DE2130369A1 - Triiodiaminobenzoic acid derivatives, process for their preparation and their use as X-ray contrast media - Google Patents

Description

DIPL-CHEM. DR. ELISABETH JUNG DIPL.-CHEM. DR. VOLKER VOSSIUS DIPL.-PHYS. DR. JÖRGEN SCHIRDEWAHN PATENT LAWYERS

MÖNCHEN 23, CLEMENSSTRASSE TELEPHONE 345087

TELECRAM ADDRESSEt INVENT / MDNCHEN TELEX 5-29 688

uZ: G 240 C (Do / Vo / Ge) Case 47908-S
BR SQUIBB & SONS, INC. New York, New York, V.Su.A.

June 18, 1971

"Triiodiaminobenzoic acid derivatives, process for their preparation and their use as X-ray contrast media "

Priority: June 19, 1970, V.St.A., No. 47 908

The invention relates to new triiodiaminobenzoic acid derivatives of the general formula (I)

COOH

N-CO-X-CO-N R R

N-CO-

ST

(D

in which R, R ₁ and R _{2 represent} a hydrogen atom or a C ^ g radical, R is a C ^ g alkyl radical and X is an alkylene

109852/1960

means rest with up to 10 carbon atoms, which are interrupted by oxygen atoms, sulfur atoms and / or -N- radicals

can, as well as their salts and C, g-alkyl esters.

The C, g-alkyl radicals can be straight-chain or branched. Specific examples are the methyl, ethyl, propyi-, Isopropyl, η-butyl, isobutyl, n-pentyl, 2-methylbutyl, Neopentyl, n-hexyl, 2-methylpentyl ,. 3-methylpentyl-, 2,2-dimethylbutyl- or 2,3-dimethylbutyl group.

Suitable salts are e.g. alkali salts, such as sodium or potassium salts, Alkaline earth salts, such as calcium salts, ammonium salts,

ι
or amine salts; for example with N-methylglucosamine.

Specific examples of C, g-alkyl esters are the methyl, Ethyl or butyl ester.

Examples of compounds of the general formula (I) according to the invention ^{are N, N l} _{-Bis- <} / ^ - (alkylureido) -3-carboxy-2,4,6-triiodopheny] Jf-adipamides, such as N ^ '- Bis-Z ^ -CS-methylureidoJ - ^ -: carbox3 "-2,4,6-triiodopheny3 ^ -adipamide, N, N'-bis- / 5- (3-ethylureido) -3-carboxy-2,4» 6-triiodopheny | / -adipamide or Ν, Ν'-bis-- / B- (3-n-butylureido) -3-carboxy-2,4,6-triiodpheny ^ -adipamide, N, N ^l -Bis- / 5 - (Dialkylureido) -3-carboxy-2,4,6-triiodopheny ^ -adipamides, such as N, N'-bis- / 5- (3,3-dimethylureido) -3-carboxy-2,4,6-triiodopheny ^ adipamid, !!, N'-Bis - ^ - d, 3-dimethylureido) -3-carboxy-2,4,6-triiodopheny3 ^ -adipamid, Njli'-Bis-ZB-Ci-methyl-S-äthylureido) -3-carboxy-2,4,6-triiodophenyl / '- adipamide or N ₁ N ^ / B- (1-ethyl-3-methylureido) -3-carboxy-2,4,6-triiodophenyl / -adipamide, N , N'-bis- / 5- (trialkylureido) -3-carboxy-2,4,6-tri-

109852/1960

iodophenylZ-adipamide, such as N, N'-bis- / 5- (1, 3,3-trimethylureido) -3-carboxy-2,4,6-tri; iodophenyl / -adipamide, NjN'-dialkyl-liJf'- bis- / 5- (alkylureido) -3-carboxy-2,4,6-triiodophenyl / -adipamides, such as N, N'-dietliyl-N, li ^l -'bis- / 5- (3 ~ methylureido) -3 -carboxy-2,4,6-trijodph.enyl7-adipamid, N, N ¹ - dialkyl-N, N'-bis- / 5- (dialkylureido) ~ J-carboxy ^^^ - trijodphenylZ-adipamide, like N, N'-diethyl-N, N ^l -biB- / 5- (3,3 ~ dimethylureido) -3-carboxy-2,4,6-triiodophenyl7-adipamide or N, N'-diethyl-N, N'-bis - / 5- (i, 3-dimethylureido) -3-carboxy-2,4 »6-triiodophenyl7-adipamide, or NjH'-dialkyl-NjN'-bis- / 5- (trialkylureido) -3-carboxy-2, 4,6-triiodophenyl7-adipamide _/ like lI, K'-I) iraethyl-N, N ^l -bis ~ / 5- (i-ethyl-3,3 ~ dimethylureido) -3-carboxy-2,4,6- triiodophenyl7-adipamide or N, N'-diethyl-N, N · bis- / 5- (1,3,3-trimethylureido) -3-carboxy-2,4,6-triiodophenyl / -adipamide, as well as the corresponding Derivatives of amides of succinic, glutaric, cork, pimeline, sebacic, 3-oxaglutaric, 3-thiaglutaric or 3-methyl-3-azaglutaric acid.

The invention also relates to a method of manufacture of the triiodiaminobenzoic acid derivatives of the general formula (I) or their salts or esters,. , which is characterized in that one iDriiododiaminobenzoic acid derivative of the general Formula (II)

(II)

in which R, R ₁ and X have the aforementioned meaning, with a

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Alkyl isocyanate of the general formula (III)

(in)

in R _5, each has the aforementioned meaning with a Blalkylearbamy! halide. the general formula (IT)

R ₂ .

M-CO-Y. (IT)

in the R ~ and R, have the aforementioned meaning and Y a Represents halogen atom, converts and optionally converts the free acids into the salts or esters in a manner known per se.

In the dialkyl carbamyl halide of the general formula (IV) Y is preferably a chlorine atom. The reaction is carried out in an inert solvent such as ethylene glycol dimethyl ether or diethylene glycol dimethyl ether or dimethylformamide. When using the dialkylcarbamyltialogenide of the general formula (IV) the condensation is preferably in the presence of a hydrogen halide acceptor such as pyridine, N-methylmorpholine or Triethylamine made. In these cases the halogen can accept hydrogen at the same time also serve as a solvent for the reaction.

The triiodiaminobenzoic acid derivatives of the general formula (II) can from the corresponding diaminobenzoic acid derivatives of the general formula (V)

109852/19 * 60

OOH

COOH

-U-CO-X-CO-S
R.

in which R, R ₁ and X have the aforementioned meaning, are prepared by iodination with iodine chloride in an aqueous medium or with sodium or potassium iodine dichloride in an aqueous medium.

Those compounds of the general formula (V) in which R ₁ denotes a hydrogen atom can be obtained by reducing the nitro compounds of the general formula (VI)

COOII

COOH

N-CO-X-CO-N

It I

in which R and X have the aforementioned meaning. Those compounds of the general formula (V) in which R ₁ is a C, g-alkyl radical can be prepared by reducing the Schiff's base of a compound of the general formula (V) in which R _{1 is} a hydrogen atom.

The nitro compounds of the general formula (VI) are by condensation of a 3-nitro-5-carboxy-phenylamine of the general Formula (VII)

109852/1960

CCOH

(VII)

in which R has the aforementioned meaning, with an acyl halide preferably the chloride, of the general formula (VIII)

Y-CO-X-CO-Y

(VIII)

in which X and Y have the aforementioned meaning. The condensation is caused by traces of strong mineral acids, such as Sulfuric acid or perchloric acid.

Another way of producing the trijodiaminobenzoic acid derivatives of the general formula (I) consists in the condensation of a trijodiaminobenzoic acid derivative of the general Formula (IX)

(IX)

R-,

in which R ₁ , Rg and R, have the aforementioned meaning, with the acyl halide of the general formula (VIII).

109852/1960

The triiodiaminobenzoic acid derivatives of the general formula (I) are suitable as X-ray contrast media for visualizing animal systems or organs. Preferably the solutions serve the pharmacologically applicable salts, e.g. the sodium or methylglucosamine salts, for intravascular injection in the field of urography and vasography, e.g. angiocardiography, arteriography, nephrography and / or Venography. The water-insoluble esters are suitable for visualization of organ cavities and cavities with external openings through which the contrast agent is introduced and afterwards Examination can be removed again. Solutions with 20 to 50 percent, preferably about 37 percent, bound iodine, i.e. solutions containing about 20 to 75 g of a compound of the general formula (I) per 100 ml of water hold to be used.

The examples illustrate the invention.

example 1

N, N '-Bis- / 5- (3-methylureido) -3-carboxy-2,4-. 6-tri .i odphenyl7 ~ adiparr.id

a) N _T N'-bis- / 5 ~ nitro-3-carbo3: yphenyl7-adipaTDid A solution of 10 g of 3-amino-5-nitrobenzoic acid in 75 ml of toluene is slowly mixed with 4.5 g of adipic acid chloride. The reaction mixture is heated on a steam bath for 6 hours. After the reaction mixture has cooled, the insolubles are filtered off, washed with toluene and air-dried. This product is suspended in dilute hydrochloric acid and, after being filtered off, washed with water. Here you get the desired

109852/1960

Compound which can be purified by recrystallization as the ammonium salt. The purified free acid melts at about 30O ⁰ C.

b) N ^ I '

A solution of TO g of N, H ^l -bis- / 5-nitro ~ 3 ~ carboxyphenyl / ~ adij> amide in the stoichiometric amount of aqueous sodium hydroxide solution is added after adding 1 g of Raney nickel at a hydrogen pressure of 3, Shaken 5 at in a Parr hydration apparatus until the calculated amount of hydrogen is consumed. "After the reaction mixture has been filtered off, the filtrate is neutralized with acetic acid. The precipitate is filtered off, washed with water and dried. This gives the desired compound, which ^{melts at about 310 0} O (decomp.).

c) N, li ^t -Bis- / 5-amino-3-carboxy-2,4,6-tri, iodophen.yl7-adiparfiid A mixture of 13.3 g lI, N'-bis- / B-amino- 3-carboxyphenyl / adipamide and 400 ml of water are slowly admixed with 100 ml of a 2N aqueous potassium iodine chloride solution while stirring vigorously. The reaction mixture is stirred for 24 hours at room temperature and then filtered. The pesticide obtained is dissolved in dilute aqueous sodium hydroxide solution and, after treatment with aqueous sodium hydrogen sulfite, filtered. After neutralization of the filtrate with dilute hydrochloric acid, the precipitate is separated by filtration, washed with water and dried at 50 ⁰ O under reduced pressure. The desired compound, which has a melting point of over 300 ° C., is obtained here. This compound can be purified by recrystallization as the ammonium salt.

109352/1960 ORIGINAL BATHROOM

d) N, I \ F'-Bis ~ / B- (3 "methylureido)" g-carboxy-2,4t6-t ri,) odphenyIL / - adiparaid

A mixture of 2 g of IT, N'-bis ~ / 5 ~ amino ~ 3 "carboxy-2,4,6-triiodophenyl / adipamide, 2 ml of methyl isocyanate and 100 ml of ethylene glycol dimethyl ether is refluxed for 24 hours. Wake off distillation of the solvent under reduced pressure, the residue is washed with dilute hydrochloric acid. The solid precipitate is filtered off and dissolved in dilute lye. The solution is filtered after adding activated charcoal, the piltrate is mixed with 20 percent hydrochloric acid until it becomes strongly acidic. the solid precipitate is filtered off and after washing with V / ater under reduced pressure at 100 ⁰ O-dried. this gives the desired N, Ή '-bis-ZB (3-Hie thylur eido) -3-carboxy-2, 4,6-triiodophenyl / adipamide ^.;

When the above process is repeated, but using equivalent amounts of the acid chlorides of succinic acid, glutaric acid, suberic acid, pimelic acid, sebacic acid, 3-oxaglutaric acid, 3-thiaglutaric acid or 3-methyl-3-azaglutaric acid, the M ", li'-bis- / 5- (3-methylureido) -3-carboxy-2,4,6-triiodophenyl / ~ suceinamide, N, Kf'-Bis - /!? - (3-methylur eido) -3-carboxy-2,4 , 6-triiodophenyl7-glutaramide, N, N'-bis- / 5 ~ (3-methylur eido) -3-carboxy-2,4,6-triiodophenyl / -kdrkäureamid, N, N'-bis- / 5- ( 3-methylureido) -3-carboxy-2,4,6-triiodophenyl / -pimelic acid amide, N, ¥ ^l -Bis- / 5- (3-methylureido) -3-carboxy-2,4,6-tri3odphenyL ^ sebacic acid amide, N, N'-Bis- / 5- (3-methylureido) -3-carboxy-2,4,6 ~ triiodophenyl7-3-oxaglutaric acid amide, N, N · -Bis - / ^ - (3-methylureido) - 3-carboxy-2,4,6-triiodophenyl / -3-thiaglutaric acid amide, or the

109852/1960

¥, Ν'BiS- / 5- (3-roethylureido) -3-carboxy-2,4,6-tri j gdphenyl / -3-methyl-3-azaglutaric acid amide.

Example 1d is repeated, but the diethyl isocyanate is replaced by equivalent Liengen ethyl or n-butyl isocyanate. Here you get the desired connections li,]? ^l -Bis- _{j (} / 5- (3-äthylureido) -3-carboxy-2,4,6-triiodophenyl / -adipamide or N, ¥ '-Bis - /!? - (3-n-butylureido) - 3-carboxy-2,4, G-triiodophenyl / adipamide.

Example 1a is repeated, but instead of 3-amino-5-nitrobenzoic acid, equivalent amounts of 3-ethylamino-5-nitrobenzoic acid, 3-ethylamino-5-nitrobenzoic acid or 3-n-butylamino-5-nitrobenzoic acid are used. This gives the desired compounds K ■, ¥ ^l -I) imethyl-l · I, ίJ ^l -bis ~ / 5- (3-methylureido) -3-carboxy-2,4,6-triiodphenylT- adiparuid, N, N'-diethyl ~ ¥, iI ^l -bis- / 5- (3-methylureido) -3-carboxy-2,4,6 ~ triiodophenyl / ^r- adipamide or K, IT'-di-n -butyl-N, IT'-bis - / ^ - (3-xβethylureido) -3-carboxy-2,4,6-triiodophenyl /. -adipamide.

Example 2

N, IT * -Bis- / 5 ~ (3, 3-dimethylureido) -3-carbox: / - 2,4,6-tri.l od ph.en? ^ L7 "-adipamide

A mixture of 2 g of N, li '~ bis- / 5-aMino-3-carboxy-2,4, r- ~ triiodophenyl / -adipamide in 20 ml of anhydrous pyridine is added dropwise with a solution of 1 g, while stirring and with cooling Dimethylcarbaniylehlorid added in 10 ml of anhydrous Benscl. The reaction mixture is stirred for 2 hours and then concentrated under reduced pressure. The residue is washed with ice and

109852/1960 BAD ORiGiNAL

mixed with dilute hydrochloric acid. The solid precipitate is dissolved in dilute aqueous sodium hydroxide solution after filtration and activated charcoal is added. After this solution has been filtered , the kit of 20 percent hydrochloric acid is added to a strongly acidic reaction. The solution is filtered ^ e / ater washed with V and dried at 6O ⁰ C under reduced pressure. This gives you the connection you want.

When Vc-rwendung equivalent amounts Diäthylcarbaraylci.lorid instead of Dimethylcarbamylchlorids obtaining the desired K, Ii '-bis- / 5- (3,3-DIAE "h / lareido) -3-carboxy ~ 2,4, 6-tri iodophenyl / -adipanid.

Example 3

H, H '-Bis- / 5i- (i-ethyl-3-niethylureio) -3 - carboxy -2, A, 6-tri; i od phenyl / ^ - adipainid

a) H, u '-Bis-ZS- ^ trr /

A Gemiüch of 10 g of M, K'-bis- / 5-amino-3-carboxyphenyl7 adipamide and 5 ml of acetaldehyde in 200 ml of anhydrous ethanol is allowed to stand for 12 hours at Rauntemperatur and then g Raney lTickel using 5 hydrogenated under pressure . After filtering off the catalyst and concentrating the filtrate under reduced pressure, the desired compound is obtained, which can be purified by recrystallization from aqueous alcohol.

109852/1960
BAD ORtQJNAU

b) ff, N ¹ 3 i μ- / 5 -a t hy 1 ami η ο - 3 - c ar b ο X ₁ V ₁ - 2 , 4, 6 -1 ri _r i ο d ρ he ny I / - adi]> ^ amid

Example 1c is using equivalent amounts of IJ, IT ^f -Bis- / 5-ethylamino-3-carboxyphenyl / -adij) amide instead of the? Ν, Ν'-bis- / 5-amirio ~ 3-carboxyphenyl7-adipamids repeated. This gives you the connection you want.

^c ) I ^ IT'-Bis- / 5- (i-ethyl "3-raethylur eldo) -3" C a.rl: o>: y-2, / !, G-tri.iod phe ny l / - ad i parnid

ψ Example 1d v / ird using equivalent numbers ίί, Η ¹ -Bis-

/5-äthylamino-3-carbwXJ-2,4,6-trijodphenyl7-ad.iparnid instead of Ii, Ii '-Bis- _/ / 5-amino-3 ~ carboxy-2, 4 , 6-triiodophenylZ-adiparnid repeated . This gives you the connection you want.

Example 4

TS ₁ TSS ¹ -Bis- / B- (1-ethyl-3, 3-dimethylureido) -3-carboxy-2, 4, 6-tri-. ] odphenylZ-adipamide

Example 2 is repeated, but equivalent amounts are used. N, li ^I -bis- / 5-ethylamino-3-carboxy-2,4,6-triiodophenyl7 ~ aäipamid instead of N, E'-bis- / 5-amino-3-carboxy-2,4,6-triiodophenyl / -adipamide used. This gives you the connection you want.

Example 5 ~

N, I \ f'-I) imethyl-W, I \ ^T> -bis- / B- (i-äth.yl-3-methylureido) -3 ~ carboxy-2, 4> 6-tri, iodophenyl / ' -adipamide

a) M, I \ ^τ '-I) imethyl-I ^^', I'ί'-bis- / 5-amino-3-cal · '' boxyphenyl7-adipamide Examples 1a and 1b are repeated, but in Example 1a the equivalent amount of 3-methylamino-5-nitroben2oic acid

109852/1960 BAD

used instead of 3-amino-5-nitrobenzoic acid. Here receives L'ian the desired connection.

b) IT, H '-dirnethyl-N, M' -bis- / 5- ethyl ainirio-3-carboxy _-2 _λ 4, 6- tri.iodophenylZ-adipamide

Example 3a and 3b is prepared using N, I \ f'-Dimethy1-11, N ¹ -bis-ZB-ethylamino ^ -carboxyphenylZ-adipainia instead of N, ii ¹ -Bis- / 5-amino ~ 3-carboxyphenyl / -adipamide repeated in Example 3a. This gives you the connection you want.

c) N, Is '-Dimethyl-N, N' -bis- / 5- (i-äthjyO. -3-me thy lure ido) -3-carboxy-

2> 4> 6-tri, iodophenyl7 - adipamide

Example 1d is prepared using equivalent amounts of N, N'-dimethyl-Ii, N ^! -bis- / 5-ethylamine.Ö ~ 3-carboxy-2,4,6-triiodophenyl / -adipamide instead of ri, i \ r'-bis- / B ~ amino-3-carboxy-2,4,6 -trijodphenyl / -adiparaid repeated. This gives you the connection you want.

In a similar way, if stoichiometric amounts of 5-ethylamino-3-nitrobenzoic acid are used instead of 5-methylamino-3-nitrobenzoic acid in Example 5a, the desired Ν, Ν ¹ -diethyl-N, N'-bis- / 5- (1 ethyl-3-methylureido) -3-carboxy-2,4,6-triiodophenyl / adipamide.

Example 6 "

ÜT, N'-Bis- / B- (1 ♦ 3> 3-trimethylureido) -3-carboxy-2,4,6-tri, iodphe-

nyl / adipamide

Example 1a is prepared using 3 g of 3-amino-5 ~ (1,3,3-trimethylureido) -2,4,6-triiodobenzoic acid instead of 3-amino-5-nitrobenzoic acid repeated. Here you get the desired

109852/1960

H -

Link.

B ei is ρ ie 1

il, WM.sr / 5- (^ -methyl ureido) -3-car) 3oiaet 3i oxy-2,4,6-tri, iodine pr-eny l / ^ adiρamid

Example 1 is obtained using equivalent methyl 3-aisino-5-nitrobenzoate instead of the 3 - Hi "iifto-5 - nitroben" zoic acid repeated. This gives you the connection you want .

Example 8

N, U "'- Pimethyl- N, ¥ ^f ~ b is- / 3- (3 ~ methylureido) -3-carl3oätI; oxy ~ 2, 4, 6-tri. Iodophenyl / -adi oarr.id

A mixture of 20 gl ^ ί, N ^l -dimethyl-M, l · ί ^f -bis- _> /5-(3-jiaethylureido)-3-carboxy-2,4,6-trijodph.enyl/-adipamide and 100 ml of anhydrous ethanol is mixed with a solution of 2 g of potassium hydroxide in 50 ml of water-free ethanol. The reaction mixture is then mixed with 4.5 ml of diethyl sulfate and then stirred for 2 * 1 hours / water "concentrated to dryness. The residue is suspended in dilute aqueous sodium hydroxide solution and, after filtration, carefully washed with water. After drying at 50 ° C. under reduced pressure, the desired compound is obtained. This can be cleaned by dissolving it in hot dimethylformamide, adding activated charcoal to the solution and diluting the piltrate with water.

109852/1960

Claims (1)

F a te η t; i η s ρ r ü eh e 1. Trijoddiami: uobeij.i; oesäurederivate of the general formula (I) COOH in which R, R ₁ and R _{2 represent} a hydrogen atom or a C ,, ^ - alkyl red, R ~ is a Cg-alkyl radical and X is an alkylene radical with up to 10 carbon atoms, which are represented by oxygen atoms, sulfur atoms and / or -N- residues can be interrupted, as well as their salts and C, g-alkyl esters 2. Compounds according to claim 1, characterized in that one radical R is a hydrogen atom and the other radical R is a means. 3. Compounds according to claim 1 and 2, characterized in that one radical R. is a hydrogen atom and the other radical R _{1 is} a C, - alkyl radical. 4. Compounds according to claim 1 to 3, characterized in that one of the radicals R _? a hydrogen atom and the other radical Rp represents a C 1-6 alkyl radical. 5. Compounds according to claim 1, characterized in that R, R ₁ and R _{2 represent} hydrogen atoms. 109852/1960 BAD 0Rt (3! NAl ■ * ■ it) ■ δ ο Compounds according to claim 1, characterized in that R, R. and Rp are C ₁ ^ -alkyl radicals. 7. A process for the preparation of the TrijOddiaminobenzoic acid derivatives or their salts or esters according to claim 1 to 6, characterized in that one Irijoddiaminobenzoic acid derivative of the general formula (II) COOH COOH N-CO-X-CO-N (ID in which R, R ₁ ταιά X have the aforementioned meaning, with an alkyl isocyanate of the general formula (III) R _x -HGO (III) in the R-, which has the aforementioned meaning, or with a dialkylcarbamyl halide of the general formula (IV) (IV) R, in which R ₂ and R, have the abovementioned meaning and Y represents a halogen atom, is reacted and, if appropriate, the free acids are converted into the salts or esters in a manner known per se. 109852/1960 ORIGINAL BATHROOM O. Use of Trijoddiamiriobenzoic acid derivatives after Claim 1 "to 6 as an X-ray contrast medium. 109852/1960