Renal-selective prodrugs for control of renal sympathetic nerve activity in the treatment of hypertension

Abstract

Renal-selective prodrugs are described which are preferentially converted in the kidney to compounds capable of inhibiting synthesis of catecholamine-type neurotransmitters involved in renal sympathetic nerve activity. The prodrugs described herein are derived from inhibitor compounds capable of inhibiting one or more of the enzymes involved in catecholamine synthesis, such compounds being classifiable as tyrosine hydroxylase inhibitors, or as dopa-decarboxylase inhibitors, or as dopamine-β-hydroxylase inhibitors. These inhibitor compounds are linked to a chemical moiety, such as a glutamic acid derivative, by a cleavable bond which is recognized selectively by enzymes located predominantly in the kidney. The liberated inhibitor compound is then available in the kidney to inhibit one or more of the enzymes involved in catecholamine synthesis. Inhibition of renal catecholamine synthesis can suppress heightened renal nerve activity associated with sodium-retention related disorders such as hypertension. Conjugates of particular interest are glutamyl derivatives of dopamine-β-hydroxylase inhibitors, of which N-acetyl-γ-glutamyl fusaric acid hydrazide (shown below) is preferred. 1

Description

FIELD OF THE INVENTION

[0002] This invention is in the field of cardiovascular therapeutics and relates to a class of compounds useful in control of hypertension. Of particular interest is a class of compounds which prevent or control hypertension by selective action on the renal sympathetic nervous system.

BACKGROUND OF THE INVENTION

[0003] Hypertension has been linked to increased sympathetic nervous system activity stimulated through any of four mechanisms, namely (1) by increased vascular resistance, (2) by increased cardiac rate, stroke volume and output, (3) by vascular muscle defects or (4) by sodium retention and renin release [J. P. Koepke et al, The Kidney in Hypertension, B. M. Brenner and J. H. Laragh (Editors), Vol. 1, p. 53 (1987)]. As to this fourth mechanism in particular, stimulation of the renal sympathetic nervous system can affect renal function and maintenance of homeostasis. For example, an increase in efferent renal sympathetic nerve activity may cause increased renal vascular resistance, renin release and sodium retention [A. Zanchetti et al, Handbook of Hypertension, Vol. 8, Ch. 8, vasoconstriction has been identified as an element in the pathogenesis of early essential hypertension in man. [R. E. Katholi, Amer. J. Physiol., 245, F1-F14 (1983)].

[0004] Proper renal function is essential to maintenance of homeostasis so as to avoid hypertensive conditions. Excretion of sodium is key to maintaining extracellular fluid volume, blood volume and ultimately the effects of these volumes on arterial pressure. Under steady-state conditions, arterial pressure rises to that pressure level which will cause balance between urinary output and water/salt intake. If a perturbation in normal kidney function occurs causing renal sodium and water retention, as with sympathetic stimulation of the kidneys, arterial pressure will increase to a level to maintain sodium output equal to intake. In hypertensive patients, the balance between sodium intake and output is achieved at the expense of an elevated arterial pressure.

[0005] During the early stages of genetically spontaneous or deoxycorticosterone acetate-sodium chloride (DOCA-NaCl) induced hypertension in rats, a positive sodium balance has been observed to precede hypertension. Also, surgical sympathectomy of the kidneys has been shown to reverse the positive sodium balance and delay the onset of hypertension [R. E. Katholi, Amer. J. Physiol., 245, F1-F14 (1983)]. Other chronic sodium retaining disorders are linked to heightened sympathetic nervous system stimulation of the kidneys. Congestive heart failure, cirrhosis and nephrosis are characterized by abnormal chronic sodium retention leading to edema and ascites. These studies support the concept that renal selective pharmacological inhibition of heightened sympathetic nervous system activity to the kidneys may be an effective therapeutic treatment for chronic sodium-retaining disorders, such as hypertension, congestive heart failure, cirrhosis, and nephrosis.

[0006] One approach to reduce sympathetic nervous system effects on renal function is to inhibit the synthesis of one or more compounds involved as intermediates in the “catecholamine cascade”, that is, the pathway involved in synthesis of the neurotransmitter norepinephrine. Stepwise, these catecholamines are synthesized in the following manner: (1) tyrosine is converted to dopa by the enzyme tyrosine hydroxylase; (2) dopa is converted to dopamine by the enzyme dopa decarboxylase; and (3) dopamine is converted to norepinephrine by the enzyme dopamine-β-hydroxylase. Inhibition of dopamine-β-hydroxylase activity, in particular, would increase the renal vasodilatory, diuretic and natriuretic effects due to dopamine. Inhibition of the action of any of these enzymes would decrease the renal vasoconstrictive, antidiuretic and antinatriuretic effects of norepinephrine. Therapeutically, these effects oppose chronic sodium retention.

[0007] Many compounds are known to inhibit the action of the catecholamine-cascade-converting enzymes. For example, the compound α-methyltyrosine inhibits the action of the enzyme tyrosine hydroxylase. The compound α-methyldopa inhibits the action of the enzyme dopa-decarboxylase, and the compound fusaric acid inhibits the action of dopamine-β-hydroxylase. Such inhibitor compounds often cannot be administered systemically because of the adverse side effects induced by such compounds. For example, the desired therapeutic effects of dopamine-β-hydroxylase inhibitors, such as fusaric acid, may be offset by hypotension-induced compensatory stimulation of the renin-angiotensin system and sympathetic nervous system, which promote sodium and water retention.

[0008] To avoid such systemic side effects, drugs may be targetted to the kidney by creating a conjugate compound that would be a renal-specific prodrug containing the targetted drug modified with a chemical carrier moiety. Cleavage of the drug from the carrier moiety by enzymes predominantly localized in the kidney releases the drug in the kidney. Gamma glutamyl transpeptidase and acylase are examples of such cleaving enzymes found in the kidney which have been used to cleave a targetted drug from its prodrug carrier within the kidney.

[0009] Renal targetted prodrugs are known for delivery of a drug selectively to the kidney. For example, the compound L-γ-glutamyl amide of dopamine when administered to dogs was reported to generate dopamine n vivo by specific enzymatic cleavage by γ-glutamyl transpeptidase [J. J. Kyncl et al, Adv. Biosc., 20, 369-380 (1979)]. In another study, γ-glutamyl and N-acyl-γ-glutamyl derivatives of the anti-bacterial compound sulfamethoxazole were shown to deliver relatively high concentrations of sulfamethoxazole to the kidney which involved enzymatic cleavage of the prodrug by acylamino acid deacylase and γ-glutamyl transpeptidase [M. Orlowski et al, J. Pharmacol. Exp. Ther., 212, 167-172 (1980)]. The N-γ-glutamyl derivatives of 2-, 3-, or 4-aminophenol and p-fluoro-L-phenylalanine have been found to be readily solvolyzed 1 vitro by γ-glutamyl transpeptidase [S. D. J. Magnan et al, J. Med. Chem., 25, 1018-1021 (1982)]. The hydralazine-like vasodilator 2-hydrazino-5-g-butylpyridine (which stimulates guanylate cyclase activity) when substituted with the N-acetyl-γ-glutamyl residue resulted in a prodrug which provided selective renal vasodilation [K. G. Hofbauer et al, J. Pharmacol. Exp. Ther., 212, 838-844 (1985)]. The dopamine prodrug γ-L-glutamyl-L-dopa (“gludopa”) has been shown to be relatively specific for the kidney and to increase renal blood flow, glomerular filtration and urinary sodium excretion in normal subjects [D. P. Worth et al, Clin. Sci. 6, 207-214 (1985)]. In another study, gludopa was reported to an effective renal dopamine prodrug whose activity can be blocked by the dopa-decarboxylase inhibitor carbidopa [R. F. Jeffrey et al, Br. J. Clin. Pharmac., 25, 195-201 (1988)].

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0010] FIG. 1 shows the acute effects of i.v. injection of vehicle and Example #3 conjugate on mean arterial pressure in rats.

[0011] FIG. 2 shows the acute effects of i.v. injection of vehicle and Example #3 conjugate on renal blood flow in rats.

[0012] FIG. 3 shows the chronic effects of i.v. infusion of vehicle and Example #464 conjugate on mean arterial pressure in spontaneously hypertensive rats.

[0013] FIG. 4 shows time-dependent formation of the dopamine-β-hydroxylase inhibitor fusaric acid from the Example #859 conjugate incubated with rat kidney homogenate.

[0014] FIG. 5 shows time-dependent formation of fusaric acid from the Example #859 conjugate incubated with a mixture of purified acylase I and gamma-glutamyl transpeptidase at pH 7.4 and 8.1.

[0015] FIG. 6 shows the concentration-dependent effect of fusaric acid and the Example #859 conjugate on norepinephrine production by dopamine-β-hydroxylase in vitro.

[0016] FIG. 7 shows dopamine-β-hydroxylase inhibition in vitro by fusaric acid, the Example #859 conjugate and possible metabolites at a concentration of 20 μM.

[0017] FIG. 8 shows the acute effects of i.v. injection of fusaric acid and Example #859 conjugate on mean arterial pressure in spontaneously hypertensive rats.

[0018] FIG. 9 shows the acute effects of i.v. injection of fusaric acid and Example #859 conjugate on renal blood flow in spontaneously hypertensive rats.

[0019] FIG. 10 shows the effects of chronic i.v. infusion of vehicle, fusaric acid, and Example #859 conjugate for 5 days on mean arterial pressure in spontaneously hypertensive rats.

[0020] FIG. 11 shows the effects of chronic i.v. infusion of vehicle and Example #863 conjugate for 4 days on mean arterial pressure in spontaneously hypertensive rats.

[0021] FIG. 12 shows the heart tissue concentrations of norepinephrine following the 5 day infusion experiment described in FIG. 10.

[0022] FIG. 13 shows the kidney tissue concentrations of norepinephrine following the 5 day infusion experiment described in FIG. 10.

[0023] FIG. 14 shows the effects of Example #859 conjugate on mean arterial pressure in anesthetized dogs after i.v. injection at three doses, plus vehicle.

[0024] FIG. 15 shows the effects of Example #859 conjugate on renal blood flow in anesthetized dogs after i.v. injection at three doses, plus vehicle.

[0025] FIG. 16 shows the effects of Example #858 conjugate on mean arterial pressure in conscious DOCA hypertensive micropigs after i.v. infusion for three days.

DESCRIPTION OF THE INVENTION

[0026] Treatment of chronic hypertension or sodium-retaining disorders such as congestive heart failure, cirrhosis and nephrosis, may be accomplished by administering to a susceptible or afflicted subject a therapeutically-effective amount of a renal-selective prodrug capable of causing selective blockage of heightened sympathetic nervous system effects on the kidney. An advantage of such renal-selective prodrug therapy resides in reduction or avoidance of adverse side effects associated with systemically-acting drugs.

[0027] A renal-selective prodrug capable of providing renal sympathetic nerve blocking action may be provided by a conjugate comprising a first residue and a second residue connected together by a cleavable bond. The first residue is derived from an inhibitor compound capable of inhibiting formation of a benzylhydroxyamine intermediate in the biosynthesis of an adrenergic neurotransmitter, and wherein said second residue is capable of being cleaved from the first residue by an enzyme located predominantly in the kidney.

[0028] The first and second residues are provided by precursor compounds having suitable chemical moieties which react together to form a cleavable bond between the first and second residues. For example, the precursor compound of one of the residues will have a reactable carboxylic acid moiety and the precursor of the other residue will have a reactable amino moiety or a moiety convertible to a reactable amino moiety, so that a cleavable bond may be formed between the carboxylic acid moiety and the amino moiety. An inhibitor compound which provides the first residue may be selected from tyrosine hydroxylase inhibitor compounds, dopa-decarboxylase inhibitor compounds, dopamine-β-hydroxylase inhibitor compounds, and mimics of any of these inhibitor compounds.

[0029] The inhibitor compounds described herein have been classified as tyrosine hydroxylase inhibitors, or as dopa-decarboxylase inhibitors, or as dopamine-β-hydroxylase inhibitors, for convenience of description. Some of the inhibitor compounds may be classifiable in more than one of these classes. For example, 2-vinyl-3-phenyl-2-aminopropionic acid derivatives are classified herein as tyrosine hydroxylase inhibitors, but such derivatives may also act as dopa-decarboxylase inhibitors. The term “inhibitor compound” means a compound of any of the three foregoing classes and which has the capability to inhibit formation of a benzylhydroxyamine intermediate involved in biosynthesis of an adrenergic neurotransmitter. Thus, a compound which does not inhibit formation of such benzylhydroxyamine intermediate is not embraced by the definition of “inhibitor compound” as used herein. For example, compounds which do not inhibit a benzylhydroxyamine intermediate are the compounds L-dopa and dopamine.

[0030] A class of compounds from which a suitable tyrosine hydroxylase inhibitor compound may be selected to provide the conjugate first residue is represented by Formula I: 2

[0031] wherein each of R1 through R3 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein R4 selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein R5 is selected from —OR6 and 3

[0032] wherein R6 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl, and wherein each of R7 and R8 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein m is a number selected from zero through six;

[0033] wherein A is a phenyl ring of the formula 4

[0034] wherein each of R9 through R13 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, carboxyalkoxy, formyl and a substituted or unsubstituted 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrol-1-yl, 2-carboxypyrrol-1-yl, imidazol-2-ylamino, indol-1-yl, carbozol9-yl, 4,5-dihydro-4-hydroxy-4-trifluoromethylthiazol3-yl, 4-trifluoromethylthiazol-2-yl, imidazol-2-yl and 4,5-dihydroimidazol-2-yl; wherein any two of the R9 through R13 groups may be taken together to form a benzoheterocylic ring selected from the group consisting of indolin-5-yl, 1-(N-benzoylcarbamimidoyl)indolin5-yl, 1-carbamimidoylindolin-5-yl, 1H-2-oxindol-5-yl, insol-5-yl, 2-mercaptobenzimidazol-5(6)-yl, 2-aminobenzimidazol-5-(6)-yl, 2-methanesulfonamidobenzimidazol-5(6)-yl, 1H-benzoxanol-2-on-6-yl, 2aminobenzothiazol-6-yl, 2-amino-4-mercaptobenzothiazol6-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-2,2-dioxo-2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-1,3-dimethyl2,2-dioxo-2,1,3-benzothiadiazol-5-yl, 4-methyl-2(H)oxoquinolin-6-yl, quinoxalin-6-yl, 2-hydroxyquinoxalin-6-yl, 2-hydroxquinoxalin-7-yl, 2,3-dihydroxyquinoxalin6-yl and 2,3-didydro-3 (4H)-oxo-1,4-benzoxazin-7-yl; 5-hydroxy-4H-pyran-4-on-2-yl, 2-hydroxypyrid-4-yl, 2-aminopyrid-4-yl, 2-carboxypyrid-4-yl and tetrazolo-[1,5-a]pyrid-7-yl;

[0035] and wherein A may be selected from 5

[0036] wherein each of R14 through R20 is independently selected from hydrido, alkyl, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, aryloxy, alkoxycarboxyl, aryl, aralkyl, cyano, cyanoalkyl, amino, monoalkylamino and dialkylamino, wherein each of R21 and R22 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; or a pharmaceutically-acceptable salt thereof.

[0037] A preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula II: 6

[0038] wherein each of R1 and R2 is hydrido; wherein m is one or two; wherein R3 is selected from alkyl, alkenyl and alkynyl; wherein R4 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein R5 is selected from —OR6 and 7

[0039] wherein R6 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl and phenyl, and wherein each of R7 and R8 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R9 through R13 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxycarbonyl, alkoxycarbonyl, alkoxy, arykoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, pyrrol-1-yl 2-carboxypyrrol-1-yl, imidazol-2-ylamino, indol-1-yl, carbazol-9-yl, 4,5-dihydro-4-trifluoromethylthiazol-3-yl, 4-trifluoromethylthiazol-2-yl, imidazol-2-yl and 4,5-dihydroimidazol-2-yl, and wherein any two of the R9 through R13 groups may be taken together to form a benzoheterocyclic ring selected from the group consisting of indolin-5-yl, 1-(N-benzoylcarbamimidoyl)indolin-5-yl, 1-carbamimidoylindolin-5-yl, 1H-2-oxindol-5-yl, indol-5-yl, 2-mercaptobenzimidazol-5(6)-yl, 2-aminobenzimidazol5-(6)-yl, 2-methanesulfonamidobenzimidazol-5(6)-yl, 1H-benzoxanol-2-on-6-yl, 2-amino-benzothiazol-6-yl, 2-amino-4-mercaptobenzothiazol-6-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-2,2-dioxo-2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-1,3-dimethyl-2,2-dioxo-2,1,3benzothiadiazol-5-yl, 4-methyl-2(H)-oxoquinolin-6-yl, quinoxalin-6-yl, 2-hydroxyquinoxalin-6-yl, 2-hydroxquinoxalin-7-yl, 2,3-dihydroxyquinoxalin-6-yl and 2,3-didydro-3(4H)-oxo-1,4-benzoxazin-7-yl; wherein R3 is —CH═CH2 or —C≡CH; wherein R5 is selected from —OR6 and 8

[0040] wherein R6 is selected from hydrido, alkyl, hydroxy, hydroxyalkyl, alkoxy, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino; and wherein each of R7 and R8 independently is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; or a pharmaceutically-acceptable salt thereof.

[0041] A first sub-class of preferred tyrosine hydroxylase inhibitor compounds consists of the following specific compounds within Formula II:

[0042] 4-cyanoamino-α-methylphenyalanine;

[0043] 3-carboxy-α-methylphenylalanine;

[0044] 3-cyano-α-methylphenylalanine methyl ester;

[0045] α-methyl-4-thiocarbamoylphenylalanine methyl ester;

[0046] 4-(aminomethyl)-α-methylphenylalanine;

[0047] 4-guanidino-α-methylphenylalanine;

[0048] 3-hydroxy-4-methanesulfonamido-α-methylphenylalanine;

[0049] 3-hydroxy-4-nitro-α-methylphenylalanine;

[0050] 4-amino-3-methanesulfonyloxy-α-methylphenylalanine;

[0051] 3-carboxymethoxy-4-nitro-α-methylphenylalanine;

[0052] α-methyl-4-amino-3-nitrophenylalanine;

[0053] 3,4-diamino-α-methylphenylalanine;

[0054] α-methyl-4-(pyrrol-1-yl)phenylalanine;

[0055] 4-(2-aminoimidazol-1-yl)-α-methylphenylalanine;

[0056] 4-(imidazol-2-ylamino)-α-methylphenylalanine;

[0057] 4-(4,5-dihydro-4-hydroxy-4-trifluoromethyl-thiazol-2yl)-a-methylphenylalanine methyl ester;

[0058] α-methyl-4-(4-trifluoromethylthiazol-2-yl) phenylalanine;

[0059] α-methyl-3-(4-trifluoromethylthiazol-2-yl)-phenylalanine;

[0060] 4-(imidazol-2-yl)-α-methylphenylalanine;

[0061] 4-(4,5-dihydroimidazol-2-yl)-α-methylphenylalanine;

[0062] 3-(imidazol-2-yl)-α-methylphenylalanine;

[0063] 3-(4,5-dihydroimidazol-2-yl)-a-methylphenylalanine;

[0064] 4-(imidazol-2-yl)phenylalanine;

[0065] 4,5-dihydroimidazol-2-yl)phenylalanine;

[0066] 3-(imidazol-2-yl)phenylalanine;

[0067] 3-(2,3-dihydro-1H-indol-4-yl)-α-methylalanine;

[0068] α-methyl-3-(1H-2-oxindol-5-yl)alanine;

[0069] 3-[1-(N-benzoylcarbamimidoyl)-2,3-dihydro-1Hindol-5-yl)-α-methylalanine;

[0070] 3-(1-carbamimidoyl-2,3-dihydro-1H-indol-5-yl-α-methylalanine;

[0071] 3-(1H-indol-5-yl-α-methylalanine;

[0072] 3-(benzimidazol-2-thione-5-yl)-α-methylalanine;

[0073] 3-(2-aminobenzimidazol-5-yl-2-methylalanine;

[0074] 2-methyl-3-(benzoxazol-2-on-6-yl)alanine;

[0075] 3-(2-aminobenzothiazol-6-yl)-2-methylalanine;

[0076] 3-(2-amino-4-mercaptobenzothiazol-6-yl)-2methylalanine;

[0077] 3-(2-aminobenzothiazol-6-yl)alanine;

[0078] 2-methyl-3-(2,1,3-benzothiadiazol-5-yl)alanine;

[0079] 3-(1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl)-2-methylalanine-2,2-dioxide;

[0080] 3-(1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl)-2-methylalanine-2,2-dioxide methyl ester;

[0081] 3-(1,3-dihydrobenzo-2,1,3-thiadiaxol-5-yl)alanine 2,2-dioxide;

[0082] 3-(1,3-dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5yl-)-2-methylalanine 2,2-dioxide;

[0083] α-methyl-3-[4-methyl-2(1H)-oxoquinolin-6-yl]alanine;

[0084] 3-[4-methyl-2(1H)-oxoquinolin-6-yl]alanine;

[0085] 2-methyl-3-(quinoxalin-6-yl)alanine;

[0086] 2-methyl-3-(2-hydroxyquinoxalin-6-yl)alanine;

[0087] 2-methyl-3-(2-hydroxyquinoxalin-7-yl)alanine;

[0088] 3-(2,3-dihydroxyquinoxalin-6-yl)-2-methylalanine;

[0089] 3-(quinoxalin-6-yl)alanine;

[0090] 3-(2,3-dihydroxyquinoxalin-6-yl)alanine;

[0091] 3-(1,4-benzoxazin-3-one-6-yl)-2-methylalanine;

[0092] 3-(1,4-benzoxazin-3-one-7-yl)alanine;

[0093] 3-(5-hydroxy-4H-pyran-4-on-2-yl)-2-methylalanine;

[0094] 3-(2-hydroxy-4-pyridyl)-2-methylalanine;

[0095] 3-(2-carboxy-4-pyridyl)-2-methylamine;

[0096] α-methyl-4-(pyrrol-1-yl)phenylalanine;

[0097] α-ethyl-4-(pyrrol-1-yl)phenylalanine;

[0098] α-propyl-4-(pyrrol-1-yl)phenylalanine;

[0099] 4-[2-(carboxy) pyrrol-1-yl) phenylalanine;

[0100] α-methyl-4-(pyrrol-1-yl)phenylalanine;

[0101] 3-hydroxy-α-4-(pyrrol-1-yl)phenylalanine;

[0102] 3-methoxy-α-4-(pyrrol-1-yl)phenylalanine;

[0103] 4-methoxy-α-3-(pyrrol-1-yl)phenylalanine;

[0104] 4-(indol-1-yl)-α-methylphenylalanine;

[0105] 4-(carbazol-9-yl)-α-methylphenylalanine;

[0106] 2-methyl-3-(2-methanesulfonylamidobenzimidazol-5-yl)alanine;

[0107] 2-methyl-3-(2-amino-4-pyridyl)alanine;

[0108] 2-methyl-3[tetrazolo-(1,5)-α-pyrid-7-yl]alanine;

[0109] D,L-α-β-(4-hydroxy-3-methyl)phenylalanine;

[0110] D,L-α-β-(4-hydroxy-3-phenyl)phenylalanine;

[0111] D,L-α-β-(4-hydroxy-3-benzyl)phenylalanine;

[0112] D,L-α-β-(4-methoxy-3-cyclohexyl)phenylalanine;

[0113] α, β, β trimethyl-β-(3,4-dihydroxyphenyl)alanine;

[0114] α, β, β trimethyl-β-(4-hydroxyphenyl)alanine;

[0115] N-methyl α, β, β trimethyl-β-(3,4-dihydroxphenyl) alanine;

[0116] D,L α, β, β trimethyl-β-(3,4-dihydroxyphenyl)alanine;

[0117] trimethyl-β-(3,4-dimethoxyphenyl)alanine;

[0118] L-α-methyl-β-3,4-dihydroxyphenylalanine;

[0119] L-α-ethyl-β-3,4-dihydroxyphenylalanine;

[0120] L-α-propyl-β-3,4-dihydroxyphenylalanine;

[0121] L-α-butyl-β-3,4-dihydroxyphenylalanine;

[0122] L-α-methyl-β-2,3-dihydroxphenylalanine;

[0123] L-α-ethyl-β-2,3-dihydroxphenylalanine;

[0124] L-α-propyl-β-2,3-dihydroxphenylalanine;

[0125] L-α-butyl-β-2,3-dihydroxphenylalanine;

[0126] L-α-methyl-4-chloro-2,3-dihydroxyphenylalanine;

[0127] L-α-ethyl-4-chloro-2,3-dihydroxyphenylalanine;

[0128] L-α-propyl-4-chloro-2,3-dihydroxyphenylalanine;

[0129] L-α-butyl-4-chloro-2,3-dihydroxyphenylalanine;

[0130] L-α-ethyl-β-4-methyl-2,3-dihydroxyphenylalanine;

[0131] L-α-methyl-β-4-methyl-2,3-dihydroxyphenylalanine;

[0132] L-α-propyl-β-4-methyl-2,3-dihydroxyphenylalanine;

[0133] L-α-butyl-β-4-methyl-2,3-dihydroxyphenylalanine;

[0134] L-α-methyl-β-4-fluoro-2,3-dihydroxyphenylalanine;

[0135] L-α-methyl-β-4-fluoro-2,3-dihydroxyphenylalanine;

[0136] L-α-propyl-β-4-fluoro-2,3-dihydroxyphenylalanine;

[0137] L-α-butyl-β-4-fluoro-2,3-dihydroxyphenylalanine;

[0138] L-α-methyll-b-4-trifluoromethyl-2,3-dihydroxyphenyl alanine

[0139] L-α-ethyl-β-4-trifluoromethyl-2,3-dihydroxyphenyl alanine

[0140] L-α-propyl-β-4-trifluoromethyl-2,3-dihydroxyphenyl alanine

[0141] L-α-butyl-β-4-trifluoromethyl-2,3-dihydroxyphenyl alanine

[0142] L-α-methyl-β-3,5-dihydroxyphenylalanine;

[0143] L-α-ethyl-β-3,5-dihydroxyphenylalanine;

[0144] L-α-propyl-β-3,5-dihydroxyphenylalanine;

[0145] L-α-butyl-β-3,5-dihydroxyphenylalanine;

[0146] L-α-methyl-β-4-chloro-3,5-dihydroxphenylalanine;

[0147] L-α-ethyl-β-4-chloro-3,5-dihydroxphenylalanine;

[0148] L-α-propyl-β-4-chloro-3,5-dihydroxphenylalanine;

[0149] L-α-butyl-β-4-chloro-3,5-dihydroxphenylalanine;

[0150] L-α-methyl-β-4-fluoro-3,5-dihydroxyphenylalanine;

[0151] L-α-ethyl-β-4-fluoro-3,5-dihydroxyphenylalanine;

[0152] L-α-propyl-β-4-fluoro-3,5-dihydroxyphenylalanine;

[0153] L-α-butyl-β-4-fluoro-3,5-dihydroxyphenylalaninei

[0154] L-α-methyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine;

[0155] L-α-ethyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine;

[0156] L-α-propyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine;

[0157] L-α-butyl-α-4-trifluoromethyl-3,5-dihydroxyphenylalanine;

[0158] L-α-methyl-2,5-dihydroxphenylalanine;

[0159] L-α-ethyl-2,5-dihydroxphenylalanine;

[0160] L-α-propyl-2,5-dihydroxphenylalanine;

[0161] L-α-butyl-2,5-dihydroxphenylalanine;

[0162] L-α-methyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0163] L-α-ethyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0164] L-α-propyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0165] L-α-butyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0166] L-α-methyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0167] L-α-ethyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0168] L-α-propyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0169] L-α-butyl-β-4-chloro-2,5-dihydroxyphenylalanine;

[0170] L-α-methyl-β-methyl-2,5-dihydroxyphenylalanine;

[0171] L-α-ethyl-β-methyl-2,5-dihydroxyphenylalanine;

[0172] L-α-propyl-β-4-methyl-2,5-dihydroxyphenylalanine;

[0173] L-α-butyl-β-4-methyl-2,5-dihydroxyphenylalanine;

[0174] L-α-methyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine;

[0175] L-α-ethyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine;

[0176] L-α-propyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine;

[0177] L-α-butyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine;

[0178] L-α-methyl-β-3,4,5-trihydroxyphenylalanine;

[0179] L-α-ethyl-β-3,4,5-trihydroxyphenylalanine;

[0180] L-α-propyl-β-3,4,5-trihydroxyphenylalanine;

[0181] L-α-butyl-β-3,4,5-trihydroxyphenylalanine;

[0182] L-α-methyl-β-2,3,4-trihydroxyphenylalanine;

[0183] L-α-ethyl-β-2,3,4-trihydroxyphenylalanine;

[0184] L-α-propyl-β-2,3,4-trihydroxyphenylalanine;

[0185] L-α-butyl-β-2,3,4-trihydroxyphenylalanine;

[0186] L-α-methyl-β-2,4,5-trihydroxyphenylalanine;

[0187] L-α-ethyl-β-2,4,5-trihydroxyphenylalanine;

[0188] L-α-propyl-β-2,4,5-trihydroxyphenylalanine;

[0189] L-α-butyl-β-2,4,5-trihydroxyphenylalanine;

[0190] L-phenylalanine;

[0191] D,L-α-methylphenylalanine;

[0192] D,L-3-iodophenylalanine;

[0193] D,L-3-iodo-α-methylphenylalanine;

[0194] 3-iodotyrosine;

[0195] 3,5-diiodotyrosine;

[0196] L-α-methylphenylalanine;

[0197] D,L-α-β-(4-hydroxy-3-methylphenyl)alanine;

[0198] D,L-α-β-(4-methoxy-3-benzylphenyl) alanine;

[0199] D,L-α-β-(4-hydroxy-3-benzylphenyl) alanine;

[0200] D,L-α-β-(4-methoxy-3-cyclohexylphenyl) alanine;

[0201] D,L-α-β-(4-hydroxy-3-cyclohexylphenyl) alanine;

[0202] D,L-α-β-(4-methoxy-3-methylphenyl) alanine;

[0203] D,L-α-β-(4-hydroxy-3-methylphenyl)alanine;

[0204] N,O-dibenzyloxycarbonyl-D,L-α-β-(4-hydroxy-3-methylphenyl)alanine;

[0205] N,O-dibenzyloxycarbonyl-D,L-α-β-(4-hydroxy-3-methylphenyl)alanine amide;

[0206] D,L-α-β-(4-hydroxy-3-methylphenyl) alanine amide;

[0207] N,O-diacetyl-D,L-α-β-(4-hydroxy-3-methylphenyl)alanine;

[0208] D,L-N-acetyl-α-β-(4-hydroxy-3-methylphenyl)alanine;

[0209] L-3,4-dihydroxy-α-methylphenylalanine;

[0210] L-4-hydroxy-3-methoxy-α-methylphenylalanine;

[0211] L-3,4-methylene-dioxy-α-methylphenylalanine;

[0212] 2-vinyl-2-amino-3-(2-methoxyphenyl)propionic acid;

[0213] 2-vinyl-2-amino-3-(2,5-dimethoxyphenyl)propionic acid;

[0214] 2-vinyl-2-amino-3-(2-imidazolyl)propionic acid;

[0215] 2-vinyl-2-amino-3-(2-methoxyphenyl) propionic acid ethyl ester;

[0216] α-methyl-β-(2,5-dimethoxyphenyl)alanine;

[0217] α-methyl-β-(2,5-dihydroxyphenyl)alanine;

[0218] α-ethyl-β-(2,5-dimethoxyphenyl)alanine;

[0219] α-ethyl-β-(2,5-dihydroxyphenyl)alanine;

[0220] α-methyl-β-(2,4-dimethoxyphenyl)alanine;

[0221] α-methyl-β-(2,4-dihydroxyphenyl)alanine;

[0222] α-ethyl-β-(2,4-dimethoxyphenyl)alanine;

[0223] α-ethyl-β-(2,4-dihydroxyphenyl)alanine;

[0224] α-methyl-β-(2,5-dimethoxyphenyl)alanine ethyl ester;

[0225] 2-ethynyl-2-amino-3-(3-indolyl)propionic acid;

[0226] 2-ethynyl-2,3-(2-methoxyphenyl)propionic acid;

[0227] 2-ethynyl-2,3-(5-hydroxyindol-3-yl)propionic acid;

[0228] 2-ethynyl-2-amino-3-(2,5-dimethoxyphenyl)propionic acid;

[0229] 2-ethynyl-2-amino-3-(2-imidazolyl)propionic acid;

[0230] 2-ethynyl-2-amino-3-(2-methoxyphenyl)propionic acid ethyl ester;

[0231] 3-carbomethoxy-3-(4-benzyloxybenzyl)-3-aminoprop-1-yne;

[0232] α-ethynyltyrosine hydrochloride;

[0233] α-ethynyltyrosine;

[0234] α-ethynyl-m-tyrosine;

[0235] α-ethynyl-β-(2-methoxyphenyl)alanine;

[0236] α-ethynyl-β-(2,5-dimethoxyphenyl)alanine; and

[0237] α-ethynylhistidine.

[0238] A second sub-class of preferred tyrosine hydroxylase inhibitor compounds consists of compounds wherein at least one of R10, R11 and R12 is selected from hydroxy, alkoxy, aryloxy, aralkoxy and alkoxycarbonyl. More preferred compounds of this second sub-class are

[0239] α-methyl-3-(pyrrol-1-yl)tyrosine;

[0240] α-methyl-3-(4-trifluoromethylthiazol-2-yl)tyrosine;

[0241] 3-(imidazol-2-yl)-α-methyltyrosine;

[0242] Lα-m-tyrosine;

[0243] L-α-ethyl-m-tyrosine;

[0244] L-α-propyl-m-tyrosine;

[0245] L-α-butyl-m-tyrosine;

[0246] Lα-p-chloro-m-tyrosine;

[0247] L-α-ethyl-p-chloro-m-tyrosine;

[0248] L-α-butyl-p-chloro-m-tyrosine;

[0249] Lα-p-bromo-m-tyrosine;

[0250] L-α-ethyl-p-bromo-m-tyrosine;

[0251] L-α-butyl-p-bromo-m-tyrosine;

[0252] Lα-p-fluoro-m-tyrosine;

[0253] Lα-p-iodo-m-tyrosine;

[0254] L-α-ethyl-p-iodo-m-tyrosine;

[0255] Lα-p-methyl-m-tyrosine;

[0256] Lα-p-ethyl-m-tyrosine;

[0257] L-α-ethyl-p-ethyl-m-tyrosine;

[0258] L-α-ethyl-p-methyl-m-tyrosine;

[0259] Lα-p-butyl-m-tyrosine;

[0260] Lα-p-trifluoromethyl-m-tyrosine;

[0261] L-3-iodotyrosine;

[0262] L-3-chlorotyrosine;

[0263] L-3,5-diiodotyrosine;

[0264] L-α-methyltyrosine;

[0265] D,L-α-methyltyrosine;

[0266] D,L-3-iodo-α-methyltyrosine;

[0267] L-3-bromo-α-methyltyrosine;

[0268] D,L-3-bromo-α-methyltyrosine;

[0269] L-3-chloro-α-methyltyrosine;

[0270] D,L-3-chloro-α-methyltyrosine; and

[0271] 2-vinyl-2-amino-3-(4-hydroxyphenyl)propionic acid.

[0272] Another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I consists of compounds 9

[0273] wherein R3 is selected from alkyl, alkenyl and alkynyl; wherein R4 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein m is a number selected from zero through five, inclusive; wherein R5 is selected from OR6 and 10

[0274] wherein R6 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl and phenyl, and wherein each of R7 and R8 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R9 through R13 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxycarbonyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, alkoxycarbonyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl.

[0275] A preferred sub-class of compounds within Formula III consists of compounds wherein at least one of R10, R11 and R12 is selected from hydroxy, alkoxy, aryloxy, aralkoxy and alkoxycarbonyl. More preferred compounds of this sub-class are methyl (+)-2-(4-hydroxyphenyl) glycinate; isopropyl and 3-methyl butyl esters of (+)-2-(4-hydroxyphenyl)glycine; (+)-2-(4-hydroxyphenyl)glycine; (−)-2-(4-hydroxyphenyl)glycine; (+)-2-(4-methoxyphenyl-glycine; and (+)-2-(4-hydroxyphenyl)glycinamide.

[0276] Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula IV: 11

[0277] wherein each of R1 and R2 is hydrido; wherein m is a number selected from zero through five, inclusive; wherein R3 is selected from alkyl, alkenyl and alkynyl; wherein R4 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R14 through R17 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, carboxyalkoxy and formyl.

[0278] A preferred sub-class of compounds within Formula IV consists of L-α-methyltryptophan; D,L-5-methyltryptophan; D,L-5-chlorotryptophan; D,L-5-bromotryptophan; D,L-5-iodotryptophan; L-5-hydroxytryptophan; D,L-5-hydroxy-α-methyltryptophan; α-ethynyltryptophan; 5-methoxymethoxy-α-ethynyltryptophan; and 5-hydroxy-α-ethynyltryptophan.

[0279] Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds wherein A is 12

[0280] wherein R6 is selected from three, inclusive. More preferred compounds in this class are 2-vinyl-2-amino-5-aminopentanoic acid and 2-ethynyl-2-amino-5-aminopentanoic acid.

[0281] Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula V: 13

[0282] wherein each of R23 and R24 is independently selected from hydrido, hydroxy, alkyl, cycloakyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein R25 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R26 through R35 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, alkoxy and formyl; wherein n is a number selected from zero through five, inclusive; or a pharmaceutically-acceptable salt thereof. A more preferred compound of this class is benzoctamine.

[0283] A class of compounds from which a suitable dopa-decarboxylase inhibitor compound may be selected to provide the conjugate first residue is represented by Formula VI: 14

[0284] wherein each of R36 through R42 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, carboxyalkoxy and formyl; wherein n is a number from zero through four; wherein each of R43 and R44 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, monoalkylcarbonylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, alkenyl, cycloalkenyl and alkynyl; wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl; with the proviso that R43 and R44 cannot both be carboxyl at the same time, with the further proviso that when R36 is hydrido then R37 cannot be carboxyl, and with the further proviso that at least one of R43 through R44 is a primary or secondary amino group; or a pharmaceutically-acceptable salt thereof.

[0285] A preferred class of compounds within Formula VI consists of compounds wherein each of R36 through R42 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, aminomethyl, carboxyalkoxy and formyl; wherein n is a number from one through three; wherein each of R43 and R44 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl and alkanoyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl.

[0286] A more preferred class of compounds within Formula VI consists of those compounds wherein each of R36 through R42 is independently selected from hydrido, hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, cyanoamino, cyano, aminomethyl, carboxyl, carboxyalkoxy and formyl; wherein n is one or two; wherein each of R43 and R44 is independently selected from hydrido, alkyl, benzyl, phenyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl and alkanoyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl.

[0287] An even more preferred class of compounds within Formula VI consists of those compounds wherein each of R36 through R42 is independently selected from hydrido, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein n is one or two; wherein each of R43 and R44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl.

[0288] A more highly preferred class of compounds within Formula VI consists of those compounds wherein each of R36 and R37 is hydrido and n is one; wherein each of R38 through R42 is independently selected from hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein each of R43 and R44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl. Compounds of specific interest are (2,3,4-trihydroxy)-benzylhydrazine, 1-(D,L-seryl-2(2,3,4-trihydroxybenzyl)hydrazine (Benserazide) and 1-(3-hydroxylbenzyl)-1-methylhydrazine.

[0289] Another more highly preferred class of compounds consists of those compounds wherein each of R36 and R37 is independently selected from hydrido, alkyl and amino and n is two; wherein each of R38 through R42 is independently selected from hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein each of R43 and R44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl. Compounds of specific interest are 2-hydrazino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid (Carbidopa), α-(monofluoromethyl)dopa, α-(difluoromethyl)dopa and α-methyldopa.

[0290] Another class of compounds from which a suitable dopa-decarboxylase inhibitor compound may be selected to provide the conjugate first residue is represented by Formula VII 15

[0291] wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, carboxyalkoxy and formyl; wherein each of R49 and R50 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl and 16

[0292] wherein R51 is selected from hydroxy, alkoxy, aryloxy, aralkoxy, amino, monoalkylamino and dialkylamino with the proviso that R49 and R50 cannot both be carboxyl at the same time, and with the further proviso that at least one of R45 through R48 is a primary or secondary amino group or a carboxyl group; or a pharmaceutically-acceptable salt thereof.

[0293] A preferred class of compounds within Formula VII consists of those compounds wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, aminomethyl, carboxyalkoxy and formyl; wherein each of R49 and R50 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkyl and alkanoyl and 17

[0294] wherein R51 is selected from hydroxy, alkoxy, phenoxy, benzyloxy, amino, monoalkylamino and dialkylamino.

[0295] A more preferred class of compounds within Formula VII consists of those compounds wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, cyanoamino, cyano, aminomethyl, carboxyalkoxy and formyl; wherein each of R49 and R50 s independently selected from hydrido, alkyl, benzyl, phenyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkyl and alkanoyl and 18

[0296] wherein R51 is selected from hydroxy, alkoxy, amino and monoalkylamino.

[0297] An even more preferred class of compounds of Formula VII consists of those compounds wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl aminomethyl, carboxyalkoxy and formyl; wherein each of R49 and R50 is independently selected from hydrido, alkyl, amino, monoalkylamino, carboxyalkyl and 19

[0298] wherein R51 is selected from hydroxy, alkoxy, amino and monoalkylamino.

[0299] A highly preferred class of compounds within Formula VII consists of those compounds wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, alkoxy and hydroxyalkyl; wherein each of R49 and R50 is independently selected from alkyl, amino, monoalkylamino, and 20

[0300] wherein R51 is selected from hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino and ethylamino.

[0301] A more highly preferred class of compounds within Formula VII consists of those compounds wherein said inhibitor compound is selected from endo-2-aminol,2,3,4-tetrahydro-1,2-ethanonaphthalene-2-carboxylic acid; ethylendo-2-amino-1,2,3,4-tetra-hydro-1,4-ethano-naphthalene-2-carboxylate hydrochloride; exo-2-aminol,2,3,4-tetrahydro-1,4-ethanonaphthalene-2-carboxylic acid; and ethyl-exo-2-amino-1,2,3,4-tetrahydro-1,4-ethano-naphthalene-2-carboxylate hydrochloride.

[0302] Another family of specific dopa-decarboxylase inhibitor compounds consists of

[0303] 2,3-dibromo-4,4-bis(4-ethylphenyl)-2-butencic acid;

[0304] 3-bromo-4-(4-methoxyphenyl)-4-oxo-2-butenoic acid;

[0305] N-(5′-phosphopyridoxyl)-L-3,4-dihydroxyphenylalanine;

[0306] N-(5′-phosphopyridoxyl)-L-m-aminotyrosine;

[0307] D,L-β-(3,4-dihydroxyphenyl)lactate;

[0308] D,L-β-(5-hydroxyindolyl-3)lactate;

[0309] 2,4-dihydroxy-5-(1-oxo-2-propenyl)benzoic acid;

[0310] 2,4-dimethoxy-5-[1-oxo-3-(2,3,4-trimethoxyphenyl-2-propenyl]benzoic acid;

[0311] 2,4-dihydroxy-5-[1-oxo-3-(2-thienyl)-2-propenyl] benzoic acid;

[0312] 2,4-dihydroxy-5-[3-(4-hydroxyphenyl)-1-oxo-2-propenyl] benzoic acid;

[0313] 5-[3-(4-chlorophenyl)-1-oxo-2-propenyl]-2,4-dihydroxy benzoic acid;

[0314] 2,4-dihydroxy-5-(1-oxo-3-phenyl-2-propenyl)benzoic acid;

[0315] 2,4-dimethoxy-5-[1-oxo-3-(4-pyridinyl)-2-propenyl] benzoic acid;

[0316] 5-[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-2,4 dimethoxy benzoic acid;

[0317] 2,4-dimethoxy-5-(1-oxo-3-phenyl-2-propenyl)benzoic acid;

[0318] 5-[3-(2-furanyl)-1-oxo-2-propenyl]-2,4-dimethoxy benzoic acid;

[0319] 2,4-dimethoxy-5-[1-oxo-3-(2-thienyl)-2-propenyl] benzoic acid;

[0320] 2,4-dimethoxy-5-[3-(4-methoxyphenyl)-1-oxo-2-propenyl] benzoic acid;

[0321] 5-[3-(4-chlorophenyl)-1-oxo-2-propenyl]-2,4-dimethoxy benzoic acid; and

[0322] 5-[3-[4-(dimethylamino)phenyl]-1-oxo-2-propenyl]-2,4 dimethoxy benzoic acid.

[0323] Another class of compounds from which a suitable dopa-decarboxylase inhibitor may be selected to provide the conjugate first residue is represented by Formula VIII: 21

[0324] wherein R52 is selected from hydrido, OR64 and 22

[0325] wherein R64is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl and phenyl, and wherein each of R65 and R66 is independently selected from hydrido, alkyl, alkanoyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl; wherein each of R53, R54 and R57 through R63 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxycarbonyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein each of R55 and R56 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, halo, haloalkyl, hydroxyalkyl and carboxyalkyl; wherein each of m and n is a number independently selected from zero through six, inclusive; or a pharmaceutically-acceptable salt thereof.

[0326] A preferred class of compounds of Formula VIII consists of those compounds wherein R52 is OR64 wherein R64 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, benzyl and phenyl; wherein each of R53, R54 and R57 through R63 is independently selected from hydrido, alkyl, cycloalkyl, hydroxy, alkoxy, benzyl and phenyl; wherein each of R55 and R56 is independently selected from hydrido, alkyl, cycloalkyl, benzyl and phenyl; wherein each of m and n is a number independently selected from zero through three, inclusive.

[0327] A more preferred class of compounds of Formula VIII consists of those compounds wherein R52 is OR64 wherein R64 is selected from hydrido and lower alkyl; wherein each of R53 through R58 is hydrido; wherein each of R59 through R63 is independently selected from hydrido, alkyl, hydroxy and alkoxy, with the proviso that two of the R59 through R63 substituents are hydroxy; wherein each of m and n is a number independently selected from zero through two, inclusive.

[0328] A preferred compound within Formula IX is 3-(3,4-dihydroxyphenyl)-2-propenoic acid, also known as caffeic acid.

[0329] Another class of compounds from which a suitable dopa-decarboxylase inhibitor compound may be selected to provide the conjugate first residue is a class of aromatic amino acid compounds comprising the following subclasses of compounds:

[0330] amino-haloalkyl-hydroxyphenyl propionic acids, such as 2-amino-2-fluoromethyl-3hydroxyphenylpropionic acid;

[0331] alpha-halomethyl-phenylalanine derivatives such as alpha-fluoroethylphenethylamine; and

[0332] indole-substituted halomethylamino acids.

[0333] Still other classes of compounds from which a suitable dopa-decarboxylase inhibitor compound may be selected to provide the conjugate first residue are as follows:

[0334] isoflavone extracts from fungi and streptomyces, such as 3′,5,7-trihydroxy-4′,6-dimethoxyisoflavone, 3′,5,7-trihydroxy-4′,8-dimethoxyisoflavone and 3′,8-dihydroxy-4′,6,7-trimethoxyisoflavone;

[0335] sulfinyl substituted dopa and tyrosine derivatives such as shown in U.S. Pat. No. 4,400,395 the content of which is incorporated herein by reference;

[0336] hydroxycoumarin derivatives such as shown in U.S. Pat. No. 3,567,832, the content of which is incorporated herein by reference;

[0337] 1-benzylcyclobutenyl alkyl carbamate derivatives such as shown in U.S. Pat. No. 3,359,300, the content of which is incorporated herein by reference;

[0338] arylthienyl-hydroxylamine derivatives such as shown in U.S. Pat. No. 3,192,110, the content of which is incorporated herein by reference; and

[0339] β-2-substituted-cyclohepta-pyrrol-8-1H-on-7-yl alanine derivatives.

[0340] Suitable dopamine-β-hydroxylase inhibitors may be generally classified mechanistically as chelating-type inhibitors, time-dependent inhibitors and competitive inhibitors.

[0341] A class of compounds from which a suitable dopamine-β-hydroxylase inhibitor may be selected to provide the conjugate first residue consists of time-dependent inhibitors represented by Formula IX: 23

[0342] wherein B is selected from aryl, an ethylenic moiety, an acetylenic moiety and an ethylenic or acetylenic moiety substituted with one or more radicals selected from substituted or unsubstituted alkyl, aryl and heteroaryl; wherein each of R67 and R68 is independently selected from hydrido, alkyl, alkenyl and alkynyl; wherein R69 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein n is a number selected from zero through five.

[0343] A preferred class of compounds of Formula IX consists of those compounds wherein B is phenyl or hydroxyphenyl; wherein R67is ethenyl or ethynyl; or an acetylenic moiety substituted with an aryl or heteroaryl radical; and wherein n is a number from zero through three.

[0344] Another preferred class of compounds of Formula IX consists of those compounds wherein B is an ethylenic or acetylenic moiety incorporating carbon atoms in the beta- and gamma-positions relative to the nitrogen atom; and wherein n is zero or one. More preferred are compounds wherein the ethylenic or acetylenic moiety is substituted at the gamma carbon with an aryl or heteroaryl radical. Even more preferred are compounds wherein said aryl radical is selected from phenyl, 2-thiophene, 3-thiophene, 2-furanyl, 3-furanyl, oxazolyl, thiazolyl and isoxazolyl, any one of which radicals may be substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cyano, alkoxy, alkoxyalkyl and cycloalkyl. More highly preferred are compounds wherein said aryl radical is selected from phenyl, hydroxyphenyl, 2-thiophene and 2-furanyl; and wherein each of R67, R68 and R69 is hydrido.

[0345] A family of specifically-preferred compounds within Formula IX consists of the compounds 3-amino-2-(2′-thienyl)propene; 3-amino-2-(2′-thienyl)butene; 3-(N-methylamino)-2-(2′-thienyl)propene; 3-amino-2-(3′-thienyl)propene; 3-amino-2-(2′furanyl)propene; 3-amino-2-(3′-furanyl)propene; 1-phenyl-3aminopropyne; and 3-amino-2-phenylpropene. Another family of specifically-preferred compounds of Formula VIII consists of the compounds (±)4-amino-3-phenyl-1-butyne; (±)4-amino-3-(3′-hydroxyphenyl)-1-butyne; (±)4-amino-3-(4′-hydroxyphenyl)-1-butyne; (±)4-amino3-phenyl-1-butene; (±)4-amino-3-(3′-hydroxyphenyl)-1-butene; and (±)4-amino-3-(4′-hydroxyphenyl)-1-butene.

[0346] Another class of compounds from which a suitable dopamine-β-hydroxylase inhibitor may be selected to provide the conjugate first residue is represented by Formula X: 24

[0347] wherein W is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein Y is selected from 25

[0348] wherein R70 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of Q and T is one or more groups independently selected from 26

[0349] wherein each of R71 through R74 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; or a pharmaceutically-acceptable salt thereof.

[0350] A preferred class of compounds within Formula X consists of compounds wherein W is heteroaryl and Y is 27

[0351] wherein R70 is selected from hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl; wherein each of R71 and R72 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from one through six, inclusive.

[0352] A more preferred class of compounds of Formula X consists of wherein R70 is selected from hydrido, alkyl, amino and monoalkylamino; wherein each of R71 and R72 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number indpendently selected from two through four, inclusive. Even more preferred are compounds wherein R70 is selected from hydrido, alkyl and amino; wherein each of R71 and R72 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three. Most preferred are compounds wherein R70 is hydrido; wherein each of R71 and R72 is hydrido; and wherein each of p and q is two.

[0353] Another class of compounds from which a suitable dopamine-β-hydroxylase inhibitor may be selected to provide the conjugate first residue is represented by Formula XI: 28

[0354] wherein E is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein F is selected from 29

[0355] wherein Z is selected from 0, S and N—R78; wherein each of R75 and R76 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, minoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein R75 and R76 may form oxo or thio; wherein r is a number selected from zero through six, inclusive; wherein each of R77 and R78 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; or a pharmaceutically acceptable salt thereof.

[0356] Another class of compounds from which a suitable dopamine-β-hydroxylase inhibitor may be selected to provide the conjugate first residue is represented by Formula XII: 30

[0357] wherein each of R82 through R85 is independently selected from hydrido, alkyl, haloalkyl, mercapto, alkylthio, cyano, alkoxy, alkoxyalkyl and cycloalkyl; wherein Y is selected from oxygen atom and sulfur atom; wherein each of R79 and R80 is independently selected from hydrido and alkyl; wherein R81 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein m is a number from one through six; or a pharmaceutically-acceptable salt thereof.

[0358] A preferred family of compounds of Formula XII consists of those compounds wherein each of R82 through R85 is independently selected from hydrido, alkyl and haloalkyl; wherein Y is selected from oxygen atom or sulfur atom; wherein each of R79, R80 and R81 is independently hydrido and alkyl; and wherein m is a number selected from one through four, inclusive.

[0359] A family of preferred specific compounds within Formula XII consists of the following compounds:

[0360] aminomethyl-5-n-butylthiopicolinate;

[0361] aminomethyl-5-n-butylpicolinate;

[0362] 2′-aminoethyl-5-n-butylthiopicolinate;

[0363] 2′-aminoethyl-5-n-butylpicolinate;

[0364] (2′-amino-1′,1′-dimethyl)ethyl-5-n-butylthiopicolinate;

[0365] (2′-amino-1′,1′-dimethyl)ethyl-5-n-butylpicolinate;

[0366] (2′-amino-1′-methyl)ethyl-5-n-butylthiopicolinate;

[0367] (2′-amino-1′-methyl)ethyl-5-n-butylpicolinate;

[0368] 3′-aminopropyl-5-n-butylthiopicolinate;

[0369] 3′-aminopropyl-5-n-butylpicolinate;

[0370] (2′-amino-2′-methyl)propyl-5-n-butylthiopicolinate;

[0371] (2′-amino-2′-methyl)propyl-5-n-butylpicolinate;

[0372] (3′-amino-1′,1′-dimethyl)propyl-5-n-butylthiopicolinate;

[0373] (3′-amino-2′,2′-dimethyl)propyl-5-n-butylpicolinate;

[0374] (3′-amino-2′,2′-dimethyl)propyl-5-n-butylpicolinate;

[0375] (3′-amino-2′,2′-dimethyl)propyl-5-n-butylthiopicolinate;

[0376] 2′-aminopropyl-5-n-butylpicolinate;

[0377] 2′-aminopropyl-5-n-butylthiopicolinate;

[0378] 4′-aminobutyl-5-n-butylthiopicolinate;

[0379] 4′-amino-3′-methyl)butyl-5-n-butylthiopicolinate;

[0380] (3′-amino-3′-methyl)butyl-5-n-butylthiopicolinate;

[0381] and (3′-amino-3′-methyl)butyl-5-n-butylpicolinate.

[0382] Another preferred class of compounds within Formula XII consists of those compounds of Formula XIII: 31

[0383] wherein each of R86, R87 and R90 through R93 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein R86 and R87 together may form oxo or thio; wherein r is a number selected from zero through six, inclusive; wherein each of R88 and R89 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl.

[0384] A more preferred class of compounds within Formula XIII consists of those compounds wherein each of R86, R87 and R90 through R93 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein r is a number selected from zero through four, inclusive; wherein each of R88 and R89 is independently selected from hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl.

[0385] An even more preferred class of compounds within Formula XIII consists of those compounds wherein each of R86, R87 and R90 through R93 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein r is a number selected from zero through three, inclusive; and wherein each of R88 and R89 is selected from hydrido, alkyl, amino and monoalkylamino. Most preferred are compounds wherein each of R90 through R93 is independently selected from hydrido and alkyl; wherein each of R86 and R87 is hydrido; wherein r is selected from zero, one and two; wherein R88 is selected from hydrido, alkyl and amino; and wherein R89 is selected from hydrido and alkyl. Especially preferred within this class is the compound 5-n-butylpicolinic acid hydrazide (fusaric acid hydrazide) shown below: 32

[0386] Another class of compounds from which a suitable dopamine-β-hydroxylase inhibitor compound may be selected to provide the conjugate first residue is represented by Formula XIV: 33

[0387] wherein each of R94 through R98 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aryloxy, alkoxy, alkylthio, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, carboxyl, tetrazolyl, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, formoyl and alkoxycarbonyl; with the proviso that at least one of R94 through R98 is 34

[0388] wherein A′ is 35

[0389] wherein R99 is selected from hydrido, alkyl, hydroxy, alkoxy, alkylthio, phenyl, phenoxy, benzyl, benzyloxy, —OR100 and 36

[0390] wherein R100 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl; wherein each of R101, R102,R103 and R104 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein t is a number selected from zero through four, inclusive; or a pharmaceutically-acceptable salt thereof.

[0391] A preferred family of compounds within Formula XIV consists of those compounds characterized as chelating-type inhibitors of Formula XV: 37

[0392] wherein each of R95 through R98 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, phenyl, benzyl, alkoxy, phenoxy, benzyloxy, alkoxyalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, cyanoamino, carboxyl, thiocarbamoyl, aminomethyl, nitro, formoyl, formyl and alkoxycarbonyl; and wherein R100 is selected from hydrido, alkyl, phenyl and benzyl.

[0393] A class of specifically-preferred compounds of Formula XV consists of

[0394] 5-n-butylpicolinic acid (fusaric acid);

[0395] 5-ethylpicolinic acid;

[0396] picolinic acid;

[0397] 5-nitropicolinic acid;

[0398] 5-aminopicolinic acid;

[0399] 5-N-acetylaminopicolinic acid;

[0400] 5-N-propionylaminopicolinic acid;

[0401] 5-N-hydroxyaminopicolinic acid;

[0402] 5-iodopicolinic acid;

[0403] 5-bromopicolinic acid;

[0404] 5-chloropicolinic acid;

[0405] 5-hydroxypicolinic acid

[0406] 5-methoxypicolinic acid;

[0407] 5-N-propoxypicolinic acid;

[0408] 5-N-butoxypicolinic acid;

[0409] 5-cyanopicolinic acid;

[0410] 5-carboxylpicolinic acid;

[0411] 5-n-butyl-4-nitropicolinic acid;

[0412] 5-n-butyl-4-methoxypicolinic acid;

[0413] 5-n-butyl-4-ethoxypicolinic acid;

[0414] 5-n-butyl-4-aminopicolinic acid;

[0415] 5-n-butyl-4-hydroxyaminopicolinic acid; and

[0416] 5-n-butyl-4-methylpicolinic acid.

[0417] Especially preferred of the foregoing class of compounds of Formula XV is the compound 5-n-butylpicolinic acid (fusaric acid) shown below: 38

[0418] Another class of compounds from which a suitable dopamine-β-hydroxylase inhibitor may be selected to provide the conjugate first residue consists of azetidine-2-carboxylic acid derivatives represented by Formula XVI: 39

[0419] wherein R105 is hydrido, hydroxy, alkyl, amino and alkoxy; wherein R106 is selected from hydrido, hydroxy and alkyl; wherein each of R107 and R108 is independently selected from hydrido, alkyl and phenalkyl; wherein R109 is selected from hydrido and 40

[0420] with R110 selected from alkyl, phenyl and phenalkyl; wherein u is a number from one to three, inclusive; and wherein v is a number from zero to two, inclusive; or a pharmaceutically-acceptable salt thereof.

[0421] A preferred class of compounds within Formula XVI consists of those compounds wherein R105 is selected from hydroxy and lower alkoxy; wherein R106 is hydrido; wherein R107 is selected from hydrido and lower alkyl; wherein R108 is hydrido; wherein R109 is selected from hydrido and 41

[0422] with R110 selected from lower alkyl and phenyl; wherein u is two; and wherein v is a number from zero to two, inclusive.

[0423] A more preferred class of compounds within Formula XVI consists of those compounds of Formula XVII: 42

[0424] wherein R111 is selected from hydroxy and lower alkyl; wherein R107 is selected from hydrido and lower alkyl; wherein R109 is selected from hydrido and 43

[0425] with R110 selected from lower alkyl and phenyl and v is a number from zero to two, inclusive.

[0426] A more preferred class of compounds within Formula XVII consists of those compounds wherein R111 is hydroxy; wherein R107 is hydrido or methyl; wherein R109 is hydrido or acetyl; and wherein n is a number from zero to two, inclusive.

[0427] Most preferred within the class of compounds of Formula XVII are the compounds 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 1-(2-mercaptoacetyl)-L-proline (also known as captopril).

[0428] Another class of compounds from which a suitable dopamine-β-hydroxylase inhibitor compound may be selected to provide the conjugate first residue is represented by Formula XVIII: 44

[0429] wherein each of R112 through R119 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aralkyl, aryl, alkoxycarbonyl, hydroxyalkyl, halo, haloalkyl, cyano, amino, aminoalkyl, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, mercapto and alkylthio; or a pharmaceutically-acceptable salt thereof.

[0430] A first preferred class of compounds within Formula XVIII consists of those compounds wherein R112 is selected from mercapto and alkylthio; wherein each of R113 and R114 is independently selected from hydrido, amino, aminoalkyl, monoalkylamino, monoalkylaminoalkyl, carboxyl and carboxyalkyl; wherein each of R115 and R119 is hydrido; and wherein each of R116, R117 and R118 is independently selected from hydrido, hydroxy, alkyl, halo and haloalkyl; or a pharmaceutically-acceptable salt thereof.

[0431] A second preferred class of compounds within Formula XVIII consists of those compounds wherein R112 is selected from amino, aminoalkyl, monoalkylamino, monoalkylaminoalkyl, carboxy and carboxyalkyl; wherein each of R113, R114, R115 and R119 is hydrido; and wherein each of R116, R117 and R118 is independently selected from hydrido, hydroxy, alkyl, halo and haloalkyl; or a pharmaceutically-acceptable salt thereof.

[0432] Compounds which fall within any of the afore-mentioned inhibitor compounds, but which lack a reactive acid or amino moiety to form a cleavable bond, may be modified or derivatized to contain such acid of amino moiety. Examples of classes of such compounds lacking an amino on acidic moiety are the following: 1-(3,5-dihaloaryl)imidazol-2-thione derivatives such as 1-(3,5-difluorobenzyl)imidazol-2-thione; and hydroxyphenolic derivatives such as resorcinol.

[0433] The second component of a conjugate of the invention is provided by a residue which forms a kidney-enzyme-cleavable bond with the residue of the first-component AII antagonist compound. Such residue is preferably selected from a class of compounds of Formula XIX: 45

[0434] wherein each of R150 and R151 may be independently selected from hydrido, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydroxyl, halo, mercapto, —OR152, —SR153 and 46

[0435] with each R152, R153 and R154 is independently selected from hydrido and alkyl; with the proviso that said Formula XIX compound is selected such that formation of the cleavable bond occurs at carbonyl moiety attached at the gamma-position carbon of said Formula XIX compound.

[0436] More preferred are compounds of Formula XIX wherein each G is hydroxy.

[0437] A more highly preferred class of compounds within Formula XIX consists of those compounds wherein each G is hydroxy; wherein R150 is hydrido; and wherein R151 is selected from 47

[0438] wherein R155 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.

[0439] A most highly preferred compound of Formula XIX is N-acetyl-γ-glutamic acid which provides a residue for the second component of a conjugate of the invention as shown below: 48

[0440] The phrase “terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino terminal moiety” characterizes a structural requirement for selection of a suitable angiotensin II antagonist compound as the “active” first residue of a conjugate of the invention. Such terminal amino moiety must be available to react with a terminal carboxylic moiety of the cleavable second residue to form a kidney-enzyme-specific hydrolyzable bond.

[0441] The first component used to form the conjugate of the invention provides a first residue derived from an inhibitor compound capable of inhibiting formation of a benzylhydroxylamine intermediate involved in the biosynthesis of an adrenergic neurotransmitter, hereinafter generally referred to as an “inhibitor compound”. In one embodiment of the invention, the first component used to form a conjugate of the invention provides a first residue containing a terminal primary or secondary amino moiety. Examples of such terminal amino moiety are amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups such as aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoneopentyl.

[0442] In another embodiment of the invention, the first component used to form the conjugate of the invention provides a first residue derived from an inhibitor compound containing a moiety convertible to a primary or secondary amino terminal moiety. An example of a moiety convertible to an amino terminal moiety is a carboxylic acid group reacted with hydrazine so as to convert the acid moiety to carboxylic acid hydrazide. The hydrazide moiety thus contains the terminal amino moiety which may then be further reacted with the carboxylic acid containing residue of the second component to form a hydrolyzable amide bond. Such hydrazide moiety thus constitutes a “linker” group between the first and second components of a conjugate of the invention.

[0443] Suitable linker groups may be provided by a class of diamino-terminated linker groups based on hydrazine as defined by Formula XX: 49

[0444] wherein each of R200 and R201 may be independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfino, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein n is zero or a number selected from three through seven, inclusive. In Table I there is shown a class of specific examples of diamino-terminated linker groups within Formula XX, identified as Linker Nos. 1-73. These linker groups would be suitable to form a conjugate between a carbonyl moiety of an inhibitor compound residue (designated as “I”) and a carbonyl moiety of a carbonyl terminated second residue such as the carbonyl moiety attached to the gamma carbon of a glutamyl residue (designated as “T”).

TABLE I
50
I = inhibitor
T = acetyl-γ-glutamyl
	LINKER NO.	n	R200	R201
	1	0	H	H
	2	0	CH3	H
	3	0	C2H5	H
	4	0	C3H7	H
	5	0	CH(CH3)2	H
	6	0	C4H9	H
	7	0	CH(CH3)CH2CH3	H
	8	0	C(CH3)3	H
	9	0	C5H9	H
	10	0	C6H11 (cyclo)	H
	11	0	C6H5	H
	12	0	CH2C6H5	H
	13	0	H	CH3
	14	0	H	C2H5
	15	0	H	C3H7
	16	0	H	CH(CH3)2
	17	0	H	C4H9
	18	0	H	CH(CH3)CH2CH3
	19	0	H	C(CH3)3
	20	0	H	C5H9
	21	0	H	C6H13
	22	0	H	C6H5
	23	0	H	CH2C6H5
	24	0	H	C6H11 (cyclo)
	25	0	C6H13	H
	26	0	CH3	CH3
	27	0	C2H5	C2H5
	28	0	C3H7	C3H7
	29	0	CH(CH3)2	CH(CH3)2
	30	0	C4H9	C4H9
	31	0	CH(CH3)CH2CH3	CH(CH3)CH2CH3
	32	0	C(CH3)3	C(CH3)3
	33	0	C5H9	C5H9
	34	0	C6H13	C6H13
	35	0	C6H11 (cyclo)	C6H11 (cyclo)
	36	0	C6H5	C6H5
	37	0	CH2C6H5	CH2C6H5
	38	3	H	H
	39	3	CH3	H
	40	3	H	CH3
	41	3	C6H5	H
	42	3	H	C6H5
	43	3	CH3	C6H5
	44	3	C6H5	CH3
	45	3	CH2C6H5	H
	46	3	H	CH2C6H5
	47	4	H	H
	48	4	CH3	H
	49	4	H	CH3
	50	4	C6H5	H
	51	4	H	C6H5
	52	4	CH3	C6H5
	53	4	C6H5	CH3
	54	4	CH2C6H5	H
	55	4	H	CH2C6H5
	56	5	H	H
	57	5	CH3	H
	58	5	H	CH3
	59	5	C6H5	H
	60	5	H	C6H5
	61	5	CH3	C6H5
	62	5	C6H5	CH3
	63	5	CH2C6H5	H
	64	5	H	CH2C6H5
	65	6	H	H
	66	6	CH3	H
	67	6	H	CH3
	68	6	C6H5	H
	69	6	H	C6H5
	70	6	CH3	C6H5
	71	6	C6H5	CH3
	72	6	CH2C6H5	H
	73	6	H	CH2C6H5

[0445] Another class of suitable diamino terminal linker groups is defined by Formula XXI: 51

[0446] wherein each of Q and T is one or more groups independently selected from 52

[0447] wherein each of R202 through R205 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl.

[0448] A preferred class of linker groups within Formula XX is defined by Formula XXII: 53

[0449] wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from one through six, inclusive; with the proviso that when each of R202 and R203 is selected from halo, hydroxy, amino, monoalkylamino and dialkylamino, then the carbon to which R202 or R203 is attached in Formula XXII is not adjacent to a nitrogen atom of Formula XXII.

[0450] A more preferred class of linker groups of Formula XXII consists of divalent radicals wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from two through four, inclusive. Even more preferred are linker groups wherein each of R202 and R203 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three. Most preferred is a linker group wherein each of R202 and R203 is hydrido; and wherein each of p and q is two; such most preferred linker group is derived from a piperazinyl group and has the structure 54

[0451] In Table II there is shown a class of specific examples of cyclized, diamino-terminated linker groups within Formula XXII. These linker groups, identified as Linker Nos. 74-95, would be suitable to form a conjugate between a carbonyl moiety of an inhibitor compound residue (designated as “I”) and a carbonyl moiety of carbonyl terminated second residue such as the carbonyl moiety attached to the gamma carbon of a glutamyl residue (designated as “T”).

TABLE II
55
I = inhibitor
T = acetyl-γ-glutamyl
LINKER
NO.	R206	R207	R208	R209	R210	R211	R212	R213
74	H	H	H	H	H	H	H	H
75	CH3	H	H	H	H	H	H	H
76	H	H	H	H	CH3	H	H	H
77	CH3	H	H	H	CH3	H	H	H
78	CH3	H	CH3	H	H	H	H	H
79	CH3	H	H	H	H	H	CH3	H
80	CH3	CH3	H	H	H	H	H	H
81	H	H	H	H	CH3	CH3	H	H
82	CH3	CH3	H	H	CH3	CH3	H	H
83	CH3	CH3	CH3	CH3	H	H	H	H
84	CH3	CH3	H	H	H	H	CH3	CH3
85	H	H	H	H	CH3	CH3	CH3	CH3
86	C6H5	H	H	H	H	H	H	H
87	H	H	H	H	C6H5	H	H	H
88	C6H5	H	H	H	C6H5	H	H	H
89	C6H5	H	H	H	H	H	C6H5	H
90	C6H5	H	C6H5	H	H	H	H	H
91	CH2C6H5	H	H	H	H	H	H	H
92	H	H	H	H	CH2C6H5	H	H	H
93	CH2C6H5	H	H	H	CH2C6H5	H	H	H
94	CH2C6H5	H	H	H	H	H	CH2C6H5	H
95	CH2C6H5	H	CH2C6H5	H	H	H	H	H

[0452] Another class of suitable diamino terminal linker groups is defined by Formula XXIII: 56

[0453] wherein each of R214 through R217 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfino, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein p is a number selected from one through six inclusive.

[0454] A preferred class of linker groups within Formula XXIII consists of divalent radicals wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p is two or three. A more preferred class of linker groups within Formula XXIII consists of divalent radicals wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido and alkyl; and wherein p is two. A specific example of a more preferred linker within Formula XXIII is the divalent radical ethylenediamino. In Table III there is shown a class of specific examples of diamino-terminated linker groups within Formula XXIII. These linker groups, identified as Linker Nos. 96-134, would be suitable to form a conjugate between a carbonyl moiety of an inhibitor compound residue (designated as “I”) and a carbonyl moiety of carbonyl terminated second residue such as the carbonyl moiety attached to the gamma carbon of a glutamyl residue (designated as “T”).

TABLE III
57
I = inhibitor
G = acetyl-γ-glutamyl
LINKER NO.	R218	R219	R220	R221	R222	R223
96	H	H	H	H	H	H
97	H	H	H	H	H	CH3
98	H	H	H	CH3	H	H
99	H	H	H	CH3	H	CH3
100	CH3	H	H	H	H	H
101	H	CH3	H	H	H	H
102	H	H	H	H	CH3	CH3
103	H	H	CH3	CH3	H	H
104	CH3	CH3	H	H	H	H
105	H	H	H	H	H	C6H5
106	H	H	H	C6H5	H	H
107	H	H	H	C6H5	H	C6H5
108	C6H5	H	H	H	H	H
109	H	C6H5	H	H	H	H
110	H	H	H	H	C6H5	C6H5
111	H	H	C6H5	C6H5	H	H
112	C6H5	C6H5	H	H	H	H
113	H	H	H	H	H	C2H5
114	H	H	H	C2H5	H	H
115	H	H	H	C2H5	H	C2H5
116	C2H5	H	H	H	H	H
117	H	C2H5	H	H	H	H
118	H	H	H	H	C2H5	C2H5
119	H	H	C2H5	C2H5	H	H
120	C2H5	C2H5	H	H	H	H
121	CH3	H	C6H5	H	H	H
122	CH3	H	H	H	C6H5	H
123	H	CH3	C6H5	H	H	H
124	H	CH3	H	H	C6H5	H
125	CH3	CH3	H	C6H5	H	H
126	CH3	CH3	H	H	H	C6H5
127	H	H	H	H	H	CH2C6H5
128	H	H	H	CH2C6H5	H	H
129	CH2C6H5	H	H	H	H	H
130	H	CH2C6H5	H	H	H	H
131	CH3	H	CH2C6H5	H	H	H
132	CH3	H	H	H	CH2C6H5	H
133	H	CH3	CH2C6H5	H	H	H
134	H	CH3	H	H	CH2C6H5	H

[0455] The term “hydrido” denotes a single hydrogen atom (H). This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or as another example, two hydrido groups may be attached to a carbon atom to form a divalent —CH2— group, that is, a “methylene” group; or as another example, one hydrido group may be attached to a carbon atom to form a trivalent 58

[0456] group. Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl”, “aralkyl” and “hydroxyalkyl”, the term “alkyl” embraces linear or branched radicals having one to about ten carbon atoms unless otherwise specifically described. Preferred alkyl radicals are “lower alkyl” radicals having one to about five carbon atoms. The term “cycloalkyl” embraces radicals having three to ten carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl and cycloheptyl. The term “haloalkyl” embraces radicals wherein any one or more of the carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term “haloalkyl” are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. Examples of a dihaloalkyl group are dibromomethyl, dichloromethyl and bromochloromethyl. Examples of a polyhaloalkyl are trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3tetrafluoropropyl groups. The term “alkoxy”, embraces linear or branched oxy-containing radicals having an alkyl portion of one to about ten carbon atoms, such as methoxy, ethoxy, isopropoxy and butoxy. The term “alkylthio” embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl and biphenyl. The term “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms “benzyl” and “phenylmethyl” are interchangeable. The terms “aryloxy” and “arylthio” denote radical respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, examples of which are phenoxy and phenylthio. The terms “sulfinyl” and “sulfonyl”, whether used alone or linked to other terms, denotes respectively divalent radicals 59

[0457] and 60

[0458] The term “acyl” whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. “Lower alkanoyl” is an example of a more preferred sub-class of acyl.

[0459] Within the classes of conjugates of the invention described herein are the pharmaceutically-acceptable salts of such conjugates including acid addition salts and base addition salts. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of conjugates of the invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of the conjugates include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding conjugates described herein by reacting, for example, the appropriate acid or base with the conjugate.

[0460] Conjugates of the invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting conjugates with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active conjugates can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

Synthetic Procedures

[0461] Conjugates of the invention are synthesized by reaction between precursors of the first and second residues. One of such precursors must contain a reactive acid moiety, and the other precursor must contain a reactive amino moiety, so that a conjugate is formed having a cleavable bond. Either precursor of the first and second residues may contain such reactive acid or amino moieties. Preferably, the precursors of the first residue are inhibitors of benzylhydroxyamine biosynthesis and will contain a reactive amino moiety or a moiety convertible to a reactive amino moiety. Many of the tyrosine hydroxylase inhibitors and dopa-decarboxylase inhibitors are characterized in having a reactive amino moiety. Inhibitor compounds lacking a reactive amino moiety, such as the dopamine-β-hydroxylase inhibitor fusaric acid, may be chemically modified to provide such reactive amino moiety. Chemical modification of these inhibitor compounds lacking a reactive amino group may be accomplished by reacting an acid or an ester group on the inhibitor compound with an amino compound, that is, a compound having at least one reactive amino moiety and another reactive hetero atom selected from 0, S and N. A suitable amino compound would be a diamino compound such as hydrazine or urea. Hydrazine, for example, may be reacted with the acid or ester moiety of the inhibitor compound to form a hydrazide derivative of such inhibitor compound.

[0462] The dopamine-β-hydroxylase inhibitor compound 5-butyl-n-butylpicolinic acid (fusaric acid) may be used as a model compound to illustrate the chemical modification of an acid-containing inhibitor compound to make a reactive amino-containing precursor for synthesizing a conjugate of the invention. In the following General Synthetic Procedures, the substituents and reagents are defined as follows: each of R79, R80, R81, R86, R87, R88, R89 and R115 is as defined above; W is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; and Z is selected from oxygen and sulfur. DCC is an abbreviation for dicyclohexylcarbodiimide. 61626364

[0463] The following Examples 1 through 1857 shown in Tables IV-XVII are highly preferred conjugates of the invention. These conjugates fall within three classes, namely, conjugates of tyrosine hydroxylase inhibitors of Tables IV-VI, conjugates of dopa-decarboxylase inhibitors of Tables VII-XI, and conjugates of dopamine-β-phydroxylase inhibitors of Tables XII-XVII. These conjugates may be prepared generally by the procedures outlined above in Schemes 1-7. Also, specific procedures for preparation of Examples 1-1857 are found in the conjugate preparations described in the examples appearing with the tables of conjugates.

[0464] The following Examples #1-#461 comprise three classes of highly preferred conjugates formed from tyrosine hydroxylase inhibitor compounds and glutamic acid derivatives. Examples #1-#3 are descriptions of specific preparations of such conjugates. Examples #4-#461, as shown in Tables IV-VI, may be prepared by procedures shown in these specific examples and in the foregoing general synthetic procedures of Schemes 1-7.

EXAMPLE 1

[0465] 65

4-amino-carboxy-1-oxobutyl-α-methyl-L-tyrosine, methyl ester

[0466] Step. 1. Preparation of Methyl α-methyl-L-tyrosinate, hydrochloride.

[0467] A solution of 11.0 g (56.4 mmol) of methyl-L-tyrosine in 100 mL of absolute methanol was cooled to 0° C. and treated with 20.1 g (169 mmol) of thionyl chloride under a nitrogen atmosphere. The reaction was allowed to warm to ambient temperature and stir at reflux for 2 days. Concentration followed by trituration with 150 mL of ether gave 13.3 g (96%) of colorless product: NMR (DMSO-d6) δ1.49 (s, 3H), 3.02 (s, 2H), 3.73 (s, 3H), 6.73 (d, J=11 Hz, 2H), 6.97 (d, J=11 Hz, 2H), 8.50-8.70 (br s, 3H), 9.50 (s, 1H).

[0468] Step. 2. Preparation of 4-amino-4-carboxy-1-oxobutyl-α-methyl-L-tyrosine, methyl ester.

[0469] Under nitrogen, a solution of 35.1 g (116 mmol) of N-Boc-L-γ-glutanic acid-α-t-butyl ester (BACHEM) in 200 mL of methylene chloride was treated with 11.95 g (58 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction was allowed to stir for 2 hr prior to filtration under a nitrogen atmosphere. The methylene chloride was removed in vacuo and the residue dissolved in 100 mL of anhydrous dimethylformamide (DMF). The anhydride solution was slowly added to a solution of 7.0 g (29 mmol) of the α-methyl tyrosine ester from step 1 and 18.73 g (145 mmol) of diisopropylethylamine (DIEA) in 100 mL of anhydrous DMF. The reaction was allowed to stir overnight and was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with cold 1M K2CO3 followed by water, dried (MgSO4), and concentrated in vacuo to give the protected coupled product; a solution of this material in 150 mL of methylene chloride was cooled to 0° C. and treated with 150 mL of trifluoracetic acid (TFA) under nitrogen. The reaction was allowed to warm to ambient temperatures and stir overnight. Concentration in vacuo gave 4-amino-4-carboxy-1-oxobutyl-α-methyl-L-tyrosine, methyl ester: NMR (DMSO-d6) δ1.20 (s, 3H), 1.90-2.20 (m, 2H), 2.23-2.38 (m, 2H), 2.95 (d, J=13 Hz, 1H), 3.26 (d, J=13 Hz), 3.57 (s, 3H), 3.92-4.06 (m, 1H), 7.06 (d, J=9 Hz, 2H), 7.12 (d, J=9 Hz, 2H)

EXAMPLE 2

[0470] 66

N-[4-(acetylamino-4-carboxy-1-oxobutyl]-α-methyl-L-tyrosine, methyl ester

[0471] The compound of Example 1 was dissolved in 100 mL of water and the pH adjusted to 9 with 1 M K2CO3. The solution was cooled to 0° C. and 3.30 mL (35 mmol) of acetic anhydride and 35 mL (35 mmol) of 1 M K2CO3 was added every 30 min. for 5 h; the pH was maintained at 9 and the reaction temperature kept below 5° C. After the last addition, the reaction was allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 6 M HCl and concentrated to 100 mL. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic 25% acetonitrile/water (0.05% TFA) gave 9.0 g (82%) of colorless product: NMR (DMSO-d6) δ1.18 (s, 3H), 1.72-2.03 (m, 2H), 1.85 (s, 3H), 2.15 (t, J=8 Hz, 2H), 2.93 (d, J=13 Hz, 1H), 3.38 (d, J=13 Hz, 1H), 3.57 (s, 3H), 4.12-4.23 (m, 1H), 7.02 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 8.06 (s, 1H), 8.12 (d, J=8 Hz, 1H).

EXAMPLE 3

[0472] 67

N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-α-methyl-L-tyrosine

[0473] A solution of 9.0 g (23.7 mmol) of the compound of Example 2 in 225 mL of water was cooled to 0° C. and treated with 3.3 g (82.5 mmol) of solid NaOH in portions over 15 min. The reaction was stirred at 0-5° C. overnight, the pH adjusted to pH 5 with 6N HCl, and concentrated to 100 mL. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic 15% acetonitrite/water (0.05% TFA) gave 5.50 g (63%) of colorless product: NMR (DMSO-d6) δ1.17 (s, 3H), 1.70-2.00 (m, 2H), 1.85 (s, 3H), 2.14 (t, J=8 Hz, 2H), 2.83 (d, J=13 Hz, 1H), 3.14 (d, J=13 Hz, 1H), 4.12-4.23 (m, 1H), 6.56 (d, J=9 Hz, 2H), 6.85 (d, J=9 Hz, 2H), 7.69 (s, 1H), 8.12 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 367 (70), 196 (52), 179 (58) 150 (100), 130 (80); HRMS. Calcd for M+H: 367.1505. Found: 367.1547. Anal. Calcd for C17H22N2O7.H2O.0.125 TFA: C, 52.00; H, 6.03; N, 7.03; F, 1.60. Found: C, 51.96; H, 6.25; N, 7.12; F, 1.60.

[0474] The following Examples #4-#109 of Table IV are highly preferred conjugates formed from tyrosine hydroxylase inhibitor compounds and glutamic acid derivatives. These tyrosine hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula I and II, above.

TABLE IV
68
EXAMPLE
NO.	R1	R9	R10	R11	R12	R5	E	P
4	CH3	H	H	OH	H	OCH3	CH3	COCH3
5	CH3	H	H	OH	H	OH	H	H
6	CH3	H	H	OH	H	OCH3	CH3	H
7	CH3	H	H	OH	H	OH	CH3	H
8	CH3	H	H	OH	H	OH	CH3	COCH3
9	CH2F	H	H	OH	H	OCH3	H	H
10	CH2F	H	H	OH	H	OCH3	H	COCH3
11	CH2F	H	H	OH	H	OCH3	CH3	H
12	CH2F	H	H	OH	H	OCH3	CH3	COCH3
13	CH2F	H	H	OH	H	OH	H	H
14	CH2F	H	H	OH	H	OH	H	COCH3
15	CH2F	H	H	OH	H	OH	CH3	H
16	CH2F	H	H	OH	H	OH	CH3	COCH3
17	CHF2	H	H	OH	H	OCH3	H	H
18	CHF2	H	H	OH	H	OCH3	H	COCH3
19	CHF2	H	H	OH	H	OCH3	CH3	H
20	CHF2	H	H	OH	H	OCH3	CH3	COCH3
21	CHF2	H	H	OH	H	OH	H	H
22	CHF2	H	H	OH	H	OH	H	COCH3
23	CHF2	H	H	OH	H	OH	CH3	H
24	CHF2	H	H	OH	H	OH	CH3	COCH3
25	CF3	H	H	OH	H	OCH3	H	H
26	CF3	H	H	OH	H	OCH3	H	COCH3
27	CF3	H	H	OH	H	OCH3	CH3	H
28	CF3	H	H	OH	H	OCH3	CH3	COCH3
29	CF3	H	H	OH	H	OH	H	H
30	CF3	H	H	OH	H	OH	H	COCH3
31	CF3	H	H	OH	H	OH	CH3	H
32	CF3	H	H	OH	H	OH	CH3	COCH3
33	C2H5	H	H	OH	H	OCH3	H	H
34	C2H5	H	H	OH	H	OCH3	H	COCH3
35	C2H5	H	H	OH	H	OCH3	CH3	H
36	C2H5	H	H	OH	H	OCH3	CH3	COCH3
37	C2H5	H	H	OH	H	OH	H	H
38	C2H5	H	H	OH	H	OH	H	COCH3
39	C2H5	H	H	OH	H	OH	CH3	H
40	C2H5	H	H	OH	H	OH	CH3	COCH3
41	C3H7	H	H	OH	H	OCH3	H	H
42	C3H7	H	H	OH	H	OCH3	H	COCH3
43	C3H7	H	H	OH	H	OCH3	CH3	H
44	C3H7	H	H	OH	H	OCH3	CH3	COCH3
45	C3H7	H	H	OH	H	OH	H	H
46	C3H7	H	H	OH	H	OH	H	COCH3
47	C3H7	H	H	OH	H	OH	CH3	H
48	C3H7	H	H	OH	H	OH	CH3	COCH3
49	CH3	H	H	NHCN	H	OH	H	COCH3
50	CH3	H	CO2H	H	H	H	OH	COCH3
51	CH3	H	CN	H	H	OH	H	COCH3
52	CH3	H	H	CH2NH2	H	OH	H	COCH3
53	CH3	H	H	CH2CH2CN	H	OH	H	COCH3
54	CH3	H	OH	CH3SO2NH	H	OH	H	COCH3
55	CH3	H	OH	NO2	H	OH	H	COCH3
56	CH3	H	CH3SO3	NH2	H	OH	H	COCH3
57	CH3	H	CO2CH3	NO2	H	OH	H	COCH3
58	CH3	H	NO2	NH2	H	OH	H	COCH3
59	CH3	H	NH2	NH2	H	OH	H	COCH3
60	CH3	H	CH3	OH	H	OH	H	COCH3
61	CH3	H	C6H5	OH	H	OH	H	COCH3
62	CH3	H	CH2C6H5	OH	H	OH	H	COCH3
63	CH3	H	C6H11 (cyclo)	CH3O	H	OH	H	COCH3
64	CH3	OH	OH	H	H	OH	H	COCH3
65	CH3	OH	OH	Cl	H	OH	H	COCH3
66	CH3	OH	OH	CH3	H	OH	H	COCH3
67	CH3	OH	OH	F	H	OH	H	COCH3
68	CH3	OH	OH	CF3	H	OH	H	COCH3
69	CH3	H	OH	H	OH	OH	H	COCH3
70	CH3	H	OH	Cl	OH	OH	H	COCH3
71	CH3	H	OH	F	OH	OH	H	COCH3
72	CH3	H	OH	CF3	OH	OH	H	COCH3
73	CH3	OH	H	H	OH	OH	H	COCH3
74	CH3	OH	H	Cl	OH	OH	H	COCH3
75	CH3	OH	H	CH3	OH	OH	H	COCH3
76	CH3	OH	H	CF3	OH	OH	H	COCH3
77	CH3	H	OH	OH	OH	OH	H	COCH3
78	CH3	OH	OH	OH	H	OH	H	COCH3
79	CH3	OH	H	OH	OH	OH	H	COCH3
80	CH3	H	H	H	H	OH	H	COCH3
81	H	H	H	H	H	OH	H	COCH3
82	H	H	I	H	H	H	H	COCH3
83	CH3	H	I	H	H	H	H	COCH3
84	H	H	I	OH	H	H	H	COCH3
85	H	H	I	H	I	H	H	COCH3
86	CH3	H	CH3	OH	H	H	H	COCH3
87	CH3	H	C6H5CH2	CH3O	H	H	H	COCH3
88	CH3	H	C6H5CH2	OH	H	H	H	COCH3
89	CH3	H	C6H11 (cyclo)	CH3O	H	H	H	COCH3
90	CH3	H	C6H11 (cyclo)	OH	H	H	H	COCH3
91	CH3	H	CH3	CH3O	H	H	H	COCH3
92	CH3	H	CH3	OH	H	H	H	COCH3
93	CH3	H	CH3	C6H5CH2CO2	H	H	H	COCH3
94	CH3	H	CH3	OH	H	H	H	COCH3
95	CH3	H	CH3	C6H5CH2CO2	H	H	H	COCH3
96	CH3	H	CH3	CH3CO2	H	H	H	COCH3
97	CH3	H	CH3O	OH	H	H	H	COCH3
98	CH3	H	—OCH2O—	H	H	H	COCH3
99	CH3	CH3O	H	H	CH3O	H	H	COCH3
100	CH3	OH	H	H	OH	H	H	COCH3
101	CH3	CH3O	H	CH3O	H	H	H	COCH3
102	CH3	OH	H	OH	H	H	H	COCH3
103	CH3	CH3O	H	H	CH3O	OC2H5	H	COCH3
104	C≡CH	CH3O	H	H	H	H	H	COCH3
105	C≡CH	CH3O	H	H	CH3O	H	H	COCH3
106	C≡CH	H	H	OH	H	H	H	COCH3
107	C≡CH	H	OH	H	H	H	H	COCH3
108	CH═CH2	CH3O	H	H	H	H	H	COCH3
109	CH═CH2	CH3O	H	H	CH3O	H	H	COCH3

[0475] The following Examples #110-#413 of Table V are hyghly preferred conjugates formed from tyrosine hydroxylase inhibitor compounds and glutamic acid derivatives. These tyrisine hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula I, above.

TABLE V
69
EXAMPLE
NO.	A	R3	R5	E	P
110	70	CH3	OCH3	H	H
111	71	CH3	OCH3	H	COCH3
112	72	CH3	OCH3	CH3	H
113	73	CH3	OCH3	CH3	COCH3
114	74	CH3	OH	H	H
115	75	CH3	OH	H	COCH3
116	76	CH3	OH	CH3	H
117	77	CH3	OH	CH3	COCH3
118	78	CH3	OCH3	H	H
119	79	CH3	OCH3	H	COCH3
120	80	CH3	OCH3	CH3	H
121	81	CH3	OCH3	CH3	COCH3
122	82	CH3	OH	H	H
123	83	CH3	OH	H	COCH3
124	84	CH3	OH	CH3	H
125	85	CH3	OH	CH3	COCH3
126	86	CH3	OCH3	H	H
127	87	CH3	OCH3	H	COCH3
128	88	CH3	OCH3	CH3	H
129	89	CH3	OCH3	CH3	COCH3
130	90	CH3	OH	H	H
131	91	CH3	OH	H	COCH3
132	92	CH3	OH	CH3	H
133	93	CH3	OH	CH3	COCH3
134	94	CH3	OCH3	H	H
135	95	CH3	OCH3	H	COCH3
136	96	CH3	OCH3	CH3	H
137	97	CH3	OCH3	CH3	COCH3
138	98	CH3	OH	H	H
139	99	CH3	OH	H	COCH3
140	100	CH3	OH	CH3	H
141	101	CH3	OH	CH3	COCH3
142	102	CH3	OCH3	H	H
143	103	CH3	OCH3	H	COCH3
144	104	CH3	OCH3	CH3	H
145	105	CH3	OCH3	CH3	COCH3
146	106	CH3	OH	H	H
147	107	CH3	OH	H	COCH3
148	108	CH3	OH	CH3	H
149	109	CH3	OH	CH3	COCH3
150	110	CH3	OCH3	H	H
151	111	CH3	OCH3	H	COCH3
152	112	CH3	OCH3	CH3	H
153	113	CH3	OCH3	CH3	COCH3
154	114	CH3	OH	H	H
155	115	CH3	OH	H	COCH3
156	116	CH3	OH	CH3	H
157	117	CH3	OH	CH3	COCH3
158	118	CH3	OCH3	H	H
159	119	CH3	OCH3	H	COCH3
160	120	CH3	OCH3	CH3	H
161	121	CH3	OCH3	CH3	COCH3
162	122	CH3	OH	H	H
163	123	CH3	OH	H	COCH3
164	124	CH3	OH	CH3	H
165	125	CH3	OH	CH3	COCH3
166	126	CH3	OCH3	H	H
167	127	CH3	OCH3	H	COCH3
168	128	CH3	OCH3	CH3	H
169	129	CH3	OCH3	CH3	COCH3
170	130	CH3	OH	H	H
171	131	CH3	OH	H	COCH3
172	132	CH3	OH	CH3	H
173	133	CH3	OH	CH3	COCH3
174	134	CH3	OCH3	H	H
175	135	CH3	OCH3	H	COCH3
176	136	CH3	OCH3	CH3	H
177	137	CH3	OCH3	CH3	COCH3
178	138	CH3	OH	H	H
179	139	CH3	OH	H	COCH3
180	140	CH3	OH	CH3	H
181	141	CH3	OH	CH3	COCH3
182	142	CH3	OCH3	H	H
183	143	CH3	OCH3	H	COCH3
184	144	CH3	OCH3	CH3	H
185	145	CH3	OCH3	CH3	COCH3
186	146	CH3	OH	H	H
187	147	CH3	OH	H	COCH3
188	148	CH3	OH	CH3	H
189	149	CH3	OH	CH3	COCH3
190	150	H	OCH3	H	H
191	151	H	OCH3	H	COCH3
192	152	H	OCH3	CH3	H
193	153	H	OCH3	CH3	COCH3
194	154	H	OH	H	H
195	155	H	OH	H	COCH3
196	156	H	OH	CH3	H
197	157	H	OH	CH3	COCH3
198	158	CH3	OCH3	H	H
199	159	CH3	OCH3	H	COCH3
200	160	CH3	OCH3	CH3	H
201	161	CH3	OCH3	CH3	COCH3
202	162	CH3	OH	H	H
203	163	CH3	OH	H	COCH3
204	164	CH3	OH	CH3	H
205	165	CH3	OH	CH3	COCH3
206	166	CH3	OCH3	H	H
207	167	CH3	OCH3	H	COCH3
208	168	CH3	OCH3	CH3	H
209	169	CH3	OCH3	CH3	COCH3
210	170	CH3	OH	H	H
211	171	CH3	OH	H	COCH3
212	172	CH3	OH	CH3	H
213	173	CH3	OH	CH3	COCH3
214	174	CH3	OCH3	H	H
215	175	CH3	OCH3	H	COCH3
216	176	CH3	OCH3	CH3	H
217	177	CH3	OCH3	CH3	COCH3
218	178	CH3	OH	H	H
219	179	CH3	OH	H	COCH3
220	180	CH3	OH	CH3	H
221	181	CH3	OH	CH3	COCH3
222	182	CH3	OCH3	H	H
223	183	CH3	OCH3	H	COCH3
224	184	CH3	OCH3	CH3	H
225	185	CH3	OCH3	CH3	COCH3
226	186	CH3	OH	H	H
227	187	CH3	OH	H	COCH3
228	188	CH3	OH	CH3	H
229	189	CH3	OH	CH3	COCH3
230	190	H	OCH3	H	H
231	191	H	OCH3	H	COCH3
232	192	H	OCH3	CH3	H
233	193	H	OCH3	CH3	COCH3
234	194	H	OH	H	H
235	195	H	OH	H	COCH3
236	196	H	OH	CH3	H
237	197	H	OH	CH3	COCH3
238	198	H	OCH3	H	H
239	199	H	OCH3	H	COCH3
240	200	H	OCH3	CH3	H
241	201	H	OCH3	CH3	COCH3
242	202	H	OH	H	H
243	203	H	OH	H	COCH3
244	204	H	OH	CH3	H
245	205	H	OH	CH3	COCH3
246	206	CH3	OCH3	H	H
247	207	CH3	OCH3	H	COCH3
248	208	CH3	OCH3	CH3	H
249	209	CH3	OCH3	CH3	COCH3
250	210	CH3	OH	H	H
251	211	CH3	OH	H	COCH3
252	212	CH3	OH	CH3	H
253	213	CH3	OH	CH3	COCH3
254	214	H	OCH3	H	H
255	215	H	OCH3	H	COCH3
256	216	H	OCH3	CH3	H
257	217	H	OCH3	CH3	COCH3
258	218	H	OH	H	H
259	219	H	OH	H	COCH3
260	220	H	OH	CH3	H
261	221	H	OH	CH3	COCH3
262	222	CH3	OCH3	H	H
263	223	CH3	OCH3	H	COCH3
264	224	CH3	OCH3	CH3	H
265	225	CH3	OCH3	CH3	COCH3
266	226	CH3	OH	H	H
267	227	CH3	OH	H	COCH3
268	228	CH3	OH	CH3	H
269	229	CH3	OH	CH3	COCH3
270	230	CH3	OCH3	H	H
271	231	CH3	OCH3	H	COCH3
272	232	CH3	OCH3	CH3	H
273	233	CH3	OCH3	CH3	COCH3
274	234	CH3	OH	H	H
275	235	CH3	OH	H	COCH3
276	236	CH3	OH	CH3	H
277	237	CH3	OH	CH3	COCH3
278	238	CH3	OCH3	H	H
279	239	CH3	OCH3	H	COCH3
280	240	CH3	OCH3	CH3	H
281	241	CH3	OCH3	CH3	COCH3
282	242	CH3	OH	H	H
283	243	CH3	OH	H	COCH3
284	244	CH3	OH	CH3	H
285	245	CH3	OH	CH3	COCH3
286	246	CH3	OCH3	H	H
287	247	CH3	OCH3	H	COCH3
288	248	CH3	OCH3	CH3	H
289	249	CH3	OCH3	CH3	COCH3
290	250	CH3	OH	H	H
291	251	CH3	OH	H	COCH3
292	252	CH3	OH	CH3	H
293	253	CH3	OH	CH3	COCH3
294	254	CH3	OCH3	H	H
295	255	CH3	OCH3	H	COCH3
296	256	CH3	OCH3	CH3	H
297	257	CH3	OCH3	CH3	COCH3
298	258	CH3	OH	H	H
299	259	CH3	OH	H	COCH3
300	260	CH3	OH	CH3	H
301	261	CH3	OH	CH3	COCH3
302	262	C≡CH	OCH3	H	H
303	263	C≡CH	OCH3	H	COCH3
304	264	C≡CH	OCH3	CH3	H
305	265	C≡CH	OCH3	CH3	COCH3
306	266	C≡CH	OH	H	H
307	267	C≡CH	OH	H	COCH3
308	268	C≡CH	OH	CH3	H
309	269	C≡CH	OH	CH3	COCH3
310	270	C≡CH	OCH3	H	H
311	271	C≡CH	OCH3	H	COCH3
312	272	C≡CH	OCH3	CH3	H
313	273	C≡CH	OCH3	CH3	COCH3
314	274	C≡CH	OH	H	H
315	275	C≡CH	OH	H	COCH3
316	276	C≡CH	OH	CH3	H
317	277	C≡CH	OH	CH3	COCH3
318	278	C≡CH2	OCH3	H	H
319	279	C≡CH2	OCH3	H	COCH3
320	280	C≡CH2	OCH3	CH3	H
321	281	C≡CH2	OCH3	CH3	COCH3
322	282	C≡CH2	OH	H	H
323	283	C≡CH2	OH	H	COCH3
324	284	C≡CH2	OH	CH3	H
325	285	C≡CH2	OH	CH3	COCH3
326	286	C≡CH	OCH3	H	H
327	287	C≡CH	OCH3	H	COCH3
328	288	C≡CH	OCH3	CH3	H
329	289	C≡CH	OCH3	CH3	COCH3
330	290	C≡CH	OH	H	H
331	291	C≡CH	OH	H	COCH3
332	292	C≡CH	OH	CH3	H
333	293	C≡CH	OH	CH3	COCH3
334	294	C≡CH	OCH3	H	H
335	295	C≡CH	OCH3	H	COCH3
336	296	C≡CH	OCH3	CH3	H
337	297	C≡CH	OCH3	CH3	COCH3
338	298	C≡CH	OH	H	H
339	299	C≡CH	OH	H	COCH3
340	300	C≡CH	OH	CH3	H
341	301	CH3	OH	CH3	COCH3
342	302	CH3	OCH3	H	H
343	303	CH3	OCH3	H	COCH3
344	304	CH3	OCH3	CH3	H
345	305	CH3	OCH3	CH3	COCH3
346	306	CH3	OH	H	H
347	307	CH3	OH	H	COCH3
348	308	CH3	OH	CH3	H
349	309	CH3	OH	CH3	COCH3
350	310	H	OCH3	H	H
351	311	H	OCH3	H	COCH3
352	312	H	OCH3	CH3	H
353	313	H	OCH3	CH3	COCH3
354	314	H	OH	H	H
355	315	H	OH	H	COCH3
356	316	H	OH	CH3	H
357	317	H	OH	CH3	COCH3
358	318	H	OCH3	H	H
359	319	H	OCH3	H	COCH3
360	320	H	OCH3	CH3	H
361	321	H	OCH3	CH3	COCH3
362	322	H	OCH3	H	H
363	323	H	OH	H	COCH3
364	324	H	OH	H	H
365	325	H	OH	CH3	COCH3
366	326	H	OCH3	H	H
367	327	H	OCH3	H	COCH3
368	328	H	OCH3	CH3	H
369	329	H	OCH3	CH3	COCH3
370	330	H	OH	H	H
371	331	H	OH	H	COCH3
372	332	H	OH	CH3	H
373	333	H	OH	CH3	COCH3
374	334	H	OCH3	H	H
375	335	H	OCH3	H	COCH3
376	336	H	OCH3	CH3	H
377	337	H	OCH3	CH3	COCH3
378	338	H	OH	H	H
379	339	H	OH	H	COCH3
380	340	H	OH	CH3	H
381	341	H	OH	CH3	COCH3
382	342	H	OCH3	H	H
383	343	H	OCH3	H	COCH3
384	344	H	OCH3	CH3	H
385	345	H	OCH3	CH3	COCH3
386	346	H	OH	H	H
387	347	H	OH	H	COCH3
388	348	H	OH	CH3	H
389	349	H	OH	CH3	COCH3
390	350	CH3	OCH3	H	H
391	351	CH3	OCH3	H	COCH3
392	352	CH3	OCH3	CH3	H
393	353	CH3	OCH3	CH3	COCH3
394	354	CH3	OH	H	H
395	355	CH3	OH	H	COCH3
396	356	CH3	OH	H	COCH3
397	357	CH3	OH	CH3	COCH3
398	C2H	CH═CH2	CH3	H	H
399	C2H5	CH═CH2	OCH3	H	COCH3
400	C2H5	CH═CH2	OCH3	CH3	H
401	C2H5	CH═CH2	OCH3	CH3	COCH3
402	C2H5	CH═CH2	OH	H	H
403	C2H5	CH═CH2	OH	H	COCH3
404	C2H5	CH═CH2	OH	H	COCH3
405	C2H5	CH═CH2	OH	CH3	COCH3
406	C2H5	C≡CH	OCH3	H	H
407	C2H5	C≡CH	OCH3	H	COCH3
408	C2H5	C≡CH	OCH3	CH3	H
409	C2H5	C≡CH	OCH3	CH3	COCH3
410	C2H5	C≡CH	OH	H	H
411	C2H5	C≡CH	OH	H	COCH3
412	C2H5	C≡CH	OH	H	COCH3
413	C2H5	C≡CH	OH	CH3	COCH3

[0476] The following Examples #414-#461 of Table VI are highly preferred conjugates formed from tyrosine hydroxylase inhibitor compounds and glutamic acid derivatives. These tyrosine hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula III, above.

TABLE VI
358
EXAMPLE
NO.	R11	R3	R5	E	P
414	OH	H	OH	H	H
415	OH	H	OH	H	COCH3
416	OH	H	OH	CH3	H
417	OH	H	OH	CH3	COCH3
418	OH	H	OCH3	H	H
419	OH	H	OCH3	H	COCH3
420	OH	H	OCH3	CH3	H
421	OH	H	OCH3	CH3	COCH3
422	OH	CH3	OH	H	H
423	OH	CH3	OH	H	COCH3
424	OH	CH3	OH	CH3	H
425	OH	CH3	OH	CH3	COCH3
426	OH	CH3	OCH3	H	H
427	OH	CH3	OCH3	H	COCH3
428	OH	CH3	OCH3	CH3	H
429	OH	CH3	OCH3	CH3	COCH3
430	OH	H	NH2	H	H
431	OH	H	NH2	H	COCH3
432	OH	H	NH2	CH3	H
433	OH	H	NH2	CH3	COCH3
434	OH	CH3	NH2	H	H
435	OH	CH3	NH2	H	COCH3
436	OH	CH3	NH2	CH3	H
437	OH	CH3	NH2	CH3	COCH3
438	OCH3	H	OH	H	H
439	OCH3	H	OH	H	COCH3
440	OCH3	H	OH	CH3	H
441	OCH3	H	OH	CH3	COCH3
442	OCH3	H	OCH3	H	H
443	OCH3	H	OCH3	H	COCH3
444	OCH3	H	OCH3	CH3	H
445	OCH3	H	OCH3	CH3	COCH3
446	OCH3	CH3	OH	H	H
447	OCH3	CH3	OH	H	COCH3
448	OCH3	CH3	OH	CH3	H
449	OCH3	CH3	OH	CH3	COCH3
450	OCH3	CH3	OCH3	H	H
451	OCH3	CH3	OCH3	H	COCH3
452	OCH3	CH3	OCH3	CH3	H
453	OCH3	CH3	OCH3	CH3	COCH3
454	OCH3	H	NH2	H	H
455	OCH3	H	NH2	H	COCH3
456	OCH3	H	NH2	CH3	H
457	OCH3	H	NH2	CH3	COCH3
458	OCH3	CH3	NH2	H	H
459	OCH3	CH3	NH2	H	COCH3
460	OCH3	CH3	NH2	CH3	H
461	OCH3	CH3	NH2	CH3	COCH3

[0477] The following Examples #462-#857 comprise five classes of highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid derivatives. Examples #462-#464 are descriptions of specific preparations of such conjugates. Examples #465-#857, as shown in Tables VII-XI, may be prepared by procedures shown in these specific examples and in the foregoing general synthetic procedures of Schemes 1-7.

EXAMPLE 462

[0478] 359

4-amino-4-carboxy-1-oxobutyl-3-hydroxy-α-methyl-L-tyrosine, methyl ester

[0479] Step. 1: Preparation of α-methyl-L-DOPA, methyl este, hydrochloride.

[0480] A suspension of 29.7 g (141 mmol) of α-methyl-L-DOPA in 300 mL of absolute methanol was cooled to −15° C. and treated with 125.8 g (1.06 mol) thionyl chloride under a nitrogen atmosphere. The reaction was allowed to warm to ambient temperature and stir at reflux for 3 days. Concentration followed by trituration with ether gave 31.7 g (97%) as an off-white solid: NMR (DMSO-d6) δ1.47 (s, 3H), 2.92 (d, J=12 Hz, 1H), 2.98 (d, J=12 Hz, 1H), 3.74 (s, 3H), 6.41 (d of d, J=9 Hz AND 2 Hz, 1H), 6.54 (d, J=2 Hz, 1H), 6.68 (d, J=9 Hz, 1H), 8.46-8.90 (br s, 3H), 8.93 (s, 1H), 8.96 (s, 1H).

[0481] Step 2: Preparation of 4-amino-4-carboxy-1-oxobutyl-3-hydroxy-α-methyl-L-tyrosine, methyl ester.

[0482] Under nitrogen, a solution of 32.7 g (108 mmol) of N-Boc-L-γ-glutamic acid-α-t-butyl ester (BACHEM) in 150 mL of methylene chloride was treated with 11.14 g (54 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction was allowed to stir for 2 hr prior to filtration under a nitrogen atmosphere. The methylene chloride was removed in vacuo and the residue dissolved in 110 mL of dimethylformamide (DMF). The anhydride solution was slowly added to a solution of 12.9 g (49 mmol) of the α-methyl-DOPA ester from step 1 and 12.6 g (98 mmol) of diisopropylethylamine (DIEA) in 50 mL of anhydrous DMF. The reaction was allowed to stir overnight and was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1N citric acid, 1N NaHCO3, water, and brine, dried (Na2SO4), and concentrated in vacuo to give the protected coupled product; a solution of this material in 100 mL of methylene chloride was cooled to 0° C. and treated with 400 mL of trifluoroacetic acid (TFA) under nitrogen. The reaction was allowed to warm to ambient temperature and stir for 72 hr. Concentration in vacuo gave 4-amino-4-carboxy-1-oxobutyl-3-hydroxy-α-methyl-L-tyrosine, methyl ester: NMR (DMSO-d6) δ1.40 (s, 3H), 1.85-2.30 (m, 2H), 2.30-2.50 (m, 2H), 2.77 (d, J=12 Hz, 1H), 3.00 (d, J=12 Hz, 1H), 3.58 (s, 3H), 3.85-4.10 (m, 1H), 6.29 (d of d, J=9 Hz and 2 Hz, 1H), 6.45 (d, J=2 Hz, 1H), 6.62 (d, J=9 Hz, 1H); MS (FAB) m/e (rel intensity) 355 (92), 225 (51), 148 (35).

EXAMPLE 463

[0483] 360

N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine, methyl ester

[0484] The compound of Example 462 was dissolved in 100 mL of degassed water and under nitrogen the pH adjusted to 9 with 1 M K2CO3. The solution was cooled to 0° C. and 12 mL (127 mmol) of acetic anhydride and 180 mL (180 mmol) of 1 M K2CO3 was added every 30 min. for 5 h; the pH was maintained at 9 and the reaction temperature kept below 5° C. After the last addition, the reaction was allowed to warm to ambient temperature overnight. The pH was adjusted to 3 with 3M HCl and concentrated to 100 mL. Purification by reverse phase chromatography (Waters Deltaprep-3000) using a 5-15% gradient of acetonitrile/water (0.05% TFA) gave 14.0 g (49%) of colorless product: NMR (DMSO-d6) δ1.15 (s, 3H), 1.70-1.83 (m, 2H), 1.85 (s, 3H), 1.87-2.00 (m, 2H), 2.15 (t, J=7 Hz, 2H), 2.75 (d, J=12 Hz, 1H), 3.00 (d, J=12 Hz, 1H), 3.55 (s, 3H), 4.10-4.22 (m, 1H), 6.29 (d of d, J=9 Hz and 2 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 7.96 (s, 1H), 8.12 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 397 (100), 365 (10), 226 (70), 166 (90), 153 (22), 130 (72), 102 (28).

EXAMPLE 464

[0485] 361

N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine

[0486] A solution of 13.5 g (102 mmol) of the compound of Example 463 in 34 mL of water was cooled to 0° C. and treated with 102 mL (102 mmol) of 1N NaOH (all solutions were degassed in vacuo and flushed with nitrogen prior to use). The reaction was stirred at ambient temperature for 5 hr and the pH adjusted to pH 1 with 6N HCl. Purification by reverse phase chromatography (Waters Deltaprep-3000) using a 2-10% gradient of acetonitrile/water (0.05% TFA) gave 8.9 g (68%) of colorless product: NMR (DMSO-d6) δ1.18 (s, 3H), 1.70-1.83 (m, 2H), 1.85 (s, 3H), 1.87-2.00 (m, 2H), 2.15 (t, J=7 Hz, 2H), 2.75 (d, J=12 Hz, 1H), 3.05 (d, J=12 Hz, 1H), 4.10-4.23 (m, 1H), 6.31 (d of d, J=9 Hz and 2 Hz, 1H), 6.47 (d, J=2 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 7.71 (s, 1H), 8.15 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 383 (23), 212 (10), 166 (18), 130 (21), 115 (23); HRMS. Calcd for M+H: 383.1454. Found: 383.1450. Anal: Calcd for C17H22N2O8.1.06 H2O.0.85 TFA: C, 48.67; H, 5.59; N, 6.46; F, 3.73. Found: C, 49.02; H, 5.73; N, 6.40; F, 3.70.

[0487] The following Examples #465-#541 of Table VII are highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid derivatives. These dopa-decarboxylase inhibitors utilized to make these conjugates are embraced by generic Formula IV, above.

TABLE VII
362
EXAMPLE
NO.	A	R1	E	P
465	363	H	CH3	COCH3
466	364	H	H	H
467	365	H	H	COCH3
468	366	H	CH3	H
469	367	H	CH3	COCH3
470	368	H	H	H
471	369	H	H	COCH3
472	370	H	CH3	H
473	371	H	CH3	COCH3
474	372	NH2	H	H
475	373	NH2	H	COCH3
476	374	NH2	CH3	H
477	375	NH2	CH3	COCH3
478	376	H	H	H
479	377	H	H	COCH3
480	378	H	CH3	H
481	379	H	CH3	COCH3
482	380	NH2	H	H
483	381	NH2	H	COCH3
484	382	NH2	CH3	H
485	383	NH2	CH3	COCH3
486	384	H	H	H
487	385	H	H	COCH3
488	386	H	CH3	H
489	387	H	CH3	COCH3
490	388	H	H	H
491	389	H	H	COCH3
492	390	H	CH3	H
493	391	H	CH3	COCH3
494	392	H	H	H
495	393	H	H	COCH3
496	394	H	CH3	H
497	395	H	CH3	COCH3
498	396	NH2	H	H
499	397	NH2	H	COCH3
500	398	NH2	CH3	H
501	399	NH2	CH3	COCH3
502	400	H	H	H
503	401	H	H	COCH3
504	402	H	CH3	H
505	403	H	CH3	COCH3
506	404	H	H	H
507	405	H	H	COCH3
508	406	H	CH3	H
509	407	H	CH3	COCH3
510	408	H	H	H
511	409	H	H	COCH3
512	410	H	CH3	H
513	411	H	CH3	COCH3
514	412	H	H	H
515	413	H	H	COCH3
516	414	H	CH3	H
517	415	H	CH3	COCH3
518	416	H	H	H
519	417	H	H	COCH3
520	418	H	CH3	H
521	419	H	CH3	COCH3
522	420	H	H	H
523	421	H	H	COCH3
524	422	H	CH3	H
525	423	H	CH3	COCH3
526	424	H	H	H
527	425	H	H	COCH3
528	426	H	CH3	H
529	427	H	CH3	COCH3
530	428	H	H	H
531	429	H	H	COCH3
532	430	H	CH3	H
533	431	H	CH3	COCH3
534	432	H	H	H
535	433	H	H	COCH3
536	434	H	CH3	H
537	435	H	CH3	COCH3
538	436	H	H	H
539	437	H	H	COCH3
540	438	H	CH3	H
541	439	H	CH3	COCH3

[0488] The following Examples #542-#577 of Table VIII are highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid derivatives. These dopa-decarboxylase inhibitors utilized to make these conjugates are embraced by generic Formula VIII, above.

TABLE VIII
440
EXAMPLE
NO.	L	M	R56	R55	E	P
542	NHNH	441	H	H	H	H
543	NHNH	442	H	H	H	COCH3
544	NHNH	443	H	H	CH3	H
545	NHNH	444	H	H	CH3	COCH3
546	NHNH	445	Br	H	H	H
547	NHNH	446	Br	H	H	COCH3
548	NHNH	447	Br	H	CH3	H
549	NHNH	448	Br	H	CH3	COCH3
550	NHNH	449	Br	Br	H	H
551	NHNH	450	Br	Br	H	COCH3
552	NHNH	451	Br	Br	CH3	H
553	NHNH	452	Br	Br	CH3	COCH3
554	NHCH2CH2NH	453	H	H	H	H
555	NHCH2CH2NH	454	H	H	H	COCH3
556	NHCH2CH2NH	455	H	H	CH3	H
557	NHCH2CH2NH	456	H	H	CH3	COCH3
558	NHCH2CH2NH	457	Br	H	H	H
559	NHCH2CH2NH	458	Br	H	H	COCH3
560	NHCH2CH2NH	459	Br	H	CH3	H
561	NHCH2CH2NH	460	Br	H	CH3	COCH3
562	NHCH2CH2NH	461	Br	Br	H	H
563	NHCH2CH2NH	462	Br	Br	H	COCH3
564	NHCH2CH2NH	463	Br	Br	CH3	H
565	NHCH2CH2NH	464	Br	Br	CH3	COCH3
566	piperazinyl	465	H	H	H	H
567	piperazinyl	466	H	H	H	COCH3
568	piperazinyl	467	H	H	CH3	H
569	piperazinyl	468	H	H	CH3	COCH3
570	piperazinyl	469	Br	H	H	H
571	piperazinyl	470	Br	H	H	COCH3
572	piperazinyl	471	Br	H	CH3	H
573	piperazinyl	472	Br	H	CH3	COCH3
574	piperazinyl	473	Br	Br	H	H
575	piperazinyl	474	Br	Br	H	COCH3
576	piperazinyl	475	Br	Br	CH3	H
577	piperazinyl	476	Br	Br	CH3	COCH3

[0489] The following Examples #578-#757 of Table IX are highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid derivatives. These dopa-decarboxylase inhibitors utilized to make these conjugates are benzoic acid type derivatives based on the list of similar compounds described earlier.

TABLE IX
477
EXAMPLE
NO.	L	R130	R131	R132	E	P
578	NHNH	H	OH	OH	H	H
579	NHNH	H	OH	OH	H	COCH3
580	NHNH	H	OH	OH	CH3	H
581	NHNH	H	OH	OH	CH3	COCH3
582	NHNH	478	OH	OH	H	H
583	NHNH	479	OH	OH	H	COCH3
584	NHNH	480	OH	OH	CH3	H
585	NHNH	481	OH	OH	CH3	COCH3
586	NHNH	482	OH	OH	H	H
587	NHNH	483	OH	OH	H	COCH3
588	NHNH	484	OH	OH	CH3	H
589	NHNH	485	OH	OH	CH3	COCH3
590	NHNH	486	OCH3	OCH3	H	H
591	NHNH	487	OCH3	OCH3	H	COCH3
592	NHNH	488	OCH3	OCH3	CH3	H
593	NHNH	489	OCH3	OCH3	CH3	COCH3
594	NHNH	490	OCH3	OCH3	H	H
595	NHNH	491	OCH3	OCH3	H	COCH3
596	NHNH	492	OCH3	OCH3	CH3	H
597	NHNH	493	OCH3	OCH3	CH3	COCH3
598	NHNH	494	OCH3	OCH3	H	H
599	NHNH	495	OCH3	OCH3	H	COCH3
600	NHNH	496	OCH3	OCH3	CH3	H
601	NHNH	497	OCH3	OCH3	CH3	COCH3
602	NHNH	498	OCH3	OCH3	H	H
603	NHNH	499	OCH3	OCH3	H	COCH3
604	NHNH	500	OCH3	OCH3	CH3	H
605	NHNH	501	OCH3	OCH3	CH3	COCH3
606	NHNH	502	OH	OH	H	H
607	NHNH	503	OH	OH	H	COCH3
608	NHNH	504	OH	OH	CH3	H
609	NHNH	505	OH	OH	CH3	COCH3
610	NHNH	506	OCH3	OCH3	H	H
611	NHNH	507	OCH3	OCH3	H	COCH3
612	NHNH	508	OCH3	OCH3	CH3	H
613	NHNH	509	OCH3	OCH3	CH3	COCH3
614	NHNH	510	OCH3	OCH3	H	H
615	NHNH	511	OCH3	OCH3	H	COCH3
616	NHNH	512	OCH3	OCH3	CH3	H
617	NHNH	513	OCH3	OCH3	CH3	COCH3
618	NHNH	514	OCH3	OCH3	H	H
619	NHNH	515	OCH3	OCH3	H	COCH3
620	NHNH	516	OCH3	OCH3	CH3	H
621	NHNH	517	OCH3	OCH3	CH3	COCH3
622	NHNH	518	OH	OH	H	H
623	NHNH	519	OH	OH	H	COCH3
624	NHNH	520	OH	OH	CH3	H
625	NHNH	521	OH	OH	CH3	COCH3
626	NHNH	522	OCH3	OCH3	H	H
627	NHNH	523	OCH3	OCH3	H	COCH3
628	NHNH	524	OCH3	OCH3	CH3	H
629	NHNH	525	OCH3	OCH3	CH3	COCH3
630	NHNH	526	OCH3	OCH3	H	H
631	NHNH	527	OCH3	OCH3	H	COCH3
632	NHNH	528	OCH3	OCH3	CH3	H
633	NHNH	529	OCH3	OCH3	CH3	COCH3
634	NHNH	530	OH	OH	H	H
635	NHNH	531	OH	OH	H	COCH3
636	NHNH	532	OH	OH	CH3	H
637	NHNH	533	OH	OH	CH3	COCH3
638	NHCH2CH2NH	H	OH	OH	H	H
639	NHCH2CH2NH	H	OH	OH	H	COCH3
640	NHCH2CH2NH	H	OH	OH	CH3	H
641	NHCH2CH2NH	H	OH	OH	CH3	COCH3
642	NHCH2CH2NH	534	OH	OH	H	H
643	NHCH2CH2NH	535	OH	OH	H	COCH3
644	NHCH2CH2NH	536	OH	OH	CH3	H
645	NHCH2CH2NH	537	OH	OH	CH3	COCH3
646	NHCH2CH2NH	538	OH	OH	H	H
647	NHCH2CH2NH	539	OH	OH	H	COCH3
648	NHCH2CH2NH	540	OH	OH	CH3	H
649	NHCH2CH2NH	541	OH	OH	CH3	COCH3
650	NHCH2CH2NH	542	OCH3	OCH3	H	H
651	NHCH2CH2NH	543	OCH3	OCH3	H	COCH3
652	NHCH2CH2NH	544	OCH3	OCH3	CH3	H
653	NHCH2CH2NH	545	OCH3	OCH3	CH3	COCH3
654	NHCH2CH2NH	546	OCH3	OCH3	H	H
655	NHCH2CH2NH	547	OCH3	OCH3	H	COCH3
656	NHCH2CH2NH	548	OCH3	OCH3	CH3	H
657	NHCH2CH2NH	549	OCH3	OCH3	CH3	COCH3
658	NHCH2CH2NH	550	OCH3	OCH3	H	H
659	NHCH2CH2NH	551	OCH3	OCH3	H	COCH3
660	NHCH2CH2NH	552	OCH3	OCH3	CH3	H
661	NHCH2CH2NH	553	OCH3	OCH3	CH3	COCH3
662	NHCH2CH2NH	554	OCH3	OCH3	H	H
663	NHCH2CH2NH	555	OCH3	OCH3	H	COCH3
664	NHCH2CH2NH	556	OCH3	OCH3	CH3	H
665	NHCH2CH2NH	557	OCH3	OCH3	CH3	COCH3
666	NHCH2CH2NH	558	OH	OH	H	H
667	NHCH2CH2NH	559	OH	OH	H	COCH3
668	NHCH2CH2NH	560	OH	OH	CH3	H
669	NHCH2CH2NH	561	OH	OH	CH3	COCH3
670	NHCH2CH2NH	562	OCH3	OCH3	H	H
671	NHCH2CH2NH	563	OCH3	OCH3	H	COCH3
672	NHCH2CH2NH	564	OCH3	OCH3	CH3	H
673	NHCH2CH2NH	565	OCH3	OCH3	CH3	COCH3
674	NHCH2CH2NH	566	OCH3	OCH3	H	H
675	NHCH2CH2NH	567	OCH3	OCH3	H	COCH3
676	NHCH2CH2NH	568	OCH3	OCH3	CH3	H
677	NHCH2CH2NH	569	OCH3	OCH3	CH3	COCH3
678	NHCH2CH2NH	570	OCH3	OCH3	H	H
679	NHCH2CH2NH	571	OCH3	OCH3	H	COCH3
680	NHCH2CH2NH	572	OCH3	OCH3	CH3	H
681	NHCH2CH2NH	573	OCH3	OCH3	CH3	COCH3
682	NHCH2CH2NH	574	OH	OH	H	H
683	NHCH2CH2NH	575	OH	OH	H	COCH3
684	NHCH2CH2NH	576	OH	OH	CH3	H
685	NHCH2CH2NH	577	OH	OH	CH3	COCH3
686	NHCH2CH2NH	578	OCH3	OCH3	H	H
687	NHCH2CH2NH	579	OCH3	OCH3	H	COCH3
688	NHCH2CH2NH	580	OCH3	OCH3	CH3	H
689	NHCH2CH2NH	581	OCH3	OCH3	CH3	COCH3
690	NHCH2CH2NH	582	OCH3	OCH3	H	H
691	NHCH2CH2NH	583	OCH3	OCH3	H	COCH3
692	NHCH2CH2NH	584	OCH3	OCH3	CH3	H
693	NHCH2CH2NH	585	OCH3	OCH3	CH3	COCH3
694	NHCH2CH2NH	586	OH	OH	H	H
695	NHCH2CH2NH	587	OH	OH	H	COCH3
696	NHCH2CH2NH	588	OH	OH	CH3	H
697	NHCH2CH2NH	589	OH	OH	CH3	COCH3
698	piperazinyl	H	OH	OH	H	H
699	piperazinyl	H	OH	OH	H	COCH3
700	piperazinyl	H	OH	OH	CH3	H
701	piperazinyl	H	OH	OH	CH3	COCH3
702	piperazinyl	590	OH	OH	H	H
703	piperazinyl	591	OH	OH	H	COCH3
704	piperazinyl	592	OH	OH	CH3	H
705	piperazinyl	593	OH	OH	CH3	COCH3
706	piperazinyl	594	OH	OH	H	H
707	piperazinyl	595	OH	OH	H	COCH3
708	piperazinyl	596	OH	OH	CH3	H
709	piperazinyl	597	OH	OH	CH3	COCH3
710	piperazinyl	598	OCH3	OCH3	H	H
711	piperazinyl	599	OCH3	OCH3	H	COCH3
712	piperazinyl	600	OCH3	OCH3	CH3	H
713	piperazinyl	601	OCH3	OCH3	CH3	COCH3
714	piperazinyl	602	OCH3	OCH3	H	H
715	piperazinyl	603	OCH3	OCH3	H	COCH3
716	piperazinyl	604	OCH3	OCH3	CH3	H
717	piperazinyl	605	OCH3	OCH3	CH3	COCH3
718	piperazinyl	606	OCH3	OCH3	H	H
719	piperazinyl	607	OCH3	OCH3	H	COCH3
720	piperazinyl	608	OCH3	OCH3	CH3	H
721	piperazinyl	609	OCH3	OCH3	CH3	COCH3
722	piperazinyl	610	OCH3	OCH3	H	H
723	piperazinyl	611	OCH3	OCH3	H	COCH3
724	piperazinyl	612	OCH3	OCH3	CH3	H
725	piperazinyl	613	OCH3	OCH3	CH3	COCH3
726	piperazinyl	614	OH	OH	H	H
727	piperazinyl	615	OH	OH	H	COCH3
728	piperazinyl	616	OH	OH	CH3	H
729	piperazinyl	617	OH	OH	CH3	COCH3
730	piperazinyl	618	OCH3	OCH3	H	H
731	piperazinyl	619	OCH3	OCH3	H	COCH3
732	piperazinyl	620	OCH3	OCH3	CH3	H
733	piperazinyl	621	OCH3	OCH3	CH3	COCH3
734	piperazinyl	622	OCH3	OCH3	H	H
735	piperazinyl	623	OCH3	OCH3	H	COCH3
736	piperazinyl	624	OCH3	OCH3	CH3	H
737	piperazinyl	625	OCH3	OCH3	CH3	COCH3
738	piperazinyl	626	OCH3	OCH3	H	H
739	piperazinyl	627	OCH3	OCH3	H	COCH3
740	piperazinyl	628	OCH3	OCH3	CH3	H
741	piperazinyl	629	OCH3	OCH3	CH3	COCH3
742	piperazinyl	630	OH	OH	H	H
743	piperazinyl	631	OH	OH	H	COCH3
744	piperazinyl	632	OH	OH	CH3	H
745	piperazinyl	633	OH	OH	CH3	COCH3
746	piperazinyl	634	OCH3	OCH3	H	H
747	piperazinyl	635	OCH3	OCH3	H	COCH3
748	piperazinyl	636	OCH3	OCH3	CH3	H
749	piperazinyl	637	OCH3	OCH3	CH3	COCH3
750	piperazinyl	638	OCH3	OCH3	H	H
751	piperazinyl	639	OCH3	OCH3	H	COCH3
752	piperazinyl	640	OCH3	OCH3	CH3	H
753	piperazinyl	641	OCH3	OCH3	CH3	COCH3
754	piperazinyl	642	OH	OH	H	H
755	pieprazinyl	643	OH	OH	H	COCH3
756	piperazinyl	644	OH	OH	CH3	H
757	piperazinyl	645	OH	OH	CH3	COCH3

[0490] The following Examples #758-#809 of Table X are highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid derivatives. These dopa-decarboxylase inhibitors utilized to make these conjugates are prepenoic acid derivatives based on the list of similar compounds described earlier.

TABLE X
646
EXAMPLE
NO.	R133	R134	R135	E	P
758	H	647	H	H	H
759	H	648	H	H	COCH3
760	H	649	H	CH3	H
761	H	650	H	CH3	COCH3
762	CH3	651	H	H	H
763	CH3	652	H	H	COCH3
764	CH3	653	H	CH3	H
765	CH3	654	H	CH3	COCH3
766	H	655	CH3	H	H
767	H	656	CH3	H	COCH3
768	H	657	CH3	CH3	H
769	H	658	CH3	CH3	COCH3
770	H	659	H	H	H
771	H	660	H	H	COCH3
772	H	661	H	CH3	H
773	H	662	H	CH3	COCH3
774	CH3	663	H	H	H
775	CH3	664	H	H	COCH3
776	CH3	665	H	CH3	H
777	CH3	666	H	CH3	COCH3
778	H	667	H	H	H
779	H	668	H	H	COCH3
780	H	669	H	CH3	H
781	H	670	H	CH3	COCH3
782	CH3	671	H	H	H
783	CH3	672	H	H	COCH3
784	CH3	673	H	CH3	H
785	CH3	674	H	CH3	COCH3
786	H	675	H	H	H
787	H	676	H	H	COCH3
788	H	677	H	CH3	H
789	H	678	H	CH3	COCH3
790	CH3	679	H	H	H
791	CH3	680	H	H	COCH3
792	CH3	681	H	CH3	H
793	CH3	682	H	CH3	COCH3
794	H	683	CH3	H	H
795	H	684	CH3	H	COCH3
796	H	685	CH3	CH3	H
797	H	686	CH3	CH3	COCH3
798	H	687	H	H	H
799	H	688	H	H	COCH3
800	H	689	H	CH3	H
801	H	690	H	CH3	COCH3
802	CH3	691	H	H	H
803	CH3	692	H	H	COCH3
804	CH3	693	H	CH3	H
805	CH3	694	H	CH3	COCH3
806	H	695	CH3	H	H
807	H	696	CH3	H	COCH3
808	H	697	CH3	CH3	H
809	H	698	CH3	CH3	COCH3

[0491] The following Examples #810-#833 of Table XI are highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid derivatives. These dopa-decarboxylase inhibitors utilized to make these conjugates are embraced by generic Formula IX, above.

TABLE XI
699
EXAMPLE
NO.	R67	R136	E	P
810	H	H	H	H
811	H	H	H	COCH3
812	H	H	CH3	H
813	H	H	CH3	COCH3
814	H	OH	H	H
815	H	OH	H	COCH3
816	H	OH	CH3	H
817	H	OH	CH3	COCH3
818	H	OCH3	H	H
819	H	OCH3	H	COCH3
820	H	OCH3	CH3	H
821	H	OCH3	CH3	COCH3
822	CH3	H	H	H
823	CH3	H	H	COCH3
824	CH3	H	CH3	H
825	CH3	H	CH3	COCH3
826	CH3	OH	H	H
827	CH3	OH	H	COCH3
828	CH3	OH	CH3	H
829	CH3	OH	CH3	COCH3
830	CH3	OCH3	H	H
831	CH3	OCH3	H	COCH3
832	CH3	OCH3	CH3	H
833	CH3	OCH3	CH3	COCH3

[0492] The following Examples #834-#857 of Table XII are highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid derivatives. These dopa-decarboxylase inhibitors utilized to make these conjugates are embraced by generic Formula IX, above.

TABLE XII
700
EXAMPLE
NO.	R138	R139	R67	E	P
834	H	H	C≡CH	H	H
835	H	H	C≡CH	H	COCH3
836	H	H	C≡CH	CH3	H
837	H	H	C≡CH	CH3	COCH3
838	OH	H	C≡CH	H	H
839	OH	H	C≡CH	H	COCH3
840	OH	H	C≡CH	CH3	H
841	OH	H	C≡CH	CH3	COCH3
842	H	OH	C≡CH	H	H
843	H	OH	C≡CH	H	COCH3
844	H	OH	C≡CH	CH3	H
845	H	OH	C≡CH	CH3	COCH3
846	H	H	CH═CH2	H	H
847	H	H	CH═CH2	H	COCH3
848	H	H	CH═CH2	CH3	H
849	H	H	CH═CH2	CH3	COCH3
850	OH	H	CH═CH2	H	H
851	OH	H	CH═CH2	H	COCH3
852	OH	H	CH═CH2	CH3	H
853	OH	H	CH═CH2	CH3	COCH3
854	H	OH	CH═CH2	H	H
855	H	OH	CH═CH2	H	COCH3
856	H	OH	CH═CH2	CH3	H
857	H	OH	CH═CH2	CH3	COCH3

[0493] The following Examples #858-#1857 comprise five classes of highly preferred conjugates composed of dopamine-β-hydroxylase inhibitor compounds and glutamic acid derivatives. Examples #858-#863 are descriptions of specific preparations of such conjugates. Examples #864-#1857, as shown in Tables XIII-XVII, may be prepared by procedures shown in-these specific examples and in the foregoing general synthetic procedures of Schemes 1-7.

EXAMPLE 858

[0494] 701

L-glutamic acid, 5-{[(5-butyl-2-pyridinyl)carbonyl]hydrazide}

[0495] Step. 1: Preparation of 5-n-Butylpicolinic (Fusaric) Acid Hydrazide.

[0496] A solution of 36.0 g (0.20 mol) of fusaric acid (Sigma) in 800 ml of absolute methanol was cooled to −10° C. by means of an ice/methanol bath and 120 ml (199 g, 1.67 mol) of SOCl2 was added dropwise over a 1 hr period. The reaction was allowed to slowly warm to ambient temperature and then stirred at reflux for 72 hr. The reaction was concentrated; the addition of 100 ml of toluene (twice) followed by reconcentration insured the complete removal of any unreacted SOCl2. The viscous syrup thus formed was dried in vacuo (0.01 mm) overnight prior to treatment with cold NaHCO3(sat). The ester was extracted with ether and dried (MgSO4). Concentration gave 32.3 g (83%) of crude methyl fusarate which was redissolved in 100 ml of absolute methanol and cooled to 0° C. Under a nitrogen atmosphere, 5.5 ml (0.174 mol) of anhydrous hydrazine was slowly added by syringe. The reaction was allowed to slowly warm to ambient temperature and stir overnight. The methanol was removed and the yellow-brown residue was dried in vacuo (0.01 mm) overnight where it solidified producing 31.7 g (98%) based on ester) of crude hydrazide. Recrystallization from ether/hexane gave colorless needles: mp 51-53° C. NMR (CDCl3) δ0.95 (t, J=7 Hz, 3H, CH2CH3); 1.30-1.45 (m, 2H, CH2CH3); 1.55-1.70 (m, 2H, CH2CH2CH2); 2.67 (t, J=7 Hz, 2H, ArCH2); 7.65 (d of d, J3,4=7 Hz and J4,6=2 Hz, 1H, ArH); 8.05 (d, J3,4=7 Hz, 1H, ArH); 8.37 (d, 1H, ArH, J4,6=2 Hz); HRMS. Calcd for M+H: 194.1270. Found: 194.1293.

[0497] Step 2: Preparation of L-glutamic acid, 5-{[(5-butyl-2-pyridinyl)carbonyl]hydrazide}.

[0498] A solution of 7.27 g (24.0 mmol) of Boc-L-γglutamic acid-α-t-butyl ester (BACHEM) in 150 ml of anhydrous THF was cooled to 0° C. under static nitrogen and treated with 2.7 ml (2.46 g, 24.4 mmol) of anhydrous N-methyl morpholine. The mixture was then slowly treated with 3.1 ml (3.26 g, 23.9 mmol) of isobutyl chloroformate and allowed to stir for 1 hr prior to the dropwise addition of a solution of 3.86 g (20.0 mmol) of fusaric acid hydrazide from step 1 in 30 ml of anhydrous THF. The reaction mixture was stirred at 0° C. for 2 hr and then allowed to warm to ambient temperature and stir overnight. The N-methylmorpholine hydrochloride was removed by filtration and the filtrate concentrated in vacuo to give 11.5 g of crude product which was a colorless glass. This material was dissolved in 50 ml of CH2Cl2 and treated with 50 ml of CF3CO2H. After 4 hr at ambient temperature, the volitiles were removed in vacio. The addition of acetonitrile caused the product to precipitate producing 3.97 g (46%) of colorless material: mp 162-164° C. (dec.); NMR (DMSO-d6) δ1.90 (t, J=7 Hz, 3H, CH2CH3); 1.30-1.45 (m, 2H, CH2CH3); 1.50-1.65 (m, 2H, CH2CH2CH2); 2.00-2.20 (m, 1H, CH2CH); 2.30-2.50 (m, 1H, CH2CH); 2.70 (t, J=7 Hz, 2H, ArCH2); 3.60 (t, J=7 Hz, 2H, COCH2); 3.95-4.05 (M, 1H, CH2CH); 7.85 (d of d, J3,4=7 Hz and J4,6=2 Hz, 1H, ArH); 7.95 (d, J3,4=7 Hz, 1H, ArH); 8.55 (d, J4,6=2 Hz, 1H, ArH).

EXAMPLE 859

[0499] 702

N-acetyl-L-glutamic acid, 5-[(5-butyl-2-pyridinyl)-carbonyl]hydrazide

[0500] A suspension of 2.85 g (6.54 mmol) of the compound of Example 858 in CH3CN/H2O (1:1) was treated with 2 equiv. of 1 M K2CO3 at 0° C. With efficient stirring, 1 ml (10.6 mmol) of acetic anhydride and 11 ml (11 mmol) of 1M K2CO3 were added every 10 min for 1 hr; since the product is soluble, the mixture became homogenous as the reaction proceeded. The reaction mixture was stirred for 1 hr, filtered, and the filtrate cooled to 0° C. The pH was adjusted to pH 4 by the careful addition of cold dilute HCl. All volitiles were removed m vacuo and the product dissolved in ethanol. Recrystallization from ethanol/petroleum ether produced 2.16 g (69%) of colorless material: mp 191.5-192.0° C.; NMR (D2O and NaOD) δ0.85 (t, J=7 Hz, 3H, CH2CH3); 1.20-1.35 (m, 2H, CH2CH3); 1.55-1.70 (m, 2H, CH2CH2CH2); 1.95-2.10 (m, 1H, CH2CH); 2.05 (s, 3H, COCH3); 2.20-2.35 (m, 1H, CH2CH); 2.45 (t, J=7 Hz, 2H, COCH2); 2.75 (t, 2H, ArCH2); 3.45-3.55 (m, 1H, CH2CH); 8.05 (s, 2H, ArH); 8.55 (s, 1H, ArH); HRMS. Calcd for M+H: 365.1825. Found 365.1860. Anal Calcd. for C17H24N4O5: C, 55.98; H, 6.58; N, 15.36. Found: C, 55.96; H, 6.64; N, 15.30.

EXAMPLE 860

[0501] 703

N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine

[0502] Step 1: Preparation of the Ethylene Diamine Amide of Fusaric

[0503] A solution of 7.8 g (130 mmol) of ethylene diamine in 400 mL of anhydrous THF under nitrogen was treated with 27 mmol of n-butyllithium at 0° C. The solution was allowed to stir for 30 min and was treated with 5.0 g (26 mmol) of neat methyl fusarate (from step 1 of Example 690) by syringe. The reaction was kept at 0° C. for 2 hr and stirred at ambient temperature overnight. The reaction was quenched with water, filtered, and concentrated in vacuo. Purification by silica gel chromatography gave 3.8 g (66%) of pure amide: NMR (DMSO-d6) δ0.90 (t, J=8 Hz, 3H), 1.23-1.38 (m, 2H), 1.52-1.64 (m, 2H), 2.67 (t, J=8 Hz, 2H), 2.74 (t, J=8 Hz, 2H), 3.18-3.30 (br s, 2H), 3.34 (q, J=8 Hz, 2H), 7.82 d of d, J=9 Hz and 2 Hz, 1H), 7.96 (d, J=9 Hz, 1H), 8.47 (d, J=2 Hz, 1H), 8.75 (t, J=8 Hz, 1H).

[0504] Step 2: Preparation of N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine.

[0505] Under nitrogen, a solution of 26.8 g (88.5 mmol) of N-Boc-L-γ-glutamic acid-α-t-butyl ester (BACHEM) in 125 mL of methylene chloride was treated with 9.14 g (44.3 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction was allowed to stir for 2 hr prior to filtration under a nitrogen atmosphere. The anhydride solution was slowly added to a solution of 8.5 g (38.5 mmol) of the ethylene diamine amide from step 1 in 100 mL of methylene chloride. The reaction was allowed to stir overnight and was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M K2CO3 followed by water, dried (MgSO4) and reconcentrated in vacuo to give the protected coupled product; a solution of this material in 250 mL of methylene chloride was cooled to 0° C. and treated with 250 mL of trifluoroacetic acid (TFA). The reaction was allowed to warm to ambient temperature and stir overnight; the course of the reaction was monitored by analytical LC. Concentration in vacuo gave N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine.

EXAMPLE 861

[0506] 704

N2-acetyl-N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine

[0507] The compound of Example 860 was dissolved in 150 mL of acetonitrile/water (1:1) and the pH adjusted to 9 with 2 M K2CO3. The solution was cooled to 0° C. and 2.27 mL (24 mmol) of acetic anhydride and 12 mL (24 mmol) of 2 M K2CO3 was added every 30 min. for 5 h; the pH was maintained at 9 and the reaction temperature kept below 5° C. After the last addition, the reaction was allowed to warm to ambient temperature overnight. The pH was adjusted to 3 with 3 M HCl and concentrated to 300 mL. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocractic 30% acetonitrile/water (0.05% TFA) gave 7.8 g (52% overall yield from the amide of step 1) of colorless product; an analytical sample was recrystallized from acetonitrile and then water: mp 156-158° C.; Anal. Calcd for C19H28N4O5.0.83 TFA: C, 57.32; H, 7.00; N, 13,96; F, 1.14%. Found: C, 57.22; H, 7.07; N, 13.88; F, 1.07.

EXAMPLE 862

[0508] 705

2-amino-5-[4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid

[0509] Step 1: Preparation of the Piperizine Amide of Fusaric Acid.

[0510] A solution of 11.20 g (130 mmol) of piperazine in 400 mL of anhydrous THF under nitrogen was treated with 27.3 mmol of n-butyllithium at 0° C. The solution was allowed to stir for 30 min and was treated with 5.0 g (26 mmol) of neat methyl fusarate (from step 1 of Example 690) by syringe. The reaction was kept at 0° C. for 2 hr and stirred at ambient temperature overnight. The reaction was quenched with water, filtered, and concentrated in vacuo Purification by silica gel chromatography using chloroform/methanol (70:30) gave 5.82 g (90%) of pure amide: NMR (CDCl3) δ0.94 (t, J=8 Hz, 3H), 1.28-1.45 (m, 2H), 1.55-1.67 (m, 2H), 1.66-1.72 (br s, 1H), 2.64 (t, J=8 Hz, 2H), 2.86 (t, J=6 Hz, 2H), 2.97 (t, J=6 Hz, 2H), 3.58 (t, J=6 Hz, 2H) 3.77 (t, J=6 Hz, 2H), 7.54-7.63 (m, 2H), 8.37-8.43 (br s, 1H).

[0511] Step 2: Preparation of 2-amino-5-[4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid.

[0512] Under nitrogen, a solution of 17.4 g (57 mmol) of N-Boc-L-γ-glutamic acid-α-t-butyl ester (BACHEM) in 100 mL of anhydrous THF was treated with 5.57 g (27 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction was allowed to stir for 2 hr prior to filtration under a nitrogen atmosphere. The anhydride solution was slowly added to a solution of 5.82 g (23.5 mmol) of the piperazine amide from step 1 in 50 mL of anhydrous THF. The reaction was allowed to stir overnight and was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M K2CO3 followed by water, dried (MgSO4), and reconcentrated in vacuo to give the protected coupled product; a solution of this material in 150 mL of methylene chloride was cooled to 0° C. and treated with 150 mL of trifluoroacetic acid (TFA) under nitrogen. The reaction was allowed to warm to ambient temperature and stir overnight; the course of the reaction was monitored by analytical LC. Concentration in vacuo gave 2-amino-5-[4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid.

EXAMPLE 863

[0513] 706

2-(acetylamino)-5-(4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid

[0514] The compound of Example 862 was dissolved in 150 mL of acetonitrile/water (1:1) and the pH adjusted to 9 with 1 M K2CO3. The solution was cooled to 0° C. and 2.36 mL (25 mmol) of acetic anhydride and 25 mL (25 mmol) of 1 M K2CO3 was added every 30 min. for 5 h; the pH was maintained at 9 and the reaction temperature kept below 5° C. After the last addition, the reaction was allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 3 M HCl and concentrated to 300 mL. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic 25% acetonitrile/water (0.05% TFA) gave 8.13 g (78%) of colorless product: MS (FAB) m/e (rel intensity) 419 (100), 258 (10), 248 (37), 205 (28); HRMS. Calcd for M+H: 419.2294. Found: 419.2250.

EXAMPLE 864

[0515] 707

N2acetyl-N-[2-[[5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine, ethyl ester

[0516] A suspension of 57.77 g (0.133 mol) of the compound of Example 858 in CH3CN/H2O (1:1) was treated with 2 equivalents of 1 M K2CO3 at 0° C. With efficient stirring, 133 mL (0.133 mol) of 1 M K2CO3 and 12.5 mL (0.133 mol) of acetic anhydride were added every thirty minutes for 5 h, until a total of 10 equivalents of 1 M K2CO3 and acetic anhydride had been added. The reaction was kept at 0° C. for 4 h then allowed to warm to room temperature overnight. The reaction mixture was filtered, the filtrate cooled to 0° C., and the pH adjusted to pH 4 by the careful addition of cold dilute HCl. All volatiles were removed in vacuo The product was dissolved in absolute ethanol and allowed to stir at reflux for 30 min. Concentration provided 45.0 g of material of which 28.0 g was purified by reverse phase chromatography (Waters Deltaprep-3000) using isocratic 30% acetonitrile/water (0.05% TFA); 9.0 g of pale lavender material was collected which was redissolved in 150 mL of acetonitrile and precipitated with 500 mL of water. This material was collected by filtration and relyophilized in acetonitrile/water (1:1) to give 8.1 g (25%) of colorless ethyl ester: NMR (DMSO-d6) d 0.86(t, J=7 Hz, 3H), 1.16 (t, J=7H, 3H), 1.21-1.34 (m, 2H), 1.49-1.61 (m, 2H), 1.82 (s, 3H), 2.22 (t, J=8 Hz, 2H), 2.65 (t, J=8 Hz, 2H), 4.02-4.11 (m, 2H), 4.15-4.24 (m, 1H), 7.78-7.83 (m, 1H), 7.87-7.92 (m, 1H), 8.21-8.27 (m, 1H), 8.47 (d, J=2H, 1H), 9.94 (d, J=2H, 1H); HRMS. Calc'd for M+H: 393.2138. Found: 393.2097.

[0517] The following Examples #865-#1097 of Table XIII are highly preferred conjugates composed of dopamine-β-hydroxylase inhibitor compounds and glutamic acid derivatives. These dopamine-β-hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XIV and XV, above.

TABLE XIII
708
EXAMPLE
NO.	L	R97	E	P
865	NHNH	C2H5	CH3	H
866	NHNH	C2H5	CH3	COCH3
867	NHNH	C3H7	H	H
868	NHNH	C3H7	H	COCH3
869	NHNH	C3H7	CH3	H
870	NHNH	C3H7	CH3	COCH3
871	NHNH	CH3	H	H
872	NHNH	CH3	H	COCH3
873	NHNH	C4H9	CH3	H
874	NHNH	C4H9	CH3	COCH3
875	NHNH	C5H11	H	H
876	NHNH	C5H11	H	COCH3
877	NHNH	C5H11	CH3	H
878	NHNH	C5H11	CH3	COCH3
879	NHNH	C6H13	H	H
880	NHNH	C6H13	H	COCH3
881	NHNH	C6H13	CH3	COCH3
882	NHNH	OCH3	H	H
883	NHNH	OCH3	H	COCH3
884	NHNH	OCH3	CH3	H
885	NHNH	OCH3	CH3	COCH3
886	NHNH	OC2H5	H	H
887	NHNH	OC2H5	H	COCH3
888	NHNH	OC2H5	CH3	H
889	NHNH	OC2H5	CH3	COCH3
890	NHNH	OC3H7	H	H
891	NHNH	OC3H7	H	COCH3
892	NHNH	OC3H7	CH3	H
893	NHNH	OC3H7	CH3	COCH3
894	NHNH	OC4H9	H	H
895	NHNH	OC4H9	H	COCH3
896	NHNH	OC4H9	CH3	H
897	NHNH	OC4H9	CH3	COCH3
898	NHNH	SCH3	H	H
899	NHNH	SCH3	H	COCH3
900	NHNH	SCH3	CH3	H
901	NHNH	SCH3	CH3	COCH3
902	NHNH	SC2H5	H	H
903	NHNH	SC2H5	H	COCH3
904	NHNH	SC2H5	CH3	H
905	NHNH	SC2H5	CH3	COCH3
906	NHNH	SC3H7	H	H
907	NHNH	SC3H7	H	COCH3
908	NHNH	SC3H7	CH3	H
909	NHNH	SC3H7	CH3	COCH3
910	NHNH	F	H	H
911	NHNH	F	H	COCH3
912	NHNH	F	CH3	H
913	NHNH	F	CH3	COCH3
914	NHNH	Cl	H	H
915	NHNH	Cl	H	COCH3
916	NHNH	Cl	CH3	H
917	NHNH	Cl	CH3	COCH3
918	NHNH	Br	H	H
919	NHNH	Br	H	COCH3
920	NHNH	Br	CH3	H
921	NHNH	Br	CH3	COCH3
922	NHNH	I	H	H
923	NHNH	I	H	COCH3
924	NHNH	I	CH3	H
925	NHNH	I	CH3	COCH3
926	NHNH	CN	H	H
927	NHNH	CN	H	COCH3
928	NHNH	CN	CH3	H
929	NHNH	CN	CH3	COCH3
930	NHNH	NO2	H	H
931	NHNH	NO2	H	COCH3
932	NHNH	NO2	CH3	H
933	NHNH	NO2	CH3	COCH3
934	NHNH	OH	H	H
935	NHNH	OH	H	COCH3
936	NHNH	OH	CH3	H
937	NHNH	OH	CH3	COCH3
938	NHCH2CH2NH	CH3	H	H
939	NHCH2CH2NH	CH3	H	COCH3
940	NHCH2CH2NH	CH3	CH3	H
941	NHCH2CH2NH	CH3	CH3	COCH3
942	NHCH2CH2NH	C2H5	H	H
943	NHCH2CH2NH	C2H5	H	COCH3
944	NHCH2CH2NH	C2H5	CH3	H
945	NHCH2CH2NH	C2H5	CH3	COCH3
946	NHCH2CH2NH	C3H7	H	H
947	NHCH2CH2NH	C3H7	H	COCH3
948	NHCH2CH2NH	C3H7	CH3	H
949	NHCH2CH2NH	C3H7	CH3	COCH3
950	NHNH	CH3	CH3	CH3
951	NHNH	CH3	CH3	COCH3
952	NHCH2CH2NH	C4H9	CH3	H
953	NHCH2CH2NH	C4H9	CH3	COCH3
954	NHCH2CH2NH	C5H11	H	H
955	NHCH2CH2NH	C5H11	H	COCH3
956	NHCH2CH2NH	C5H11	CH3	H
957	NHCH2CH2NH	C5H11	CH3	COCH3
958	NHCH2CH2NH	C6H13	H	H
959	NHCH2CH2NH	C6H13	H	COCH3
960	NHCH2CH2NH	C6H13	CH3	H
961	NHCH2CH2NH	C6H13	CH3	COCH3
962	NHCH2CH2NH	OCH3	H	H
963	NHCH2CH2NH	OCH3	H	COCH3
964	NHCH2CH2NH	OCH3	CH3	H
965	NHCH2CH2NH	OCH3	CH3	COCH3
966	NHCH2CH2NH	OC2H5	H	H
967	NHCH2CH2NH	OC2H5	H	COCH3
968	NHCH2CH2NH	OC2H5	CH3	H
969	NHCH2CH2NH	OC2H5	CH3	COCH3
970	NHCH2CH2NH	OC3H7	H	H
971	NHCH2CH2NH	OC3H7	H	COCH3
972	NHCH2CH2NH	OC3H7	CH3	H
973	NHCH2CH2NH	OC3H7	CH3	COCH3
974	NHCH2CH2NH	OC4H9	H	H
975	NHCH2CH2NH	OC4H9	H	COCH3
976	NHCH2CH2NH	OC4H9	CH3	H
977	NHCH2CH2NH	OC4H9	CH3	COCH3
978	NHCH2CH2NH	SCH3	H	H
979	NHCH2CH2NH	SCH3	H	COCH3
980	NHCH2CH2NH	SCH3	CH3	H
981	NHCH2CH2NH	SCH3	CH3	COCH3
982	NHCH2CH2NH	SC2H5	H	H
983	NHCH2CH2NH	SC2H5	H	COCH3
984	NHCH2CH2NH	SC2H5	CH3	H
985	NHCH2CH2NH	SC2H5	CH3	COCH3
986	NHCH2CH2NH	SC3H7	H	H
987	NHCH2CH2NH	SC3H7	H	COCH3
988	NHCH2CH2NH	SC3H7	CH3	H
989	NHCH2CH2NH	SC3H7	CH3	COCH3
990	NHCH2CH2NH	F	H	H
991	NHCH2CH2NH	F	H	COCH3
992	NHCH2CH2NH	F	CH3	H
993	NHCH2CH2NH	F	CH3	COCH3
994	NHCH2CH2NH	Cl	H	H
995	NHCH2CH2NH	Cl	H	COCH3
996	NHCH2CH2NH	Cl	CH3	H
997	NHCH2CH2NH	Cl	CH3	COCH3
998	NHCH2CH2NH	Br	H	H
999	NHCH2CH2NH	Br	H	COCH3
1000	NHCH2CH2NH	Br	CH3	H
1001	NHCH2CH2NH	Br	CH3	COCH3
1002	NHCH2CH2NH	I	H	H
1003	NHCH2CH2NH	I	H	COCH3
1004	NHCH2CH2NH	I	CH3	H
1005	NHCH2CH2NH	I	CH3	COCH3
1006	NHCH2CH2NH	CN	H	H
1007	NHCH2CH2NH	CN	H	COCH3
1008	NHCH2CH2NH	CN	CH3	H
1009	NHCH2CH2NH	CN	CH3	COCH3
1010	NHCH2CH2NH	NO2	H	H
1011	NHCH2CH2NH	NO2	H	COCH3
1012	NHCH2CH2NH	NO2	CH3	H
1013	NHCH2CH2NH	NO2	CH3	COCH3
1014	NHCH2CH2NH	OH	H	H
1015	NHCH2CH2NH	OH	H	COCH3
1016	NHCH2CH2NH	OH	CH3	H
1017	NHCH2CH2NH	OH	CH3	COCH3
1018	piperzinyl	CH3	H	H
1019	piperzinyl	CH3	H	COCH3
1020	piperzinyl	CH3	CH3	H
1021	piperzinyl	CH3	CH3	COCH3
1022	piperzinyl	C2H5	H	H
1023	piperzinyl	C2H5	H	COCH3
1024	piperzinyl	C2H5	CH3	H
1025	piperzinyl	C2H5	CH3	COCH3
1026	piperzinyl	C3H7	H	H
1027	piperzinyl	C3H7	H	COCH3
1028	piperzinyl	C3H7	CH3	H
1029	piperzinyl	C3H7	CH3	COCH3
1030	NHNH	C2H5	H	H
1031	NHNH	C2H5	H	COCH3
1032	piperzinyl	C4H9	CH3	H
1033	piperzinyl	C4H9	CH3	COCH3
1034	piperzinyl	C5H11	H	H
1035	piperzinyl	C5H11	H	COCH3
1036	piperzinyl	C5H11	CH3	H
1037	piperzinyl	C5H11	CH3	COCH3
1038	piperzinyl	C6H13	H	H
1039	piperzinyl	C6H13	H	COCH3
1040	piperzinyl	C6H13	CH3	H
1041	piperzinyl	C6H13	CH3	COCH3
1042	piperzinyl	OCH3	H	H
1043	piperzinyl	OCH3	H	COCH3
1044	piperzinyl	OCH3	CH3	H
1045	piperzinyl	OCH3	CH3	COCH3
1046	piperzinyl	OC2H5	H	H
1047	piperzinyl	OC2H5	H	COCH3
1048	piperzinyl	OC2H5	CH3	H
1049	piperzinyl	OC2H5	CH3	COCH3
1050	piperzinyl	OC3H7	H	H
1051	piperzinyl	OC3H7	H	COCH3
1052	piperzinyl	OC3H7	CH3	H
1053	piperzinyl	OC3H7	CH3	COCH3
1054	piperzinyl	OC4H9	H	H
1055	piperzinyl	OC4H9	H	COCH3
1056	piperzinyl	OC4H9	CH3	H
1057	piperzinyl	OC4H9	CH3	COCH3
1058	piperzinyl	SCH3	H	H
1059	piperzinyl	SCH3	H	COCH3
1060	piperzinyl	SCH3	CH3	H
1061	piperzinyl	SCH3	CH3	COCH3
1062	piperzinyl	SC2H5	H	H
1063	piperzinyl	SC2H5	H	COCH3
1064	piperzinyl	SC2H5	CH3	H
1065	piperzinyl	SC2H5	CH3	COCH3
1066	piperzinyl	SC3H7	H	H
1067	piperzinyl	SC3H7	H	COCH3
1068	piperzinyl	SC3H7	CH3	H
1069	piperzinyl	SC3H7	CH3	COCH3
1070	piperzinyl	F	H	H
1071	piperzinyl	F	H	COCH3
1072	piperzinyl	F	CH3	H
1073	piperzinyl	F	CH3	COCH3
1074	piperzinyl	Cl	H	H
1075	piperzinyl	Cl	H	COCH3
1076	piperzinyl	Cl	CH3	H
1077	piperzinyl	Cl	CH3	COCH3
1078	piperzinyl	Br	H	H
1079	piperzinyl	Br	H	COCH3
1080	piperzinyl	Br	CH3	H
1081	piperzinyl	Br	CH3	COCH3
1082	piperzinyl	I	H	H
1083	piperzinyl	I	H	COCH3
1084	piperzinyl	I	CH3	H
1085	piperzinyl	I	CH3	COCH3
1086	piperzinyl	CN	H	H
1087	piperzinyl	CN	H	COCH3
1088	piperzinyl	CN	CH3	H
1089	piperzinyl	CN	CH3	COCH3
1090	piperzinyl	NO2	H	H
1091	piperzinyl	NO2	H	COCH3
1092	piperzinyl	NO2	CH3	H
1093	piperzinyl	NO2	CH3	COCH3
1094	piperzinyl	OH	H	H
1095	piperzinyl	OH	H	COCH3
1096	piperzinyl	OH	CH3	H
1097	piperzinyl	OH	CH3	COCH3

[0518] The following Examples #1098-#1137 of Table XIV are highly preferred conjugates composed of dopamine-β-hydroxylase inhibitor compounds and glutamic acid derivatives. These dopamine-β-hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XIV, above.

TABLE XIV
709
EXAMPLE
NO.	R94	t	E	P
1098	CO2H	0	H	H
1099	CO2H	0	H	COCH3
1100	CO2H	0	CH3	H
1101	CO2H	0	CH3	COCH3
1102	CN4H	0	H	H
1103	CN4H	0	H	COCH3
1104	CN4H	0	CH3	H
1105	CN4H	0	CH3	COCH3
1106	CO2H	1	H	H
1107	CO2H	1	H	COCH3
1108	CO2H	1	CH3	H
1109	CO2H	1	CH3	COCH3
1110	CN4H	1	H	H
1111	CN4H	1	H	COCH3
1112	CN4H	1	CH3	H
1113	CN4H	1	CH3	COCH3
1114	CO2H	2	H	H
1115	CO2H	2	H	COCH3
1116	CO2H	2	CH3	H
1117	CO2H	2	CH3	COCH3
1118	CN4H	2	H	H
1119	CN4H	2	H	COCH3
1120	CN4H	2	CH3	H
1121	CN4H	2	CH3	COCH3
1122	CO2H	3	H	H
1123	CO2H	3	H	COCH3
1124	CO2H	3	CH3	H
1125	CO2H	3	CH3	COCH3
1126	CN4H	3	H	H
1127	CN4H	3	H	COCH3
1128	CN4H	3	CH3	H
1129	CN4H	3	CH3	COCH3
1130	CO2H	4	H	H
1131	CO2H	4	H	COCH3
1132	CO2H	4	CH3	H
1133	CO2H	4	CH3	COCH3
1134	CN4H	4	H	H
1135	CN4H	4	H	COCH3
1136	CN4H	4	CH3	H
1137	CN4H	4	CH3	COCH3

[0519] The following Examples #1138-#1377 of Table XV are highly preferred conjugates composed of dopamine-β-hydroxylase inhibitor compounds and glutamic acid derivatives. These dopamine-β-hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XVIII, above.

TABLE XV
710	711
EXAMPLE
NO.	n	R11	R114	R116	R117	R118	E	P
1138	0	X	H	H	OH	H	H	H
1139	0	X	H	H	OH	H	H	COCH3
1140	0	X	H	H	OH	H	CH3	H
1141	0	X	H	H	OH	H	CH3	COCH3
1142	0	X	H	H	F	H	H	H
1143	0	X	H	H	F	H	H	COCH3
1144	0	X	H	H	F	H	CH3	H
1145	0	X	H	H	F	H	CH3	COCH3
1146	0	X	H	H	CF3	H	H	H
1147	0	X	H	H	CF3	H	H	COCH3
1148	0	X	H	H	CF3	H	CH3	H
1149	0	X	H	H	CF3	H	CH3	COCH3
1150	0	X	H	OH	OH	H	H	H
1151	0	X	H	OH	OH	H	H	COCH3
1152	0	X	H	OH	OH	H	CH3	H
1153	0	X	H	OH	OH	H	CH3	COCH3
1154	0	X	H	F	H	F	H	H
1155	0	X	H	F	H	F	H	COCH3
1156	0	X	H	F	H	F	CH3	H
1157	0	X	H	F	H	F	CH3	COCH3
1158	0	X	H	CF3	H	CF3	H	H
1159	0	X	H	CF3	H	CF3	H	COCH3
1160	0	X	H	CF3	H	CF3	CH3	H
1161	0	X	H	CF3	H	CF3	CH3	COCH3
1162	0	H	X	H	OH	H	H	H
1163	0	H	X	H	OH	H	H	COCH3
1164	0	H	X	H	OH	H	CH3	H
1165	0	H	X	H	OH	H	CH3	COCH3
1166	0	H	X	H	F	H	H	H
1167	0	H	X	H	F	H	H	COCH3
1168	0	H	X	H	F	H	CH3	H
1169	0	H	X	H	F	H	CH3	COCH3
1170	0	H	X	H	CF3	H	H	H
1171	0	H	X	H	CF3	H	H	COCH3
1172	0	H	X	H	CF3	H	CH3	H
1173	0	H	X	H	CF3	H	CH3	COCH3
1174	0	H	X	OH	OH	H	H	H
1175	0	H	X	OH	OH	H	H	COCH3
1176	0	H	X	OH	OH	H	CH3	H
1177	0	H	X	OH	OH	H	CH3	COCH3
1178	0	H	X	F	H	F	H	H
1179	0	H	X	F	H	F	H	COCH3
1180	0	H	X	F	H	F	CH3	H
1181	0	H	X	F	H	F	CH3	COCH3
1182	0	H	X	CF3	H	CF3	H	H
1183	0	H	X	CF3	H	CF3	H	COCH3
1184	0	H	X	CF3	H	CF3	CH3	H
1185	0	H	X	CF3	H	CF3	CH3	COCH3
1186	1	X	H	H	OH	H	H	H
1187	1	X	H	H	OH	H	H	COCH3
1188	1	X	H	H	OH	H	CH3	H
1189	1	X	H	H	OH	H	CH3	COCH3
1190	1	X	H	H	F	H	H	H
1191	1	X	H	H	F	H	H	COCH3
1192	1	X	H	H	F	H	CH3	H
1193	1	X	H	H	F	H	CH3	COCH3
1194	1	X	H	H	CF3	H	H	H
1195	1	X	H	H	CF3	H	H	COCH3
1196	1	X	H	H	CF3	H	CH3	H
1197	1	X	H	H	CF3	H	CH3	COCH3
1198	1	X	H	OH	OH	H	H	H
1199	1	X	H	OH	OH	H	H	COCH3
1200	1	X	H	OH	OH	H	CH3	H
1201	1	X	H	OH	OH	H	CH3	COCH3
1202	1	X	H	F	H	F	H	H
1203	1	X	H	F	H	F	H	COCH3
1204	1	X	H	F	H	F	CH3	H
1205	1	X	H	F	H	F	CH3	COCH3
1206	1	X	H	CF3	H	CF3	H	H
1207	1	X	H	CF3	H	CF3	H	COCH3
1208	1	X	H	CF3	H	CF3	CH3	H
1209	1	X	H	CF3	H	CF3	CH3	COCH3
1210	1	H	X	H	OH	H	H	H
1211	1	H	X	H	OH	H	H	COCH3
1212	1	H	X	H	OH	H	CH3	H
1213	1	H	X	H	OH	H	CH3	COCH3
1214	1	H	X	H	F	H	H	H
1215	1	H	X	H	F	H	H	COCH3
1216	1	H	X	H	F	H	CH3	H
1217	1	H	X	H	F	H	CH3	COCH3
1218	1	H	X	H	CF3	H	H	H
1219	1	H	X	H	CF3	H	H	COCH3
1220	1	H	X	H	CF3	H	CH3	H
1221	1	H	X	H	CF3	H	CH3	COCH3
1222	1	H	X	1H	OH	H	H	H
1223	1	H	X	1H	OH	H	H	COCH3
1224	1	H	X	1H	OH	H	CH3	H
1225	1	H	X	1H	OH	H	CH3	COCH3
1226	1	H	X	F	H	F	H	H
1227	1	H	X	F	H	F	H	COCH3
1228	1	H	X	F	H	F	CH3	H
1229	1	H	X	F	H	F	CH3	COCH3
1230	1	H	X	CF3	H	CF3	H	H
1231	1	H	X	CF3	H	CF3	H	COCH3
1232	1	H	X	CF3	H	CF3	CH3	H
1233	1	H	X	CF3	H	CF3	CH3	COCH3
1234	2	X	H	H	OH	H	H	H
1235	2	X	H	H	OH	H	H	COCH3
1236	2	X	H	H	OH	H	CH3	H
1237	2	X	H	H	OH	H	CH3	COCH3
1238	2	X	H	H	F	H	H	H
1239	2	X	H	H	F	H	H	COCH3
1240	2	X	H	H	F	H	CH3	H
1241	2	X	H	H	F	H	CH3	COCH3
1242	2	X	H	H	CF3	H	H	H
1243	2	X	H	H	CF3	H	H	COCH3
1244	2	X	H	H	CF3	H	CH3	H
1245	2	X	H	H	CF3	H	CH3	COCH3
1246	2	X	H	OH	OH	H	H	H
1247	2	X	H	OH	OH	H	H	COCH3
1248	2	X	H	OH	OH	H	CH3	H
1249	2	X	H	OH	OH	H	CH3	COCH3
1250	2	X	H	F	H	F	H	H
1251	2	X	H	F	H	F	H	COCH3
1252	2	X	H	F	H	F	CH3	H
1253	2	X	H	F	H	F	CH3	COCH3
1254	2	X	H	CF3	H	CF3	H	H
1255	2	X	H	CF3	H	CF3	H	COCH3
1256	2	X	H	CF3	H	CF3	CH3	H
1257	2	X	H	CF3	H	CF3	CH3	COCH3
1258	2	H	X	H	OH	H	H	H
1259	2	H	X	H	OH	H	H	COCH3
1260	2	H	X	H	OH	H	CH3	H
1261	2	H	X	H	OH	H	CH3	COCH3
1262	2	H	X	H	F	H	H	H
1263	2	H	X	H	F	H	H	COCH3
1264	2	H	X	H	F	H	CH3	H
1265	2	H	X	H	F	H	CH3	COCH3
1266	2	H	X	H	CF3	H	H	H
1267	2	H	X	H	CF3	H	H	COCH3
1268	2	H	X	H	CF3	H	CH3	H
1269	2	H	X	H	CF3	H	CH3	COCH3
1270	2	H	X	OH	OH	H	H	H
1271	2	H	X	OH	OH	H	H	COCH3
1272	2	H	X	OH	OH	H	CH3	H
1273	2	H	X	OH	OH	H	CH3	COCH3
1274	2	H	X	F	H	F	H	H
1275	2	H	X	F	H	F	H	COCH3
1276	2	H	X	F	H	F	CH3	H
1277	2	H	X	F	H	F	CH3	COCH3
1278	2	H	X	CF3	H	CF3	H	H
1279	2	H	X	CF3	H	CF3	H	COCH3
1280	2	H	X	CF3	H	CF3	CH3	H
1281	2	H	X	CF3	H	CF3	CH3	COCH3
1282	3	X	H	H	OH	H	H	H
1283	3	X	H	H	OH	H	H	COCH3
1284	3	X	H	H	OH	H	CH3	H
1285	3	X	H	H	OH	H	CH3	COCH3
1286	3	X	H	H	F	H	H	H
1287	3	X	H	H	F	H	H	COCH3
1288	3	X	H	H	F	H	CH3	H
1289	3	X	H	H	F	H	CH3	COCH3
1290	3	X	H	H	CF3	H	H	H
1291	3	X	H	H	CF3	H	H	COCH3
1292	3	X	H	H	CF3	H	CH3	H
1293	3	X	H	H	CF3	H	CH3	COCH3
1294	3	X	H	OH	OH	H	H	H
1295	3	X	H	OH	OH	H	H	COCH3
1296	3	X	H	OH	OH	H	CH3	H
1297	3	X	H	OH	OH	H	CH3	COCH3
1298	3	X	H	F	H	F	H	H
1299	3	X	H	F	H	F	H	COCH3
1300	3	X	H	F	H	F	CH3	H
1301	3	X	H	F	H	F	CH3	COCH3
1302	3	X	H	CF3	H	CF3	H	H
1303	3	X	H	CF3	H	CF3	H	COCH3
1304	3	X	H	CF3	H	CF3	CH3	H
1305	3	X	H	CF3	H	CF3	CH3	COCH3
1306	3	H	X	H	OH	H	H	H
1307	3	H	X	H	OH	H	H	COCH3
1308	3	H	X	H	OH	H	CH3	H
1309	3	H	X	H	OH	H	CH3	COCH3
1310	3	H	X	H	F	H	H	H
1311	3	H	X	H	F	H	H	COCH3
1312	3	H	X	H	F	H	CH3	H
1313	3	H	X	H	F	H	CH3	COCH3
1314	3	H	X	H	CF3	H	H	H
1315	3	H	X	H	CF3	H	H	COCH3
1316	3	H	X	H	CF3	H	CH3	H
1317	3	H	X	H	CF3	H	CH3	COCH3
1318	3	H	X	OH	OH	H	H	H
1319	3	H	X	OH	OH	H	H	COCH3
1320	3	H	X	OH	OH	H	CH3	H
1321	3	H	X	OH	OH	H	CH3	COCH3
1322	3	H	X	F	H	F	H	H
1323	3	H	X	F	H	F	H	COCH3
1324	3	H	X	F	H	F	CH3	H
1325	3	H	X	F	H	F	CH3	COCH3
1326	3	H	X	CF3	H	CF3	H	H
1327	3	H	X	CF3	H	CF3	H	COCH3
1328	3	H	X	CF3	H	CF3	CH3	H
1329	3	H	X	CF3	H	CF3	CH3	COCH3
1330	4	X	H	H	OH	H	H	H
1331	4	X	H	H	OH	H	H	COCH3
1332	4	X	H	H	OH	H	CH3	H
1333	4	X	H	H	OH	H	CH3	COCH3
1334	4	X	H	H	F	H	H	H
1335	4	X	H	H	F	H	H	COCH3
1336	4	X	H	H	F	H	CH3	H
1337	4	X	H	H	F	H	CH3	COCH3
1338	4	X	H	H	CF3	H	H	H
1339	4	X	H	H	CF3	H	H	COCH3
1340	4	X	H	H	CF3	H	CH3	H
1341	4	X	H	H	CF3	H	CH3	COCH3
1342	4	X	H	OH	OH	H	H	H
1343	4	X	H	OH	OH	H	H	COCH3
1344	4	X	H	OH	OH	H	CH3	H
1345	4	X	H	OH	OH	H	CH3	COCH3
1346	4	X	H	F	H	F	H	H
1347	4	X	H	F	H	F	H	COCH3
1348	4	X	H	F	H	F	CH3	H
1349	4	X	H	F	H	F	CH3	COCH3
1350	4	X	H	CF3	H	CF3	H	H
1351	4	X	H	CF3	H	CF3	H	COCH3
1352	4	X	H	CF3	H	CF3	CH3	H
1353	4	X	H	CF3	H	CF3	CH3	COCH3
1354	4	H	X	H	OH	H	H	H
1355	4	H	X	H	OH	H	H	COCH3
1356	4	H	X	H	OH	H	CH3	H
1357	4	H	X	H	OH	H	CH3	COCH3
1358	4	H	X	H	F	H	H	H
1359	4	H	X	H	F	H	H	COCH3
1360	4	H	X	H	F	H	CH3	H
1361	4	H	X	H	F	H	CH3	COCH3
1362	4	H	X	H	CF3	H	H	H
1363	4	H	X	H	CF3	H	H	COCH3
1364	4	H	X	H	CF3	H	CH3	H
1365	4	H	X	H	CF3	H	CH3	COCH3
1366	4	H	X	OH	OH	H	H	H
1367	4	H	X	OH	OH	H	H	COCH3
1368	4	H	X	OH	OH	H	CH3	H
1369	4	H	X	OH	OH	H	CH3	COCH3
1370	4	H	X	F	H	F	H	H
1371	4	H	X	F	H	F	H	COCH3
1372	4	H	X	F	H	F	CH3	H
1373	4	H	X	F	H	F	CH3	COCH3
1374	4	H	X	CF3	H	CF3	H	H
1375	4	H	X	CF3	H	CF3	H	COCH3
1376	4	H	X	CF3	H	CF3	CH3	H
1377	4	H	X	CF3	H	CF3	CH3	COCH3

[0520] The following Examples #1378-#1497 of Table XVI are highly preferred conjugates composed of dopamine-β-hydroxylase inhibitor compounds and glutamic acid derivatives. These dopamine-β-hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XVIII, above.

TABLE XVI
712
EXAMPLE
NO.	n	R116	R117	R118	E	P
1378	0	H	OH	H	H	H
1379	0	H	OH	H	H	COCH3
1380	0	H	OH	H	CH3	H
1381	0	H	OH	H	CH3	COCH3
1382	0	H	F	H	H	H
1383	0	H	F	H	H	COCH3
1384	0	H	F	H	CH3	H
1385	0	H	F	H	CH3	COCH3
1386	0	H	CF3	H	H	H
1387	0	H	CF3	H	H	COCH3
1388	0	H	CF3	H	CH3	H
1389	0	H	CF3	H	CH3	COCH3
1390	0	OH	OH	H	H	H
1391	0	OH	OH	H	H	COCH3
1392	0	OH	OH	H	CH3	H
1393	0	OH	OH	H	CH3	COCH3
1394	0	F	H	F	H	H
1395	0	F	H	F	H	COCH3
1396	0	F	H	F	CH3	H
1397	0	F	H	F	CH3	COCH3
1398	0	CF3	H	CF3	H	H
1399	0	CF3	H	CF3	H	COCH3
1400	0	CF3	H	CF3	CH3	H
1401	0	CF3	H	CF3	CH3	COCH3
1402	1	H	OH	H	H	H
1403	1	H	OH	H	H	COCH3
1404	1	H	OH	H	CH3	H
1405	1	H	OH	H	CH3	COCH3
1406	1	H	F	H	H	H
1407	1	H	F	H	H	COCH3
1408	1	H	F	H	CH3	H
1409	1	H	F	H	CH3	COCH3
1410	1	H	CF3	H	H	H
1411	1	H	CF3	H	H	COCH3
1412	1	H	CF3	H	CH3	H
1413	1	H	CF3	H	CH3	COCH3
1414	1	OH	OH	H	H	H
1415	1	OH	OH	H	H	COCH3
1416	1	OH	OH	H	CH3	H
1417	1	OH	OH	H	CH3	COCH3
1418	1	F	H	F	H	H
1419	1	F	H	F	H	COCH3
1420	1	F	H	F	CH3	H
1421	1	F	H	F	CH3	COCH3
1422	1	CF3	H	CF3	H	H
1423	1	CF3	H	CF3	H	COCH3
1424	1	CF3	H	CF3	CH3	H
1425	1	CF3	H	CF3	CH3	COCH3
1426	2	H	OH	H	H	H
1427	2	H	OH	H	H	COCH3
1428	2	H	OH	H	CH3	H
1429	2	H	OH	H	CH3	COCH3
1430	2	H	F	H	H	H
1431	2	H	F	H	H	COCH3
1432	2	H	F	H	CH3	H
1433	2	H	F	H	CH3	COCH3
1434	2	H	CF3	H	H	H
1435	2	H	CF3	H	H	COCH3
1436	2	H	CF3	H	CH3	H
1437	2	H	CF3	H	CH3	COCH3
1438	2	OH	OH	H	H	H
1439	2	OH	OH	H	H	COCH3
1440	2	OH	OH	H	CH3	H
1441	2	OH	OH	H	CH3	COCH3
1442	2	F	H	F	H	H
1443	2	F	H	F	H	COCH3
1444	2	F	H	F	CH3	H
1445	2	F	H	F	CH3	COCH3
1446	2	CF3	H	CF3	H	H
1447	2	CF3	H	CF3	H	COCH3
1448	2	CF3	H	CF3	CH3	H
1449	2	CF3	H	CF3	CH3	COCH3
1450	3	H	OH	H	H	H
1451	3	H	OH	H	H	COCH3
1452	3	H	OH	H	CH3	H
1453	3	H	OH	H	CH3	COCH3
1454	3	H	F	H	H	H
1455	3	H	F	H	H	COCH3
1456	3	H	F	H	CH3	H
1457	3	H	F	H	CH3	COCH3
1458	3	H	CF3	H	H	H
1459	3	H	CF3	H	H	COCH3
1460	3	H	CF3	H	CH3	H
1461	3	H	CF3	H	CH3	COCH3
1462	3	OH	OH	H	H	H
1463	3	OH	OH	H	H	COCH3
1464	3	OH	OH	H	CH3	H
1465	3	OH	OH	H	CH3	COCH3
1466	3	F	H	F	H	H
1467	3	F	H	F	H	COCH3
1468	3	F	H	F	CH3	H
1469	3	F	H	F	CH3	COCH3
1470	3	CF3	H	CF3	H	H
1471	3	CF3	H	CF3	H	COCH3
1472	3	CF3	H	CF3	CH3	H
1473	3	CF3	H	CF3	CH3	COCH3
1474	4	H	OH	H	H	H
1475	4	H	OH	H	H	COCH3
1476	4	H	OH	H	CH3	H
1477	4	H	OH	H	CH3	COCH3
1478	4	H	F	H	H	H
1479	4	H	F	H	H	COCH3
1480	4	H	F	H	CH3	H
1481	4	H	F	H	CH3	COCH3
1482	4	H	CF3	H	H	H
1483	4	H	CF3	H	H	COCH3
1484	4	H	CF3	H	CH3	H
1485	4	H	CF3	H	CH3	COCH3
1486	4	OH	OH	H	H	H
1487	4	OH	OH	H	H	COCH3
1488	4	OH	OH	H	CH3	H
1489	4	OH	OH	H	CH3	COCH3
1490	4	F	H	F	H	H
1491	4	F	H	F	H	COCH3
1492	4	F	H	F	CH3	H
1493	4	F	H	F	CH3	COCH3
1494	4	CF3	H	CF3	H	H
1495	4	CF3	H	CF3	H	COCH3
1496	4	CF3	H	CF3	CH3	H
1497	4	CF3	H	CF3	CH3	COCH3

[0521] The following Examples #1498-#1857 of Table XVII are highly preferred conjugates composed of dopamine-β-hydroxylase inhibitor compounds and glutamic acid derivatives. These dopamine-β-hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XVIII, above.

TABLE XVII
713
EX-
AMPLE
NO.	n	L	R116	R117	R118	E	P
1498	0	NHNH	H	OH	H	H	H
1499	0	NHNH	H	OH	H	H	COCH3
1500	0	NHNH	H	OH	H	CH3	H
1501	0	NHNH	H	OH	H	CH3	COCH3
1502	0	NHNH	H	F	H	H	H
1503	0	NHNH	H	F	H	H	COCH3
1504	0	NHNH	H	F	H	CH3	H
1505	0	NHNH	H	F	H	CH3	COCH3
1506	0	NHNH	H	CF3	H	H	H
1507	0	NHNH	H	CF3	H	H	COCH3
1508	0	NHNH	H	CF3	H	CH3	H
1509	0	NHNH	H	CF3	H	CH3	COCH3
1510	0	NHNH	OH	OH	H	H	H
1511	0	NHNH	OH	OH	H	H	COCH3
1512	0	NHNH	OH	OH	H	CH3	H
1513	0	NHNH	OH	OH	H	CH3	COCH3
1514	0	NHNH	F	H	F	H	H
1515	0	NHNH	F	H	F	H	COCH3
1516	0	NHNH	F	H	F	CH3	H
1517	0	NHNH	F	H	F	CH3	COCH3
1518	0	NHNH	CF3	H	CF3	H	H
1519	0	NHNH	CF3	H	CF3	H	COCH3
1520	0	NHNH	CF3	H	CF3	CH3	H
1521	0	NHNH	CF3	H	CF3	CH3	COCH3
1522	0	NHCH2CH2NH	H	OH	H	H	H
1523	0	NHCH2CH2NH	H	OH	H	H	COCH3
1524	0	NHCH2CH2NH	H	OH	H	CH3	H
1525	0	NHCH2CH2NH	H	OH	H	CH3	COCH3
1526	0	NHCH2CH2NH	H	F	H	H	H
1527	0	NHCH2CH2NH	H	F	H	H	COCH3
1528	0	NHCH2CH2NH	H	F	H	CH3	H
1529	0	NHCH2CH2NH	H	F	H	CH3	COCH3
1530	0	NHCH2CH2NH	H	CF3	H	H	H
1531	0	NHCH2CH2NH	H	CF3	H	H	COCH3
1532	0	NHCH2CH2NH	H	CF3	H	CH3	H
1533	0	NHCH2CH2NH	H	CF3	H	CH3	COCH3
1534	0	NHCH2CH2NH	OH	OH	H	H	H
1535	0	NHCH2CH2NH	OH	OH	H	H	COCH3
1536	0	NHCH2CH2NH	OH	OH	H	CH3	H
1537	0	NHCH2CH2NH	OH	OH	H	CH3	COCH3
1538	0	NHCH2CH2NH	F	H	F	H	H
1539	0	NHCH2CH2NH	F	H	F	H	COCH3
1540	0	NHCH2CH2NH	F	H	F	CH3	H
1541	0	NHCH2CH2NH	F	H	F	CH3	COCH3
1542	0	NHCH2CH2NH	CF3	H	CF3	H	H
1543	0	NHCH2CH2NH	CF3	H	CF3	H	COCH3
1544	0	NHCH2CH2NH	CF3	H	CF3	CH3	H
1545	0	NHCH2CH2NH	CF3	H	CF3	CH3	COCH3
1546	0	piperazinyl	H	OH	H	H	H
1547	0	piperazinyl	H	OH	H	H	COCH3
1548	0	piperazinyl	H	OH	H	CH3	H
1549	0	piperazinyl	H	OH	H	CH3	COCH3
1550	0	piperazinyl	H	F	H	H	H
1551	0	piperazinyl	H	F	H	H	COCH3
1552	0	piperazinyl	H	F	H	CH3	H
1553	0	piperazinyl	H	F	H	CH3	COCH3
1554	0	piperazinyl	H	CF3	H	H
1555	0	piperazinyl	H	CF3	H	H	COCH3
1556	0	piperazinyl	H	CF3	H	CH3	H
1557	0	piperazinyl	H	CF3	H	CH3	COCH3
1558	0	piperazinyl	OH	OH	H	H	H
1559	0	piperazinyl	OH	OH	H	H	COCH3
1560	0	piperazinyl	OH	OH	H	CH3	H
1561	0	piperazinyl	OH	OH	H	CH3	COCH3
1562	0	piperazinyl	F	H	F	H	H
1563	0	piperazinyl	F	H	F	H	COCH3
1564	0	piperazinyl	F	H	F	CH3	H
1565	0	piperazinyl	F	H	F	CH3	COCH3
1566	0	piperazinyl	CF3	H	CF3	H	H
1567	0	piperazinyl	CF3	H	CF3	H	COCH3
1568	0	piperazinyl	CF3	H	CF3	CH3	H
1569	0	piperazinyl	CF3	H	CF3	CH3	COCH3
1570	1	NHNH	H	OH	H	H	H
1571	1	NHNH	H	OH	H	H	COCH3
1572	1	NHNH	H	OH	H	CH3	H
1573	1	NHNH	H	OH	H	CH3	COCH3
1574	1	NHNH	H	F	H	H	H
1575	1	NHNH	H	F	H	H	COCH3
1576	1	NHNH	H	F	H	CH3	H
1577	1	NHNH	H	F	H	CH3	COCH3
1578	1	NHNH	H	CF3	H	H	H
1579	1	NHNH	H	CF3	H	H	COCH3
1580	1	NHNH	H	CF3	H	CH3	H
1581	1	NHNH	H	CF3	H	CH3	COCH3
1582	1	NHNH	OH	OH	H	H	H
1583	1	NHNH	OH	OH	H	H	COCH3
1584	1	NHNH	OH	OH	H	CH3	H
1585	1	NHNH	OH	OH	H	CH3	COCH3
1586	1	NHNH	F	H	F	H	H
1587	1	NHNH	F	H	F	H	COCH3
1588	1	NHNH	F	H	F	CH3	H
1589	1	NHNH	F	H	F	CH3	COCH3
1590	1	NHNH	CF3	H	CF3	H	H
1591	1	NHNH	CF3	H	CF3	H	COCH3
1592	1	NHNH	CF3	H	CF3	CH3	H
1593	1	NHNH	CF3	H	CF3	CH3	COCH3
1594	1	NHCH2CH2NH	H	OH	H	H	H
1595	1	NHCH2CH2NH	H	OH	H	H	COCH3
1596	1	NHCH2CH2NH	H	OH	H	CH3	H
1597	1	NHCH2CH2NH	H	OH	H	CH3	COCH3
1598	1	NHCH2CH2NH	H	F	H	H	H
1599	1	NHCH2CH2NH	H	F	H	H	COCH3
1600	1	NHCH2CH2NH	H	F	H	CH3	H
1601	1	NHCH2CH2NH	H	F	H	CH3	COCH3
1602	1	NHCH2CH2NH	H	CF3	H	H	H
1603	1	NHCH2CH2NH	H	CF3	H	H	COCH3
1504	1	NHCH2CH2NH	H	CF3	H	CH3	H
1605	1	NHCH2CH2NH	H	CF3	H	CH3	COCH3
1606	1	NHCH2CH2NH	OH	OH	H	H	H
1607	1	NHCH2CH2NH	OH	OH	H	H	COCH3
1608	1	NHCH2CH2NH	OH	OH	H	CH3	H
1609	1	NHCH2CH2NH	OH	OH	H	CH3	COCH3
1610	1	NHCH2CH2NH	F	H	F	H	H
1611	1	NHCH2CH2NH	F	H	F	H	COCH3
1612	1	NHCH2CH2NH	F	H	F	CH3	H
1613	1	NHCH2CH2NH	F	H	F	CH3	COCH3
1614	1	NHCH2CH2NH	CF3	H	CF3	H	H
1615	1	NHCH2CH2NH	CF3	H	CF3	H	COCH3
1616	1	NHCH2CH2NH	CF3	H	CF3	CH3	H
1617	1	NHCH2CH2NH	CF3	H	CF3	CH3	COCH3
1618	1	piperazinyl	H	OH	H	H	H
1619	1	piperazinyl	H	OH	H	H	COCH3
1620	1	piperazinyl	H	OH	H	CH3	H
1621	1	piperazinyl	H	OH	H	CH3	COCH3
1622	1	piperazinyl	H	F	H	H	H
1623	1	piperazinyl	H	F	H	H	COCH3
1624	1	piperazinyl	H	F	H	CH3	H
1625	1	piperazinyl	H	F	H	CH3	COCH3
1626	1	piperazinyl	H	CF3	H	H	H
1627	1	piperazinyl	H	CF3	H	H	COCH3
1628	1	piperazinyl	H	CF3	H	CH3	H
1629	1	piperazinyl	H	CF3	H	CH3	COCH3
1630	1	piperazinyl	OH	OH	H	H	H
1631	1	piperazinyl	OH	OH	H	H	COCH3
1632	1	piperazinyl	OH	OH	H	CH3	H
1633	1	piperazinyl	OH	OH	H	CH3	COCH3
1634	1	piperazinyl	F	H	F	H	H
1635	1	piperazinyl	F	H	F	H	COCH3
1636	1	piperazinyl	F	H	F	CH3	H
1637	1	piperazinyl	F	H	F	CH3	COCH3
1638	1	piperazinyl	CF3	H	CF3	H	H
1639	1	piperazinyl	CF3	H	CF3	H	COCH3
1640	1	piperazinyl	CF3	H	CF3	CH3	H
1641	1	piperazinyl	CF3	H	CF3	CH3	COCH3
1642	2	NHNH	H	OH	H	H	H
1643	2	NHNH	H	OH	H	H	COCH3
1644	2	NHNH	H	OH	H	CH3	H
1645	2	NHNH	H	OH	H	CH3	COCH3
1646	2	NHNH	H	F	H	H	H
1647	2	NHNH	H	F	H	H	COCH3
1648	2	NHNH	H	F	H	CH3	H
1649	2	NHNH	H	F	H	CH3	COCH3
1650	2	NHNH	H	CF3	H	H	H
1651	2	NHNH	H	CF3	H	H	COCH3
1652	2	NHNH	H	CF3	H	CH3	H
1653	2	NHNH	H	CF3	H	CH3	COCH3
1654	2	NHNH	OH	OH	H	H	H
1655	2	NHNH	OH	OH	H	H	COCH3
1656	2	NHNH	OH	OH	H	CH3	H
1657	2	NHNH	OH	OH	H	CH3	COCH3
1658	2	NHNH	F	H	F	H	H
1659	2	NHNH	F	H	F	H	COCH3
1660	2	NHNH	F	H	F	CH3	H
1661	2	NHNH	F	H	F	CH3	COCH3
1662	2	NHNH	CF3	H	CF3	H	H
1663	2	NHNH	CF3	H	CF3	H	COCH3
1664	2	NHNH	CF3	H	CF3	CH3	H
1665	2	NHNH	CF3	H	CF3	CH3	COCH3
1666	2	NHCH2CH2NH	H	OH	H	H	H
1667	2	NHCH2CH2NH	H	OH	H	H	COCH3
1668	2	NHCH2CH2NH	H	OH	H	CH3	H
1669	2	NHCH2CH2NH	H	OH	H	CH3	COCH3
1670	2	NHCH2CH2NH	H	F	H	H	H
1671	2	NHCH2CH2NH	H	F	H	H	COCH3
1672	2	NHCH2CH2NH	H	F	H	CH3	H
1673	2	NHCH2CH2NH	H	F	H	CH3	COCH3
1674	2	NHCH2CH2NH	H	CF3	H	H	H
1675	2	NHCH2CH2NH	H	CF3	H	H	COCH3
1676	2	NHCH2CH2NH	H	CF3	H	CH3	H
1677	2	NHCH2CH2NH	H	CF3	H	CH3	COCH3
1678	2	NHCH2CH2NH	OH	OH	H	H	H
1679	2	NHCH2CH2NH	OH	OH	H	H	COCH3
1680	2	NHCH2CH2NH	OH	OH	H	CH3	H
1681	2	NHCH2CH2NH	OH	OH	H	CH3	COCH3
1682	2	NHCH2CH2NH	F	H	F	H	H
1683	2	NHCH2CH2NH	F	H	F	H	COCH3
1684	2	NHCH2CH2NH	F	H	F	CH3	H
1685	2	NHCH2CH2NH	F	H	F	CH3	COCH3
1686	2	NHCH2CH2NH	CF3	H	CF3	H	H
1687	2	NHCH2CH2NH	CF3	H	CF3	H	COCH3
1688	2	NHCH2CH2NH	CF3	H	CF3	CH3	H
1689	2	NHCH2CH2NH	CF3	H	CF3	CH3	COCH3
1690	2	piperazinyl	H	OH	H	H	H
1691	2	piperazinyl	H	OH	H	H	COCH3
1692	2	piperazinyl	H	OH	H	CH3	H
1693	2	piperazinyl	H	OH	H	CH3	COCH3
1694	2	piperazinyl	H	F	H	H	H
1695	2	piperazinyl	H	F	H	H	COCH3
1696	2	piperazinyl	H	F	H	CH3	H
1697	2	piperazinyl	H	F	H	CH3	COCH3
1698	2	piperazinyl	H	CF3	H	H	H
1699	2	piperazinyl	H	CF3	H	H	COCH3
1700	2	piperazinyl	H	CF3	H	CH3	H
1701	2	piperazinyl	H	CF3	H	CH3	COCH3
1702	2	piperazinyl	OH	OH	H	H	H
1703	2	piperazinyl	OH	OH	H	H	COCH3
1704	2	piperazinyl	OH	OH	H	CH3	H
1705	2	piperazinyl	OH	OH	H	CH3	COCH3
1706	2	piperazinyl	F	H	F	H	H
1707	2	piperazinyl	F	H	F	H	COCH3
1708	2	piperazinyl	F	H	F	CH3	H
1709	2	piperazinyl	F	H	F	CH3	COCH3
1710	2	piperazinyl	CF3	H	CF3	H	H
1711	2	piperazinyl	CF3	H	CF3	H	COCH3
1712	2	piperazinyl	CF3	H	CF3	CH3	H
1713	2	piperazinyl	CF3	H	CF3	CH3	COCH3
1714	3	NHNH	H	OH	H	H	H
1715	3	NHNH	H	OH	H	H	COCH3
1716	3	NHNH	H	OH	H	CH3	H
1717	3	NHNH	H	OH	H	CH3	COCH3
1718	3	NHNH	H	F	H	H	H
1719	3	NHNH	H	F	H	H	COCH3
1720	3	NHNH	H	F	H	CH3	H
1721	3	NHNH	H	F	H	CH3	COCH3
1722	3	NHNH	H	CF3	H	H	H
1723	3	NHNH	H	CF3	H	H	COCH3
1724	3	NHNH	H	CF3	H	CH3	H
1725	3	NHNH	H	CF3	H	CH3	COCH3
1726	3	NHNH	OH	OH	H	H	H
1727	3	NHNH	OH	OH	H	H	COCH3
1728	3	NHNH	OH	OH	H	CH3	H
1729	3	NHNH	OH	OH	H	CH3	COCH3
1730	3	NHNH	F	H	F	H	H
1731	3	NHNH	F	H	F	H	COCH3
1732	3	NHNH	F	H	F	CH3	H
1733	3	NHNH	F	H	F	CH3	COCH3
1734	3	NHNH	CF3	H	CF3	H	H
1735	3	NHNH	CF3	H	CF3	H	COCH3
1736	3	NHNH	CF3	H	CF3	CH3	H
1737	3	NHNH	CF3	H	CF3	CH3	COCH3
1738	3	NHCH2CH2NH	H	OH	H	H	H
1739	3	NHCH2CH2NH	H	OH	H	H	COCH3
1740	3	NHCH2CH2NH	H	OH	H	CH3	H
1741	3	NHCH2CH2NH	H	OH	H	CH3	COCH3
1742	3	NHCH2CH2NH	H	F	H	H	H
1743	3	NHCH2CH2NH	H	F	H	H	COCH3
1744	3	NHCH2CH2NH	H	F	H	CH3	H
1745	3	NHCH2CH2NH	H	F	H	CH3	COCH3
1746	3	NHCH2CH2NH	H	CF3	H	H	H
1747	3	NHCH2CH2NH	H	CF3	H	H	COCH3
1748	3	NHCH2CH2NH	H	CF3	H	CH3	H
1749	3	NHCH2CH2NH	H	CF3	H	CH3	COCH3
1750	3	NHCH2CH2NH	OH	OH	H	H	H
1751	3	NHCH2CH2NH	OH	OH	H	H	COCH3
1752	3	NHCH2CH2NH	OH	OH	H	CH3	H
1753	3	NHCH2CH2NH	OH	OH	H	CH3	COCH3
1754	3	NHCH2CH2NH	F	H	F	H	H
1755	3	NHCH2CH2NH	F	H	F	H	COCH3
1756	3	NHCH2CH2NH	F	H	F	CH3	H
1757	3	NHCH2CH2NH	F	H	F	CH3	COCH3
1758	3	NHCH2CH2NH	CF3	H	CF3	H	H
1759	3	NHCH2CH2NH	CF3	H	CF3	H	COCH3
1760	3	NHCH2CH2NH	CF3	H	CF3	CH3	H
1761	3	NHCH2CH2NH	CF3	H	CF3	CH3	COCH3
1762	3	piperazinyl	H	OH	H	H	H
1763	3	piperazinyl	H	OH	H	H	COCH3
1764	3	piperazinyl	H	OH	H	CH3	H
1765	3	piperazinyl	H	OH	H	CH3	COCH3
1766	3	piperazinyl	H	F	H	H	H
1767	3	piperazinyl	H	F	H	H	COCH3
1768	3	piperazinyl	H	F	H	CH3	H
1769	3	piperazinyl	H	F	H	CH3	COCH3
1770	3	piperazinyl	H	CF3	H	H	H
1771	3	piperazinyl	H	CF3	H	H	COCH3
1772	3	piperazinyl	H	CF3	H	CH3	H
1773	3	piperazinyl	H	CF3	H	CH3	COCH3
1774	3	piperazinyl	OH	OH	H	H	H
1775	3	piperazinyl	OH	OH	H	H	COCH3
1776	3	piperazinyl	OH	OH	H	CH3	H
1777	3	piperazinyl	OH	OH	H	CH3	COCH3
1778	3	piperazinyl	F	H	F	H	H
1779	3	piperazinyl	F	H	F	H	COCH3
1780	3	piperazinyl	F	H	F	CH3	H
1781	3	piperazinyl	F	H	F	CH3	COCH3
1782	3	piperazinyl	CF3	H	CF3	H	H
1783	3	piperazinyl	CF3	H	CF3	H	COCH3
1784	3	piperazinyl	CF3	H	CF3	CH3	H
1785	3	piperazinyl	CF3	H	CF3	CH3	COCH3
1786	4	NHNH	H	OH	H	H	H
1787	4	NHNH	H	OH	H	H	COCH3
1788	4	NHNH	H	OH	H	CH3	H
1789	4	NHNH	H	OH	H	CH3	COCH3
1790	4	NHNH	H	F	H	H	H
1791	4	NHNH	H	F	H	H	COCH3
1792	4	NHNH	H	F	H	CH3	H
1793	4	NHNH	H	F	H	CH3	COCH3
1794	4	NHNH	H	CF3	H	H	H
1795	4	NHNH	H	CF3	H	H	COCH3
1796	4	NHNH	H	CF3	H	CH3	H
1797	4	NHNH	H	CF3	H	CH3	COCH3
1798	4	NHNH	OH	OH	H	H	H
1799	4	NHNH	OH	OH	H	H	COCH3
1800	4	NHNH	OH	OH	H	CH3	H
1801	4	NHNH	OH	OH	H	CH3	COCH3
1802	4	NHNH	F	H	F	H	H
1803	4	NHNH	F	H	F	H	COCH3
1804	4	NHNH	F	H	F	CH3	H
1805	4	NHNH	F	H	F	CH3	COCH3
1806	4	NHNH	CF3	H	CF3	H	H
1807	4	NHNH	CF3	H	CF3	H	COCH3
1808	4	NHNH	CF3	H	CF3	CH3	H
1809	4	NHNH	CF3	H	CF3	CH3	COCH3
1810	4	NHCH2CH2NH	H	OH	H	H	H
1811	4	NHCH2CH2NH	H	OH	H	H	COCH3
1812	4	NHCH2CH2NH	H	OH	H	CH3	H
1813	4	NHCH2CH2NH	H	OH	H	CH3	COCH3
1814	4	NHCH2CH2NH	H	F	H	H	H
1815	4	NHCH2CH2NH	H	F	H	H	COCH3
1816	4	NHCH2CH2NH	H	F	H	CH3	H
1817	4	NHCH2CH2NH	H	F	H	CH3	COCH3
1818	4	NHCH2CH2NH	H	CF3	H	H	H
1819	4	NHCH2CH2NH	H	CF3	H	H	COCH3
1820	4	NHCH2CH2NH	H	CF3	H	CH3	H
1821	4	NHCH2CH2NH	H	CF3	H	CH3	COCH3
1822	4	NHCH2CH2NH	OH	OH	H	H	H
1823	4	NHCH2CH2NH	OH	OH	H	H	COCH3
1824	4	NHCH2CH2NH	OH	OH	H	CH3	H
1825	4	NHCH2CH2NH	OH	OH	H	CH3	COCH3
1826	4	NHCH2CH2NH	F	H	F	H	H
1827	4	NHCH2CH2NH	F	H	F	H	COCH3
1828	4	NHCH2CH2NH	F	H	F	CH3	H
1829	4	NHCH2CH2NH	F	H	F	CH3	COCH3
1830	4	NHCH2CH2NH	CF3	H	CF3	H	H
1831	4	NHCH2CH2NH	CF3	H	CF3	H	COCH3
1832	4	NHCH2CH2NH	CF3	H	CF3	CH3	H
1833	4	NHCH2CH2NH	CF3	H	CF3	CH3	COCH3
1834	4	piperazinyl	H	OH	H	H	H
1835	4	piperazinyl	H	OH	H	H	COCH3
1836	4	piperazinyl	H	OH	H	CH3	H
1837	4	piperazinyl	H	OH	H	CH3	COCH3
1838	4	piperazinyl	H	F	H	H	H
1839	4	piperazinyl	H	F	H	H	COCH3
1840	4	piperazinyl	H	F	H	CH3	H
1841	4	piperazinyl	H	F	H	CH3	COCH3
1842	4	piperazinyl	H	CF3	H	H	H
1843	4	piperazinyl	H	CF3	H	H	COCH3
1844	4	piperazinyl	H	CF3	H	CH3	H
1845	4	piperazinyl	H	CF3	H	CH3	COCH3
1846	4	piperazinyl	OH	OH	H	H	H
1847	4	piperazinyl	OH	OH	H	H	COCH3
1848	4	piperazinyl	OH	OH	H	CH3	H
1849	4	piperazinyl	OH	OH	H	CH3	COCH3
1850	4	piperazinyl	F	H	F	H	H
1851	4	piperazinyl	F	H	F	H	COCH3
1852	4	piperazinyl	F	H	F	CH3	H
1853	4	piperazinyl	F	H	F	CH3	COCH3
1854	4	piperazinyl	CF3	H	CF3	H	H
1855	4	piperazinyl	CF3	H	CF3	H	COCH3
1856	4	piperazinyl	CF3	H	CF3	CH3	H
1857	4	piperazinyl	CF3	H	CF3	CH3	COCH3

Biological Evaluation

[0522] Conjugates of the invention were evaluated biologically by in vitro and in vivo assays to determine the ability of the conjugates to selectively inhibit renal sympathetic nerve activity and lower blood pressure. Three classes of conjugates of the invention were evaluated for their ability to inhibit the enzymes of the catecholamine cascade selectively within the kidney. These inhibitor conjugates variously inhibit tyrosine hydroxylase, dopa-decarboxylase and dopamine-β-hydroxylase in order to interfere ultimately with the synthesis of norepinephrine in the kidney.

[0523] Assays I and II evaluate in vivo the acute and chronic effects of Ex. #3 conjugate (a tyrosine hydroxylase inhibitor conjugated with N-acetyl-γ-glutamyl) in rats. Assay III evaluates the chronic effects bf Ex. #464 conjugate (a dopa-decarboxylase inhibitor conjugated with N-acetyl-γ-glutamyl) in rats.

[0524] Assay IV and V describes in vitro experiments performed to determine if the Ex. #859 conjugate was capable of being specifically metabolized by enzymes known to be abundant in the kidney. In Assay IV, the Ex. #859 conjugate was incubated with either rat kidney homogenate or a solution containing purified kidney enzymes to characterize resulting metabolites. In Assay V, experiments were performed to determine the potency of the Ex. #858 and Ex. #859 conjugates and potential metabolites as inhibitors of purified dopamine-β-hydroxylase.

[0525] Assays VI through IX describe in vivo experiments performed to characterize and compare the effects of fusaric acid and various conjugates of fusaric acid (Ex. #859, Ex. #861 and Ex. #863) on spontaneously hypertensive rats (SHR) by acute administration i.v. and i.d. and by chronic administration i.v. Assay X describes analysis of catecholamine levels in tissue from rats used in the chronic administration experiment of Assay VIII. Assays XI and XII describe in vivo experiments in dogs to determine the renal and mean arterial pressure effects of fusaric acid and Ex. #859 conjugate. Assay XIII describes mechanisms of the antihypertensive response to Ex. #859 conjugate, Assay XIV describes the antihypertensive efficacy of Ex. #859 conjugate in a second species (DOCA hypertensive micropig).

Assay I: Acute In Vivo Effects of Ex. #3 Conjuaate

[0526] Sprague-Dawley rats were anesthetized with inactin (100 mg/kg, i.p.) and catheters were implanted into a carotid artery for measurement of mean arterial pressure (Gould model 3800 chart recorder; Statham pressure transducer model no. P23DB) and into a jugular vein for compound administrations (i.v.). In addition, a flow probe was implanted around the left renal artery for measurement of renal blood flow using Carolina Medical Electronics flow probes. Rats were allowed 60 min to stabilize before 10 minutes of control recordings of mean arterial pressure and renal blood flow were obtained. Control measurements were followed by intravenous injection of Ex. #3 conjugate and saline vehicle. As shown in Table XVIII and in FIGS. 1 and 2, the Ex. #3 conjugate had no acute effects on mean arterial pressure (MAP), but increased renal blood flow (RBF).

TABLE XVIII
Acute In Vivo Effects of Ex. #3 Conjugate
	Time After Injection (min)
	Zero	15	30	45	60
	Vehicle (0.5 ml 0.9% NaCl i.v.)
MAP (mm	78	76	75	80	82
Hg)
RBF (ml/	4.9	4.5	4.2	4.6	4.7
min)
	Ex. #3 Conjugate (100 mg/kg i.v.)
MAP (mm	76 ± 5	77 ± 5	73 ± 4	70 ± 2	71 ± 6
Hg)
RBF (ml/	4.8 ± 0.8	7.1 ± 0.1	6.2 ± 0.3	5.9 ± 0.1	5.9 ± 0.1
min)

Assay II: Chronic In Vivo Effects of Ex. #3 Conjugate

[0527] The Ex. #3 conjugate and saline vehicle were infused continuously for four days in spontaneously hypertensive rats. Mean arterial pressure was measured (Gould Chart Recorder, model 3800; Statham P23Db pressure transducer) via an indwelling femoral artery catheter between 10:00 a.m. and 2:00 p.m. each day. The Ex. #3 conjugate was infused at 5 mg/hr and the saline vehicle was infused at 300 μL,/hr. via a jugular vein catheter with a Harvard infusion pump. Results are shown in Table XIX.

TABLE XIX
Chronic In Vivo Effects of Ex. #3 Conjugate
	Time After Injection (days)
	Zero	1	2	3	4
	Vehicle (300 μL/hr)
MAP (mm Hg)	181 ± 8	172 ± 6	170 ± 7	174 ± 6	182 ± 3
	Ex. #3 Conjugate (5 mg/hr)
MAP (mm Hg)	164 ± 3	175 ± 5	174 ± 5	172 ± 2	N.A.

Assay III: Chronic In Vivo Effects of Ex. #464 Conjugate

[0528] The Ex. #464 conjugate and saline vehicle were infused continuously for four days in spontaneously hypertensive rats. Mean arterial pressure was measured (Gould Chart Recorder, model 3800; Statham P23Db pressure transducer) via an indwelling femoral artery catheter between 10:00 a.m. and 2:00 p.m. each day. The Ex. #464 conjugate was infused at 10 mg/hr and the saline vehicle was infused at 300 μL/hr. As shown in Table XX and in FIG. 3, mean arterial pressure was lowered significantly over the four-day period.

TABLE XX
Chronic In Vivo Effects of Ex. #464 Conjugate
	Time After Injection (days)
	Zero	1	2	3	4
	Vehicle (300 μL/hr)
MAP (mm Hg)	181 ± 8	172 ± 6	170 ± 7	174 ± 6	182 ± 3
	Ex. #464 Conjugate (10 mg/hr)
MAP (mm Hg)	179 ± 6	169 ± 5	161 ± 4	163 ± 5	159 ± 8

Assay IV: In Vitro Evaluation of Enzyme Metabolism Effects of Ex. #859 Conjugate

[0529] A freshly excised rat kidney was homogenized in 10 ml cold buffer (100 mM Tris, 15 mM glycylglycine, pH 7.4) with a Polytron Tissue Homogenizer (Brinkmann). The resulting suspension, diluted with buffer, was incubated in the presence of the Ex. #859 conjugate at 37° C. At various times aliquots were removed, deproteinized with an equal volume of cold trichloroacetic acid (25%) and centrifuged. The supernatant was injected onto a C-18 reverse-phase HPLC column and eluted isocratically with a mixture of acetonitrile and water (20:80 v/v) containing trifluoroacetic acid (0.05%). Eluted compounds were monitored by absorbance at 254 nm and compared to standards run under identical conditions. In the assay using pure kidney enzyme homogenate, the Ex. #859 conjugate was also incubated under the same conditions as described except that 5 mg of gamma-glutamyl transpeptidase (Sigma, 23 units/mg) and 10 mg of acylase I (Sigma, 4800 units/mg) were added in place of the homogenate. Analysis by HPLC was performed in a manner identical to that used for the kidney homogenate experiment. Following incubation of the Ex. #859 conjugate with kidney homogenate, there was a linear increase in the amount of fusaric acid liberated, as shown in FIG. 4. No fusaric acid hydrazide or gamma-glutamyl fusaric acid hydrazide was observed; nor was any metabolism observed in the buffer control incubations. These data (Table XXI, FIG. 4) show that renal tissue is able to metabolize the Ex. #859 conjugate to fusaric acid, which then remains stable under these conditions. Data from experiments using the purified enzymes show results similar to those seen for the kidney homogenate experiment, with only fusaric acid and the unreacted compound being present (see Table XXII, FIG. 5).

TABLE XXI
Formation of Fusaric Acid From the Ex. #859
Conjugate Incubated with Kidney Homogenate
	Time (hrs.):
		0.00	0.17	1.25	17.00	41.00
	Fusaric	0.00	0.27	0.57	2.37	5.94
	Acid (μg/ml):

[0530]

TABLE XXII
Formation of Fusaric Acid From Ex. #859 Conjugate
Incubated with Purified Transpeptidase and Acylase
	Time (hrs.):
		3	24	72	96	120
	Fusaric	0.00	2.56	12.15	15.44	18.75
	Acid
	(μg/ml):
	@ pH 7.4
	Fusaric	0.00	1.12	4.46	5.22	6.55
	Acid
	(μg/ml):
	@ pH 8.1

Assay V: In Vitro Evaluation of DBH Inhibition by Ex. #859 Conjugate

[0531] In order to characterize the relative potency of the Ex. #859 conjugate and its various potential metabolites as inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1), the enzyme activity was determined in vitro in the presence of these compounds. DBH, purified from bovine adrenals (Sigma) was incubated at 37° C. in buffer containing 20 mM dopamine as substrate. The reaction was stopped by addition of 0.5 M perchloric acid. The precipitate was removed and the product of the enzyme activity (norepinephrine), contained in the clear supernatant, was analyzed by HPLC. The chromatographic separation used a reversed phase C-18 column run isocratically with 0.2 M ammonium acetate (pH 5.2) as the mobile phase. The amount of norepinephrine produced by the enzyme-substrate mixture was analyzed by measuring the peak intensity (absorbance) at 280 nm for norepinephrine as it was eluted at 4.5 minutes, using a photo-diode array detector. The result of adding either fusaric acid or the Ex. #859 conjugate to the incubate at various concentrations is shown in Table XXIII and FIG. 6. Above concentrations of 1 uM, fusaric acid inhibits the enzyme, while at concentrations up to 100 uM the Ex. #859 conjugate has no appreciable activity (Table XXIII and FIG. 6). Fusaric acid and Ex. #859 and two more possible metabolites (Ex #858 and fusaric acid hydrazide) were tested at 20 uM. Only fusaric acid had significant inhibitory effects on dopamine-β-hydroxylase activity (Table XXIV and FIG. 7).

TABLE XXIII
DBH Inhibition by Fusaric Acid and the Ex. #859 Conjugate
	Concentration (μM):
	0.01	0.10	0.50	1.00	5.00	10.00	50.00	100.00
Norepi-	0.59	0.59	0.60	0.53	0.25	0.14	0.00	0.00
nephrine
Peak
Intensity
(Abs 280) in
the
presence of
Fusaric
Acid:
Norepi-		0.51		0.52		0.61		0.53
nephrine
Peak
Intensity
(Abs 280) in
the presence
of Ex. #859
Conjugate

[0532]

TABLE XXIV
DBH Inhibition by Fusaric Acid, Ex #859 Conjugate
and Various Potential Metabolites
	Test	Ex.	Ex.	Fusaric Acid	Fusaric
	Compound (20 μM):	#859	#858	Hydrazide	Acid
	% Inhibition	1.5	0.0	13.8	75.4

Assay VI: Acute In Vivo Effects of Ex #859 and Ex #863 Conjugates

[0533] Spontaneously hypertensive rats were anesthetized with inactin (100 mg/kg, i.p.) and catheters were implanted into a carotid artery for measurement of mean arterial pressure (Gould model 3800 chart recorder; Statham pressure transducer model no. P23DB) and into a jugular vein for compound administrations (i.v. or i.d.). In addition, a flow probe was implanted around the left renal artery for measurement of renal blood flow using pulsed Doppler flowmetry. Rats were allowed 60 min to stabilize before 10 minutes of control recordings of mean arterial pressure and renal blood flow were obtained. Control measurements were followed by intravenous injection of 50 mg/kg of fusaric acid or the Ex. #859 conjugate. As shown in FIGS. 8 and 9 and Table XXV, fusaric acid (a systemic dopamine-β-hydroxylase inhibitor) decreased mean arterial pressure and increased renal blood flow throughout the 60 minute post-injection observation period. In sharp contrast, the Ex. #859 conjugate had no acute effects on mean arterial pressure, but increased renal blood flow to a greater degree than fusaric acid (Table XXV and FIGS. 8 and 9). Similar results were found when these compounds were administered through a catheter implanted into the duodenum (i.d.). The Ex. #859 conjugate had no effect on mean arterial pressure at a dose of 100 mg/kg (n=4) during a 60 minute observation period. Renal blood flow (n=4) was unchanged 15 minutes after injection of the Ex. #859 conjugate but increased from 1.1 KHz (control period) to 3.5 KHz at 30 minutes postinjection. Renal blood flow remained at this level for the following 30 minute observation period. These data indicate that the Ex. #859 conjugate is active and displays renal selectivity whether administered i.d. or i.v. Results for Ex. #863 conjugate were similar to Ex. #859 and are shown in Table XXVI: Ex. #863 had no effect on mean arterial pressure, but increased renal blood flow, indicating renal selectivity.

TABLE XXV
Acute Effects of Fusaric Acid and Ex. #859 conjugate on
Blood Pressure and Renal Blood Flow
	Time (min)
		Zero	15	30	45	60
	Fusaric Acid (50 mg/kg i.v.)
	MAP (mm Hg)	155	111	106	103	99
	RBF (KHz)	2.5	3.1	3.2	3.4	3.9
	Ex. #859 Conjugate (50 mg/kg i.v.)
	MAP (mm Hg)	156	163	164	157	159
	RBF (KHz)	2.4	3.8	4.0	4.6	4.8

[0534]

TABLE XXVI
Acute Effects of Ex. #863 Conjugate
	Time (min)
	Zero	15	30	45	60
	Ex. #863 (100 mg/kg i.v.)
MAP (mm Hg)	149 ± 14	N.A.	N.A.	N.A.	147 ± 14
RBF (KHz)	1.6 ± 0.2	N.A.	N.A.	N.A.	4.3 ± 0.3
N.A. = Not Available

Assay VII: Comparison of Fusaric Acid, Fusaric Acid Hydrazide and Ex. #859 Conjugate on Arterial Pressure in Spontaneously Hypertensive Rats (SHR)

[0535] Mean arterial pressure effects of fusaric acid hydrazide (100 mg/kg, i.v.), fusaric acid (100 mg/kg, i.v.) and Ex. #859 conjugate (250 mg/kg, i.v.) are shown in Table XXVII during a vehicle control period and 60 min post-injection of compound in anesthetized SHR. Rats were prepared as described above, minus the renal artery flow probe.

TABLE XXVII
Acute Effects of Fusaric Acid, Fusaric Acid Hydrazide
and Ex. #859 Conjugate on Blood Pressure
	COMPOUND	ZERO	60 MIN
	Fusaric Acid (n = 4)	164 ± 10 mmHg	110 ± 21 mmHg
	Fusaric Acid	159 ± 8 mmHg	104 ± 13 mmHg
	Hydrazide (n = 4)
	Ex. #859 Conjugate	151 ± 9 mmHg	146 ± 15 mmHg
	(n = 4)

[0536] The data show that the hypotensive effects of the fusaric acid hydrazide is similar to fusaric acid. The Ex. #859 conjugate had no effect on mean arterial pressure (Table XXV, XXVII and FIG. 8). The observation of no effect on mean arterial blood pressure confirms the expectation that the Ex. #859 conjugate does not act systemically.

Assay VIII: Chronic Tn Vivo Effects of Ex. #859 Conjugate

[0537] The Ex. #859 conjugate and saline vehicle were infused continuously for 5 days in SHR. Mean arterial pressure was measured (Gould Chart Recorder, model 3800; Statham P23Db pressure transducer) via an indwelling femoral artery catheter between 10:00 a.m. and 2:00 p.m. each day. The Ex. #859 conjugate (5 mg/hr), fusaric acid (2.5 mg/hr), and saline (100 μ1/hr) were infused via a jugular vein catheter with a Harvard infusion pump. Compared to the control vehicle fusaric acid and the Ex. #859 conjugate lowered mean arterial pressure similarly. Mean arterial pressure did not change in the saline vehicle group. Results are shown in Table XXVIII. and FIG. 10.

TABLE XXVIII
Chronic Effects of Fusaric Acid and Ex. #859 Conjugate
on Blood Pressure
	Time (days)
	Zero	1	2	3	4	5
	Vehicle (25 μL/hr)
MAP (mm	139 ± 2	139 ± 4	143 ± 4	146 ± 4	145 ± 7	146 ± 4
Hg) (SE)
	Fusaric Acid (2.5 mg/hr)
MAP (mm	148 ± 6	118 ± 5	114 ± 7	122 ± 5	114 ± 6	114 ± 3
Hg) (SE)
	Ex. #859 Conjugate (5 mg/hr)
MAP (mm	146 ± 5	122 ± 9	115 ± 9	119 ± 11	121 ± 7	115 ± 8
Hg) (SE)

Assay IX: Chronic In Vivo Effects of Ex. #861 and Ex #863 Conjugates

[0538] The conjugates of Ex. #861 and #863 and saline vehicle were infused continuously for 4 days in spontaneously hypertensive rats. Mean arterial pressure was measured (Gould Chart Recorder, model 3800; Statham P23Db pressure transducer) via an indwelling femoral artery catheter between 10:00 a.m. and 2:00 p.m. each day. The Ex. #861 and Ex. #863 conjugates were infused at 5 mg/hr and the saline vehicle was infused at 100 μl/hr via a jugular vein catheter with a Harvard infusion pump. Results are shown in Table XXIX. The Ex. #863 conjugate lowered mean arterial pressure as shown in FIG. 11. Mean arterial pressure did not change for the Ex. #861 conjugate and the saline vehicle group (Table XXIX). It is believed that at a higher dose of the Ex. #861 conjugate, blood pressure lowering effects would be observed.

TABLE XXIX
Chronic Effects of Ex. #861 and Ex. #863 Conjugates
on Blood Pressure
	Time (days)
	Zero	1	2	3	4
Vehicle	171 ± 6	172 ± 6	164 ± 6	169 ± 4	162 ± 4
Ex. #861	177 ± 3	173 ± 3	172 ± 4	172 ± 3	163 ± 9
Ex. #863	177 ± 5	152 ± 6	146 ± 7	142 ± 7	154 ± 7

Assay X: Catecholamine Analysis of Tissue from Rats Treated with Ex. #859 Conjugate

[0539] In order to evaluate the renal selectivity of DBH inhibition by the Ex. #859 conjugate, the catecholamine levels of heart and kidneys, both of which have been shown to be highly sensitive to DBH inhibition [Racz, K. et al., Europ, J. Pharmacol., 109, 1 (1985)], were measured following chronic infusion of the Ex. #859 conjugate, fusaric acid and saline vehicle in rats. Following 5 days of infusion, the kidney was exposed through a small flank incision, made in the anesthetized rat, and the renal artery and vein were ligated. Following this the kidney was rapidly excised distal to the ligation and frozen in liquid nitrogen. Similarly, the heart was excised and frozen subsequent to the removal of both kidneys. The frozen tissues were stored in closed containers at −80° C. Tissue samples were thawed on ice and their weight recorded prior to being placed in a flat bottom tube. The cold extraction solvent (2 ml/g tissue) was then added and the sample was homogenized with a Polytron. Extraction Solvent: 0.1 M perchloric acid (3 ml of 70% PCA to 500 ml); 0.4 mM Na metabisulphite (38 mg/500 ml). The volume was then measured and 0.05 ml of a 1 uM/L solution of dihydroxybenzylamine (DHBA) in extraction solvent was added for every 0.95 ml of homogenate to yield a 50 nM/L internal standard concentration. The homogenate was then mixed and centrifuged at 4° C., 3000 rpm for 35 minutes. A 2 ml aliquot of the supernatant was then neutralized by adding 0.5 ml of 2 M Tris, pH 8.8 and mixing. The sample was then placed on an alumina column (40 mg, Spe-ed CAT cartridge; Applied Separations; Bethlehem, Pa.) and the catecholamines were bound, washed and eluted using a vacuum manifold system (Adsorbex SPU, EM Science, Cherry Hill, N.J.) operating at ca. 4 ml/min. until the column was dry. Washes of 1 ml H20—0.5 ml MeOH—1 ml H20 were followed by elution with 1 ml of extraction solvent. A 200 μl sample of the eluant was injected onto a C-18 reversed phase analytical HPLC column, 5 um, 4.6 mm×250 mm (e.g., Beckman #235335, LKB 2134-630 Spherisorb ODS-2) and eluted with a recycled mobile phase run at ambient temperature and a flow rate of 0.5 ml/min (ca. 75 bar). Mobile Phase: 0.02 M Na2HP04 in 75/25(v/v) H20/MeOH 0.007% SDS pH 3.5 (conc. H3P04). The separated catecholamines were detected with a LKB 2143 electrochemical detector at a potential setting of 500 mV using a teflon flow cell spacer of 2.2 μl and a time constant of 2 sec. Peak heights were measured and recorded along with the chromatogram tracing using a Spectra-Physics 4270 integrator. Sample runs were preceded by injection of a mixture of calibration standards (200 ul) containing 50 nM/L of epinephrine (Epi), norepinephrine (NE), dopamine (DA), and DHBA in extraction solvent. The peak heights for each sample run were corrected by dividing the peak height of the DHBA in the standard by the peak height of the DHBA in each sample. The resulting factor (calculated for each sample) was used to correct for losses due to dilution, non-specific binding to the tissue precipitate, incomplete elution, etc. Concentrations were calculated by multiplying the peak heights for Epi, NE and DA by that samples correction factor and then dividing this value by the peak height of the respective standard. When this number is multiplied by the concentration of the standard (in this case 50 nM/L) the concentration of the catecholamine in the homogenate is obtained. This value is multiplied by the volume of the homogenate (determined previously) to get the total catecholamine content of the tissue expressed in moles/g tissue. The resolution and retention times for a mixture of standards run under the conditions described in the previous section are shown in Table XXX.

TABLE XXX
Retention
Time (min.) Compound
12.10       3,4-dihydroxylphenylacetic acid (DOPAC)
18.24       norepinephrine (NE)
21.82       epinephrine (Epi)
23.19       homovanillic acid (HVA)
30.56       dihydroxybenzylamine (DHBA)
42.58       dopamine (DA)

[0540] The linear response to various standards run over a 100 fold concentration range was excellent with values for both the correlation coefficient (r) and the coefficient of determination (r-squared) being >0.9999 for all standards, while the rank correlation (Spearman's rho) was 1.0. To confirm the precision and accuracy of the values, tissue analysis was performed on a control group of Sprague-Dawley rats. The cumulative results are within the range of values reported in the literature [(e.g. Racz, K. et al, J. Cardiovasc. Pharmacol., 8, 676 (1986)]. The precision in the efficiency of extraction measured by the addition of an internal standard (DHBA) was also excellent with a fractional efficiency of 0.779(SE=0.066) for the kidney extraction and 0.771(SE=0.083) for the heart extracts. Relative to vehicle administration, both the Ex. #859 conjugate and fusaric acid decreased kidney norepinephrine concentration; however, only fusaric acid decreased heart norepinephrine concentration (see Table XXXI and FIGS. 12 and 13). These data indicate that the Ex. #859 conjugate is renal selective with chronic infusion.

TABLE XXXI
Effect of Fusaric Acid and Ex. #859 conjugate on Tissue
Norepinephrine Concentration Following 5 Days of Infusion
	Tissue:	Kidney	Heart
	Vehicle (25 μL/hr)
	Norepinephrine:	889 (72)	2,248 (164)
	(pMol/g) (SD)
	Fusaric Acid (2.5 mg/hr)
	Norepinephrine:	519 (42)	862 (147)
	(pMol/g) (SD)
	Ex. #859 Conjugate (5 mg/hr)
	Norepinephrine:	589 (54)	2,444 (534)
	(pMol/g) (SD)

Assay XI: Intrarenal Administration of Fusaric Acid in Anesthetized Dogs

[0541] In one anesthetized dog, bolus doses of fusaric acid (0.1-5.0 mg/kg) were administered into the renal artery. Mean arterial pressure (MAP), renal blood flow (RBF) and urinary sodium excretion (UNaV) were measured. Bolus intrarenal injection of isotonic saline or 0.1 mg/kg of fusaric acid had no effect on any measure; however, 0.5, 1.0, and 5.0 mg/kg fusaric acid caused dose-related increases in renal blood flow, but had no significant effect on mean arterial pressure or urinary sodium excretion (see Table XXXII).

TABLE XXXII
Effect of Intrarenal Injection of Fusaric Acid on Blood Pressure,,
Sodium Excretion and Renal Blood Flow in the Dog
Dose (mg/kg):	Saline	0.1	0.5	1.0	5.0
Δ RBF (ml/min):	0	0	+46	+58	+132
UNa V (μEq/min):	42.8	21.2	23.8	21.1	34.8
MAP (mm Hg):	136	136	136	138	140

[0542] Similar results were also found in a second experiment where non-depressor doses of fusaric acid were infused into the renal arteries of two dogs (see Table XXXIII).

TABLE XXXIII
Effect of Intrarenal Infusion of Fusaric Acid
on Blood Pressure, Sodium Excretion and Renal
Blood Flow in the Dog
		Dog #1		Dog #2
		Fusaric Acid		Fusaric Acid
		Saline		Saline
	Infusion:	(1.25 mg/kg/min)		(0.75 mg/kg/min)
	Δ RBF (ml/min):	140	240	236	315
	UNa V (μEqlmin):	95	82	44	13
	MAP (mm Hg):	136	136	140	148

[0543] These data indicate that intrarenal administration of fusaric acid increases renal blood flow in anesthetized dogs without altering systemic mean arterial pressure.

Assay XII: Acute In Vivo Effects of Ex. #859 Conjugate

[0544] This experiment was run to determine the renal selectivity of conjugate of the invention in dogs. Male mongrel dogs (15-20 kg/n=8; Antech, Inc., Barnhard, Mo.) were anesthetized with sodium pentobarbital (30 mg/kg as i.v. bolus, and 4-6 mg/kg/hr infusion) and catheters were placed in the femoral veins for compound injection or pentobarbital infusion, and the femoral artery for arterial pressure recording. An electromagnetic flow probe (Carolina Medical Electronics, Inc., King, N.C.) was placed around the left renal artery for measurement of renal blood flow. Renal blood flow and arterial pressure were recorded on a Gould chart recorder. After surgery, 20-30 minutes were allowed for variables to stabilize. Then a 20 minute control measurement was followed by injection of Ex. #859 conjugate at doses of 20 and 60 mg/kg, i.v., to two different groups of dogs. Variables were monitored for the next three hours. Results are shown in Table XXXIV and FIGS. 14 and 15.

TABLE XXXIV
Renal Selectivity of Ex. #859 Conjugate in Dogs
Time After Injection of Ex. #859 Conjugate
	Zero	1 Hour	2 Hour	3 Hour
Mean Arterial
Pressure (mmHg)
7 mg/kg	114 ± 6	116 ± 5	113 ± 4	114 ± 4
20 mg/kg	120 ± 3	124 ± 2	125 ± 3	125 ± 4
60 mg/kg	123 ± 3	124 ± 1	126 ± 3	120 ± 4
Vehicle	115 ± 4	114 ± 3	115 ± 4	114 ± 3
Renal Blood
Flow (ml/min)
7 mg/kg	92 ± 5	92 ± 5	111 ± 14	118 ± 23
20 mg/kg	88 ± 11	107 ± 14	122 ± 20	126 ± 24
60 mg/kg	131 ± 21	145 ± 21	168 ± 28	176 ± 32
Vehicle	87 ± 7	89 ± 5	92 ± 4	92 ± 4

Assay XIII: Acute In Vivo Effects of Ex. #859 Conjugate

[0545] This experiment was run to determine the roles of the renal sympathetic nerves and dopamine in the antihypertensive response to Ex. #859. For renal blood flow experiments, male SHR (11-13 weeks of age; Harlan Sprague-Dawley, Inc., Indianapolis, Ind.) were anesthetized (Inactin, 100 mg/kg, i.p.), catheters were implanted in a jugular vein and carotid artery, and an electromagnetic flow probe (Carolina Medical Electronics, Inc., King, N.C.) was placed on the left renal artery. Care was taken not to damage the renal nerves. A tracheal catheter maintained airway patency. The SHR were placed on a heated pad to maintain normal body temperature (Harvard Apparatus, South Natick, Mass.). In one group of SHR (n=6) surgical renal denervation was performed (prior to implanting the flow probe) through a left flank incision by surgically stripping the renal artery and vein of adventitia and cutting all visible renal nerve bundles under a dissection microscope (×25) and coating the vessels with a solution of 10% phenol in 95% ethanol, as previously described (9,10). In a second group of SHR (n=6) bulbocapnine (a dopamine receptor antagonist) was infused at 100 μg/kg/min starting 30 minutes prior to injection of Ex. #859 (50 mg/kg, i.v.) and continued for the duration of the study. In a third group of SHR (n=6) Ex. #859 (50 mg/kg, i.v.) was administered alone. In a final group of SHR (n=6) vehicle (0.9% NaCl) was administered. SHR were allowed 60 minutes for stabilization after surgery. After the stabilization period, 15 minutes of control mean arterial pressure and renal blood flow were obtained. Mean arterial pressure and renal blood flow were recorded for one hour.

[0546] For antihypertensive experiments, male SHR (11-13 weeks of age; Harlan Sprague-Dawley, Inc.; Indianapolis, Ind.) were habituated for 3-4 days in individual experimental cages, which became their home cages for the duration of the study. Five to seven days before experimentation, SHR were anesthetized with chloral hydrate (400 mg/kg; Sigma Chemical Co., St. Louis, Mo.) and catheters were implanted into a femoral artery and vein. The catheters were led to the back of the neck, exteriorized, and channeled through a tether and swivel system (Alice King Chatham, Los Angeles, Calif.). Surgical renal denervation was performed as above. SHR that did not resume normal food and water consumption were omitted from the study. Mean arterial pressure was measured via a pressure transducer (Model P23Db, Statham, Oxnard, Calif.) and displayed on a chart recorder (Gould, model 3800, Cleveland, Ohio). In separate groups of conscious SHR, Ex. #859 (5 mg/kg/hr, n=6) was infused alone, Ex. #859 (5 mg/kg/hr, n=6) was coinfused with bulbocapnine (100 μg/kg/min), or Ex. #859 (10 mg/kg/hr, n=6) was infused 5-7 days after surgical renal denervation. Surgical renal denervation was performed as described above. After a one hour control measure of mean arterial pressure, compounds were infused for four hours and mean arterial pressure was measured continuously.

[0547] In anesthetized SHR, mean arterial pressure was not changed in any group (Table XXXV). Similarly, vehicle had no effect on renal blood flow in anesthetized SHR (Table XXXV). Renal blood flow was increased 60 minutes after injection of Ex. #859 alone, but renal blood flow was not changed by Ex. #859 during bulbocapnine infusion or after surgical renal denervation (Table XXXV).

[0548] In conscious SHR, continuous infusion of Ex. #859 was antihypertensive over a four hour period (Table XXXVI). Coinfusion of Ex. #859 with bulbocapnine lowered mean arterial pressure similar to Ex. #859 alone (Table XXXVI). Bulbocapnine alone had no effect on mean arterial pressure over the four hour period (Table XXXVI). In contrast, surgical denervation of the kidneys prevented the antihypertensive response to Ex. #859 (Table XXXVI). Renal denervation also lowered baseline mean arterial pressure relative to vehicle (Table XXXVI).

TABLE XXXV
Role of Dopamine and Renal Nerves on
Responses to Ex. #859 Conjugate
	Mean Arterial	Renal Blood
	Pressure (mmHg)	Flow (ml/min)
Vehicle n = 6
Time 0 minutes	151 ± 8	8 ± 1
Time 60 minutes	151 ± 6	9 ± 1
Ex. #859 n = 6
Time 0 minutes	149 ± 8	7 ± 2
Time 60 minutes	149 ± 7	12 ± 2
Bulbocapnine + SC-47792 n = 6
Time 0 minutes	148 ± 7	7 ± 1
Time 60 minutes	146 ± 7	7 ± 1
Renal Denervation + SC-47792 n = 6
Time 0 minutes	143 ± 6	6 ± 1
Time 60 minutes	139 ± 7	6 ± 1

[0549]

TABLE XXXVI
Role of Dopamine and Renal Nerves on Antihypertensive
Response to Ex. #859 Conjugate
Time (hours)	0	1	2	3	4
Vehicle (n = 6)	186 ± 8	186 ± 8	184 ± 7	180 ± 8	179 ± 8
Ex. #859 (n = 6)	177 ± 6	172 ± 6	170 ± 7	164 ± 7	154 ± 6
DNX (n = 6)	157 ± 3	155 ± 4	53 ± 4	150 ± 4	147 ± 4
BULBO (n = 6)	168 ± 8	158 ± 6	148 ± 5	140 ± 7	140 ± 5
BULBO (n = 6)	160 ± 6	156 ± 7	161 ± 11	159 ± 6	157 ± 7
alone

Assay XIV: Chronic In Vivo Effects of Ex. #859 Conjugate in DOCA Hypertensive Micropigs

[0550] This study examines the efficacy of Ex. #859 in deoxycorticosterone acetate (DOCk) hypertensive micropigs (Charles River; 6 months of age). Micropigs were made hypertensive by implanting subcutaneously DOCA strips (100 mg/kg) under isoflurane anesthesia. Hypertension stabilizes after one month. Mean arterial pressure was measured using a Gould chart recorder and Statham P23dB transducers. After one month Ex. #859 conjugate was infused for three days at 5 mg/kg/hr).

[0551] Vehicle infusion (200 ml/day) had no effect on mean arterial pressure over the three day study period Table XXXVI and FIG. 16). Example #859 normalized mean arterial pressure (Table XXXVI and FIG. 16).

TABLE XXXVI
Effects of Ex. #859 on Mean Arterial Pressure in DOCA
Hypertensive Micropigs
	Vehicle	Day 1	Day 2	Day 3
		115 ± 3	115 ± 4	118 ± 2
	Ex. #859	151 ± 4	132 ± 4	119 ± 3

Composition of the Invention

[0552] Also embraced within this invention is a class of pharmaceutical compositions comprising one or more conjugates described above in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The conjugates of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the conjugates of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art. The conjugates and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

[0553] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a human may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.

[0554] The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose solutions or water may be used as a suitable carrier. A suitable daily dose is from about 0.1 to 100 mg/kg body weight injected per day in multiple doses depending on the disease being treated.

[0555] A preferred daily dose would be from about 1 to 30 mg/kg body weight. Conjugates indicated for prophylactic therapy will preferably be administered in a daily dose generally in a range from about 0.1 mg to about 100 mg per kilogram of body weight per day. A more preferred dosage will be a range from about 1 mg to about 100 mg per kilogram of body weight. Most preferred is a dosage in a range from about 1 to about 50 mg per kilogram of body weight per day. A suitable dose can be administered, in multiple sub-doses per day. These sub-doses may be administered in unit dosage forms. Typically, a dose or sub-dose may contain from about 1 mg to about 100 mg of conjugate per unit dosage form. A more preferred dosage will contain from about 2 mg to about 50 mg of conjugate per unit dosage form. Most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per unit dose.

[0556] The dosage regimen for treating a disease condition with the conjugates and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical condition of the patient, the severity of the disease, the route of administration, and the particular compound employed, and thus may vary widely.

[0557] For therapeutic purposes, the conjugates of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the conjugates may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of conjugate in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The conjugates may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solutions, and/or various buffer solutions. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. Appropriate dosages, in any given instance, of course depend upon the nature and severity of the condition treated, the route of administration, including the weight of the patient.

[0558] Representative carriers, diluents and adjuvants include for example, water, lactose, gelatin, starches, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical compositions may be made up in a solid form such as granules, powders or suppositories or in a liquid form such as solutions, suspensions or emulsions. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.

[0559] Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

1. A conjugate comprising a first residue and a second residue, said first and second residues connected together by a cleavable bond, wherein said first residue is provided by an inhibitor compound capable of inhibiting biosynthesis of an adrenergic neurotransmitter, and wherein said second residue is capable of being cleaved from said first residue by an enzyme located predominantly in the kidney.

2. Conjugate of claim 1 wherein said first and second residues are provided by precursor compounds, wherein the precursor compound of one of said first and second residues has a reactable carboxylic acid moiety and the precursor of the other of said first and second residues has a reactable amino moiety or a moiety convertible to a reactable amino moiety, whereby a cleavable bond may be formed between said carboxylic acid moiety and said amino moiety.

3. Conjugate of claim 2 wherein said inhibitor compound providing said first residue is selected from tyrosine hydroxylase inhibitor compounds, dopa-decarboxylase inhibitor compounds, dopamine-β-hydroxylase inhibitor compounds, and mimics of said inhibitor compounds.

4. Conjugate of claim 3 wherein said tyrosine hydroxylase inhibitor compound is of the formula

5. Conjugate of claim 4 wherein said inhibitor compound is of the formula

6. Conjugate of claim 5 wherein said inhibitor compound is selected from the group consisting of 4-cyanoamino-a-methylphenyalanine; 3-carboxy-a-methylphenylalanine; 3-cyano-a-methylphenylalanine methyl ester; α-methyl-4-thiocarbamoylphenylalanine methyl ester; 4-(aminomethyl)-a-methylphenylalanine; 4-guanidino-a-methylphenylalanine; 3-hydroxy-4-methanesulfonamido-a-methylphenylalanine; 3-hydroxy-4-nitro-a-methylphenylalanine; 4-amino-3-methanesulfonyloxy-a-methylphenylalanine; 3-carboxymethoxy-4-nitro-a-methylphenylalanine; α-methyl-4-amino-3-nitrophenylalanine; 3,4-diamino-a-methylphenylalanine; α-methyl-4-(pyrrol-1-yl)phenylalanine; 4-(2-aminoimidazol-1-yl)-a-methylphenylalanine; 4-(imidazol-2-ylamino)-a-methylphenylalanine; 4-(4,5-dihydro-4-hydroxy-4-trifluoromethyl-thiazol-2-yl)a-methylphenylalanine methyl ester; α-methyl-4-(4-trifluoromethylthiazol-2-yl)phenylalanine; α-methyl-3-(4-trifluoromethylthiazol-2-yl)-phenylalanine; 4-(imidazol-2-yl)-a-methylphenylalanine; 4-(4,5-dihydroimidazol-2-yl)-a-methylphenylalanine; 3-(imidazol-2-yl)-a-methylphenylalanine; 3-(4,5-dihydroimidazol-2-yl)-a-methylphenylalanine; 4-(imidazol-2-yl) phenylalanine; 4,5-dihydroimidazol-2-yl) phenylalanine; 3-(imidazol-2-yl)phenylalanine; 3-(2,3-dihydro-1H-indol-4-yl)-a-methylalanine; α-methyl-3-(1H-2-oxindol-5-yl)alanine; 3-[1-(N-benzoylcarbamimidoyl)-2,3-dihydro-1Hindol-5-yl)]-a-methylalanine; 3-1[-carbamimidoyl-2,3-dihydro-1H-indol-5-yl-a-methylalanine; 3-(1H-indol-5-yl)-a-methylalanine; 3-(benzimidazol-2-thione-5-yl)-a-methylalanine; 3-(2-aminobenzimidazol-5-yl-2-methylalanine; 2-methyl-3-(benzoxazol-2-on-6-yl)alanine; 3-(2-aminobenzothiazol-6-yl)-2-methylalanine; 3-(2-amino-4-mercaptobenzothiazol-6-yl)-2-methylalanine; 3-(2-aminobenzothiazol-6-yl)alanine; 2-methyl-3-(2,1,3-benzothiadiazol-5-yl)alanine; 3-(1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl)-2methylalanine-2,2-dioxide; 3-(1,3-dihydrobenzo-2,1,3-thiadiazol-5-yl)-2-methylalanine-2,2-dioxide methyl ester; 3-(1,3-dihydrobenzo-2,1,3-thiadiaxol-5-yl)alanine 2,2-dioxide; 3-(1,3-dihydro-1,3-dimethylbenzo-2,1,3-thiadiazol-5yl-)-2-methylalanine 2,2-dioxide; α-methyl-3-[4-methyl-2(1H)-oxoquinolin-6-yl]alanine; 3-[4-methyl-2(1H)-oxoquinolin-6-yl]alanine; 2-methyl-3-(quinoxalin-6-yl)alanine; 2-methyl-3-(2-hydroxyquinoxalin-6-yl)alanine; 2-methyl-3-(2-hydroxyquinoxalin-7-yl)alanine; 3-(2,3-dihydroxyquinoxalin-6-yl)-2-methylalanine; 3-(quinoxalin-6-yl)alanine; 3-(2,3-dihydroxyquinoxalin-6-yl)alanine; 3-(1,4-benzoxazin-3-one-6-yl)-2-methylalanine; 3-(1,4-benzoxazin-3-one-7-yl)alanine; 3-(5-hydroxy-4H-pyran-4-on-2-yl)-2-methylalanine; 3-(2-hydroxy-4-pyridyl)-2-methylalanine; 3-(2-carboxy-4-pyridyl)-2-methylamine; α-methyl-4-(pyrrol-1-yl)phenylalanine; α-ethyl-4-(pyrrol-1-yl)phenylalanine; α-propyl-4-(pyrrol-1-yl)phenylalanine; 4-[2-(carboxy)pyrrol-1-yl)phenylalanine; α-methyl-4-(pyrrol-1-yl)phenylalanine; 3-hydroxy-α-methyl-4-(pyrrol-1-yl)phenylalanine; 3-methoxy-α-methyl-4-(pyrrol-1-yl)phenylalanine; 4-methoxy-α-methyl-3-(pyrrol-1-yl)phenylalanine; 4-(indol-1-yl)-a-methylphenylalanine; 4-(carbazol-9-yl)-a-methylphenylalanine; 2-methyl-3-(2-methanesulfonylamidobenzimidazol-5-yl)alanine; 2-methyl-3-(2-amino-4-pyridyl)alanine; 2-methyl-3[tetrazolo-(1,5)-a-pyrid-7-yl]alanine; D,L-α-methyl-β-(4-hydroxy-3-methyl)phenylalanine; D,L-α-methyl-β-(4-hydroxy-3-phenyl)phenylalanine; D,L-α-methyl-β-(4-hydroxy-3-benzyl)phenylalanine; D,L-α-methyl-β-(4-methoxy-3-cyclohexyl) phenylalanine; a, b, b trimethyl-β-(3,4-dihydroxyphenyl)alanine; a, b, b trimethyl-β-(4-hydroxyphenyl)alanine; N-methyl a, b, b, trimethyl-β-(3,4-dihydroxphenyl)alanine; D,L a, b, b trimethyl-β-(3,4-dihydroxyphenyl)alanine; a, b, b trimethyl-β-(3,4-dimethoxyphenyl)alanine; L-α-methyl-β-3,4-dihydroxyphenylalanine; L-α-ethyl-β-3,4-dihydroxyphenylalanine; L-α-propyl-β-3,4-dihydroxyphenylalanine; L-α-butyl-β-3,4-dihydroxyphenylalanine; L-α-methyl-β-2,3-dihydroxphenylalanine; L-α-ethyl-β-2,3-dihydroxphenylalanine; L-α-propyl-β-2,3-dihydroxphenylalanine; L-α-butyl-β-2,3-dihydroxphenylalanine; L-α-methyl-4-chloro-2,3-dihydroxyphenylalanine; L-α-ethyl-4-chloro-2,3-dihydroxyphenylalanine; L-α-propyl-4-chloro-2,3-dihydroxyphenylalanine; L-α-butyl-4-chloro-2,3-dihydroxyphenylalanine; L-α-ethyl-β-4-methyl-2,3-dihydroxyphenylalanine; L-α-methyl-β-4-methyl-2,3-dihydroxyphenylalanine; L-α-propyl-β-4-methyl-2,3-dihydroxyphenylalanine; L-α-butyl-β-4-methyl-2,3-dihydroxyphenylalanine; L-α-methyl-β-4-fluoro-2,3-dihydroxyphenylalanine; L-α-ethyl-β-4-fluoro-2,3-dihydroxyphenylalanine; L-α-propyl-β-4-fluoro-2,3-dihydroxyphenylalanine;L-α-butyl-β-4-fluoro-2,3-dihydroxyphenylalanine; L-α-methyl-β-4-trifluoromethyl-2,3-dihydroxyphenylalanine L-α-ethyl-β-4-trifluoromethyl-2,3-dihydroxyphenyl alanine L-α-propyl-β-4-trifluoromethyl-2,3-dihydroxyphenylalanine L-α-butyl-β-4-trifluoromethyl-2,3-dihydroxyphenyl alanine L-α-methyl-β-3,5-dihydroxyphenylalanine; L-α-ethyl-β-3,5-dihydroxyphenylalanine; L-α-propyl-β-3,5-dihydroxyphenylalanine; L-α-butyl-β-3,5-dihydroxyphenylalanine; L-α-methyl-β-4-chloro-3,5-dihydroxphenylalanine; L-α-ethyl-β-4-chloro-3,5-dihydroxphenylalanine; L-α-propyl-β-4-chloro-3,5-dihydroxphenylalanine; L-α-butyl-β-4-chloro-3,5-dihydroxphenylalanine; L-α-methyl-β-4-fluoro-3,5-dihydroxyphenylalanine; L-α-ethyl-β-4-fluoro-3,5-dihydroxyphenylalanine; L-propyl-β-4-fluoro-3,5-dihydroxyphenylalanine; L-butyl-β-4-fluoro-3,5-dihydroxyphenylalanine; L-methyl-β-4-tri fluoromethyl-3,5-dihydroxyphenyl alanine; L-α-ethyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine; L-α-propyl-β-4-trifluoromethyl-3,5-dihydroxyphenylalanine; L-α-butyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine; L-α-methyl-2,5-dihydroxphenylalanine; L-α-ethyl-2,5-dihydroxphenylalanine; L-α-propyl-2,5-dihydroxphenylalanine; L-α-butyl-2,5-dihydroxphenylalanine; L-α-methyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-ethyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-propyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-butyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-methyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-ethyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-propyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-butyl-β-4-chloro-2,5-dihydroxyphenylalanine; L-α-methyl-β-methyl-2,5-dihydroxyphenylalanine; L-α-ethyl-β-methyl-2,5-dihydroxyphenylalanine; L-α-propyl-β-methyl-2,5-dihydroxyphenylalanine; L-α-butyl-β-methyl-2,5-dihydroxyphenylalanine; L-α-methyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine; L-α-ethyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine; L-α-propyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine; L-α-butyl-β-4-trifluoromethyl-2,5-dihydroxyphenyl alanine; L-α-methyl-β-3,4,5-trihydroxyphenylalanine; L-α-ethyl-β-3,4,5-trihydroxyphenylalanine; L-α-propyl-β-3,4,5-trihydroxyphenylalanine; L-α-butyl-β-3,4,5-trihydroxyphenylalanine; L-α-methyl-β-2,3,4-trihydroxyphenylalanine; L-α-ethyl-β-2,3,4-trihydroxyphenylalanine; L-α-propyl-β-2,3,4-trihydroxyphenylalanine; L-α-butyl-β-2,3,4-trihydroxyphenylalanine; L-α-methyl-β-2,4,5-trihydroxyphenylalanine; L-α-ethyl-β-2,4,5-trihydroxyphenylalanine; L-α-propyl-β-2,4,5-trihydroxyphenylalanine; L-α-butyl-β-2,4,5-trihydroxyphenylalanine; L-phenylalanine; D,L-a-methylphenylalanine; D,L-3-iodophenylalanine; D,L-3-iodo-a-methylphenylalanine; 3-iodotyrosine; 3,5-diiodotyrosine; L-a-methylphenylalanine; D,L-α-methyl-β-(4-hydroxy-3-methylphenyl)alanine; D,L-α-methyl-β-(4-methoxy-3-benzylphenyl)alanine; D,L-α-methyl-β-(4-hydroxy-3-benzylphenyl)alanine; D,L-α-methyl-β-(4-methoxy-3-cyclohexylphenyl)alanine; D,L-α-methyl-β-(4-hydroxy-3-cyclohexylphenyl)alanine; D,L-α-methyl-β-(4-methoxy-3-methylphenyl)alanine; D,L-α-methyl-β-(4-hydroxy-3-methylphenyl)alanine; N,O-dibenzyloxycarbonyl-D,L-α-methyl-β-(4-hydroxy-3 methylphenyl)alanine; N,O-dibenzyloxycarbonyl-D,L-α-methyl-β-(4-hydroxy-3 methylphenyl)alanine amide; D,L-α-methyl-β-(4-hydroxy-3-methylphenyl)alanine amide; N,O-diacetyl-D,L-α-methyl-β-(4-hydroxy-3-methyl-phenyl)alanine; D,L-N-acetyl-α-methyl-β-(4-hydroxy-3-methylphenyl)alanine; L-3,4-dihydroxy-a-methylphenylalanine; L-4-hydroxy-3-methoxy-a-methylphenylalanine; L-3,4-methylene-dioxy-a-methylphenylalanine; 2-vinyl-2-amino-3-(2-methoxyphenyl)propionic acid; 2-vinyl-2-amino-3-(2,5-dimethoxyphenyl)propionic acid; 2-vinyl-2-amino-3-(2-imidazolyl)propionic acid; 2-vinyl-2-amino-3-(2-methoxyphenyl)propionic acid ethyl ester; α-methyl-β-(2,5-dimethoxyphenyl)alanine; α-methyl-β-(2,5-dihydroxyphenyl)alanine; α-ethyl-β-(2,5-dimethoxyphenyl)alanine; α-ethyl-β-(2,5-dihydroxyphenyl)alanine; α-methyl-β-(2,4-dimethoxyphenyl)alanine; α-methyl-β-(2,4-dihydroxyphenyl)alanine; α-ethyl-β-(2,4-dimethoxyphenyl)alanine; α-ethyl-β-(2,4-dihydroxyphenyl)alanine; α-methyl-β-(2,5-dimethoxyphenyl)alanine ethyl ester; 2-ethynyl-2-amino-3-(3-indolyl)propionic acid; 2-ethynyl-2,3-(2-methoxyphenyl)propionic acid; 2-ethynyl-2,3-(5-hydroxyindol-3-yl)propionic acid; 2-ethynyl-2-amino-3-(2,5-dimethoxyphenyl)propionic acid; 2-ethynyl-2-amino-3-(2-imidazolyl)propionic acid; 2-ethynyl-2-amino-3-(2-methoxyphenyl)propionic acid ethyl ester; 3-carbomethoxy-3-(4-benzyloxybenzyl)-3-aminoprop-1-yne; α-ethynyltyrosine hydrochloride; α-ethynyltyrosine; α-ethynyl-m-tyrosine; α-ethynyl-β-(2-methoxyphenyl)alanine; α-ethynyl-β-(2,5-dimethoxyphenyl)alanine; and α-ethynylhistidine.

7. Conjugate of claim 5 wherein at least one of R10, R11 and R12 is selected from hydroxy, alkoxy, aryloxy, aralkoxy and alkoxycarbonyl; or a pharmaceutically-acceptable salt thereof.

8. Conjugate of claim 7 wherein said inhibitor compound is selected from the group consisting of α-methyl-3-(pyrrol-1-yl)tyrosine; α-methyl-3-(4-trifluoromethylthiazol-2-yl)tyrosine; 3-(imidazol-2-yl)-b-methyltyrosine; L-α-methyl-m-tyrosine; L-α-ethyl-m-tyrosine; L-α-propyl-m-tyrosine; L-butyl-m-tyrosine; L-α-methyl-p-chloro-m-tyrosine; L-α-ethyl-p-chloro-m-tyrosine; L-α-butyl-p-chloro-m-tyrosine; L-α-methyl-p-bromo-m-tyrosine; L-α-ethyl-p-bromo-m-tyrosine; L-α-butyl-p-bromo-m-tyrosine; L-α-methyl-p-fluoro-m-tyrosine; L-α-methyl-p-iodo-m-tyrosine; L-α-ethyl-p-iodo-m-tyrosine; L-α-methyl-p-methyl-m-tyrosine; L-α-methyl-p-ethyl-m-tyrosine; L-α-ethyl-p-ethyl-m-tyrosine; L-α-ethyl-p-methyl-m-tyrosine; L-α-methyl-p-butyl-m-tyrosine; L-α-methyl-p-trifluoromethyl-m-tyrosine; L-3-iodotyrosine; L-3-chlorotyrosine; L-3,5-diiodotyrosine; L-a-methyltyrosine; D,L-a-methyltyrosine; D,L-3-iodo-a-methyltyrosine; L-3-bromo-a-methyltyrosine; D,L-3-bromo-a-methyltyrosine; L-3-chloro-a-methyltyrosine; D,L-3-chloro-a-methyltyrosine; and 2-vinyl-2-amino-3-(4-hydroxyphenyl)propionic acid.

9. Conjugate of claim 4 wherein said inhibitor compound is of the formula

10. Conjugate of claim 9 wherein at least one of R10, R11 and R12 is selected from hydroxy, alkoxy, aryloxy, aralkoxy and alkoxycarbonyl; or a pharmaceutically-acceptable salt thereof.

11. Conjugate of claim 10 wherein said inhibitor compound is selected from the group consisting of methyl(+)-2-(4-hydroxyphenyl)glycinate; isopropyl and 3-methyl butyl esters of (+)-2-(4-hydroxyphenyl)glycine; (+)-2-(4-hydroxyphenyl)glycine; 2-(4-hydroxyphenyl)glycine; (+)-2-(4-methoxyphenylglycine; and (+)-2-(4-hydroxyphenyl)glycinamide.

12. Conjugate of claim 4 wherein said inhibitor compound is of the formula

13. Conjugate of claim 12 wherein said inhibitor compound is selected from the group consisting of L-α-methyltryptophan; D,L-5-methyltryptophan; D,L-5-chlorotryptophan; D,L-5-bromotryptophan; D,L-5-iodotryptophan; L-5-hydroxytryptophan; D,L-5-hydroxy-a-methyltryptophan; α-ethynyltryptophan; 5-Methoxymethoxy-α-ethynyltryptophan; and 5-Hydroxy-α-ethynyltryptophan.

14. Conjugate of claim 4 wherein A is

15. Conjugate of claim 14 wherein said inhibitor compound is selected from the group consisting of 2-vinyl-2-amino-5-aminopentanoic acid and 2-ethynyl-2-amino-5-aminopentanoic acid.

16. Conjugate of claim 4 wherein said inhibitor compound is of the formula

17. Conjugate of claim 16 wherein said inhibitor compound is benzoctamine.

18. Conjugate of claim 3 wherein said inhibitor compound is a dopa-decarboxylase inhibitor of the formula

19. Conjugate of claim 18 wherein each of R36 through R42 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, aminomethyl, carboxyalkoxy and formyl; wherein n is a whole number from one through three; wherein each of R43 and R44 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl and alkanoyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl; or a pharmaceutically-acceptable salt thereof.

20. Conjugate of claim 19 wherein each of R36 through R42 is independently selected from hydrido, hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, cyanoamino, cyano, minomethyl, carboxyl, carboxyalkoxy and formyl; wherein n is one or two; wherein each of R43 and R44 is independently selected from hydrido, alkyl, benzyl, phenyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl and alkanoyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl; or a pharmaceutically-acceptable salt thereof.

21. Conjugate of claim 20 wherein each of R36 through R42 is independently selected from hydrido, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein n is one or two; wherein each of R43 and R44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl; or a pharmaceutically-acceptable salt thereof.

22. Conjugate of claim 21 wherein each of R36 and R42 is hydrido and n is one; wherein each of R33 through R42 is independently selected from hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein each of R43 and R44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl; and wherein any R43 and R44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl; or a pharmaceutically-acceptable salt thereof.

23. Conjugate of claim 22 wherein said inhibitor compound is selected from (2,3,4-trihydroxy)benzylhydrazine; 1-(D,L-seryl-2-(2,3,4-trihydroxybenzyl)hydrazine; and l-(3-hydroxyl-benzyl)-1-methylhydrazine.

24. Conjugate of claim 21 wherein each of R36 and R37 is independently selected from hydrido, alkyl and amino and n is two; wherein each of R38 through R42 is independently selected from hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein each of R43 and R44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl; or a pharmaceutically-acceptable salt thereof.

25. Conjugate of claim 24 wherein said inhibitor compound is selected from 2-hydrazino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid; α-(monofluoromethyl) dopa; α-(difluoromethyl) dopa; and α-methyldopa.

26. Conjugate of claim 3 wherein said inhibitor compound is a dopa-decarboxylase inhibitor of the formula

27. Conjugate of claim 26 wherein each of R45 through R43 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, aminomethyl, carboxyalkoxy and formyl; wherein each of R49 and R50 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkyl and alkanoyl and

28. Conjugate of claim 27 wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, cyanoamino, cyano, aminomethyl, carboxyalkoxy and formyl; wherein each of R49 and R50 is independently selected from hydrido, alkyl, benzyl, phenyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkyl and alkanoyl and

29. Conjugate of claim 28 wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl aminomethyl, carboxyalkoxy and formyl; wherein each of R49 and R50 is independently selected from hydrido alkyl, amino, monoalkylamino, carboxyalkyl and

30. Conjugate of claim 29 wherein each of R45 through R48 is independently selected from hydrido, hydroxy, alkyl, alkoxy and hydroxyalkyl; wherein each of R49 and R50 is independently selected from alkyl, amino, monoalkylamino, and

31. Conjugate of claim 30 wherein said inhibitor compound is selected from endo-2-amino-1,2,3,4-tetrahydro-1,4-ethanonaphthalene2-carboxylic acid; ethyl-endo-2-amino-1,2,3,4-tetrahydro-1,4-ethanonaphthalene-2-carboxylate hydrochloride; exo-2-amino-1,2,3,4-tetrahydro-1,4-ethanonaphthalene2-carboxylic acid; and ethyl-exo-2-amino-1,2,3,4-tetrahydro-1,4-ethanonaphthalene-2-carboxylate hydrochloride.

32. Conjugate of claim 3 wherein said inhibitor compound is a dopa-decarboxylase inhibitor selected from 2,3-dibromo-4,4-bis(4-ethylphenyl)-2-butenoic acid; 3-bromo-4-(4-methoxyphenyl)-4-oxo-2-butenoic acid; N-(5′-phosphopyridoxyl)-L-3,4-dihydroxyphenylalanine; N-(5′-phosphopyridoxyl)-L-m-aminotyrosine; D,L-b-(3,4-dihydroxyphenyl)lactate; D,L-b-(5-hydroxyindolyl-3)lactate; 2,4-dihydroxy-5-(1-oxo-2-propenyl)benzoic acid; 2,4-dimethoxy-5-[1-oxo-3-(2,3,4-trimethoxyphenyl-2 propenyl]benzoic acid; 2,4-dihydroxy-5-[1-oxo-3-(2-thienyl)-2-propenyl] benzoic acid; 2,4-dihydroxy-5-[3-(4-hydroxyphenyl)-1-oxo-2-propenyl] benzoic acid; 5-[3-(4-chlorophenyl)-1-oxo-2-propenyl]-2,4-dihydroxy benzoic acid; 2,4-dihydroxy-5-(1-oxo-3-phenyl-2-propenyl)benzoic acid; 2,4-dimethoxy-5-[1-oxo-3-(4-pyridinyl)-2-propenyl] benzoic acid; 5-[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-2,4 dimethoxy benzoic acid; 2,4-dimethoxy-5-(1-oxo-3-phenyl-2-propenyl)benzoic acid; 5-[3-(2-furanyl)-1-oxo-2-propenyl]-2,4-dimethoxy benzoic acid; 2,4-dimethoxy-5-[1-oxo-3-(2-thienyl)-2-propenyl] benzoic acid; 2,4-dimethoxy-5-[3-(4-methoxyphenyl)-1-oxo-2-propenyl] benzoic acid; 5-[3-(4-chlorophenyl)-1-oxo-2-propenyl]-2,4-dimethoxy benzoic acid; and 5-[3-[4-(dimethylamino)phenyl]-1-oxo-2-propenyl]-2,4 dimethoxy benzoic acid.

33. Conjugate of claim 3 wherein said inhibitor compound is a dopa-decarboxylase inhibitor of th formula:

34. Conjugate of claim 33 wherein R52 is OR64 wherein R64 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, benzyl and phenyl; wherein each of R53, R54 and R57 through R63 is independently selected from hydrido, alkyl, cycloalkyl, hydroxy, alkoxy, benzyl and phenyl; wherein each of R55 and R56 is independently selected from hydrido, alkyl, cycloalkyl, benzyl and phenyl; wherein each of m and n is a number independently selected from zero through three, inclusive; or a pharmaceutically-acceptable salt thereof.

35. Conjugate of claim 34 wherein R52 is OR64 wherein R64 is selected from hydrido and lower alkyl; wherein each of R53 through R58 is hydrido; wherein each of R59 through R63 is independently selected from hydrido, alkyl, hydroxy and alkoxy, with the proviso that two of the R59 through R63 substituents are hydroxy; wherein each of m and n is a number independently selected from zero through two, inclusive; or a pharmaceutically-acceptable salt thereof.

36. Conjugate of claim 35 which is 3-(3,4-dihydroxyphenyl)-2-propenoic acid.

37. Conjugate of claim 26 wherein said dopa-decarboxylase inhibitor is a compound selected from amino-haloalkyl-hydroxyphenyl propionic acids; alpha-halomethyl-phenylalanine derivatives; and indole-substituted halomethylamino acids.

38. Conjugate of claim 26 wherein said dopa-decarboxylase inhibitor is a compound selected from isoflavone extracts from fungi and streptomyces; sulfinyl substituted dopa and tyrosine derivatives; hydroxycoumarin derivatives; 1-benzylcyclobutenyl alkyl carbamate derivatives; aryl/thienyl-hydroxylamine derivatives; and b-2-substituted-cyclohepta-pyrrol-8 1H-on-7-yl alanine derivatives.

39. Conjugate of claim 3 wherein said dopamine-β-hydroxylase inhibitor compound is of the formula

40. Conjugate of claim 39 wherein B is an ethylenic or an acetylenic moiety substituted with an aryl or heteroaryl radical; and wherein n is a number from one through three; or a pharmaceutically-acceptable salt thereof.

41. Conjugate of claim 39 wherein B is an ethylenic or acetylenic moiety incorporating carbon atoms in the beta- and gamma-positions relative to the nitrogen atom; and wherein n is one; or a pharmaceutically-acceptable salt thereof.

42. Conjugate of claim 41 wherein said ethylenic or acetylenic moiety is substituted at the gamma carbon with an aryl or heteroaryl radical; or a pharmaceutically-acceptable salt thereof.

43. Conjugate of claim 42 wherein said aryl radical is selected from phenyl, 2-thiophene, 3-thiophene, 2-furanyl, 3-furanyl, oxazolyl, thiazolyl and isoxazolyl, any one of which radicals may be substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cyano, alkoxy, alkoxyalkyl and cycloalkyl; or a pharmaceutically-acceptable salt thereof.

44. Conjugate of claim 43 wherein said aryl radical is selected from phenyl, hydroxyphenyl, 2-thiophene and 2-furanyl; and wherein each of R67, R68 and R69 is hydrido; or a pharmaceutically-acceptable salt thereof.

45. Conjugate of claim 44 wherein said inhibitor compound is selected from the group consisting of 3-amino-2-(2′-thienyl)propene; 3-amino-2-(2′-thienyl)butene; 3-(N-methylamino)-2-(2′-thienyl) propene; 3-amino-2-(3′-thienyl)propene; 3-amino-2-(2′-furanyl)propene; 3-amino-2-(3′-furanyl)propene; 1-phenyl-3-aminopropyne; and 3-amino-2-phenylpropene.

46. Conjugate of claim 44 wherein said inhibitor compound is selected from the group consisting of (±)4-amino-3-phenyl-1-butyne; (±)4-amino-3-(3′-hydroxyphenyl)-1-butyne; (±)4-amino-3-(4′-hydroxyphenyl)-1-butyne; (±)4-amino-3-phenyl-1-butene; (±)4-amino-3-(3′-hydroxyphenyl)-1-butene; and (±)4-amino-3-(4′-hydroxyphenyl)-1-butene.

47. Conjugate of claim 3 wherein said inhibitor compound is of the formula

48. Conjugate of claim 47 wherein W is heteroaryl and Y is

49. Conjugate of claim 48 wherein R70 is selected from hydrido, alkyl, amino and monoalkylamino; wherein each of R71 and R72 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number indpendently selected from two through four, inclusive; or a pharmaceutically-acceptable salt thereof.

50. Conjugate of claim 49 wherein R70 is selected from hydrido, alkyl and amino; wherein each of R71 and R72 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three; or a pharmaceutically-acceptable salt thereof.

51. Conjugate of claim 50 wherein R70 is hydrido; wherein each of R71 and R72 is hydrido; and wherein each of p and q is two; or a pharmaceutically-acceptable salt thereof.

52. Conjugate of claim 3 wherein said inhibitor compound is of the formula

53. Conjugate of claim 3 wherein said dopamine-β-hydroxylase inhibitor compound is of the formula

54. Conjugate of claim 53 wherein each of R82 through R85 is independently selected from hydrido, alkyl and haloalkyl; wherein Y is selected from oxygen atom or nitrogen atom; wherein each of R79, R80 and R81 is independently hydrido and alkyl; and wherein m is a number selected from one through four, inclusive; or a pharmaceutically-acceptable salt thereof.

55. Conjugate of claim 54 wherein said inhibitor compound is selected from aminomethyl-5-n-butylthiopicolinate; aminomethyl-5-n-butylpicolinate; 2′-aminoethyl-5-n-butylthiopicolinate; 2′-aminoethyl-5-n-butylpicolinate; (2′-amino-1′,1′-dimethyl)ethyl-5-n-butylthiopicolinate; (2′-amino-1′,1′-dimethyl)ethyl-5-n-butylpicolinate; (2′-amino-1′-methyl)ethyl-5-n-butylthiopicolinate; (2 1-amino-1′-methyl)ethyl-5-n-butylpicolinate; 3′-aminopropyl-5-n-butylthiopicolinate; 3′-aminopropyl-5-n-butylpicolinate; (2′-amino-2′-methyl)propyl-5-n-butylthiopicolinate; (2′-amino-2′-methyl)propyl-5-n-butylpicolinate; (3′-amino-1′,1′-dimethyl)propyl-5-n-butylthiopicolinate; (3′-amino-1′,1′-dimethyl)propyl-5-n-butylpicolinate; (3′-amino-2′,2′-dimethyl)propyl-5-n-butylthiopicolinate; (3′-amino-2′,2′-dimethyl)propyl-5-n-butylpicolinate; 2′-aminopropyl-5-n-butylthiopicolinate; 2′-aminopropyl-5-n-butylpicolinate; 4′-aminobutyl-5-n-butylthiopicolinate; 4′-amino-3′-methyl)butyl-5-n-butylthiopicolinate; (3′-amino-3′-methyl)butyl-5-n-butylthiopicolinate; and (3′-amino-3′-methyl)butyl-5-n-butylpicolinate.

56. Conjugate of claim 47 wherein said inhibitor compound is of the formula

57. Conjugate of claim 56 wherein each of R86, R87 and R90 through R93 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein r is a number selected from zero through four, inclusive; wherein each of R88 and R89 is independently selected from hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl; or a pharmaceutically-acceptable salt thereof.

58. Conjugate of claim 57 wherein each of R86, R87 and R90 through R93 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein r is anumber selected from zero through three, inclusive; and wherein each of R88 and R89 is selected from hydrido, alkyl, amino and monoalkylamino; or a pharmaceutically-acceptable salt thereof.

59. Conjugate of claim 58 wherein each of R90 through R93 is independently selected from hydrido and alkyl; wherein each of R86 and R87 is hydrido; wherein r is selected from zero, one and two; wherein R88 is selected from hydrido, alkyl and amino; and wherein R89 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof.

60. Conjugate of claim 59 wherein said inhibitor compound is 5-n-butylpicolinic acid hydrazide.

61. Conjugate of claim 3 wherein said dopamine-β-hydroxylase inhibitor compound is of the formula

62. Conjugate of claim 61 wherein said inhibitor compound is of the formula

63. Conjugate of claim 62 wherein said inhibitor compound is selected from 5-n-butylpicolinic acid; 5-ethylpicolinic acid; lcollnlc acId; 5-nitropicolinic acid; 5-aminopicolinic acid; 5-N-acetylaminopicolinic acid; 5-N-propionylaminopicolinic acid; 5-N-hydroxyaminopicolinic acid; 5-iodopicolinic acid; 5-bromopicolinic acid; 5-chloropicolinic acid; 5-hydroxypicolinic acid 5-methoxypicolinic acid; 5-N-propoxypicolinic acid; 5-N-butoxypicolinic acid; 5-cyanopicolinic acid; 5-carboxylpicolinic acid; 5-n-butyl-4-nitropicolinic acid; 5-n-butyl-4-methoxypicolinic acid; 5-n-butyl-4-ethoxypicolinic acid; 5-n-butyl-4-aminopicolinic acid; 5-n-butyl-4-hydroxyaminopicolinic acid; and 5-n-butyl-4-methylpicolinic acid.

64. Conjugate of claim 63 wherein said inhibitor compound is 5-n-butylpicolinic acid.

65. Conjugate of claim 3 wherein said dopamine-β-hydroxylase inhibitor compound is of the formula

66. Conjugate of claim 65 wherein R105is selected from hydroxy and lower alkoxy; wherein R106 is hydrido; wherein R107 is selected from hydrido and lower alkyl; wherein R108 is hydrido; wherein R109 is selected from hydrido and

67. Conjugate of claim 66 wherein said inhibitor compound is of the formula

68. Conjugate of claim 67 wherein R111 is hydroxy; wherein R107 is hydrido or methyl; wherein R109 is hydrido or acetyl; and wherein n is a number from zero to two, inclusive; or a pharmaceutically-acceptable salt thereof.

69. Conjugate of claim 68 wherein said inhibitor compound is 1-(3-mercapto-2-methyl-loxopropyl)-L-proline.

70. Conjugate of claim 3 wherein said dopamine-β-hydroxylase inhibitor compound is of the formula

71. Conjugate of claim 70 wherein R112 is selected from mercapto and alkylthio; wherein each of R113 and R114 is independently selected from hydrido, amino, aminoalkyl, monoalkylamino, monoalkylaminoalkyl, carboxyl and carboxyalkyl; wherein each of R115 and R119 is hydrido; and wherein each of R116, R117 and R118 is independently selected from hydrido, hydroxy, alkyl, halo and haloalkyl; or a pharmaceutically-acceptable salt thereof.

72. Conjugate of claim 71 wherein R112 is selected from amino, aminoalkyl, monoalkylamino, monoalkylaminoalkyl, carboxy and carboxyalkyl; wherein each of R113, R114, R115 and R119 is hydrido; and wherein each of R116, R117 and R118 is independently selected from hydrido, hydroxy, alkyl, halo and haloalkyl; or a pharmaceutically-acceptable salt thereof.

73. Conjugate of claim 2 wherein said precursor compound providing the second residue has a reactable acid moiety.

74. Conjugate of claim 73 wherein said second residue precursor compound of said conjugate is selected from a class of glutamic acid derivatives of the formula

75. Conjugate of claim 74 wherein R110 wherein each G is hydroxy; wherein R150 is hydrido; and wherein R151 is selected from

76. Conjugate of claim 2 wherein said first and second residues are connected through a cleavable bond provided by a linker group between said first and second residues.

77. Conjugate of claim 76 wherein said linker group is selected from a class of diamino-terminated linker groups of the formula

78. Conjugate of claim 77 wherein each of R200 and R201 is hydrido; and wherein n is zero.

79. Conjugate of claim 76 wherein said linker group is selected from diamino terminal linker groups of the formula

80. Conjugate of claim 79 wherein said linker group is of the formula

81. Conjugate of claim 80 wherein said linker group is selected from divalent radicals wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from two through four, inclusive.

82. Conjugate of claim 81 wherein each of R202 and R203 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three.

83. Conjugate of claim 82 wherein each of R202 and R203 is hydrido; and wherein each of p and q is two.

84. Conjugate of claim 76 wherein said linker group is selected from diamino terminal linker groups of the formula

85. Conjugate of claim 84 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p is two or three.

86. Conjugate of claim 86 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido and alkyl; and wherein p is two.

87. Conjugate of claim 86 wherein each of R214 through R217 is hydrido; and wherein p is two.

88. Conjugate of claim 3 selected from the group consisting of 4-amino-4-carboxy-1-oxobutyl-α-methyl-L-tyrosine, methyl ester; N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-α-methyl-L-tyrosine, methyl ester; N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-α-methyl-L-tyrosine; 4-amino-4-carboxy-1-oxobutyl-3-hydroxy-α-methyl-L-tyrosine, methyl ester; N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine, methyl ester; N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine; L-glutamic acid, 5-{[(5-butyl-2-pyridinyl)carbonyl]hydrazide}; N-acetyl-L-glutamic acid, 5-[(5-butyl-2-pyridinyl)-carbonyl]hydrazide; N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine; N2-acetyl-N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine; 2-amino-5-[4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid; 2-(acetylamino)-5-(4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid; and N2-acetyl-N-[2-[[5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine, ethyl ester.

89. Conjugate of claim 8 which comprises a first residue provided by a tyrosine hydroxylase inhibitor compound and a second residue provided by a gamma glutamic acid derivative.

90. Conjugate of claim 89 which is 4-amino-4-carboxy-1-oxobutyl-α-methyl-L-tyrosine, methyl ester.

91. Conjugate of claim 89 which is N-[4-(acetylamino)-4-carboxy-1-oxobutyl)-α-methyl-L-tyrosine, methyl ester.

92. Conjugate of claim 89 which is N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-α-methyl-L-tyrosine; 4-amino-4-carboxy-1-oxobutyl-3-hydroxy-α-methyl-L-tyrosine, methyl ester.

93. Conjugate of claim 25 which comprises a first residue provided by a dopa-decarboxylase inhibitor compound and a second residue provided by a gamma glutamic acid derivative.

94. Conjugate of claim 93 which is 4-amino-4-carboxy-1-oxobutyl-3-hydroxy-α-methyl-L-tyrosine, methyl ester.

95. Conjugate of claim 93 which is N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine, methyl ester.

96. Conjugate of claim 93 which is N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine.

97. Conjugate of claim 64 which comprises a first residue provided by a dopamine-β-hydroxylase inhibitor compound and a second residue provided by a gamma glutamic acid derivative.

98. Conjugate of claim 97 which is L-glutamic acid, 5-{[(5-butyl-2-pyridinyl)carbonyl]hydrazide}.

99. Conjugate of claim 97 which is N-acetyl-L-glutamic acid, 5-[(5-butyl-2-pyridinyl)-carbonyl]hydrazide.

100. Conjugate of claim 97 which is N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine.

101. Conjugate of claim 97 which is N2-acetyl-N-[2-[[(5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine.

102. Conjugate of claim 97 which is 2-amino-5-[4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid.

103. Conjugate of claim 97 which is 2-(acetylamino)-5-(4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid.

104. Conjugate of claim 97 which is N2-acetyl-N-[2-[[5-butyl-2-pyridinyl)carbonyl]amino]ethyl]-L-glutamine, ethyl ester.

105. A pharmaceutical composition comprising one or more pharmaceutically-acceptable carriers or diluents and a therapeutically-effective amount of a conjugate of claim 1.

106. A method for treating a hypertensive-related disorder or a sodium-retaining disorder, said method comprising administering to a patient afflicted with or susceptible to said disorder a therapeutically-effective amount of a conjugate of claim 1.

107. The method of claim 106 wherein said hypertensive-related disorder is chronic hypertension.

108. The method of claim 106 wherein said sodium-retaining disorder is congestive heart failure.

109. The method of claim 106 wherein said sodium-retaining disorder is cirrhosis.

110. The method of claim 106 wherein said sodium-retaining disorder is nephrosis.