CA1187897A

CA1187897A - N-substituted iminodiacetic acids

Info

Publication number: CA1187897A
Application number: CA000392015A
Authority: CA
Inventors: Adrian D. Nunn; Michael D. Loberg
Original assignee: ER Squibb and Sons LLC
Current assignee: Bracco International BV
Priority date: 1980-12-29
Filing date: 1981-12-10
Publication date: 1985-05-28
Also published as: SE8703623D0; DE3151686A1; SE466788B; ZA818943B; IT1140400B; SE8703623L; BE891534A; ATA561381A; SE461015B; IE813110L; JPH0237345B2; DE3151686C2; SE8107806L; IT8125861A0; AT377975B; JPH02160727A; GB2090252B; NL8105845A; FR2497197B1; JPH0316327B2

Abstract

Abstract N-SUBSTITUTED IMINODIACETIC ACIDS

New compounds having the formula

Description

N-SUBSTITIJTED I~INODI.a.CETIC ACIDS

The present invention relates to a compound having the formula IO

R2 ~ - (CH ) -NH-C-CH2-M/

R3 ~ 4 CH2-C-OH

or a pharmaceutically acceptable, water soluble salt thereof, wherein Rl and R4 are each independently hydrogen, methyl or ethyl; one of R2 and R3 is alkyl of 1 to 4 carbons and the other is bromine or iodine; and n is 0, 1 or 2; and this invention also encompasses compositions comprising the compounds of formula I (and salts thereof) and a reducing agent, which are suitable for complexing with technetium-93m. In formula I, and throughout the specification, the symbols are as defined above.
Complexes of technetium-99m and a compound of formula I are useful for the external imaging of the hepatobiliary system. The complexes have good specificity (i.e., when injected into a mammal a large percentage of the complex passes through the liver into the bile) and they exhibit rapid transport from liver to bile allowing for good biliary measurements.

~7~

With the exception of the brain, the liver ls the organ most frequently examined by nuclear medicine procedures. .`~ost of these studies involve the intravenous administration of labeled particles such as Tc-99m sulfur colloid which are effectively trapped b~ the Kupffer cells. The diagnostic information thus obtained is useful for studying liver morphology and ~ pffer cell function. The optimum agent or these studies would have rapid, exclusive uptake into healthy Kupffer cells and would be biodegradeable and non-toxic.
Radionuclide studies are also used to measure hepatocyte function and bile duct patency (including gallbladder function).
The optimum agent for these studies would have rapid, exclusive uptake by the hepatocytes, rapid intrahepatic transit, and prompt excre-tion into the biliary system. ~ligh specificity is required to obtain maximum diagnostic information while limiting patient radiation dose. The time to maximum liver concentration (tmaX) and the time for the liver concentration to decrease to '78~

--3~

5~ of the concentration at tma~ (t50) should both be short to reduce the time re~uired for a study. This is important in patients that cannot be immobilized for long ?eriods of time.
Shorter study times increase the number oE
patients that can be ~andled in a given period of time maximizing the use of imaging equipment.
A short t50 also means an increase in the ratio of radioactivity within the bile to that within the liver, thereby resolving the intrahepatic ducts from the liver and thus improvinq the quality of the image and of the resultant diagnosis.
Until recently, most of the nuclear medicine biliary function studies were performed with I-131 rose bengal or I-131 bromosulfophthalein.
~lthough r-131 rose bengal is usually the standard for comparing liver function agents, its photon energy is not optimum for gamma camera imaging, and the patient exposure to non-diagnostic beta radiation limits the dose .~hich can safely be administered. Image resolution and, therefore, diagnostic in~ormation is limited.
The development of Tc-99m penicillamine by Tubis et al (Radiopharmaceuticals, Subramanian et a~
eds., Tne Society of Nuclear l~ledicine, Inc., New Yor~, 1975, pgs 55-62) in 1974 was a significant step in overcoming -the limitations of the iodine-131 label and in stimulating research interest in technetium-99m labeled s7~3~7 hepatobiliary agents. Among ~he most useful technetium-99m labeled agen-ts developed to date are the N-substituted iminodiacetic acids (hepatoiminodiacetic acids-HIDA's). Lober~ et al., in United States ~atent 4,017,596 disclose, lnter alia, the use OL a chelate of technetium-39m and a substituted iminodiacetic acid for e~ternal organ imaging. Eckelman et al., in United States patent 3,725,295 disclose the labeling o~
diethylenetriaminepentaacetic acid (DTPA) with technetium-99m.
The various HIDA derivatives which have been disclosed in the literature can be represented by the formula O

~ 2 n 2 \CH -C-OH

The analogs discussed include the 2,6-dimethyl derivative (Loberg et al., ~. S. patent 4,017,596);

2,6-diethyl, 2,6-diisopropyl, 2-butoxy, 4-butoxy, 4-butyl, 4-isopropyl, 4-ethoxy and 4-iodo derivatives (~.~istow et al., Radiolo~y, 128:793-794, 1978); 2,3-dimethyl, 2,4-dimethyl, 2,5-dimethyl,

3,4-dimethyl and 3,5-dimethyl derivatives (Van Wyk et al., Eur. J. Nucl. ~led., 4:445-448, (1979)i and 2,4,6-trisubstituted derivatives wherein at least two of the substituents are alkyl of 1 to 4 carbons, the third substituen-t 7~

is hydrogen or alkyl of 1 to 4 carbons, and together the substituents contain at least three carbons (Belyian patent 855,107); and 2,6-dimethyl, 2,6-diethyl, 2,6-diisopropyl,

4-methyl, 4-ethyl, ~-isopropyl, 4-n-butyl, 4-n-pentyl, 4-t-butyl, 4-phenyl, d -methoxy, 3,5-dimethyl, 2,4,6-trimethyl, 2,4,5-trimethyl, 4-fluoro, 2,4-difluoro, 2,5-difluoro, and 2,3,4,5,6-pentafluoro derivatives (l~iolten et al., 3rd Int. Symp. Radiopharm. Chem., St. Louis,Mo., June 1980). Fields et al, Journal of Labelled Compounds and Radiopharmaceuticals, XV: 387-399 (L978) disclose N-(2-phenethylcarbamoylmethyl)-iminodiacetic acid.
Van ~yk et al., Eur. J. Nucl. rAed., 4:445-448, 1979, in their work with dimeth~yl HIDA derivatives have shown that steric effects of substituents are important for biliary uptake. Chiotellis et al., Int. J. Nucl. ~led. Biol., 7:1-7, 1980, working with 4-butyl HIDA compounds, nave shown that molecular size of substituents is iInportant for biliary uptake.

~71~3~117 Compounds of formula I
of the present invention~and salts thereof, can be labeled with technetium-99m and subsequently administered intravenously into a pat-ient for the purpose of imaging the hepatobiliary system.
The radiolabeling of compounds of formula I, and salts thereof, can be accomplished using procedures well known in the art. In a preferred procedure, technetium-99m in the form of an aqueous sodium pertechnetate solution (Na99mTcO4) is combined with a reducing agent and a compound of formula I, or salt thereof. r~ihile the order of mixing of the three above-described components is not critical it is most preferred that the reducing agent be flrst combined with a compound of formula I of this invention. This composition (a non-radioactive composition) can then be supplied to radiochemists, technicians, radiophar~acists, doctors and the like for labeling with technetium-99m just prior to use.
Stannous ion is the preferred reducing agent. Exemplary stannous reducing agents are stannous chloride and stannous fluoride.
Technetium-99m in the form of an aqueous solution of sodium pertechnetate is readily obtainable from commercially available molybdenum-99/
technetium-99m generators which are conventionally eluted with saline.
Ihe compounds of formula I of this invention can be prepared using as starting materials nitrilo-tri~cetic acid, acetic anhydride, and an amine 7~

_7-derivative having the formula Rl R2 ~ (C 2)n 2 -Nitrilo-triacetic acid and acetic anhydride are first reacted to give nitrilotriacetic anhydride ~hich is then reacted with an amine of formula II to give the corresponding compound of formula I. The reactions proceed most readily if the reactants are present in stoichiometric amounts.
The compounds of formula I can be converted to pharmaceutically acceptable, water-soluble salts using art-recogni~ed procedures. Preferred salts are alkali metal salts and alkaline earth metal salts.
The compounds of formula I (and salts thereof) can be prepared for complexing with technetium-99m using art-recognized procedures. For example, a "wet ki-t" can be prepared by first dissolving a compound of formula I (or salt thereof) in base (e.g., sodium hydroxide)to give a solution of about pH 6 to 7. To this solution is added an acidic solution of reducing agent (e.cJ., stannous fluoride)in nydrochloric acid. Water can be added to give the desired vol~e. To this solution technetium-99m, preferably an aqueous solution of sodium pertechnetate, can be added. Lyophilized kits can be prepared usiny the above-described pr~cedure, except that prior to the addition ~7~

of technetium-99m the solution is lyophilized.
The lyophilized material may be stored in an inert atmosphere.
Preferred compounds of this invention are those compounds o~ formula I wherein n is 0.
Par-ticularly preferred are those compounds having the formula III
CH3 ~CH2-C-OH
R2 ~NH-C-CH2-N
R3 H3 o or a pharmaceutically acceptable, water soluble salt thereof, wherein one of R2 and R3 is methyl or ethyl and the other is bromine or iodine.
The following examples are specific embodiments of this invention.

71~97 Example 1 2,2'-[12-[(3-bromo-2,4,6~trimethylphenyl)amino-]-2-oxoethyllimino]bisacetic acid A) 3-Bromo-2,4,6-trimethylaniline Concentrated hydrochloric acid (80 ml) is cooled in an ice-water bath to 5C. 2,4,6-Trimethylaniline (13.5 g) is added over a period of 20 minutes with vigorous stirring while keeping the temperature below 15 C. The thick slurry is cooled to 3C and 16.8 g of bromine in 80 ml of concentrated hydrochloric acid is added over a period of 25 minutes. The slurry is heated in a water bath for one hour and then cooled in an ice bath for one hour. The reaction mixture is then filtered and the salt is washed with three 50 ml portions of cold distille~
water. After drying, the crude product is dissolved in 600 ml of ~istilled water, treated with 3.0 g of Darco and filtered on a Hyflo-bed to give a solution. ~eutralization with concentrated ammonium hydroxide gives a milky solution from which the product solidifies upon cooling to 10 C. After refrigeration for about 16 hours, the tan product is filtered, washed with cold distilled water and dried under vacuum for about 16 hours to give 12.0 g of the title compound, melting point 34.0-35 0C.

* Trade Mark 78g7 _la -B) 2,2'-[[2-[(3-bromo-2,4,6-trimethylPhenyl)amino]-2-oxoethyl]imino]bisacetic acid A suspension of 9.56 g of nitrilotriacetic acid in pyridine (dried over molecular sieves) is prepared with the exclusion of moisture (CaSO4 drying tube) and heated to 50C. Acetic anhydride (S.ll g) is added dropwise. The reaction mixture clears and is heated to 100C.
After maintaining the temperature for 40 minutes, the reaction mixture is cooled to 55C and a solution of 10.7 q 3-bramo-2,4,6-trimethylaniline in 25 ml of dry pyridine is added slowly. The reaction is heated to 100C and after 1.5 hours at this temperature, the solution is cooled in an ice-~ath. The reaction mixture is rotary evaporated to a semisolid which is dissolved in 125 ml of 10~ sodium hydroxide w/v. The basic layer is then extracted with two 100 ml portions of methylene chloride. Distilled water (100 ml~
is added to the basic layer which is then brought to pH 3 with concentrated hydrochloric acid to give a precipitate. After refrigeration for a~out 16 hours, the crude product is riltered, washed with cold distilled water and dried under vacuum at 40C. The crude product is dissolved in 100 ml of 60% aqueous ethanol, treated with 3.0 g of Darco and filtered hot through a *
Hyflo-bed to give a solution. Crystals precipitate and are filtered, washed with three 25 ml portions of 50% aqueous ethanol and dried under vacuum at 40C. The reaction yields 9.1 g of the title compound, melting point 198-200C, dec.

* Trade Mark 7~

ExamDle 2 2,2'-[[2-[(3-[(3-Bromo-2,6-dlethvl-~-methylphenyl)-amino]-2-oxoethyl~imino]~isacetic acid A) 3-Bromo-2,6-diethyl-~-rnethylaniline Concentrated ~ICl (l0 ml) is cooled to 5C
in an ice-water bath and l.63 g o- 2,6-diethyl-~-methylaniline is added dropwise to give a slurry.
Bromine (l.59 g) with l0 ml of concentrated HCl is added dropwise over 30 minutes. The reaction is allowed to stir for 3.75 hours and 25 ml of distilled water is added. After cooling for 1.0 hour, the reaction mixture is filtered and washed twice with 25 ml of cold distilled water.
After drying under vacuum for aDout 16 hours, the crude solid (2.3 g) is dissolved in l00 ml of 10% NaOH and extracted with a l50 ml portion and with a l00 ml portion of methylene chloride.
After drying over sodium sulfate, the methylene chloride solution is rotary evaporated to l.9 g of crude product.

B) 2~2~-[[2-[(3-Bromo-2~6-dietI~vl-~-methylphenyl)-amino]-2-oxoethvl]imino]bisacetic acid -A slurry of l.3~ g of nitrilotriacetic acid in 15 ml of dry pyridine (dried over molecular sieves) is prepared and heated to ~6C. ~cetic anhydride (0.72 g) lS added (i ml pyridine rinse) and the solution is heated to l00C. Ater heating for 0.5 hour, the solution is allowed to cool to ~16C and a solution of 1.7 g of crude 3-bromo-2,6-diethyl-~-methylaniline in 6 ml of pyridine ~7~

is slowly added. The solution is heated at lOQC for 2 hours, cooled, and .otary evaporated to a pasty product. The ?roduc~ is disso]ved in 25 ml of 10~ sodium hydroxi_e ~nd the resulting solution is extracted twice wit:rl 25 ml portions of methylene chloride. The aqueous solution is diluted with 50 ml of distilled water, neutralized wit~ concentrated HC1 to pH 3 0, and refrigerated for about 16 hours. ~iltration gives a solid which upon drying for 3 hours at 60 C under vacuum gives 1.4 g of crude product. ~ecrystalli~a~tion from 25 ml of 506 e-thanol gives 1.04 g of needles, melting point 194.5-195.5C.

Example 3 2,2'-[[2-[(3-Iodo-4-methylphenyl)amino]-2-oxoethyl]-imino]bisacetic acid A slurry of 4.78 g of nitrilotriacetic acid in 40 ml of dry pyridine (dried over molecular sieves~ is neated to 60C. ~cet c anhvdride (2.55 g) is added slowly and the solution is heated to 100 C. After heating or 0.5 hour, the solution is cooled to 40C and a solution of

5.3 g of 3-iodo-4-methylaniline in 20 ~1 of dry pyridine is added over 25 minutes. The solution is heated at 100 C for 1.0 hour.
The reaction is cooled and rotary evaporated to a residue which is dissoived in 65 ml of 106 sodium hydroxide. ~his solution is extracted twice with 50 ml portions of methylene chloride diluted with 100 ml of distilled water, and RE~64 neutralized with concentrated HCl to pH 3.2.
The crude product is refrigerated for about 16 hours, filtered, washed twice with 50 ml portions of distilled water, and dried under vacuum at 40 C. The crude product (8.0 g) is recrystallized after Darco treatment to yield 5.7 g of product, melting point 213.5 - 215.0C(dec).

Example 4 2,2'-l~2-[(4-Bromo-3-methylphenyl)amino]-2-_oethyl]imino]bisacetic acid A slurry of 9.56 g of nitrilotriacetic acid in 80 ml of dry pyridine (dried over molecular sieves) is heated to 55C. Acetic anhydride (7.66 g) is added and th.e solution is heated to 100C. After heating for 0.5 hour, the solution is cooled to 55C and 9.30 g of 4-bromo-3-methylaniline is added with a 5 ml pyridine rinse. The solution is heated at 100 C for 1.0 hour. The reaction is cooled and rotary evaporated to a pasty solid which is dissolved in 120 ml of aqueous ammonium hydroxide (30 ml concentrated ammonium hydroxide/90 ml distilled water). The clear brown solution is extracted with two 100 ml portions of methylene chloride and neutralized to pH 3 with 35 ml of concentrated HCl. The white solid is filtered, washed with three 25 ml portions of cold distilled water, and dried under vacuum for 2.75 hours at 60 C.
The crude produc-t (12.9 g) is recrystallized fro~ 360 ml of 50~ ethanol to give 9.85 g of product, melting point 206.5-209.0C.

* Trade Mark ~ ~7;~i97 xample 5 2,2'-[L2-~(3-Bromo-4-methvl?hen~ l)amino~-2-oxoethyl]-imino]Disacetic acid A slurrv of ~.78 q or nltrilotriacetic acid 5 in 40 ml o. dry pyrldine (dried over molecular sieves) is prepared and i-~eated to 50 C. Acetic anhydricle (2.55 q) is added slowlv and the solution is heated to 100 C. After heating for 0.5 hour, the solution is coolecl to 42 C and 4.81 q of 10 3-bromo-4-methylaniline in 5 ml c- pyridine is slowly added. The solution is neated to 100 C.
After heating for 2.0 hours, the reaction is cooled and rotary evaporated. This material is dissolved in 75 ml of lO?s sodium hydroxide, and 15 extracted twice with 50 ml _ortlons of methylene chloride The aqueous portion is diluted with 100 ml of distilled water, neutralized to pH
3.2 with concentrated HCl, and rerrigerated for about 16 hours overnight. The reaction is 20 filtered and washed with cold distilled water.
After drving for 3 hours under vacuum at 60 C, 7.14 g of crude ?roduct is obtained, melting point 206.0-208.0 C. Recrystallization from 150 ml Oc 75?5 ethanol qives 6.4 g of solld, 25 melting point 209.0-210.0C.

~&7~

Exa~,?le 6 Formulations for comple~ing with technetium-99m The table below presents e.~emplary formulations of com~ounds of formula I ;~ith stannous fluoride reducins agent. The formulations are prepared by dissolving the ligand in 0.l6 .`~1 sodium hydroxide to give a solution of final ~H Ot about 6 -to 7.5.
To this is added 0.01 ml of a 70 mg/ml solution of stannous fluoride in 61~ hydrochloric acid and the volume is brought to 5 ml with water for injection. The formulations intne followins table have a ~referred molar ra.io of li~and:tin of 150:1.

9~

. .
~D u~ (` U~ I`

~O Q) I
O ~ er ~r er ~ .
C
~ C o o o o o o _ ~ ~
~ Ul ~
o hr~;
~' C C~ ~ O
o,~ ~
~: .-1 ~0 ~ I
_~ ~ I I
~ _l ~ ~
E~ ~, ~ O O
'D ~11 ~ O -~ -~1 _ U~ O ~
_~~ . ,1 C
~. u~ g ~ ~ ~
V ~ ~ ~ C ~ ~ ~
U~ ~ ~ C~~ U ~ ~J
V ~ ~ U
~D ~N X ~
~r --o, ~ ~,g ~, ~ u C ~y ~J ~
N eo ' ,g ~ ' .

o~~ o ~ o~ o~
~ ~I c I ,_ g, _ ~c ,~
h C_ ,,~ "~ ~o ,,C~rrh~ ,,C~ 1~ ,1 O~ ~ U ~ c ~ ~c ~ g O-- C --I II ~ U ~ :~ I :~ I
N ~1~ ~' --1 1 ,C ~ C N ,C
C I O I ~ O -- O I O I O
tr!iN ~- C ~ o ~ O ~`I
."~ C` aJ ~ ` I` I ` I

Claims

The embodiments of the invention in which an ex-clusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound having the formula I:

or a pharmaceutically acceptable, water soluble salt thereof, wherein R1 and R4 are each independently hydrogen, methyl or ethyl;
one of R2 and R3 is alkyl of 1 to 4 carbons and the other is bromine or iodine; and n is 0, 1 or 2;
which comprises either:
a) reacting an amine derivative having the form-ula II:

with nitrilotriacetic anhydride; or b) reacting a compound of formula I with an acid or a base to provide a pharmaceutically accept-able, water soluble salt thereof.

2. The process of claim 1a) wherein the reactants are used in stoichiometric amounts.

3. The process of claim 1a) wherein the nitrilo-triacetic anhydride is generated in situ.

4. The process of claim 3 wherein the nitrilotri-acetic anhydride is generated in situ from nitrilotri-acetic acid and acetic anhydride.

5. The process of claim 1a) wherein there is pre-sent an inert diluent or solvent.

6. The process of claim 5 wherein the diluent or solvent is pyridine.

7. The process of claim 1b) wherein a compound of formula I is reacted with an alkali metal or alka-line earth metal salt or base to provide a pharmaceu-tically acceptable water soluble alkali metal or alka-line earth metal salt thereof.

8. The process of claim 1 wherein n is 0 and the compound thus prepared has the formula:

or a pharmaceutically acceptable, water soluble salt thereof.

9. The process of claim 1 wherein R1 and R4 are both methyl.

10. The process of claim 8 wherein R1 and R4 are both methyl.

11. The process of claim 1 wherein one of R2 and R3 is methyl or ethyl.

12. The process of claim 8 wherein one of R2 and R3 is methyl or ethyl.

13. The process of claim 1 wherein one of R2 and R3 is methyl or ethyl and R1 and R4 are both methyl.

14. The process of claim 8 wherein one of R2 and R3 is methyl or ethyl and R1 and R4 are both methyl.

15. The process of claim 1 wherein there is thus prepared 2,2'-[[2-[(3-bromo-2,4,6-trimethylphenyl)amino]-2-oxoethyl]imino]bisacetic acid or a pharmaceutically acceptable water soluble salt thereof.

16. The process of claim 1 wherein there is thus prepared 2,2'-[[2-[(3-bromo-2,6-diethyl-4-methylphenyl)-amino]-2-oxoethyl]imino]bisacetic acid or a pharmaceu-tically acceptable water soluble salt thereof.

17. The process of claim 1 wherein there is thus prepared 2,2'-[[2-[(3-iodo-4-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid or a pharmaceutically acceptable water soluble salt thereof.

18. The process of claim 1 wherein there is thus prepared 2,2'-[[2-[(4-bromo-3-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid or a pharmaceutically acceptable water soluble salt thereof.

19. The process of claim 1 wherein there is thus prepared 2,2'-[[2-[(3-bromo-4-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid or a pharmaceutically acceptable water soluble salt thereof.

20. A compound having the formula I:
or a pharmaceutically acceptable, water soluble salt thereof, wherein R1 and R4 are each independently hydrogen, methyl or ethyl;
one of R2 and R3 is alkyl of 1 to 4 carbons and the other is bromine or iodine; and n is 0, 1 or 2;
when prepared by the process of claim 1.

21. A compound, as defined in claim 20, or a salt thereof, when prepared by the process of claim 2.

22. A compound, as defined in claim 20, or a salt thereof, when prepared by the process of claim 3 or 4.

23. A compound, as defined in claim 20, or a salt thereof, when prepared by the process of claim 5 or 6.

24. A compound, as defined in claim 20, in the form of a salt thereof, when prepared by the process of claim 7.

25. A compound having the formula:

wherein R1, R2, R3 and R4 are defined as in claim 20, or a pharmaceutically acceptable, water soluble salt thereof, when prepared by the process of claim 8.

26. A compound, as defined in claim 20, wherein R1 and R4 are both methyl, when prepared by the pro-cess of claim 9.

27. A compound, as defined in claim 20, wherein R1 and R4 are both methyl, when prepared by the pro-cess of claim 10.

28. A compound, as defined in claim 20, wherein one of R2 and R3 is methyl or ethyl, when prepared by the process of claim 11.

29. A compound, as defined in claim 20, wherein one of R2 and R3 is methyl or ethyl, when prepared by the process of claim 12.

30. A compound, as defined in claim 20, wherein one of R2 and R3 is methyl or ethyl and R1 and R4 are both methyl, when prepared by the process of claim 13.

31. A compound, as defined in claim 20, wherein one of R2 and R3 is methyl or ethyl and R1 and R4 are both methyl, when prepared by the process of claim 14.

32. The compound 2,2'-[[2-[(3-bromo-2,4,6-trimeth-ylphenyl)amino]-2-oxoethyl]imino]bisacetic acid, or a pharmaceutically acceptable water soluble salt thereof, when prepared by the process of claim 15.

33. The compound 2,2'-[[2-[(3-bromo-2,6-diethyl-4-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid, or a pharmaceutically acceptable water soluble salt thereof, when prepared by -the process of claim 16.

34. The compound 2,2'-[[2-[[(3-iodo-4-methylphenyl)-amino]-2-oxoethyl]imino]bisacetic acid, or a pharmaceu-tically acceptable water soluble salt thereof, when pre-pared by the process of claim 17.

35. The compound 2,2'-[[2-[(4-bromo-3-methylphenyl)-amino]-2-oxoethyl]imino]bisacetic acid, or a pharmaceu-tically acceptable water soluble salt thereof, when pre-pared by the process of claim 18.

36. The compound 2,2'-[[2-[(3-bromo-4-methylphenyl)-amino]-2-oxoethyl]imino]bisacetic acid, or a pharmaceu-tically acceptable water soluble salt thereof, when pre-pared by the process of claim 19.