WO1992001667A1 - Renal-selective prodrugs for control of renal sympathetic nerve activity in the treatment of hypertension - Google Patents

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

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Publication number
WO1992001667A1
WO1992001667A1 PCT/US1991/000611 US9100611W WO9201667A1 WO 1992001667 A1 WO1992001667 A1 WO 1992001667A1 US 9100611 W US9100611 W US 9100611W WO 9201667 A1 WO9201667 A1 WO 9201667A1
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WIPO (PCT)
Prior art keywords
amino
hydrido
methyl
alkyl
conjugate
Prior art date
Application number
PCT/US1991/000611
Other languages
French (fr)
Inventor
David B. Reitz
John P. Koepke
Edward H. Blaine
Joseph R. Schuh
Robert E. Manning
Glenn J. Smits
Original Assignee
G.D. Searle & Co.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US1990/004168 external-priority patent/WO1991001724A1/en
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Publication of WO1992001667A1 publication Critical patent/WO1992001667A1/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/66—Nitrogen atoms not forming part of a nitro radical

Definitions

  • 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.
  • 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)].
  • stimulation of the renal sympathetic nervous system can affect renal function and maintenance of homeostasis.
  • 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.
  • 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)].
  • 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.
  • activity to the kidneys may be an effective therapeutic treatment for chronic sodium-retaining disorders, such as hypertension, congestive heart failure, cirrhosis, and nephrosis.
  • catecholamine cascade the pathway involved in synthesis of the neurotransmitter norepinephrine. Stepwise, these catecholamines are
  • norepinephrine by the enzyme dopamine- ⁇ -hydroxylase.
  • the compound ⁇ -methyltyrosine inhibits the action of the enzyme tyrosine hydroxylase.
  • ⁇ -methyldopa inhibits the action of the enzyme dopadecarboxylase
  • the compound fusaric acid inhibits the action of dopamine- ⁇ -hydroxylase.
  • Such inhibitor compounds often cannot be administered systemically because of the adverse side effects induced by such compounds.
  • the desired therapeutic effects of dopamine- ⁇ -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.
  • 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.
  • Renal targetted prodrugs are known for delivery of a drug selectively to the kidney.
  • the compound L- ⁇ -glutamyl amide of dopamine when administered to dogs was reported to generate dopamine in vivo by specific enzymatic cleavage by ⁇ -glutamyl transpeptidase [J. J. Kyncl et al, Adv. Biosc., 20, 369-380 (1979)].
  • ⁇ -glutamyl and N-acyl- ⁇ -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 ⁇ -glutamyl transpeptidase [M. Orlowski et al, J. Pharmacol. Exp.
  • vasodilator 2-hydrazino-5-g-butylpyridine which stimulates guanylate cyclase activity
  • a prodrug which provided selective renal vasodilation
  • the dopamine prodrug ⁇ -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.
  • 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.
  • Figure 1 shows the acute effects of i .v.
  • Figure 3 shows the chronic effects of i.v.
  • Example #464 conjugate on mean arterial pressure in spontaneously hypertensive rats.
  • Figure 4 shows time-dependent formation of the dopamine- ⁇ -hydroxylase inhibitor fusaric acid from the Example #859 conjugate incubated with rat kidney
  • Figure 5 shows time-dependent formation of fusaric acid from the Example #859 conjugate incubated with a mixture of purified acylase I and gamma-glutamyl
  • Figure 6 shows the concentration-dependent effect of fusaric acid and the Example #859 conjugate on norepinephrine production by dopamine- ⁇ -hydroxylase in vitro.
  • Figure 7 shows dopamine- ⁇ -hydroxylase inhibition in vitro by fusaric acid, the Example #859 conjugate and possible metabolites at a concentration of 20 ⁇ M.
  • Figure 8 shows the acute effects of i.v.
  • Figure 9 shows the acute effects of i.v.
  • Figure 10 shows the effects of chronic i.v.
  • Figure 11 shows the effects of chronic i.v.
  • Figure 12 shows the heart tissue concentrations of norepinephrine following the 5 day infusion experiment described in Figure 10.
  • Figure 13 shows the kidney tissue concentrations of norepinephrine following the 5 day infusion experiment described in Figure 10.
  • Figure 14 shows the effects of Example #859 conjugate on mean arterial pressure in anesthetized dogs after i.v. injection at three doses, plus vehicle.
  • Figure 15 shows the effects of Example #859 conjugate on renal blood flow in anesthetized dogs after i.v. injection at three doses, plus vehicle.
  • Figure 16 shows the effects of Example #858 conjugate on mean arterial pressure in conscious DOCA hypertensive micropigs after i.v. infusion for three days.
  • renal-selective prodrug therapy resides in reduction or avoidance of adverse side effects
  • 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.
  • 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.
  • 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- ⁇ -hydroxylase inhibitor compounds and mimics of any of these inhibitor compounds.
  • the inhibitor compounds described herein have been classified as tyrosine hydroxylase inhibitors, or as dopa-decarboxylase inhibitors, or as dopamine- ⁇ -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.
  • 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.
  • 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.
  • a compound which does not inhibit formation of such benzylhydroxyamine intermediate is not embraced by the definition of "inhibitor compound” as used herein.
  • benzylhydroxyamine intermediate are the compounds L-dopa and dopamine.
  • 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:
  • each of R 1 through R 3 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino,
  • R 4 selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein R 5 is selected from -OR 6 and
  • R 6 is selected from hydrido, alkyl
  • each of R 7 and R 8 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
  • cycloalkylalkyl alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino,
  • each of R 9 through R 13 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino,
  • each of R 14 through R 20 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 R 21 and R 22 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.
  • a preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula II:
  • each of R 1 and R 2 is hydrido; wherein m is one or two; wherein R 3 is selected from alkyl, alkenyl and alkynyl; wherein R 4 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and
  • R 5 is selected from -OR 6 and
  • R 6 is selected from
  • each of R 7 and R 8 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 R 9 through R 13 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxycarbonyl, alkoxycarbonyl,
  • R 6 is selected from
  • each of R 7 and R 8 independently is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; or a pharmaceutically-acceptable salt thereof.
  • hydroxylase inhibitor compounds consists of the following specific compounds within Formula II:
  • a second sub-class of preferred tyrosine hydroxylase inhibitor compounds consists of compounds wherein at least one of R 10 , R 11 and R 12 is selected from hydroxy, alkoxy, aryloxy, aralkoxy and alkoxycarbonyl. More preferred compounds of this second sub-class are
  • R 3 is selected from alkyl, alkenyl and alkynyl; wherein R 4 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;
  • R 5 is selected from OR 6 and
  • R 6 is selected from
  • each of R 7 and R 8 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 R 9 through R 13 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxycarbonyl, alkoxy, aryl
  • Formula III consists of compounds wherein at least one of R 10 , R 11 and R 12 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.
  • Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula IV:
  • each of R 1 and R 2 is hydrido; wherein m is a number selected from zero through five, inclusive; wherein R 3 is selected from alkyl, alkenyl and alkynyl; wherein R 4 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 R 14 through R 17 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy,
  • a preferred sub-class of compounds within Formula IV consists of L- ⁇ -methyltryptophan; D,L-5- methyltryptophan; D,L-5-chlorotryptophan; D,L-5- bromotryptophan; D, L-5-iodotry ⁇ tophan; L-5- hydroxytryptophan; D,L-5-hydroxy- ⁇ -methyltryptophan; ⁇ - ethynyltryptophan; 5-methoxymethoxy- ⁇ -ethynyltryptophan; and 5-hydroxy- ⁇ -ethynyltryptophan.
  • Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds wherein A is
  • R 6 is selected from
  • More preferred compounds in this class are 2-vinyl-2-amino-5-aminopentanoic acid and 2-ethynyl-2- amino-5-aminopentanoic acid.
  • Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula V:
  • each of R 23 and R 24 is independently selected from hydrido, hydroxy, alkyl, cycloakyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino,
  • R 25 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 R 26 through R 35 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alk
  • 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:
  • each of R 36 through R 42 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 R 43 and R 44 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, monoalkylcarbonylamino, alkylsulfinyl, alkylsulfonyl, aryls
  • R 43 and R 44 cannot both be carboxyl at the same time, with the further proviso that when R 36 is hydrido then R 37 cannot be carboxyl, and with the further proviso that at least one of R 43 through R 44 is a primary or secondary amino group; or a
  • a preferred class of compounds within Formula VI consists of compounds wherein each of R 36 through R 42 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxyl,
  • n is a number from one through three; wherein each of R 43 and R 44 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,
  • Formula VI consists of those compounds wherein each of R 36 through R 42 is independently selected from hydrido, hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy,
  • alkoxyalkyl haloalkyl, hydroxyalkyl, amino
  • R 4 ⁇ and R 44 is independently selected from hydrido, alkyl, benzyl, phenyl, alkoxyalkyl, haloalkyl,
  • any R 43 and R 44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbonyl.
  • An even more preferred class of compounds within Formula VI consists of those compounds wherein each of R 36 through R 42 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 R 43 and R 44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl; and wherein any R 43 and R 44 substituent having a substitutable position may be further substituted with one or more groups selected from
  • a more highly preferred class of compounds within Formula VI consists of those compounds wherein each of R 36 and R 37 is hydrido and n is one; wherein each of R 38 through R 42 is independently selected from hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein each of R 43 and R 44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl and carboxyalkyl; and wherein any R 43 and R 44 substituent having a substitutable position may be further substituted with one or more groups selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxy
  • 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.
  • Another more highly preferred class of compounds consists of those compounds wherein each of R 36 and R 37 is independently selected from hydrido, alkyl and amino and n is two; wherein each of R 38 through R 42 is independently selected from hydroxy, alkyl, alkoxy, haloalkyl,
  • each of R 43 and R 44 is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino,
  • each of R 45 through R 48 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 R 49 and R 50 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, halo
  • alkanoyl alkenyl, cycloalkenyl, alkynyl and
  • R 51 is selected from hydroxy, alkoxy,
  • R 49 and R 50 cannot both be carboxyl at the same time, and with the further proviso that at least one of R 45 through R 48 is a primary or secondary amino group or a carboxyl group; or a pharmaceutically- acceptable salt thereof.
  • a preferred class of compounds within Formula VII consists of those compounds wherein each of R 45 through R 48 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 R 49 and R 50 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino,
  • Formula VII consists of those compounds wherein each of R 45 through R 48 is independently selected from hydrido, hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy,
  • R 51 is selected from hydroxy, alkoxy, amino
  • An even more preferred class of compounds of Formula VII consists of those compounds wherein each of R 45 through R 48 is independently selected from hydrido, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl, carboxyalkyl aminomethyl, carboxyalkoxy and formyl; wherein each of R 49 and R 50 is independently selected from hydrido, alkyl, amino,
  • R 51 is selected from hydroxy, alkoxy, amino and monoalkylamino.
  • a highly preferred class of compounds within Formula VII consists of those compounds wherein each of R 45 through R 48 is independently selected from hydrido, hydroxy, alkyl, alkoxy and hydroxyalkyl; wherein each of R 49 and R 50 is independently selected from alkyl, amino, monoalkylamino, and wherein R 51 is selected from hydroxy, methoxy,
  • a more highly preferred class of compounds within Formula VII consists of those compounds wherein said inhibitor compound is selected from endo-2-amino1,2,3,4- 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-amino 1,2,3,4-tetrahydro- 1,4-ethanonaphthalene-2-carboxylic acid; and ethyl-exo-2- amino-1,2,3,4-tetrahydro-1,4-ethano-naphthalene-2- carboxylate hydrochloride.
  • Another family of specific dopa-decarboxylase inhibitor compounds consists of
  • R 52 is selected from hydrido, OR 64 and
  • R 64 is selected from
  • R 65 and R 66 is independently selected from hydrido, alkyl, alkanoyl, amino,
  • R 53 , R 54 and R 57 through R 63 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl,
  • each of R 55 and R 56 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.
  • a preferred class of compounds of Formula VIII consists of those compounds wherein R 52 is OR64 wherein R 64 is selected from hydrido, alkyl, cycloalkyl,
  • each of R 53 , R 54 and R 57 through R 63 is independently selected from hydrido, alkyl, cycloalkyl, hydroxy, alkoxy, benzyl and phenyl; wherein each of R 55 and R 56 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.
  • VIII consists of those compounds wherein R 52 is OR 64 wherein R 64 is selected from hydrido and lower alkyl;
  • each of R 53 through R 58 is hydrido; wherein each of R 59 through R 63 is independently selected from hydrido, alkyl, hydroxy and alkoxy, with the proviso that two of the R 59 through R 63 substituents are hydroxy; wherein each of m and n is a number independently selected from zero through two, inclusive.
  • a preferred compound within Formula IX is 3- (3,4-dihydroxyphenyl)-2-propenoic acid, also known as caffeic acid.
  • 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 : - amino-haloalkyl-hydroxyphenyl propionic acids, such as 2-amino-2-fluoromethyl-3hydroxy- phenylpropionic acid;
  • alpha-halomethyl-phenylalanine derivatives such as alpha-fluoroethylphenethylamine; and - indole-substituted halomethylamino acids.
  • - 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; - sulfinyl substituted dopa and tyrosine
  • Suitable dopamine- ⁇ -hydroxylase inhibitors may be generally classified mechanistically as chelating-type inhibitors, time-dependent inhibitors and competitive inhibitors.
  • a class of compounds from which a suitable dopamine- ⁇ -hydroxylase inhibitor may be selected to provide the conjugate first residue consists of time-dependent inhibitors represented by Formula IX:
  • 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
  • R 67 and R 68 are independently selected from hydrido, alkyl, alkenyl and alkynyl; wherein R 69 is
  • n is a number selected from zero through five.
  • a preferred class of compounds of Formula IX consists of those compounds wherein B is phenyl or
  • R 67 is ethenyl or ethynyl; or an acetylenic moiety substituted with an aryl or heteroaryl radical; and wherein n is a number from zero through three.
  • 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.
  • 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 R 67 , R 68 and R 69 is hydrido.
  • 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-lbutyne; ( ⁇ )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.
  • Another class of compounds from which a suitable dopamine- ⁇ -hydroxylase inhibitor may be selected to provide the conjugate first residue is represented by Formula X:
  • W is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein Y is selected from
  • R 70 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
  • each of R 71 through R 74 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
  • a preferred class of compounds within Formula X consists of compounds wherein W is heteroaryl and Y is
  • R 70 is selected from hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl; wherein each of R 71 and R 72 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino,
  • a more preferred class of compounds of Formula X consists of wherein R 70 is selected from hydrido, alkyl, amino and monoalkylamino; wherein each of R 71 and R 72 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number
  • R 70 is selected from hydrido, alkyl and amino; wherein each of R 71 and R 72 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.
  • R 70 is hydrido; wherein each of R 71 and R 72 is hydrido; and wherein each of p and q is two.
  • E is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein F is selected from.
  • Z is selected from O, S and N-R 78 ; wherein each of R 75 and R 76 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl,
  • R 75 and R 76 may form oxo or thio; wherein r is a number selected from zero through six, inclusive; wherein each of R 77 and R 78 is
  • each of R 82 through R 85 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 R 79 and R 80 is independently selected from hydrido and alkyl;
  • R 81 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.
  • a preferred family of compounds of Formula XII consists of those compounds wherein each of R 82 through R 85 is independently selected from hydrido, alkyl and
  • Y is selected from oxygen atom or sulfur atom; wherein each of R 79 , R 80 and R 81 is independently hydrido and alkyl; and wherein m is a number selected from one through four, inclusive.
  • a family of preferred specific compounds within Formula XII consists of the following compounds :
  • r is a number selected from zero through six, inclusive; wherein each of R 88 and R 89 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.
  • a more preferred class of compounds within Formula XIII consists of those compounds wherein each of R 86 , R 87 and R 90 through R 93 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 R 89 is independently selected from hydrido, alkyl, amino,
  • An even more preferred class of compounds within Formula XIII consists of those compounds wherein each of R 86 , R 87 and R 90 through R 93 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 R 88 and R 89 is selected from hydrido, alkyl, amino and monoalkylamino.
  • each of R 90 through R 93 is independently selected from hydrido and alkyl; wherein each of R 86 and R 87 is hydrido; wherein r is selected from zero, one and two; wherein R 88 is selected from hydrido, alkyl and amino; and wherein R 89 is selected from hydrido and alkyl.
  • each of R 94 through R 98 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,
  • R 100 is selected from
  • R 101 , R 102 , R 103 and R 104 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.
  • each of R 95 through R 98 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 R 100 is selected from hydrido, alkyl, phenyl and benzyl.
  • a class of specifically-preferred compounds of Formula XV consists of
  • 5-aminopicolinic acid 5-N-acetylaminopicolinic acid;
  • 5-n-butyl-4-methylpicolinic acid Especially preferred of the foregoing class of compounds of Formula XV is the compound 5-n-butylpicolinic acid (fusaric acid) shown below:
  • Another class of compounds from which a suitable dopamine- ⁇ -hydroxylase inhibitor may be selected to provide the conjugate first residue consists of azetidine-2- carboxylic acid derivatives represented by Formula XVI:
  • R 105 is hydrido, hydroxy, alkyl, amino and alkoxy; wherein R 106 is selected from hydrido, hydroxy and alkyl; wherein each of R 107 and R 108 is independently selected from hydrido, alkyl and phenalkyl; wherein R 109 is selected from hydrido and with R 110 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.
  • XVI consists of those compounds wherein R 105 is selected from hydroxy and lower alkoxy; wherein R 106 is hydrido; wherein R 107 is selected from hydrido and lower alkyl;
  • R 108 is hydrido; wherein R!09 is selected from hydrido and with R 110 selected from lower alkyl and phenyl;
  • a more preferred class of compounds within Formula XVI consists of those compounds of Formula XVII:
  • R 111 is selected from hydroxy and lower alkyl
  • R 107 is selected from hydrido and lower alkyl
  • R 109 is selected from hydrido and with R 110 selected from lower alkyl and phenyl and v is a number from zero to two, inclusive.
  • a more preferred class of compounds within Formula XVII consists of those compounds wherein R 111 is hydroxy; wherein R 107 is hydrido or methyl; wherein R 109 is hydrido or acetyl; and wherein n is a number from zero to two, inclusive.
  • each of R 112 through R 119 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.
  • a first preferred class of compounds within Formula XVIII consists of those compounds wherein R 112 is selected from mercapto and alkylthio; wherein each of R 113 and R 114 is independently selected from hydrido, amino, aminoalkyl, monoalkylamino, monoalkylaminoalkyl, carboxyl and carboxyalkyl; wherein each of R 115 and R 119 is hydrido; and wherein each of R 116 , R 117 and R 118 is independently selected from hydrido, hydroxy, alkyl, halo and haloalkyl; or a pharmaceutically-acceptable salt thereof.
  • a second preferred class of compounds within Formula XVIII consists of those compounds wherein R 112 is selected from amino, aminoalkyl, monoalkylamino,
  • 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.
  • the second component of a conjugate of the invention is provided by a residue which forms a kidneyenzyme-cleavable bond with the residue of the first-component All antagonist compound.
  • Such residue is preferably selected from a class of compounds of Formula XIX:
  • each of R 150 and R 151 may be independently selected from hydrido, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydroxyl, halo, mercapto, -OR 152 , -S R153 and with each
  • R 152 , R 153 and R 154 is independently selected from hydrido and alkyl; with the proviso that said Formula XIX compound is selected such that formation of the cleavable bond
  • Formula XIX consists of those compounds wherein each G is hydroxy; wherein R 150 is hydrido; and wherein R 151 is selected from wherein R 155 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, neopentyl, n-hexyl and chloromethyl.
  • R 155 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, neopentyl, n-hexyl and chloromethyl.
  • a most highly preferred compound of Formula XIX is
  • N-acetyl- ⁇ -glutamic acid which provides a residue for the second component of a conjugate of the invention as shown below:
  • 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.
  • 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".
  • the first component used to form a conjugate of the invention provides a first residue containing a terminal primary or secondary amino moiety.
  • terminal amino moiety are amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups such as aminomethyl, aminoethyl, aminopropyl, aminoisopropyl,
  • 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.
  • 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.
  • Suitable linker groups may be provided by a class of diamino-terminated linker groups based on hydrazine as defined by Formula XX:
  • each of R 200 and R 201 may be independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfino,
  • each of Q and T is one or more groups independently selected from
  • each of R 202 through R 205 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.
  • a preferred class of linker groups within Formula XX is defined by Formula XXII:
  • each of R 202 and R 203 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino,
  • R 202 and R 203 independently selected from one through six, inclusive; with the proviso that when each of R 202 and R 203 is selected from halo, hydroxy, amino, monoalkylamino and dialkylamino, then the carbon to which R 202 or R 203 is attached in Formula XXII is not adjacent to a nitrogen atom of Formula XXII.
  • a more preferred class of linker groups of Formula XXII consists of divalent radicals wherein each of R 202 and R 203 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number
  • linker groups wherein each of R 202 and R 203 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.
  • linker group wherein each of R 202 and R 203 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
  • each of R 214 through R 217 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,
  • a preferred class of linker groups within Formula XXIII consists of divalent radicals wherein each of R 214 and
  • R 215 is hydrido; wherein each of R 216 and R 217 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 R 214 and R 215 is hydrido; wherein each of R 216 and R 217 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.
  • hydroido 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 -CH 2 - group, that is, a "methylene” group; or as another example, one hydrido group may be attached to a carbon atom to form a trivalent group.
  • 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 .
  • cycloalkyl embraces radicals having three to ten carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl and cycloheptyl.
  • 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
  • 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.
  • 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.
  • 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.
  • aryl embraces aromatic radicals such as phenyl, naphthyl and biphenyl.
  • aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl.
  • benzyl and "phenylmethyl” are interchangeable.
  • 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.
  • sulfinyl and “sulfonyl”, whether used alone or linked to other terms, denotes respectively divalent radicals and
  • acyl whether used alone,
  • 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.
  • compositions of such conjugates including acid addition salts and base addition salts.
  • 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.
  • 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 examples 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, ⁇ -hydroxybutyric, malonic, galactaric and galacturonic acid.
  • organic acids examples of which
  • 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, megl ⁇ mine (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.
  • 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
  • optically active acid or base examples include 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.
  • 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.
  • 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 examples of the tyrosine hydroxylase inhibitors and dopa-decarboxylase inhibitors.
  • Inhibitor compounds lacking a reactive amino moiety such as the dopamine- ⁇ -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 O, 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.
  • the dopamine- ⁇ -hydroxylase inhibitor compound 5-butyl-n-butylpicolinic 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.
  • each of R 79 , R 80 , R 81 , R 86 , R 87 , R 88 , R 89 and R 115 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.
  • 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- ⁇ -hydroxylase inhibitors of Tables XII-XVII.
  • 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.
  • 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.
  • the anhydride solution was slowly added to a solution of 7.0 g (29 mmol) of the ⁇ -methyl tyrosine ester from step 1 and 18.73 g (145 mmol) of diisopropylethylamine (DIEA) in 100 mL of anhydrous DMF.
  • DIEA diisopropylethylamine
  • the reaction was allowed to stir overnight and was concentrated in vacuo.
  • the residue was dissolved in ethyl acetate, washed with cold 1M K 2 CO 3 followed by water, dried (MgSO 4 ) , 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.
  • TFA trifluoracetic acid
  • Example 2 N-[4-(acetylamino)-4-carboxy-1-oxobutyl]- ⁇ -methyl-L-tvrosine, methyl ester.
  • the compound of Example 1 was dissolved in 100 mL of water and the pH adjusted to 9 with 1 M K 2 CO 3 .
  • the solution was cooled to 0°C and 3.30 mL (35 mmol) of acetic anhydride and 35 mL (35 mmol) of 1 M K 2 CO 3 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.
  • 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.
  • Examples #110-#413 of Table V 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, above .
  • Examples #414-#461 of Table VI are highly preferred conjugates formed from tyrosine hydroxylase inhibitor compounds and glutamic acid derivatives. These tyrosine
  • Examples #462-#857 comprise five classes of highly preferred conjugates composed of dopa-decarboxylase inhibitor compounds and glutamic acid
  • 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.
  • Step. 1 Preparation of ⁇ -methyl-L-DOPA, methyl ester, hydrochloride.
  • Step 2 Preparation of 4-amino-4-carboxy-1-oxobutyl-3- hydroxy- ⁇ -methyl-L-tyrosine, methyl ester.
  • the anhydride solution was slowly added to a solution of 12.9 g (49 mmol) of the ⁇ -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.
  • DIEA diisopropylethylamine
  • Example 462 The compound of Example 462 was dissolved in 100 mL of degassed water and under nitrogen the pH adjusted to 9 with 1 M K 2 CO 3 . The solution was cooled to 0°C and 12 mL
  • 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.
  • 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.
  • 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 propenoic acid derivatives based on the list of similar compounds described earlier.
  • 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.
  • 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.
  • the following Examples #858-#1857 comprise five classes of highly preferred conjugates composed of dopamine- ⁇ -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.
  • Step. 1 Preparation of 5-n-Butylpicolinic (Fusaric) Acid Hydrazide.
  • Step 2 Preparation of L-glutamic acid, 5- ⁇ [ 5-hutyl-2-pyridinyl) carbonyl]hydrazide.
  • step l Preparation of the ethylene diamine amid, of fusaric acid.
  • Step 2 Preparation of N-[2-[[(5-butyl-2-pyridinyl) carbonyl] amino] ethyl]-L-glutamine.
  • Example 860 The compound of Example 860 was dissolved in 150 mL of acetonitrile/water (1:1) and the pH adjusted to 9 with 2 M K 2 CO 3
  • Step 1 Preparation of the piperizine amide of fusaric acid.
  • Step 2 Preparation of 2-amino-5-[ 4- [ (5-butyl-2 -pyridinyl) carbonyl]-1-piperazinyl]-5-oxopentanoic acid.
  • Example 862 The compound of Example 862 was dissolved in 150 mL of acetonitrile/water (1:1) and the pH adjusted to 9 with 1 M K 2 CO 3 . The solution was cooled to 0°C and 2.36 mL (25 mmol) of acetic anhydride and 25 mL (25 mmol) of 1 M K 2 CO 3 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.
  • Examples #865-#1097 of Table XIII are highly preferred conjugates composed of dopamine- ⁇ -hydroxylase inhibitor compounds and glutamic acid derivatives. These dopamine- ⁇ -hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XIV and XV, above.
  • Examples #1098-#1137 of Table XIV are highly preferred conjugates composed of dopamine- ⁇ - hydroxylase inhibitor compounds and glutamic acid
  • Examples #1138-#1377 of Table XV are highly preferred conjugates composed of dopamine- ⁇ - hydroxylase inhibitor compounds and glutamic acid derivatives. These dopamine- ⁇ -hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XVIII, above.
  • Examples #1378-#1497 of Table XVI are highly preferred conjugates composed of dopamine- ⁇ - hydroxylase inhibitor compounds and glutamic acid
  • 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- ⁇ -hydroxylase in order to
  • 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
  • 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
  • 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 ⁇ L/hr.
  • mean arterial pressure was lowered significantly over the four-day period.
  • the supernatant was injected onto a C-18 reverse-phase HPLC column and eluted isocratically with a mixture of
  • kidney enzyme homogenate 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
  • DBH dopamine beta-hydroxylase
  • 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.).
  • a flow probe was implanted around the left renal artery for
  • 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.
  • Ex. #859 conjugate had no effect on mean arterial pressure (Table XXV, XXVII and Figure 8). The observation of no effect on mean arterial blood pressure confirms the expectation that the Ex. #859 conjugate does not act systemically.
  • 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 ⁇ l/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 Figure 10.
  • 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 ⁇ l/hr via a jugular vein catheter with a Harvard infusion pump. Results are shown in Table XXIX.
  • 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
  • Norepinephrine 519(42) 862(147) (pMol/g) (SD)
  • bolus doses of fusaric acid were administered into the renal artery.
  • Mean arterial pressure (MAP), renal blood flow (RBF) and urinary sodium excretion (U Na V) were measured.
  • 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,
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are tablets or capsules.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • conjugates of this invention are ordinarily combined with one or more
  • 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
  • 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.
  • Representative carriers, diluents and adjuvants include for example, water, lactose, gelatin, starches, magnesium stearate, talc, vegetable oils, gums,
  • 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

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 kydney. 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-η-glutamyl fusaric acid hydrazide [represented in formula (a)] is preferred.

Description

RENAL-SELECTIVE PRODRUGS FOR CONTROL OF
RENAL SYMPATHETIC NERVE ACTIVITY IN
THE TREATMENT OF HYPERTENSION Related Application
This application is a continuation-in-part of U.S. Application Ser. No. PCT/US90/04168 filed 25 July 1990, which is a continuation-in-part of U.S. Application Ser. No. 07/386,527 filed 27 July 1989.
Field of the Invention
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
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)]. 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. 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.
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.
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 dopadecarboxylase, 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.
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. 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 in 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 in 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. 69, 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
Figure 1 shows the acute effects of i .v.
injection of vehicle and Example #3 conjugate on mean arterial pressure in rats. Figure 2 shows the acute effects of i.v.
injection of vehicle and Example #3 conjugate on renal blood flow in rats.
Figure 3 shows the chronic effects of i.v.
infusion of vehicle and Example #464 conjugate on mean arterial pressure in spontaneously hypertensive rats.
Figure 4 shows time-dependent formation of the dopamine-β-hydroxylase inhibitor fusaric acid from the Example #859 conjugate incubated with rat kidney
homogenate.
Figure 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.
Figure 6 shows the concentration-dependent effect of fusaric acid and the Example #859 conjugate on norepinephrine production by dopamine-β-hydroxylase in vitro.
Figure 7 shows dopamine-β-hydroxylase inhibition in vitro by fusaric acid, the Example #859 conjugate and possible metabolites at a concentration of 20 μM.
Figure 8 shows the acute effects of i.v.
injection of fusaric acid and Example #859 conjugate on mean arterial pressure in spontaneously hypertensive rats.
Figure 9 shows the acute effects of i.v.
injection of fusaric acid and Example #859 conjugate on renal blood flow in spontaneously hypertensive rats.
Figure 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.
Figure 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.
Figure 12 shows the heart tissue concentrations of norepinephrine following the 5 day infusion experiment described in Figure 10. Figure 13 shows the kidney tissue concentrations of norepinephrine following the 5 day infusion experiment described in Figure 10. Figure 14 shows the effects of Example #859 conjugate on mean arterial pressure in anesthetized dogs after i.v. injection at three doses, plus vehicle.
Figure 15 shows the effects of Example #859 conjugate on renal blood flow in anesthetized dogs after i.v. injection at three doses, plus vehicle.
Figure 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 Treatment of chronic hypertension or sodiumretaining 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.
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.
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.
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.
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:
Figure imgf000011_0002
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
wherein R6 is selected from hydrido, alkyl,
Figure imgf000011_0001
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; wherein A is a phenyl ring of the formula
Figure imgf000012_0001
wherein each of R9 through R 13 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;
and wherein A may be selected from
Figure imgf000013_0002
and
Figure imgf000013_0001
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.
A preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula II:
Figure imgf000014_0002
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
wherein R6 is selected from
Figure imgf000014_0001
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,l,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
wherein R6 is selected from
Figure imgf000015_0001
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.
A first sub-class of preferred tyrosine
hydroxylase inhibitor compounds consists of the following specific compounds within Formula II:
4-cyanoamino-α-methylphenyalanine;
3-carboxy-α-methylphenylalanine;
3-cyano-α-methylphenylalanine methyl ester;
α-methyl-4-thiocarbamoylρhenylalanine methyl ester;
4-(aminomethyl)-α-methylphenylalanine;
4-guanidino-α-methylphenylalanine;
3-hydroxy-4-methanesulfonamido-α-methylphenylalanine;
3-hydroxy-4-nitro-α-methylphenylalanine; 4-amino-3-methanesulfonyloxy-α-methylphenylalanine;
3-carboxymethoxy-4-nitro-α-methylphenylalanine;
α-methyl-4-amino-3-nitrophenylalanine;
3,4-diamino-α-methylphenylalanine;
α-methyl-4-(pyrrol-1-yl)phenylalanine;
4-(2-aminoimidazol-1-yl)-α-methylphenylalanine;
4-(imidazol-2-ylamino)-α-methylphenylalanine;
4-(4,5-dihydro-4-hydroxy-4-trifluoromethyl-thiazol-2yl)-a- methylphenylalanine methyl ester;
α-methyl-4-(4-trifluoromethylthiazol-2-yl)phenylalanine; α-methyl-3-(4-trifluoromethylthiazol-2-yl)-phenylalanine;
4-(imidazol-2-yl)-α-methylphenylalanine;
4-(4,5-dihydroimidazol-2-yl)-α-methylphenylalanine;
3-(imidazol-2-yl)-α-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)-α-methylalanine;
α-methyl-3-(lH-2-oxindol-5-yl) alanine;
3-[1-(N-benzoylcarbamimidoyl)-2,3-dihydro-lHindol-5-yl)-α-methylalanine;
3-(1-carbamimidoyl-2,3-dihydro-1H-indol-5-yl-α-methylalanine;
3-(1H-indol-5-yl-α-methylalanine;
3-(benzimidazol-2-thione-5-yl)-α-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)-2methylalanine;
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-4-(pyrrol-1-yl) phenylalanine;
3-methoxy-α-4-(pyrrol-1-yl)phenylalanine;
4-methoxy-α-3-(pyrrol-1-yl) phenylalanine;
4-(indol-1-yl)-α-methylphenylalanine;
4-(carbazol-9-yl)-α-methylphenylalanine;
2-methyl-3-(2-methanesulfonylamidobenzimidazol-5- yl) alanine;
2-methyl-3-(2-amino-4-pyridyl) alanine;
2-methyl-3[tetrazolo-(1,5)-α-pyrid-7-yl] alanine;
D,L-α-β-(4-hydroxy-3-methyl)phenylalanine;
D,L-α-β-(4-hydroxy-3-phenyl)phenylalanine; D,L-α-β-(4-hydroxy-3-benzyl)phenylalanine;
D,L-α-β-(4-methoxy-3-cyclohexyl)phenylalanine;
α, β, β trimethyl-β-(3,4-dihydroxyphenyl) alanine;
a, β, β trimethyl-β-(4-hydroxyphenyl) alanine;
N-methyl α, β, β trimethyl-β-(3,4-dihydroxphenyl) alanine;
D,L α, β, β trimethyl-β-(3,4-dihyroxyphenyl) alanine;
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-methyll-b-4-trifluoromethyl-2,3-dihydroxyphenylalanine
L-α-ethyl-β-4-trifluoromethyl-2,3-dihydroxyphenylalanine L-α-propyl-β-4-trifluoromethyl-2,3-dihydroxyphenyl alanine
L-α-butyl-β-4-trifluoromethyl-2,3-dihydroxyphenylalanine
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-α-propyl-β-4-fluoro-3,5-dihydroxyphenylalanine;
L-α-butyl-β-4-fluoro-3,5-dihydroxyphenylalaninei
L-α-methyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine; L-α-ethyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine;
L-α-propyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine;
L-α-butyl-α-4-trifluoromethyl-3,5-dihydroxyphenylalanine;
L-α-methyl-2,5-dihydroxphenylalanine;
L-α-ethyl-2,5-dihydroxphenylalanine;
L-α-propyl-2,5-dihydroxρhenylalanine;
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-dihydroxyphenylalanine; 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-α-methylphenylalanine;
D,L-3-iodophenylalanine;
D,L-3-iodo-α-methylphenylalanine;
3-iodotyrosine;
3,5-diiodotyrosine;
L-α-methylphenylalanine;
D,L-α-β-(4-hydroxy-3-methylphenyl) alanine;
D,L-α-β-(4-methoxy-3-benzylphenyl) alanine;
D,L-α-β-(4-hydroxy-3-benzylphenyl) alanine;
D,L-α-β-(4-methoxy-3-cyclohexylphenyl) alanine;
D,L-α-β-(4-hydroxy-3-cyclohexylphenyl) alanine;
D,L-α-β-(4-methoxy-3-methylphenyl) alanine;
D,L-α-β-(4-hydroxy-3-methylphenyl) alanine;
N, O-dibenzyloxycarbonyl-D,L-α-β-(4-hydroxy-3-methylphenyl) alanine;
N, O-dibenzyloxycarbonyl-D,L-α-β-(4-hydroxy-3-methylphenyl) alanine amide;
D,L-α-β-(4-hydroxy-3-methylphenyl) alanine amide;
N,O-diacetyl-D,L-α-β-(4-hydroxy-3-methylphenyl) alanine; D,L-N-acetyl-α-β-(4-hydroxy-3-methylphenyl) alanine;
L-3,4-dihydroxy-α-methylphenylalanine;
L-4-hydroxy-3-methoxy-α-methylphenylalanine;
L-3,4-methylene-dioxy-α-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.
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
α-methyl-3-(pyrrol-1-yl)tyrosine;
α-methyl-3-(4-trifluoromethylthiazol-2-yl) tyrosine;
3-(imidazol-2-yl)-α-methyltyrosine; Lα-m-tyrosine;
L-α-ethyl-m-tyrosine;
L-α-propyl-m-tyrosine;
L-α-butyl-m-tyrosine;
Lα-p-chloro-m-tyrosine;
L-α-ethyl-p-chloro-m-tyrosine;
L-α-butyl-p-chloro-m-tyrosine;
Lα-p-bromo-m-tyrosine;
L-α-ethyl-p-bromo-m-tyrosine;
L-α-butyl-p-bromo-m-tyrosine;
Lα-p-fluoro-m-tyrosine;
Lα-p-iodo-m-tyrosine;
L-α-ethyl-p-iodo-m-tyrosine;
Lα-p-methyl-m-tyrosine;
Lα-p-ethyl-m-tyrosine;
L-α-ethyl-p-ethyl-m-tyrosine;
L-α-ethyl-p-methyl-m-tyrosine;
Lα-p-butyl-m-tyrosine;
Lα-p-trifluoromethyl-m-tyrosine;
L-3-iodotyrosine;
L-3-chlorotyrosine;
L-3,5-diiodotyrosine;
L-α-methyltyrosine;
D,L-α-methyltyrosine;
D,L-3-iodo-α-methyItyrosine;
L-3-bromo-α-methyltyrosine;
D,L-3-bromo-α-methyltyrosine;
L-3-chloro-α-methyltyrosine;
D, L-3-chloro-α-methyltyrosine; and
2-vinyl-2-amino-3-(4-hydroxyphenyl) propionic acid.
Another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I consists of compounds
Figure imgf000023_0001
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
wherein R6 is selected from
Figure imgf000023_0002
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.
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.
Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula IV:
Figure imgf000024_0001
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, cyanoamiro, carboxyl, cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, carboxyalkoxy and formyl. 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-iodotryρtophan; L-5- hydroxytryptophan; D,L-5-hydroxy-α-methyltryptophan; α- ethynyltryptophan; 5-methoxymethoxy-α-ethynyltryptophan; and 5-hydroxy-α-ethynyltryptophan.
Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds wherein A is
wherein R6 is selected from
Figure imgf000025_0001
three, inclusive. More preferred compounds in this class are 2-vinyl-2-amino-5-aminopentanoic acid and 2-ethynyl-2- amino-5-aminopentanoic acid.
Still another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula V:
Figure imgf000025_0002
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.
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:
Figure imgf000026_0001
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.
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, mono- alkylamino, 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.
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 R4^ 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.
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. 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.
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.
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
Figure imgf000030_0001
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
wherein R51 is selected from hydroxy, alkoxy,
Figure imgf000030_0002
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.
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
Figure imgf000031_0001
wherein R51 is selected from hydroxy, alkoxy, phenoxy, benzyloxy, amino, monoalkylamino and dialkylamino.
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
wherein R51 is selected from hydroxy, alkoxy, amino
Figure imgf000031_0002
and monoalkylamino.
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
Figure imgf000032_0001
wherein R51 is selected from hydroxy, alkoxy, amino and monoalkylamino.
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
Figure imgf000032_0002
wherein R51 is selected from hydroxy, methoxy,
ethoxy, propoxy, butoxy, amino, methylamino and ethylamino.
A more highly preferred class of compounds within Formula VII consists of those compounds wherein said inhibitor compound is selected from endo-2-amino1,2,3,4- 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-amino 1,2,3,4-tetrahydro- 1,4-ethanonaphthalene-2-carboxylic acid; and ethyl-exo-2- amino-1,2,3,4-tetrahydro-1,4-ethano-naphthalene-2- carboxylate hydrochloride.
Another family of specific dopa-decarboxylase inhibitor compounds consists of
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-β-(3,4-dihydroxyphenyl) lactate;
D,L-β-(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.
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:
Figure imgf000034_0001
wherein R52 is selected from hydrido, OR64 and
wherein R64 is selected from
Figure imgf000034_0002
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.
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. 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. A preferred compound within Formula IX is 3- (3,4-dihydroxyphenyl)-2-propenoic acid, also known as caffeic acid.
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 : - amino-haloalkyl-hydroxyphenyl propionic acids, such as 2-amino-2-fluoromethyl-3hydroxy- phenylpropionic acid;
- alpha-halomethyl-phenylalanine derivatives such as alpha-fluoroethylphenethylamine; and - indole-substituted halomethylamino acids.
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:
- 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; - sulfinyl substituted dopa and tyrosine
derivatives such as shown in U.S. Patent No. 4,400,395 the content of which is incorporated herein by reference; - hydroxycoumarin derivatives such as shown in
U.S. Patent No. 3,567,832, the content of which is incorporated herein by reference;
- 1-benzylcyclobutenyl alkyl carbamate derivatives such as shown in U.S. Patent No.
3,359,300, the content of which is incorporated herein by reference;
- arylthienyl-hydroxylamine derivatives such as shown in U.S. Patent No. 3,192,110, the content of which is incorporated herein by reference; and
- β-2-substituted-cyclohepta-pyrrol-8-1H-on-7-yl alanine derivatives. Suitable dopamine-β-hydroxylase inhibitors may be generally classified mechanistically as chelating-type inhibitors, time-dependent inhibitors and competitive inhibitors.
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:
Figure imgf000037_0001
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.
A preferred class of compounds of Formula IX consists of those compounds wherein B is phenyl or
hydroxyphenyl; wherein R67 is ethenyl or ethynyl; or an acetylenic moiety substituted with an aryl or heteroaryl radical; and wherein n is a number from zero through three.
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.
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-lbutyne; (±)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. 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:
Figure imgf000039_0001
wherein W is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein Y is selected from
Figure imgf000039_0002
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
Figure imgf000039_0003
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. A preferred class of compounds within Formula X consists of compounds wherein W is heteroaryl and Y is
Figure imgf000040_0001
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.
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.
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 :
Figure imgf000041_0002
wherein E is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein F is selected from.
Figure imgf000041_0001
wherein Z is selected from O, 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
pharmaceuticallyacceptable salt thereof.
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:
Figure imgf000042_0001
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. 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.
A family of preferred specific compounds within Formula XII consists of the following compounds :
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'-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.
Another preferred class of compounds within Formula XII consists of those compounds of Formula XIII:
Figure imgf000044_0001
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.
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.
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:
Figure imgf000045_0001
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:
Figure imgf000046_0001
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
Figure imgf000046_0002
wherein A' is or wherein R99 is selected
Figure imgf000046_0003
Figure imgf000046_0004
from hydrido, alkyl, hydroxy, alkoxy, alkylthio, phenyl, phenoxy, benzyl, benzyloxy,
-QRIOO an^ wherein R100 is selected from
Figure imgf000046_0005
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.
A preferred family of compounds within Formula XIV consists of those compounds characterized as chelatingtype inhibitors of Formula XV:
Figure imgf000047_0001
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.
A class of specifically-preferred compounds of Formula XV consists of
5-n-butylpicolinic acid (fusaric acid);
5-ethylpicolinic acid;
picolinic acid;
5-nitropicolinic acid;
5-aminopicolinic acid; 5-N-acetylaminopicolinic acid;
5-N-propionylaminopicolinic acid;
5-N-hydroxyaminopicolinic acid;
5-ιodopιcolinιc 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. Especially preferred of the foregoing class of compounds of Formula XV is the compound 5-n-butylpicolinic acid (fusaric acid) shown below:
Figure imgf000048_0001
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:
Figure imgf000049_0001
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
Figure imgf000049_0002
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. 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 R!09 is selected from hydrido and with R110 selected from lower alkyl and phenyl;
Figure imgf000049_0003
wherein u is two; and wherein v is a number from zero to two, inclusive. A more preferred class of compounds within Formula XVI consists of those compounds of Formula XVII:
Figure imgf000050_0002
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
Figure imgf000050_0001
with R110 selected from lower alkyl and phenyl and v is a number from zero to two, inclusive.
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.
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).
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:
Figure imgf000051_0001
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.
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. 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. Compounds which fall within any of the aforementioned 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. The second component of a conjugate of the invention is provided by a residue which forms a kidneyenzyme-cleavable bond with the residue of the first-component All antagonist compound. Such residue is preferably selected from a class of compounds of Formula XIX:
Figure imgf000052_0001
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 with each
Figure imgf000053_0003
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.
More preferred are compounds of Formula XIX wherein each G is hydroxy.
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
Figure imgf000053_0001
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. 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:
Figure imgf000053_0002
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. 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. 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. Suitable linker groups may be provided by a class of diamino-terminated linker groups based on hydrazine as defined by Formula XX:
Figure imgf000055_0001
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").
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Another class of suitable diamino terminal linker groups is defined by Formula XXI:
Figure imgf000061_0004
wherein each of Q and T is one or more groups independently selected from
and
Figure imgf000061_0002
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.
A preferred class of linker groups within Formula XX is defined by Formula XXII:
Figure imgf000061_0001
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.
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
Figure imgf000062_0001
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").
Figure imgf000064_0001
Figure imgf000065_0001
Another class of suitable diamino terminal linker groups is defined by Formula XXIII:
Figure imgf000066_0001
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.
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 gorups 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") .
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
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 group.
Figure imgf000070_0001
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
Figure imgf000071_0001
and The term "acyl" whether used alone,
Figure imgf000071_0002
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.
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, meglυmine (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.
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
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 O, 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. 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.
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
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-hydroxylase 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.
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.
Figure imgf000083_0001
4-amino-4-carboxy-1-oxnbnty; -α-methyl-L-tyro sine, methyl ester. step. 1. Preparation of methyl α-methyl-L-tyrosinate, hydrochloride .
A solution of 11 . 0 g (56. 4 mmol) of α-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 ) δ 1.49
(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) .
Step. 2. Preparation of 4-amino-4-carboxy-1 -oxohutyl-α-methyl-L-tyrosine, methyl ester.
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) δ 1.20 (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).
Figure imgf000085_0001
N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-α-methyl-L-tvrosine, methyl ester. 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) δ 1.18 (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).
Figure imgf000086_0001
N-[4-(acetylamino)-4-carboxy-1-oxobntyl]-α-methyl-L-tyrosine,
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) δ 1.17 (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.
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.
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
The following Examples #110-#413 of Table V 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, above .
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
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.
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
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.
Figure imgf000155_0001
4-amino-4-carboxy-1-oxobutyl-3-hydroxy-α-methyl-L-tyrosine, methyl ester. Step. 1 : Preparation of α-methyl-L-DOPA, methyl ester, hydrochloride.
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 31.7g (97%) as an off-white solid: NMR (DMSO-d6) δ 1.47 (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) .
Step 2: Preparation of 4-amino-4-carboxy-1-oxobutyl-3- hydroxy-α-methyl-L-tyrosine, methyl ester.
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) δ 1.40 (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).
Figure imgf000157_0001
N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine, methyl ester.
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 5h; 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 14.0g (49%) of colorless product: NMR (DMSO-d6) δ 1.15 (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 2Hz, 1H), 6.43 (d, J = 2Hz, 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).
Figure imgf000158_0001
N-[4-(acetylamino)-4-carboxy-1-oxobutyl]-3-hydroxy-α-methyl-L-tyrosine.
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-dg) δ 1.18 (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. 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.
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
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.
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
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.
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
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 propenoic acid derivatives based on the list of similar compounds described earlier.
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
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.
Figure imgf000220_0001
Figure imgf000221_0001
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.
Figure imgf000222_0001
Figure imgf000223_0001
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.
Figure imgf000224_0001
L-glutamic acid, 5-{ [ (5-butyl-2-pyridinyl) carbonyl]hydrazide}
Step. 1: Preparation of 5-n-Butylpicolinic (Fusaric) Acid Hydrazide.
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 (0.01mm) 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 31.7g (98%) based on ester) of crude hydrazide.
Recrystallization from ether/hexane gave colorless needles : mp 51-53°C NMR (CDCI3) δ 0.95 (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, J2, 4 = 7 Hz, 1H, ArH); 8.37 (d, 1H, ArH, J4,6 = 2 Hz); HRMS. Calcd for M + H: 194.1270. Found: 194.1293.
Step 2: Preparation of L-glutamic acid, 5-{ [ 5-hutyl-2-pyridinyl) carbonyl]hydrazide..
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 CH2CI2 and treated with 50 ml of CF3CO2H. After 4 hr at ambient
temperataure, the volitiles were removed in vacuo. 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) δ 1.90 (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).
Figure imgf000226_0001
N-acetyl-L-glutamic acid. 5-[(5-butyl-2-pyridinyl)-carbonyl] hydrazide
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 IM 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 in vacuo and the product dissolved in ethanol. Recrystallization from ethanol/petroleum ether produced 2.16g (69%) of colorless material: mp 191.5-192.0°C; NMR (D2O and NaOD)δ 0.85 (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.
Figure imgf000227_0001
N-[2-[[(5-butyl-2-pyridinyl) carbonyl] amino] ethyl]-L-glutamine. step l: Preparation of the ethylene diamine amid, of fusaric acid.
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) δ 0.90 (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) .
Step 2: Preparation of N-[2-[[(5-butyl-2-pyridinyl) carbonyl] amino] ethyl]-L-glutamine.
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 IM 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.
Figure imgf000228_0001
N2-acetyl-N- [2- [ [ (5-butyl-2-pvridinyl) carbonyl] amino] ethyl]-L-glutamine.
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.
Figure imgf000229_0001
2-amino-5-[4-[(5-butyl-2-pyridinyl) carbonyl]-1-piperazinyl]-5-oxopentanoic acid.
Step 1: Preparation of the piperizine amide of fusaric acid.
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-buytyllithium 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)δ 0.94 (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) .
Step 2 : Preparation of 2-amino-5-[ 4- [ (5-butyl-2 -pyridinyl) carbonyl]-1-piperazinyl]-5-oxopentanoic acid.
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 sti for 2 hr prior to filtration under a nitrogen atmosphere. The anhydride solution was slowly added to a solution of 5.82 g (23. 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.
Figure imgf000231_0001
2-(acetylamino)-5-(4-[(5-butyl-2-pyridinyl)carbonyl]-1-piperazinyl]-5-oxopentanoic acid.
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.
Figure imgf000232_0001
N2-acetyl-N-[2-[[5-butyl-2-pyridinyl) carbonyl] amino] ethyl]-L-glutamine, ethyl ester.
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 = 7Hz, 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 = 8Hz, 2H), 2.65(t, J = 8Hz, 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.
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.
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
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.
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
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.
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
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.
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
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.
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
BIOLOGICAL EVALUΑTION
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. 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 of Ex. #464
conjugate (a dopa-decarboxylase inhibitor conjugated with N-acetyl-γ-glutamyl) in rats.
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.
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 Conjugate
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 Hg) 78 76 75 80 82
RBF (ml/min) 4.9 4.5 4.2 4.6 4.7
Ex . #3 Conjugate (100 mg/kg i .v .)
MAP (mm Hg) 76±5 77 ±5 73±4 70 ±2 71 ± 6 RBF (ml/min) 4.8±0.8 7.1±0.1 6.2± 0.3 5.9±0.1 5.9±0.1
Assay II: Chronic In Vivo Effects of Ex. #3 Conjugate
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 Chroni c In Vivo Effects of Ex. #3 Conjugate Time After Injection (days .
Zero 1 2 3 4
Vehicle (300 μ.L/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
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.
Figure imgf000298_0001
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 TV: In Vitro Evaluation of Enzyme Metaboli sm Effects of Ex. #859 Conjugate
A freshly excised rat kidney was homogenized in
10 ml cold buffer (100 mM Tris, 15mM 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 Figure 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, Figure 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, Figure 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
Acid (μg/ml): 0.00 0.27 0.57 2.37 5.94
TABLE XXII
Formation of Fusaric Acid From Ex. #859 Conjugate Incubated with Purified Transpeptidase and Acylase
Time (hrs.) : 3 24 72 96 120
Fusaric
Acid (μg/ml): 0.00 2.56 12.15 15.44 18.75 @ pH 7.4
Fusaric
Acid (μg/ml): 0.00 1.12 4.46 5.22 6.55
@ pH 8.1 Assay V; In Vitro Evaluation of DBH Inhibition by Ex. #859
Conjugate
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 Figure 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 Figure 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 Figure 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- - - - - - - -- - - - - - - -- - - - - - - -- - - - - - - -- - - - - - - -- - - - - - - -- - - - - - - -- - - - - - - -- - - - - - - -- - - - - - - -- - - - -
Norepinephrine
Peak Intensity
(Abs 280) in the
presence of
Fusaric Acid: 0.59 0.59 0.60 0.53 0.25 0.14 0.00 0.00
Norepinephrine
Peak Intensity
(Abs 280) in the
presence of
Ex. #859 Conjugate 0.51 0.52 0.61 0.53
TABLE XXIV
DBH Inhibition by Fusaric Acid, Ex . #859 Conjugate
and Various Potential Metabolites
Test Ex. Ex. Fusaric Acid Fusaric
Compound (20μM) : #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
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 Figures 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 Figures 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 (50mg/kg i.v.)
MAP (mm Hg) 155 11l 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 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)
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 ZEBO 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)
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 Figure 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 In Vivo Effects of Ex. #859 Conjugate
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 μl/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 Figure 10.
TABLE XXVIII
Chronic Effects of Fusaric Acid and Ex. #859 Conjugate on Blood Pressure
Time (days)
Zero 1 2 3
Vehicle (25 μL/hr)
MAP (mm Hg) 139±2 139±4 143±4 146±4 145±7 146±4
(SE)
Fusaric Acid (2.5 mg/hr)
MAP (mm Hg) 148±6 118±5 114±7 122±5 114±6 114±3
(SE)
Ex. #859 Conjugate (5 mg/hr)
MAP (mm Hg) 146±5 122±9 115±9 119±11 121±7 115±8
(SE)
Assay IX: Chronic In Vivo Effects of Ex. #861 and Ex. #863
Conjugates
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
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, NJ) operating at ca. 4 ml/min. until the column was dry. Washes of 1 ml H2O - 0.5 ml MeOH - 1 ml H2O 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 urn, 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 Na2HPO4 in 75/25 (v/v) H2O/MeOH 0.007% SDS pH 3.5 (cone. H3PO4). 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)
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 >.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=.066) for the kidney extraction and 0.771 (SE=.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 Figures 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
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 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
Infusion: Fusaric Acid Fusaric Acid
Saline (1.25 mg/kg/min) Saline (0.75mg/kg/min)
Δ RBF (ml/min) : 140 240 236 315 UNa V(μEqlmin) : 95 82 44 13
MAP (mm Hg) : 136 136 140 148
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
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, NC) 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 Figures 14 and 15.
TABLE XXXTV
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
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, IN) 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, NC) 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, MA) . 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 (X25) 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. For antihypertensive experiments, male SHR (11-13 weeks of age; Harlan Sprague-Dawley, Inc.; Indianapolis, IN) 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, CA). 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, CA) and displayed on a chart recorder (Gould, model 3800, Cleveland, OH) . 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.
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) .
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 Pressure (mmHg) Eenai Blood 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
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 alone ± 7
Assay XIV; Chronic In Vivo Effects of Ex. #859 Conjugate in
DOCA Hypertensive Micropigs
This study examines the efficacy of Ex. #859 in deoxycorticosterone acetate (DOCA) 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).
Vehicle infusion (200 ml/day) had no effect on mean arterial pressure over the three day study period Table XXXVI and Figure 16). Example #859 normalized mean arterial pressure (Table XXXVI and Figure 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
Compositions of the Invention
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.
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. 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.
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.
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.
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. 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. 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

WHAT IS CLAIMED IS;
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
Figure imgf000329_0001
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 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 R^ is selected from -OR6 and wherein R6 is selected from hydrido, alkyl,
Figure imgf000330_0001
cycloalkyl, cycloalkylalkyl, aralkyl and aryl, and wherein each of R7 and R3 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; aralkyl; wherein m is a number selected from zero through six; wherein A is a phenyl ring of the formula
Figure imgf000330_0002
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-trifluoro-methylthiazol-3-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) indolin-5-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, 2-aminobenzothiazol-6-yl, 2-amino-4-mercaptobenzothiazol-6-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-2,2-dioxo2,1,3-benzothiadiazol-5-yl, 1, 3-dihydro-1,3-dimethyl-2,2-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-dihydroxyquinoxalin-6-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 or tetrazolo-[1,5-a]pyrid-7-yl; and wherein A may be selected from
Figure imgf000331_0001
Figure imgf000331_0003
and ,
Figure imgf000331_0002
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.
5. Conjugate of Claim 4 wherein said inhibitor compound is of the formula
Figure imgf000332_0001
wherein each of R1 and R2 is hydrido; wherein m is one; 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
and wherein R6 is selected from
Figure imgf000332_0002
hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl and phenyl, and wherein each of R7 and R3 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-2oxindol-5-yl, indol-5-yl, 2-mercaptobenzimidazol-5 (6) yl, 2-aminobenzimidazol-5-(6)-yl, 2-methanesulfonamidobenzimidazol-5(6)-yl, 1H-benzoxanol-2-on-6-yl, 2-aminobenzothiazol-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-2,1,3-benzothiadiazol-5-yl, 4-methyl-2 (H) oxoquinolin-6-yl, quinoxalin-6-yl, 2-hydroxyquinoxalin6-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 wherein R6 is selected
Figure imgf000333_0001
from hydrido, alkyl, hydroxy, hydroxyalkyl, alkoxy, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino; and wherein each of R7 and R3 independently is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; or a pharmaceutically-acceptable salt thereof.
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-l-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-l,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-dihyroxyphenyl) 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-dihydroxyphenyl alanine
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-α-propyl-β-4-fluoro-3,5-dihydroxyphenylalanine;
L-α-butyl-β-4-fluoro-3,5-dihydroxyphenylalanine;
L-α-methyl-β-4-trifluoromethyl-3,5-dihydroxyphenylalanine; L-α-ethyl-β-4-trifluoromethyl-3,5-dihydroxyphenyl alanine;
L-α-propyl-β-4-trifluoromethyl-3,5-dihydroxyphenylal anlne;
L-α-butyl-β-4-trifluoromethyl-3,5-dihydroxyphenylalanine;
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-dihydroxyphenylalanine;
L-α-ethyl-β-4-trifluoromethyl-2,5-dihydroxyphenylalanine; L-α-propyl-β-4-trifluoromethyl-2,5-dihydroxyphenylalanine;
L-α-butyl-β-4-trifluoromethyl-2,5-dihydroxyphenylalanine;
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-methylphenyl) 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-dimethoxyρhenyl) 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-α-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
Figure imgf000341_0001
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
wherein R6 is selected from
Figure imgf000341_0002
hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl and phenyl, and wherein each of R7 and R3 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; or a
pharmaceutically-acceptable salt thereof.
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
Figure imgf000342_0001
wherein each of R1 and R2 is hydrido; 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 each of R14 through R17 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cyclo-alkylalkyl, 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; or a
pharmaceutically-acceptable salt thereof.
13. Conjugate of Claim 12 wherein said
inhibitor compound is selected from the group consisting of L-a-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 and m is a number selected from zero to three,
Figure imgf000343_0001
inclusive; or a pharmaceutically-acceptable salt thereof.
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
Figure imgf000344_0001
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 to five, inclusive; or a pharmaceutically-acceptable salt thereof.
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
Figure imgf000345_0001
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 whole 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, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, alkenyl, cycloalkenyl and alkynyl; 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; 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 must be a primary or secondary amino group; or a pharmaceutically-acceptable salt thereof.
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 1-(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
Figure imgf000348_0001
wherein each of R45 through R43 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 P50 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl and
Figure imgf000349_0001
wherein R50 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 R43 is a primary or secondary amino group or a carboxyl group; or a pharmaceutically- acceptable salt thereof.
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
Figure imgf000349_0002
wherein R50 is selected from hydroxy, alkoxy, phenoxy, benzyloxy, amino, monoalkylamino and dialkylamino; or a pharmaceutically-acceptable salt thereof.
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
Figure imgf000350_0001
wherein R51 is selected from hydroxy, alkoxy, amino and monoalkylamino; or a pharmaceutically-acceptable salt thereof.
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
Figure imgf000350_0002
wherein R51 is selected from hydroxy, alkoxy, amino and monoalkylamino; or a pharmaceutically-acceptable salt thereof.
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
O
Figure imgf000350_0003
wherein R51 is selected from hydroxy, methoxy,
ethoxy, propoxy, butoxy, amino, methylamino and ethylamino; or a pharmaceutically-acceptable salt thereof.
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-proρenyl] 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 the formula:
Figure imgf000352_0001
wherein R52 is selected from hydrido, OR64 and wherein R64 is selected from
Figure imgf000352_0002
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, 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.
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-81H-on-7-yl alanine derivatives.
39. Conjugate of Claim 3 wherein said dopamine-β-hydroxylase inhibitor compound is of the formula
Figure imgf000354_0001
wherein B is selected from 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 and alkyl; 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 one through five; or a pharmaceutically-acceptable salt thereof.
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
Figure imgf000356_0001
wherein W is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein Y is selected from
Figure imgf000356_0002
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
Figure imgf000356_0003
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.
48. Conjugate of Claim 47 wherein W is
heteroaryl and Y is
Figure imgf000357_0001
wherein R70 is selected from hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyli 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; or a pharmaceutically-acceptable salt thereof.
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 R70 and R72 is hydrido; and wherein each of p and q is two; or a pharmaceuticallyacceptable salt thereof.
52. Conjugate of Claim 3 wherein said inhibitor compound is of the formula
Figure imgf000358_0002
wherein E is selected from alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein F is selected from
Figure imgf000358_0001
wherein Z is selected from O, 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 arylsulfonyli or a
pharmaceuticallyacceptable salt thereof.
53. Conjugate of Claim 3 wherein said dopamine-β-hydroxylase inhibitor compound is of the formula
Figure imgf000359_0001
wherein each of R82 through R85 is independently selected from hydrido, alkyl, haloalkyl, mercapto, alkylthio, cyano, alkoxy, alkoxyalkyl and cycloalkyli wherein Y is selected from oxygen atom and sulfur atom; wherein each of R79 and R80 is independently selected from hydrido and alkyl;
wherein R59 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.
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 '-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
Figure imgf000360_0001
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; or a pharmaceutically- acceptable salt thereof.
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
Figure imgf000362_0004
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, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, formoyl and alkoxycarbonyl; with the proviso that at least one of R94 through R98 is
Figure imgf000362_0001
wherein A' is
Figure imgf000362_0002
wherein R99 is selected from hydrido, alkyl, hydroxy, alkoxy, alkylthio, phenyl, phenoxy, benzyl, benzyloxy,
-OR100 and wherein R100 is selected from
Figure imgf000362_0003
hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl; wherein each of R101 and R102 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.
62. Conjugate of Claim 61 wherein said
inhibitor compound is of the formula
Figure imgf000363_0001
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; or a pharmaceutically-acceptable salt thereof.
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
Figure imgf000364_0001
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 with R110 selected from alkyl, phenyl and phenalkyl;
Figure imgf000364_0002
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.
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
with R110 selected from lower alkyl and phenyl;
Figure imgf000365_0001
wherein u is two; and wherein v is a number from zero to two, inclusive; or a pharmaceutically-acceptable salt thereof.
67. Conjugate of Claim 66 wherein said
inhibitor compound is of the formula
Figure imgf000365_0002
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
Figure imgf000365_0003
with R110 selected from lower alkyl and phenyl and v is a number from zero to two, inclusive; or a
pharmaceutically-acceptable salt thereof.
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
Figure imgf000366_0001
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.
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 pharmaceuticallyacceptable 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
Figure imgf000367_0002
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 with
Figure imgf000367_0001
each R152, R153 and R154 is independently selected from hydrido and alkyl; with the proviso that said glutamic acid derivative is selected such that formation of the cleavable bond occurs at the carbonyl moiety attached at the gammaposition carbon of said gamma-glutamic acid derivative.
75. Conjugate of Claim 74 wherein RHO wherein each G is hydroxy; wherein R150 is hydrido; and wherein R151 is selected from
Figure imgf000368_0003
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.
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
Figure imgf000368_0002
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.
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
Figure imgf000368_0001
wherein each of Q and T is one or more groups independently selected from
and
Figure imgf000369_0002
Figure imgf000369_0003
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.
80. Conjugate of Claim 79 wherein said linker group is of the formula
Figure imgf000369_0001
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 not adjacent to a nitrogen atom.
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
Figure imgf000370_0001
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.
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-l-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.
PCT/US1991/000611 1990-07-25 1991-01-28 Renal-selective prodrugs for control of renal sympathetic nerve activity in the treatment of hypertension WO1992001667A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003070755A2 (en) * 2002-02-22 2003-08-28 Synt:Em Compounds, compositions and method for transporting cyclosporin molecules through the blood brain barrier

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4165382A (en) * 1977-10-17 1979-08-21 Jose Pozuelo Method of pharmacologically treating schizophrenia with alpha-methyl-para-tyrosine
US4230883A (en) * 1977-12-12 1980-10-28 Merck & Co., Inc. Preparation of hydroxyphenylalanine hydrohalide salts
US4296119A (en) * 1978-04-24 1981-10-20 Massachusetts Institute Of Technology Process and composition for reducing blood pressure in animals

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4165382A (en) * 1977-10-17 1979-08-21 Jose Pozuelo Method of pharmacologically treating schizophrenia with alpha-methyl-para-tyrosine
US4230883A (en) * 1977-12-12 1980-10-28 Merck & Co., Inc. Preparation of hydroxyphenylalanine hydrohalide salts
US4296119A (en) * 1978-04-24 1981-10-20 Massachusetts Institute Of Technology Process and composition for reducing blood pressure in animals

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D.P. WORTH et al., "r-L-Glutamyl-L-DOPA is a dopamine prodrug, relatively specific for the kidney in normal subjects", CLINICAL SCIENCE 69, 207-214, 1985. *
F.M. SMITS et al., "Preferential renal vasodilator effects of CGP 22979A in conscious spontaneously hypertensive rats", J. PHARM. EXP. THERAPEUTICS, 232(3) 845-849. *
K.G. HOFBAUER et al., "CGP 22979A, a renal vasodilator with natriuretic properties", J. PHARMA. EXP. THERAPEUTICS, 232(3), 838-844, 1985. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003070755A2 (en) * 2002-02-22 2003-08-28 Synt:Em Compounds, compositions and method for transporting cyclosporin molecules through the blood brain barrier
WO2003070755A3 (en) * 2002-02-22 2004-03-04 Synt Em Compounds, compositions and method for transporting cyclosporin molecules through the blood brain barrier

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