CA2093502C - Hydrazoadenosines - Google Patents
Hydrazoadenosines Download PDFInfo
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- CA2093502C CA2093502C CA002093502A CA2093502A CA2093502C CA 2093502 C CA2093502 C CA 2093502C CA 002093502 A CA002093502 A CA 002093502A CA 2093502 A CA2093502 A CA 2093502A CA 2093502 C CA2093502 C CA 2093502C
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- linear
- amino
- branched alkyl
- ribofuranosyl
- purine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention discloses a compound of the formula:
(see formula one) where R1 is hydrogen or the group -C(R3)(R5)-R4, where R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl or phenyl, C2 to C10 aralkyl, C4 to C8 heteroaryl wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R2 is hydrogen, or taken together with R5, forms a chemical bond, and R is a monosaccharide radical selected from the group consisting essentially of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose. The compounds prepared by the present invention are therapeutically effective adenosine receptor agonists in mammals. Thus, they are effective for treating conditions which respond to selective adenosine A2 receptor stimulation (particularly adenosine-2). Accordingly, the compounds of the present invention are useful for treating hypertension, thrombosis and atherosclerosis and for causing coronary vasodilation.
(see formula one) where R1 is hydrogen or the group -C(R3)(R5)-R4, where R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl or phenyl, C2 to C10 aralkyl, C4 to C8 heteroaryl wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R2 is hydrogen, or taken together with R5, forms a chemical bond, and R is a monosaccharide radical selected from the group consisting essentially of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose. The compounds prepared by the present invention are therapeutically effective adenosine receptor agonists in mammals. Thus, they are effective for treating conditions which respond to selective adenosine A2 receptor stimulation (particularly adenosine-2). Accordingly, the compounds of the present invention are useful for treating hypertension, thrombosis and atherosclerosis and for causing coronary vasodilation.
Description
2~~~~~~
IiYD~I4ZZOL~DENOS I N ES
The present invention relates to the synthesis and utility of 2-substituted adenosines. More particularly, this invention relates to the preparation of 2-hydrazeno adenosines and their use as AZ receptor agonists.
Adenosine (9-~-D-ribofuranosyl-9H-purin-6-amine) was characterized in the late '20s as having hypotensive and bradycardia activity. Since then, considerable research in the molecular modification of adenosine has led to the general conclusion that cardiovascular activity is limited to analogs having intact purine and ,e-ribofuranosyl rings.
1 o Further research more clearly defined how the activity of these adenosine analogs affected the purinergic receptors in peripheral cell membranes, particularly the A1 and AZ receptors.
High selectivity combined with significant affinity at the AZ receptor in rat membranes was observed for certain adenosine amines bearing a two-carbon chain i5 to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethyl amino)adenosine, a 14-fold AZ selective compound, was modified by introduction of a variety of substituents in the benzene ring and in the side chain. Some of these changes led to improved AZ affinity and increased selectivity. Replacement of the phenyl moiety by a cyclohexenyl group produced a 210-fold selective agonist, whereas 2 o the cyclohexanyl analog was S30-fold selective at the AZ site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists. See Francis et al., ~, Med.
Chem., ~4 2570-2579 (1991).
A series of 2-alkoxyadenosines were prepared and tested for agonist activity 2 5 at the A1 and AZ adenosine receptors of the atrioventricular node and coronary arteries (vasodilation). Activities at the A1 receptor site were low and did not show a clear relationship to the size or hydrophobicity of the C-2 substituent. All the analogs were more potent at the AZ receptor, activity varying directly with the size and hydrophobicity of the alkyl group. The most potent analog in this series, 2-(2 2~~a~~3 cyclohexylethoxy)adenosine, had an ECso of 1 nM for coronary vasodilation and was 8700-fold selective for the A2 receptor. See Ueeda et al., 3. Med. Chem., 34 (4) 1334-1339 (1991).
It has now been discovered that 2-hydrazono-adenosines display superior selectivity as coronary vasodilators and AIAR agonists.
The compounds of the present invention have the following formula:
R~ N~ ~ N\ I
N ~ i /N
2 \NH N
R
where R1 is hydrogen or the group -C(R3)(RS)-R4, where R3 and R4 are the same or different and are hydrogen, Cl to C12 linear or branched alkyl, C3 to C~
cycloalkyl, C6 to Clo aryl unsubstituted or substituted with Cl to C6 linear or branched alkyl, Cl to C6 linear or branched alkoxy, vitro, amino, amino substituted with at least one Cl to C6 linear or branched alkyl or phenyl, CZ to Clo aralkyl, C4 to C$ heteroaryl wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and RZ is hydrogen, or taken together with R5, forms a chemical bond, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose.
In the compounds of the present invention, it is preferred that Rl is -C(R3)(RS-R4, where RZ is taken together with RS to form a chemical bond, i.e., the preferred compounds of the present invention are those of the formula:
_2_ NHZ
N
R3 ~ ~ ~> I I
\C ~N~N N N
H R
Ra where R1, R3 and Ra are defined above.
In the compounds of formula II, it is preferred that Ra is hydrogen or ethyl.
We have made and tested SHA-202, in which R3 = Ra = ethyl and R3 is ethyl, C3 to C~ cycloalkyl (e.g., cyclohexyl), C6 and Clo aryl unsubstituted (phenyl, 1-naphthyl or 2-naphthyl) or substituted with at least one Cl to C6 linear or branched alkyl (4-methyl or 3-methyl), halogen (chloro, fluoro, bromo), Cl to C6 linear or branched alkoxy (4-methoxy or 3-methoxy), vitro (4-vitro or 3-vitro), amino (4-amino or amino) or Ca to Cg heteroaryl where the heteroatom is nitrogen or sulfur (2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiophenyl).
l0 The following are illustrative of the compounds of the present invention:
6- -amino-2-{2-[(2-naphthyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(3-methylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(2-pyridyl)methylene]diazanyl }-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(4-chlorophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(1-naphthyl)methyleve]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6- -amino-2-diazanyl-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-((4-fluorophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(2-thienyl)methylene]diazanyl }-9-(p-D-ribofuranosyl )-9H-purine;
6- -amino-2-{2-[(4-methylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[1-(4-fluorophenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-[2-{phenylmethylene)diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(cyclohexyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-nitrophenyl))methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(3-aminophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(3-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-aminophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[1-(phenyl)ethylidene]diazanyl}-9-(a-D-ribofuranosyl)-9H-purine;
b-amino-2-{2-[(4-methoxyphenyl)methylene]diazanyl}-9-(a-D-ribofuranosyl)-9H-purine;
l0 6- -amino-2-{2-[(3-nitrophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(6-methoxy-2-naphthyl)methylene]diazanyl}-9-(,0-D-ribofuranosyl)-purine;
6-amino-2-{2-[(2,3-dimethylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-91,~-I-purine;
6-amino-2-{2-[(2-imidazolyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-bromophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(6-methoxy-1-naphthyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-purine;
6-amino-2-{2-[(3-thienyl)methylene]diazanyl}-9-(p-D-r:ibofuranosyl)-9H-purine;
6-amino-2-{2-[(4-ethylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[1-(4-sec-butylphenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9I~-purine;
6-amino-2-{2-[(cyclopentyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-ethoxyphenyl)methyleneJdiazanyl}-9-(p-D-ribofuranosyl)-9I~- -purine;
6-amino-2-{2-[(3-N-methyl-aminophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
IiYD~I4ZZOL~DENOS I N ES
The present invention relates to the synthesis and utility of 2-substituted adenosines. More particularly, this invention relates to the preparation of 2-hydrazeno adenosines and their use as AZ receptor agonists.
Adenosine (9-~-D-ribofuranosyl-9H-purin-6-amine) was characterized in the late '20s as having hypotensive and bradycardia activity. Since then, considerable research in the molecular modification of adenosine has led to the general conclusion that cardiovascular activity is limited to analogs having intact purine and ,e-ribofuranosyl rings.
1 o Further research more clearly defined how the activity of these adenosine analogs affected the purinergic receptors in peripheral cell membranes, particularly the A1 and AZ receptors.
High selectivity combined with significant affinity at the AZ receptor in rat membranes was observed for certain adenosine amines bearing a two-carbon chain i5 to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethyl amino)adenosine, a 14-fold AZ selective compound, was modified by introduction of a variety of substituents in the benzene ring and in the side chain. Some of these changes led to improved AZ affinity and increased selectivity. Replacement of the phenyl moiety by a cyclohexenyl group produced a 210-fold selective agonist, whereas 2 o the cyclohexanyl analog was S30-fold selective at the AZ site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists. See Francis et al., ~, Med.
Chem., ~4 2570-2579 (1991).
A series of 2-alkoxyadenosines were prepared and tested for agonist activity 2 5 at the A1 and AZ adenosine receptors of the atrioventricular node and coronary arteries (vasodilation). Activities at the A1 receptor site were low and did not show a clear relationship to the size or hydrophobicity of the C-2 substituent. All the analogs were more potent at the AZ receptor, activity varying directly with the size and hydrophobicity of the alkyl group. The most potent analog in this series, 2-(2 2~~a~~3 cyclohexylethoxy)adenosine, had an ECso of 1 nM for coronary vasodilation and was 8700-fold selective for the A2 receptor. See Ueeda et al., 3. Med. Chem., 34 (4) 1334-1339 (1991).
It has now been discovered that 2-hydrazono-adenosines display superior selectivity as coronary vasodilators and AIAR agonists.
The compounds of the present invention have the following formula:
R~ N~ ~ N\ I
N ~ i /N
2 \NH N
R
where R1 is hydrogen or the group -C(R3)(RS)-R4, where R3 and R4 are the same or different and are hydrogen, Cl to C12 linear or branched alkyl, C3 to C~
cycloalkyl, C6 to Clo aryl unsubstituted or substituted with Cl to C6 linear or branched alkyl, Cl to C6 linear or branched alkoxy, vitro, amino, amino substituted with at least one Cl to C6 linear or branched alkyl or phenyl, CZ to Clo aralkyl, C4 to C$ heteroaryl wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and RZ is hydrogen, or taken together with R5, forms a chemical bond, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose.
In the compounds of the present invention, it is preferred that Rl is -C(R3)(RS-R4, where RZ is taken together with RS to form a chemical bond, i.e., the preferred compounds of the present invention are those of the formula:
_2_ NHZ
N
R3 ~ ~ ~> I I
\C ~N~N N N
H R
Ra where R1, R3 and Ra are defined above.
In the compounds of formula II, it is preferred that Ra is hydrogen or ethyl.
We have made and tested SHA-202, in which R3 = Ra = ethyl and R3 is ethyl, C3 to C~ cycloalkyl (e.g., cyclohexyl), C6 and Clo aryl unsubstituted (phenyl, 1-naphthyl or 2-naphthyl) or substituted with at least one Cl to C6 linear or branched alkyl (4-methyl or 3-methyl), halogen (chloro, fluoro, bromo), Cl to C6 linear or branched alkoxy (4-methoxy or 3-methoxy), vitro (4-vitro or 3-vitro), amino (4-amino or amino) or Ca to Cg heteroaryl where the heteroatom is nitrogen or sulfur (2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiophenyl).
l0 The following are illustrative of the compounds of the present invention:
6- -amino-2-{2-[(2-naphthyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(3-methylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(2-pyridyl)methylene]diazanyl }-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(4-chlorophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(1-naphthyl)methyleve]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6- -amino-2-diazanyl-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-((4-fluorophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(2-thienyl)methylene]diazanyl }-9-(p-D-ribofuranosyl )-9H-purine;
6- -amino-2-{2-[(4-methylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[1-(4-fluorophenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6- -amino-2-[2-{phenylmethylene)diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(cyclohexyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-nitrophenyl))methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine;
6- -amino-2-{2-[(3-aminophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(3-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-aminophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[1-(phenyl)ethylidene]diazanyl}-9-(a-D-ribofuranosyl)-9H-purine;
b-amino-2-{2-[(4-methoxyphenyl)methylene]diazanyl}-9-(a-D-ribofuranosyl)-9H-purine;
l0 6- -amino-2-{2-[(3-nitrophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(6-methoxy-2-naphthyl)methylene]diazanyl}-9-(,0-D-ribofuranosyl)-purine;
6-amino-2-{2-[(2,3-dimethylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-91,~-I-purine;
6-amino-2-{2-[(2-imidazolyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-bromophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(6-methoxy-1-naphthyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-purine;
6-amino-2-{2-[(3-thienyl)methylene]diazanyl}-9-(p-D-r:ibofuranosyl)-9H-purine;
6-amino-2-{2-[(4-ethylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[1-(4-sec-butylphenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9I~-purine;
6-amino-2-{2-[(cyclopentyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
6-amino-2-{2-[(4-ethoxyphenyl)methyleneJdiazanyl}-9-(p-D-ribofuranosyl)-9I~- -purine;
6-amino-2-{2-[(3-N-methyl-aminophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine;
~~~~~~w , 6-amino-2-{~-[ 1-(4-methylphenyl)ethylidene]diazanyl}-9-(/3-D-ribofuranosyl)-9H-purine;
6-amino-2-~2-[{3-furyl)methylene]diazanyl}-9-({3-D-ribofuranosyl)-9H-purine;
and 6-amino-2-~2-[{3-indolizinyl)methylene]diazanyl~-9-((3-D-ribofuranosyl)-9H-purine.
The compounds of the present invention are prepared by the procedure illustrated in the following reaction scheme:
N..~ N NHZNH2 N~i ~ R3R~C0 Ni ~ N
I ~ y C1~'b ~ HaNN N~ j R~RxC-NNH
ftib Rin Rib Hydrazine displaces the chloro group of 2-chloroadenosine, 1, readily and in high yield. Thus, aldehydes (where Rs is hydrogen and R4 is one of the groups described previously but not hydragen), a ketone where R3 and R4 are the same or different and are described previously (but not hydrogen), xeact with 2-hydrazinoadenasine, 2, under .relatively mild conditions, e.g., at room temperature or with moderate heating, to yield hydxazones, 3. The phenylhydrazones are resistant to reduction {e.g., NaZS2U4, Na$H4, or low pressure HZ over Pd/C). Separation of the pure compounds is readily accomplished by commexcial methods (e.g., filtratian, xecrystallization.) The compounds prepared by the above route are all therapeutically effective L5 adenosine ieceptox agonists in mammals. Thus, they are effective for treating conditions which respond to selective adenosine AZ receptor stimulation (particularly adenosine-2).
Accordingly, the compounds of the present invention are useful for treating hypertension, ~~J~3~'~l thrombosis and atherosclerosis and for causing coronary vasodilation.
Bioassay MethQdolmey ,Ref., "j. Med. Chem. 1991, ?4. 1349);
A Langendorff guinea pig heart preparation paced at 260 beaislmin: via the left atrium served for assays of A, adenosine receptor and A~ adenosine receptor agonist activity. The perfusion buffer consisted of 120 mM NaCI, 27 mM NaHC03, 3.? rnM
KCl, 1.3 mM KHzYUa, l).ii4 mM MgSUQ, 1.:~ mM t:aC;l2, 'mM pyruvate, and SmM
glucose. The buffer was saturated with 95°fo C?zl5% CO~, equilibrated at 37°C in a heat exchanger and delivered at a pressure equivalent to 55 mm Hg. Continuous drainage of the left ventricle by means of a catheter inserted across the mitral valve insured that this 1 o cardiac chamber did no external work. An electrode in the right ventricle monitored the electrocardiogram. Timed collections of cardiac effluent in a graduated cylinder during the steady-state phase of the flow responses to compound administration measured total coronary flow, which was also monitored by an in-line electromagnetic #lowmeter in the aortic perfusion cannula. The quotient of the ratio of compound infusion (mol/min) divided by coronary flow rate (L/min) equals agonist concentration in the perfusate. The rate of agonist infusion was increased stepwise at intervals of 3-4 minutes until the appearance of second degree heart block (Wenckebach point). The ECSO of prolongation of the stimulus-QRS interval (ECM-SQPR), the concentration of compound needed to prolong the interval by 50% of the maximum response, refteets activity at the A, 2 o Adenosine receptor. Logit transformation of the coronary flow data and solution of the regression of logit (coronary flow) on log [compound] for logit=0 yielded arr estimate of ~CSO of coronary vasodilation (ECso-CF), an index of AZ adenosine receptor activity.
The quotient of the EC~o of stimulus-QRS prolongation divided by the ECS~, of coronary 2~~~Q~
(Wenckebach point). The ECso of prolongation of the stimulus-QRS interval (ECso SQPR), the concentration of compound needed to prolong the interval by 50% of the maximum response, reflects activity at the A1 Adenosine receptor. Legit transformation of the coronary flow data and solution of the regression of logit (coronary flow) on log [compound) for logit=0 yielded an estimate of ECso of coronary vasodilation (ECso-CF), an index of AZ adenosine receptor activity.
The quotient of the ECso of stimulus-QRS prolongation divided by the ECso of coronary vasodilation provided an index of selectivity. Values of the index > 1 indicate selectivity for the AZ adenosine receptor.
EXAMPLES
The following Examples are illustrative only and should not be regarded as limiting the invention in any way.
Ger~er~_l~Vlgyhod for the Pre~,~,r_ation of 2-(ArlalkYlh>rdrazinoadeno-sines:
Heating at reflex 1.5 gm. (5.05 mmol) of 2-hydrazinoadenosine and 6.1 mmol of aliphatic aldehyde in 50 ml. methanol resulted in the disappearance of starting material in 2-24 hours, monitored by HPLC. Evaporation of solvent and trituration of the residue with hexane prepared the product for purification by means of medium pressure reverse-phase chromatography (reverse-phase (C-18)HPLC was also used as another method). Isocratic elutions with methanol/water and concentration resulted 2 o in pure material. The reaction of aldehydes boiling at less than 65 ° proceeds at room temperature, going to completion in 24-48 hours. The reaction of aromatic aldehydes proceeded as above; however, when the reaction mixture cooled, the crude product crystallized out of solution. This product was then recrystallized from ~a~3~~
methanol/water to give the pure product.
Example 1 2-[2-(4-Chlorobenzylidene)hydrazino]adenosine 6-amino-2-{2-[4-chlorophenyl)methylene]diazanyl)-9-(,B-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 46.63/46.92 N 22.39/22.91 H 4.60/4.39 Cl 8.10/8.20 Yield 85%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.64-5.43(m, 8H, ribose), 5.86(d, 1H, anomeric), 7.50(m, 4H, NH2 & phenyl H-2 & H-6), 7.86(d, 2H, phenyl H-3 & H-5), 8.20(s, 2H, H-8 &
1o phC~=NNH), 11.27(br s, 1H, phCH=NN~).
Biological Data:
ECso-CF 4.5 nM ECso-SQPR 14,125 nM
Wenckbach 30,374 nM Selectivity 5,480 (SQPR/CF) Exam In a 2 2-[2-(4-Fluorobenzylidene)hydrazino]adenosine 6-amino-2-{2-[(4-fluorophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9~-purine Analysis: Calculated/Found C 47.44/47.73 N 22.78/23.09 H 4.92/4.75 F 4.41/4.40 _g_ t7 ~..~ ~~ i~J
f~~:~b~'~~ ~~
Yield 66%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-d ):3.62-5.62(m, 8H, ribose), 5.90(d, 1H, anomeric), 7.27(rn, 4H, NHZ
& phenyl H-2 & H-6), 7.86(m, 2H, phenyl H-3 & H-5), 8.17(d, 2H, H-8 &
phCH=NNH), 10.75(br s, 1H, phCH=NNH).
Biological Data:
ECSO-CF 2.5 nM ECso-SQPR 12,589 nM
Wenckbach 30,903 nM Selectivity 8,500 (SQPR/CF) Ex m I
2-{2-[(Cyclohexyl)methylene]hydrazino}adenosine 6-amino-2-{2-((cyclohexyl)methylene]diazanyl}-9-(,B-D-ribofuranosyl)-9H-purine Yield 66%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:1.00-1.90(m, 10H, cyclohexyl), 2.20(m, 1H, C~-CH=NNH), 3.55-5.52(m, 8H, ribose), 5.80(d,1H, anomeric), 6.90(br s, 2H, NHZ), 7.23(d, 1H, CH-C,I~- =NNH), 8.00(s, 1H, H-8), 10.75(br s, 1H, CH-CH=NN~-I).
Biological Data:
ECSO-CF 0.3 nM ECso-SQPR 3,548 nM
Wenckbach 5,922 nM Selectivity 16,472 (SQPR/CF) Example 4 2-{2-[(2-Naphthyl)methylene]hydrazino}adenosine _g_ 6-amino-2-{2-[(2-naphthyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 56.37/56.62 N 21.91/21.94 H 5.03/5.07 Yield 91%, Purified: Recrystallized from MeOH
NMR (DMSO-d ):3.55-5.54(m, 8H, ribose), 5.90(d, 1H, anomeric), 7.18(br s, 2H, NHZ), 8.40-8.39(m, 7H, naphthyl), 8.09(x, 2H, H-8 & phCH=NNH), 10.00(br s, 1H, phCH =NNH).
Biological Data:
ECso-CF 4.2 nM ECso-SQPR 2,615 nM
1o Wenckbach 10,058 nM Selectivity 767 (SQPR/CF) Example 5 2-{2-[(3-Pyridyl)methylene]hydrazino}adenosine 6-amino-2-{2-[(3-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine UV No, a(e)=252nm (19,700), 291 nm (15,500), 329nm (24,300) ~5 Yield 82%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-c~):3.60-5.60(m, 8H, ribose), 4.88(d, 1H, anomeric), 7.20(br s, 2H, NHZ), 7.55(m, 1H, pyridyl H-5), 8.10(d, 2H, H-8 & pydCH=NNH), 8.30-8.92(m, 3H, pryidyl H-2, H-4 & H-6), 10.95 (br s, 1H, pydCH=NNH).
2~~~~~~
Biological Data:
ECso-CF 15.0 nM ECso-SQPR 32,359 nM
Wenckbach 63,460 nM Selectivity 2,657 (SQPR/CF) Exam lie 6 2-{2-[(4-Pyridyl)methylene]hydrazino}adenosine 6- -amino-2-{2-[(4-pyridyl)methylene]diazanyl~-9-(p-D-ribofuranosyl)-9H-purine UVa(e)=248nm (17,400), 286nm (12,900, 335nm (25,500) Yield 72%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.53-5.60(m, 8H, ribose), 5.87(d, 1H, anomeric), 7.12(br s, 2H, 1o NH2), 7.72(d, 2H, pyridyl H-3 & H-5), 8.13(d, 2H, H-8 & pydCI-~=NNH), 8.62(d, 2H, pyridyl H-2 & H-6), 11.06(br s, 1H, pydCH=NNH).
Biological Data:
ECso-CF 11.0 nM ECso-SQPR 26,607 nM
Wenckbach 67,999 nM Selectivity 2,817 (SQPR/CF) Example 7 2-[2-(Benzylidene)hydrazino]adenosine 6-amino-2-[2-(phenylmethylene)diazanyl]-9-(a-D-ribofuranosyl)-91-x-purine Analysis: Calculated/Found C 52.27/53.05 N 24.10/23.87 H 5.81/5.63 2~~3~~~
Yield 70%, Purified: Recrystallized from MeOH/H.,O
NMR (DMSO-$0:3.13-5.62(m, 8H, ribose), 5.82(d, 1H, anomerie), 7.11(br s, 2H, NHZ), 7.28-7.85(m, SH, phenyl), 8.09(d, 2H, H-8 & phCH=NNH), 10.70(br s, 1H, phCH=NNH).
Biological Data:
ECM-CF 2.3 nM ECM-SQPPR 84,140 nM
Wenckbach 216,272 nM Selectivity 43,347 (SQPR/CF) Example 8 (Comparative) 2-Hydrazinoadenosine 6-amino-2-diazanyl-9-(~B-D-ribofuranosyl)-9H-purine UV No, a( a ) =258nm ( 10,000), 278nm (9,000) Yield 86%, Purified: Recrystallized from /H20 Biological Data:
ECso-CF 80.4 nM ECso-SQPR 14,569 nM
Wenckbach 18,197 nM Selectivity 301 (SQPR/CF) Ex 1 2-[2-(4-Methylbenzylidene)hydrazinoJadenosine 6-amino-2-{2-[(4-methylphenyl)methyleneJdiazanyl}-9-(a-D-ribofuranosyl)-9I~- -purine ~~ D
Analysis: Calculated/Found C 54.13/54.12 N 24.55/24.40 H 5.30/5.36 Yield 75%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-d ):2.32(s, 3H, CH3), 3.55-5.58(m, 8H, ribose), 5.86(d, 1H, anomeric), 7.05(br s, 2H, NHZ), 7.21(d, 2H, phenyl H-3 & H-5), 7.68(d, 2H, phenyl H-2 & H-6), 8.08(d, 2H, H-8 & phCH=NNH), 10.75(br s, 1H, phCH=NNH).
Biological Data:
ECso-CF 3.3 nmol ECso-SQPPR 39,811 nmol Wenckbach 103,514 nmol Selectivity 14,144 (SQPR/CF) 1o Example 10 2-{2-(1-(4-Fluorophenyl)ethylideneJhydrazino}adenosine 6-amino-2-{2-( 1-(4-fluorophenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9I-~-purine Analysis: Calculated/Found C 51.80/51.85 N 23.49/24.43 H 4.83/4.88 F 4.55/4.64 Yield 73%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-~):2.22(s, 3H, CH3), 3.53-5.60(m, SH, ribose), 5.82(d, 1H, anomeric), 7.00(br s, 2H, NHZ), 7.21(d, 2H, phenyl H-2 & H-6), 7.90(m, 2H, phenyl H-3 & H-5), 8.04(s, 1H, H-8), 9.20(br s, 1H, phC(CH3)-NNH).
Biological Data:
2 o ECso-CF 3.2 nM ECSO-SQPR 4,201 nM
Wenckbach 7,300 nM Selectivity 1,822 (SQPR/CF) Example 11 2-[2-(4-Methoxybenzylidene)hydrazino]adenosine 6-amino-2-{2-[(4-methoxyphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 51.49/51.80 N 23.35/23.34 H 5.16/5.54 Yield 75%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-c, i~):3.54-5.39(m, SH, ribose), 5.82(d, 1H, anomeric), 6.83-7.20(m, 4H, NH2 & phenyl H-3 & H-5), 7.73(m, 2H, phenyl H-2 & H-6), 8.17(d, 2H, H-8 &
to phC~=NNH), 10.45(br s, 1H, phCH=NN)' ).
Biological Data:
ECso-CF 1.7 nM ECso-SQPR 23,000 nM
Wenckbach 50,000 nM Selectivity 14,000 (SQPR/CF) Exam In a 12 2-{2-(1-Phenyl)ethylidene]hydrazino}adenosine 6-amino-2-{2-[1-(phenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine UVa(e)=247nm (17,000), 288 sh (18,900), 309nm (23,100) 2~~~~~
Yield 89%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-d ):2.32(s, 3H, CH3), 3.51-5.60(m, 8H, ribose), 5.88(d, 1H, anomeric), 7.04(br s, 2H, NHZ), 7.45(m, 3H, phenyl H-3, H-4 & H-5), 7.90(m, 2H, phenyl H-& H-6), 8.14(s, 1H, H-8), 9.29(br s, 1H, phC(CH3)=NNH).
Biological Data:
ECso-CF 13 nM ECso-SQPR 3,000 Wenckbach 11,000 nM Selectivity 380 Examgle 13 2-{2-[(2-Pyridyl)methylene]hydrazino}adenosine 6-amino-2-{2-[(2-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9~,-I-purine tlVa(e)=253nm (16,300), 285nm (12,900), 331nm (25,800) Yield 85%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.56-5.59(m, 8H, ribose), 5.87(d, 1H, anomeric), 7.15-7.40 (m, 3H, NH2 & pyridyl H-5), 7.70-8.20(m, 4H, pyridyl H-3, H-4, purinyl H-8 and pydCH=,NNH), 8.67(m, 1H, pyridyl H-6), 10.98(br s, 1H, pydCH=NNH).
Biological Data:
ECso-CF 5.7 nM ECso SQPR
Wenckbach 110,000 Selectivity 42,000 2 0 Example 14 2-{2-[(1-Naphthyl)methylene]hydrazio}adenosine 6-amino-2-{2-[(1-naphthyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Yield 89%, Purified: Recrystallized from MeOH
NMR (DMSO-d ):3.41-5.61(m, 8H, ribose), 5.90(d, 1H, anomeric), 7.18(br s, 2H, NHZ), 7.47-8.20(m, 8H, naphthyl, purinyl H-8 and napCH=NNH), 8.88(s, 1H, naphthyl H-8), 10.89(br s, 1H, napCH=NNH).
Biological Data:
ECso-CF 9.5 nM ECso-SQPR 830 nM
Wenckbach 2,000 nM Selectivity 110 to Example 15 2-{2-[(2-Thienyl)methylene]hydrazino} adenosine 6-amino-2-{2-[(2-thienyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-91-x,-purine Yield 76%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.47-5.52(m, 8H, ribose), 5.85(d, 1H, anomeric), 7.00-7.60(m, SH, NHZ & thienyl), 8.05(s, 1H, H-8), 8.30(s, 1H, thienyl CH=NNH), 10.60(br s, 1H, thienyl CH=NNH).
Biological Data:
ECso-CF 14 nM ECSO-SQPR 42,000 nM
Wenckbach 93,000 nM Selectivity 4400 Example 16 2-[2-(3-Methylbenzylidene)hydrazino]adenosine 6- -amino-2-{2-[(3-methylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Yield 79%, Purified: Recrystallized from MeOH
NMR (DMSO-~):2.32(s, 3H, CH3), 3.54-5.54(m, SH, ribose), 5.82(d, 1H, anorneric), 7.00-7.73(m, 6H, NHZ & phenyl), 8.08(s, 2H, H-8 & phCH=NNH), 10.65(br s, 1H, phCH=NNH).
Biological Data:
ECso-CF 4.4 nM ECSO-SQPR 17,000 Wenckbach 47,000 nM Selectivity 4700 1o In a similar manner, the following compounds are prepared:
Exam I~e 17 2-[2-(4-Nitrobenzylidene)hydrazino]adenosine 6-amino-2-t2-[(4-nitrophenyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9I-~-purine Analysis: Calculated/Found C 47.55/47.33 N 26.10/25.89 H 3.99/4.13 Yield 79%, Purified: Recrystallized from MeOH
Example 18 2-[2-(3-Nitrobenzylidene)hydrazino]adenosine ~~~e~'1~~~
6-amino-2-{2-[(3-nitrophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 47.55/47.36 N 26.10/26.16 H 3.99/3.74 Yield 75%, Purified: Recrystallized from MeOH
Example 19 2-[2-(4-Aminobenzylidene)hydrazine]adenosine 6-amino-2-{2-[(4-aminophenyl)methyleneJdiazanyl}-9-(p-D-ribofuranosyl)-9H-purine Example 20 2-[2-(3-Aminobenzylidene)hydrazine]adenosine 6-amino-2-{2-[(3-aminophenyl)methylene]diazanyl}-9-(-D-ribofuranosyl)-9H-purine 2~~~~~~~
TABLE
BIOASSAY RESULTS
N ~ N
R3~~~N~NH
N N
Rib SUBSTITUEN3' -LOG ECM
R3 R4 A' AZ
Ph H 4.08 8.64 4-F Ph H 4.90 8.61 4-Cl Ph H 4.85 8.35 4-Me0 Ph H 4.64 8.76 4-Me Ph H 4.40 8.49 4-F Ph CH3 5.38 8.49 2-Naphthyl H 5.58 8.38 Cyclohexyl H 5.45 9.59 3-Me-1-Bu H 4.68 9.33 1-Pent H 4.41 8.99 2-C HexylethylH 5.01 9.16 3-Ph Propyl H 4.18 8.71 3-C HexylpropylH 4.18 8.75 3-Cyclo- H 4.86 9.49 hexenyl omparative Adenosine 5.47 7.69 2-Amino-adenosine 4.95 6.65 2-Hydrazino-adenosine 4.70 7.1U
Ph - phenyl Rib - ribose
6-amino-2-~2-[{3-furyl)methylene]diazanyl}-9-({3-D-ribofuranosyl)-9H-purine;
and 6-amino-2-~2-[{3-indolizinyl)methylene]diazanyl~-9-((3-D-ribofuranosyl)-9H-purine.
The compounds of the present invention are prepared by the procedure illustrated in the following reaction scheme:
N..~ N NHZNH2 N~i ~ R3R~C0 Ni ~ N
I ~ y C1~'b ~ HaNN N~ j R~RxC-NNH
ftib Rin Rib Hydrazine displaces the chloro group of 2-chloroadenosine, 1, readily and in high yield. Thus, aldehydes (where Rs is hydrogen and R4 is one of the groups described previously but not hydragen), a ketone where R3 and R4 are the same or different and are described previously (but not hydrogen), xeact with 2-hydrazinoadenasine, 2, under .relatively mild conditions, e.g., at room temperature or with moderate heating, to yield hydxazones, 3. The phenylhydrazones are resistant to reduction {e.g., NaZS2U4, Na$H4, or low pressure HZ over Pd/C). Separation of the pure compounds is readily accomplished by commexcial methods (e.g., filtratian, xecrystallization.) The compounds prepared by the above route are all therapeutically effective L5 adenosine ieceptox agonists in mammals. Thus, they are effective for treating conditions which respond to selective adenosine AZ receptor stimulation (particularly adenosine-2).
Accordingly, the compounds of the present invention are useful for treating hypertension, ~~J~3~'~l thrombosis and atherosclerosis and for causing coronary vasodilation.
Bioassay MethQdolmey ,Ref., "j. Med. Chem. 1991, ?4. 1349);
A Langendorff guinea pig heart preparation paced at 260 beaislmin: via the left atrium served for assays of A, adenosine receptor and A~ adenosine receptor agonist activity. The perfusion buffer consisted of 120 mM NaCI, 27 mM NaHC03, 3.? rnM
KCl, 1.3 mM KHzYUa, l).ii4 mM MgSUQ, 1.:~ mM t:aC;l2, 'mM pyruvate, and SmM
glucose. The buffer was saturated with 95°fo C?zl5% CO~, equilibrated at 37°C in a heat exchanger and delivered at a pressure equivalent to 55 mm Hg. Continuous drainage of the left ventricle by means of a catheter inserted across the mitral valve insured that this 1 o cardiac chamber did no external work. An electrode in the right ventricle monitored the electrocardiogram. Timed collections of cardiac effluent in a graduated cylinder during the steady-state phase of the flow responses to compound administration measured total coronary flow, which was also monitored by an in-line electromagnetic #lowmeter in the aortic perfusion cannula. The quotient of the ratio of compound infusion (mol/min) divided by coronary flow rate (L/min) equals agonist concentration in the perfusate. The rate of agonist infusion was increased stepwise at intervals of 3-4 minutes until the appearance of second degree heart block (Wenckebach point). The ECSO of prolongation of the stimulus-QRS interval (ECM-SQPR), the concentration of compound needed to prolong the interval by 50% of the maximum response, refteets activity at the A, 2 o Adenosine receptor. Logit transformation of the coronary flow data and solution of the regression of logit (coronary flow) on log [compound] for logit=0 yielded arr estimate of ~CSO of coronary vasodilation (ECso-CF), an index of AZ adenosine receptor activity.
The quotient of the EC~o of stimulus-QRS prolongation divided by the ECS~, of coronary 2~~~Q~
(Wenckebach point). The ECso of prolongation of the stimulus-QRS interval (ECso SQPR), the concentration of compound needed to prolong the interval by 50% of the maximum response, reflects activity at the A1 Adenosine receptor. Legit transformation of the coronary flow data and solution of the regression of logit (coronary flow) on log [compound) for logit=0 yielded an estimate of ECso of coronary vasodilation (ECso-CF), an index of AZ adenosine receptor activity.
The quotient of the ECso of stimulus-QRS prolongation divided by the ECso of coronary vasodilation provided an index of selectivity. Values of the index > 1 indicate selectivity for the AZ adenosine receptor.
EXAMPLES
The following Examples are illustrative only and should not be regarded as limiting the invention in any way.
Ger~er~_l~Vlgyhod for the Pre~,~,r_ation of 2-(ArlalkYlh>rdrazinoadeno-sines:
Heating at reflex 1.5 gm. (5.05 mmol) of 2-hydrazinoadenosine and 6.1 mmol of aliphatic aldehyde in 50 ml. methanol resulted in the disappearance of starting material in 2-24 hours, monitored by HPLC. Evaporation of solvent and trituration of the residue with hexane prepared the product for purification by means of medium pressure reverse-phase chromatography (reverse-phase (C-18)HPLC was also used as another method). Isocratic elutions with methanol/water and concentration resulted 2 o in pure material. The reaction of aldehydes boiling at less than 65 ° proceeds at room temperature, going to completion in 24-48 hours. The reaction of aromatic aldehydes proceeded as above; however, when the reaction mixture cooled, the crude product crystallized out of solution. This product was then recrystallized from ~a~3~~
methanol/water to give the pure product.
Example 1 2-[2-(4-Chlorobenzylidene)hydrazino]adenosine 6-amino-2-{2-[4-chlorophenyl)methylene]diazanyl)-9-(,B-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 46.63/46.92 N 22.39/22.91 H 4.60/4.39 Cl 8.10/8.20 Yield 85%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.64-5.43(m, 8H, ribose), 5.86(d, 1H, anomeric), 7.50(m, 4H, NH2 & phenyl H-2 & H-6), 7.86(d, 2H, phenyl H-3 & H-5), 8.20(s, 2H, H-8 &
1o phC~=NNH), 11.27(br s, 1H, phCH=NN~).
Biological Data:
ECso-CF 4.5 nM ECso-SQPR 14,125 nM
Wenckbach 30,374 nM Selectivity 5,480 (SQPR/CF) Exam In a 2 2-[2-(4-Fluorobenzylidene)hydrazino]adenosine 6-amino-2-{2-[(4-fluorophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9~-purine Analysis: Calculated/Found C 47.44/47.73 N 22.78/23.09 H 4.92/4.75 F 4.41/4.40 _g_ t7 ~..~ ~~ i~J
f~~:~b~'~~ ~~
Yield 66%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-d ):3.62-5.62(m, 8H, ribose), 5.90(d, 1H, anomeric), 7.27(rn, 4H, NHZ
& phenyl H-2 & H-6), 7.86(m, 2H, phenyl H-3 & H-5), 8.17(d, 2H, H-8 &
phCH=NNH), 10.75(br s, 1H, phCH=NNH).
Biological Data:
ECSO-CF 2.5 nM ECso-SQPR 12,589 nM
Wenckbach 30,903 nM Selectivity 8,500 (SQPR/CF) Ex m I
2-{2-[(Cyclohexyl)methylene]hydrazino}adenosine 6-amino-2-{2-((cyclohexyl)methylene]diazanyl}-9-(,B-D-ribofuranosyl)-9H-purine Yield 66%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:1.00-1.90(m, 10H, cyclohexyl), 2.20(m, 1H, C~-CH=NNH), 3.55-5.52(m, 8H, ribose), 5.80(d,1H, anomeric), 6.90(br s, 2H, NHZ), 7.23(d, 1H, CH-C,I~- =NNH), 8.00(s, 1H, H-8), 10.75(br s, 1H, CH-CH=NN~-I).
Biological Data:
ECSO-CF 0.3 nM ECso-SQPR 3,548 nM
Wenckbach 5,922 nM Selectivity 16,472 (SQPR/CF) Example 4 2-{2-[(2-Naphthyl)methylene]hydrazino}adenosine _g_ 6-amino-2-{2-[(2-naphthyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 56.37/56.62 N 21.91/21.94 H 5.03/5.07 Yield 91%, Purified: Recrystallized from MeOH
NMR (DMSO-d ):3.55-5.54(m, 8H, ribose), 5.90(d, 1H, anomeric), 7.18(br s, 2H, NHZ), 8.40-8.39(m, 7H, naphthyl), 8.09(x, 2H, H-8 & phCH=NNH), 10.00(br s, 1H, phCH =NNH).
Biological Data:
ECso-CF 4.2 nM ECso-SQPR 2,615 nM
1o Wenckbach 10,058 nM Selectivity 767 (SQPR/CF) Example 5 2-{2-[(3-Pyridyl)methylene]hydrazino}adenosine 6-amino-2-{2-[(3-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine UV No, a(e)=252nm (19,700), 291 nm (15,500), 329nm (24,300) ~5 Yield 82%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-c~):3.60-5.60(m, 8H, ribose), 4.88(d, 1H, anomeric), 7.20(br s, 2H, NHZ), 7.55(m, 1H, pyridyl H-5), 8.10(d, 2H, H-8 & pydCH=NNH), 8.30-8.92(m, 3H, pryidyl H-2, H-4 & H-6), 10.95 (br s, 1H, pydCH=NNH).
2~~~~~~
Biological Data:
ECso-CF 15.0 nM ECso-SQPR 32,359 nM
Wenckbach 63,460 nM Selectivity 2,657 (SQPR/CF) Exam lie 6 2-{2-[(4-Pyridyl)methylene]hydrazino}adenosine 6- -amino-2-{2-[(4-pyridyl)methylene]diazanyl~-9-(p-D-ribofuranosyl)-9H-purine UVa(e)=248nm (17,400), 286nm (12,900, 335nm (25,500) Yield 72%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.53-5.60(m, 8H, ribose), 5.87(d, 1H, anomeric), 7.12(br s, 2H, 1o NH2), 7.72(d, 2H, pyridyl H-3 & H-5), 8.13(d, 2H, H-8 & pydCI-~=NNH), 8.62(d, 2H, pyridyl H-2 & H-6), 11.06(br s, 1H, pydCH=NNH).
Biological Data:
ECso-CF 11.0 nM ECso-SQPR 26,607 nM
Wenckbach 67,999 nM Selectivity 2,817 (SQPR/CF) Example 7 2-[2-(Benzylidene)hydrazino]adenosine 6-amino-2-[2-(phenylmethylene)diazanyl]-9-(a-D-ribofuranosyl)-91-x-purine Analysis: Calculated/Found C 52.27/53.05 N 24.10/23.87 H 5.81/5.63 2~~3~~~
Yield 70%, Purified: Recrystallized from MeOH/H.,O
NMR (DMSO-$0:3.13-5.62(m, 8H, ribose), 5.82(d, 1H, anomerie), 7.11(br s, 2H, NHZ), 7.28-7.85(m, SH, phenyl), 8.09(d, 2H, H-8 & phCH=NNH), 10.70(br s, 1H, phCH=NNH).
Biological Data:
ECM-CF 2.3 nM ECM-SQPPR 84,140 nM
Wenckbach 216,272 nM Selectivity 43,347 (SQPR/CF) Example 8 (Comparative) 2-Hydrazinoadenosine 6-amino-2-diazanyl-9-(~B-D-ribofuranosyl)-9H-purine UV No, a( a ) =258nm ( 10,000), 278nm (9,000) Yield 86%, Purified: Recrystallized from /H20 Biological Data:
ECso-CF 80.4 nM ECso-SQPR 14,569 nM
Wenckbach 18,197 nM Selectivity 301 (SQPR/CF) Ex 1 2-[2-(4-Methylbenzylidene)hydrazinoJadenosine 6-amino-2-{2-[(4-methylphenyl)methyleneJdiazanyl}-9-(a-D-ribofuranosyl)-9I~- -purine ~~ D
Analysis: Calculated/Found C 54.13/54.12 N 24.55/24.40 H 5.30/5.36 Yield 75%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-d ):2.32(s, 3H, CH3), 3.55-5.58(m, 8H, ribose), 5.86(d, 1H, anomeric), 7.05(br s, 2H, NHZ), 7.21(d, 2H, phenyl H-3 & H-5), 7.68(d, 2H, phenyl H-2 & H-6), 8.08(d, 2H, H-8 & phCH=NNH), 10.75(br s, 1H, phCH=NNH).
Biological Data:
ECso-CF 3.3 nmol ECso-SQPPR 39,811 nmol Wenckbach 103,514 nmol Selectivity 14,144 (SQPR/CF) 1o Example 10 2-{2-(1-(4-Fluorophenyl)ethylideneJhydrazino}adenosine 6-amino-2-{2-( 1-(4-fluorophenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9I-~-purine Analysis: Calculated/Found C 51.80/51.85 N 23.49/24.43 H 4.83/4.88 F 4.55/4.64 Yield 73%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-~):2.22(s, 3H, CH3), 3.53-5.60(m, SH, ribose), 5.82(d, 1H, anomeric), 7.00(br s, 2H, NHZ), 7.21(d, 2H, phenyl H-2 & H-6), 7.90(m, 2H, phenyl H-3 & H-5), 8.04(s, 1H, H-8), 9.20(br s, 1H, phC(CH3)-NNH).
Biological Data:
2 o ECso-CF 3.2 nM ECSO-SQPR 4,201 nM
Wenckbach 7,300 nM Selectivity 1,822 (SQPR/CF) Example 11 2-[2-(4-Methoxybenzylidene)hydrazino]adenosine 6-amino-2-{2-[(4-methoxyphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 51.49/51.80 N 23.35/23.34 H 5.16/5.54 Yield 75%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-c, i~):3.54-5.39(m, SH, ribose), 5.82(d, 1H, anomeric), 6.83-7.20(m, 4H, NH2 & phenyl H-3 & H-5), 7.73(m, 2H, phenyl H-2 & H-6), 8.17(d, 2H, H-8 &
to phC~=NNH), 10.45(br s, 1H, phCH=NN)' ).
Biological Data:
ECso-CF 1.7 nM ECso-SQPR 23,000 nM
Wenckbach 50,000 nM Selectivity 14,000 (SQPR/CF) Exam In a 12 2-{2-(1-Phenyl)ethylidene]hydrazino}adenosine 6-amino-2-{2-[1-(phenyl)ethylidene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine UVa(e)=247nm (17,000), 288 sh (18,900), 309nm (23,100) 2~~~~~
Yield 89%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-d ):2.32(s, 3H, CH3), 3.51-5.60(m, 8H, ribose), 5.88(d, 1H, anomeric), 7.04(br s, 2H, NHZ), 7.45(m, 3H, phenyl H-3, H-4 & H-5), 7.90(m, 2H, phenyl H-& H-6), 8.14(s, 1H, H-8), 9.29(br s, 1H, phC(CH3)=NNH).
Biological Data:
ECso-CF 13 nM ECso-SQPR 3,000 Wenckbach 11,000 nM Selectivity 380 Examgle 13 2-{2-[(2-Pyridyl)methylene]hydrazino}adenosine 6-amino-2-{2-[(2-pyridyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9~,-I-purine tlVa(e)=253nm (16,300), 285nm (12,900), 331nm (25,800) Yield 85%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.56-5.59(m, 8H, ribose), 5.87(d, 1H, anomeric), 7.15-7.40 (m, 3H, NH2 & pyridyl H-5), 7.70-8.20(m, 4H, pyridyl H-3, H-4, purinyl H-8 and pydCH=,NNH), 8.67(m, 1H, pyridyl H-6), 10.98(br s, 1H, pydCH=NNH).
Biological Data:
ECso-CF 5.7 nM ECso SQPR
Wenckbach 110,000 Selectivity 42,000 2 0 Example 14 2-{2-[(1-Naphthyl)methylene]hydrazio}adenosine 6-amino-2-{2-[(1-naphthyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Yield 89%, Purified: Recrystallized from MeOH
NMR (DMSO-d ):3.41-5.61(m, 8H, ribose), 5.90(d, 1H, anomeric), 7.18(br s, 2H, NHZ), 7.47-8.20(m, 8H, naphthyl, purinyl H-8 and napCH=NNH), 8.88(s, 1H, naphthyl H-8), 10.89(br s, 1H, napCH=NNH).
Biological Data:
ECso-CF 9.5 nM ECso-SQPR 830 nM
Wenckbach 2,000 nM Selectivity 110 to Example 15 2-{2-[(2-Thienyl)methylene]hydrazino} adenosine 6-amino-2-{2-[(2-thienyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-91-x,-purine Yield 76%, Purified: Recrystallized from MeOH/H20 NMR (DMSO-0:3.47-5.52(m, 8H, ribose), 5.85(d, 1H, anomeric), 7.00-7.60(m, SH, NHZ & thienyl), 8.05(s, 1H, H-8), 8.30(s, 1H, thienyl CH=NNH), 10.60(br s, 1H, thienyl CH=NNH).
Biological Data:
ECso-CF 14 nM ECSO-SQPR 42,000 nM
Wenckbach 93,000 nM Selectivity 4400 Example 16 2-[2-(3-Methylbenzylidene)hydrazino]adenosine 6- -amino-2-{2-[(3-methylphenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Yield 79%, Purified: Recrystallized from MeOH
NMR (DMSO-~):2.32(s, 3H, CH3), 3.54-5.54(m, SH, ribose), 5.82(d, 1H, anorneric), 7.00-7.73(m, 6H, NHZ & phenyl), 8.08(s, 2H, H-8 & phCH=NNH), 10.65(br s, 1H, phCH=NNH).
Biological Data:
ECso-CF 4.4 nM ECSO-SQPR 17,000 Wenckbach 47,000 nM Selectivity 4700 1o In a similar manner, the following compounds are prepared:
Exam I~e 17 2-[2-(4-Nitrobenzylidene)hydrazino]adenosine 6-amino-2-t2-[(4-nitrophenyl)methylene]diazanyl}-9-(Q-D-ribofuranosyl)-9I-~-purine Analysis: Calculated/Found C 47.55/47.33 N 26.10/25.89 H 3.99/4.13 Yield 79%, Purified: Recrystallized from MeOH
Example 18 2-[2-(3-Nitrobenzylidene)hydrazino]adenosine ~~~e~'1~~~
6-amino-2-{2-[(3-nitrophenyl)methylene]diazanyl}-9-(p-D-ribofuranosyl)-9H-purine Analysis: Calculated/Found C 47.55/47.36 N 26.10/26.16 H 3.99/3.74 Yield 75%, Purified: Recrystallized from MeOH
Example 19 2-[2-(4-Aminobenzylidene)hydrazine]adenosine 6-amino-2-{2-[(4-aminophenyl)methyleneJdiazanyl}-9-(p-D-ribofuranosyl)-9H-purine Example 20 2-[2-(3-Aminobenzylidene)hydrazine]adenosine 6-amino-2-{2-[(3-aminophenyl)methylene]diazanyl}-9-(-D-ribofuranosyl)-9H-purine 2~~~~~~~
TABLE
BIOASSAY RESULTS
N ~ N
R3~~~N~NH
N N
Rib SUBSTITUEN3' -LOG ECM
R3 R4 A' AZ
Ph H 4.08 8.64 4-F Ph H 4.90 8.61 4-Cl Ph H 4.85 8.35 4-Me0 Ph H 4.64 8.76 4-Me Ph H 4.40 8.49 4-F Ph CH3 5.38 8.49 2-Naphthyl H 5.58 8.38 Cyclohexyl H 5.45 9.59 3-Me-1-Bu H 4.68 9.33 1-Pent H 4.41 8.99 2-C HexylethylH 5.01 9.16 3-Ph Propyl H 4.18 8.71 3-C HexylpropylH 4.18 8.75 3-Cyclo- H 4.86 9.49 hexenyl omparative Adenosine 5.47 7.69 2-Amino-adenosine 4.95 6.65 2-Hydrazino-adenosine 4.70 7.1U
Ph - phenyl Rib - ribose
Claims (11)
1. A compound of formula II:
where:
R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with at least one substituent selected from halogen, C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl, and phenyl, C2 to C10 aralkyl, or C4 to C8 heteroaryl, wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose.
where:
R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with at least one substituent selected from halogen, C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl, and phenyl, C2 to C10 aralkyl, or C4 to C8 heteroaryl, wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose.
2. The compound according to claim 1, wherein R4 is hydrogen or methyl.
3. The compound according to claim 2, wherein R3 is C3 to C7 cycloalkyl.
4. The compound according to claim 2, wherein R3 is C6 to C10 aryl unsubstituted.
5. The compound according to claim 2, wherein R3 is C6 to C10 aryl substituted with at least one C1 to C6 linear or branched alkyl.
6. The compound according to claim 2, wherein R3 is C6 to C10 aryl substituted with at least one substituent selected from halogen, C1 to C6 linear or branched alkoxy, nitro, and amino.
7. The compound according to claim 2, wherein R3 is C4 to C8 heteroaryl, wherein said hetero atom is nitrogen or sulfur.
8. The compound according to any one of claims 1 to 7 for use in a therapeutic method for selectively stimulating the A2 adenosine receptor.
9. The compound according to any one of claims 1 to 7 for use in a therapeutic method for causing coronary vasodilation in a mammal.
10. Use of a compound of formula II:
where:
R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with at least one substituent selected from halogen, C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl, and phenyl, C2 to C10 aralkyl, or C4 to C8 heteroaryl, wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose;
for the manufacture of a medicament for therapeutically selectively stimulating the A2 adenosine receptor.
where:
R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with at least one substituent selected from halogen, C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl, and phenyl, C2 to C10 aralkyl, or C4 to C8 heteroaryl, wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose;
for the manufacture of a medicament for therapeutically selectively stimulating the A2 adenosine receptor.
11. Use of a compound of formula II:
where:
R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with at least one substituent selected from halogen, C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl, and phenyl, C2 to C10 aralkyl, or C4 to C8 heteroaryl, wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose;
for the manufacture of a medicament for therapeutically causing coronary vasodilation in a mammal requiring such vasodilation.
where:
R3 and R4 are the same or different and are hydrogen, C1 to C12 linear or branched alkyl, C3 to C7 cycloalkyl, C6 to C10 aryl unsubstituted or substituted with at least one substituent selected from halogen, C1 to C6 linear or branched alkyl, C1 to C6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C1 to C6 linear or branched alkyl, and phenyl, C2 to C10 aralkyl, or C4 to C8 heteroaryl, wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R is a monosaccharide radical selected from the group consisting of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose;
for the manufacture of a medicament for therapeutically causing coronary vasodilation in a mammal requiring such vasodilation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US873,440 | 1992-04-24 | ||
| US07/873,440 US5278150A (en) | 1992-04-24 | 1992-04-24 | 2-hydrazoadenosines and their utility for the treatmeat of vascular conditions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2093502A1 CA2093502A1 (en) | 1993-10-25 |
| CA2093502C true CA2093502C (en) | 2004-06-22 |
Family
ID=25361637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002093502A Expired - Lifetime CA2093502C (en) | 1992-04-24 | 1993-04-06 | Hydrazoadenosines |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US5278150A (en) |
| EP (1) | EP0567094B1 (en) |
| JP (1) | JP3395912B2 (en) |
| CA (1) | CA2093502C (en) |
| DE (1) | DE69323643T2 (en) |
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|---|---|---|---|---|
| US5477857A (en) * | 1993-09-10 | 1995-12-26 | Discovery Therapeutics, Inc. | Diagnostic uses of hydrazinoadenosines |
| US6514949B1 (en) | 1994-07-11 | 2003-02-04 | University Of Virginia Patent Foundation | Method compositions for treating the inflammatory response |
| US5877180A (en) * | 1994-07-11 | 1999-03-02 | University Of Virginia Patent Foundation | Method for treating inflammatory diseases with A2a adenosine receptor agonists |
| US6448235B1 (en) | 1994-07-11 | 2002-09-10 | University Of Virginia Patent Foundation | Method for treating restenosis with A2A adenosine receptor agonists |
| US5817641A (en) * | 1994-07-21 | 1998-10-06 | Thomas Jefferson University | Treatment of enterotoxigenic diarrhea with 2-substituted adenosine derivatives |
| CA2295195C (en) | 1997-06-18 | 2009-12-15 | Discovery Therapeutics, Inc. | Compositions and methods for preventing restenosis following revascularization procedures |
| US5972903A (en) * | 1997-10-07 | 1999-10-26 | Regents Of The University Of California Corporation | Method for promoting angiogenesis using heparin and adenosine |
| JP2003506310A (en) | 1997-10-07 | 2003-02-18 | リージェンツ オブ ザ ユニバーシティー オブ カリフォルニア | Treatment of occlusive peripheral vascular disease and coronary artery disease with a combination of heparin and an adenosine A2 agonist or with adenosine |
| US6117878A (en) * | 1998-02-24 | 2000-09-12 | University Of Virginia | 8-phenyl- or 8-cycloalkyl xanthine antagonists of A2B human adenosine receptors |
| US7427606B2 (en) * | 1999-02-01 | 2008-09-23 | University Of Virginia Patent Foundation | Method to reduce inflammatory response in transplanted tissue |
| US6232297B1 (en) | 1999-02-01 | 2001-05-15 | University Of Virginia Patent Foundation | Methods and compositions for treating inflammatory response |
| US7378400B2 (en) * | 1999-02-01 | 2008-05-27 | University Of Virginia Patent Foundation | Method to reduce an inflammatory response from arthritis |
| US6322771B1 (en) | 1999-06-18 | 2001-11-27 | University Of Virginia Patent Foundation | Induction of pharmacological stress with adenosine receptor agonists |
| DE10041478A1 (en) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | New pharmaceutical composition |
| US6670334B2 (en) | 2001-01-05 | 2003-12-30 | University Of Virginia Patent Foundation | Method and compositions for treating the inflammatory response |
| GB2372742A (en) * | 2001-03-03 | 2002-09-04 | Univ Leiden | C2,5'-Disubstituted and N6,C2,5'-trisubstituted adenosine derivatives and their different uses |
| GB2372741A (en) * | 2001-03-03 | 2002-09-04 | Univ Leiden | C2,8-Disubstituted adenosine derivatives and their different uses |
| US20030027793A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal treatment of parkinson's disease |
| US20030026830A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine |
| JP4514452B2 (en) * | 2001-10-01 | 2010-07-28 | ユニバーシティ オブ バージニア パテント ファウンデーション | 2-propyladenosine analogs having A2A agonist activity and compositions thereof |
| AU2003263846B2 (en) * | 2002-08-15 | 2009-12-17 | Gilead Palo Alto, Inc. | Partial and full agonists of A1 adenosine receptors |
| US20050033044A1 (en) * | 2003-05-19 | 2005-02-10 | Bristol-Myers Squibb Pharma Company | Methods for preparing 2-alkynyladenosine derivatives |
| KR101267202B1 (en) * | 2004-05-26 | 2013-05-24 | 이노텍 파마슈티컬스 코포레이션 | Purine derivatives as adenosine a1 receptor agonists and methods of use thereof |
| WO2006015357A2 (en) | 2004-08-02 | 2006-02-09 | University Of Virginia Patent Foundation | 2-propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity |
| WO2006023272A1 (en) * | 2004-08-02 | 2006-03-02 | University Of Virginia Patent Foundation | 2-polycyclic propynyl adenosine analogs having a2a agonist activity |
| WO2006028618A1 (en) * | 2004-08-02 | 2006-03-16 | University Of Virginia Patent Foundation | 2-polycyclic propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity |
| JP5011112B2 (en) * | 2004-09-20 | 2012-08-29 | イノテック ファーマシューティカルズ コーポレイション | Pharmaceuticals for the treatment of inflammatory diseases containing purine derivatives |
| EP1841355A4 (en) * | 2005-01-12 | 2012-09-05 | King Pharmaceuticals Res & Dev | Method of detecting myocardial dysfunction in patients having a history of asthma or bronchospasm |
| NZ568694A (en) | 2005-11-09 | 2011-09-30 | Zalicus Inc | Method, compositions, and kits for the treatment of medical conditions |
| JP5203214B2 (en) * | 2005-11-30 | 2013-06-05 | イノテック ファーマシューティカルズ コーポレイション | Purine compounds and methods of use thereof |
| US20080027022A1 (en) * | 2006-02-08 | 2008-01-31 | Linden Joel M | Method to treat gastric lesions |
| WO2007120972A2 (en) | 2006-02-10 | 2007-10-25 | University Of Virginia Patent Foundation | Method to treat sickle cell disease |
| US8188063B2 (en) * | 2006-06-19 | 2012-05-29 | University Of Virginia Patent Foundation | Use of adenosine A2A modulators to treat spinal cord injury |
| JP2008285478A (en) * | 2007-04-16 | 2008-11-27 | Santen Pharmaceut Co Ltd | Therapeutic agent for glaucoma comprising adenosine a2a receptor agonist as effective component |
| US7558455B2 (en) * | 2007-06-29 | 2009-07-07 | Ethicon Endo-Surgery, Inc | Receiver aperture broadening for scanned beam imaging |
| US8058259B2 (en) * | 2007-12-20 | 2011-11-15 | University Of Virginia Patent Foundation | Substituted 4-{3-[6-amino-9-(3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid esters as A2AR agonists |
| US20110044904A1 (en) * | 2008-02-29 | 2011-02-24 | Moorman Allan R | Crystal forms of 2--adenosine |
| CN102014959B (en) | 2008-03-10 | 2016-01-20 | 康奈尔大学 | The adjustment of blood-brain barrier permeability |
| KR20120115344A (en) | 2010-01-11 | 2012-10-17 | 이노텍 파마슈티컬스 코포레이션 | Combination, kit and method of reducing intraocular pressure |
| BR112012023749A2 (en) | 2010-03-26 | 2016-08-23 | Inotek Pharmaceuticals Corp | method for reducing intraocular pressure in humans using n6-cyclopentyladenosine (cpa), cpa derivatives or prodrugs thereof |
| MX2014009086A (en) | 2012-01-26 | 2015-06-05 | Inotek Pharmaceuticals Corp | Anhydrous polymorphs of (2r,3s,4r,5r)-5-(6-(cyclopentylamino)-9h- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl) } methyl nitrate and processes of preparation thereof. |
| WO2014152723A1 (en) | 2013-03-15 | 2014-09-25 | Inotek Pharmaceuticals Corporation | Ophthalmic formulations |
| US20220378816A1 (en) * | 2019-06-21 | 2022-12-01 | Academy Of Military Medical Sciences | 2-benzylidene hydrazinoadenosine compounds having a2a adenosine receptor agonistic activity |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4224438A (en) * | 1970-07-14 | 1980-09-23 | Boehringer Mannheim Gmbh | Adenosine-5'-carboxylic acid amides |
| DE2034785A1 (en) * | 1970-07-14 | 1972-01-20 | Boehnnger Mannheim GmbH, 6800 Mann heim Waldhof | Adenosine 5 carboxylic acid derivatives |
| JPS4935635B1 (en) * | 1970-12-28 | 1974-09-25 | ||
| US4140851A (en) * | 1977-11-21 | 1979-02-20 | The United States Of America As Represented By The Department Of Health, Education And Welfare | Synthesis and antitumor activity of 2,4,5-trisubstituted-pyrrolo2,3-d]-pyrimidine nucleosides |
| JP2619710B2 (en) * | 1989-02-27 | 1997-06-11 | 日本製紙 株式会社 | Method for producing 2 ', 3'-dideoxypurine nucleosides |
| US5155098A (en) * | 1989-06-09 | 1992-10-13 | Hoechst-Roussel Pharmaceuticals Inc. | N-heteroaryl-purin-6-amines, and pharmaceutical compositions and methods employing them |
-
1992
- 1992-04-24 US US07/873,440 patent/US5278150A/en not_active Expired - Lifetime
-
1993
- 1993-04-06 CA CA002093502A patent/CA2093502C/en not_active Expired - Lifetime
- 1993-04-21 EP EP93106460A patent/EP0567094B1/en not_active Expired - Lifetime
- 1993-04-21 JP JP11666393A patent/JP3395912B2/en not_active Expired - Lifetime
- 1993-04-21 DE DE69323643T patent/DE69323643T2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0567094A2 (en) | 1993-10-27 |
| EP0567094A3 (en) | 1994-03-30 |
| JP3395912B2 (en) | 2003-04-14 |
| DE69323643D1 (en) | 1999-04-08 |
| EP0567094B1 (en) | 1999-03-03 |
| CA2093502A1 (en) | 1993-10-25 |
| US5278150A (en) | 1994-01-11 |
| DE69323643T2 (en) | 1999-07-29 |
| JPH06128281A (en) | 1994-05-10 |
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