US 2004O1 O1523A1. (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0101523 A1 Reitz et al. (43) Pub. Date: May 27, 2004

(54) RENAL-SELECTIVE PRODRUGS FOR Publication Classification CONTROL OF RENAL SMPATHETIC NERVE ACTIVITY IN THE TREATMENT OF (51) Int. Cl...... A61K 38/43; C12N 9/99 HYPERTENSION (52) U.S. Cl...... 424/94.1; 435/184 (75) Inventors: David B. Reitz, Chesterfield, MO (US); John P. Koepke, St. Louis, MO (US); (57) ABSTRACT Edward H. Blaine, University City, MO (US); Joseph R. Schuh, St. Louis, MO (US); Robert E. Manning, St. Renal-Selective prodrugs are described which are preferen Louis, MO (US); Glenn J. Smits, tially converted in the kidney to compounds capable of Ellisville, MO (US) inhibiting Synthesis of catecholamine-type neurotransmit ters involved in renal Sympathetic nerve activity. The pro drugs described herein are derived from inhibitor com Correspondence Address: pounds capable of inhibiting one or more of the enzymes J. Timothy Keane involved in catecholamine Synthesis, Such compounds being PHARMACIA CORPORATION of Pfizer Inc., classifiable as tyrosine hydroxylase inhibitors, or as dopa Corporate Patent Department decarboxylase inhibitors, or as dopamine-B-hydroxylase P.O. BOX 1027 inhibitors. These inhibitor compounds are linked to a chemi Chesterfield, MO 63006 (US) cal moiety, Such as a glutamic acid derivative, by a cleavable bond which is recognized Selectively by enzymes located predominantly in the kidney. The liberated inhibitor com (73) Assignee: G.D. Searle & Co., Chicago, IL pound is then available in the kidney to inhibit one or more of the enzymes involved in catecholamine Synthesis. Inhi (21) Appl. No.: 10/689,919 bition of renal catecholamine Synthesis can Suppress height ened renal nerve activity associated with Sodium-retention (22) Filed: Oct. 20, 2003 related disorderS Such as hypertension. Conjugates of par Related U.S. Application Data ticular interest are glutamyl derivatives of dopamine-B- hydroxylase inhibitors, of which N-acetyl-y-glutamyl (63) Continuation of application No. 10/151,211, filed on fusaric acid hydrazide (shown below) is preferred. May 20, 2002, now abandoned, which is a continu ation of application No. 09/678,015, filed on Oct. 2, 2000, now abandoned, which is a continuation of N application No. 09/444,888, filed on Nov. 22, 1999, O O CO2H now abandoned, which is a continuation of applica 2n tion No. 08/639,493, filed on Apr. 29, 1996, now N C-N-N-C-CH-CH-CH abandoned, which is a continuation of application No. 08/280,170, filed on Jul. 25, 1994, now abandoned, H. H. -n which is a continuation-in-part of application No. =o PCT/US90/04168, filed on Jul 25, 1990, which is a CH continuation-in-part of application No. 07/386,527, filed on Jul. 27, 1989, now abandoned. Patent Application Publication May 27, 2004 Sheet 1 of 16 US 2004/0101523 A1

Acute In Vivo Effects of Vehicle and Example #3 Conjugate 100

8 O

6 O

4. O -o- vehicle -O- Example #3

2 O

O 1S 30 4S 60 Time (minutes)

Figure 1 Patent Application Publication May 27, 2004 Sheet 2 of 16 US 2004/0101523 A1

Acute In Vivo Effects of Example #3 Conjugate

s-O- Vehicle -O- Example #3 Conjugate

O 5 30 4S 60 Tine (minutes) Patent Application Publication May 27, 2004 Sheet 3 of 16 US 2004/0101523 A1

Chronic Infusion of Example #464 Conjugate

2OO Or Vehicle -O- Example #464 Conjugate

190

18O

170

160

150

Time (days)

Figure 3 Patent Application Publication May 27, 2004 Sheet 4 of 16 US 2004/0101523 A1 Formation of Fusaric Acid From Example #859 Conjugate by Rat Kidney Homogenate 34.5 2

O O 20 30 40 50 Tine (hours) Patent Application Publication May 27, 2004 Sheet 5 of 16 US 2004/0101523 A1

Enzymatic Formation of Fusaric Acid From Example #859 Conjugate

20

15

O

S

O 20 40 60 80 OO 120 1 40 Time (hours) Patent Application Publication May 27, 2004 Sheet 6 of 16 US 2004/0101523 A1 Effect of Fusaric Acid and Example #859 Conjugate on Dopamine-6-Hydroxylase Activity In Vitro

0.6 as e N 0.5 2 s - 0. s S. S 03

O2 s s 0.1

-O Fusaric Acid 0.0 -O- Example #859 Conjugate

.0 ... 1 10 100 Concentration (M)

Figure 6 Patent Application Publication May 27, 2004 Sheet 7 of 16 US 2004/0101523 A1

Dopamine-?3-Hydroxylase Inhibition by Exampie #859 Conjugate and Related Compounds

1 OO Example #859 Conjugate Example #858 Conjugate QP Fusaric Acid Hydrazide us

Fusaic Acid Ne

6 O

40

20

Test Compound (20 M)

Figure 7 Patent Application Publication May 27, 2004 Sheet 8 of 16 US 2004/0101523 A1

Acute In Vivo Effects of Fusaric Acid or Example #859 Conjugate on Mean Arterial Pressure

18O

160

140 -O- Fusaic Acid -o- Example #859 Conjugate

120

OO

8 O O S 30 4S 60 Tine (minutes) Patent Application Publication May 27, 2004 Sheet 9 of 16 US 2004/0101523 A1

Acute In Vivo Effects of Fusaric Acid and Example #859 Conjugate on Renal Blood Flow TO Fusaric Acid 5 mO Example #859 Conjugate

4.

O S 3O 4S 60 Tine (minutes) Patent Application Publication May 27, 2004 Sheet 10 of 16 US 2004/0101523 A1

Chronic In Vivo Effects of Saline, Fusaric Acid and Example #859 Conjugate

200

180 s Vehicle On Fusaric Acid -O-Example #859 Conjugate

160

140

20

100 O 2 3 4 S 6 Time (days)

Figure 10 Patent Application Publication May 27, 2004 Sheet 11 of 16 US 2004/0101523 A1 Chronic Infusion of Example #863 Conjugate

Or Vehicle 8 O -O- Example #863 Conjugate

170

160

150

140 O 2 3 4 Time (days)

Figure 11 Patent Application Publication May 27, 2004 Sheet 12 of 16 US 2004/0101523 A1

Heart Norepinephrine Levels Following 5 Day Infusion of Vehicle, Fusaric Acid, and Example #859 Conjugate

3OOO

2OOO

1 OOO

Vehicle Fusaric Acid Example #859 Conjugate Patent Application Publication May 27, 2004 Sheet 13 of 16 US 2004/0101523 A1

Kidney Norepinephrine Levels Following S Day Infusion of Vehicle, Fusaric Acid, and Example #859 Conjugate 1 OOO

68

20 O

Vehicle Fusaric Acid ExampleConjugate #859

Figure 13 Patent Application Publication May 27, 2004 Sheet 14 of 16 US 2004/0101523 A1

Mean Arterial Pressure Response to Example #859 Conjugate after I.V. Injection in Dogs 200 Vehicle a 7 mg/kg

150 D 60 mg/kg

125 2 OO % 75 2 50 2% 2 O 2 3 Time (hours)

FIGURE 14 Patent Application Publication May 27, 2004 Sheet 15 of 16 US 2004/0101523 A1

Renal Blood Flow Response to Example #859 Conjugate after I.V. Injection in Dogs 200 Vehicle 175 a 7 mg/kg B 20 mg/kg 150 D 60 mg/kg

125

OO

75

50

25

0 1. |2 3 Time (hours)

FIGURE 15 Patent Application Publication May 27, 2004 Sheet 16 of 16 US 2004/0101523 A1

Effects of Ex. 859 in DOCA Hypertensive Micropigs 180

-OH vehicleEXAMPLE 200 #859 m/day 5 mg/kg 5 n=3

160

150

140

30

20

110

100 1. 2 3. 4 Time (days)

FIGURE 16 US 2004/0101523 A1 May 27, 2004

RENAL-SELECTIVE PRODRUGS FOR CONTROL neys may be an effective therapeutic treatment for chronic OF RENAL SMPATHETIC NERVE ACTIVITY IN Sodium-retaining disorders, Such as hypertension, conges THE TREATMENT OF HYPERTENSION tive heart failure, cirrhosis, and nephrosis. RELATED APPLICATION 0006. One approach to reduce sympathetic nervous sys tem effects on renal function is to inhibit the synthesis of one 0001. This application is a continuation-in-part of U.S. or more compounds involved as intermediates in the "cat Application Ser. No. PCT/US90/04168 filed 25 Jul. 1990, echolamine cascade', that is, the pathway involved in Syn which is a continuation-in-part of U.S. application Ser. No. thesis of the neurotransmitter norepinephrine. Stepwise, 07/386,527 filed 27 Jul 1989. these catecholamines are Synthesized in the following man ner: (1) tyrosine is converted to dopa by the enzyme tyrosine FIELD OF THE INVENTION hydroxylase; (2) dopa is converted to dopamine by the 0002 This invention is in the field of cardiovascular enzyme dopa decarboxylase; and (3) dopamine is converted therapeutics and relates to a class of compounds useful in to norepinephrine by the enzyme dopamine-B-hydroxylase. control of hypertension. Of particular interest is a class of Inhibition of dopamine-B-hydroxylase activity, in particular, compounds which prevent or control hypertension by Selec would increase the renal vasodilatory, diuretic and natri tive action on the renal Sympathetic nervous System. uretic effects due to dopamine. Inhibition of the action of any of these enzymes would decrease the renal vasocon Strictive, antidiuretic and antinatriuretic effects of norepi BACKGROUND OF THE INVENTION nephrine. Therapeutically, these effects oppose chronic 0.003 Hypertension has been linked to increased sympa Sodium retention. thetic nervous System activity Stimulated through any of four mechanisms, namely (1) by increased vascular resistance, 0007 Many compounds are known to inhibit the action (2) by increased cardiac rate, Stroke Volume and output, (3) of the catecholamine-cascade-converting enzymes. For by vascular muscle defects or (4) by Sodium retention and example, the compound C.-methyltyrosine inhibits the action renin release J. P. Koepke et al, The Kidney in Hyperten of the enzyme tyrosine hydroxylase. The compound C.-me Sion, B. M. Brenner and J. H. Laragh (Editors), Vol. 1, p. 53 thyldopa inhibits the action of the enzyme dopa-decarboxy (1987). As to this fourth mechanism in particular, stimula lase, and the compound fuSaric acid inhibits the action of tion of the renal Sympathetic nervous System can affect renal dopamine-B-hydroxylase. Such inhibitor compounds often function and maintenance of homeostasis. For example, an cannot be administered Systemically because of the adverse increase in efferent renal Sympathetic nerve activity may Side effects induced by Such compounds. For example, the cause increased renal vascular resistance, renin release and desired therapeutic effects of dopamine-B-hydroxylase Sodium retention A. Zanchetti et al., Handbook of Hyper inhibitors, Such as fuSaric acid, may be offset by hypoten tension, Vol. 8, Ch. 8, vasoconstriction has been identified as Sion-induced compensatory Stimulation of the renin-angio an element in the pathogenesis of early essential hyperten tensin System and Sympathetic nervous System, which pro sion in man. R. E. Katholi, Amer. J. Physiol., 245, F1-F14 mote Sodium and water retention. (1983)). 0008 To avoid such systemic side effects, drugs may be 0004 Proper renal function is essential to maintenance of targetted to the kidney by creating a conjugate compound homeostasis So as to avoid hypertensive conditions. Excre that would be a renal-specific prodrug containing the tar tion of Sodium is key to maintaining extracellular fluid getted drug modified with a chemical carrier moiety. Cleav volume, blood volume and ultimately the effects of these age of the drug from the carrier moiety by enzymes pre Volumes on arterial preSSure. Under Steady-State conditions, dominantly localized in the kidney releases the drug in the arterial preSSure rises to that pressure level which will cause kidney. Gamma glutamyl transpeptidase and acylase are balance between urinary output and water/Salt intake. If a examples of Such cleaving enzymes found in the kidney perturbation in normal kidney function occurs causing renal which have been used to cleave a targetted drug from its Sodium and water retention, as with Sympathetic Stimulation prodrug carrier within the kidney. of the kidneys, arterial pressure will increase to a level to 0009 Renal targetted prodrugs are known for delivery of maintain Sodium output equal to intake. In hypertensive a drug Selectively to the kidney. For example, the compound patients, the balance between Sodium intake and output is L-y-glutamyl amide of dopamine when administered to dogs achieved at the expense of an elevated arterial pressure. was reported to generate dopamine in Vivo by Specific 0005. During the early stages of genetically spontaneous enzymatic cleavage by Y-glutamyl transpeptidase J. J. or deoxycorticosterone acetate-sodium chloride (DOCA Kyncl et al, Adv. BioSc., 20, 369-380 (1979)). In another NaCl) induced hypertension in rats, a positive Sodium bal Study, Y-glutamyl and N-acyl-y-glutamyl derivatives of the ance has been observed to precede hypertension. Also, anti-bacterial compound Sulfamethoxazole were shown to Surgical Sympathectomy of the kidneys has been shown to deliver relatively high concentrations of Sulfamethoxazole reverse the positive Sodium balance and delay the onset of to the kidney which involved enzymatic cleavage of the hypertension R. E. Katholi, Amer. J. Physiol., 245, F1-F14 prodrug by acylamino acid deacylase and Y-glutamyl (1983)). Other chronic sodium retaining disorders are linked transpeptidase M. Orlowski et al., J. Pharmacol. Exp. Ther, to heightened Sympathetic nervous System Stimulation of the 212, 167-172 (1980)). The N-y-glutamyl derivatives of 2-, kidneyS. Congestive heart failure, cirrhosis and nephrosis 3-, or 4-aminophenol and p-fluoro-L-phenylalanine have are characterized by abnormal chronic Sodium retention been found to be readily solvolyzed in vitro by Y-glutamyl leading to edema and ascites. These Studies Support the transpeptidase S. D. J. Magnan et al., J. Med. Chem., 25, concept that renal Selective pharmacological inhibition of 1018-1021 (1982). The hydralazine-like vasodilator 2-hy heightened sympathetic nervous System activity to the kid drazino-5-g-butylpyridine (which stimulates guanylate US 2004/0101523 A1 May 27, 2004 cyclase activity) when substituted with the N-acetyl-y- 0023 FIG. 14 shows the effects of Example #859 con glutamyl residue resulted in a prodrug which provided jugate on mean arterial pressure in anesthetized dogs after selective renal vasodilation K. G. Hofbauer et al., J. Phar i.V. injection at three doses, plus vehicle. macol. Exp. Ther..., 212, 838-844 (1985). The dopamine prodrug Y-L-glutamyl-L-dopa ("gludopa”) has been shown 0024 FIG. 15 shows the effects of Example #859 con to be relatively Specific for the kidney and to increase renal jugate on renal blood flow in anesthetized dogs after i.V. blood flow, glomerular filtration and urinary Sodium excre injection at three doses, plus vehicle. tion in normal subjects D. P. Worth et al., Clin. Sci. 69, 0025 FIG. 16 shows the effects of Example #858 con 207-214 (1985)). In another study, gludopa was reported to jugate on mean arterial pressure in conscious DOCA hyper an effective renal dopamine prodrug whose activity can be tensive micropigs after i.v. infusion for three dayS. blocked by the dopa-decarboxylase inhibitor carbidopa R. F. Jeffrey et al, Br. J. Clin. Pharmac., 25, 195-201 (1988). DESCRIPTION OF THE INVENTION 0026 Treatment of chronic hypertension or sodium-re BRIEF DESCRIPTION OF THE DRAWING taining disorderS Such as congestive heart failure, cirrhosis FIGURES and nephrosis, may be accomplished by administering to a Susceptible or afflicted Subject a therapeutically-effective 0010 FIG. 1 shows the acute effects of i.v. injection of amount of a renal-Selective prodrug capable of causing vehicle and Example #3 conjugate on mean arterial pressure Selective blockage of heightened Sympathetic nervous Sys in rats. tem effects on the kidney. An advantage of Such renal 0.011 FIG. 2 shows the acute effects of i.v. injection of Selective prodrug therapy resides in reduction or avoidance vehicle and Example #3 conjugate on renal blood flow in of adverse side effects associated with Systemically-acting ratS. drugs. 0012 FIG.3 shows the chronic effects of i.v. infusion of 0027. A renal-selective prodrug capable of providing vehicle and Example #464 conjugate on mean arterial pres renal Sympathetic nerve blocking action may be provided by Sure in Spontaneously hypertensive rats. a conjugate comprising a first residue and a Second residue connected together by a cleavable bond. The first residue is 0013 FIG. 4 shows time-dependent formation of the derived from an inhibitor compound capable of inhibiting dopamine-B-hydroxylase inhibitor fuSaric acid from the formation of a benzylhydroxyamine intermediate in the Example #859 conjugate incubated with rat kidney homo biosynthesis of an adrenergic neurotransmitter, and wherein genate. Said Second residue is capable of being cleaved from the first 0.014 FIG. 5 shows time-dependent formation of fusaric residue by an enzyme located predominantly in the kidney. acid from the Example #859 conjugate incubated with a 0028. The first and second residues are provided by mixture of purified acylase I and gamma-glutamyl transpep precursor compounds having Suitable chemical moieties tidase at pH 7.4 and 8.1. which react together to form a cleavable bond between the 0.015 FIG. 6 shows the concentration-dependent effect first and Second residues. For example, the precursor com of fuSaric acid and the Example #859 conjugate on norepi pound of one of the residues will have a reactable carboxylic nephrine production by dopamine-B-hydroxylase in Vitro. acid moiety and the precursor of the other residue will have a reactable amino moiety or a moiety convertible to a 0016 FIG. 7 shows dopamine-B-hydroxylase inhibition reactable amino moiety, So that a cleavable bond may be in vitro by fusaric acid, the Example #859 conjugate and formed between the carboxylic acid moiety and the amino possible metabolites at a concentration of 20 uM. moiety. An inhibitor compound which provides the first residue may be selected from tyrosine hydroxylase inhibitor 0017 FIG. 8 shows the acute effects of i.v. injection of compounds, dopa-decarboxylase inhibitor compounds, fuSaric acid and Example #859 conjugate on mean arterial dopamine-B-hydroxylase inhibitor compounds, and mimics preSSure in Spontaneously hypertensive rats. of any of these inhibitor compounds. 0018 FIG. 9 shows the acute effects of i.v. injection of 0029. The inhibitor compounds described herein have fusaric acid and Example #859 conjugate on renal blood been classified as tyrosine hydroxylase inhibitors, or as flow in Spontaneously hypertensive rats. dopa-decarboxylase inhibitors, or as dopamine-B-hydroxy 0019 FIG. 10 shows the effects of chronic i.v. infusion of lase inhibitors, for convenience of description. Some of the vehicle, fusaric acid, and Example #859 conjugate for 5 days inhibitor compounds may be classifiable in more than one of on mean arterial pressure in Spontaneously hypertensive these classes. For example, 2-Vinyl-3-phenyl-2-aminopropi ratS. onic acid derivatives are classified herein as tyrosine hydroxylase inhibitors, but Such derivatives may also act as 0020 FIG. 11 shows the effects of chronic i.v. infusion of dopa-decarboxylase inhibitors. The term “inhibitor com vehicle and Example #863 conjugate for 4 days on mean pound” means a compound of any of the three foregoing arterial preSSure in Spontaneously hypertensive rats. classes and which has the capability to inhibit formation of 0021 FIG. 12 shows the heart tissue concentrations of a benzylhydroxyamine intermediate involved in biosynthe norepinephrine following the 5 day infusion experiment sis of an adrenergic neurotransmitter. Thus, a compound described in FIG. 10. which does not inhibit formation of such benzylhy droxyamine intermediate is not embraced by the definition 0022 FIG. 13 shows the kidney tissue concentrations of of “inhibitor compound” as used herein. For example, norepinephrine following the 5 day infusion experiment compounds which do not inhibit a benzylhydroxyamine described in FIG. 10. intermediate are the compounds L-dopa and dopamine. US 2004/0101523 A1 May 27, 2004

0.030. A class of compounds from which a suitable yl, 4,5-dihydro-4-hydroxy-4-trifluoromethylthiazol3-yl, tyrosine hydroxylase inhibitor compound may be selected to 4-trifluoromethylthiazol-2-yl, imidazol-2-yl and 4,5-dihy provide the conjugate first residue is represented by Formula droimidazol-2-yl; wherein any two of the R through R' I: groups may be taken together to form a benzoheterocylic ring Selected from the group consisting of indolin-5-yl, 1-(N-benzoylcarbamimidoyl)indolini5-yl, 1-carbamim (I) idoylindolin-5-yl, 1H-2-oxindol-5-yl, insol-5-yl, 2-mercap R1 R3 O tobenzimidazol-5(6)-yl, 2-aminobenzimidazol-5-(6)-yl, l|l Is 2-methanesulfonamidobenzimidazol-5(6)-yl, 1H-benzox A. -ce anol-2-on-6-yl, 2-aminobenzothiazol-6-yl, 2-amino-4-mer R2 N-R captobenzothiazoló-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-di m hydro-2,2-dioxo-2,1,3-benzothiadiazol-5-yl, 1,3-dihydro-1, H 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-di 0031) wherein each of R through R is independently hydroxyquinoxalinó-yl and 2,3-didydro-3(4H)-oxo-1,4- Selected from hydrido, hydroxy, alkyl, cycloalkyl, benzoxazin-7-yl; 5-hydroxy-4H-pyran-4-on-2-yl, 2-hy cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, droxypyrid-4-yl, 2-aminopyrid-4-yl, 2-carboxypyrid-4-yl alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, and tetrazolo-1,5-apyrid-7-yl; and wherein A may be alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein R' Selected from Selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, R14 monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, R5 arylsulfinyl and arylsulfonyl; wherein R is selected from -OR and R16 Ul R18, R19 U R20 and R17 H H R21 M -N Y: 0032) wherein R is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl, and wherein 0034) wherein each of R'' through R' is independently each of R7 and R is independently selected from hydrido, Selected from hydrido, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, aryloxy, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, car alkoxycarboxyl, aryl, aralkyl, cyano, cyanoalkyl, amino, boxyl, amino, cyanoamino, monoalkylamino, dialkylamino, monoalkylamino and dialkylamino, wherein each of R and alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; R’ is independently selected from hydrido, alkyl, wherein m is a number Selected from Zero through Six; cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, wherein A is a phenyl ring of the formula alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, car boxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; or R10 R9 a pharmaceutically-acceptable Salt thereof. 0035) A preferred class of tyrosine hydroxylase inhibitor compounds within Formula I is provided by compounds of Formula II:

(II) R10 R9 0033 wherein each of R through R" is independently R1 R3 O Selected from hydrido, hydroxy, alkyl, cycloalkyl, | | | || cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalky R11 -ce lamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, 12 13 R2 i. -R alkenyl, cycloalkenyl, alkynyl, cyanoamino, carboxyl, R R H cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, carboxyalkoxy, formyl and a Sub stituted or unsubstituted 5- or 6-membered heterocyclic ring 0036) wherein each of R and R is hydrido; wherein m Selected from the group consisting of pyrrol-1-yl, 2-car is one or two; wherein R is selected from alkyl, alkenyl and boxypyrrol-1-yl, imidazol-2-ylamino, indol-1-yl, carboZol9 alkynyl; wherein R" is selected from hydrido, alkyl,

US 2004/0101523 A1 May 27, 2004

0270. Another preferred class of tyrosine hydroxylase 0274 Still another preferred class of tyrosine hydroxy inhibitor compounds within Formula I consists of com lase inhibitor compounds within Formula I is provided by pounds compounds of Formula Iv:

(IV) (III) R10 R9 R3 O | || R11 -c-r

R 12 R"13 -R

0271 wherein R is selected from alkyl, alkenyl and alkynyl; wherein R" is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, 0275 wherein each of R and R is hydrido; wherein m alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, car is a number Selected from Zero through five, inclusive; boxyl, amino, cyanoamino, monoalkylamino, dialkylamino, wherein R is selected from alkyl, alkenyl and alkynyl; alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein R" is selected from hydrido, alkyl, cycloalkyl, wherein m is a number Selected from Zero through five, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, inclusive; wherein R is selected from OR and aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein each of R'' through R7 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, car boxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alky nyl, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminom ethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, carboxyalkoxy and formyl. 0272 wherein R is selected from hydrido, alkyl, 0276 A preferred sub-class of compounds within For cycloalkyl, cycloalkylalkyl, phenalkyl and phenyl, and mula IV consists of L-O-methyltryptophan; D.L-5-methyl wherein each of R and R is independently selected from tryptophan, D.L-5-chlorotryptophan, D.L-5-bromotryp hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, tophan, D.L-5-iodotryptophan; L-5-hydroxytryptophan; cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxy D.L-5-hydroxy-O-methyltryptophan; C.-ethynyltryptophan; carbonyl, carboxyl, amino, cyanoamino, monoalkylamino, 5-methoxymethoxy-O-ethynyltryptophan; and 5-hydroxy dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and O-ethynyltryptophan. arylsulfonyl; wherein each of R through R" is indepen 0277 Still another preferred class of tyrosine hydroxy dently Selected from hydrido, hydroxy, alkyl, cycloalkyl, lase inhibitor compounds within Formula I is provided by cycloalkylalkyl, aralkyl, aryl, alkoxycarbonyl, alkoxy, ary compounds wherein A is loxy, aralkoxy, alkoxyalkyl, haloalkyl, alkoxycarbonyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialky lamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalk enyl and alkynyl. 0273 A preferred sub-class of compounds within For mula III consists of compounds wherein at least one of R', R'' and R' 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-methylbutyl esters of (+)-2-(4-hydroxyphe 0278 wherein R is selected from three, inclusive. More nyl)glycine; (+)-2-(4-hydroxyphenyl)glycine, (-)-2-(4-hy preferred compounds in this class are 2-Vinyl-2-amino-5- droxyphenyl)glycine; (+)-2-(4-methoxyphenyl-glycine; and aminopentanoic acid and 2-ethynyl-2-amino-5-aminopen (+)-2-(4-hydroxyphenyl)glycinamide. tanoic acid. US 2004/0101523 A1 May 27, 2004

0279 Still another preferred class of tyrosine hydroxy independently Selected from hydrido, alkyl, cycloalkyl, lase inhibitor compounds within Formula I is provided by hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, compounds of Formula V: aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, monoalkyl carbonylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,

(V) arylsulfonyl, alkenyl, cycloalkenyl and alkynyl, wherein any R" and R" 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 R" and R' cannot both be carboxyl at the same time, with the further proviso that when R is hydrido then R' cannot be carboxyl, and with the further proviso that at least one of R" through R' is a primary or Secondary amino group; or a pharmaceuti cally-acceptable Salt thereof. 0283) A preferred class of compounds within Formula VI consists of compounds wherein each of R through R' is independently Selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, 0280 wherein each of R and R is independently alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, amino, Selected from hydrido, hydroxy, alkyl, cycloakyl, cycloalky monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, lalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalky cyano, aminomethyl, carboxyalkoxy and formyl; wherein n lamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alk is a number from one through three; wherein each of R" and enyl, cycloalkenyl and alkynyl; wherein R is selected from R" is independently selected from hydrido, alkyl, hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxy haloalkyl, hydroxyalkyl, amino, mono-alkylamino, dialky carbonyl, carboxyl, amino, cyanoamino, monoalkylamino, lamino, carboxyl, carboxyalkyl and alkanoyl; and wherein dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and any R' and R' substituent having a substitutable position arylsulfonyl; wherein each of R through R is indepen may be further Substituted with one or more groups selected dently Selected from hydrido, hydroxy, alkyl, cycloalkyl, from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, alkoxycarbonyl. haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalky 0284. A more preferred class of compounds within For lamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, mula VI consists of those compounds wherein each of R alkenyl, cycloalkenyl, alkynyl, cyanoamino, carboxyl, through R' is independently selected from hydrido, cyano, thiocarbamoyl, aminomethyl, alkylsulfanamido, hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy, alkoxy nitro, alkylsulfonyloxy, alkoxy and formyl; wherein n is a alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, number Selected from Zero through five, inclusive, or a dialkylamino, carboxyl, carboxyalkyl, alkanoyl, pharmaceutically-acceptable Salt thereof. A more preferred cyanoamino, cyano, aminomethyl, carboxyl, carboxyalkoxy compound of this class is benzoctamine. and formyl; wherein n is one or two; wherein each of R' 0281. A class of compounds from which a suitable dopa and R" is independently selected from hydrido, alkyl, decarboxylase inhibitor compound may be Selected to pro benzyl, phenyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, vide the conjugate first residue is represented by Formula cyano, amino, monoalkylamino, dialkylamino, carboxyl, VI: carboxyalkyl and alkanoyl; and wherein any R' and R' Substituent having a Substitutable position may be further Substituted with one or more groups Selected from hydroxy (VI) alkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbo R39 R38 nyl. R36 R43 0285) An even more preferred class of compounds within R40 l \ Formula VI consists of those compounds wherein each of R through R' is independently selected from hydrido, k Yeti hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, R41 R42 monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein n is one or two, wherein 0282) wherein each of R through R' is independently each of R" and R" is independently selected from hydrido, Selected from hydrido, hydroxy, alkyl, cycloalkyl, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, carboxyl and carboxyalkyl; and wherein any R' and R' haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalky Substituent having a Substitutable position may be further lamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, Substituted with one or more groups Selected from hydroxy alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, thiocar alkyl, halo, haloalkyl, carboxyl, alkoxyalkyl, alkoxycarbo bamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfo nyl. nyloxy, carboxyalkoxy and formyl; wherein n is a number 0286 A more highly preferred class of compounds within from zero through four; wherein each of R" and R' is Formula VI consists of those compounds wherein each of US 2004/0101523 A1 May 27, 2004

R and R7 is hydrido and n is one; wherein each of R lamino with the proviso that R' and R' cannot both be through R' is independently selected from hydroxy, alkyl, carboxyl at the same time, and with the further proviso that alkoxy, haloalkyl, hydroxyalkyl, amino, monoalkylamino, at least one of R" through R" is a primary or secondary carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and amino group or a carboxyl group; or a pharmaceutically formyl; wherein each of R" and R" is independently acceptable Salt thereof. Selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, 0291. A preferred class of compounds within Formula amino, monoalkylamino, carboxyl and carboxyalkyl, and VII consists of those compounds wherein each of R' wherein any R' and R" substituent having a substitutable through R" is independently selected from hydrido, position may be further Substituted with one or more groups hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, Selected from hydroxyalkyl, halo, haloalkyl, carboxyl, alkoxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl. Compounds of Specific inter halo, cyano, amino, monoalkylamino, dialkylamino, car est are (2,3,4-trihydroxy)-benzylhydrazine, 1-(D.L-seryl boxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alky 2(2,3,4-trihydroxybenzyl)hydrazine (Benserazide) and 1-(3- nyl, cyanoamino, cyano, aminomethyl, carboxyalkoxy and hydroxylbenzyl)-1-methylhydrazine. formyl; wherein each of R' and R is independently 0287 Another more highly preferred class of compounds Selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, consists of those compounds wherein each of RandR is aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, independently Selected from hydrido, alkyl and amino and in amino, monoalkylamino, dialkylamino, carboxyalkyl and is two; wherein each of R through R' is independently alkanoyl and Selected from hydroxy, alkyl, alkoxy, haloalkyl, hydroxy alkyl, amino, monoalkylamino, carboxyl, carboxyalkyl, aminomethyl, carboxyalkoxy and formyl; wherein each of O R and R' is independently selected from hydrido, alkyl, haloalkyl, hydroxyalkyl, amino, monoalkylamino, carboxyl o CR51 and carboxyalkyl. Compounds of Specific interest are 2-hy drazino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid 0292 wherein R is selected from hydroxy, alkoxy, (Carbidopa), C.-(monofluoromethyl)dopa, C.-(difluorometh phenoxy, benzyloxy, amino, monoalkylamino and dialky yl)dopa and C.-methyldopa. lamino. 0288 Another class of compounds from which a suitable 0293. A more preferred class of compounds within For dopa-decarboxylase inhibitor compound may be Selected to mula VII consists of those compounds wherein each of R' provide the conjugate first residue is represented by Formula through R" is independently selected from hydrido, VII hydroxy, alkyl, benzyl, phenyl, alkoxy, benzyloxy, alkoxy alkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalky (VII) lamino, dialkylamino, carboxyl, carboxyalkyl, alkanoyl, R45 cyanoamino, cyano, aminomethyl, carboxyalkoxy and formyl; wherein each of R' and R's independently R6 Selected from hydrido, alkyl, benzyl, phenyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkyl and alkanoyl and

O 0289 wherein each of R" through R" is independently o CR51 Selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, alkoxyalkyl, 0294 wherein R is selected from hydroxy, alkoxy, haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino, amino and monoalkylamino. dialkylamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, cyano, thiocarbamoyl, 0295) An even more preferred class of compounds of aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, Formula VII consists of those compounds wherein each of carboxyalkoxy and formyl; wherein each of R' and R is R" through R" is independently selected from hydrido, independently Selected from hydrido, alkyl, cycloalkyl, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, amino, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, monoalkylamino, carboxyl, carboxyalkyl aminomethyl, car hydroxyalkyl, cyano, amino, monoalkylamino, dialky boxyalkoxy and formyl; wherein each of R' and R is lamino, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alky independently Selected from hydrido, alkyl, amino, nyl and monoalkylamino, carboxyalkyl and

O O | o CR51 o CR51

0290 wherein R is selected from hydroxy, alkoxy, 0296 wherein R is selected from hydroxy, alkoxy, aryloxy, aralkoxy, amino, monoalkylamino and dialky amino and monoalkylamino. US 2004/0101523 A1 May 27, 2004

0297. A highly preferred class of compounds within 0317 2,4-dimethoxy-5-1-oxo-3-(2-thienyl)-2-prope Formula VII consists of those compounds wherein each of nylbenzoic acid; R" through R" is independently selected from hydrido, hydroxy, alkyl, alkoxy and hydroxyalkyl; wherein each of 0318 2,4-dimethoxy-5-3-(4-methoxyphenyl)-1-oxo R and R is independently selected from alkyl, amino, 2-propenylbenzoic acid; monoalkylamino, and 0319 5-3-(4-chlorophenyl)-1-oxo-2-propenyl-2,4- dimethoxybenzoic acid; and O 0320 5-3-4-(dimethylamino)phenyl)-1-oxo-2-pro

o CR51 penyl-2,4 dimethoxybenzoic acid. 0321) Another class of compounds from which a suitable 0298 wherein R is selected from hydroxy, methoxy, dopa-decarboxylase inhibitor may be Selected to provide the ethoxy, propoxy, butoxy, amino, methylamino and ethy conjugate first residue is represented by Formula VIII: lamino. 0299. A more highly preferred class of compounds within (VIII) Formula VII consists of those compounds wherein said R60 R59 inhibitor compound is Selected from endo-2-amino1,2,3,4- R57 R56 R55 R53 O tetrahydro-1,2-ethanonaphthalene-2-carboxylic acid; ethyl 61 | || || ||s endo-2-amino-1,2,3,4-tetra-hydro-1,4-ethano-naphthalene R CFC CR R58 R54 2-carboxylate hydrochloride; exo-2-amino1,2,3,4- i. tetrahydro-1,4-ethanonaphthalene-2-carboxylic acid; and R62 R63 ethyl-exo-2-amino-1,2,3,4-tetrahydro-1,4-ethano-naphtha lene-2-carboxylate hydrochloride. 0300 Another family of specific dopa-decarboxylase 0322 wherein R is selected from hydrido, OR'' and inhibitor compounds consists of 0301) 2,3-dibromo-4,4-bis(4-ethylphenyl)-2-butenoic R65 M acid; -N 0302) 3-bromo-4-(4-methoxyphenyl)-4-oxo-2- Yo butenoic acid; 0303 N-(5-phosphopyridoxyl)-L-3,4-dihydroxyphe nylalanine; 0323 wherein R' is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl and phenyl, and 0304) N-(5-phosphopyridoxyl)-L-m-aminotyrosine; wherein each of RandR is independently selected from 0305 D.L-B-(3,4-dihydroxyphenyl)lactate; hydrido, alkyl, alkanoyl, amino, monoalkylamino, dialky lamino, phenyl and phenalkyl; wherein each of R, R and 0306 D.L-B-(5-hydroxyindolyl-3)lactate; R7 through R is independently selected from hydrido, 0307 2,4-dihydroxy-5-(1-oxo-2-propenyl)benzoic hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxycarbonyl, hydroxyalkyl, halo, cyano, amino, acid; monoalkylamino, dialkylamino, carboxyl, carboxyalkyl, 0308) 2,4-dimethoxy-5-1-oxo-3-(2,3,4-trimethox alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein each of yphenyl-2-propenylbenzoic acid; R and R is independently selected from hydrido, alkyl, 0309 2,4-dihydroxy-5-1-oxo-3-(2-thienyl)-2-prope cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, halo, nylbenzoic acid; haloalkyl, hydroxyalkyl and carboxyalkyl, wherein each of m and n is a number independently Selected from Zero 0310 2,4-dihydroxy-5-3-(4-hydroxyphenyl)-1-oxo through Six, inclusive; or a pharmaceutically-acceptable Salt 2-propenylbenzoic acid; thereof. 0311 5-3-(4-chlorophenyl)-1-oxo-2-propenyl-2,4- 0324. A preferred class of compounds of Formula VIII dihydroxybenzoic acid; consists of those compounds wherein R’ is OR wherein 0312 2,4-dihydroxy-5-(1-oxo-3-phenyl-2-propenyl R is Selected from hydrido, alkyl, cycloalkyl, cycloalkyla lkyl, benzyl and phenyl; wherein each of R, R and R7 )benzoic acid; through R is independently selected from hydrido, alkyl, 0313 2,4-dimethoxy-5-1-oxo-3-(4-pyridinyl)-2-pro cycloalkyl, hydroxy, alkoxy, benzyl and phenyl, wherein penylbenzoic acid; each of RandR is independently selected from hydrido, 0314) 5-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl alkyl, cycloalkyl, benzyl and phenyl; wherein each of m and 2,4 dimethoxybenzoic acid; n is a number independently Selected from Zero through three, inclusive. 0315 2,4-dimethoxy-5-(1-oxo-3-phenyl-2-propenyl 0325 A more preferred class of compounds of Formula )benzoic acid; VIII consists of those compounds wherein R is OR' 0316 5-3-(2-furanyl)-1-oxo-2-propenyl-2,4- wherein R' is selected from hydrido and lower alkyl; dimethoxybenzoic acid; wherein each of R through R is hydrido; wherein each of US 2004/0101523 A1 May 27, 2004

R” through R is independently selected from hydrido, 0340 wherein B is selected from aryl, an ethylenic moi alkyl, hydroxy and alkoxy, with the proviso that two of the ety, an acetylenic moiety and an ethylenic or acetylenic R” through R. Substituents are hydroxy; wherein each of m moiety Substituted with one or more radicals Selected from and n is a number independently Selected from Zero through Substituted or unsubstituted alkyl, aryl and heteroaryl; two, inclusive. wherein each of R7 and R is independently selected from 0326. A preferred compound within Formula IX is 3-(3, hydrido, alkyl, alkenyl and alkynyl; wherein R is selected 4-dihydroxyphenyl)-2-propenoic acid, also known as caffeic from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, acid. cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxy 0327. Another class of compounds from which a suitable carbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dopa-decarboxylase inhibitor compound may be Selected to dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and provide the conjugate first residue is a class of aromatic arylsulfonyl, and wherein n is a number Selected from Zero amino acid compounds comprising the following Subclasses through five. of compounds: 0328 amino-haloalkyl-hydroxyphenyl propionic 0341) A preferred class of compounds of Formula IX acids, Such as 2-amino-2-fluoromethyl-3-hydroxy consists of those compounds wherein B is phenyl or hydrox phenylpropionic acid; yphenyl; wherein R is ethenyl or ethynyl; or an acetylenic moiety Substituted with an aryl or heteroaryl radical; and 0329 alpha-halomethyl-phenylalanine derivatives Such as alpha-fluoroethylphenethylamine; and wherein n is a number from Zero through three. indole-Substituted halomethylamino acids. 0342 Another preferred class of compounds of Formula 0330 IX consists of those compounds wherein B is an ethylenic or 0331 Still other classes of compounds from which a acetylenic moiety incorporating carbon atoms in the beta Suitable dopa-decarboxylase inhibitor compound may be and gamma-positions relative to the nitrogen atom; and Selected to provide the conjugate first residue are as follows: wherein n is Zero or one. More preferred are compounds 0332 isoflavone extracts from fungi and streptomy wherein the ethylenic or acetylenic moiety is Substituted at ces, such as 3',5,7-trihydroxy-4,6-dimethoxyisofla the gamma carbon with an aryl or heteroaryl radical. Even vone, 3',5,7-trihydroxy-4,8-dimethoxyisoflavone more preferred are compounds wherein Said aryl radical is and 3',8-dihydroxy-4, 6,7-trimethoxy isoflavone; Selected from phenyl, 2-thiophene, 3-thiophene, 2-furanyl, 0333 sulfinyl substituted dopa and tyrosine deriva 3-furanyl, oxazolyl, thiazolyl and isoxazolyl, any one of which radicals may be Substituted with one or more groups tives such as shown in U.S. Pat. No. 4,400,395 the Selected from halo, hydroxyl, alkyl, haloalkyl, cyano, content of which is incorporated herein by reference; alkoxy, alkoxyalkyl and cycloalkyl. More highly preferred 0334 hydroxycoumarin derivatives such as shown are compounds wherein Said aryl radical is Selected from in U.S. Pat. No. 3,567,832, the content of which is phenyl, hydroxyphenyl, 2-thiophene and 2-furanyl; and incorporated herein by reference; wherein each of R, R and R is hydrido. 0335 l-benzylcyclobutenyl alkyl carbamate deriva 0343 A family of specifically-preferred compounds tives such as shown in U.S. Pat. No. 3,359,300, the within Formula IX consists of the compounds 3-amino-2- content of which is incorporated herein by reference; (2'-thienyl)propene; 3-amino-2-(2-thienyl)butene; 3-(N- 0336 arylthienyl-hydroxylamine derivatives such methylamino)-2-(2-thienyl)propene; 3-amino-2-(3'-thienyl as shown in U.S. Pat. No. 3,192,110, the content of )propene; 3-amino-2-(2'furanyl)propene; 3-amino-2-(3'- which is incorporated herein by reference, and furanyl)propene; 1-phenyl-3aminopropyne; and 3-amino-2- 0337 B-2-substituted-cyclohepta-pyrrol-8-1H-on phenylpropene. Another family of Specifically-preferred compounds of Formula VIII consists of the compounds 7-yl alanine derivatives. (+)4-amino-3-phenyl-1-butyne; (+)4-amino-3-(3'-hydrox 0338 Suitable dopamine-B-hydroxylase inhibitors may yphenyl)-1-butyne; (+)4-amino-3-(4-hydroxyphenyl)-1-bu be generally classified mechanistically as chelating-type tyne; (+)4-amino3-phenyl-1-butene; (+)4-amino-3-(3'-hy inhibitors, time-dependent inhibitors and competitive inhibi droxyphenyl)-1-butene; and (+)4-amino-3-(4- torS. hydroxyphenyl)-1-butene. 0339. A class of compounds from which a suitable dopamine-B-hydroxylase inhibitor may be selected to pro 0344) Another class of compounds from which a suitable vide the conjugate first residue consists of time-dependent dopamine-B-hydroxylase inhibitor may be selected to pro inhibitors represented by Formula IX: vide the conjugate first residue is represented by Formula X:

(IX) (X) | B C N V R68 H 0345 wherein W is selected from alkyl, cycloalkyl, alk enyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, US 2004/0101523 A1 May 27, 2004 aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein Y is preferred are compounds wherein R" is selected from Selected from hydrido, alkyl and amino; wherein each of R7 and R' is independently Selected from hydrido, amino, monoalky lamino and carboxyl, and wherein each of p and q is independently Selected from the numbers two and three. Most preferred are compounds wherein R' is hydrido; r wherein each of R'' and R' is hydrido; and wherein each of -N N R70 p and q is two. 0351. Another class of compounds from which a suitable S dopamine-B-hydroxylase inhibitor may be selected to pro vide the conjugate first residue is represented by Formula 0346) wherein R' is selected from hydrido, alkyl, XI: cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, car boxyl, amino, cyanoamino, monoalkylamino, dialkylamino, (XI) alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; O wherein each of Q and T is one or more groups indepen E-C-F dently selected from 0352 wherein E is selected from alkyl, cycloalkyl, alk enyl, alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl; wherein F is Selected from knC s CEC and --CEC-H R75 R77 A 0347 wherein each of R7 through R7 is independently -Z C N Selected from hydrido, hydroxy, alkyl, cycloalkyl, V cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, R76 H alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, 0353 wherein Z is selected from O, S and N-R7; alkanoyl, alkenyl, cycloalkenyl and alkynyl, or a pharma wherein each of R' and R' is independently selected from ceutically-acceptable Salt thereof. hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, 0348. A preferred class of compounds within Formula X hydroxyalkyl, halo, cyano, amino, minoalkylamino, dialky consists of compounds wherein W is heteroaryl and Y is lamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalk enyl and alkynyl; wherein R' and R' may form oxo or thio; wherein r is a number Selected from Zero through Six, inclusive; wherein each of R77 and R 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 accept able Salt thereof. 0354 Another class of compounds from which a suitable dopamine-B-hydroxylase inhibitor may be selected to pro vide the conjugate first residue is represented by Formula 0349 wherein R' is selected from hydrido, alkyl, amino, XII: monoalkylamino, dialkylamino, phenyl and phenalkyl, wherein each of R7 and R' is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzy (XII) loxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, R83 monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number inde R84 R82 5 3 pendently Selected from one through Six, inclusive. O R79 81 Q 1.119 | J. 0350 A more preferred class of compounds of Formula X R85 N C-Y-C N consists of wherein R' is selected from hydrido, alkyl, V amino and monoalkylamino; wherein each of R'' and R' is R80 H independently Selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number indpen 0355 wherein each of R through R is independently dently Selected from two through four, inclusive. Even more Selected from hydrido, alkyl, haloalkyl, mercapto, alkylthio, US 2004/0101523 A1 May 27, 2004 cyano, alkoxy, alkoxyalkyl and cycloalkyl, wherein Y is 0380 Another preferred class of compounds within For Selected from Oxygen atom and Sulfur atom; wherein each of mula XII consists of those compounds of Formula XIII: R'' and R is independently selected from hydrido and alkyl; wherein R is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, (XIII) alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, car boxyl, 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. 0356. A preferred family of compounds of Formula XII consists of those compounds wherein each of R° through R is independently selected from hydrido, alkyl and haloalkyl, wherein Y is Selected from oxygen atom or Sulfur 0381 wherein each of R, R7 and R through R is atom; wherein each of R', R and R is independently independently Selected from hydrido, hydroxy, alkyl, hydrido and alkyl, and wherein m is a number Selected from cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, one through four, inclusive. aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, 0357. A family of preferred specific compounds within amino, monoalkylamino, dialkylamino, carboxy, carboxy Formula XII consists of the following compounds: alkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein aminomethyl-5-n-butylthiopicolinate; R and R together may form oxo or thio; wherein r is a 0358) number Selected from Zero through six, inclusive, wherein 0359 aminomethyl-5-n-butylpicolinate; each of RandR is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, 0360 2-aminoethyl-5-n-butylthiopicolinate; alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, car 0361 2-aminoethyl-5-n-butylpicolinate; boxyl, amino, cyanoamino, monoalkylamino, dialkylamino, 0362 (2-amino-1", 1'-dimethyl)ethyl-5-n-butylthiopi alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl. colinate; 0382. A more preferred class of compounds within For mula XIII consists of those compounds wherein each of R, 0363 (2-amino-1", 1'-dimethyl)ethyl-5-n-butylpicoli R7 and R through R is independently selected from nate, hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzy 0364 (2-amino-1'-methyl)ethyl-5-n-butylthiopicoli loxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, nate, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl, wherein r is a number Selected from Zero through 0365 (2-amino-1'-methyl)ethyl-5-n-butylpicolinate; four, inclusive; wherein each of R and R is indepen 0366 3'-aminopropyl-5-n-butylthiopicolinate; dently Selected from hydrido, alkyl, amino, monoalky lamino, dialkylamino, phenyl and phenalkyl. 0367 3'-aminopropyl-5-n-butylpicolinate; 0383 An even more preferred class of compounds within 0368 (2-amino-2'-methyl)propyl-5-n-butylthiopicoli Formula XIII consists of those compounds wherein each of nate, R, R7 and R' through R is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, 0369 (2-amino-2'-methyl)propyl-5-n-butylpicolinate; carboxy, carboxyalkyl and alkanoyl; and wherein r is a 0370 (3'-amino-1' 1'-dimethyl)propyl-5-n-butylthi number Selected from Zero through three, inclusive, and opicolinate, wherein each of RandR is selected from hydrido, alkyl, amino and monoalkylamino. Most preferred are compounds 0371 (3'-amino-1", 1'-dimethyl)propyl-5-n-butylpi wherein each of R' through R is independently selected colinate; from hydrido and alkyl; wherein each of R and R7 is 0372 (3'-amino-2 2'-dimethyl)propyl-5-n-butylthi hydrido; wherein r is Selected from Zero, one and two; opicolinate, wherein R is selected from hydrido, alkyl and amino; and wherein R is selected from hydrido and alkyl. Especially 0373) (3'-amino-2, 2'-dimethyl)propyl-5-n-butylpi preferred within this class is the compound 5-n-butylpi colinate; colinic acid hydrazide (fusaric acid hydrazide) shown 0374 2-aminopropyl-5-n-butylthiopicolinate; below: 0375 2-aminopropyl-5-n-butylpicolinate; 0376 4'-aminobutyl-5-n-butylthiopicolinate; 21 0377 4-amino-3'-methyl)butyl-5-n-butylthiopicoli N NH n nate, 0378 (3'-amino-3'-methyl)butyl-5-n-butylthiopicoli nate, 0379 and (3'-amino-3'-methyl)butyl-5-n-butylpicoli 0384 Another class of compounds from which a suitable nate. dopamine-B-hydroxylase inhibitor compound may be US 2004/0101523 A1 May 27, 2004

Selected to provide the conjugate first residue is represented 0389. A preferred family of compounds within Formula by Formula XIV: XIV consists of those compounds characterized as chelat ing-type inhibitors of Formula XV: (XIV) R96 96 (XV) R R97 R95 R97 R95

R98 N R94 O O R98 N Josio

0385) wherein each of R' through R is independently 0390 wherein each of R through R' is independently Selected from hydrido, hydroxy, alkyl, cycloalkyl, phenyl, Selected from hydrido, hydroxy, alkyl, cycloalkyl, benzyl, alkoxy, phenoxy, benzyloxy, alkoxyalkyl, hydroxy cycloalkylalkyl, aralkyl, aryl, aryloxy, alkoxy, alkylthio, alkyl, halo, cyano, amino, monoalkylamino, dialkylamino, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, amino, monoalkylamino, dialkylamino, amido, alkylamido, alkanoyl, cyanoamino, carboxyl, thiocarbamoyl, aminom hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, ethyl, nitro, formoyl, formyl and alkoxycarbonyl, and cycloalkenyl, alkynyl, cyanoamino, carboxyl, tetrazolyl, wherein R' is selected from hydrido, alkyl, phenyl and thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, benzyl. alkylsulfonyloxy, formoyl and alkoxycarbonyl; with the 0391) A class of specifically-preferred compounds of proviso that at least one of R' through R' is Formula XV consists of 0392) 5-n-butylpicolinic acid (fusaric acid); - (-CH2-), A 0393) 5-ethylpicolinic acid; 0394 picolinic acid; 0386 wherein A' is 0395 5-nitropicolinic acid; 0396) 5-aminopicolinic acid; O R101 0397) 5-N-acetylaminopicolinic acid; A -CR99 or -N 0398) 5-N-propionylaminopicolinic acid; R102 0399) 5-N-hydroxyaminopicolinic acid; 04.00 5-iodopicolinic acid; 0387 wherein R' is selected from hydrido, alkyl, 0401) 5-bromopicolinic acid; hydroxy, alkoxy, alkylthio, phenyl, phenoxy, benzyl, ben 5-chloropicolinic acid; Zyloxy, 0402 0403) 5-hydroxypicolinic acid 04.04 5-methoxypicolinic acid; 0405 5-N-propoxypicolinic acid; O R104, 0406) 5-N-butoxypicolinic acid; 0407) 5-cyanopicolinic acid; 5-carboxylpicolinic acid; 0388 wherein R' is selected from hydrido, alkyl, 0408) cycloalkyl, cycloalkylalkyl, phenyl and benzyl, wherein 04.09 5-n-butyl-4-nitropicolinic acid; each of R', R', R'' and R' is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, 0410 5-n-butyl-4-methoxypicolinic acid; cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxy 0411 5-n-butyl-4-ethoxypicolinic acid; carbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and 0412 5-n-butyl-4-aminopicolinic acid; arylsulfonyl, wherein t is a number Selected from Zero 0413 5-n-butyl-4-hydroxyaminopicolinic acid; and through four, inclusive, or a pharmaceutically-acceptable Salt thereof. 0414 5-n-butyl-4-methylpicolinic acid. US 2004/0101523 A1 May 27, 2004

0415 Especially preferred of the foregoing class of com 0421. A more preferred class of compounds within For pounds of Formula XV is the compound 5-n-butylpicolinic mula XVI consists of those compounds of Formula XVII: acid (fusaric acid) shown below: (XVII) CHCH2CH2CH2 R107 O O Ol R10's--CH-i-ÖH-6-N SR 111 N COH 0422 wherein R'' is selected from hydroxy and lower alkyl; wherein R' is selected from hydrido and lower alkyl; wherein R' is selected from hydrido and 0416) Another class of compounds from which a suitable dopamine-B-hydroxylase inhibitor may be selected to pro vide the conjugate first residue consists of azetidine-2- O carboxylic acid derivatives represented by Formula XVI:

(XVI) 0423 with R' selected from lower alkyl and phenyl and R 106 V is a number from Zero to two, inclusive. 0424. A more preferred class of compounds within For in l CH |R mula XVII consists of those compounds wherein R' is R109-S-CH CH-C-N-CH-CR10 hydroxy; wherein R'97 is hydrido or methyl; wherein R' is w hydrido or acetyl, and wherein n is a number from Zero to two, inclusive. 0425 Most preferred within the class of compounds of 0417 wherein R' is hydrido, hydroxy, alkyl, amino and Formula XVII are the compounds 1-(3-mercapto-2-methyl alkoxy; wherein R' is selected from hydrido, hydroxy and 1-oxopropyl)-L-proline and 1-(2-mercaptoacetyl)-L-proline alkyl; wherein each of R'' and R' is independently (also known as captopril). selected from hydrido, alkyl and phenalkyl; wherein R' is 0426. Another class of compounds from which a suitable dopamine-B-hydroxylase inhibitor compound may be selected from hydrido and Selected to provide the conjugate first residue is represented by Formula XVIII:

R110C (XVIII) 113 R N X-RI 0418 with R' selected from alkyl, phenyl and phe R114 nalkyl, wherein u is a number from one to three, inclusive; CH and wherein V is a number from Zero to two, inclusive, or a pharmaceutically-acceptable Salt thereof. R115 R119 0419) A preferred class of compounds within Formula XVI consists of those compounds wherein R' is selected R116 R118 from hydroxy and lower alkoxy; wherein R' is hydrido; R117 wherein R' is selected from hydrido and lower alkyl; wherein R' is hydrido; wherein R' is selected from hydrido and 0427 wherein each of R' through R' is independently Selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aralkyl, aryl, alkoxy carbonyl, hydroxyalkyl, halo, haloalkyl, cyano, amino, ami noalkyl, monoalkylamino, dialkylamino, carboxyl, carboxy R110C alkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, mercapto and alkylthio; or a pharmaceutically-acceptable Salt thereof. 0428 A first preferred class of compounds within For mula XVIII consists of those compounds wherein R' is 0420 with R' selected from lower alkyl and phenyl; selected from mercapto and alkylthio; wherein each of R' wherein u is two; and wherein V is a number from Zero to and R''' is independently selected from hydrido, amino, two, inclusive. aminoalkyl, monoalkylamino, monoalkylaminoalkyl, car US 2004/0101523 A1 May 27, 2004 boxyl and carboxyalkyl; wherein each of R'' and R' is is hydroxy; wherein R' is hydrido; and wherein R'' is hydrido; and wherein each of R', R'7 and R'' is inde Selected from pendently Selected from hydrido, hydroxy, alkyl, halo and haloalkyl, or a pharmaceutically-acceptable Salt thereof. O 0429. A second preferred class of compounds within -CR 155 Formula XVIII consists of those compounds wherein R' is Selected from amino, aminoalkyl, monoalkylamino, monoalkylaminoalkyl, carboxy and carboxyalkyl, wherein 0436 wherein R is selected from methyl, ethyl, n-pro each of R', R'', R'' and R'' is hydrido; and wherein pyl, isopropyl, n-butyl, Sec-butyl, iso-butyl, tert-butyl, each of R'', R'7 and R'' is independently selected from n-pentyl, neopentyl, n-hexyl and chloromethyl. hydrido, hydroxy, alkyl, halo and haloalkyl, or a pharma ceutically-acceptable Salt thereof. 0437. A most highly preferred compound of Formula XIX is N-acetyl-y-glutamic acid which provides a residue 0430 Compounds which fall within any of the aforemen for the Second component of a conjugate of the invention as tioned inhibitor compounds, but which lack a reactive acid shown below: 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 COOH on acidic moiety are the following: 1-(3,5-dihaloaryl)imi - CCH2CH2CHNHCCH dazol-2-thione derivatives such as 1-(3,5-difluoroben Y B C. Zyl)imidazol-2-thione; and hydroxyphenolic derivatives O Such as resorcinol. 0431. The second component of a conjugate of the inven 0438. The phrase “terminal primary or secondary amino tion is provided by a residue which forms a kidney-enzyme moiety or a moiety convertible to a primary or Secondary cleavable bond with the residue of the first-component AII amino terminal moiety' characterizes a structural require antagonist compound. Such residue is preferably Selected ment for Selection of a Suitable angiotensin II antagonist from a class of compounds of Formula XIX: 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 (XIX) O Second residue to form a kidney-enzyme-specific hydrolyZ able bond. C GCCHCHCH RS 0439. The first component used to form the conjugate of Y B C \/ the invention provides a first residue derived from an N inhibitor compound capable of inhibiting formation of a V R151 benzylhydroxylamine intermediate involved in the biosyn thesis of an adrenergic neurotransmitter, hereinafter gener ally referred to as an “inhibitor compound'. In one embodi ment of the invention, the first component used to form a 0432 wherein each of R'' and R'' may be indepen conjugate of the invention provides a first residue containing dently Selected from hydrido, alkylcarbonyl, alkoxycarbo a terminal primary or Secondary amino moiety. Examples of nyl, alkoxyalkyl, hydroxyalkyl and haloalkyl, and wherein Such terminal amino moiety are amino and linear or G is selected from hydroxyl, halo, mercapto, - OR 152, branched aminoalkyl moieties containing linear or branched -SR and alkyl groups Such as aminomethyl, aminoethyl, aminopro pyl, aminoisopropyl, aminobutyl, aminoSecbutyl, ami noisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoneopentyl. NR154 / 0440. 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 0433 with each R', R' and R'' is independently containing a moiety convertible to a primary or Secondary selected from hydrido and alkyl, with the proviso that said amino terminal moiety. An example of a moiety convertible Formula XIX compound is selected such that formation of to an amino terminal moiety is a carboxylic acid group the cleavable bond occurs at carbonyl moiety attached at the reacted with hydrazine So as to convert the acid moiety to gamma-position carbon of Said Formula XIX compound. carboxylic acid hydrazide. The hydrazide moiety thus con tains the terminal amino moiety which may then be further 0434 More preferred are compounds of Formula XIX reacted with the carboxylic acid containing residue of the wherein each G is hydroxy. Second component to form a hydrolyzable amide bond. Such hydrazide moiety thus constitutes a “linker group between 0435 A more highly preferred class of compounds within the first and Second components of a conjugate of the Formula XIX consists of those compounds wherein each G invention. US 2004/0101523 A1 May 27, 2004

0441 Suitable linker groups may be provided by a class of diamino-terminated linker groups based on hydrazine as TABLE I-continued defined by Formula XX:

XX R200 R201 R200 R201 (XX) I = inhibitor -- cur T = acetyl-Y-glutamyl

LINKER 0442 wherein each of R'' and R' may be indepen NO. R200 R201 dently Selected from hydrido, alkyl, cycloalkyl, cycloalky 34 O CH3 CH3 lalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, 35 O CH1(cyclo) CH1(cyclo) amino, monoalkylamino, dialkylamino, cyanoamino, car 36 O CHs CHs boxyalkyl, alkylsulfino, alkylsulfonyl, arylsulfinyl and aryl 37 O CHCH CHCH Sulfonyl, and wherein n is Zero or a number Selected from 38 3 H H three through seven, inclusive. In Table I there is shown a 39 3 CH H class of Specific examples of diamino-terminated linker 40 3 H CH, 41 3 CHs H groups within Formula XX, identified as Linker Nos. 1-73. 42 3 H CHs These linker groups would be Suitable to form a conjugate 43 3 CH CHs between a carbonyl moiety of an inhibitor compound residue 44 3 CHs CH (designated as “I”) and a carbonyl moiety of a carbonyl 45 3 CHCH H terminated Second residue Such as the carbonyl moiety 46 3 H CHCH attached to the gamma carbon of a glutamyl residue (des 47 4 H H ignated as “T”). 48 4 CH H 49 4 H CH TABLE I 50 4 CHs H 51 4 H CHs 52 4 CH, CHs 53 4 CHs CH R200 R201 54 4 CHCH H 55 4 H CHCH I = inhibitor 56 5 H H T = acetyl-Y-glutamyl 57 5 CH, H 58 5 H LINKER 59 5 CHs H NO. R200 R201 60 5 H CHs 61 5 CH CHs 1. O H H 62 5 CHs CH 2 O CH H 63 5 CHCH H 3 O CHs H 4 O CH, H 64 5 H CHCH 5 O CH(CH), H 65 6 H H 6 O CHg H 66 6 CH H 7 O CH(CH)CHCH, H 67 6 H CH 8 O C(CH)3 H 68 6 CHs H 9 O C5Ho H 1O O CH1(cyclo) H 69 6 H CHs 11 O CHs H 70 6 CH CHs 12 O CHCH H 71 6 CHs CH 13 O H CH 72 6 CHCH H 14 O H CHs 73 6 H CHCH 15 O H CH, 16 O H CH(CH), 17 O H CHg 18 O H CH(CH)CHCH, 19 O H C(CH), 0443 Another class of suitable diamino terminal linker 2O O H C5Ho groups is defined by Formula XXI: 21 O H CH3 22 O H CHs 23 O H CHCH 24 O H CH1(cyclo) (XXI) 25 O CH3 H 26 O CH CH 27 O CHs CHs 28 O CH, CH, 29 O CH(CH), CH(CH), 3O O CHg CHg 31 O CHCH.)cK2CH, CH(CH)Qi2CH, 32 O C(CH), C(CH), 33 O C5Ho C5Ho US 2004/0101523 A1 May 27, 2004

0444 wherein each of Q and T is one or more groups boxyalkyl and alkanoyl; and wherein each of p and q is a independently Selected from number independently Selected from one through Six, inclu sive; with the proviso that when each of R'' and R' is Selected from halo, hydroxy, amino, monoalkylamino and R202 R204 R205 dialkylamino, then the carbon to which R' or R' is attached in Formula XXII is not adjacent to a nitrogen atom C and CEC of Formula XXII. kn 0448. A more preferred class of linker groups of Formula XXII consists of divalent radicals wherein each of R'' and R” is independently selected from hydrido, hydroxy, alkyl, 0445 wherein each of R' through R' is independently alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and Selected from hydrido, hydroxy, alkyl, cycloalkyl, alkanoyl; and wherein each of p and q is a number inde cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, pendently Selected from two through four, inclusive. Even alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, more preferred are linker groups wherein each of R'' and monoalkylamino, dialkylamino, carboxy, carboxyalkyl, R” is independently selected from hydrido, amino, alkanoyl, alkenyl, cycloalkenyl and alkynyl. monoalkylamino and carboxyl; and wherein each of p and q is independently Selected from the numbers two and three. 0446. A preferred class of linker groups within Formula Most preferred is a linker group wherein each of R° and XX is defined by Formula XXII: R 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 (XXII) R202

R203 R202 0449 In Table II there is shown a class of specific examples of cyclized, diamino-terminated linker groups R203 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 0447 wherein each of R' and R is independently (designated as “I”) and a carbonyl moiety of carbonyl Selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, terminated Second residue Such as the carbonyl moiety alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, attached to the gamma carbon of a glutamyl residue (des halo, amino, monoalkylamino, dialkylamino, carboxy, car ignated as “T”).

R206 w R211 R207 R210

I = inhibitor T = acetyl-Y-glutamyl

LINKER No. R206 R207 R208 R209 R210 R211 22 R213

74 H. H. H. H. H. H. H. H 75 CH, H. H. H. H. H. H. H 76 H H. H. H CH, H. H. H 77 CH, H. H. H CH, H. H. H 78 CH, H CH, H. H. H. H. H 79 CH, H. H. H. H. H CHH 80 CH, CH, H H. H. H. H. H 81 H H. H. H CH, CH, H H 82 CH CH, H H CH, CH, H H 83 CH, CH, CH, CH, H H. H. H 84 CH CH, H H. H. H CH, CH 85 H. H. H. H CH, CH, CH, CH US 2004/0101523 A1 May 27, 2004

-continued R")-(-RiR209 R212 I-N N-T

R206 SR211 R207 R210

I = inhibitor T = acetyl-Y-glutamyl

LINKER No. R2O6 R2O7 R208 R209 R210 R211 22 R213

86 CHs H H H H H H H 87 H H H H CHs H H H 88 CHs H H H CHs H H H 89 CHs H H H H H CH5H 90 CHs H CHs H H HH H 91 CHCH H H H H HH H 92 H H H H CHCH HH H 93 CHCH H H H CHCH H H H 94 CHCH H H H H H CHCHH 95 CHCH H CHCH H H H H H

0450 Another class of Suitable diamino terminal linker 0452. A preferred class of linker groups within Formula groups is defined by Formula XXIII: XXIII consists of divalent radicals wherein each of R'' and R’ is hydrido; wherein each of R'' and R-7 is indepen dently Selected from hydrido, alkyl, phenalkyl, phenyl, (XXIII) alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl, and R214 R216 R215 wherein p is two or three. A more preferred class of linker | | | | | groups within Formula XXIII consists of divalent radicals -N-C-HN wherein each of R'' and R' is hydrido; wherein each of lar R'' and R7 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 0451 wherein each of R' through R7 is independently Specific examples of diamino-terminated linker gorups Selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, within Formula XXIII. These linker groups, identified as Linker Nos. 96-134, would be suitable to form a conjugate hydroxyalkyl, alkoxyalkyl, aralkyl, aryl, haloalkyl, amino, between a carbonyl moiety of an inhibitor compound residue monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, (designated as “I”) and a carbonyl moiety of carbonyl alkylsulfino, alkylsulfonyl, arylsulfinyl and arylsulfonyl, terminated Second residue Such as the carbonyl moiety and wherein p is a number Selected from one through Six attached to the gamma carbon of a glutamyl residue (des inclusive. ignated as “T”).

TABLE III R220 R222

I-N-C-C-N-T R218 R221 R223 R219

I = inhibitor G = acetyl-Y-glutamyl

LINKER NO. R218 R219 R220 R221 R222 R223

96 H H H H H H 97 H H H H H CH, 98 H H H CH H H 99 H H H CH H CH 1OO CH, H H H H H US 2004/0101523 A1 May 27, 2004 21

TABLE III-continued R220 R222 I-N-C-C-N-Tki ka ka ki

I = inhibitor G = acetyl-Y-glutamyl

LINKER NO. R218 R219 R220 R221 R222 R223 O1 H CH, H H H O2 H H H H CH O3 H H CH CH H 04 CH CH H H H O5 H H H H H O6 H H H CHs H O7 H. H H CHs H 08 CHs H H H H O9 H CHs H H H 10 H H H H CHs 11 H H C5Hs CHs H 12 CHs CHs H H H 13 H H H H H 14 H H H CHs H 15 H. H H CHs H 16 CHs H H H H 17 H CHs H H H 18 H H H H CHs C 2 Hs 19 H H CHs CHs H 20 CHs CHs H H H 21 CH H CHs H H 22 CH, H H H CHs 23 H CH CHs H H 24 H CH, H H CHs 25 CH, CH H CHs H 26 CH CH H H H C 6 Hs 27 H. H H H H C H 2 C 6 Hs 28 H H H CHCHs H 29 CHCHs H H H H 3O H CHCHs H H H 31 CH H CHCHs H H 32 CH, H H H CHCH 33 H CH CHCHs H H 34 H CH H H CHCH

0453 The term “hydrido” denotes a single hydrogen cyclobutyl, cyclohexyl and cycloheptyl. The term atom (H). This hydrido group may be attached, for example, “haloalkyl embraces radicals wherein any one or more of to an oxygen atom to form a hydroxyl group, or as another the carbon atoms is Substituted with one or more halo example, two hydrido groups may be attached to a carbon groups, preferably Selected from bromo, chloro and fluoro. atom to form a divalent -CH2-group, that is, a “meth Specifically embraced by the term “haloalkyl” are monoha ylene' group; or as another example, one hydrido group may loalkyl, dihaloalkyl and polyhaloalkyl groups. A monoha be attached to a carbon atom to form a trivalent loalkyl 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 -CH different halo groups. Examples of a dihaloalkyl group are V dibromomethyl, dichloromethyl and bromochloromethyl. Examples of a polyhaloalkyl are trifluoromethyl, 2,2,2- trifluoroethyl, perfluoroethyl and 2,2,3,3-tetrafluoropropyl 0454) group. Where the term “alkyl is used, either alone groups. The term “alkoxy', embraces linear or branched or within other terms such as “haloalkyl”, “aralkyl and oxy-containing radicals having an alkyl portion of one to “hydroxyalkyl', the term “alkyl” embraces linear or about ten carbon atoms, Such as methoxy, ethoxy, iSopro branched radicals having one to about ten carbon atoms poxy and butoxy. The term “alkylthio’ embraces radicals unless otherwise specifically described. Preferred alkyl radi containing a linear or branched alkyl group, of one to about cals are “lower alkyl radicals having one to about five ten carbon atoms attached to a divalent Sulfur atom, Such as carbon atoms. The term “cycloalkyl embraces radicals a methylthio group. The term “aryl” embraces aromatic having three to ten carbon atoms, Such as cyclopropyl, radicals Such as phenyl, naphthyl and biphenyl. The term US 2004/0101523 A1 May 27, 2004 22

“aralkyl embraces aryl-Substituted alkyl radicals. Such as 0458 Conjugates of the invention can possess one or benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phe more asymmetric carbon atoms and are thus capable of nylbutyl and diphenylethyl. The terms “benzyl and “phe existing in the form of optical isomers as well as in the form nylmethyl” are interchangeable. The terms “aryloxy” and of racemic or non-racemic mixtures thereof. The optical “arylthio’ denote radical respectively, aryl groups having an isomers can be obtained by resolution of the racemic mix oxygen or Sulfur atom through which the radical is attached tures according to conventional processes, for example by to a nucleus, examples of which are phenoxy and phe formation of diastereoisomeric Salts by treatment with an nylthio. The terms “sulfinyl' and “sulfonyl', whether used optically active acid or base. Examples of appropriate acids alone or linked to other terms, denotes respectively divalent are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltar radicals taric 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 SO the use of a chiral chromatography column optimally chosen / to maximize the Separation of the enantiomers. Still another available method involves synthesis of covalent diastereoi Someric molecules by reacting conjugates with an optically 0455 and pure acid in an activated form or an optically pure isocy anate. The Synthesized diastereoisomers can be separated by conventional means Such as chromatography, distillation, crystallization or Sublimation, and then hydrolyzed to SO 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. 0456. The term “acyl” whether used alone, or within a term Such as acyloxy, denotes a radical provided by the Synthetic Procedures residue after removal of hydroxyl from an organic acid, 0459 Conjugates of the invention are synthesized by examples of Such radical being acetyl and benzoyl. “Lower reaction between precursors of the first and Second residues. alkanoyl” is an example of a more preferred Sub-class of One of Such precursors must contain a reactive acid moiety, acyl. and the other precursor must contain a reactive amino moiety, So that a conjugate is formed having a cleavable 0457. Within the classes of conjugates of the invention bond. Either precursor of the first and Second residues may described herein are the pharmaceutically-acceptable Salts contain Such reactive acid or amino moieties. Preferably, the of Such conjugates including acid addition Salts and base precursors of the first residue are inhibitors of benzylhy addition Salts. The term “pharmaceutically-acceptable Salts' droxyamine biosynthesis and will contain a reactive amino embraces Salts commonly used to form alkali metal Salts and moiety or a moiety convertible to a reactive amino moiety. to form addition salts of free acids or free bases. The nature Many of the tyrosine hydroxylase inhibitors and dopa of the Salt is not critical, provided that it is pharmaceutically decarboxylase inhibitors are characterized in having a reac acceptable. Suitable pharmaceutically-acceptable acid addi tive amino moiety. Inhibitor compounds lacking a reactive tion Salts of conjugates of the invention may be prepared amino moiety, Such as the dopamine-B-hydroxylase inhibi from an inorganic acid or from an organic acid. Examples of tor fuSaric acid, may be chemically modified to provide Such Such inorganic acids are hydrochloric, hydrobromic, reactive amino moiety. Chemical modification of these inhibitor compounds lacking a reactive amino group may be hydroiodic, nitric, carbonic, Sulfuric and phosphoric acid. accomplished by reacting an acid or an ester group on the Appropriate organic acids may be selected from aliphatic, inhibitor compound with an amino compound, that is, a cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxy compound having at least one reactive amino moiety and lic and Sulfonic classes of organic acids, example of which another reactive hetero atom selected from O, S and N. A are formic, acetic, propionic, Succinic, glycolic, gluconic, Suitable amino compound would be a diamino compound lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, Such as hydrazine or urea. Hydrazine, for example, may be fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, reacted with the acid or ester moiety of the inhibitor com p-hydroxybenzoic, Salicyclic, phenylacetic, mandelic, pound to form a hydrazide derivative of Such inhibitor embonic (pamoic), methansulfonic, ethaneSulfonic, 2-hy compound. droxyethaneSulfonic, pantothenic, benzeneSulfonic, toluene Sulfonic, Sulfanilic, meSylic, cyclohexylaminoSulfonic, 0460 The dopamine-f-hydroxylase inhibitor compound Stearic, algenic, B-hydroxybutyric, malonic, galactaric and 5-butyl-n-butylpicolinic acid (fusaric acid) may be used as a model compound to illustrate the chemical modification of galacturonic acid. Suitable pharmaceutically-acceptable an acid-containing inhibitor compound to make a reactive base addition Salts of the conjugates include metallic Salts amino-containing precursor for Synthesizing a conjugate of made from aluminium, calcium, lithium, magnesium, potas the invention. In the following General Synthetic Proce sium, Sodium and Zinc or organic Salts made from dures, the Substituents and reagents are defined as follows: N,N'dibenzylethylenediamine, chloroprocaine, choline, each of R7, RSO, RS, R, R7, R, R and R115 is as diethanolamine, ethylenediamine, meglumine (N-methyl defined above; W is selected from alkyl, cycloalkyl, alkenyl, glucamine) and procaine. All of these salts may be prepared alkynyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, by conventional means from the corresponding conjugates aralkyl, heterocycloalkyl and heteroaryl; and Z is Selected described herein by reacting, for example, the appropriate from oxygen and Sulfur. DCC is an abbreviation for dicy acid or base with the conjugate. clohexylcarbodiimide.

US 2004/0101523 A1 May 27, 2004 26

-continued Procedure 6:

O

Il OH O O O HO-C-CH-CH-CH DCC - ? - D 115 N-H C-R

CEO H ?us w-6-N-(c)-N-R88 ls a ot W-C-N-(C)-N-C-CH-CH-CHlike -n CFO

Rus Procedure 7:

O

Il OH O O O HO-C-CH-CH-CH DCC -f- P115 N-H C-R = H ki H-N-(C)-N-Hl ke le

foll H-N-(C)-N-C-CH-CH-CHk ke le -n CFO O ?us w-cis-O

O R86 O COH W-C-N-(C)-N-C-CH2-CH-CH R89 R87 R88 N-H i-o R115

0461 The following Examples 1 through 1857 shown in Tables VII-XI, and conjugates of dopamine-B-hydroxylase Tables IV-XVII are highly preferred conjugates of the inven inhibitors of Tables XII-XVII. These conjugates may be tion. These conjugates fall within three classes, namely, prepared generally by the procedures outlined above in conjugates of tyrosine hydroxylase inhibitors of Tables Schemes 1-7. Also, Specific procedures for preparation of IV-VI, conjugates of dopa-decarboxylase inhibitors of Examples 1-1857 are found in the conjugate preparations US 2004/0101523 A1 May 27, 2004 27 described in the examples appearing with the tables of EXAMPLE 2 conjugates. 0469 0462. The following Examples #1-#461 comprise three classes of highly preferred conjugates formed from tyrosine hydroxylase inhibitor compounds and glutamic acid deriva CH H O COH tives. Examples #1-#3 are descriptions of Specific prepara tions of Such conjugates. Examples #4-#461, as shown in Tables IV-VI, may be prepared by procedures shown in these to-K)-cis-----it-a- Specific examples and in the foregoing general Synthetic loch, -n procedures of Schemes 1-7. =o

EXAMPLE 1. hi, 0463 0470 N-4-(acetylamino)-4-carboxy-1-oxobutyl-O-me thyl-L-tyrosine, Methyl Ester. f" foll 0471. The compound of Example 1 was dissolved in 100 to-K)-cis-----it-at mL of water and the pH adjusted to 9 with 1 M KCO. The COCH NH2 solution was cooled to 0° C. and 3.30 mL (35 mmol) of acetic anhydride and 35 mL (35 mmol) of 1 M KCO was added every 30 min. for 5 h; the pH was maintained at 9 and 0464) 4-amino-4-carboxy-1-oxobutyl-C.-methyl-L-ty the reaction temperature kept below 5° C. After the last rosine, Methyl Ester addition, the reaction was allowed to warm to ambient 0465 Step. 1. Preparation of Methyl O-methyl-L-tyrosi temperature overnight. The pH was adjusted to 4 with 6 M HCl and concentrated to 100 mL. Purification by reverse nate, Hydrochloride. phase chromatography (Waters Deltaprep-3000) using iso 0466 A solution of 11.0 g (56.4 mmol) of C.-methyl-L- cratic 25% acetonitrile/water (0.05%TFA) gave 9.0 g (82%) tyrosine in 100 mL of absolute methanol was cooled to 0°C. of colorless product: NMR (DMSO-d) & 1.18 (s, 3H), and treated with 20.1 g (169 mmol) of thionyl chloride under 1.72-2.03 (m, 2H), 1.85 (s, 3H), 2.15 (t, J=8 Hz, 2H), 2.93 a nitrogen atmosphere. The reaction was allowed to warm to ambient temperature and stir at reflux for 2 dayS. Concen (d, J=13 Hz, 1H), 3.38 (d, J=13 Hz, 1H), 3.57 (s, 3H), tration followed by trituration with 150 mL of ether gave 4.12-4.23 (m, 1H), 7.02 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 13.3 g (96%) of colorless product: NMR (DMSO-d) & 1.49 2H), 8.06 (s, 1H), 8.12 (d, J=8 Hz, 1H). (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 (brs, 3H), 9.50 (s, 1H). EXAMPLE 3 0467 Step. 2. Preparation of 4-amino-4-carboxy-1-ox 0472) obutyl-C.-methyl-L-tyrosine, Methyl Ester 0468. Under nitrogen, a solution of 35.1 g (116 mmol) of CH H O CO2H N-Boc-L-y-glutanic acid-C-t-butyl ester (BACHEM) in 200 mL of methylene chloride was treated with 11.95 g (58 mmol) of solid dicyclohexylcarbodiimide (DCC). The reac to-K)-cis-----it-a-lo -n tion was allowed to stir for 2 hr prior to filtration under a nitrogen atmosphere. The methylene chloride was removed =o in vacuo and the residue dissolved in 100 mL of anhydrous dimethylformamide (DMF). The anhydride solution was lu, slowly added to a solution of 7.0 g (29 mmol) of the C.-methyl tyrosine ester from step 1 and 18.73 g (145 mmol) of diisopropylethylamine (DIEA) in 100 mL of anhydrous 0473 N-4-(acetylamino)-4-carboxy-1-oxobutyl-O-me DMF. The reaction was allowed to stir overnight and was thyl-L-tyrosine. concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with cold 1 M KCO followed by water, 0474. A solution of 9.0 g (23.7 mmol) of the compound dried (MgSO), and concentrated in vacuo to give the of Example 2 in 225 mL of water was cooled to 0° C. and protected coupled product; a Solution of this material in 150 treated with 3.3 g (82.5 mmol) of solid NaOH in portions mL of methylene chloride was cooled to 0° C. and treated over 15 min. The reaction was stirred at 0-5 C. overnight, with 150 mL of trifluoracetic acid (TFA) under nitrogen. The the pH adjusted to pH 5 with 6NHCl, and concentrated to reaction was allowed to warm to ambient temperatures and 100 mL. Purification by reverse phase chromatography Stir overnight. Concentration in vacuo gave 4-amino-4- (Waters Deltaprep-3000) using isocratic 15% acetonitrite/ carboxy-1-oxobutyl-O-methyl-L-tyrosine, methyl ester: water (0.05% TFA) gave 5.50 g (63%) of colorless product: NMR (DMSO-d) & 1.20 (s, 3H), 1.90-2.20 (m, 2H), 2.23 NMR (DMSO-d) & 1.17 (s, 3H), 1.70-2.00 (m, 2H), 1.85 (s, 2.38 (m, 0.2H), 2.95 (d, J=13 Hz, 1H), 3.26 (d, J=13 Hz), 3H), 2.14 (t, J=8 Hz, 2H), 2.83 (d, J=13 Hz, 1H), 3.14 (d. 3.57 (s, 3H), 3.92-4.06 (m, 1H), 7.06 (d, J=9 Hz, 2H), 7.12 J=13 Hz, 1H), 4.12-4.23 (m, 1H), 6.56 (d, J=9 Hz, 2H), 6.85 (d, J=9 Hz, 2H). (d, J=9 Hz, 2H), 7.69 (s, 1H), 8.12 (d, J=8 Hz, 1H); MS US 2004/0101523 A1 May 27, 2004 28

(FAB) m/e (rel intensity) 367 (70), 196 (52), 179 (58) 150 0475. The following Examples #4-#109 of Table IV are (100), 130 (80); HRMS. Calcd for M+H: 367.1505. Found: highly preferred conjugates formed from tyrosine hydroxy 367.1547. Anal. Calcd for C2HNO,.H.O.0.125 TFA: C, lase inhibitor compounds and glutamic acid derivatives. 52.00; H, 6.03; N, 7.03; F, 1.60. Found: C, 51.96; H, 6.25; These tyrosine hydroxylase inhibitors utilized to make these N, 7.12; F, 1.60. conjugates are embraced by generic Formula I and II, above.

TABLE IV R10 R9 ot R11 al--s-c-citch-h i- O -H 12 R R5 PH2 EXAMPLE NO. R. R9 R10 R11 R12 R E P

4 CH H H OH H OCH CH, COCH 5 CH H H OH H OH H H 6 CH H H OH H OCH CH, H 7 CH H H OH H OH CH, H 8 CH, H H OH H OH CH, COCH, 9 CHF H H OH H OCH H H 1O CHF H H OH H OCH H COCH, 11 CHF H H OH H OCH CH, H 12 CHF H H OH H OCH OCH COCH 13 CHF H H OH H OH H H 14 CHF H H OH H OH H COCH, 15 CHF H H OH H OH CH, H 16 CHF H H OH H OH CH, COCH 17 CHF, H H OH H OCH, H H 18 CHF, H H OH H H COCH, 19 CHF, H H OH H OCH CH, H 2O CHF, H H OH H OCH, CH, COCH, 21 CHF, H H OH H OH H H 22 CHF, H H OH H OH H COCH, 23 CHF, H H OH H OH CH, H 24 CHF, H H OH H OH CH, COCH 25 CF, H H OH H OCH H H 26 CF, H H OH H OCH H COCH, 27 CF, H H OH H OCH, CH, H 28 CF, H H OH H OCH CH, COCH 29 CF, H H OH H OH H H 3O CF, H H OH H OH H COCH, 31 CF, H H OH H OH CH, H 32 CF, H H OH H OH CH, COCH, 33 CHs H H OH H OCH H H 34 CHs H H OH H OCH, H COCH, 35 CHs H H OH H OCH CH, H 36 CHs H H OH H OCH CH, COCH 37 CHs H H OH H OH H H 38 CHs H H OH H OH H COCH, 39 CHs H H OH H OH CH, H 40 CHs H H OH H OH CH, COCH 41 CH, H H OH H OCH H H 42 CH, H H OH H OCH H COCH, 43 CH, H H OH H OCH CH, H 44 CH, H H OH H OCH, CH, COCH, 45 CH, H H OH H OH H H 46 CH, H H OH H OH H COCH, 47 CH, H H OH H OH CH, H 48 CH, H H OH H OH CH, COCH 49 CH H H NHCN H OH H COCH, 50 CH H COH H H H OH COCH, 51 CH H H H H OH H COCH, 52 CH H H CH-NH H OH H COCH, 53 CH H H CHCHCN H OH H COCH, US 2004/0101523 A1 May 27, 2004 29

TABLE IV-continued R9 R H O COE | | || -C-CHCH-CH at-i-CEO N-H R 12 k PH2 EXAMPLE NO. R10 R11 R 12 54 OH CHSONH COCH, 55 OH NO, COCH, 56 CHSO NH, COCH, 57 COCH NO, COCH, 58 NO, NH, COCH, 59 NH, NH, COCH, 60 CH OH COCH, 61 CHs OH COCH, 62 CHCH, OH COCH, 63 C.H. (cyclo) CHO COCH, 64 OH H COCH, 65 OH Cl COCH, 66 OH CH COCH, 67 OH F COCH, 68 OH CF, COCH, 69 OH H COCH, 70 OH Cl COCH, 71 OH F COCH, 72 OH CF, COCH, 73 H H COCH, 74 H Cl COCH, 75 H CH COCH, 76 H CF, COCH, 77 OH OH COCH, 78 OH OH COCH, 79 H OH OH COCH, 8O H H COCH, 81 H H COCH, 82 I H COCH, 83 I H COCH, 84 I OH COCH, 85 I H COCH, 86 CCH OH COCH, 87 CHCH, CHO COCH, 88 CHCH, OH COCH, 89 C.H. (cyclo) CHO COCH, 90 C.H. (cyclo) OH COCH, 91 CH CHO COCH, 92 CH OH COCH, 93 CH, CHCHCO, COCH, 94 CH H 95 CH CHCHCO, g H 96 CH CHCO, COCH, 97 CHO OH COCH, 98 -OCHO COCH, 99 H H O COCH, 1OO H H o COCH, 101 H CH, g COCH, 102 H OH COCH, 103 H H CHO COCH, 104 C=CH H H COCH, 105 C=CH H H CHO COCH, 106 C=CH H OH COCH, 107 C=CH OH H COCH, 108 CH=CH, H H COCH, 109 CH=CH, H H CHO COCH,

0476. The following Examples #110-#413 of Table V are highly preferred conjugates formed from tyrosine hydroxy lase inhibitor compounds and glutamic acid derivatives. These tyrosine hydroxylase inhibitors utilized to make these conjugates are embraced by generic Formula I, above. US 2004/0101523 A1 May 27, 2004

TABLE V R H O ot A-CH-C-N-C-CH-CH-CH CEO - H P EXAMPLE NO. Rs E 110 CH OCH H

111 CH OCH H COCH,

112 CH OCH CH

113 CH, OCH, CH, COCH,

114 CH, OH H

115 CH OH H COCH,

116 CH OH CH US 2004/0101523 A1 May 27, 2004

TABLE V-continued fo! a-ch-- N-C-CH- cu-" CFO N-H R5 P EXAMPLE NO. A. R3 R E

117 CH OH CH COCH,

N

H

118 CH OCH H

O N

H

119 CH OCH H COCH,

O N

H

12O CH OCH CH

O N

H

121 CH, OCH, CH, COCH,

O N

H

122 CH OH H

O N

H

123 CH OH H COCH,

O N

H

124 CH OH CH

O N US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O ot A-CH-C-N-C-CH2- CH- " E O - H P EXAMPLE NO. Rs E 125 CH OH CH COCH,

XaA.O

126 CH, OCH, H

127 CH OCH H COCH,

128 CH OCH CH

129 CH OCH CH COCH,

130 CH OH H

131 CH, OH H COCH,

132 NYS-\YS-\NYS-\NYS-\NYY-\YS-\YS-\NYS-\R5 CH OH CH

133 CH OH CH COCH, US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O ot A-CH-C-N-C-CH-CH-CH CEO - H P EXAMPLE NO. A. Rs E

134 CH OCH H

135 CH OCH H COCH,

136 CH OCH CH

137 CH OCH CH COCH,

138 CH OH H

139 CH OH H COCH,

140 CH OH CH

141 CH OH CH COCH,

142 CH OCH H O

143 N-H CH OCH H COCH, O

144 N-H CH OCH CH O

145 N-H CH OCH CH COCH, O US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O fo! A-CH-C-N-C-CH-CH-CH E O - H P EXAMPLE NO. R E

146 H CH OH H ONX= O 147 CH OH H COCH,

148 CH OH CH

149 CH OH CH COCH,

150 CH OCH H

151 CH, OCH, H COCH,

152 CH OCH CH

153 CH OCH CH COCH,

154 CH, OH, H

155 CH OH H COCH,

156 CH OH CH US 2004/0101523 A1 May 27, 2004

TABLE V-continued ot a-ch-- N-C-CH- cit-h CFO N-H R5 P EXAMPLE NO. A. R3 Rs E

157 CH OH CH COCH, N NH2 S

158 SH CH OCH H

A NH2 S

159 SH CH, OCH, H COCH,

/ NH2 S

160 SH CH OCH CH

/ NH2 S

161 SH CH OCH CH COCH,

/ NH2 S

162 SH CH OH H

M NH2 S

163 SH CH OH H COCH,

M NH2 S

164 SH CH OH CH

M NH2 US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O fo! A-CH-C-N-C-CH-CH-CH E O - H P EXAMPLE NO. A. Rs E

165 SH CH, OH CH, COCH,

166 CH OCH H

167 CH OCH H COCH,

168 CH OCH CH

169 CH OCH CH COCH,

170 CH OH H

171 CH OH H COCH,

172 CH OH CH

173 CH OH CH COCH,

174 CH, OCH, H

175 CH OCH H COCH, US 2004/0101523 A1 May 27, 2004 37

TABLE V-continued

R H O COE A-CH-C-N-C-CH-CH-CH CEO N-H R5 P EXAMPLE NO.

176 N-H CH, OCH, CH,

177 N-H CH OCH CH COCH,

N-H

178 N-H CH OH H

N-H

179 N-H CH, OH H COCH,

N-H

18O N-H CH OH CH

N-H

181 N-H CH OH CH COCH,

N-H

182 CH, OCH, H 21 SeaT 183 afneT CH, OCH, H COCH, 184 anaT CH OCH CH US 2004/0101523 A1 May 27, 2004

TABLE V-continued fo! a-ch--N-(-chi-qi-y CFO N-H R5 P EXAMPLE NO. A. R3 Rs E P

185 H CH, OCH, CH, COCH,

N O

cCH

186 H CH OH H H

N O

cCH

187 H CH OH H COCH,

N O

cCH

188 H CH OH CH H

N O

CCH

189 H CH, OH CH, COCH,

N O

cCH 190 afneT H OCH H H CH US 2004/0101523 A1 May 27, 2004

TABLE V-continued fo! a-ch--N-(-chi-qi-y CFO N-H R5 P EXAMPLE NO. A. R3 Rs E P

191 H H OCH, H COCH,

N O

cCH

192 H H OCH CH H

N O

cCH

193 H H OCH CH COCH,

N O

cCH

194 H H OH H H

N O

CCH

195 H H OH H COCH,

N O

cCH 196 afneT H OH CH H CH US 2004/0101523 A1 May 27, 2004 40

TABLE V-continued a-ch----ch-a-hR H O COE =o -i.

EXAMPLE NO. A. R3 Rs E 197 H H OH CH COCH, lo

21

198 N CH OCH H n

2 N

199 N CH OCH H COCH, n

2 N

N CH OCH CH N

2 N N CH, OCH, CH, COCH, n

2 N

N CH OH H n

2 N

N CH OH H COCH, n

2 N

204 N CH OH CH n

2 N 205 CH OH CH COCH,

N OH CH OCH, H n

2 N US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 O ot A-CH-C-N-C-CH-CH-CH CEO - H P EXAMPLE NO. A. Rs OH CH OCH H COCH,

OH CH, OCH CH,

209 OH CH OCH CH COCH,

210 OH CH OH H

211 OH CH, OH H COCH,

212 OH CH OH CH

213 OH CH OH CH COCH,

214 OH CH OCH H

215 OH CH OCH H COCH,

216 OH CH OCH CH

217 OH CH, OCH, CH, COCH, US 2004/0101523 A1 May 27, 2004 42

TABLE V-continued a-ch----ch-ch-laR H O COE =o -n

EXAMPLE NO. A. R3 R E

218 N OH CH OH H n

2 N

219 N OH CH OH H COCH, n

2 N

N OH CH OH CH n

2 N

221 N OH CH OH CH COCH, n

2 N

222 N OH CH OCH H n

2 N OH

223 N OH CH, OCH, H COCH, n

2 N OH

224 N OH CH OCH CH n

2 N OH

225 N OH CH OCH CH COCH, n

2 N OH

226 N OH CH, OH H n

2 N OH

227 N OH CH OH H COCH, n

2 N OH US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O ot A-CH-C-N-C-CH-CH-CH CEO - H P EXAMPLE NO. Rs E 228 CH OH CH

DCO H 229 N O H CH OH CH COCH,

4. O H 230 N OCH H 4 231 N OCH H COCH, 4. 232 N OCH CH 4. 233 NN OCH CH COCH, 234 N OH H 4. 235 N OH H COCH, 4. 236 N OH CH 4. 237 N OH CH, COCH, % 238 N O H OCH, H 2 N O H US 2004/0101523 A1 May 27, 2004 44

TABLE V-continued fo! a-ch-- N-C-CH- cu-" =o -H R5 P EXAMPLE NO. A. R3 R E

239 N OH H OCH H COCH, N

2 N OH

240 N OH H OCH, CH, n

2 N OH

241 N OH H OCH CH COCH, N

2 N OH

242

243 COCH,

244 N OH n

2 N OH

245 N OH H OH CH COCH, N

2 N OH

246 O CH, OCH, H

H

247 O CH OCH H COCH, US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O fo! A-CH-C-N-C-CH-CH-CH CEO - H R5 P EXAMPLE NO. R3 Rs E 248 CH, OCH, CH,

249 D CH OCH CH COCH,

250 D CH OH H

251 D CH OH H COCH,

252 D CH OH CH

253 D CH OH CH COCH,

254 OCH H D H 255 D H OCH H COCH, US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O fo! A-CH-C-N-C-CH-CH-CH CEO - H P EXAMPLE NO. Rs E 256 OCH, CH,

257 D OCH CH COCH,

258 OH H

259 OH H COCH,

260 OH CH

261 OH CH COCH,

ND

262 CH OCH H

O

263 CH, OCH, H COCH, US 2004/0101523 A1 May 27, 2004

TABLE V-continued R H O fo! A-CH-C-N-C-CH-CH-CH CEO - H P EXAMPLE NO. A. Rs E 264 CH, OCH, CH,

HO

265 CH OCH CH COCH,

266 CH OH H

267 CH OH H COCH,

268 CH OH CH

269 CH, OH CH, COCH,

270 CH OCH H

O H

271 CH OCH H COCH,

O H US 2004/0101523 A1 May 27, 2004

TABLE V-continued fo! a-ch-- N-C-CH- cu-" CFO N-H R5 P EXAMPLE NO. R3 R E

272 CH OCH CH

OH

273 CH OCH CH COCH,

OH

274 CH OH H

OH

275 CH OH H COCH,

OH

276 CH, OH CH,

OH

277 CH OH CH COCH,

OH

278 CH OCH H

CO2H

279 CH OCH H COCH,

CO2H US 2004/0101523 A1 May 27, 2004

TABLE V-continued fo! a-ch--N-(-chi-qi-y CFO N-H R5 P EXAMPLE NO. R3 Rs E

28O CH OCH CH

CO2H

281 CH OCH CH COCH,

CO2H

282 CH OH H

CO2H

283 CH, OH H COCH,

CO2H

284 CH OH CH

CO2H

285 CH OH CH COCH,

CO2H

286 NYS-\NYY-\ CH OCH H 287 CH, OCH, H COCH, US 2004/0101523 A1 May 27, 2004

TABLE V-continued

R H O | | || ot A-CH -n-c-ch2- cit-h CFO - H P EXAMPLE NO. A. Rs E

288 CH OCH CH

289 CH OCH CH COCH,

290 CH OH H

291 CH, OH H COCH,

292 Y-\NYS-\NYS-\R5Y-\NYS-\NYS-\NYNY CH OH CH

293 CH OH CH COCH,

294 N CH OCH H 21 N

295 CH, OCH, H COCH, Cl N H2 US 2004/0101523 A1 May 27, 2004

TABLE V-continued fo!

a-ch--N-c-ch-cu-"CEO N-H R5 P EXAMPLE NO. A. R3 Rs E 296 N CH, OCH, CH, 21 N NH2

297 N CH OCH CH COCH, 21 N NH2

298 N CH OH H 2 N NH2

299 N CH, OH H COCH, 21 N NH2

3OO N CH OH CH 2 N NH2

301 N CH OH CH COCH, 21 N NH2

3O2 CH=CH OCH, H f \

H

303 CH=CH OCH, H COCH, \ N US 2004/0101523 A1 May 27, 2004 52

TABLE V-continued ot a-ch--N-c-ch-cu-" =o -H R5 P EXAMPLE NO. R3 Rs E

304 CH=CH OCH, CH

305 CH=CH OCH, CH COCH,

306 CHECH OH H

307 CHECH OH H COCH,

CHECH OH CH,

309 CHECH OH CH, COCH,

310 CH=CH OCH, H US 2004/0101523 A1 May 27, 2004 53

TABLE V-continued fo! a-ch-- N-C-CH- cu-" =o -H R5 P EXAMPLE NO. R3 R E

311 CH=CH OCH, H COCH,

312 CH=CH OCH, CH,

313 CH=CH OCH, CH, COCH,

314 CHECH OH H

315 CHECH OH H COCH,

316 CHECH OH CH

317 CHECH OH CH COCH, US 2004/0101523 A1 May 27, 2004

TABLE V-continued R3 H O ot A-CH-C-N-C-CH-CH-CH CEO - H P EXAMPLE NO. A. Rs 31.8 CH=CH, OCH H

319 CH=CH, OCH H COCH,

CH=CH, OCH CH

321 CH=CH, OCH, CH, COCH,

322 CH=CH, OH H

323 CH=CH, OH H COCH,

324 CH=CH, OH CH

325 CH=CH, OH CH COCH,

326 OCH H HO US 2004/0101523 A1 May 27, 2004 55

TABLE V-continued ot a-ch--N-c-ch-cu-" =o -h R5 P EXAMPLE NO. A. R3 Rs E 327 HO ( C=CH OCH H COCH,

N

H 328 HO ( C=CH OCH CH

N

H 329 HO ( C=CH OCH CH COCH,

N

H 330 HO ( C=CH OH H

N

H 331 HO ( C=CH OH H COCH,

N

H 332 HO ( C=CH OH CH

N

H 333 HO ( C=CH OH CH COCH,

N

H US 2004/0101523 A1 May 27, 2004 56

TABLE V-continued fo! a-ch--N-(-chi-qi-y CFO N-H

P EXAMPLE NO. A. R3 R E

334 C=CH OCH H CHO

335 C=CH OCH, H COCH, CHO

336 C=CH OCH, CH, CHO

337 C=CH OCH CH COCH, CHO

338 C=CH OH H CHO

339 C=CH OH H COCH, CHO

340 C=CH OH CH CHON1s-QN1s-QN1s-QN1s-QN1s-QN1s-QN1s-QR5 US 2004/0101523 A1 May 27, 2004 57

TABLE V-continued ot a-ch--N-c-ch-cu-" =o -h R5 P EXAMPLE NO. A. R3 Rs E 341 CHO, ( C=CH OH CH COCH,

N

H 342 HO ( CH OCH H

N

H 343 HO ( CH OCH H COCH,

N

H 344 HO ( CH OCH CH

N

H 345 HO ( CH OCH CH COCH,

N

H 346 HO ( CH OH H

N

H 347 HO ( CH OH H COCH,

N

H US 2004/0101523 A1 May 27, 2004 58

TABLE V-continued fo! a-ch--N-(-chi-qi-y =o -h R5 P EXAMPLE NO. A. R3 Rs E 348 HO ( CH OH CH

N

H 349 HO ( CH, OH CH, COCH,

N

H 350 OH ( H OCH, H

N

H 351 OH ( H OCH, H COCH,

N

H 352 OH ( H OCH CH

N

H 353 OH ( H OCH CH COCH,

N

H 354 OH ( H OH H

N

H US 2004/0101523 A1 May 27, 2004 59

TABLE V-continued ot a-ch--N-c-ch-cu-" =o -H R5 P EXAMPLE NO. A. R3 Rs E

355 H OH H COCH, OH OS H

356 H OH CH OH OS H

357 H OH CH COCH, OH OS H

358 H OCH H C H

359 H OCH H COCH, c H

360 H OCH CH c H

361 H OCH CH COCH, C H US 2004/0101523 A1 May 27, 2004 60

TABLE V-continued

R3 H O COE A-CH-C-N-C-CH-CH-CH CFO N-H

P EXAMPLE NO. Rs E

362 OH H

363 OH H COCH,

364 OH CH

365 OH CH, COCH,

366 OCH, H

367 OCH, H COCH,

368 OCH CH US 2004/0101523 A1 May 27, 2004 61

TABLE V-continued R3 H O fo! A-CH-C-N-C-CH-CH-CH

E O N-H

P EXAMPLE NO. A. Rs E

369 OCH CH COCH,

370 OH H

371 OH H COCH, 372 BBBB OH CH 373 OH CH COCH, B

374 OCH H Cl

375 OCH H COCH, Cl N1s-QN1s-QN1s-QN1s-QN1s-QN1s-QN1s-QR5 US 2004/0101523 A1 May 27, 2004 62

TABLE V-continued ot a-ch--N-c-ch-cu-" =o -h R5 P EXAMPLE NO. A. R3 Rs E

376 H OCH CH Cl c H

377 H OCH CH COCH, Cl c H

378 H OH H Cl c H

379 H OH H COCH, Cl c H

H OH CH Cl c H

381 H OH CH COCH, Cl c

382 H OCH H CH N1s-Qh US 2004/0101523 A1 May 27, 2004 63

TABLE V-continued ot a-ch--N-c-ch-cu-" =o -h R5 P EXAMPLE NO. A. R3 Rs E 387 CH3 ( H OCH H COCH,

N

H 384 CH3 ( H OCH CH

N

H 385 CH3 ( H OCH CH COCH,

N

H 386 CH3 ( H OH H

N

H 387 CH3 ( H OH H COCH,

N

H 388 CH3 ( H OH CH

N

H 389 CH3 ( H OH CH COCH,

N

H US 2004/0101523 A1 May 27, 2004

TABLE V-continued ot a-ch--N-c-ch-cu-" CFO N-H R5 P EXAMPLE NO. A. R3 Rs E

390 CH OCH H

391 CH OCH H COCH,

392 CH OCH CH

393 CH, OCH, CH, COCH,

394 CH OH H

395 CH OH H COCH, 396 1s-Q1s-Q1s-Q1s-Q1s-Q1s-Q1s-Q CH OH CH US 2004/0101523 A1 May 27, 2004

TABLE V-continued ot

a-ch--N-c-ch-cu-"CEO N-H R5 P EXAMPLE NO. A. R3 Rs E P 397 CH OH CH COCH,

H 398 CH CH=CH2 CH, H H 399 CHs CH=CH2 OCH, H COCH, 400 CHs CH=CH2 OCH, CH H 4O1 CHs CH=CH2 OCH, CH COCH, 402 CHs CH=CH2 OH H H 403 CHs CH=CH2 OH H COCH, 404 CHs CH=CH2 OH H COCH, 405 CHs CH=CH2 OH CH COCH, 4O6 CHs C=CH OCH H H 4O7 CHs C=CH OCH, H COCH, 408 CHs C=CH OCH CH H 409 CHs C=CH OCH CH COCH, 410 CHs C=CH OH H H 411 CHs C=CH OH H COCH, 412 CHs C=CH OH H COCH, 413 CHs C=CH OH CH COCH,

0477 The following Examples #414-#461 of Table VI are highly preferred conjugates formed from tyrosine TABLE VI-continued hydroxylase inhibitor compounds and glutamic acid deriva tives. These tyrosine hydroxylase inhibitors- - - - - utilized- to make R3| H| O|| COE these conjugates are embraced by generic Formula III, R11 C-N-C-CHCH-CH above. i- O -H TABLE VI R5 P R H O COE EXAMPLE | | || NO. R11 R3 R E P R11 C-N-C-CHCH-CH 429 OH CH, OCH CH, COCH CEO N-H 430 OH H NH, H H 431 OH H NH, H COCH, R5 P 432 OH H NH, CH, H 433 OH H NH, CH, COCH EXAMPLE 434 OH CH NH, H H NO. R11 R3 Rs E P 435 OH CH, NH, H COCH, 436 OH CH, NH, CH, H 414 OH H OH H H 437 OH CH, NH, CH, COCH 415 OH H OH H COCH, 4.38 OCH H OH H H 416 OH H OH CH, H 439 OCH, H OH H COCH, 417 OH H OH CH, COCH 440 OCH H OH CH, H 418 OH H OCH H H 441 OCH H OH CH, COCH 419 OH H OCH, H COCH, 442 OCH H OCH H H 42O OH H OCH CH H 443 OCH, H OCH, H COCH, 421 OH H OCH CH, COCH 444 OCH H OCH CH, H 422 OH CH, OH H H 445 OCH H OCH CH, COCH 423 OH CH, OH H COCH, 446 OCH, CH, OH H H 424 OH CH, OH CH, H 447 OCH CH, OH H COCH, 425 OH CH, OH CH, COCH 448 OCH CH, OH CH, H 426 OH CH, OCH, H H 449 OCH, CH, OH CH, COCH, 427 OH CH, OCH H COCH, 450 OCH CH, OCH H H 428 OH CH, OCH CH, H 451 OCH CH, OCH H COCH, US 2004/0101523 A1 May 27, 2004 66

mmol) of solid dicyclohexylcarbodiimide (DCC). The reac TABLE VI-continued tion 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 dimethyl ot formamide (DMF). The anhydride solution was slowly all-()------CEO N-H added to a solution of 12.9 g (49 mmol) of the C-methyl DOPA ester from step 1 and 12.6 g (98 mmol) of diisopro R5 P pylethylamine (DIEA) in 50 mL of anhydrous DMF. The EXAMPLE reaction was allowed to Stir overnight and was concentrated NO. R11 R3 Rs E P in vacuo. The residue was dissolved in ethyl acetate, washed with 1N citric acid, 1N NaHCO, water, and brine, dried 452 OCH CH OCH CH H 453 OCH, CH, OCH, CH, COCH, (Na2SO), and concentrated in vacuo to give the protected 454 OCH H NH, H H coupled product; a solution of this material in 100 mL of 455 OCH H NH, H COCH, 456 OCH H NH, CH H methylene chloride was cooled to 0°C. and treated with 400 457 OCH, H NH, CH, COCH, mL of trifluoroacetic acid (TFA) under nitrogen. The reac 458 OCH CH NH, H H tion was allowed to warm to ambient temperature and Stir for 459 OCH CH NH, H COCH, 460 OCH CH NH, CH H 72 hr. Concentration in vacuo gave 4-amino-4-carboxy-1- 461 OCH, CH, NH, CH, COCH, oxobutyl-3-hydroxy-C.-methyl-tyrosine, methyl ester: NMR (DMSO-d) & 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, 0478. The following Examples #462-#857 comprise five classes of highly preferred conjugates composed of dopa 3H), 3.85-4.10 (m, 1H), 6.29 (d of d, J=9 Hz and 2 Hz, 1H), decarboxylase inhibitor compounds and glutamic acid 6.45 (d, J=2 Hz, 1H), 6.62 (d, J=9 Hz, 1H); MS (FAB) m/e derivatives. Examples #462-#464 are descriptions of spe (rel intensity) 355 (92), 225 (51), 148 (35). cific preparations of such conjugates. Examples #465-#857, as shown in Tables VII-XI, may be prepared by procedures EXAMPLE 463 shown in these Specific examples and in the foregoing general Synthetic procedures of Schemes 1-7 0485)

EXAMPLE 462 CH H O CO2H 0479) HO ci----ch-ch-la loch, -n CH H O CO2H HO = O HO ch,----ch-ch-n doch, l, l, HO 0486 N-4-(acetylamino)-4-carboxy-1-oxobutyl-3-hy 0480 4-amino-4-carboxy-1-oxobutyl-3-hydroxy-O-me droxy-O-methyl-L-tyrosine, Methyl Ester. thyl-L-tyrosine, Methyl Ester. 0487. The compound of Example 462 was dissolved in 0481 Step. 1: Preparation of O-methyl-L-DOPA, Methyl 100 mL of degassed water and under nitrogen the pH Ester, Hydrochloride. adjusted to 9 with 1 M KCO. The solution was cooled to 0482. A suspension of 29.7 g (141 mmol) of C.-methyl 0° C. and 12 mL (127mmol) of acetic anhydride and 180 mL L-DOPA in 300 mL of absolute methanol was cooled to -15 (180 mmol) of 1 M KCO was added every 30 min. for 5 C. and treated with 125.8 g (1.06 mol)thionyl chloride under h; the pH was maintained at 9 and the reaction temperature a nitrogen atmosphere. The reaction was allowed to warm to kept below 5° C. After the last addition, the reaction was ambient temperature and stir at reflux for 3 dayS. Concen allowed to warm to ambient temperature overnight. The pH tration followed by trituration with ether gave 31.7 g (97%) was adjusted to 3 with 3 M HCl and concentrated to 100 mL. as an off-white solid: NMR (DMSO-d) & 1.47 (s, 3H), 2.92 Purification by reverse phase chromatography (Waters (d, J=12 Hz, 1H), 2.98 (d, J=12 Hz, 1H), 3.74 (s, 3H), 6.41 Deltaprep-3000) using a 5-15% gradient of acetonitrile/ (d of d, J=9 Hz AND 2 Hz, 1H), 6.54 (d, J=2 Hz, 1H), 6.68 water (0.05% TFA) gave 14.0 g (49%) of colorless product: (d, J=9 Hz, 1H), 8.46-8.90 (brs, 3H), 8.93 (s, 1H), 8.96 (s, NMR (DMSO-d) & 1.15 (s, 3H), 1.70-1.83 (m, 2H), 1.85 (s, 1H). 3H), 1.87-2.00 (m, 2H), 2.15 (t, J=7 Hz, 2H), 2.75 (d, J=12 0483 Step 2: Prepraration of 4-amino-4-carboxy-1-ox HZ, 1H), 3.00 (d, J=12 Hz, 1H), 3.55 (s, 3H), 4.10-4.22 (m, obutyl-3-hydroxy-O-methyl-L-tyrosine, Methyl Ester. 1H), 6.29 (d of d, J=9 Hz and 2 Hz, 1H), 6.43 (d, J=2 Hz, 0484 Under nitrogen, a solution of 32.7 g (108 mmol) of 1H), 6.60 (d, J=9 Hz, 1H), 7.96 (s, 1H), 8.12 (d. J=8 Hz, 1H); N-Boc-L-y-glutamic acid-O-t-butyl ester (BACHEM) in 150 MS (FAB) m/e (rel intensity) 397 (100), 365 (10), 226 (70), mL of methylene chloride was treated with 11.14 g (54 166 (90), 153 (22), 130 (72), 102 (28). US 2004/0101523 A1 May 27, 2004 67

EXAMPLE 464 hr and the pH adjusted to pH1 with 6NHCl. Purification by 0488 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-d) & CH H O COH 1.18 (s, 3H), 1.70-1.83 (m, 2H), 1.85 (s, 3H), 1.87-2.00 (m, HO ch,----ch-ch-la 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, 0.1H), 6.31 (d of d, J=9 Hz and log -i. 2 Hz, 1H), 6.47 (d, J=2 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 7.71 HO =o (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. hi, Calcd for M+H: 383.1454. Found: 383.1450. Anal: Calcd for C2HNOs 1.06 H.O.0.85 TFA: C, 48.67; H, 5.59; N, 0489 N-4-(acetylamino)-4-carboxy-1-oxobutyl-3-hy 6.46; F, 3.73. Found: C, 49.02; H, 5.73; N, 6.40; F, 3.70. droxy-O-methyl-L-tyrosine. 0491. The following Examples #465-#541 of Table VII 0490 A solution of 13.5 g (102 mmol) of the compound are highly preferred conjugates composed of dopa-decar of Example 463 in 34 mL of water was cooled to 0 C. and boxylase inhibitor compounds and glutamic acid deriva treated with 102 mL (102 mmol) of 1N NaOH (all solutions tives. These dopa-decarboxylase inhibitors utilized to make were degassed in vacuo and flushed with nitrogen prior to these conjugates are embraced by generic Formula IV, use). The reaction was stirred at ambient temperature for 5 above.

TABLE VII O COE | A-N-C-CHCH-CH R1 - H P

EXAMPLE NO. A. R1 E P 465 OH OH H CH, COCH,

--c-s-s-ch, OH CH2OH

466 OH OH H H H -N- -- OH H

467 OH OH H H COCH, -N- - - OH H 468 OH OH H CH, H -N- - - OH H

469 OH OH H CH, COCH -N- -3- OH US 2004/0101523 A1 May 27, 2004 68

TABLE VII-continued

O COE A-N-C-CHCH-CH R1

P

EXAMPLE NO.

470 OH

-N-CH CH -()

471 OH H COCH,

-N-CH CH -()

472 OH CH

-N-CH CH -()

473 OH CH COCH,

-N-CH CH -()

474 OH OH NH, -CH - - OH 475 OH OH NH, H COCH, -CH - - OH 476 OH OH NH, CH o CH2 -3- OH 477 OH OH NH, CH COCH, o CH2 - - OH US 2004/0101523 A1 May 27, 2004 69

TABLE VII-continued

O COE A-N-C-CHCH-CH R1 N-H

P

EXAMPLE NO.

478 OH t ---cu, H CO2H - -

479 OH H COCH, t ---as H CO2H - -

48O OH CH t ---cu, H CO2H - -

481 OH CH COCH, t ---as H CO2H - -

482 OH NH, th o -ch, OH CO2H

483 OH NH, H COCH, th o -ch, OH CO2H

484 OH NH, CH th o -ch, OH CO2H

485 OH NH, CH COCH, th o -ch, OH CO2H US 2004/0101523 A1 May 27, 2004 70

TABLE VII-continued

O COE

A---cha-hR1 -h

EXAMPLE NO. A. R. E P

486 OH H. H. H CHF --ch, OH lon 487 OH H H COCH, CHF --ch, OH lot 488 OH H CH, H CHF --ch,log OH

489 OH H CH, COCH, CHF --ch, OH lot

490 OH H. H. H CHF --ch, OH lon 491 OH H H COCH, CHF --ch, OH lot 492 OH H CH, H CHF --ch, OH lon

493 OH H CH, COCH, CHF --al. OH US 2004/0101523 A1 May 27, 2004 71

TABLE VII-continued

O COE A-N-C-CHCH-CH R1 N-H

P

EXAMPLE NO.

494 OH t ---a H COCH - -

495 OH H COCH, t ---cu, H COCH - -

496 OH CH t ---as H COCH - -

497 OH CH COCH, t ---cu, H COCH - -

498 OH NH, th o -ch, OH COCH

499 OH NH, H COCH, th o -ch, OH COCH

500 OH NH, CH th o -ch, OH COCH

OH NH, CH COCH, th o -ch, OH COCH US 2004/0101523 A1 May 27, 2004 72

TABLE VII-continued

O COE

A---cha-hR1 -h

EXAMPLE NO. A. R. E P

502 OH H H H CHF --ch, OH loch, 503 OH H H COCH, CHF --ch, OH loch, SO4 OH H CH, H CHF --ch, OH loch, 505 OH H CH, COCH, CHF --ch, OH loch,

SO6 OH H H H CHF --ch, OH loch, 507 OH H H COCH, CHF --ch, OH loch, 508 OH H CH, H CHF --ch, OH loch, 509 OH H CH, COCH, CHF ––ct, OH COCH US 2004/0101523 A1 May 27, 2004 73

TABLE VII-continued

O COE

A---cha-hR1 -h

EXAMPLE NO. A. R. E P

510 OH H H H CH --ch, OH loch, 511 OH H H COCH, CH --ch, OH loch, 512 OH H CH, H CH --ch, OH loch, 513 OH H CH, COCH, CH --ch, OH loch,

514 OH H H H CH --ch, OH loch, 515 OH H H COCH, CH --ch, OH lon 516 OH H CH, H CH --ch, OH lot 517 OH H CH, COCH, CH --ch. OH US 2004/0101523 A1 May 27, 2004 74

TABLE VII-continued

O COE

A---cha-hR1 -h

EXAMPLE NO. A. R. E P

518 OH H H H CF --ch, OH loch, 519 OH H H COCH, CF --ch, OH loch, 52O OH H CH, H CF --ch, OH loch, 521 OH H CH, COCH, CF --ch, OH loch,

522 OH H H H CF --ch, OH lon 523 OH H H COCH, CF --ch, OH lon 524 OH H CH, H CF --ch, OH lot 525 OH H CH, COCH, CF --ch. OH US 2004/0101523 A1 May 27, 2004 75

TABLE VII-continued

O COE A- --cha-h R1 - H

EXAMPLE NO. A. R. E P

526 OH H H H CHs o -CH, OH loch, 527 OH H H COCH, C2H5 o -CH, OH loch, 528 OH H CH, H CHs o -CH, OH loch, 529 OH H CH, COCH, C2H5 o -CH, OH loch,

530 OH H H H CHs o -CH, OH lon 531 OH H H COCH, C2H5 o -ch, OH lon 532 OH H CH, H CHs o -CH, OH lot 533 OH H CH, COCH, C2H5 o -ch, OH US 2004/0101523 A1 May 27, 2004 76

TABLE VII-continued COE A-N-C-CHCH-CH R1 - H P

EXAMPLE NO. A.

534 OH CH7 -C-CH OH COCH

535 OH COCH, CH7 -C-CH OH COCH

536 OH CH7 o -ch, OH COCH

537 OH COCH, CH7 o -ch, OH COCH

538 OH CH7 o -ch, OH CO2H

539 OH COCH, CH7 o -ch, OH CO2H

540 OH CH, CH7 o -ch, OH CO2H

541 OH CH COCH, CH7 -C-CH OH CO2H US 2004/0101523 A1 May 27, 2004 77

0492. The following Examples #542-#577 of Table VIII tives. These dopa-decarboxylase inhibitors utilized to make are highly preferred conjugates composed of dopa-decar these conjugates are embraced by generic Formula VIII, boxylase inhibitor compounds and glutamic acid deriva above.

TABLE VIII O O COE V C=C-C-L-C-CH-CH-CH R58

P

EXAMPLE NO. L M

542 NHNH O H

O H

543 NHNH COCH,

O H

544 NHNH CH,

O H

545 NHNH CH, COCH,

O H 546 NHNH ( )OCH Br 547 NHNH ( )OCH Br COCH, 548 NHNH l{}OCH Br CH 549 NHNH ( )OCH Br CH COCH, 550 NHNH Br Br -CH -K)- CHs

US 2004/0101523 A1 May 27, 2004 79

TABLE VIII-continued

M O O COE V C=C-C-L-C-CH-CH-CH R58 R55

P

EXAMPLE NO. L M Rs6 Rss E 560 NHCHCH-NH OCH Br H CH O

-C

561 NHCHCH-NH OCH Br H CH COCH, O

-C

562 NHCHCH-NH Br H -CH CH5

563 NHCHCH-NH Br H COCH, -CH -K)-cal 564 NHCHCH-NH Br CH -CH -K)- C2H5

565 NHCHCH-NH Br CH COCH, -CH -K)-cal 566 piperazinyl - OH- H H 567 piperazinyl - OH- H H COCH, 568 piperazinyl - OH- H CH 569 piperazinyl - OH- H CH COCH, US 2004/0101523 A1 May 27, 2004

TABLE VIII-continued

M O O COE V

58 =-c-f-c-ch-a-h R R55 -n P

EXAMPLE NO. L. M Rs6 Rss E P 570 piperazinyl OCH Br H H H

-C

571 piperazinyl OCH Br H H COCH,

-C

572 piperazinyl OCH Br H CH, H

-C 573 piperazinyl ( )OCH Br H CH, COCH

574. piperazinyl Br Br H H -CH CH5

575 piperazinyl Br Br H COCH,

576 piperazinyl Br Br CH, H -CH C2H5

57.7 piperazinyl Br Br CH, COCH -CH CH5

0493) The following Examples #578-#757 of Table IX tives. These dopa-decarboxylase inhibitors utilized to make are highly preferred conjugates composed of dopa-decar- these conjugates are benzoic acid type derivatives based on boxylase inhibitor compounds and glutamic acid deriva- the list of Similar compounds described earlier.

US 2004/0101523 A1 May 27, 2004 82

TABLE IX-continued R131 O O COE L-C-CH-CH-CH N-H R132 S. R130 EXAMPLE NO. L R130 592 NHNH CH OCH

OCH3 OCH 593 NHNH OCH OCH CH COCH, OCH3

OCH OCH

594 NHNH o OCH, OCH, \ /

595 NHNH o OCH OCH COCH, \ /

596 NHNH o OCH OCH CH \ /

597 NHNH o OCH OCH CH COCH, \ / 598 NHNH OCH OCH

---OCH 599 NHNH OCH, OCH, COCH,

---OCH NHNH OCH OCH CH

---OCH NHNH OCH, OCH, CH, COCH, OCH

--OCH US 2004/0101523 A1 May 27, 2004

TABLE IX-continued

R131 O fo! L-C-CH- ci-fi N-H R132 R130

EXAMPLE NO. R130 R131 R132

NHNH OCH, OCH

603 NHNH OCH, OCH H COCH,

604 NHNH OCH, OCH, CH, H

605 NHNH OCH, OCH CH, COCH

606 NHNH OH OH –K)- OH NHNH OH OH H COCH,

608 NHNH OH OH –K)- OH 609 NHNH OH OH CH, COCH -()– OH 610 NHNH OCH, OCH C

611 NHNH OCH, OCH H COCH, C

612 NHNH OCH, OCH C

613 NHNH OCH, OCH CH, COCH C