WO1991001724A1 - Renal-selective prodrugs for the treatment of hypertension - Google Patents

Renal-selective prodrugs for the treatment of hypertension Download PDF

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Publication number
WO1991001724A1
WO1991001724A1 PCT/US1990/004168 US9004168W WO9101724A1 WO 1991001724 A1 WO1991001724 A1 WO 1991001724A1 US 9004168 W US9004168 W US 9004168W WO 9101724 A1 WO9101724 A1 WO 9101724A1
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WO
WIPO (PCT)
Prior art keywords
amino
hydrido
methyl
alkyl
hydroxy
Prior art date
Application number
PCT/US1990/004168
Other languages
English (en)
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
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to PCT/US1991/000611 priority Critical patent/WO1992001667A1/en
Publication of WO1991001724A1 publication Critical patent/WO1991001724A1/en
Priority to KR1019910700319A priority patent/KR920700625A/ko
Priority to US10/151,211 priority patent/US20030220521A1/en
Priority to US10/689,919 priority patent/US20040101523A1/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives
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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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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • 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.
  • 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
  • catecholamine cascade the pathway involved in synthesis of the neurotransmitter norepinephrine. Stepwise, these catecholamines are
  • norepinephrine by the enzyme dopamine- ⁇ -hydroxylase.
  • the compound a-methyltyrosine inhibits the action of the enzyme tyrosine hydroxylase.
  • the compound a-methyldopa inhibits the action of the enzyme dopa-decarboxylase, and 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, 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 two doses.
  • Figure 15 shows the effects of Example #859 conjugate on renal blood flow in anesthetized dogs after i.v. injection at two doses.
  • Treatment of chronic hypertension or sodium-retaining disorders such as congestive heart failure, cirrhosis and nephrosis, may be accomplished by
  • 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.
  • 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.
  • 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.
  • 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.
  • a class of compounds from which a suitable tyrosine hydroxylase inhibitor compound may be selected to provide the conjugate first residue is represented by
  • 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 -CR 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
  • 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
  • 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,
  • benzoheterocyclic ring selected from the group consisting of indolin-5-yl, 1- (N-benzoylcarbamimidoyl) indolin-5-yl, 1- carbamimidoylindolin-5-yl, 1H-2-oxindol-5-yl, indol-5-yl, 2-mercaptobenzimidazol-5(6)-yl, 2-aminobenzimidazol5-(6)- yl, 2-methanesulfonamidobenzimidazol-5(6)-yl, 1H- benzoxanol-2-on-6-yl, 2-amino-benzothiazol-6-yl, 2-amino-4- mercaptobenzothiazol-6-yl, 2,1,3-benzothiadiazol-5-yl, 1,3- dihydro-2,2-dioxo-2,1, 3-benzothiadiazol-5-yl, 1,3-dihydro- 1,3-dimethyl-2,2-dioxo-2
  • R 6 is selected from
  • each of R7 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
  • Another preferred class of tyrosine hydroxylase inhibitor compounds within Formula I consists of compounds
  • R 3 is selected from alkyl, alkenyl and alkynyl
  • 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,
  • Formula IV consists of L- ⁇ -methyltryptophan; D,L-5- methyltryptophan; D,L-5-chlorotryptophan; D,L-5- bromotryptophan; D,L-5-iodotryptophan; 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.
  • 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, cycloalkylalkylalkyl
  • 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, and with the further proviso that at least one of R 43 through R 44 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 R 42 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxyl,
  • R 43 and R 44 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl and alkanoyl; 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, alkoxycarbonyl.
  • 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 43 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
  • 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,
  • 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
  • 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-aminol,2,3,4- tetrahydro-1,2-ethanonaphthalene-2-carboxylic acid; ethylendo-2-amino-1,2,3,4-tetra-hydro-1,4-ethano-naphthalene-2- carboxylate hydrochloride; exo-2-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 OR 64 wherein R 64 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, benzyl and phenyl; wherein 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.
  • R 52 is OR 64 wherein R 64 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, benzyl and phenyl; wherein each of R 53 , R 54 and R 57 through R 63 is independently selected
  • VIII consists of those compounds wherein R5 2 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-3hydroxyphenylpropionic 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 substituted or unsubstituted alkyl, aryl and heteroaryl; wherein each of R 67 and R 68 is independently selected from hydrido, alkyl, alkenyl and alkynyl; wherein R 69 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfony
  • 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
  • alkyl 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
  • 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.
  • 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 R 88 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
  • each of 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
  • each of R95 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.
  • XVT 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 109 is selected from hydrido and with R 110 selected from lower alkyl and phenyl;
  • a more preferred class of compounds within Formula XVT 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.
  • Formula XVIII consists of those compounds wherein R 112 is selected from amino, aminoalkyl, monoalkylamino,
  • 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-2thione; and hydroxyphenolic
  • 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.
  • This inhibitor compound must contain 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 XIX:
  • 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,
  • Linker Nos. 1-73 These linker groups would be suitable to form a conjugate between a carbonyl moiety of an All antagonist (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 (designatedas "T").
  • 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 IV is defined by Formula XXI:
  • 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 XXI is not adjacent to a nitrogen atom of Formula XXI.
  • a more preferred class of linker groups of Formula V 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 VI consists of divalent radicals wherein each of R 214 and R 215 is hydrido; wherein each of R 62 and R 63 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 XXII 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 XXII is the divalent radical ethylenediamino.
  • Table III there is shown a class of specific examples of diamino-terminated linker gorups within Formula XXII. These linker groups, identified as Linker Nos. 96-134, would be suitable to form a conjugate between a carbonyl moiety of an All antagonist (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").
  • hydro denotes a single hydrogen atom (H) which may be attached, for example, to an oxygen atom to form a hydroxyl group.
  • alkyl is used, either alone or within other terms such as
  • haloalkyl "aralkyl” and “hydroxyalkyl”
  • 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 2,2,3,3tetrafluoro ⁇ ropyl 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 denotes respectively divalent radicals and
  • acyl whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl.
  • “Lower alkanoyl” is an exairple of a more preferred sub-class of acyl.
  • conjugates of the invention include acid- addition salts and base addition salts.
  • pharmaceuticallyacceptable 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, ⁇ -hydroxy butyric, 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, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding conjugates described herein by reacting, for example, the appropriate acid or base with the conjugate.
  • 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.
  • Examples 1-1857 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- ⁇ -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.
  • Step. 1 Preparation of methyl ⁇ -methyl-L-tyrosinate, hydrochloride .
  • 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 (TEA) under nitrogen.
  • TAA trifluoracetic acid
  • Example 2 N-[4-(acetylamino)-4-carboxy-4-oxobutyl]- ⁇ -methyl-L-tyrosine, 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 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.
  • Step. 1 Preparation of ⁇ -methyl-L-DOPA, methyl ester
  • 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 (127 mmol) of acetic anhydride and 180 mL (180 mmol) of 1 M K 2 CO 3 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.
  • 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.
  • 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 the ethylene diamine amide of fusaric acid.
  • step 2 Preparation of N-[2-[[(5-frutyl-2-pyridinyl) carbonyl] aminolethyl]-L-gluatmine.
  • 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.
  • the compound of Exairple 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 #864-#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
  • Examples #1098-#1137 of Table XIV 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, above.
  • Exairples #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 derivatives. These dopamine- ⁇ -hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula XVIII, above.
  • 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- ⁇ -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.
  • 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.
  • 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
  • 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.
  • 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. TABLE XXVIII Chronic Effects of Fusaric Acid and Ex. #859 Conjugate on Blood Pressure
  • 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.
  • DHBA dihydroxybenzylamine
  • 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 H 2 O - 0.5 ml MeOH - 1 ml H 2 O were followed by elution with 1 ml of extraction solvent.
  • a 200 ⁇ l 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).
  • Norepinephrine 889(72) 2,248(164) (pMol/g) (SD)
  • Norepinephrine 519(42) 862(147) (pMol/g) (SD)
  • Norepinephrine 589(54) 2,444(534) (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
PCT/US1990/004168 1989-07-27 1990-07-25 Renal-selective prodrugs for the treatment of hypertension WO1991001724A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/US1991/000611 WO1992001667A1 (en) 1990-07-25 1991-01-28 Renal-selective prodrugs for control of renal sympathetic nerve activity in the treatment of hypertension
KR1019910700319A KR920700625A (ko) 1989-07-27 1991-03-27 고혈압 치료를 위한 신장에 선택적인 프로드러그(Prodrug)
US10/151,211 US20030220521A1 (en) 1989-07-27 2002-05-20 Renal-selective prodrugs for control of renal sympathetic nerve activity in the treatment of hypertension
US10/689,919 US20040101523A1 (en) 1989-07-27 2003-10-20 Renal-selective prodrugs for control of renal smpathetic nerve activity in the treatment of hypertension

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US386,527 1989-07-27

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WO1992002257A2 (en) * 1990-08-10 1992-02-20 G.D. Searle & Co. Renal-selective angiotensin ii antagonists for treatment of hypertension
US5614508A (en) * 1995-06-07 1997-03-25 Warner-Lambert Company Amino acid derivatives of substituted quinoxaline 2,3-dione derivatives as glutamate receptor antagonists
WO1999058526A1 (en) * 1998-05-13 1999-11-18 Dong Wha Pharm. Ind. Co., Ltd. Novel 2,5-pyridinedicarboxylic acid derivatives
US6080743A (en) * 1995-08-31 2000-06-27 Novartis Ag 2,3-dioxo-1,2,3,4-tetrahydro-quinoxalinyl derivatives
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
EP1264596A2 (en) * 2001-06-05 2002-12-11 Kao Corporation Use of a ferulic acid derivative as a preventive or remedy for hypertension
WO2006059245A2 (en) * 2004-11-16 2006-06-08 Neurochem (International) Limited Compounds for the treatment of cns and amyloid associated diseases
CN1293868C (zh) * 2004-12-29 2007-01-10 朱旭祥 α－环丙氨酸在制备治疗心脑血管疾病药物中的应用
WO2009002964A1 (en) * 2007-06-26 2008-12-31 Lexicon Pharmaceuticals, Inc. Methods of treating serotonin-mediated diseases and disorders
US7612226B2 (en) 2005-04-28 2009-11-03 Pfizer Inc. Amino acid derivatives
US7750028B2 (en) 1997-06-10 2010-07-06 Novartis Ag Crystal modifications of 1-(2,6-difluorobenzyl)-1H-1, 2,3-triazole-4-carboxamide
US7875622B2 (en) 2007-07-11 2011-01-25 Lexicon Pharmaceuticals, Inc. Methods and compositions for treating pulmonary hypertension and related diseases and disorders
US7939505B2 (en) 2007-05-04 2011-05-10 Marina Biotech, Inc. Amino acid lipids and uses thereof
EP3811942A4 (en) * 2018-06-21 2022-04-20 Consejo Superior de Investigaciones Científicas (CSIC) USE OF TYROSINE HYDROXYLASE INHIBITORS FOR THE TREATMENT OF AORTIC ANEURYSM

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JOP20190049A1 (ar) * 2016-09-23 2019-03-20 Bial Portela & C? S A مثبطات دوبامين-b-هيدروكسيلاز

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Cited By (26)

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Publication number Priority date Publication date Assignee Title
WO1992002257A3 (en) * 1990-08-10 1992-04-02 Searle & Co Renal-selective angiotensin ii antagonists for treatment of hypertension
WO1992002257A2 (en) * 1990-08-10 1992-02-20 G.D. Searle & Co. Renal-selective angiotensin ii antagonists for treatment of hypertension
US5614508A (en) * 1995-06-07 1997-03-25 Warner-Lambert Company Amino acid derivatives of substituted quinoxaline 2,3-dione derivatives as glutamate receptor antagonists
US6080743A (en) * 1995-08-31 2000-06-27 Novartis Ag 2,3-dioxo-1,2,3,4-tetrahydro-quinoxalinyl derivatives
US8076362B2 (en) 1997-06-10 2011-12-13 Novartis Ag Crystal modification A of 1-(2,6-difluorobenzyI)-1 H-1,2,3-triazole-4-carboxamide and dosage forms and formulations thereof
US7750028B2 (en) 1997-06-10 2010-07-06 Novartis Ag Crystal modifications of 1-(2,6-difluorobenzyl)-1H-1, 2,3-triazole-4-carboxamide
WO1999058526A1 (en) * 1998-05-13 1999-11-18 Dong Wha Pharm. Ind. Co., Ltd. Novel 2,5-pyridinedicarboxylic acid derivatives
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
EP1264596A2 (en) * 2001-06-05 2002-12-11 Kao Corporation Use of a ferulic acid derivative as a preventive or remedy for hypertension
EP1264596A3 (en) * 2001-06-05 2003-01-08 Kao Corporation Use of a ferulic acid derivative as a preventive or remedy for hypertension
US6894077B2 (en) 2001-06-05 2005-05-17 Kao Corporation Preventive or remedy for hypertension
US7939563B2 (en) 2001-06-05 2011-05-10 Kao Corporation Remedy for hypertension
US7534815B2 (en) 2001-06-05 2009-05-19 Kao Corporation Preventive or remedy for hypertension
WO2006059245A2 (en) * 2004-11-16 2006-06-08 Neurochem (International) Limited Compounds for the treatment of cns and amyloid associated diseases
WO2006059245A3 (en) * 2004-11-16 2006-10-05 Neurochem Int Ltd Compounds for the treatment of cns and amyloid associated diseases
CN1293868C (zh) * 2004-12-29 2007-01-10 朱旭祥 α－环丙氨酸在制备治疗心脑血管疾病药物中的应用
US7612226B2 (en) 2005-04-28 2009-11-03 Pfizer Inc. Amino acid derivatives
US7939505B2 (en) 2007-05-04 2011-05-10 Marina Biotech, Inc. Amino acid lipids and uses thereof
US8501824B2 (en) 2007-05-04 2013-08-06 Marina Biotech, Inc. Amino acid lipids and uses thereof
US8877729B2 (en) 2007-05-04 2014-11-04 Marina Biotech, Inc. Amino acid lipids and uses thereof
US9339461B2 (en) 2007-05-04 2016-05-17 Marina Biotech, Inc. Arginine-based lipids for delivery of therapeutics
US9731016B2 (en) 2007-05-04 2017-08-15 Marina Biotech, Inc. Tyrosine-based lipids for delivery of therapeutics
WO2009002964A1 (en) * 2007-06-26 2008-12-31 Lexicon Pharmaceuticals, Inc. Methods of treating serotonin-mediated diseases and disorders
US7875622B2 (en) 2007-07-11 2011-01-25 Lexicon Pharmaceuticals, Inc. Methods and compositions for treating pulmonary hypertension and related diseases and disorders
US8410121B2 (en) 2007-07-11 2013-04-02 Lexicon Pharmaceuticals, Inc. Methods of treating pulmonary hypertension
EP3811942A4 (en) * 2018-06-21 2022-04-20 Consejo Superior de Investigaciones Científicas (CSIC) USE OF TYROSINE HYDROXYLASE INHIBITORS FOR THE TREATMENT OF AORTIC ANEURYSM

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