JP2003517423A - N6-substituted adenosine-5'-uronamide as adenosine receptor modulator - Google Patents

Abstract

(57) Abstract: A series of adenosine-5'-uronamide derivatives having an N ⁶ -arylurea, alkarylurea, heteroarylurea, arylcarbonyl, alkarylcarbonyl or heteroarylcarbonyl group, wherein adenosine A ₁ , or affinity for a ₃ receptors, and, in some instances, have been disclosed what has selectivity. These compounds, in pharmaceutical compositions for the treatment of disorders caused by A ₁ or A ₃ receptor overactivity, or clinical applications for detecting the relative binding of another compound to the A ₁ or A ₃ receptors Can be used.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to certain N ⁶ -substituted adenosine-5′-uronamide derivatives and pharmaceuticals as compounds having activity as agonists of adenosine receptors, especially adenosine A ₁ and A ₃ receptors. Their use, in practice.

BACKGROUND OF THE INVENTION The three major classes of adenosine receptors, classified as A ₁ , A ₂ and A ₃ , are pharmacologically characterized and based on cloned sequences. Defined ^1-4 . The A ₁ receptor binds through the G _i protein to inhibit adenylate cyclase, and binds to other second messenger systems including inhibition or promotion of phosphoinositol turnover and activation of ion channels. It is shown. The A ₂ receptor is further divided into two subtypes, A _2A and A _2B , where adenosine agonists activate adenylate cyclase with high and low affinity, respectively. The sequence of the A ₃ receptor was first identified in a rat testis cDNA library, and this sequence was later cloned from a rat brain cDNA library by homology to other G-protein coupled receptors, but with a novel, functional It was shown to correspond to a typical adenosine receptor.

[0003]   Many selective agonists and antagonists₁ ^10-15And A_2a ^16-19
Has been developed for receptor subtypes. Some of these have high blood pressure ¹⁷ , Parkinson's disease²⁰, Cognitive deficit^{twenty one}, Schizophrenia^{twenty two}, Epilepsy and renal failure^{twenty three}treatment of
Has shown promise as a powerful therapeutic agent. A_2bSelection for receptors
And / or high affinity agonists and antagonists are not well known
Yes.

The discovery of the A ₃ receptor has opened new therapeutic perspectives in the purine field. In particular, the A ₃ receptor mediates the processes of inflammation, hypotension, and mast cell degranulation. This receptor apparently also has a role in the central nervous system. A ₃ selective agonists IB-MECA induces behavioral depression, chronic administration to prevent cerebral ischemia. High concentration A ₃ selective agonists of has been found to induce apoptosis in HL-60 human leukemia cells. These and other findings make the A ₃ receptor a promising therapeutic target. Selective agonists for the A ₃ receptor are being explored as potent anti-inflammatory or potential anti-ischemic agents in the brain. A ₃ antagonists include anti-asthma, antidepressants, anti-arrhythmias, renal protection,
Under development as an anti-Parkinson and cognitive enhancer.

Selective agonist ²⁴ and antagonist ^25-28 ligands have been developed for the A ₃ receptor. In the field of agonists, IB-MECA (N ^6- (3-iodobenzyl) adenosine-5′-methyluronamide) shows a Ki value of 1.1 mM at the rat A ₃ receptor and 50 at the A ₁ or A _2a receptor ²⁹ . It shows double selectivity. A related agonist, [ ¹²⁵ I] AB-MECA (N ^6- (4-amino-3-iodobenzyl) adenosine-5′-methyluronamide) ^30, is a useful radiation for screening novel derivatives at the cloned A ₃ receptor. It became a ligand.

More recently, the substituent is 2-chloro, 3-chloro or 4-methoxy, (
N ⁶ -. (Substituted phenylcarbamoyl) adenosine-5'-Mechiruuronamido) is prepared (Baraldi et al Advance ACS Abstr acts , December 15, 1995), and the low nanomolar range (
Affinity at the A ₃ receptor was revealed at a Ki value of 10 nm or less). However, another close substituent, eg 3-bromo, showed a 10-fold loss in activity and affinity for the A ₃ receptor (Baraldi et al.
al. , J. Med. Chem . 39: 802-806 (1996)). Furthermore, 2-chloro, 3-chloro and 4-methoxy substituents is a high affinity for A ₃ receptors, and showed a high selectivity for A ₂ receptor, selectivity for A ₁ receptors high None (the ratio of A ₃ to A ₁ activity was between 4 and 15).

[0007] Many of the previously synthesized A ₃ adenosine receptor agonists are structurally related to adenosine itself, where the ribose moiety is largely intact. Ribose is generally resistant to 5'-alkylamido groups. Generally, for adenosine agonists, the structural position of adenosine that provides the flexibility of substitution is N ⁶
And C ₂ position. At the N ⁶ position, most alkyl or aryl derivatives are A ₁ selective. The C ₂ position, many C-, N-, or O- derivative is A _2a selective. The benzyl derivative at the N ⁶ position has been shown to be A ₃ selective.

[0008] With respect to another adenosine receptor, the A ₁ and A ₃ receptors have high affinity and selectivity for the A ₁ and A ₃ receptors, it is Conveniently to provide an alternative modulator.

Therefore, it is an object of the present invention to provide compounds and their methods of preparation and use which are agonists or partial agonists of adenosine receptors, in particular adenosine A ₁ and A ₃ receptors.

SUMMARY OF THE INVENTION Compounds useful as potent and in some cases selective agonists of the adenosine A ₁ and A ₃ receptors, and methods of making and using them are disclosed.

[0011]   The compound has the following general formula:

[Chemical 2]

Wherein R is hydrogen, alkyl, substituted alkyl, or aryl; R ¹ is heteroaryl-NR-C (X), heteroaryl-C (X)-, alkaryl-NR-C (X )-, Substituted alkaryl-NR-C (X)-, aryl-NR-C (X)-, aryl-C (X)-, alkaryl-C (X)-, or substituted alkaryl-C (X). )-, R ² is hydrogen, alkyl, substituted alkyl, or aryl-NH-C (X)-.
, And X are O, S, or NR, provided that R ² is H and R ¹ is aryl-NH-
When C (X)-and X are O, the substituents on the aryl ring are not halo, methoxy or trifluoromethyl. R ³ and R ⁴ are independently halo, ether, azido, alkyl, alkoxy,
Carboxy, nitrile, nitro, trifluoro, aryl, alkaryl, thio,
Separately selected from the group consisting of thioesters, thioethers, amines, amides, and substituents commonly used in the field of nucleoside chemistry to modify these positions. Such modifications are expected to provide compounds with activity as partial agonists.

R ¹ is heteroaryl-NR-C (X)-, heteroaryl-C (X)-,
Aryl-C (X)-, alkaryl-C (X)-, or substituted alkaryl-
When C (X)-, the compound tends to exhibit affinity and, in some cases, selectivity for the adenosine A ₁ receptor. R ¹ is alkaryl-N
R-C (X)-, substituted alkaryl-NR-C (X)-, or aryl-NR
-C (X) - When the compounds tend to show affinity and selectivity for the A ₃ receptor. Suitable substituents are p-sulfonamido, p-nitro, p-phenyl, 2,4-dichloro, p-methoxy, m-chloro, o-chloro and p-.
Including nitro.

The compounds can be used in mammals, including humans, in a manner that inhibits adenylate cyclase (A ₁ and A ₃ ) in whole or in part. The method provides a compound of formula I sufficient to inhibit adenylate cyclase in whole or in part in a mammal.
Administering an effective amount of a compound of

In addition, the compounds can be used in competitive binding assays to determine the activity of other compounds to bind to the A ₁ or A ₃ receptors.

The compound may be used in a pharmaceutical formulation comprising a compound of formula I and one or more excipients.

DETAILED DESCRIPTION OF THE INVENTION The present application specifically describes compounds useful as agonists or partial agonists of adenosine receptors having activity as A ₁ or A ₃ agonists or partial agonists, and methods for their preparation and use. Disclose.

The compounds can be used in a method of treatment of mammals, including humans, which have an overactivity of adenosine receptors, in particular A ₁ or A ₃ receptors. The method comprises administering to the mammal an effective amount of a compound of formula I sufficient to modulate the adenosine receptor in the mammal. The compound may be used in a pharmaceutical formulation comprising a compound of formula I and one or more excipients.

[0019]   Definition   As used herein, the compound is adenylate cyclase (A ₁ And A₃A), adenosine A₁Or A₃The Agoni
In the competitive binding assay,¹²⁵I] -AB-MECA
You can

As used herein, a compound is a partial agonist of adenosine A ₁ or A ₃ if it can partially inhibit adenylate cyclase (A ₁ and A ₃ ) [ ¹²⁵ I] -AB-MECA can be substituted in the binding assay.

As used herein, a compound is an antagonist of the adenosine A ₁ or A ₃ receptor if it is capable of preventing inhibition because it is an agonist and [ ¹²⁵ I] in a competitive binding assay. -AB-MECA can be substituted.

As used herein, a compound is a compound if the ratio of A ₂ / A ₁ and A ₃ / A ₁ activities is greater than about 50, preferably between 50 and 100, and more preferably Greater than about 100 is selective for the A ₁ receptor. A compound is selective for the A ₃ receptor if the ratio of A ₁ / A ₃ and A ₂ / A ₃ activity is greater than about 50, preferably between 50 and 100, and more preferably greater than about 100. Target.

As used herein, the term “alkyl” is preferably from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms (“lower alkyl”) and most preferably Refers to a monovalent straight chain, branched or cyclic alkyl group having 1 to 6 carbon atoms. The term is methyl, ethyl, n-propyl, iso
-Propyl, n-butyl, iso-butyl, n-hexyl, and the like groups. The terms "alkylene" and "lower alkylene" refer to the divalent radical of the corresponding alkane. Further, as used herein, another structural unit having a name derived from an alkane, such as alkoxy, alkanoyl, alkenyl, cycloalkenyl, etc., is 10 or less when the term "lower" is attached. It has a carbon chain of carbon atoms of. In these cases, for example, alkenyl (minimum 2
Carbons) and cycloalkyl (minimum 3 carbons), "lower" is understood to mean a number of carbons greater than or equal to the minimum, if the minimum number of carbons is greater than 1. To be done.

[0024]   As used herein, the term "substituted alkyl" refers to 1 to 5 substituents,
It preferably has 1 to 3 substituents, and is an alkoxy, substituted alkoxy or cycloalkyl group.
Alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl
, Acylamino, acyloxy, amino, substituted aminoaminoacyl, amino
Syloxy, oxyacylamino, cyano, halo, hydroxyl, keto, thioke
G, carbonyl, carbonylalkyl, thiol, thioalkoxy, substituted thioa
Lucoxy, aryl, aryloxy, heteroaryl, heteroaryloxy
, Heterocycle, hydroxyamino, alkoxyamino, nitro, -SO-alkyl
, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂ -Alkyl, -SO₂-Substituted alkyl, -SO₂-Aryl, -SO₂-Heteroa
Reel and mono- and di-alkylamino, mono- and di- (substituted a
Alkyl) amino, mono- and di-arylamino, mono- and di-heteroa
Lille amino, mono- and di-heterocyclic amino, and alkyl, aryl
, Unpaired having different substituents selected from heteroaryl and heterocycle
1 to 5 substituents selected from nominal di-substituted amines, preferably 1 to 3
It means an alkyl group having a substituent. As used here, the prefix "
Another structural unit having "substitution" includes one or more of the above-mentioned substituents.
Is intended.

As used herein, the term “alkoxy” refers to the group “alkyl-O—”, where alkyl is as defined above. A preferred alkoxy group is, for example,
Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t
ert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,
2-dimethylbutoxy and the like are included.

As used herein, the term “alkenyl” preferably has 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and at least 1, preferably Refers to an alkenyl group having 1-2 alkenyl unsaturations. Suitable alkenyl groups include ethenyl (-CH = CH _2), n- propenyl (-C
H ₂ CH = CH _2), including iso- propenyl _{(-C (CH 3) = CH} 2) and the like.

As used herein, the term “alkynyl” preferably has 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and at least 1 of alkynyl unsaturation. , Preferably 1-2 alkynyl unsaturations,
Refers to an alkynyl group.

As used herein, the term “acyl” includes alkyl-C (O)-, substituted alkyl-C (O)-, cycloalkyl-C (O)-, substituted cycloalkyl-C.
(O)-, aryl-C (O)-, heteroaryl-C (O)-, and heterocyclic-C (O)-groups, in which alkyl, substituted alkyl, cycloalkyl, substituted cyclo Alkyl, aryl-, heteroaryl, and heterocycle are as defined above.

As used herein, the term “acylamino” means that each R is independently hydrogen,
An -C (O) NRR group that is an alkyl, substituted alkyl, aryl, heteroaryl, or heterocycle, wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocycle are as defined above. .

As used herein, the term “aryl” is monocyclic (eg, phenyl)
Or having multiple fused (fused) rings (eg, naphthyl or anthryl),
An unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms. Suitable aryls include phenyl, naphthyl, etc. By definition for an aryl substituent,
Unless otherwise disturbed, such aryls may be optionally substituted with 1 to 5 substituents, and hydroxy, acyl, alkyl, alkoxy,
Alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carbonyl, carboxylalkyl, cyano, halo, nitro, heteroaryl , Heteroaryloxy, heterocycle, heterocyclooxy, aminoacyloxy, oxyacylamino,
Thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -S
O- heteroaryl - le, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ -
It may be substituted with preferably 1 to 3 substituents selected from the group consisting of aryl, —SO ₂ -heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.

As used herein, the term “cycloalkyl” refers to a cyclic alkyl group of 3 to 12 carbon atoms having a monocyclic or multiple condensed ring. Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc., or multiple ring structures such as adamantanyl, etc.

As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo, and preferably either fluoro or chloro.

As used herein, the term “heteroaryl” is selected from the group consisting of oxygen, nitrogen and sulfur in at least one ring (if there is more than one ring). 1 to 15 carbon atoms and 1 to 4 heteroatoms.

Unless stated otherwise by the definition of a substituent, such a heteroaryl group may be optionally substituted with 1 to 5 substituents and hydroxy, acyl, alkyl, alkoxy. , Alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, aryloxy, azido, carbonyl, carboxylalkyl, cyano, halo, nitro, hetero Aryl, heteroaryloxy, heterocycle, heterocyclooxy,
Aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -S
O- substituted alkyl, -SO- aryl, -SO- heteroaryl - le, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl, -SO ₂ - heteroaryl -
Optionally substituted with 1 to 3 substituents selected from the group consisting of: Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.

“Heterocycle” or “heterocyclic” means a monocyclic ring of 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen within the ring. A monovalent saturated or unsaturated group having multiple condensed rings.

Unless otherwise defmed by the definition of a heterocyclic substituent, such heterocyclic group is alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, It may be optionally substituted with 1 to 5 substituents selected from the group consisting of thioalkoxy, substituted thioalkoxy, thioaryloxy, trihalomethyl and the like.
Such heterocyclic groups can also have single rings or multiple condensed rings.

For any of the above groups, including one or more substituents, such groups are, of course, sterically impracticable and / or synthetically impossible substitutions or substitutions. It is understood that the style is not included.

“Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound of formula I, which salt is derived from a variety of organic and inorganic counterions well known in the art. , And include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule has a basic function, salts of organic or inorganic acids, such as hydrochlorides, bromates, Tartrate, mesylate, acetate, maleate, oxalate and the like can be used as pharmaceutically acceptable salts.

The term “protecting group” or “protecting group (bl
"ocking group" refers to a reaction that occurs with a compound (including intermediates, such as aminolactams, aminolactones, etc.) when attached to one or more hydroxy, amino or carboxyl groups. Preventative and protecting groups refer to groups that can be removed by conventional chemical or enzymatic steps to regenerate a hydroxy, amino or carboxyl group. Suitable removable amino protecting groups are t-butoxycarbonyl (t-BOC), benzyloxycarbonyl (C), which can be removed by conventional conditions compatible with the nature of the product.
BZ), etc. and conventional substituents such as.

The following abbreviations are used herein: Abbreviations: [ ¹²⁵ I] AB-MECA, [ ¹²⁵ I] N ^6- (4-amino-3-iodobenzyl) adenosine-5′-N-methyluronamido; CHO cells, Chinese hamster ovary cells; CGS21680, 2- [4-[(2-carboxyethyl) phenyl] ethyl-amino] -5'-N-ethylcarboxamide-adenosine; CI
-MB-MECA, 2-chloro -N ⁶ - (3- iodobenzyl) adenosine -5
'-N-Mechiruuronamido; (R) -PLA, (R ) -N 6 - ( phenylisopropyl) adenosine; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid, I-AB-MECA, N 6 - (4- Amino - 3-iodobenzyl) ^{adenosine-5'-N-Mechiruuronamido; IB-MECA, N 6 -} (3- iodobenzyl) adenosine-5'-N-Mechiruuronamido; Ki, equilibrium inhibition constant; NECA, 5'-N- ethyl Carboxamide-adenosine; THF, tetrahydrofuran; Tris, tris (hydroxymethyl) aminomethane.

Preparation of Compounds Those skilled in organic chemistry will recognize that reactive and labile functional groups must often be protected before a particular reaction, or series of reactions, and after the final reaction is complete. , I know correctly that I have to return them to their original form. Usually, the group is protected by converting it to a relatively stable derivative. For example, hydroxyl groups are converted to ether groups and amine groups are converted to amides or carbamates. Protecting and de-protecting
ing), as well as "blocking" and "deprotection" (de-bl).
method, also known as T.Ocking), is well known and widely practiced in the art, for example, T.W. Green, Protective Groups
in Organic Synthesis, John Wiley, Ne
w York (1981) or Protective Groups in
Organic Chemistry, Ed. J. F. W. See McOmie, Plenum Press, London (1973).

The compound may be prepared as described below. Generally, N-
The 2'- and 3'-hydroxy groups of alkylcarboxamide-adenosine, such as 5 '-(N-ethylcarboxamide) adenosine (NECA), are protected. A suitable protecting group is the isopropylidene ring, but other protecting groups can be used and are intended to be within the scope of this invention.

2 ′, 3′-O-isopropylidene-N ^6- (substituted-carbonylamino) -adenosine-5′-alkyluronamide is a N ⁶ -amine group with a suitable acid chloride or other suitable. It can be prepared from isopropylidene-protected N-alkylcarboxamide-adenosine by reaction with various activated carboxylic acid derivatives, such as anhydrides, using a conventional amidation reaction (shown in Figure 2a). 2 ', 3'-O-isopropylidene--N ⁶ - (substituted - carbamoylamino) - adenosine-5'-alkyl uronium cyanamide is, N ⁶ - by reaction of an amine group with a suitable isocyanate, known chemical The reaction can be used to prepare from an isopropylidene-protected N-alkylcarboxamide-adenosine (shown in Figure 2b). The protecting group is removed to give the desired compound.

The 2 ′ and / or 3′-hydroxy groups are halo, ether, ester, azido, alkyl, alkoxy, carboxy, nitrile, nitro, trifluoro, aryl, alkaryl, thio, thioester, thioether, amine or amide. In those embodiments that are substituted with groups, the chemical reaction is such that the thio and amine groups inhibit the coupling reaction, and therefore the N ⁶ amine group is suitable before coupling with the acid chloride or isocyanate. The reaction proceeds in essentially the same manner except that it must first be protected with a protecting group.

Methods of Using the Compounds The compounds can be used in all indications for which agonists and antagonists of the A ₁ or A ₃ receptors are effective.

Compounds that effectively modulate the A ₁ receptor can be used for: protection against hypoxia and / or ischemia-induced injury (eg stroke, infarction); adenosine sensitive hearts Treatment of arrhythmias; analgesia (ie, analgesics); anticonvulsants; cardioprotection, short-term (eg, percutaneous angioplasty (PTDA), angioplasty, and cardiac surgery) and long-term (myocardial infarction) Prevention, especially in high-risk patients,
Reduction of infarct disorders, especially in high-risk patients); Neuroprotection: stroke prevention, stroke treatment, and treatment of epilepsy; pain management, including different forms of neuropathic pain in general, eg, Diabetic neuropathy, postherpetic neuralgia; Anti-lipid use: reduction of free fatty acids, triglycerides, glucose; Treatment of GI disorders such as diarrhea, irritable bowel disease, irritable bowel syndrome, incontinence; treatment of glaucoma; treatment of sleep apnea; cardiac disarrhythmia (paroxysmal) Treatment of supraventricular tachycardia) ・ Use in combination with anesthetic for postoperative pain; ・ Treatment of inflammation - diagnostic use, for example, medical situations mentioned above, 1 or for detecting more presence, or, A ₁ screening assay to determine the effectiveness of other compounds that bind to Ado receptor (i.e., Diagnostic uses (through competitive inhibition as determined by various binding assays) for which Jacobs
on and Van Rhee, a purinergic approach to experimental therapy,
Edited by Jacobson and Jarvis, Wiley, New York
, 1997, pp. 101-128; Mathott et al. , Br it. J. Pharmacol. 116: 1597-1964 (1995
); Van der Wenden et al. , J. Med. Ch em. , 38: 4000-4006 (1995); and van Cale.
nbergh, J .; Med. Chem. , 40: 3765-3772 (19
97), the contents of which are incorporated herein by reference.

Compounds that effectively modulate the A ₃ receptor can be used:
・ Treatment of hypertension; ・ Mast cell degranulation; ・ Antineoplastic agent; ・ Cardiac hypoxia;

These are described, for example, in Jacobson, TIPS May 1998, pp. 1
85-191, the contents of which are incorporated herein by reference.

The compounds may be administered via any pharmaceutically acceptable method. Suitable administration methods include oral, rectal, topical or parenteral (including subcutaneous, intramuscular and intravenous) administration, with oral or parenteral administration being preferred.

The amount of compound necessary to be effective as an agonist or partial agonist of the adenosine receptor will, of course, vary with the particular mammal to be treated and will ultimately be at the discretion of a medical or veterinarian physician. Factors to consider include the condition being treated, the route of administration, the nature of the formulation, the body weight of the mammal, the body surface area, the age and general condition, and the particular compound being administered. However, suitable effective doses are in the range of about 0.1 μg / kg to about 10 mg / kg body weight per day,
Preferably, it is in the range of about 1 mg / kg to about 3 mg / kg per day.

The total daily dose may be a single dose, multiple doses, for example 2 to 6 times per day, or by intravenous infusion over an appropriately selected period. Methods of administration above or below the ranges described above are within the scope of the present invention and may be administered to an individual patient, if and when necessary. For example, for a 75 kg mammal,
The dosage range is about 75 mg to about 220 mg per day, with a typical dosage being about 150 mg per day. If separate multiple doses are ordered,
Treatments are typically given 50 mg of compound 3 times per day.

Formulations The compounds described above are preferably administered in a formulation containing the active ingredient, ie a compound of formula I, together with a carrier which is compatible with the mode of administration. Suitable pharmaceutically acceptable carriers are known to those skilled in the art.

The composition optionally comprises other therapeutically active ingredients such as antiviral, antitumor, antibacterial, anti-inflammatory, analgesic, and immunosuppressive agents. The carrier must be pharmaceutically acceptable in a way compatible with the other ingredients of the formulation and not injurious to its recipient.

Formulations are oral, rectal, topical or parenteral (including subcutaneous, intramuscular and intravenous)
A carrier suitable for administration can be included. Preferred carriers are those suitable for oral or parenteral administration.

Formulations suitable for parenteral administration include sterile aqueous preparations of the active compound which are preferably isotonic with the blood of the recipient. Such formulations may contain distilled water, 5% dextrose in distilled water or saline. Suitable formulations also include concentrated solutions or solids containing a compound of formula I which upon dilution with a suitable solvent give a solution suitable for parenteral administration.

For enteral administration, the compound is a capsule containing a predetermined amount of the active ingredient,
Of a separate unit such as a cachet, a tablet or a troche; a powder or granules; or a suspension or solution of an aqueous or non-aqueous liquid, eg, a syrup, an elixir, an emulsion or a water solution. It can also be incorporated into an inert carrier. Suitable carriers are starch or sucrose and include lubricants, binders, and other materials of the same character.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared by mixing the active compound in a free-flowing form, for example a powder or granules, optionally mixed with auxiliary ingredients such as binders, lubricants, inert diluents, surface-active or dispersing agents, Manufactured by compression on a suitable machine. Molded tablets are made by molding in a suitable machine a mixture of the powdered active compound with a suitable carrier.

A syrup or suspension is made by adding the active compound to a concentrated aqueous solution of sugar, for example sucrose, to which any auxiliary ingredient may be added. Such co-ingredients include flavoring agents, agents that delay sugar crystallization or agents that increase the solubility of other ingredients, such as polyhydric alcohols, such as glycerin or sorbitol.

The compound may be a solution, an ointment, a cream, a gel, a lotion, or a polymerized material (eg Pluronic ^™ , B) which may be prepared by conventional methods of pharmacy.
It can be administered locally by local adaptation of ASF). In addition to solutions, ointments, creams, gels, lotions, or polymerized bases and active ingredients, such topical formulations may contain preservatives, perfumes, and also active agents.

Formulations for rectal administration may be formulated with conventional carriers, such as suppository-based cocoa butter or Wi.
It may be presented as a suppository containing tepsol S55 (trademark of Dynamite Nobel Chemical, Germany).

Alternatively, the compound may be administered in liposomes or microspheres (or microparticles). Methods of preparing liposomes and microspheres for administration to patients are well known to those of skill in the art. U.S. Pat. No. 4,789,734, the contents of which are incorporated herein by reference, describes a method of encapsulating biological material in liposomes. As a prerequisite, the material is dissolved in an aqueous solution, the appropriate phospholipids and lipids are added, optionally also the active agent, and if necessary the material is dialyzed or sonicated. For a review of known methods, see G. Gregoriadis, Chapter
14, "Lipossomes," Drug Carriers in Bio
logy and Medicine, pp. 287-341 (Academi
c Press, 1979). Microspheres formed of polymers or proteins are well known to those of skill in the art and can be prepared for direct entry into the bloodstream via the gastrointestinal tract. Alternatively, the compound can be incorporated into microspheres and the microsphere or complex of microspheres implanted in the body for slow release over a period ranging from days to months. For example, U.S. Pat. Nos. 4,906,474, 4,925,673 and 3,625,21.
See No. 4. These contents are incorporated herein by reference.

Suitable microparticles are those prepared from biodegradable polymers such as polyglycolide, polylactide and copolymers thereof. One of skill in the art can readily determine an appropriate delivery system based on various factors, including the desired drug release time and the desired dosage.

The formulations are conveniently presented in unit dose and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers, or finally solid carriers, and, if necessary, shaping the product into the desired unit dosage form. Is prepared.

In addition to the ingredients mentioned above, the formulation may also comprise any one or more accessory ingredients utilized in the art of pharmaceutical formulation such as diluents, buffers, flavoring agents, binders, surfactants. , Thickeners, lubricants, suspensions, preservatives (including antioxidants), others,
including.

Measurement of Activity of Compound The activity of a compound can be easily measured by a usual experimental method using, for example, any of the following assays.

Rat A ₁ and A _2A Adenosine Receptor Binding Assay Membrane Preparation: Male, Wistar rats (200-250 g) were decapitated and whole brain (except brainstem, striatum and cerebellum) was minced in ice. Brain tissue was adjusted to 50 mM Tris-HCl, p
It can be destroyed with Polytron (setting 5) in 20 vols of H7.4. The homogenate was centrifuged at 48,000 g for 10 minutes and the pellet was pelleted with 2 IU / ml of adenosine deaminase, typeVI (Sigma Che.
medical Company, St. Louis, Mo. , USA) in Tris-HCl. After incubation at 37 ° C for 30 minutes,
The membrane is centrifuged and the pellet stored at -70 ° C. Striatal tissue is 10 mM-M
gCl _2, 25vo of 50mM Tris -HCl buffer containing pH7.4
It can be homogenized with Polytron in 1. 4 homogenates
It can be centrifuged at 8,000 g for 10 minutes at 4 ° C. and resuspended in Tris-HCl buffer containing 2 IU / ml adenosine deaminase. After incubation for 30 minutes at 37 ° C, the membrane is centrifuged and the pellet stored at -70 ° C.

Radioligand binding assay: [ ³ H] -DPCPX (1,3-dipropyl-8-cyclopentylxanthine) binding to rat brain membranes is essentially as described by Bruns et al. , Proc. Natl. Acad. Sci. USA , 77: 5547-5551 (19.
80), according to the method previously described, the content of which is hereby incorporated by reference. In this way, the replacement experiment is 1n
0.25 ml buffer containing M [ ³ H] -DPCPX, rat brain diluted membrane 1
00 μl (100 μg protein / assay), and at least 6-8 different concentrations of test compound are run. Non-specific binding was determined in the presence of 10 μM CHA (N ⁶ cyclohexyl adenosine), which is always ≦ 10% of total binding. The incubation time is typically around 120 minutes at 25 ° C.

Bound and free radioactivity was measured by the Brandel cell harvester (Gai).
Thersburg, MD, USA) using Whatman GF / B
The assay mixture can be separated by filtration through a glass fiber filter. The incubation mixture is diluted with 3 ml ice-cold incubation buffer, rapidly vacuum filtered and the filter is washed 3 times with 3 ml incubation buffer. Radioactivity bound to the filter can be measured by liquid scintillation spectrometry. The protein concentration is determined by a known method,
For example, it can be measured using bovine albumin as a reference standard.

[0069]   Human Cloning A ₃ Adenosine Receptor Binding Assay   Receptor binding assay: The binding assay is the Salvatore et a
l. ，Proc. Natl. Acad. Sci. USA, 90: 103
65-10369 (1993),
Its contents are hereby incorporated by reference. Tired of using this method
In a Japanese experiment, human recombinant A₃Adenosine receptor (Research B
iochemical International, Natick, MA,
USA) and a suitable amount of membrane (8 mg protein) obtained from HEK-293 cells.
Quality / ml) in the range of 0.1 to 5 nM at 10 to 12 different concentrations [[^{12 Five} I] Incubate with AB-MECA. The competition experiment is 0.3 nM [¹²⁵I]
AB-MECA, 50 mM Tris-HCl buffer, 10 mM MgCl₂,
pH 7.4, and diluted membrane (12.4 mg protein / ml) 20 μl
In a final volume of 100 μl containing 2 times and a low volume of ligand tested.
At least 6-8 times with different concentrations. Incubation time is typically
, At 37 ° C. for about 60 minutes.

Bound and free radioactivity are separated by filtering the assay mixture through Whatman GF / B glass fiber filters using a Brandel cell harvester. Non-specific binding is defined as binding in the presence of 50 μM R-PIA and can be as high as about 30%. The incubation mixture is diluted with 3 ml ice-cold incubation buffer, rapidly vacuum filtered and the filter is washed 3 times with 3 ml incubation buffer. Radioactivity bound to the filter is Beckman gamma 5500B
Count with a γ counter. The protein concentration can be measured by a known method, for example, using bovine albumin as a reference standard.

Other suitable methods of conducting binding studies are described by Baraldi et al. , J. Me d. Chem. , 39: 802-806 (1996).

Data Analysis The inhibitory binding constant (Ki) value was calculated according to the Cheng & Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol. , 22:
3099-3108 (1973), the contents of this document are incorporated herein by _{reference, Ki = IC 50 / (1+} [C *] / K D *), wherein [C ^*] is the radioligand The concentration, K _D ^*, was calculated from the IC ₅₀ according to its dissociation constant.

A program that fits the curve of the weighted nonlinear least squares method, for example, LIGAND
Can be used for computer analysis of saturation and inhibition experiments. Data are typically expressed as the geometric mean in parentheses with 95% or 99% confidence limits.

Pharmacology All synthesized compounds were tested for affinity at rat A ₁ and A _2A and human A ₃ receptors.

EXAMPLES The following examples demonstrate the interpretation of the invention, but should not be construed as limiting. The symbols and conventions used in these examples are the most up-to-date, international, chemical literature, eg, the Journal of the Ame.
rican Chemical Society ("J. Am. Chem. So
c. )) And Tetrahedron, are intended to be consistent with those used.

Experimental Section Chemistry: Reactions were routinely monitored by thin layer chromatography (TLC) on silica gel (precoated F254 Merck plates) with visualization of the product in aqueous iodine or potassium permanganate. Infrared spectrum (IR) is Perk
It was measured with an in-Elmer 257 device. ¹ H-NMR is performed by Brucker A
The peak position was given in ppm (δ) with the field below tramethylsilane as internal standard on a C200 Spectrometer with CDCl ₃ or DMSO-d ₆ and the J value given in Hz. Light petroleum ether is the boiling fraction at 46-60 ° C. Melting points are determined on a Buchi-Tuttoli instrument and are uncorrected. Chromatography was performed on Merck 60-200 mesh silica gel. All reported products showed IR and ¹ H-NMR spectra consistent with the assigned structure. The organic solvent was dried over anhydrous magnesium sulfate. Elemental analysis by Dipartimento
Di Chemica, University of Ferrara microanalysis laboratory, C, H and N were within 0.4% of theory.

[0077] Example 1: 2 ', 3'-O-isopropylidene--N ⁶ - (substituted - carbonylamino) General procedure 2 for the preparation of adenosine-5'-N-Echiruuronamido', 3' Isopropylidene- NECA (0.43 mmol) was dissolved in freshly distilled dioxane (4 ml) and the appropriate acid chloride (1.3 eq) and catalytic amount of triethylamine (2-3 drops) were added. The mixture was refluxed under an argon atmosphere for 15 hours. The solvent was then removed under reduced pressure, the residue was purified by flash chromatography _{(CH 2 Cl 2 -EtOAc20%)} , to give the desired compound.

Example 2 Preparation of 2 ′, 3′-O-isopropylidene-N ^6- (4-biphenyl-carbonylamino) adenosine-5′-N-ethyluronamide Following the procedure outlined in Example 1, The title compound was prepared as a pale yellow foam in 80% yield. IR (solventless) cm ^-1 3445, 1720, 164
0,1575. ¹ HNMR (CDCl ₃ ) δ: 0.84 (t, 3H, J = 7); 1
． 39 (s, 3H); 1.62 (s, 3H); 3.02-3.11 (m, 2H)
4.71 (d, 1H, J = 2); 5.39-5.46 (m, 2H); 6.19
(D, 1H, J = 2); 6.66 (t, 1H, J = 2); 7.40-7.74 (
m, 7H); 8.09-8.16 (m, 3H); 8.74 (s, 1H); 9.4
4 (bs, 1H). Elemental analysis _{(C 28 H 28 N 6 O} 5), Calculated: C, 63.63;
H, 5.34; N, 15.90, Found: C, 63.80; H, 5.37; N,
15.82.

Example 3 Preparation of 2 ′, 3′-O-isopropylidene-N ^6- (2,4-dichlorobenzyl-carbonylamino) adenosine-5′-N-ethyluronamide Outlined in Example 1. Following the procedure, the title compound was prepared as a white foam in 67% yield. IR (solventless) cm ^-1 3440, 1730, 1625
, 1565, 1210. ¹ HNMR (CDCl ₃ ) δ: 0.82 (t, 3H, J =
7); 1.17 (s, 3H); 1.26 (s, 3H); 2.99-3.13 (m
, 2H); 4.32 (s, 2H); 4.72 (d, 1H, J = 1.8); 5.3.
8-5.48 (m, 2H); 6.16 (d, 1H, J = 1.8); 6.56 (t
, 1H, J = 2); 7.20-7.32 (m, 3H); 7.41 (s, 1H);
8.20 (s, 1H); 8.67 (s, 1H). Elemental analysis value (C ₂₃ H ₂₄ N ₇ O ₅ C
l ₂ ), calculated: C, 57.73; H, 5.06; N, 20.49, found: C
, 57.62; H, 4.99; N, 20.42.

Example 4 Preparation of 2 ′, 3′-O-isopropylidene-N ^6- (4-methoxyphenyl-carbonylamino) adenosine-5′-N-ethyluronamide Following the procedure outlined in Example 1. The title compound was prepared as a white solid in 85% yield. IR (solventless) cm ^-1 3445, 1715, 1640,
1555, 1210. ¹ HNMR (CDCl ₃ ) δ: 0.85 (t, 3H, J = 7
); 1.40 (s, 3H); 1.63 (s, 3H); 3.03-3.12 (m,
2H); 3.90 (s, 3H); 4.72 (d, 1H, J = 2); 5.41-5
． 49 (m, 2H); 6.16 (d, 1H, J = 2); 6.61 (t, 1H, J
= 2); 7.01 (d, 2H, J = 9); 8.02 (s, 2H, J = 9);
10 (s, 1H); 8.74 (s, 1H); 9.09 (bs, 1H). Elemental analysis _{(C 23 H 26 N 6 O} 6), Calculated: C, 57.26; H, 5.43 ; N, 17.4
2, Found: C, 57.15; H, 5.35; N, 17.28.

[0081] Example 5 2 ', 3'-O-isopropylidene-N⁶-(2-chlorophenyl-
Preparation of carbonylamino) adenosine-5'-N-ethyluronamide   Following the procedure outlined in Example 1, the title compound is obtained as a white foam.
It was prepared with a yield of 72%. IR (solventless) cm^-1  3435, 1720, 1620
, 1550, 1230.¹HNMR (CDCl₃) Δ: 0.83 (t, 3H, J =
7); 1.39 (s, 3H); 1.62 (s, 3H); 3.00-3.07 (m
, 2H); 4.71 (d, 1H, J = 2); 5.41-5.44 (m, 2H);
6.18 (d, 1H, J = 2); 6.67 (t, 1H, J = 2); 7.30-7
． 44 (m, 3H); 7.71-7.76 (m, 1H); 8.16 (s, 1H)
8.69 (s, 1H); 10.24 (bs, 1H). Elemental analysis value (C_{twenty two}H_{twenty three}N ₇ O_FiveCl), calculated: C, 52.75; H, 4.63; N, 19.57, found.
: C, 52.59; H, 4.58; N, 19.43.

[0082] Example 6 2 ', 3'-O-isopropylidene-N⁶-(Phenyl-carbonyl
Preparation of Amino) adenosine-5'-N-ethyluronamide   Following the procedure outlined in Example 1, the title compound is converted into a pale yellow foam.
Was prepared with a yield of 90%. IR (solventless) cm^-1  3425, 1730, 164
0,1555,1240.¹HNMR (CDCl₃) Δ: 0.79 (t, 3H, J
= 7); 1.39 (s, 3H); 1.61 (s, 3H); 2.91-3.03 (
m, 2H); 4.71 (d, 1H, J = 2); 5.45-5.52 (m, 2H)
6.18 (d, 1H, J = 2); 6.40 (t, 1H, J = 2); 7.27-
7.53 (m, 3H); 7.83-7.87 (m, 2H); 8.19 (s, 1H
); 8.63 (s, 1H); 9.18 (bs, 1H). Elemental analysis value (C_{twenty two}H_{twenty four}N ₆ O_Five), Calculated: C, 58.40; H, 5.35; N, 18.57, found: C
, 58.23; H, 5.28; N, 18.45.

[0083] Example 7 2 ', 3'-O-isopropylidene--N ⁶ - (substituted - carbonylamino) General procedure 2 for the preparation of adenosine-5'-N-Echiruuronamido', 3'-isopropylidene Ridene- NECA (0.43 mmol) was dissolved in freshly distilled THF (4 ml) and the appropriate isocyanate (1.3 eq) and catalytic amount of triethylamine (2 drops) were added. The mixture under argon atmosphere 1
Refluxed for 8 hours. The solvent was then removed under reduced pressure, the residue was purified by flash chromatography _{(CH 2 Cl 2 -EtOAc20%)} , to give the desired compound.

[0084] Example 8: 2 ', 3'-O- isopropylidene--N ⁶ - according to the procedure outlined in Example 7 of (benzylcarbamoyl amino) adenosine-5'-N-Echiruuronamido the title compound Melting point 109-111
Prepared as a white solid at 0 C in 82% yield. IR (KBr) cm ^-1 344
0,1740,1610,1550,1210. ¹ HNMR (CDCl ₃ ) δ: 0
． 76 (t, 3H, J = 7); 1.21 (s, 3H); 1.63 (s, 3H);
2.96-3.03 (m, 2H); 4.64 (d, 1H, J = 6); 4.71 (
d, 1H, J = 1.8); 5.44-5.48 (m, 2H); 6.16 (d, 1)
H, J = 2); 6.52 (t, 1H, J = 2); 7.26-7.38 (m, 5H
); 8.14 (s, 1H); 8.45 (s, 1H); 8.46 (s, 1H); 9
． 79 (bs, 1H). Elemental analysis _{(C 26 H 31 N 7 O} 5), Calculated: C, 59.8
7; H, 5.99; N, 18.80, Found: C, 60.00; H, 6.03;
N, 18.88.

[0085] Example 9: 2 ', 3'-O- isopropylidene--N ⁶ - procedure outlined in Example 7 of - (4-sulfonamide phenylcarbamoylamino) adenosine-5'-N-Echiruuronamido According to, the title compound was prepared as a white solid, mp 207 ° C., yield 60%. IR (KBr) cm ^-1 3450-32
50, 1730, 1610, 1565, 1360, 1230. ¹ H NMR (CD
Cl ₃ ) δ: 0.57 (t, 3H, J = 7); 1.35 (s, 3H); 1.54
(S, 3H); 2.96-3.03 (m, 2H); 4.60 (d, 1H, J = 2)
); 5.47-5.50 (m, 2H); 6.47 (d, 1H, J = 2); 6.6
0 (t, 1H, J = 2); 7.26 (d, 2H, J = 9); 7.74 (d, 2H)
, J = 9); 8.60 (s, 1H); 8.64 (s, 1H); 9.22 (s, 1)
H); 10.47 (bs, 1H); 12.05 (s, 1H). Elemental analysis _{(C 22 H 26 N 8 O} 7 S), Calculated: C, 48.35; H, 4.79 ; N, 20.50, Found: C, 48.27; H, 4.79 N, 20.63.

[0086] Example 10: 2 ', 3'-O- isopropylidene--N ⁶ - Preparation Example 7 - (4-acetyl-phenylcarbamoylamino) adenosine-5'-N-Echiruuronamido according to the procedure outlined The title compound was prepared as a white solid with a melting point of 204 ° C. in 77% yield. IR (KBr) cm ^-1 3430, 17
40, 1720, 1630, 1545, 1240. ¹ HNMR (CDCl ₃ ) δ:
0.83 (t, 3H, J = 7); 1.42 (s, 3H); 1.64 (s, 3H)
2.61 (s, 3H); 2.99-3.08 (m, 2H); 4.74 (d, 1)
H, J = 2); 5.47-5.55 (m, 2H); 6.21 (d, 1H, J = 2)
); 6.47 (t, 1H, J = 2); 7.74 (d, 2H, J = 9); 7.98
(D, 2H, J = 9); 8.21 (s, 1H); 8.63 (s, 1H); 8.6
7 (bs, 1H); 12.01 (s, 1H). Elemental analysis _{(C 22 H 26 N 8 O} 7),
Calculated: C, 51.36; H, 5.09; N, 21.78, Found: C, 51.
35; H, 5.12; N, 21.66.

[0087] Example 11: 2 ', 3'-O- isopropylidene--N ⁶ - Summary - (carbamoylamino (R)-.alpha.-phenyl-ethyl) Preparation Example 7 of adenosine-5'-N-Echiruuronamido Following the procedure described, the title compound was obtained, mp 110-111
Prepared as a white solid at 0 C in 65% yield. IR (KBr) cm ^-1 343
0, 1730, 1620, 1555, 1230. ¹ HNMR (CDCl ₃ ) δ: 0
． 68 (t, 3H, J = 7); 1.41 (s, 3H); 1.63 (s, 3H);
1.64 (d, 3H, J = 7); 2.87-2.96 (m, 2H); 4.71 (
d, 1H, J = 1.8); 5.16 (m, 1H); 5.48-5.51 (m, 2)
H); 6.16 (d, 1H, J = 2); 6.52 (bs, 1H); 7.25-7
． 408 (m, 5H); 8.15 (s, 1H); 8.51 (s, 1H); 9.8
4 (bs, 1H); 10.94 (s, 1H). Elemental analysis _{(C 23 H 29 N 7 O} 5),
Calculated: C, 57.13; H, 6.05; N, 20.28, Found: C, 57.
01; H, 5.99; N, 20.33.

[0088] Example 12: 2 ', 3'-O- isopropylidene--N ⁶ - a - (carbamoylamino (S)-.alpha.-phenylethyl) Overview in Example 7 of adenosine-5'-N-Echiruuronamido Following the procedure described, the title compound was obtained, mp 109-111
Prepared as a white solid at 0 C in 82% yield. IR (KBr) cm ^-1 344
5, 1725, 1615, 1560, 1230. ¹ HNMR (CDCl ₃ ) δ: 0
． 85 (t, 3H, J = 7); 1.40 (s, 3H); 1.63 (s, 3H);
1.64 (d, 3H, J = 7); 3.00-3.09 (m, 2H); 4.72 (
d, 1H, J = 1.8); 5.17 (m, 1H); 5.39-5.50 (m, 2)
H); 6.14 (d, 1H, J = 2); 6.57 (bs, 1H); 7.26-7
． 45 (m, 5H); 8.12 (s, 1H); 8.51 (s, 1H); 9.81
(Bs, 1H); 10.87 (s, 1H). Elemental analysis _{(C 23 H 29 N 7 O} 5), Calculated: C, 57.13; H, 6.05 ; N, 20.28, Found: C, 57.2
5; H, 6.11; N, 20.37.

[0089] Example 13: 2 ', 3'-O- isopropylidene--N ⁶ - Preparation Example 7 (5-methyl - - isoxazol-3-yl carbamoylamino) adenosine-5'-N-Echiruuronamido Following the procedures outlined, the title compound was prepared as a white solid, mp 120 ° C., yield 83%. IR (KBr) cm ^-1 3450, 17
20, 1620, 1550, 1215. ¹ HNMR (CDCl ₃ ) δ: 0.82 (
t, 3H, J = 7); 1.20 (s, 3H); 1.41 (s, 3H); 2.44
(S, 3H); 3.00-3.07 (m, 2H); 4.74 (d, 1H, J = 2)
); 5.46-5.50 (m, 2H); 6.21 (d, 1H, J = 2); 6.5
5 (t, 1H, J = 2); 6.70 (s, 1H); 8.37 (s, 1H);
63 (s, 1H); 9.39 (bs, 1H); 12.34 (bs, 1H). Elemental analysis _{(C 20 H 24 N 8 O} 6), Calculated: C, 50.84; H, 5.12 ; N, 23
． 72, Found: C, 50.96; H, 5.18; N, 23.64.

[0090] Example 14: 2 ', 3'-O- isopropylidene--N ⁶ - Preparation Example of - (1,3,4-thiadiazol-2-yl carbamoylamino) adenosine-5'-N-Echiruuronamido 7 The title compound was prepared as a yellow solid, mp 148 ° C, in 74% yield, following the procedure as outlined in. IR (KBr) cm ^-1 3430, 17
30, 1615, 1560, 1240. ¹ HNMR (CDCl ₃ ) δ: 0.86 (
t, 3H, J = 7); 1.44 (s, 3H); 1.67 (s, 3H); 3.07
-3.14 (m, 2H); 4.78 (d, 1H, J = 1.8); 4.78 (d,
1H, J = 1.8); 5.47-5.51 (m, 2H); 6.24 (d, 1H,
J = 1.8); 6.52 (t, 1H, J = 2); 8.36 (s, 1H); 8.7
5 (s, 1H); 8.91 (bs, 1H); 9.40 (bs, 1H); 11.7
2 (bs, 1H). Elemental analysis _{(C 18 H 21 N 9 O} 6 S), Calculated: C, 45.47
H, 4.45; N, 26.51, found: C, 45.39; H, 4.44; N.
, 26.46.

[0091] Example 15: 2 ', 3'-O- isopropylidene--N ⁶ - was outlined in - (phenylcarbamoylamino 4-n-propyloxy) Preparation Example 7 of adenosine-5'-N-Echiruuronamido Following the procedure, the title compound was prepared as a pale yellow foam in 70% yield. IR (solventless) cm ^-1 3440, 1725, 16
20, 1555, 1220. ¹ HNMR (CDCl ₃ ) δ: 0.71 (t, 3H,
J = 7); 0.90 (s, 3H, J = 7); 1.40 (s, 3H); 1.62 (
s, 3H); 1.81-2.03 (m, 2H); 2.95-3.01 (m, 2H).
); 3.90 (t, 2H, J = 7); 4.71 (d, 1H, J = 1.8);
46-5.51 (m, 2H); 6.19 (d, 1H, J = 1.8); 6.51 (
t, 1H, J = 2); 6.89 (d, 2H, J = 9); 7.48 (d, 2H, J
= 9); 8.25 (s, 1H); 8.56 (s, 1H); 8.80 (bs, 1H)
); 11.48 (s, 1H). Elemental analysis _{(C 22 H 26 N 7 O} 5), Calculated: C, 5
6.52; H, 5.39; N, 20.97, Found: C, 56.44; H, 5.
42; N, 21.03.

[0092] Example 16: 2 ', 3'-O- isopropylidene--N ⁶ - bis - were outlined in Example 7 of - (4-nitrophenyl carbamoylamino) adenosine-5'-N-Echiruuronamido Following the procedure, the title compound was prepared as a yellow solid, mp 261 ° C. in 65% yield. IR (KBr) cm ^-1 3430, 17
30, 1620, 1555, 1210. ¹ HNMR (DMSOd ₆ ) δ: 0.56
(T, 3H, J = 7); 1.34 (s, 3H); 1.54 (s, 3H); 2.6
7-2.83 (m, 2H); 4.61 (d, 1H, J = 1.8); 5.47-5
． 50 (m, 2H); 6.47 (d, 1H, J = 1.8); 7.61 (t, 1H)
, J = 2); 7.71 (d, 2H, J = 9); 7.91 (d, 2H, J = 9);
8.22 (d, 2H, J = 9); 8.24 (s, 1H); 8.64 (d, 2H,
J = 9); 9.72 (s, 1H); 10.63 (bs, 1H); 12.24 (s
, 1H). Elemental analysis value (C ₂₉ H ₂₈ N ₁₀ O ₁₀ ), calculated value: C, 51.48; H, 4
． 17; N, 20.70, found: C, 51.56; H, 4.16; N, 20.
69.

[0093] Example 17: 2 ', 3'-O- isopropylidene--N ⁶ - bis - Preparation Example of (5-chloro - - pyridin-2-yl carbamoylamino) adenosine-5'-N-Echiruuronamido 7 The title compound was prepared as a yellow foam in 60% yield, following the procedure outlined in. IR (solventless) cm ^-1 3440, 1710, 163
0,1540,1220. ¹ HNMR (CDCl ₃ ) δ: 0.58 (t, 3H, J
= 7); 1.35 (s, 3H); 1.54 (s, 3H); 2.71-2.85 (
m, 2H); 4.60 (d, 1H, J = 2); 5.47-5.51 (m, 2H)
6.47 (d, 1H, J = 2); 7.52 (t, 1H, J = 2); 7.79-
7.92 (m, 4H); 8.34-8.38 (m, 2H); 8.60 (s, 1H)
); 8.65 (s, 1H); 10.66 (bs, 1H); 12.22 (bs, 1)
H). Elemental analysis _{(C 27 H 26 N 8 O} 6 Cl 2), Calculated: C, 51.52; H, 4
． 16; N, 17.80, found: C, 51.55; H, 4.13; N, 17.
84.

[0094] Example 18: N ⁶ - 1NHCl solution General procedure isopropylidene derivatives for the preparation of substituted adenosine-5'-N-Echiruuronamido (0.084 mmol) (5 ml
) And dioxane (5 ml) solution was stirred at 65 ° C. for 1 hour. Then the solvent was removed under reduced pressure and the residue was crystallized from ethanol to give the desired compound.

Example 19: N ^6- (4-biphenyl-carbonylamino) -adenosine-5
Preparation of'-N-Ethyluronamide Following the procedure outlined in Example 18, the title compound was prepared as a white solid, mp 221 ° C, in 65% yield. IR (KBr) cm ^-1 3500-3
100, 1720, 1615, 1550. ¹ HNMR (DMSOd ₆ ) δ: 1.0
7 (t, 3H, J = 7); 3.17-3.24 (m, 2H); 4.23-4.2
5 (m, 1H); 4.36 (d, 1H, J = 2); 4.71-4.73 (m, 1)
H); 5.70 (d, 1H, J = 8); 5.79 (d, 1H, J = 4); 6.1
3 (d, 1H, J = 8); 7.43-7.53 (m, 3H); 7.78-7.8.
9 (m, 4H); 8.16 (d, 2H, J = 11); 8.46 (t, 1H, J =
4); 8.80 (s, 1H); 8.82 (s, 1H); 11.34 (bs, 1H)
). Elemental analysis value (C ₂₅ H ₂₄ N ₆ O ₅ ), calculated value: C, 61.47; H, 4.95;
N, 17.20, Found: C, 61.57; H, 5.00; N, 17.28.

[0096] Example 20: N ⁶ - (2,4- dichlorobenzyl - carbonylamino) - Following the procedure outlined in Example 18 of adenosine-5'-N-Echiruuronamido, the title compound, mp 132 -13
Prepared as a white solid at 4 ° C in 55% yield. IR (KBr) cm ^-1 34
50-3050, 1730, 1635, 1545, 1230. ¹ H NMR (DM
SOd ₆ ) δ: 1.08 (t, 3H, J = 7); 3.18-3.25 (m, 2H)
); 3.34 (s, 2H); 4.12-4.15 (m, 1H); 4.30 (s,
1H); 4.49-4.62 (m, 2H); 5.57 (d, 1H, J = 8); 5
． 77 (d, 1H, J = 4); 5.95 (d, 1H, J = 8); 7.44-7.
51 (m, 3H); 8.19 (s, 1H); 8.39 (s, 1H); 8.95 (
bs, 1H). Elemental analysis _{(C 20 H 20 N 6 O} 5), Calculated: C, 56.60; H,
4.75; N, 19.80, Found: C, 56.60; H, 4.77; N, 19
． 84.

[0097] Example 21: N ⁶ - (4- methoxyphenyl - carbonylamino) - Following the procedure outlined in Example 18 of adenosine-5'-N-Echiruuronamido, the title compound, mp 167-16
Prepared as a white solid at 9 ° C in 80% yield. IR (KBr) cm ^-1 35
50-3150, 1710, 1640, 1530, 1270. ¹ H NMR (DM
SOd ₆ ) δ: 1.07 (t, 3H, J = 7); 3.15-3.23 (m, 2H)
); 3.86 (s, 3H); 4.20-4.24 (m, 1H); 4.35 (d,
1H, J = 2); 4.70-4.75 (m, 1H); 5.69 (d, 1H, J =
7); 5.77 (d, 1H, J = 4); 6.11 (d, 1H, J = 7); 7.0
8 (d, 2H, J = 9); 8.04 (d, 2H, J = 9); 8.44 (bs, 1)
H); 8.77 (s, 1H); 8.78 (s, 1H); 11.12 (s, 1H)
. Elemental analysis _{(C 20 H 22 N 6 O} 6), Calculated: C, 54.30; H, 5.01 ; N
, 18.99, found: C, 54.38; H, 4.98; N, 19.02.

[0098] Example 22: N ⁶ - (4- chlorophenyl - carbonylamino) - Following the procedure outlined in Example 18 of adenosine-5'-N-Echiruuronamido, the title compound, mp 179-18
Prepared as a white solid at 0 ° C in 78% yield. IR (KBr) cm ^-1 35
10-3050, 1720, 1660, 1510, 1250. ¹ H NMR (DM
SOd ₆ ) δ: 1.06 (t, 3H, J = 7); 3.15-3.22 (m, 2H)
); 4.22 (bs, 1H); 4.34 (s, 1H); 4.68-4.70 (m
, 1H); 5.66 (d, 1H, J = 7); 5.76 (d, 1H, J = 4); 6
． 10 (d, 1H, J = 7); 7.43-7.61 (m, 4H); 8.44 (b
s, 1H); 8.67 (s, 1H); 8.82 (bs, 1H); 11.53 (b
s, 1H). Elemental analysis value (C ₁₉ H ₁₉ N ₆ O ₅ ), calculated value: C, 55.47; H, 4
． 66; N, 20.43, found: C, 55.53; H, 4.72; N, 20.
Fifty.

Example 23: N ^6- (phenyl-carbonylamino) -adenosine-5′-N
-Preparation of Ethyluronamide Following the procedure outlined in Example 18, the title compound was obtained, mp 157-15.
Prepared as a white solid at 9 ° C in 67% yield. IR (KBr) cm ^-1 35
00-3000, 1715, 1630, 1535, 1260. ¹ H NMR (DM
SOd ₆ ) δ: 1.03 (t, 3H, J = 7); 3.16-3.19 (m, 2H
); 3.74 (bs, 1H); 4.22 (bs, 1H); 4.36 (s, 1H)
4.51-4.63 (m, 1H); 6.13 (d, 1H, J = 6.8);
48-7.59 (m, 3H); 8.04-8. 11 (m, 2H); 8.52 (b
s, 1H); 8.79 (s, 1H); 8.83 (s, 1H); 11.22 (s,
1H). Elemental analysis value (C ₁₉ H ₂₀ N ₆ O ₅ ), calculated value: C, 55.34; H, 4.8
9; N, 20.38, found: C, 55.47; H, 4.93; N, 20.43.
.

[0100] Example 24: N ⁶ - (benzylcarbamoyl amino) - adenosine-5'-N
Preparation of Ethyluronamide Following the procedure outlined in Example 18, the title compound was obtained, mp 184-18.
Prepared as a white solid at 6 ° C. in 70% yield. IR (KBr) cm ^-1 35
00-3100, 1675, 1620, 1565, 1520, 1310. ¹ HN
MR (DMSOd ₆ ) δ: 1.06 (t, 3H, J = 7); 3.10-3.20
(M, 2H); 4.05 (bs, 1H); 4.17-4.20 (m, 1H); 4
． 36 (s, 1H); 4.47-4.50 (m, 2H); 4.55-4.65 (
m, 1H); 6.05-6.10 (m, 1H); 7.17-7.40 (m, 5H
); 8.30-8.40 (m, 1H); 8.62 (s, 1H); 8.86 (s,
1H); 9.50-9.60 (m, 1H); 10.30 (bs, 1H). Elemental analysis _{(C 20 H 24 N 7 O} 5), Calculated: C, 54.29; H, 5.47 ; N, 22.
16, Found: C, 54.36; H, 5.52; N, 22.08.

[0102] Example 25: N ⁶ - (4- sulfonamide - phenylcarbamoyl) - Following the procedure outlined in Example 18 of adenosine-5'-N-Echiruuronamido, the title compound, mp 183-18
Prepared as a white solid at 5 ° C. in 63% yield. IR (KBr) cm ^-1 35
50-3050, 1715, 1630, 1545, 1370, 1250. ¹ HN
MR (DMSOd ₆ ) δ: 1.07 (t, 3H, J = 7); 3.16-3.26
(M, 2H); 4.21 (bs, 1H); 4.36 (s, 1H); 4.63-4
． 69 (m, 1H); 5.62 (d, 1H, J = 6.8); 5.78 (d, 1H)
, J = 4); 6.11 (d, 1H, J = 6.8); 7.31 (bs, 2H); 7
． 81 (s, 4H); 8.49 (bs, 1H); 8.75 (s, 1H); 8.8
9 (s, 1H); 9.69 (bs, 1H); 11.92 (bs, 1H). Elemental analysis value (C ₁₉ H ₂₂ N ₈ O ₇ S), calculated value: C, 45.06; H, 4.38; N, 22
． 12, Found: C, 45.15; H, 4.36; N, 22.07.

Example 26: N ^6- (4-Acetyl-phenylcarbamoyl) -adenosine-
Preparation of 5′-N-Ethyluronamide Following the procedure outlined in Example 18, the title compound was prepared as a white solid, mp 187 ° C., yield 83%. IR (KBr) cm ^-1 3550-3
100, 1740, 1720, 1630, 1525, 1215. ¹ H NMR (D
2. MSOd ₆ ) δ: 1.08 (t, 3H, J = 7); 2.55 (s, 2H);
16-3.23 (m, 2H); 4.18-4.20 (m, 1H); 4.21 (d
, 1H, J = 2); 4.45 (bs, 1H); 4.64-4.69 (m, 1H).
6.11 (d, 1H, J = 7); 7.77 (d, 2H, J = 9); 7.98 (
d, 2H, J = 9); 8.49 (bs, 1H); 8.76 (s, 1H); 8.8
8 (s, 1H); 10.62 (bs, 1H); 11.94 (bs, 1H). Elemental analysis _{(C 21 H 23 N 7 O} 6), Calculated: C, 53.73; H, 4.94 ; N, 20
． 89, found: C, 53.80; H, 4.95; N, 20.93.

[0103] Example ^{27: N 6 - ((R} ) -α- phenyl ethylcarbamoyl) - Following the procedure outlined in Example 18 of adenosine-5'-N-Echiruuronamido, the title compound, mp 153 -15
Prepared as a white solid at 5 ° C. in 65% yield. IR (KBr) cm ^-1 35
50-3100, 1720, 1635, 1535, 1240. ¹ H NMR (DM
SOd ₆ ) δ: 1.05 (t, 3H, J = 7); 1.51 (d, 3H, J = 8)
3.14-3.21 (m, 2H); 3.35-3.41 (m, 1H); 4.2
0 (s, 1H); 4.36 (s, 1H); 4.93-5.00 (m, 3H); 6
． 09 (d, 1H, J = 6.8); 7.25-7.39 (m, 5H); 8.48
(Bs, 1H); 8.65 (s, 1H); 8.89 (s, 1H); 9.51 (b
s, 1H); 10.38 (bs, 1H). Elemental analysis _{(C 21 H 26 N 7 O} 5), Calculated: C, 53.50; H, 5.34 ; N, 20.80, Found: C, 53.55
H, 5.38; N, 20.85.

Example 28: Preparation of N ⁶ -((S) -α-phenylethylcarbamoyl) -adenosine-5′-N-ethyluronamide Following the procedure outlined in Example 18, the title compound was obtained, mp 151 Prepared as a white solid at 0 C in 72% yield. IR (KBr) cm ^-1 3550-3
100, 1725, 1630, 1525, 1240. ¹ HNMR (DMSOd ₆ )
δ: 1.06 (t, 3H, J = 7); 1.49 (d, 3H, J = 8); 3.15
-3.21 (m, 2H); 3.28-3.39 (m, 1H); 4.00 (bs,
1H); 4.35 (s, 1H); 4.61-4.66 (m, 1H); 4.95-
5.01 (m, 1H); 6.07 (d, 1H, J = 6.8); 7.24-7.3
9 (m, 5H); 8.48 (bs, 1H); 8.64 (s, 1H); 8.83 (
s, 1H); 9.57 (bs, 1H); 10.12 (bs, 1H). Elemental analysis _{(C 21 H 25 N 7 O} 5), Calculated: C, 53.50; H, 5.34 ; N, 20.80
Found: C, 53.44; H, 5.34; N, 20.77.

[0105] Example 29: N ⁶ - The procedure was followed as outlined in Example 18 of adenosine-5'-N-Echiruuronamido, the title compound - (5-methyl - 3-yl - carbamoyl) Was prepared as a white solid with a melting point of 197 ° C. in a yield of 58%. IR (KBr) cm ^-1 3550-3
050, 1715, 1620, 1535, 1240. ¹ HNMR (DMSOd ₆ )
δ: 1.06 (t, 3H, J = 7); 2.40 (s, 3H); 3.12-3.2
5 (m, 2H); 4.21-4.23 (m, 1H); 4.36 (d, 1H, J =
2); 4.64-4.70 (m, 1H); 5.68 (m, 2H); 6.09 (d
, 1H, J = 6.8); 6.67 (s, 1H); 8.46 (t, 1H, J = 6)
8.74 (s, 1H); 8.84 (s, 1H); 10.75 (bs, 1H);
12.19 (bs, 1H). Elemental analysis value (C ₁₇ H ₂₀ N ₈ O ₆ ), calculated value: C, 47
． 22; H, 4.66; N, 25.91, found: C, 47.14; H, 4.6.
9; N, 25.96.

[0106] Example 30: N ⁶ - (1,3,4- thiadiazol-2-yl - carbamoyl) - Following the procedure outlined in Example 18 of adenosine-5'-N-Echiruuronamido the title compound Was prepared as a white solid with a melting point of 197 ° C. in a yield of 65%. IR (KBr) cm ^-1 3450-3
100, 1720, 1635, 1515, 1240. ¹ HNMR (DMSOd ₆ )
δ: 1.06 (t, 3H, J = 7); 3.15-3.22 (m, 2H); 3.7
2 (bs, 2H); 4.21-4.24 (m, 1H); 4.36 (d, 1H, J
= 2); 4.65-4.70 (m, 1H); 6.12 (d, 1H, J = 6.8)
8.45 (t, 1H, J = 7); 8.80 (s, 1H); 8.89 (s, 1H)
); 9.19 (s, 1H); 10.35 (bs, 1H); 11.38 (bs, 1)
H). Elemental analysis value (C ₁₅ H ₁₇ N ₄ O ₅ S), calculated value: C, 49.31; H, 4.6
9; N, 15.33, found: C, 49.22; H, 4.72; N, 15.33.
.

[0107] Example 31: N⁶-(4-n-propoxy-phenylcarbamoyl) -adeno
Preparation of syn-5'-N-ethyluronamide   Following the procedure outlined in Example 18, the title compound is prepared in mp 270 ° C. white.
Prepared as a colored solid in 66% yield. IR (KBr) cm^-1  3450-3
050, 1720, 1630, 1535, 1240.¹HNMR (DMSOd₆)
δ: 0.95 (t, 3H, J = 7); 1.09 (t, 3H, J = 7); 1.65
-1.75 (m, 2H); 3.06-3.23 (m, 2H); 3.67 (bs,
2H); 3.89 (t, 2H, J = 7); 4.18-4.20 (m, 1H); 4
． 33 (s, 1H); 4.51-4.61 (m, 1H); 6.05 (d, 1H,
J = 6.8); 6.91 (d, 2H, J = 9); 7.52 (d, 2H, J = 9)
7.92 (t, 1H, J = 7); 8.22 (s, 1H); 8.52 (s, 1H
); 9.65 (bs, 1H); 11.52 (bs, 1H). Elemental analysis value (C_{twenty two}H ₂₇ N₇O₆), Calculated: C, 5.61; H, 5.61; N, 20.19, found:
C, 54.50; H, 5.66; N, 20.06.

[0108] Example 32: N⁶-Bis- (4-nitrophenylcarbamoyl) -adenosine
Preparation of -5'-N-ethyluronamide   Following the procedure outlined in Example 18, the title compound is obtained in white, mp 213 ° C.
Prepared as a colored solid in 52% yield. IR (KBr) cm^-1  3500-3
050, 1720, 1630, 1545, 1340, 1220.¹HNMR (D
MSOd₆) Δ: 1.07 (t, 3H, J = 7); 3.12-3.23 (m, 2)
H); 4.21-4.23 (m, 1H); 4.35 (d, 1H, J = 2);
64-4.69 (m, 1H); 5.69 (bs, 2H); 6.09 (d, 1H,
J = 6.8); 7.68 (d, 2H, J = 9); 7.91 (d, 2H, J = 9)
8.18-8.29 (m, 4H); 8.83 (s, 1H); 9.69 (s, 1)
H); 10.68 (bs, 1H); 12.26 (bs, 1H). Elemental analysis value (C ₂₆ H₂₉N_TenO_Ten), Calculated: C, 48.67; H, 4.56; N, 21.83,
Found: C, 48.74; H5 4.60; N5 21.88.

[0109] Example 33: N ⁶ - bis - (5-chloro - pyridin-2-yl - carbamoyl) - Following the procedure outlined in Example 18 of adenosine-5'-N-Echiruuronamido the title compound Was prepared as a white solid with a melting point of 220 ° C. in a yield of 68%. IR (KBr) cm ^-1 3550-3
100, 1725, 1630, 1525, 1250. ¹ HNMR (DMSOd ₆ )
δ: 1.06 (t, 3H, J = 7); 3.15-3.22 (m, 2H); 4.2
2-4.24 (m, 1H); 4.36 (d, 2H, J = 2); 4.64-4.6.
9 (m, 1H); 5.95 (bs, 2H); 6.10 (d, 1H, J = 6.8)
7.80-8.06 (m, 6H); 8.39 (t, 1H, J = 7); 8.76
(S, 1H); 8.93 (s, 1H); 10.39 (bs, 1H); 12.11
(Bs, 1H). Elemental analysis value (C ₂₄ H ₂₂ N ₈ O ₆ Cl ₂ ), calculated value: C, 48.9
1; H, 3.76; N, 19.01, found: C, 49.01; H, 3.77;
N, 18.89.

Example 34. Binding Assays Methods of ^Performing Receptor Binding Assays Methods for preparing rat brain membranes and Chinese hamster ovary (CHO) cell membranes have been reported ^30,38,44 . For binding experiments, the membrane homogenate was frozen and stored at -20 ° C for more than 2 months. Adenosine deaminase (ADA) is Boehr
purchased from Inger Mannheim (Indianapolis, Ind.), [ ³ H] R-PIA was purchased from Amersham (Arlington Height).
s, IL), and [ ³ H] CGS21680 is a DuPont NE.
Purchased from N (Boston, MA). [ ¹²⁵ I] -AB-MECA is Ola
Prepared as described by h et al. ³⁰ .

[0111]   [¹²⁵I] -AB-MECA of rat A₃Stable transfer of receptor clones
CHO cells or human A₃HEK-293 stably expressing the receptor
Binding to cells was performed essentially as described^28,30,38,44. A
The assay was performed with 100 μl of the membrane suspension, [¹²⁵I] -AB-MECA (final concentration 0.3
nM) 50 μl, and 50 mM Tris / 10m containing 50 μl inhibitor
M MgCl₂With 1 mM EDTA buffer (pH adjusted to 8.26 at 5 ° C)
, Made in a glass tube. Inhibitors were dissolved in DMSO by conventional methods.
The concentration of DMSO during the incubation did not exceed 1%; this concentration was [^{12 Five} It did not affect the binding of [I] -AB-MECA. 1 hour incubation
, 37 ° C., and the Brandell cell harvester (
Brandm, Gaithersburg, MD)
It was stopped by rapid filtration with an GF / B filter. Tube
It was washed 3 times with 3 mL of stuffer. Radioactivity is Beckman gamma 550
It was measured with a 0Bγ counter.

Non-specific binding was measured in the presence of 200 μM NECA. Ki value is 1.48
Cheng-Prusof, assuming a K _{d of} nM [ ¹²⁵ I] -AB-MECA.
Calculated according to f ⁴⁵ . [ ³ H] R- for A ₁ receptors from rat cortical membranes
Binding of PIA and [ ³ H] C to A _2A receptor on rat striatal membrane
Coupling of GS21680 was performed as described ⁴⁶ . Adenosine deaminase (
2 units / mL) was present during membrane preparation. No additional deaminase was added during the incubation with the radioligand.

[ ³⁵ S] GTP-y-S Binding [ ³⁵ S] GTP-y-S (Amersham, Chicago IL, specific activity 1275 Ci / mmole) was bound to the rat by the general method ⁴⁷ of Lorenzen et al. It was performed using RBL-2H3 mast cells. The membrane is 50 mM Tris,
Adenosine deaminase was suspended in a buffer containing 3 units / mL of adenosine deaminase, 100 mM NaCl, and 10 mM MgCl ₂ (pH 7.4) and a concentration of protein of 1 to 10 μg per tube. Membrane suspensions were prepared in 10 GDP, R-PIA and / or riboflavin in a final volume of 125 μL buffer at 30 ° C., 60 ° C.
Pre-incubated for 1 minute, transferred to ice and left for 20 minutes. [ ³⁵ S] GTP-γ-S was added to a final concentration of 0.1 nM in a total volume of 500 μL and the mixture was incubated for 3 minutes for 3 min.
Incubated at 0 ° C. Non-specific binding is 10 μM GT-γ-S (Si
gma, St. Quantification in the presence of Louis MO). The reaction mixture was incubated using a Brandell cell harvester using GF / B.
It was stopped by a glass filter and washed with the same buffer.

[0114]Results and discussion   Using the derivatives 3a-o (compounds of Examples 19-33, described in order), rat brain A ₁ , A_2AAnd A₃Affinity at receptor tested by radioligand binding assay
The results obtained are summarized in Table 1.

[0115]

[Table 1]

[0116]

[Table 2]

[0117]

[Table 3]

[0118] As Baradldi revealed certain N ⁶ - substituted - arylcarbamoyl - adenosine - Uronamido is a full agonist to inhibit adenylate cyclase through the rat A ₃ receptor, the compounds adenosine A ₁ It showed relatively high activity for the receptor ³⁹ . There are similarities between the A ₁ and A ₃ receptors. By slightly changing the chain length at the N ⁶ -position, the affinity for the A ₁ or A ₃ receptors can be changed. This bond data is N ⁶ −
Or alkaryl - - presence of carbamoyl chain, to bring the interaction between the A ₃ receptor subtype, it has revealed the aryl in position. The data also reveal that substitution with heteroaryl-carbamoyl, heteroaryl-carboxamide, aryl-carboxamide, and alkaryl-carboxamide at the N ⁶ -position results in an interaction with the A ₁ receptor subtype. There is.

[0119]   In the series of urea derivatives (compound 3f-o), the substituted phenyl group (compound
3g, h and m) or a substituted benzyl group (compounds 3f, i and j) is A ₁ And A₂A compared to its affinity for the receptor₃To adenosine receptors
Leads to a relatively high affinity and selectivity.

Derivatives 3g, 3h and 3m showed relatively high affinity at the A ₃ receptor (9.7-107 nM) with varying degrees of A ₃ / A ₁ selectivity. In particular, compound 3g is less active than IB-MECA (9.7 nM vs. 1.1 nM), but is comparable to IB-MECA at either A ₃ vs. A ₁ or A _2A receptors,
Showed selectivity for.

Compound 3g also showed a relatively high affinity at the human A ₃ adenosine receptor, within the nanomolar range (56.1 ± 9.1 nM), regardless of species It was confirmed that it has a relatively high affinity for the receptor. Lipophilic para substituents on the phenyl ring, plays a prominent role in A ₃ affinity.

Substitution of the phenyl ring with a heterocycle (as in compound 3k-1) is accomplished by substitution of A _{3 of} the compound
It loses its affinity and selectivity for the receptor, causing increased affinity for the A ₁ receptor subtype.

A 2-substitution at the N ⁶ -position (eg compound 3n-o) diminishes activity at the A _2A and A ₃ receptors, but has a relatively high affinity for the A ₁ receptor. .

In the benzylic series, compounds 3f, i, and j exhibited SAR patterns comparable to the phenyl series of Baraldi ³⁹ . In fact, unsaturated compound 3f showed affinity and selectivity at the A ₃ receptor very similar to previously reported phenyl derivatives.

The stereochemistry of the N ⁶ -position substituents is also important in determining the affinity of these compounds for the A ₃ receptor. For example, comparing two diastereomeric compounds 3i and 3j with the N ⁶ -position substituents in opposite configurations, the R-isomer (3i) shows that in the rat A ₃ adenosine receptor subtype, S- It is more potent and selective than the isomer (3j). Those skilled in the art will use conventional enantiomeric purification methods to separate compounds with the stereocenter adjacent to the N ⁶ -position, and
Only routine experimentation can be used to evaluate individual stereoisomers for their affinity and selectivity.

In a functional group assay, compound 3g was shown to act as a full agonist on the rat A ₃ receptor. Assay, guanine nucleotides, and A ₃ receptors on rat RBL-2H3 mast cells membranes containing a high density, comprising the agonist-induced inhibition of binding.

FIG. 1 shows that compound 3g was shown to be a potent A ₃ agonist, I-AB-MECA and Cl-IB-MECA, with approximately [ ³⁵ S] GTP-γ-S binding increasing in a dose-dependent manner. It was shown to be equally effective and had a greater titer than NECA.

[0128]   Example 35. Pharmaceutical formulation   (A) Transdermal system-for 1000 patches

[Table 4]

The silicone fluid and the active compound are mixed with one another and colloidal silicon dioxide is added to increase the viscosity. This material is then added to the final heat sealed polymer laminate including: Polyester Release Liner- (po
Lyster release liner), skin contact adhesives made of silicone or acrylic polymers, polyolefin control membranes, and impermeable backing membranes made of polyester multilayer laminates. The resulting laminated sheet is then cut into 10 square centimeter patches.

[0130]   (B) Oral tablets-for 1000 tablets

[Table 5]

The active compound and starch are granulated with water and dried. Magnesium stearate is added to the dried granules and the mixture is mixed thoroughly. The compounded mixture is compressed into tablets.

[0132]   (C) Injection-1mL ampoule, for 1000 ampoule

[Table 6]

The active compound and buffer are dissolved in polyethylene glycol at about 50 ° C. Water for injection is then added with stirring and the resulting solution is filtered, filled into ampoules, sealed and sterilized in an autoclave.

[0134]   (D) Continuous injection-for 1000 mL

[Table 7]

References: The following references were referenced here. These documents are incorporated herein by reference in their entirety.

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2. Machhout, C.I. Sande, J .; V. Libert, F .; ;
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Definition of subclasses of adenosine
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-Alkyladenosine-5'-uronamides: bifunc
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One skilled in the art can recognize and ascertain many equivalents to the particular embodiments of the invention described herein using only routine experimentation. Such equivalents are intended to be covered by the following claims.

[Brief description of drawings]

FIG. 1 shows various adenosine agonists, 5 ′-(N-ethylcarboxamide).
Adenosine (NECA), N ⁶ - sulfonamide - phenylcarbamoyl) adenosine-5'-N-Echiruuronamido, 2-chloro -N ⁶ - (3- iodobenzyl) adenosine-5'-N-Mechiruuronamido (CI-IB-MECA ), And N ^6- (4-amino-3-iodobenzyl) adenosine-5′-N-methyluronamide (I-AB-MECA) against [ ³⁵ S] GTP-γ on RBL-2H3 rat mast cell membranes. 7 is a graph showing the effect of the combination of —S.

[FIG. 2A]   2A is a reaction scheme for making compounds of Formula I. FIG.

FIG. 2B   FIG. 2B is a reaction scheme for making compounds of Formula I.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/14 A61P 9/14 11/16 11/16 25/04 25/04 25/08 25/08 25 / 28 25/28 27/06 27/06 29/00 29/00 35/00 35/00 C07H 19/167 C07H 19/167 19/173 19/173 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AL, AM, AT, AU, AZ, BA, B , BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE , SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW F term (reference) 4C057 BB02 CC03 DD01 LL41 LL42 4C086 AA01 AA02 AA03 BA03 CB07 EA11 GA02 GA06 MA01 NA14 ZA04 ZA15 ZA33 ZA36 ZA42 ZB11 ZB26 ZC35

Claims (28)

[Claims] 1. A compound of the following formula: Wherein R is hydrogen, alkyl, substituted alkyl, alkaryl or aryl; R ¹ is heteroaryl-NR-C (X), heteroaryl-C (X)-, alkaryl-NR-C. (X)-, substituted alkaryl-NR-C (X)-, aryl-NR-C (X)-, aryl-C (X)-, alkaryl-C (X)-, or substituted alkaryl-C. (X) -, R ² is hydrogen, alkyl, substituted alkyl, alkaryl or aryl -NH
—C (X) —, R ³ and R ⁴ are independently hydroxy, hydrogen, halo, ether, azide, alkyl, alkoxy, carboxy, nitrile, nitro, trifluoro, aryl, alkaryl, thio, thioester, thioether, Selected from the group consisting of amines and amides, and X is O, S or NR, wherein R ² is H and R ¹ is aryl-NH—C (X)
When -and X are O, the substituents on the aryl ring are not halo, methoxy or trifluoromethyl. 2. The compound according to claim 1, wherein R is hydrogen. 3. The compound according to claim 1, wherein R ¹ is alkaryl-NR-C (X)-. 4. The compound according to claim 1, wherein R ¹ is a substituted alkaryl-NR-C (X)-. 5. The compound according to claim 1, wherein R ¹ is aryl-NR-C (X)-. 6. The compound according to claim 1, wherein R ¹ is aryl-C (X)-. 7. The compound according to claim 1, wherein R ¹ is alkaryl-C (X)-. 8. The compound of claim 1, wherein R ¹ is a substituted alkaryl-C (X)-. 9. R ¹ is heteroaryl-NR—C (X) —.
The described compound. 10. The compound of claim 1, wherein R ¹ is heteroaryl-C (X)-. 11. The compound according to claim 1, wherein R ² is hydrogen. 12. The compound according to claim 1, wherein X is O. 13. N ^6- (4-Biphenyl-carbonylamino) -adenosine-5′-N-ethyluronamide, N ^6- (2,4-dichlorobenzyl-carbonylamino) -adenosine-5 ′.
-N- Echiruuronamido, N ⁶ - (4-methoxyphenyl - carbonylamino) - adenosine-5'-N
- Echiruuronamido, N ⁶ - (4-chlorophenyl - carbonylamino) - adenosine-5'-N-
Echiruuronamido, N ⁶ - (phenyl - carbonylamino) - adenosine-5'-N-Echiruuronamido, N ⁶ - (benzyl - carbamoylamino) - adenosine-5'-N-Echiruuronamido, N ⁶ - (4-sulfonamide - phenyl Carbamoyl) -adenosine-5'-
N- Echiruuronamido, N ⁶ - (4-Acetyl - phenylcarbamoyl) - adenosine-5'-N- ^{Echiruuronamido, N 6 - ((R)} -α- phenyl ethylcarbamoyl) - adenosine-5'-N
- ^{Echiruuronamido, N 6 - ((S)} -α- phenyl ethylcarbamoyl) - adenosine-5'-N
- Echiruuronamido, N ⁶ - (5-methyl - 3-yl - carbamoyl) - adenosine-5'-N-Echiruuronamido, N ⁶ - (1,3,4-thiadiazol-2-yl - carbamoyl) - adenosine -5'-N-Echiruuronamido, N ⁶ - (4-n- propoxy - phenylcarbamoyl) - adenosine-5'-
N- Echiruuronamido, N ⁶ - bis - (4-nitro-phenylcarbamoyl) - adenosine-5'-N-
Echiruuronamido, and N ⁶ - bis - (5-chloro - pyridin-2-yl - carbamoyl) - adenosine-5'-N-Echiruuronamido, selected from the group consisting of compounds. 14. tumor, treating hypertension, mast cell degranulation, or cardiac hypoxia, or take preventative against cerebral ischemia, a method, to a patient in need of such treatment, A ₃ A method comprising administering an effective amount of a compound according to claim 1 which is an agonist or partial agonist of the receptor. 15. The method of claim 14, wherein R is hydrogen. 16. The method according to claim 1, wherein R ¹ is alkaryl-NR-C (X)-.
4. The method described in 4. 17. The method of claim 14, wherein R ¹ is a substituted alkaryl-NR-C (X)-. 18. The method of claim 14, wherein R ¹ is aryl-NR—C (X)-. 19. The method of claim 14, wherein R ² is hydrogen. 20. The method of claim 14, wherein X is O. 21. The compound is N ^6- (benzylcarbamoylamino) -adenosine-5′-N-ethyluronamide, N ^6- (4-sulfonamido-phenylcarbamoyl) -adenosine-5′-.
N- Echiruuronamido, N ⁶ - (4-Acetyl - phenylcarbamoyl) - adenosine-5'-N- ^{Echiruuronamido, N 6 - ((R)} -α- phenyl ethylcarbamoyl) - adenosine-5'-N
- ^{Echiruuronamido, N 6 - ((S)} -α- phenyl ethylcarbamoyl) - adenosine-5'-N
- Echiruuronamido, N ⁶ - (4-n- propoxy - phenylcarbamoyl) - adenosine-5'-
N- Echiruuronamido, and N ⁶ - bis - (4-nitro-phenylcarbamoyl) - adenosine-5'-N-
15. The method of claim 14, selected from the group consisting of ethyluronamide. 22. Prevention against hypoxia, prevention of ischemia-induced damage, cardioprotection, neuroprotection, pain management, reduction of free fatty acids, triglycerides or glucose levels, adjunctive therapy for diabetes, adenosine sensitive cardiac non-. A method of providing treatment of arrhythmia, treatment of GI disorders, treatment of convulsions, treatment of glaucoma; treatment of sleep apnea, treatment of paroxysmal supraventricular tachycardia, or treatment of inflammation, said treatment. To a patient in need thereof of a compound of formula I that is active as an agonist or partial agonist of the A ₁ receptor, which is effective for treating the disorder. 23. The method of claim 23, wherein R ¹ is aryl-C (X)-. 24. The method of claim 23, wherein R ¹ is alkaryl-C (X)-. 25. The method of claim 23, wherein R ¹ is a substituted alkaryl-C (X)-.
The method described. 26. The method of claim 23, wherein R ¹ is heteroaryl-NR—C (X)-. 27. The method of claim 23, wherein R ¹ is heteroaryl-C (X)-. 28. The compound is N ^6- (4-biphenyl-carbonylamino) -adenosine-5′-N-ethyluronamide, N ^6- (2,4-dichlorobenzyl-carbonylamino) -adenosine-5 ′.
-N- Echiruuronamido, N ⁶ - (4-methoxyphenyl - carbonylamino) - adenosine-5'-N
- Echiruuronamido, N ⁶ - (4-chlorophenyl - carbonylamino) - adenosine-5'-N-
Echiruuronamido, N ⁶ - (phenyl - carbonylamino) - adenosine-5'-N-Echiruuronamido, N ⁶ - (5-methyl - 3-yl - carbamoyl) - adenosine-5'-N-Echiruuronamido, N ⁶ - (1,3,4-thiadiazol-2-yl - carbamoyl) - adenosine-5'-N-Echiruuronamido, and N ⁶ - bis - (5-chloro - pyridin-2-yl - carbamoyl) - adenosine 5 ' 24. The method of claim 23, selected from the group consisting of: -N-ethyluronamide.