1. A method for the synthetic preparation of a compound having the structure of Formula (I):
wherein
R1, and R6, are each separately selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or separately selected from the group consisting of saturated C1-C24 alkyl, unsaturated C2-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, \u2014CO\u2014O\u2014R7, alkylthio, monohalogenated alkyl, polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CH2CO\u2014R7, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, \u2014SO-alkyl, \u2014SO-aryl, \u2014SO-heteroaryl, \u2014SO2-alkyl, \u2014SO2-aryl, and \u2014SO2-heteroaryl;
R7 is selected from a hydrogen atom or a halogen atom, or selected from the group consisting of saturated C1-C24 alkyl, unsaturated C2-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, and phenyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, \u2014SO-alkyl, \u2014SO-aryl, \u2014SO-heteroaryl, \u2014SO2-alkyl, \u2014SO2-aryl, and \u2014SO2-heteroaryl;
R4 is a tert-butyl group;
R1\u2032 and R1\u2033 are each independently selected from the group consisting of a hydrogen atom, a halogen atom, hydroxy, and cyano, or independently selected from the group consisting of saturated C1-C24 alkyl, unsaturated C2-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, azido, phenyl, carboxy, \u2014CO\u2014O\u2014R7, alkylthio, monohalogenated alkyl, polyhalogenated alkyl, halogenated carbonyl, and carbonyl-CH9CO\u2014R7, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, \u2014SO-alkyl, \u2014SO-aryl, \u2014SO-heteroaryl, \u2014SO2-alkyl, \u2014SO2-aryl, and SO2-heteroaryl;
R1, R1\u2032 and R1\u2033 are either covalently bound to one another or are not covalently bound to one another;
R2, R3, and R5 are each separately selected from the group consisting of a hydrogen atom or a halogen atom, or separately selected from the group consisting of saturated C1-C12 alkyl, unsaturated C2-C12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl groups, each optionally substituted with one or more of alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxy, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro, \u2014SO-alkyl, \u2014SO-aryl, \u2014SO-heteroaryl, \u2014SO2-alkyl, \u2014SO2-aryl, and \u2014SO2-heteroaryl;
X1 and X2 are separately selected from the group consisting of an oxygen atom, a sulfur atom, or a nitrogen atom substituted with R5;
Y is selected from the group consisting of (i) a nitrogen atom substituted with R5, (ii) an oxygen atom, (iii) a sulfur atom, (iv) an oxidized sulfur atom, and (v) a methylene group substituted with one or more R5;
n is an integer equal to zero, one or two;
Z, for each separate n, if non-zero, and Z1, Z2, Z3 and Z4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom; and
the dashed bonds may be either single or double bonds;
said method comprising:
reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate; and
reacting said intermediate with a benzaldehyde to produce said compound.
2. The method according to claim 1, wherein each of R2, R3, R5 and R6 is a hydrogen atom.
3. The method according to claim 1, wherein each of X1 and X2 is an oxygen atom.
4. The method according to claim 1, wherein R1 comprises a substituted phenyl.
5. The method according to claim 4, wherein said substituted phenyl group is methoxybenzene.
6. The method according to claim 1, wherein n is equal to zero or one.
7. The method according to claim 1, wherein n is equal to one.
8. The method according to claim 1, wherein n is equal to one and Z, Z1, Z2, Z3 and Z4 are each a carbon atom.
9. The method of claim 1, wherein Y is a nitrogen atom substituted with hydrogen.
10. The method of claim 1, wherein said intermediate has the structure:
11. The method of claim 1, wherein said imidazolecarboxaldehyde has the structure:
12. The method of claim 1, wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in the presence of a cesium salt.
13. The method of claim 1, wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in the presence of cesium carbonate.
14. The method of claim 1, wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in a deoxygenated atmosphere.
15. The method of claim 1, wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed in the presence of dimethylformamide (DMF).
16. The method of claim 1, wherein said reacting a diacyldiketopiperazine with an imidazolecarboxaldehyde to produce an intermediate is performed at room temperature.
17. The method of claim 1, wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in the presence of a cesium salt.
18. The method of claim 1, wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in the presence of cesium carbonate.
19. The method of claim 1, wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in a deoxygenated atmosphere.
20. The method of claim 1, wherein reacting said intermediate with a benzaldehyde to produce said compound is performed in the presence of DMF.
21. The method of claim 1, wherein reacting said intermediate with a benzaldehyde to produce said compound is performed at 80\xb0 C.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An implantable depot for releasing a biologically active substance locally into the renal arteries.
2. An implantable depot as in claim 1, further comprising a biodegradable vascular implant which releases the biologically active substance, wherein the implant is implantable within the aorta near the renal arteries or within at least one renal artery.
3. An implantable depot as in claim 1, further comprising a reservoir for holding the biologically active substance.
4. An implantable depot as in claim 3, further comprising a pump connected to the reservoir for delivering the biologically active substance from the reservoir to the renal arteries.
5. An implantable depot as in claim 3, further comprising a port which is transcutaneously accessible to replenish the reservoir with biologically active substance.
6. An implantable depot as in any one of claims 1 to 5, wherein the biologically active substance is selected from the group consisting of vasodilators, antioxidants, and diuretics.
7. An implantable depot as in claim 6, wherein the biologically active substance comprises a vasodilator selected from the group consisting of papavarine, fenoldopam mesylate, calcium-channel blockers, acetylcholine, nifedipine, nitroglycerine, nitroprusside, adenosine, dopamine, and theophylline.
8. An implantable depot as in claim 6, wherein the biologically active substance comprises an antioxidant selected from the group consisting of acetylcystein.
9. An implantable depot as in claim 6, wherein the biologically active substance comprises a diuretic selected from the group consisting of mannitol and furosemide.
10. An implantable depot as in claim 6, wherein the biologically active substance comprises a natriuretic selected from the group consisting of atrial natiuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natgriuretic peptide.
11. A method for delivering biologically active substance to a patient’s renal arteries, said method comprising:
implanting a depot which, when implanted, can release the substance preferentially into at least one renal artery.
12. A method as in claim 11, wherein the implant is a biodegradable implant which is implanted in the vasculature proximate the target renal artery(ies).
13. A method as in claim 12, wherein the implant is implanted in the aorta above the renal arteries.
14. A method as in claim 12, wherein the implant is implanted in at least one renal artery.
15. A method as in claim 11, wherein the implant comprises a refillable reservoir.
16. A method as in claim 15, further comprising periodically refilling the reservoir via a transcutaneous access route.
17. A method as in claim 15, further comprising pumping the biologically active substance from the reservoir to at least one renal artery.
18. A method as in any one of claims 11 to 17, wherein the biologically active substance is selected from the group consisting of vasodilators, antioxidants, and diuretics.
19. A method as in claim 18, wherein the biologically active substance comprises a vasodilator selected from the group consisting of papavarine, fenoldopam mesylate, calcium-channel blockers, acetylcholine, nifedipine, nitroglycerine, nitroprusside, adenosine dopamine, and theophylline.
20. A method as in claim 19, wherein the biologically active substance comprises an antioxidant selected from the group consisting of acetylcystein.
21. A method as in claim 19, wherein the biologically active substance comprises a diuretic selected from the group consisting of mannitol and furosemide.
22. A method as in claim 19, wherein the biologically active substance comprises a natriuretic selected from the group consisting of atrial natiuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide.