CA2119968A1

CA2119968A1 - Iodinated aromatic propanedioates

Info

Publication number: CA2119968A1
Application number: CA002119968A
Authority: CA
Inventors: Edward R. Bacon
Original assignee: Edward R. Bacon; Sterling Winthrop Inc.; Eastman Kodak Company; Particulate Prospects Corp.; Nanosystems L.L.C.
Current assignee: Nanosystems LLC
Priority date: 1993-03-29
Filing date: 1994-03-25
Publication date: 1994-09-30
Also published as: US5264610A; EP0618189B1; NZ260194A; DE69403534D1; DE69403534T2; ATE153998T1; IL109138A0; US5328404A; ES2102761T3; AU670357B2; AU5906594A; PH30892A; NO941162D0; FI941458A0; EP0618189A1; CZ68894A3; FI941458A; JPH06321868A; NO941162L; SK36094A3

Abstract

IODINATED AROMATIC PROPANEDIOATES
ABSTRACT

Compounds having the structure wherein (Z?COO is the residue of an iodinated aromatic acid;
R1 and R2 are independently alkyl, fluoroalkyl, cycloalkyl, aryl or aralkyl; and R3 is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, cyano, sulfonate, carboxamido, sulfonamido, CO2 - alkyl, CO2 -aryl or CO2 - aralkyl;
are useful as contrast agents in x-ray imaging compositions and methods.

Description

996~
IODINATED AROMATIC PROPANEDIOATES

FIELD OF INVENTION

This invention relates to iodinated aromatic propanedioates which are particularly useful as contrast agents for x-ray imaging.
~: , BACKGROUND OF THE INVENTION

X-ray imaging is a well known and extremely ~aluable tool for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for ima~e enhancement in medical x-ray imaging procedures is widespread.
An excellent background on iodinated and other contrast agents fGr medical imaging is provided by D.P. Swanson et al, Pharmaceuticals in Medical Imaging, 1990, MacMillan Publ;ishing Company.
The following references describe various iodine containing compounds useful in preparing x-ray contrast compositions.
U.S. Patent 3,097,228 describes derivatives of 2,4,6-triiodobenzoyloxyalkanoic acids having the structure '~
CoOR4 :
COOCH
R~
.. :

R ~(RHR

wherein R~ is H or lower alkyl; R2 is H or lower-alkanoyl; and R3 is H or lower alkanoylamino and R9 is lower alkyl.
U.S. Patent 3,199,479 describes iodinated benzoic acid esters having the formula `~

g~6~

COOH
COOCH

I~I

wherein X is an iodine atom or an amino group and R is selected from H, alkyl, alkoxyalkyl, i.e., -~ CH2-tm-O-R", wherein R" ~s alkyl and m is 1 or 2, phenyl and a particular iodinated aromatic group.
However, these references do not disclose or suggest compounds featuring an ester group linked to an alkanoate group ; on an iodinated aromatic ring.
EP-A 498,982 describes nanoparticulate x-ray contrast 10 compositions which have proven to be extremely useful in medical -imaging. However, particulate contrast agents in certain in vivo applications can exhibit less than fully satisfactory solubility profiles and/or enzymatic degradation, e.g./ in plasma and blood.
It would be desirable to provide compounds for use as x-ray contrast agents having improved en~ymatic degradability and appropriate solubility profiles.

SUMMARY OF THE INVENTXON

We have discovered and prepared novel iodinated aromatic propanedioates which are useful as contrast agents i~ x- -ray imag~ng compositions and methods.
More specifically, in accordance with this invention, there are provided compounds having the structure 25 1 (I) ~ o 1 2 : 11 2 .1L ~

wherein (Z-tCOO is the residue of an iodinated aromatic acid;
R1 and R2 are independently alkyl, fluoroalkyl, cycloalkyl, aryl or aralkyl;
R3 is B, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, cyano, sulfonate, carboxamido, sulfonamido, CO2 - alkyl, CO2 -aryl or CO2 - aralkyl.
This invention further provides an x-ray contrast composition comprising the above-described compound and a method for medical x-ray diagnostic imaging which comprises administering to the body of a test subject an effective contrast producing amount of the above-described x-ray contrast composition.
It is an advantageous feature of this invention that novel compounds are provided which find particular utility as x-ray contrast agents.
It is another advantageous feature of this invention that compounds are provided having improved enzymatic degradability and appropriate solubility profiles.
DESCRIPTION OF PREFERRED EMBODIMENTS
. . .
In structural formula I above, (Z ~COO is the residue ,~ -of an iodinated acid. The iodinated aromatic acid can comprise one, two, three or more iodine atoms per molecule. Preferred species contain at least two, and more preferably, at least three iodine atoms per molecule. The iodinated compounds can contain substituents which do not deleteriously effect the contrast enhancing capability of the compound.
Illustrati~e examples of suitable aromatic acids ~-include diatrizoic acid, metrizoic acid, urokonic ac~c, iothalamic acid, trimesic acid, ~ 4 ~ 2~ 26299-110 ioxaglic acid (hexabrix), ioxitalamic acid, tetraiodoterephthalic acid, iodipamide, and the like. In preferred embodiments, (Z-t-COO is the residue of a substituted triiodobenzoic acid such as an acyl (e.g.~ lower alkanoyl having 1 to 4 carbon atoms), carbamyl, and/or acylamino substituted triiodobenzoic acid.
Especially preferred are the residue of 2,4,6-triiodobenzoic acid substituted at the 3-position or both the 3- and 5-positions with acylamino of the formula -N-R4 (wherein R4 is hydrogen or alkyl having 1 to 4 carbon atoms and R5 is alkanoyl having 1 to 4 carbon atoms) such as acetylamino and acetyl(methyl)amino (namely N methylacetylamino) or with alkoxycarbonyl of the formula -CO2CH(CO2C2H5)2.
Rl and R2 independently represent linear or branched alkyl, preferably containing from 1 to 20, more preferably 1 to ~-8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like; fluoroalkyl, the alkyl portion of which is as describ~ed above and containing from 1 to (2m ~ 1) fluorine atoms (where m = the number of carbon atoms in the alkyl group) such as trifluoromethyl; cycloalkyl, preferably containing from 3 to 8 carbon atoms such as cyclopropyl, cyclo-butyl, cyclopentyl and cyclohexyl; aryl, preferably containing from 6 to 10 carbon atoms, such as phenyl and naphthyl; or aralkyl, preferably containing from 7 to 12 carbon atoms, such as benzyl, Preferred groups for Rl and R
are alkyl containing 1 to 8 carbon atoms, especially alkyl containing 1 to 4 carbon atoms; phenyl and benzyl.

-- 2~ 19~68 R3 represents H; alkyl as defined above; fluoroalkyl, the alkyl portion of which is as described above and containing from 1 to (2m + 1) fluorine atoms (where m = the number of carbon atoms in the alkyl group) such as trifluoromethyl;
cycloalkyl as defined above; aryl as defined above; aralkyl as defined above; alkoxy, the alkyl portion of whi~h contains from 1 to 20 carbon atoms as described above; aryloxy, the aryl portion of which preferably contains from 6 to 10 carbon atoms as described above; cyano; sulfonate; carboxamido; sulfonamido;
CO2 - alkyl (i.e., alkoxycarbonyl), the alkyl portion of which ;
is as defined above; CO2 - aryl (i.e., aryloxycarbonyl), the aryl portion of which is as defined above; CO2 - aralkyl (i.e., aralkyloxycarbonyl), the aralkyl portion of which is as defined above, and the like. Preferred groups for R3 are H and alkyl containing 1 to 8 carbon atoms.
The alkyl, cycloalkyl, aryl, aralkyl and alkoxy groups in structure I above can be unsubstituted or substituted with various substituents which do not adversely affect the stability ~
or efficacy of the compounds as X-ray contrast agents such as ~-alkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, acyloxy, :
' ' ':
:

-- 5 _ halogen, such as fluorine, chlorine, bromine and iodine, acylamino, carboalkoxy, carbamyl and the like. However, reactive substitutents such as halogen are not preferred on the carbon atoms, if present on activated positions in the molecule.
The compounds of this invention can be prepared by contacting the carboxylate of an iodinated aromatic acid with a functionalized propanedioate having the formula 72Rl :
X _ C _--R3 wherein X is a leaving group and R1-R3 are as defined above, in a suitable solvent. Suitable leaving groups include halogen, such as Br, I and Cl, sulfonyloxy, such as methanesulfonyloxy and ~oluenesulfonyloxy. The carboxylates of iodinated aromatic acids and functionalized propanedioates useful as the starting materials in the preparation of the compounds of this invention are known compounds and/or can be prepared by techniques known in the art. For example, suitable propanedioates include commercially available bromopropanedioate derivatives as exemplified below. A general reaction scheme is as follows:
CO2Rl ( ~coo-+x_f _ R3 The reaction can take place at various temperatures ranging between -78C and 100C, and preferably -90C and 50C.
For convenience, the reaction can take place at ambient pressure, however, higher and lower pressures are contemplated.
i The reaction can take place in any suitable solvent.
Suitable solvents include N,N-dimethylformamide (DMF).

The following are specific illustrative samples of preferred compounds of this invention that have been prepared:

- 6 ~ 8 26299~110 1,3-Bis(ethoxy)-1,3-bis(oxo)-2-propyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate [alternatively, diethoxycarbonylmethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate] (WIN 67721);
1,3-Bis(ethoxy)-1,3-bis(oxo)-2-methylpropyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate [alternatively, l,l-diethoxycarbonylethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate] (WIN 67975~
1,3~Bis(2-propoxy)-1,3-bis(oxo)-2-propyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate [alternatively, dipropoxycarbonylmethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate] (WIN 68165);
1,3-Bis(ethoxy)-1,3-bis(oxo)-2-propyl 3-acetylamino-5-acetyl-(methyl)amino-2,4,6-triiodobenzoate [alternatively, diethoxy- :. ;
carbonylmethyl 3-acetylamino-5-N-methylacetylamino-2,4,6-triiodobenzoate] (WIN 68747);
1,3-Bis(ethoxy)-1,3-bis(oxo)-2-methylpropyl 3-acetylamino-5-N-methylacetylamino-2,4,6-triiodobenzoate [alternatively, 1,1-diethoxycarbonylethyl 3-acetylamino-5-N-methylacetylamino-2,4,6-triiodobenzoate] (WIN 68841);
1,3-Bis(2-propoxy)-1,3-bis(oxo)-2-propyl 3-acetylamino-5-N- : :~
methylacetylamino-2,4,6-triiodobenzoate [alternatively dipropoxy- ~ -carbonylmethyl 3-acetylamino-5-N-methylacetylamino-2,4,6- ~ :
triiodobenzoate] (WIN 68941);
Bis-(1,3-bis(ethoxy)-1,3-bis(oxo)-2-propyl) 2,4,6-triiodo-5-. acetylaminoisophthalate [alternatively, bis(diethoxycarbonylmethyl) ~ .
2,4,6-triiodo-5-acetylaminoisophthlate] (WIN 68886);
1,3-Bis(ethoxy)-1,3-bis(oxo)-2-propyl 3-acetylamino-2,4,6- -:~
triiodobenzoate [alternatively, diethoxycarbonylmethyl 3-acetyl-amino-2,4,6-triiodobenzoate] (WIN 68299); and - 6a - --` 2~ 9g~8 26299-110 1,3-Bis(ethoxy)-1,3-bis(oxo)-2-methylpropyl 3~acetylamino-2,4,6-triiodobenzoate [alternatively, l,l-diethoxycarbonylethyl 3-acetylamino-2,4,6-triiodobenzoate] (WIN 68694).
Preferred compounds of this invention conform to structure I
above, as indicated below:

~ 8 26299-110 WIN z R3 R2 Rl -:

67721 ¦ H C2~5 CH3CONH NHCOCH3 ~.
67975 nn CH3 C2H5 C2H5 68165 nn H i-C3H7 i C3H7 68747 H C2HS C2H5 :~
I ~ I

CH3CONH ~ NCOCH3 ..

68841 "" CH3 c2~5 C2H5 68341 n H i-C3H7 i-C3H7 68886I ~ I C2H5 C2H5 ~ .

1J~
CH3CONH I CO2CH~C02C2H5)2 68299 ¦ ~ C2H5 C2H~
I ~ I

68694 nn C83 C2H5 C2H5 .
When used as an x-ray contrast agent, the compound of this invention preEerably comprises at least about 35%, more 5 preferably 40% iodine by weight. ~ :
In pre:Eerred embodiments, the compounds of this invention can be formulated into particulate x ray contrast ~ ;

- - 8 - 21~6~ 26299-110 compositions, preferably nanoparticulate X-ray contrast compositions, as described in commonly-owned European Pa-tent No. 498,482. Such nanoparticulate compositions can be prepared by dispersing the compounds of the invention in a liquid dispersion medium, and wet grinding the compound in the presence of rigid grinding media and a surface modifier to form the nanoparticles. Alternatively, the surface modifier can be contacted with the compound after attrition.
The X-ray contrast compositions o this invention comprise the above-described compounds, preferably in the form of particles, and a physiologically acceptable carrier therefor.
For example, the particles can be dispersed in an aqueous liquid which serves as the carrier for the X-ray contrast agent. Other suitable carriers include liquid carriers such as mixed aqueous and nonaqueous solvents, such as alcohol; gels; gases, such as air; and powders.
The X~ray contrast composition can comprise from about 1-99.9, preferably 2-45 and more preferably 10-25% by weight of the above-described particles, the reaminder of the composition being the carrier, additives and the like. Compositions up to about 100% by weight of the particles are contemplated when the composition is in a lyophilized form.
The dose of the contrast agent to be administered can be selected according to techniques known to those skilled in the art such that a sufficient contrast enhancing effect is obtained. Typical doses can range from 50 to 350 mg of iodine per kilogram of body weight of the subject for many imaging - 9 ~ . 1 9 ~ ~ ~
; 26299-110 applications. For some applications, e.g., lymphography, lower doses, e.g., 0.5-20 mg I/kg, can be effective.
The X-ray contrast composition can contain one or more conventional additives used to control and/or enhance the properties of the X-ray contrast agent. For example, thickening agents sush as dextran or human serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting agents, mixing agents, and other drugs and the like can be added. A partial listing of certain specific additives ~ -includes gums, sugars such as dextran, human serum albumin, gelatin, sodium alginate, agar, dextrin, pectin and sodium ~;~
carboxymethyl cellulose. Such additives, surface active agents, preservatives and the like can be incorporated into the compositions of the invention.
A method for diagnostic imaging for use in accordance with this invention comprises administering to the body of a test subject in need of an X-ray, an effective contrast producing amount of the above-described X-ray contrast composition. In addition to human patients, the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like. Thereafter, at least a portion of the body containing the administered contrast agent is exposed to X-rays to produce an X-ray image pattern corresponding to the presence of the contrast agent. The image pattern can then be visualized. For example, any X-ray visualization technique, preferably, a high contrast technique such as computed tomography, can be applied in a conventional manner. Alternatively, the image ;
pattern can be observed directly on an X-ray sensitive phosphor screen-silver halide photographic film combination.
The compositions of this invention can be administered by a variety of routes depending on the type of procedure and the anatomical orientation of this tissue being examined.
Suitable administration routes include intravascular (arterial or venous) administration by catheter, intravenous injection, rectal administration, subcutaneous adminstration, intramuscular administration, intralesional administration, intrathecal administration, intracisternal administration, oral administra-tion, administration via inhalation, administration directlyinto a body cavity, e.g., arthrography, and the like.
In addition to preferred applications, i.e., for blood pool, liver, spleen and lymph node imaging the X~ray contrast compositions of this invention are also expected to be useful as contrast agents for any organ or body cavity. For example, the 9~

compositions of this invention are expected to be useful as angiographic contrast media, urographic contrast media, myelographic contrast media, gastrointestinal contrast media, cholecystographic and cholangiographic contrast media, arthrographic contrast media, hysterosalpingographic contrast media, oral contrast media and bronchographic contras~ media.
The following examples further illustrate the invention.

Example 1 Preparation of WIN 67721 To a solution of sodium hypaque t98.8g, 155.3 mmoles) in dry DMF (600 ml) was added, in several portions, a solution of diethyl 2-bromomalonate in 50 ml of DMF, and the reaction mixture was stirred for 12 hrs at ambient temperature. The solution was then added dropwise, rapidly, to 5 l of ice water and the ---resulting white precipitate was collected, washed with water follow~d by ether. The solid was dried at 110C under vacuum to -~ ~-give 110.6g (92~) of analytically pure product, mp 258-265~C
20 (dec. 279C); CI-MS: MH+ 773. The lH-NMR (300 MHz) spectral data was consistent with the desired material. Calculated for ClgHlgI3N2Og: C 28.00, H 2.48, I 99.31, N 3.63, Found: C 27.80, H 2.25, I 99.55, N 3.53. - ~;
.~ .
Example 2 Preparation of WIN 67975 A solution of sodium hypaque (50g, 79 mmole) in 150 ml of dry DMF was treated with 16.6 ml (87 mmole) of diethyl 2-bromo-2-methylmalonate and the reaction mixture was heated for 12 hrs on a steam bath. After cooling, the solution was added to ice water and the resulting precipitate was collected by filtration, rinsed with water, ethyl acetate and dried under vacuum. The product was recrystallized from DMF-water to give q8.9g (69%) of pure material, mp 268-269C (dec.); CI-MS: MH~ 787. The 1H-NMR (300 MHz) spectral data was consistent with the desired material.

Calculated for C1gH21I3N2Og: C 29.03, H 2.69, N 3.56, I 48.43;
Found: C 28.82, H 2.56, N 3.57, I 48.83.

Example 3 Preparation of WIN 68747 To a solution of the sodium salt of metrizoic acid (68.7g, 92 mmole) in 175 ml of dry DMF was added 17.3 ml (100 mmole) of diethyl 2-bromomalonate and the mixture was stirred for 72 hrs at ambient temperature. The solution was then poured into 2.5 l of water and the crude white product was collected and washed with ether and dried at 110C under vacuum to give 72.8g (99%) of analytically pure solid, mp 200 - 203C; CI-MS: MH+ 787. The lH-NMR (300 MHz) spectral data was consistent with the proposed structure. Calculated for C1gH21I3N2Og: C 29.03, H 2.69, N 3.56, I 48.43,; Found: C 28.88, H 2.47, N 3.50, I ~8.11.

Examples 4 - 9 In a manner similar to the procedures described in Examples 1 - 3 above, the other compounds set forth in the Table above were prepared. In each case, the MS and spectral data (300 MHz) were consistent with the desired product.

The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that vaxiations and modifications can be effected within the spirit and scope of the invention.

Claims

1. A compound having the structure (I) wherein (Z?COO is the residue of an iodinated aromatic acid;
R1 and R2 are independently alkyl, fluoroalkyl, cycloalkyl, aryl, or aralkyl; and R3 is H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, cyano, sulfonate, carboxamido, sulfonamido, CO2 - alkyl, CO2 - aryl, or CO2 - aralkyl.

2. The compound of claim 1 wherein (Z?COO is the residue of an iodinated aromatic acid selected from:
diatrizoic acid, metrizoic acid, urokonic acid, iothalamic acid, trimesic acid, ioxagalic acid, ioxitalamic acid, tetraiodoterephthalic acid and iodipamide.

3. The compound of claim 1 wherein (Z?COO is the residue of diatrizoic acid.

4. The compound of claim 1 wherein R1 and R2 are trifluoromethyl.

5. The compound of claim 1 wherein R3 is H, methyl, or trifluoromethyl.

6. A compound having the structure (I) [wherein:
(Z?COO is the residue of 2,4,6-triiodobenzoic acid which may at the 3-position or at the 3- and 5-positions have one or two substituents selected from the group consisting of acetylamino, N-methylacetylamino and -CO2CH(CO2C2H5)2;
R1 and R2 are independently represent C1-20alkyl, C1-20fluoroalkyl, C3-8cycloalkyl, C6-10aryl or C7-12aralkyl; and R3 represents hydrogen, C1-20alkyl, C1-20fluoroalkyl, C3-8cycloalkyl, C6-10aryl, C7-12aralkyl, C1-20alkoxy, C6-10aryloxy, cyano, sulfonate, carboxamido, sulfonamido, C1-20alkoxy-carbonyl, C6-10aryloxy-carbonyl or C7-12aryloxy-carbonyl].

7. The compound of claim 6, wherein Z is a group of the formula:

, , or .

8. The compound of claim 6, wherein:
R1 and R2 are each C1-8alkyl, phenyl or benzyl; and R3 is hydrogen or methyl.

9. The compound of claim 7, wherein:
R1 and R2 are each C1-8alkyl, phenyl or benzyl; and R3 is hydrogen or methyl.

10. Diethoxycarbonylmethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate.

11. 1,1-Diethoxycarbonylethyl-3,5-bis(acetylamino)-2,4,6-triiodobenzoate.

12. Dipropoxycarbonylmethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate.

13. Diethoxycarbonylmethyl 3-acetylamino-5-N-methylacetyl-amino-2,4,6-triiodobenzoate.

14. 1,1-Diethoxycarbonylethyl 3-acetylamino-5-N-methyl-acetylamino-2,4,6-triiodobenzoate.

15. Dipropoxycarbonylmethyl 3-acetylamino-5-N-methylacetyl-amino-2,4,6-triiodobenzoate.

16. Bis(diethoxycarbonylmethyl) 2,4,6-triiodo-5-acetyl-aminoisophthalate.

17. Diethoxycarbonylmethyl 3-acetylamino-2,4,6-triiodo-benzoate.

18. 1,1-Diethoxycarbonylethyl 3-acetylamino-2,4,6-triiodo-benzoate.

19. An X-ray contrast composition comprising an effective amount of the compound of any one of claims 1 through 18 in admixture with a pharmaceutically acceptable carrier.

20. The X-ray contrast composition according to claim 19, wherein the compound is in the form of nanoparticles and is contained in an amount of 2 to 45% by weight of the composition.

21. A process for producing a compound of the formula (I) as defined in claim 1 or 6, which comprises:
reacting a carboxylate of the formula:
(Z?COO-(which is defined in claim 1 or 6) with a compound of the formula:

(wherein R1, R2 and R3 are as defined in claim 1 or 6, and X is a leaving group selected from the group consisting of Br, I, Cl, methanesulfonyloxy and toluenesulfonyloxy) at a temperature of from -40°C to +50°C in a suitable solvent.

22. The process according to claim 21, wherein X is Br; the carboxylate is sodium salt; and the solvent is DMF.

23. A method for diagnostic imaging, which comprises:
administering to the body of a test subject an X-ray imaging effective amount of the compound of any one of claims 1 through 18 in admixture with a pharmaceutically acceptable carrier, exposing at least a portion of the body containing the administered compound to X-rays to produce an X-ray image pattern corresponding to the presence of the compound, and visualizing the image pattern or observing the image pattern directly on an X-ray sensitive phosphor screen-silver halide photographic film combination.