-furyl) [1, 2, 4] -triazolo (triazolo) [1, 3, 5] triazin-5-ylamino ] ethyl) phenol) is present from Simon Poucher, Zeneca Pharmaceuticals, Cheshire, UK. Stock solutions (1 mM and 10mM in DMSO) were prepared and stored at-20 ℃.

B. Preparation of human neutrophils

By a one-step ficoll-diatrizoate isolation procedure (a. ferrante et al, j. immunol. meth., 36, 109 (1980)). Purified human neutrophils (. about.98% neutrophils, and > 95% viable cells, as determined by trypan blue exclusion) containing < 1 platelet/5 neutrophils and < 50pg/ml endotoxin (limulus amoebocyte lysate) were obtained from standard heparinized (10U/ml) venous blood.

C. Chemiluminescence method for sensitizing and stimulating release of inflammatory reactive oxygen species from human neutrophils

Luminol-enhanced chemiluminescence, a method of measuring neutrophil oxidative activity, relies not only on the production of peroxidase, but also on the activation of the lysosomal granule enzyme myeloperoxidase. Light is emitted by unstable energetic oxygen species produced by activated neutrophils. In a shaking water bath, in a sample containing 0.1% human serum albumin (1ml), test A_2APurified neutrophils (5-10X 105/ml) were incubated for 30 minutes at 37 ℃ in Hanks balanced salt solution with or without agonist, with or without rolipram, and with or without tumor necrosis factor-alpha (1U/ml). Then using chronologueLuminometer (Crono-log Corp., Havertown, Pa.) read luminol (1X 10-4M) enhanced f-met-leu-phe (1mcM) at 37 ℃ stimulated chemiluminescence for 2-4 minutes. Chemiluminescence is reported as the relative peak luminescence (═ curve height) compared to samples containing tnf- α and no agonist or rolipram.

Example 8: blood pressure test in vivo in rats

Sprague-Dawley rats (average weight, 250-. Prior to each trial, vehicle controls were injected prior to each drug to determine baseline blood pressure readings. The drug IV was bolus injected through the jugular vein catheter using a volume of 200 microliters of saline, and the catheter was flushed with another 300 microliters of saline. To measure Blood pressure, the centerline of the carotid catheter was connected to a pressure transducer of a Digi-Med Blood pressure Analyzer. All systolic, diastolic, mean pressure, and heart rate were recorded in real time at 30-60 second intervals. Data were recorded until mean blood pressure returned to baseline and held constant for 20 minutes. Data are presented as fractions of mean blood pressure averaged over 10 minutes prior to drug injection. Blood pressure was recorded and plotted against time as a method to determine the potency of the compound and the biological half-life.

The compounds of examples 1 and 2 were tested against the following control compounds:

control

The results are illustrated in figures 1 and 2.

All publications, patents, and patent documents are incorporated by reference herein, as if individually incorporated by reference. Various specific and preferred embodiments and techniques are described. It will be understood, however, that many variations and modifications may be made while remaining within the spirit and scope of the invention.

The present invention provides a therapeutic method for suppressing an immune response comprising administering to a mammal in need of such treatment an anti-inflammatory effective amount of a compound of formula (I).

The invention provides a therapeutic composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier, and further comprising a type IV phosphodiesterase inhibitor, wherein the type IV phosphodiesterase inhibitor is rolipram, cilomilast, or roflumilast.

In the composition of the present invention, the carrier is a liquid carrier.

The compositions of the present invention are suitable for oral, intravenous, ophthalmic, parenteral, aerosol, transdermal administration.

The present invention provides methods for preventing or treating a pathological condition or symptom in a mammal, wherein A is involved_2AThe activity of adenosine receptors and agonism of such activity is desired, comprising administering to said mammal, which is a human or an equine, an effective amount of a compound of formula (I).

Preferably, the pathological condition or symptom is caused by autoimmune stimulation (autoimmune disease), allergic disease, skin disease, infectious disease, wasting disease, open wounds, organ, tissue or cell transplantation, side effects of drug therapy, cardiovascular disorders, dialysis, gout, chemical or thermal trauma.

More preferably, the pathological condition is an open wound.

More preferably, the pathological condition is inflammation. Even more preferably, the inflammation is caused by a pathogenic microorganism. Even more preferably, the inflammation is caused by a viral organism.

The present invention provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of an inflammatory response.

Preferably, the medicament comprises a liquid carrier.

Preferably, the medicament is suitable for parenteral, aerosol or transdermal administration.

Claims

1. A compound having the formula (I):

wherein

Z is CR³R⁴R⁵；

Each R¹Independently is hydrogen;

each R²Independently is hydrogen;

R⁴and R⁵Together with the atoms to which they are attached form a saturated ring having 5, 6 or 7 ring atoms, optionally containing 1 amine (-NR) in the ring^a-)；

Any of which contains R⁴And R⁵Is substituted by 1R⁶Substituted by groups; wherein

Each R⁶Independently is (C)₁-C₈) Alkyl, or-CO₂R^a；

R³Is hydrogen or OH;

each R⁷Independently is hydrogen;

x is-C (O) NR^cR^f，

R^eIs cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

R^fis hydrogen;

R^ais hydrogen;

m is 0, or 1;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R is comprised⁴，R⁵And the ring to which they are attached is cyclohexane or piperidine.

3. The compound of claim 1, wherein R^eIs cyclopropyl, or cyclobutyl.

4. The compound of claim 1, wherein R^eIs cyclopropyl.

5. The compound of claim 1, wherein R^eIs a cyclobutyl group.

6. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

7. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for inhibiting an inflammatory response wherein said inhibiting an inflammatory response involves a_2AThe activity of adenosine receptors and agonism of this activity is desirable.

8. A therapeutic composition comprising a compound of any one of claims 1-6 in combination with a pharmaceutically acceptable carrier.

9. The composition of claim 8, further comprising a phosphodiesterase type IV inhibitor.

10. The composition of claim 9, wherein the type IV phosphodiesterase inhibitor is rolipram, cilomilast, or roflumilast.

11. The composition of claim 8, wherein the carrier is a liquid carrier.

12. The composition of any one of claims 8-11, which is suitable for oral, ocular, parenteral, aerosol, or transdermal administration.

13. Use of a compound of any one of claims 1-6 for the manufacture of a medicament for preventing or treating a pathological state or condition in a mammal, wherein the prevention or treatment of a pathological state or condition in a mammal involves a_2AThe activity of adenosine receptors and agonism of this activity is desirable.

14. The use of claim 13, wherein the mammal is a human or a horse.

15. Use according to claim 13 or 14, wherein the pathological condition or symptom is caused by autoimmune stimulation, allergic diseases, skin diseases, infectious diseases, wasting diseases, open wounds, organ transplantation, tissue or cell transplantation, side effects of drug therapy, cardiovascular disorders, dialysis, gout, chemical wounds or thermal wounds.

16. The use of claim 15, wherein the pathological condition is an open wound.

17. The use of claim 13, wherein the pathological condition is inflammation.

18. The use of claim 17, wherein the inflammation is caused by a pathogenic organism.

19. The use of claim 17, wherein the inflammation is caused by a viral organism.

20. The use of claim 17, wherein the medicament is administered in combination with an antipathogenic agent.

21. The use of claim 18, wherein the pathogen is a bacterium and the antipathogenic agent is an antibiotic.

22. The use of claim 19, wherein the pathogen is a virus and the antipathogenic agent is an antiviral agent.

23. The use of claim 19, wherein the pathogen is a yeast or a fungus and the antipathogenic agent is an antifungal agent.

24. The use of claim 21, wherein the inflammation is caused by e.coii.

25. The use of claim 21, wherein the bacteria cause hemolytic uremic syndrome.

26. The use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the diagnosis of myocardial perfusion abnormalities in a mammal comprising:

(a) parenterally administering to said mammal an amount of said compound; and

(b) performing a technique on the mammal to detect the presence of a coronary stenosis, to assess the severity of a coronary stenosis, or both.

27. The use of claim 26, wherein the mammal is a human or a horse.

28. The use of claim 26 or 27, wherein said abnormal myocardial perfusion is selected from the group consisting of coronary artery disease, ventricular dysfunction and differences in blood flow through disease-free coronary vessels and abnormally stenotic coronary vessels.

29. The use of claim 26 or 27, wherein the technique for detecting the presence and severity of coronary artery disease is selected from radiopharmaceutical myocardial perfusion imaging, ventricular function imaging, or a technique for determining coronary blood flow rate.

30. The use of claim 29, wherein said radiopharmaceutical myocardial perfusion imaging is selected from planar scintigraphy, single photon emission computed tomography, positron emission tomography, magnetic resonance imaging, perfusion contrast echocardiography, digital subtraction angiography, or ultrarapid X-ray computed tomography.

31. The use of claim 30, wherein a radiopharmaceutical is used in combination with myocardial perfusion imaging of said radiopharmaceutical, the radiopharmaceutical comprising a member selected from the group consisting of thallium-201, technetium-99 m, nitrogen-13, rubidium-82, iodine-123 and oxygen-15.

32. The use of claim 31, wherein the radiopharmaceutical myocardial perfusion imaging is planar scintigraphy and the radiopharmaceutical is thallium-201.

33. The use of claim 29, wherein the ventricular function imaging is selected from echocardiography, contrast agent ventricular angiography, or radionuclide ventricular angiography.

34. The use of claim 33, wherein the ventricular function imaging is echocardiography.

35. The use of claim 29, wherein the method of determining coronary blood flow rate is selected from the group consisting of doppler flow catheters, digital subtraction angiography, and radiopharmaceutical imaging techniques.

36. The use of claim 30, wherein the method of determining coronary blood flow rate is a doppler flow catheter.

37. The use of claim 27, comprising the steps of:

(a) administering to said human by intravenous injection or bolus injection an amount of a compound of formula I effective to provide coronary artery dilation;

(b) administering to the human a radiopharmaceutical agent comprising thallium-201, or technetium-99 m; and

(c) scintigraphy is performed on the human to detect the presence and assess the severity of coronary artery disease.

38. The use of claim 37, wherein the agent is Tc-99 m-sesami.

39. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the prophylaxis or treatment of a pathological condition or symptom in a mammalUse, wherein the prevention or treatment of a pathological state or condition in a mammal involves A₃The activity of adenosine receptors and agonism of this activity is desirable.

40. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of an inflammatory response wherein said treatment of an inflammatory response involves A_2AThe activity of adenosine receptors and agonism of this activity is desirable.

41. The use of claim 40, wherein the medicament comprises a phosphodiesterase type IV inhibitor.

42. The use of claim 40, wherein the phosphodiesterase type IV inhibitor is rolipram.

43. The use of claim 42, wherein the medicament comprises a liquid carrier.

44. The use of claim 40, wherein the medicament is suitable for parenteral, aerosol or transdermal administration.

45. The composition of claim 12, which is suitable for intravenous administration.