NZ272026A - X-ray contrast enhancement agents: iodinated aromatic compounds - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £72026 9 27 02,.

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D pr>- r.-sr. r, ~ i* "-1 r\ -'v h yr-. ' '•-■ ■•'■■ ,,■; . : L\X'/ L^^Vuu-^U-J NEW ZEALAND PATENTS ACT, 1953 No.: Date: Divided out of No. 248702 Filed on 23 September 1993 SUBSTITUTION OF APPUCAHT UNDER SECTION 24 iNacxt&^sto^ W-k COMPLETE SPECIFICATION IODINATED WETTING AGENTS A-3^ 11' 6 <\T 4dK CtWPANH We, STERLING WINTIIROP INC, a corporation created and existing under the <5t*te at t/«*s Jersey, 3tf5 STAre. -rmaer laws of the State of Delaware, and having a place of business at 90 Park-Avenue, 1i<PCHE.sr£R t4b<o New-York, New York 10016, USA hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page 1A) f -/A' 27'2df®> This specification is divided out of New Zealand Patent Specification NZ 248702 (hereinafter referred to as "that invention").

FIELD OF THE INVENTION This and/or that invention relate to iodinated aromatic compounds which are particularly useful as wetting agents.

BACKGROUND OF THE INVENTION X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for image enhancement in medical x-ray imaging procedures is 15 widespread. An excellent background on iodinated and other contrast agents for medical imaging is provided by D.P.

Swanson et al, Pharmaceuticals in Medical Imaging, 1990, MacMillan Publishing Company.

EP-A 4 98,482 describes nanoparticulate x-ray 20 contrast compositions which have proven to be extremely useful in medical imaging. The particles consist of a poorly soluble diagnostic agent having adsorbed thereon a non-crosslinked surface modifier, the particles having a mean particle size of less than about 400 (nm).

The present invention is directed to a method of medical x-ray diagnostic imaging which comprises administering compositions of novel iodinated surfactants which are particularly useful as surface modifiers in nanoparticle formulations.

SUMMARY OF. THE INVENTION We have discovered and prepared novel iodinated aromatic compounds which are particularly useful as wetting agents in x-ray contrast compositions.

This invention relates to a method of diagnostic imaging for use in medical procedures, comprising administering to the body of a test subject an effective 35 contrast producing amount of an x-ray contrast composition as claimed in New Zealand Patent Specification NZ 248702.

More specifically, in accordance with that invention, there are provided novel compounds having the structure (I) / (Z-)— COO - L - CO2M wherein (Z)-COO is a residue of an iodii?fcMiiJ£sB^§matic acid; M is H, a cation, -tCH2CH20hnH, or -(CH2CH (OH) OfpH; m is an integer from 1 to 150; p is an integer from 1 to 50; and L is one or more divalent linking groups selected from, alkylene, cycloalkylene, arylene, arylenealkylene, and alkylenearylene.

It is an advantageous feature of that . invention that iodinated wetting agents are provided for x-ray contrast compositions which agents contribute to contrast enhancement.

It is another advantageous feature that the wetting agents of that invention can be used in vivo to change the 15 interaction of particles with the reticuloendothelial system, thus enabling the particles to be retained in the blood pool or targeted to specific organs.

Still another advantageous feature is that the use of the wetting agents of that invention can result in very small 20 particles, e.g., less than about 100 nm in size, exhibiting both unique biological distribution, i.e., passive tumor targeting, and enhanced pharmaceutical stability.

DESCRIPTION OF PREFERRED EMBODIMENTS The compounds of that invention are described herein primarily in connection with their preferred utility, i.e., as wetting agents for particulate x-ray contrast agents. However, the compounds are also expected to be useful as wetting agents for 30 therapeutic agents and in various other applications.

In structural formula I above, (Z-KJOO is the residue of -an iodinated aromatic 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 35 least three iodine atoms per molecule. The iodinated compounds can contain substituents which do not deleteriously effect the contrast enhancing capability of the compound.

Illustrative examples of suitable aromatic acids include diatrizoic acid, metrizoic acid, urokonic acid, iothalamic acid, * trimesic acid, ioxaglic acid (hexabrix), ioxitalamic acid, tetraiodoterephthalic acid, iodipamide, and the like. ' In preferred embodiments, (Z+COO is the residue of a substituted triiodobenzoic acid such as an acyl, carbamyl, and/or acylamino substituted triiodobenzoic acid.

In a particularly preferred embodiment, Z represents wherein n«*l, 2 or 3, each R independently is H, Ci-Cis alkyl, or Ci-Cis 20 fluoroalkyl, and R1 and R2 are independently H or Ci-Cis alkyl.

M is H; a cation, such as an alkaline or alkaline earth cation such as Na+' K+, Li+, Ca++, Ba++, or an ammonium cation such as NH4+, tetramethylammonium, and the like; -tCH2CH20fnvH, or 25 -fCH2CH (OH)OfpH» wherein m - an integer from 1 to 150, and p «= an integer from 1 to 50.

L represents a divalent linking group preferably selected from alkylene containing from 1 to 20, preferably 1 to 8 carbon atoms such as methylene, ethylene, propylene, butylene, pentylene, 30 hexylene, heptylene and the like; cycloalkylene, preferably containing from 3 to 12 carbon atoms such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like; arylene, preferably containing from 6 to 10 carbon atoms such- as phenylene and naphthylene; arylenealkylene, the alkylene and arylene portions I of which are as described above; and alkylenearylene, the alkylene and arylene portions of which are as describe above.

The alkylene, cycloalkylene, arylene, alkylenearylene and arylenealkylene groups in Structure I above can be unsubstituted or 5 substituted with various substituents which do not ..adversely affect the stability or efficacy of the compounds. Suitable substituents include alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, aryloxy, acyloxy, halogen, acylamino, carboalkoxy, carbamyl and the like. However, reactive substituents are not 10 preferred on the carbon atom adjacent to the ester group.

The compounds of that invention can be prepared by reacting the carboxylate of an iodinated aromatic acid with a functionalized acid having the formula X-L-CO2M wherein X is a leaving group and L and M are as defined above, in a suitable 15 solvent. Suitable leaving groups include halogen, such as Br, I, and CI, sulfonyloxy, such as methanesulfonyloxy and toluenesulfonyloxy. The carboxylates of iodinated aromatic acids and functionalized acids useful as the starting materials in the preparation of the compounds of this invention are known compounds 20 and/or can be prepared by techniques known in the art. For example, suitable acids include commercially available bromoacids and chloroacids. A general reaction scheme is as follows: z-cocr + X-L-CO2M »-i The reaction can take place at various temperatures 25 ranging between -78°C and 100°C, and preferably -40°C to 50°C.

For convenience, the reaction can take place at ambient pressure, however, higher and lower pressures are contemplated.

Alternatively, the compounds of that invention, when M=H or a cation, can be prepared in.a two-step synthesis. First, the 30 carboxylate of an iodinated aromatic acid can be reacted with a functionalized ester as described by Bacon et al in commonly owned -U.S. Patent No. 3,322,679, entitled Iodinated Aroyloxy Esters, filed On December 16, 1992, or i>y Singh et al in commonly owned European Patent No. 93203302.0, entitled Iodinated Aromatic Compounds, filed on December 14, 1992, the disclosures of which are hereby incorporated by reference in their entirety. Thereafter, the ester can be converted into the 27202S corresponding acid by hydrolysis using techniques well known in the art.

The following are specific specific illustrative examples of preferred compounds of that invention that have been prepared: -t(3 *,5'-bis(acetylamino)-2',4•,6 * -triiodophenyl)carbonyloxy]pentanoic acid (WIN 68040), 6-[(3',5'-bis(acetylamino)-2',4',6•-triiodophenyl)carbonyloxy]hexanoic acid (WIN 68056), 7-[(3',5'-bis(acetylamino)-2•,4•,6'-triiodophenyl)carbonyloxy]heptanoic acid (WIN 68167), 8-[(3',5•-bis(acetylamino)-2 •, 4 ■, 6' -triiodophenyl)carbonyloxy]octanoic acid (WIN 68237), and 4-[(3',51-bis(acetylamino)-2•,41,6•-triiodophenyl)carbonyloxymethyl]benzoic acid (WIN 68016).

Preferred compounds of that invention having Structure I above, wherein Z is the residue of diatrizoic acid and M=H, are set forth below: WIN L 68040 (CH2)4 68056 (CH2)5 68167 (CH2)6 68273 (CH2)7 68016 -CH2-C6H4- When used as a wetting agent in an x-ray contrast composition, the compound of that invention can comprise up to about 40% or higher iodine by weight.

In preferred embodiments, the compounds of that invention can be formulated as wetting agents into particulate x-ray contrast compositions, preferably as surface modifiers in nanoparticulate x-ray contrast compositions, as described in commonly-owned EPO 498,482, the disclosure of which is hereby incorporated by reference in its entirety. Such nanoparticulate compositions can be prepared by dispersing a poorly 27209 •..cs soluble x-ray contrast agent in a liquid dispersion medium, and wet grinding the agent in the presence of rigid grinding media and a wetting agent of that invention to form the nanoparticles. Alternatively, the wetting 5 agent can be contacted with the contrast agent aftey ' attrition.

The relative amount of the particulate x-ray contrast agent and wetting agent can vary widely and the optimal amount of the wetting agent can depend, for 10 example, upon the particular contrast agent and wetting agent selected, the hydrophilic lipophilic balance of the wetting agent, its water solubility, the surface tension of water solutions of the wetting agent, etc. The wetting agent can be present in an amount of 0.1-90%, preferably 15 1-75%, more preferably 2-50% and most preferably 2-25% by weight based on the total combined dry weight of the particulate contrast agent and wetting agent.

The x-ray contrast compositions of that invention comprise the above-described compounds, 20 preferably as a wetting agent for a particulate contrast agent, 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 25 such as mixed aqueous and nonaqueous solvents, such as alcohol; eels; 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 remainder 30 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 35 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 2720 range from 50 to 350 mg of iodine per kilogram of body weight of the subject for many imaging 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 contaiji 'one or more conventional additives used to control and/or enhance the properties of the x-ray contrast agent. For example, thickening agents such as dextran or human serum albumin, buffers, viscosity regulating agents, suspending 10 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 15 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 medical procedures in accordance with this invention 20 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, 25 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 30 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 35 halide photographic film combination.

The compositions of that Invention can be administered by a variety of routes depending on the type ■2720| 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, 5 subcutaneous administration, intramuscular administration, intralesional administration, intrathecal administration, intracisternal administration, oral administration, administration via inhalation, administration directly into a body cavity, e.g., arthrography, and the like. 10 in addition to preferred applications, i.e., for blood pool, liver, spleen and lymph node imaging, the x-ray contrast compositions of that invention are also expected to be useful as contrast agents for any organ or body cavity. For example, the compositions of that 15 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 20 contrast media, oral contrast media and bronchographic contrast media.

The following examples further illustrate that invention.

Example 1. Preparation of WIN 68016 A mixture of WIN 67923, i.e., 4-(ethoxycarbonyl)phenyl 3,5-bis(acetylamino)2,4, 6-triiodobenzoate, (11.8 g, 15.2 mmol) prepared by reacting 30 sodium diatrizoate and ethyl 4-bromomethylbenzoate, as described by Singh et al, cited above, and sodium hydroxide (0.8 g, 20.0 mmol) in 100 ml of water and 50 ml of methanol was stirred and heated under reflux for 5 hrs. The methanol was removed under reduced pressure and the remaining solution 35 was filtered to remove some insoluble solids. The filtrate was acidified with concentrated HC1 whereupon a white solid precipitated. The precipitate was collected, washed with 272025 water and dried under vacuum at 80°-85°C to give 9.8 g of a white granular solid, mp 289-292°C (dec.); CI-MS: MH+ 749. The 1H-NMR (300 MHZ) spectral data was consistent with the desired product. Calculated for C19H15I3N2O6: C 30.51, H 2.02, 5 I 50.89, N 3.74; Found: C 30.35, H 1.91, I 51.05, 1^,3'. 62.

Example 2 preparation of WIN 68Q56 A mixture of the ester, WIN 67722, i.e., 6-ethoxy-6-10 oxohexyl-3,5-bis(acetamide)2,4,6-triiodobenzoate, prepared as described by Bacon et al, cited above, (5.6 g, 7.3 mmol) and powdered 95% potassium hydroxide (1.6g, 24.1 mmol) in 25 ml of water was heated on a steam bath for 15 minutes. After cooling, the resulting solution was filtered 15 and acidified with glacial acetic acid. The precipitate that formed was collected, washed with a solution (1:1) of ethanol-ethyl ether and dried to give the crude product (93%) . Recrystallization from DMF gave analytically pure material, mp 251-255°C; CI-MS: MH+ 729. The 1H-NMR (300 MHZ) spectral date 20 was consistent with the desired material. Calculated for C17H19I3N2O6: C 28.05, H 2.63, I 52.29, N 3.85; Found: C 28.05, H 2.63, I 52.39, N 3.78.

Example ..3 Wetting Agent for X-Ray Nanopartlrrle WIN 68056 was mixed at concentrations of 0.5 to 3% with WIN 67722 together with water sufficient to prepare a 10% suspension of WIN 67722. After milling for 7 days, the particle size was reduced to approximately 110 to 130 nm, as 30 determined by standard light scattering techniques.

Example 4 Wetting Agent for X-Ray Nannpartinle WIN 68016 was treated as described above together with WIN 67722 and resulted in particles with an average size 35 of less than 110 nm as determined by standard light scattering techniques. vmv The foregoing specification, including the specific embodiments and examples is intended to be illustrative of this and/ or that invention and is not to be taken as limiting. Numerous other variations and modifications can be effected without 5 departing from the true spirit and scope of the pr^gent invention. -11

Claims (7)

WHAT WE CLAIM IS:

1. A method of medical x-ray diagnostic imaging which comprises administering to the body of a mammal a contrast effective amount of an x-ray contrast composition comprising a compound having the structure (Z)~ COO - L - C02M wherein (Z)-COO is 3 residue of an iodinated aromatic acid; M is H, a cation, (CH2CH20)niH/ or ' (CH2CH(0H)0)pH; m is an integer from 1 to 150; p is an integer from 1 to 50; and L is one or more divalent linking groups selected from alkylene, cycloalkylene, arylene, arylenealkylene, and alkylenearylene.

2. The method of claim 1 wherein said x-ray contrast composition comprises a compound having the structure defined in claim 1 wherein (Z)— COO is a 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 method of claim 1 wherein said x-ray contrast composition comprises a compound having the structure defined in claim 1 wherein (Z)-COO is a residue of diatrizoic acid.

4. The method of claim 1 wherein said x-ray contrast composition comprises a compound having the structure defined in claim 1 selected from the group consisting of 5-[(3',5'-bis(acetylamino)-2',4',6'-triiodophenyl)carbonyloxy]pentanoic acid, 6-[(3',5'-bis(acetylamino)-2',4',6'-triiodophenyl)carbonyloxy]hexanoic acid, 272026 - 12 - 7-[(3',5'-bis(acetylamino)-2',4',6' -triiodophenyl) carbonyloxy]heptanoic acid, 8- [ (3',5'-bis(acetylamino)-2',4',6'-triiodophenyl)carbonyloxy]octanoic acid, and 4- [ (3' ,5'-bis(acetyj.amino)-2' ,4' ,6'-triiodophenyl)carbonyloxy]benzoic acid.

5. The method of claim 1 wherein said x-ray contrast composition comprises a compound having the structure defined in claim 1 wherein Z represents wherein n=1, 2 or 3, each R independently is H, C^C-jg alkyl, or C|-C18 fluoroalkyl, and R1 and R2 are independently H or Ct-C18 alkyl.

6. The method of claim 1 substantially as herein described with reference to the examples.

7. The method of any one of claims 1-6 wherein the x-ray contrast composition further includes a pharmaceutically acceptable carrier. Fjy the authorised agents A. J. PARK & SON