Fenoldopam 4',8-bis-hydrogen sulfate and dopaminergic use thereof

Fenoldopam 4',8-bis-hydrogen sulfate and its salts are useful prodrugs to obtain extended dopaminergic activity. A useful species is the monoammonium salt.

This invention concerns new sulfate derivatives of the renal dopaminergic 
agent, fenoldopam. More specifically, the compounds of this invention are 
6-chloro-7,8-dihydroxy-1-(4'-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzaz 
epin, 4',8-bis-hydrogen sulfate and its pharmaceutically acceptable salts. 
DESCRIPTION OF THE PRIOR ART 
U.S. Pat. No. 4,388,240 describes the preparation and isolation of three 
monosulfate esters of fenoldopam. No mention is made of any disulfate 
esters. 
DESCRIPTION OF THE INVENTION 
The compounds of this invention have the following structural formula: 
##STR1## 
in which X.sup..sym. is H.sup..sym. or a pharmaceutically acceptable 
cation. The monoammonium salt is preferred. 
The ammonium salt of the compounds of this invention (formula I in which 
X.sup..sym. is NH.sub.4.sup..sym.) is prepared by O-esterification of 
fenoldopam using a 50% excess of sulfur trioxide pyridine complex 
(Py.SO.sub.3) in a mixture of dry pyridine and dimethylformamide. The 
syrupy reaction mixture from the sulfation is purified using preparative 
high performance liquid chromatography over a C.sub.18 reverse phase 
column using a mobile phase of 12% methanol/88% 0.05 N ammonium acetate 
buffer. The first fraction eluted from the column contains the 
4',8-bis-hydrogen sulfate as the monoammonium salt. 
The ammonium salt of formula I is stable when purified but, upon 
neutralization, it slowly disproportionates into the 4' and 8-monosulfate 
esters of fenoldopam and fenoldopam itself. The free dibasic disulfate 
ester is prepared during the sulfation reaction and is converted to its 
relatively stable salt form during the work-up of the reaction mixture. 
The parent bis-hydrogen sulfate was not isolated. 
The compounds of this invention are useful as a long-acting prodrug of 
fenoldopam, especially for parenteral use. In the anesthetized renal dog 
protocol, which is described in detail in U.S. Pat. No. 4,197,297, 
ammonium salt (formula 1 in which X.sup..sym. is NH.sub.4.sup..sym.) had 
a renal vascular resistance ED.sub.15 of 69 .mu.g/kg during the test 
period of intravenous infusion but a potent 100% increase in renal blood 
flow was observed over a lengthy post drug period. The renal dopaminergic 
activity lasted for two hours without a significant change in heart rate 
or blood pressure. 
While the mono-8-sulfate ester of fenoldopam had an ED.sub.15 of 19 
.mu.g/kg in this test, no drug effect was observed in the post-drug period 
of the protocol. 
The salts of formula I are particularly useful to prepare parenteral 
products which produce biological utilities similar to those of the parent 
compound but over an extended period. Exemplary of the uses of the 
compounds are for treatment of hypertension or severe kidney dysfunction. 
The compounds of this invention are administered intravenously by infusion 
using an effective, nontoxic dose selected from the range of 0.02-1.5 
mcg/kg/min for a human patient of average weight. An effective dosage unit 
of from 5-35 mg is administered from 1-5 times daily for intramuscular 
use. 
Pharmaceutical dosage unit preparatives are prepared using extenders such 
as mannitol, preservatives or inert buffers to maintain isotonic 
properties. Freeze dried or sterile dispersible powders in pouches, dosage 
unit ampoules or multidose vials are typical parenteral carrier forms. 
These are administered intravenously or intramuscularly as needed to 
induce an antihypertensive effect in a human patient in need thereof. Oral 
dosage units containing from 75-500 mg of the ester combined with a solid 
carrier in the form of a capsule, tablet or the like are prepared by 
methods known to the art. These are administered from 1-3 times daily to a 
patient in need of dopaminergic treatment. 
Other pharmaceutically acceptable salts are included in this invention. 
Certain alkali metal, alkaline earth metal or organic amine salts are 
known to the art to be so used. These are prepared as described herein, by 
forming the mono-salt prior to purification. Among the cations of this 
group (X.sup..sym. of formula 1) are sodium or potassium. It should be 
noted that one acid group is usually internally neutralized by the basic 
center at position 3. 
Also included in this invention are the bis-hydrogen sulfate esters of 
separated optical isomers of fenoldopam, especially of the R-isomer. These 
are prepared as described herein using, as starting materials, the isomers 
which are prepared as described in the art.

The following example is intended to illustrate this invention. All 
temperatures are Centrigrade. 
EXAMPLE 1 
Sulfur trioxide pyridine complex 
Chlorosulfonic acid (3.0 ml, 0.0454 mol, 150 M %) was added slowly to a 
solution of dry pyridine (9.84 ml, 0.121 mol) in dry dimethylformamide (60 
ml) which had been cooled to -10.degree.. The resulting clear solution was 
stirred for 10 minutes at room temperature. 
O-Sulfation of fenoldopam 
The freshly prepared pyridine complex solution was added all at once to a 
stirred solution of fenoldopam as the methane sulfonate salt (12.06 g, 
0.030 mol, 100 M %) in dry pyridine (180 ml). The mixture was stirred for 
0.5 hours at room temperature, then, heated on a steam bath for 0.5 hours. 
The resulting dark amber solution was chilled for 0.5 hours at 
-10.degree., filtered to remove pyridinium salts, transferred into a tared 
1-necked, 2-L, round bottom flask and evaporated on a Buchi rotavap. At 
70.degree., at reduced pressure, the excess pyridine complex began to 
sublime (0.5 hr) and a syrupy residue was formed. At this point, the 
cold-traps were cleaned and the syrupy residue was rotavaped at 
70.degree., at reduced pressure, for 45 minutes to remove most of the 
volatiles, thereby leaving 23.83 g of syrup. The syrup should weigh no 
more than 26.91 g--the theoretical weight of the total solid content of 
the reaction mixture. 
The syrup was dissolved in 90 ml of mobile phase (MP) [12% methanol, 88% 
buffer (0.05 N ammonium acetate, pH 4)]. The flask was scratched to induce 
crystallization, then, left standing at room temperature for 3 hours. The 
resulting crystalline solid was filtered, washed with 50 ml of the mobile 
phase mixture and dried to give 6.41 g of solid which is mostly 
4'-sulfate. The combined filtrate and washing (140 ml) contains 7.0 g of 
0-sulfates and traces of fenoldopam. The pH is adjusted to pH 3.4-4.0 with 
hydrochloric acid or aqueous ammonia as needed. 
Chromatography 
The partially purified reaction mixture was further purified by preparative 
reverse phase high performance liquid chromatography (HPLC). 
______________________________________ 
Preparative HPLC 
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Apparatus: JY-100 CHROMATOS 
Column: 40 mm .times. 45 cm 
Solid Phase (SP): 
Whatman, Partisil 40 ODS-3 (192 g) 
length 37 cm (Lot #100627) 
Mobile Phase (MP): 
12% methanol 
88% buffer (0.05 N NH.sub.4 OAc, pH 4) 
Flow Rate: 50 ml/min 
Pressure: 2.0 bar 
Detector: GOW-MAC 80-850 LC/LV 
preparative detector 
280 nm 
Attenuation: AUFS 0.64 
______________________________________ 
The sample (140 ml) was injected at 5-10 ml/min. Then, the flow rate was 
adjusted to 50 ml/min. 
The first fraction, containing the 4',8-bis ester, eluted between 18 and 26 
min (k'=3.46) (500 ml); 4'-SO.sub.3 eluted between 38 and 48 min (k'=6.88) 
(700 ml); and the fraction containing 7-SO.sub.3 /8-SO.sub.3 (23:75%) 
mixture eluted between 60-85 min (k'=11.50) (1000-1400 ml). 
Isolation of fenoldopam 4',8-bis-hydrogen sulfate 
The 4',8-bis-hydrogen sulfate was purified by concentrating the designated 
fraction on a rotavap at 50.degree., aspirator pressure, then 
lyophilizing. The resulting solid residue crystallized as the ammonium 
salt upon trituration with methanol. The product was washed with methanol 
and air dried to give an analytically pure ammonium hydrate of fenoldopam 
4',8-bis-hydrogen sulfate, mp, 160.degree. softens, 180.degree. melts, 
185.degree. resolidifies, 200.degree.-205.degree. dec. 
Analytical 
The preparative reactions and chromatographic fractions were analyzed by 
analytical HPLC. 
______________________________________ 
Column: WHATMAN, Partisil 5 ODS-3 RAC II-10 
Mobile Phase: 
same as preparative HPLC 
Flow Rate: 2 mil/min 
Pressure: 13.8 .times. 10.sup.-6 Pa 
Detector: 275 nm 
Compound Retention (min) 
k' 
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4',8-diSO.sub.3 
2.63 3.46 
4'-SO.sub.3 3.93 5.66 
7-SO.sub.3 6.16 9.44 
8-SO.sub.3 6.88 10.66 
fenoldopam 7.83 12.27 
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Anal. Calcd. for C.sub.16 H.sub.16 ClNO.sub.9 S.sub.2.NH.sub.3.2.5 H.sub.2 
O: C, 36.40; H, 4.58; N, 5.31. Found: C, 37.00; H, 4.40; N, 5.30.