DE1915196A1 - Iodinated aniline derivatives and processes for their preparation - Google Patents

Description

PATENT LAWYERS

DR. F. ZUMSTEIN - DR. E. ASSMANN DR. R. KOENIQSBERQER - DIPL.-PHYS. R. HOLZBAUER TELEPHONE: 8234 76 and 221911 TELEARAMS: zumpat CHECK ACCOUNT! MUNICH 91139

BANK ACCOUNT: BANKHAUS H. AUFHÄUSER

8 MUNICH 2,

BRÄUHAUSSTRASSE 4 / III

Bzv'fsi

in the

STERLING ERUG.IffO,
ew York,?!, ϊ _5ϊ USA

-and experienced in their manufacture c

'ie Ε ^ ίΐηίαη «; regards? jodi. & vte aniline derivatives of the general

"Y4

i 15. *. t .... K '"^ Y and

Hi

! 1-K-OO-Y'-COOR " i ·

in which 3Γ a Misdrigalkylengruppe _t in which 2 or 3 carbon atoms separate the carboxyl groups from one another, a vinylene orasr a ins ^ i _T .3 - "prop; - lengruppe means _t in which the 2-carbon atom is replaced by O _5. S _t SO or SOp,

^Γ β sine insertion achbiiidung or Alkylenbrüclce \ qiit 1 to 8 Eori.l -, nstoffatOB \ 3tt or one such G roup is defined by 1

90984771236

BATH ORIGINAL

up to 3 representatives from the group O _t S _? SO and SOg is interrupted, whereby these representatives, if there is more than one, are separated from one another by at least two carbon atoms,

R (Niearigalkanoyl) NH, (Lower alkanoyl) NHGH ₂ , (Lower alkanoyl) £ (lower alkyl), (Lower alkoxy-lower alkanoyl) NH, (Ni8drigalkoxy-lower alkanoyl) K'CQ-lower alkyl), H ₂ NCO ₉ (lower alkyl) MICO _f (Medrigalkyl ^ NOO , ^ CO ^ * HOOO-Y ¹ -CO-HH or EOOG-Y ^e -CO-NCM lower alkyl) _t

R ^{1 is} hydrogen, lower alkyl or hydroxy-lower alkyl and

R "denotes hydrogen or lower alkyl.

The invention relates in particular to cyclic imides and anilic acids of 2, 4 _§ 6-'i'pijodanilinen, which carry a substituted amino group or a substituted carbamyl group in the 3-position ^ -

The invention also relates to methods of making them Links *

In the above formula A Y represents a lower alkylene group ,, in the 2 ödere 3 carbon atom ^ carbonyl groups separated from each other and Y can therefore sine optionally substituted by a lower alkyl substituted ethylene * · or propylene group may be _a The group Y may be 2 bi3 6 carbon atoms and includes the groups -OH ₂ OH ₂ -J -CH ₂ OH ₃ OH ₂ -., -OH (CH ₅ ) CH ₂ -, -CH ₂ CH (CH ₃ ) OH ₂ ", -OH (OH ₅ ) OH ( OH ₅ ) -., -CH ₂ CH (O ₂ H ₅ ) OH ₂ -, -CH (CH ₅ ) -CH ₂ GH ₂ -, -OH (OH ₅ ) CH (CH ₅ ) Oh (CH ₅ ) - , -CH ₂ C (OH ₅ ) ₂ CH ₂ - and the like ο Y can consist of a 2-oxa or 2-ThIa-I _t 3 "= - propylene group with 2 to 4 carbon atoms, for example -CH ₂ OCH ₂ -, -CH ₂ SCH ₂ -, -CH ₂ SOCH ₂ -, -CH ₂ SO ₂ CH ₂ -, -CH (OH ₅ ) OCH ₂ -, -CH (CH ₅ ) -OCH (CH ₅ ) - and the like. The group Y ¹ in the above formula B denotes a single bond or a divalent bridge with 1 to 8 carbon atoms, which separates the carbonyl and carboxyl groups from each other.

When R in the above formulas X and B (lower alkanoyl) NH,

909847/1236

BAD ORJGi _NAL

(Lower alkanoyl) NHGH ₃₁ (lower alkanoyl) N- (lower alkyl), (lower alcohol: jcy ~ lower alkanoyl) HH or (lower alkoxy-lower alkanoyl) N (lower alkyl), the lower alkanoyl group has Λ to 6 carbon atoms and thus includes, for example, formyl, acetyl, propionyl , Butyryl, isobutyryl, valeryl, oaproyl, and the like

When R (lower alkanoyl) N (lower alkyl), (lower alkoxy-lower alkanoyl) H (lower alkyl), (lower alkyJjNHCO, (lower filkyDg-NCO or HOOC-Y ⁵ -CO-N (lower alkyl) and / or R ¹ lower alkyl and / or R " Mean lower alkyl, the lower alkyl group has 1 "to 4 carbon atoms and includes, for example, methyl ^ ethyl, propyl, isopropyl and butylο

V / onn R (lower alkoxy-lower alkanoyl) NH or (lower alkoxy-lower alkanoyX) N (lower alkyl) means, the lower = alkoxy groups have 1 to 4 carbon atoms and include, for example Methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

The compounds according to the invention of the above-mentioned general Formulas A and B are made through the carboxylation of compounds of the following formulas C or 1): GOOH

and R45 .. 5A-Ji-CO-Y'-GOOR "

wherein Y, Y ', R ₁ R ⁵ and R "have the meanings given above be-85teen-Di« decarboxylation is carried out by adding a compound of the formula C or O either in the form of the free acid or in the form of a Be «·· heated in an organic solvent. A preferred method is to dissolve the free acid or halide, for example aas sodium salt, in dimethyl

909847/1236

BATH ORIGINAL

heat formamide to a temperature between about 8 5 and 14-0 ^{0 G}

The carboxylic acid intermediates of the formulas C and D are the subject of the patent »..., _e . (Patent application P 10 958 637) and are manufactured as described below <-

The process for preparing the compounds of Formulas C and D varies according to the structure desired, as follows; .1-, ) Compounds of the formula C «in which R (lower alkanoyl) N (lower alkyl), (lower alkoxy-lower alkane o-

ypNClowalky l ). (Low AlkyI) M iCQ. (Lower alkyl) ^ NCO, 'dö * ■ * - »-. ~ '2- *.

Y ^ "Ν or HOOO-Y-CO-NC-lower alkyl) means. ^ CO- ^

a) When using a dibasic acid anhydride; A compound of the general formula

JOOH

(E)

in which R has the meaning given above under 1.) and Q is hydrogen or lower alkanoyl _? is ^erllitzt with an acid anhydride of the formula QCTco- ^ ° ^{Wönn Y} represents ^a lower alkylene group, the reaction is preferably a strong acid catalyst in the presence of, for example, sulfuric acid or phosphoric performed when the reaction with a compound of formula B _t in the Q lower alkanoyl means _t / trrct? ß.fe rriedrigalkanoylgruppe and is replaced by the cyclic imide group.

b) When using a succinyl or glutary chloride A compound of the formula E in which Q is hydrogen,

909847/1236

is with a compound of the formula Cl-OO-Y-CO-Cl, in which Y means a lower alkylene group in which two or three carbon Atoms separate the carbonyl groups from each other in one heated inert solvent

2-> Compounds of the formula D , in which R ^? Means hydrogen.

^a "£ 'has the same meanings as Y _t R" means Waaser sfcoffj,

Bite compounds can be removed by alkaline hydrolysis of the ents.-reohönder » Compounds of formula C are prepared ,, The \ '.-..- iö - .: 3ung takes place at liaumtaiaperatm · in aqueous solution under .sι Id.iti Conditions c

h -I ^ liat ... A% P .. meanings given under Ia) _11; '■: ■''asu' / compounds can be made by f ubiudimg the formula E, in which Q means hydrogen 'with j'. in the half-ester-half acid chloride of the formula Gl-GO-Y'-CO-OR "in an inert solvent, whereby a compound d-.τ * Formula D is obtained, in which R" means lower alkyl ο Die Hydro-1, jo der vl.iiii-: j? igyn supplies an anilic acid of the formula D _t in which R ".7 --s &rstoff" means o

of the formulas C and D, in which R (Nied rigalka xic / ^: ". ·!".? or \ üf.iedrigalkoary- ° lowip; a lkanoy l ) means MH .

- ^ -Ά Il ~ i ΓΙΙΙΙ 'Hill!' ΙίΙΙ Λ I Mi— ili> l mW I M'll I PBII IW H j '<II JlI Hill Bi I Mil 1 ^ —11 HI P I Il M ■■!> I i ■ ■ I ■■> ■■ < ^ HWIiHlTlWT * Ii-T iiiW * g ** - - ^ - i - ** ^ ** -. ^^^^^, ^^

¹ : 1.56e compounds can be prepared according to the following reaction scheme ΥΊ-.Λ ; .- = 'Aixii no-3-'ö, itrobenzoic acid:

909847/1236 ORIGINAL BATHROOM

- 6 - COOH

O ₂ N- COOH

(G)

KJGl, BHCO-Y-OOOH

(H)

J;

ο GOOH

jsr-ί. U-

(j)

EHCO-Y-COOH

, KJCl,

CD (O CO

COOH

Alkanecarboxylic acid _Λ anhydride

COOH

. / H- ^ ifiedrigalkanoy])

COOH

■ NHCO-Y-COOE

(D, H * H ₂ N, R ¹ and R "- H)

All ancarboxylic acid ashydride

COOH

NH-

(Low ^ alkanoyl

HHCO-Y-σθΟΗ

BAD ORiQlNAL

The 3 "* amino-5-nitrobenzoic acid is reacted with an anhydride of the formula 0 (CO) ₂ Y to form the cyclic imide Fo. The latter can either be hydrogenated under acidic or neutral conditions to form the cyclic aminoimide G or it can be under basic conditions are hydrolyzed to form the corresponding nitroanilic acid H. Me Nitroanilic acid can in turn be hydrogenated to aminoanilic acid J «When the cyclic amino imide G is iodinated, a compound of the formula C is obtained, in which R denotes HgN and the iodination of aminoanilic acid J yields a compound of the Formula D _T in which R is HgN and R 'H. The primary amino group can then, if desired, be acylated with a lower alkoxy-lower alkanoic anhydride to form a compound of the formula C _t in which R (lower alkanoyl) HH or (lower alkoxy-lower alkanoyl) ) RH means, or a compound of the formula D in which R (Nied rigalkanoyl) HH or (JJiedrigalkoxy-lower alkanoyl) NH and R ^{1 is} hydrogen.

4,) Compounds of the formulas C and D «in which the groups in the 3- and 3- positions are identical.

These are most conveniently prepared from 3 »5-diamino-2,4 _t 6-triiodobenzoic acid = the latter is reacted with at least 2 equivalents of an anhydride of the formula 0 (CO) ^ Y to form: a compound of the formula C, in which RY ( CO) ^ means »which can then be hydrolyzed to a compound of the formula D in which B HOOG-Y-CONH and R '" mean hydrogen. The starting material can also be a 3-K'iedri6alkanoyl-amino-5> -amino- 2 4-6 «1; riood-benzoic acid or a 3» 5-bis (lower alkanoyl

ymino) r> enzoic acid. In the reaction with the anhydride of the lower alkanoyl groups are replaced Alternatively, by cyclic imide groups a to Process 2 analogous method (b) are applied, d * h _o the reaction of the 3 '5-diamino · = 2 / i, 6-triood ~ benzoic acid with a half ester-half acid chloride de: - Formula Cl-COY ¹ -CO-OR ", whereby a compound of the formula B-is formed * in d« - ER ¹¹ OCO-Y ¹ -COKH, R ^c H and R "" lower alkyl be! "ϊ ·· 'α ⁺ en.

909847/1236

BATH

^ ₀ ) Compounds of the formula D. in which R 'lower alkyl or hydroxyny drigalkrl means et _t

These compounds can be prepared by N-alkylating the corresponding compounds in which R 'is hydrogen. "The alkylation is carried out by the action of a lower alkyl" or hydroxy-lower alkyl halide, sulfate, alkyl sulfonate or aryl sulfonate in the presence of aqueous alkali The starting material is a compound of the formula D in which R (lower alkanoyl) NH or HOOO-Y · -CO-NH means _f the alkylation takes place on both nitrogen atoms at the same time.

The compounds of the formulas 0 and H ₁ in which Y and / or Y ^{1 are} alkylene groups which are interrupted by 80 or SO 2 can also be prepared by oxidation of the corresponding sulfide '(.-S -) compounds with a peracid or hydrogen peroxide . The reaction takes place at room temperature in an inert organic solvent.

Alternatively, the compounds of the formulas A and B according to the invention can be prepared from compounds of the general formula K. will:

(K)

in which R ⁰ H ₃ N, (lower alkanoyl) NH, (lower alkanoyl) NH0H ₂ , (lower alkanoyDNC-lower alkyljHgHOO, (ir-lower alkyl) NHCO, (lower alkyl) ₂ NCp, Y "*" ⁰⁰ ^ _or HOOC-Y-OO-ffC-lower alkyl), where Y has the meaning given above, and Q is hydrogen or lower alkanoyl,

by following processes analogous to those described above for the preparation of compounds of the formulas 0 and D, _s

909847/1236

BATH

forms the cyclic imides and anilic acids. The compounds of the formula K can in turn be prepared by decarboxylation of the compounds of the formula E or by other known processes, such as those explained, for example, in the following exemplary embodiments .

The structures of the compounds according to the invention were determined by synthesis, by element analysis and by determining the 2 neutralization equivalent. The course of the reactions was followed by thin-layer chromatography

according to the invention. Compounds of Formula B _? which represent carboxylic acids can be obtained in the form of their salts derived from inorganic bases or organic amines «. hi ^ rozzvgb are the pharmaceutically acceptable salts, for example o: ie Nat'riiiM-ϊ Magnesium- ,, Calcium- and N-Methylglucosaminalae _? whether all bases can be used, either as derivatives for characterization; or as intermediates in the purification d & v acidiiβ Me salts of the compounds according to the invention v '/ i / rdsn as full equivalents of the claimed free acids and they therefore belong to the present lärfin & img,

The compounds of the formulas A and B are v / rii-tful as Röiitgeu-Koiitrastmedisn aur visualization of the gall bladder (OholeeystcgrMphiö) o The compounds according to the invention have their intravenous toxicity (corresponding to I-jJ ^ - jV / erten) in the range of 600 to? 'OO mg / kg in mice .--, Bio compounds with a lower l'oxissität, ^ cq **' ^ 50 ° Dig / '. kg or higher are primarily in In the form of their water-soluble, pharmaceutically acceptable salae, they can be used as intravenous oil cystographic agents = The compounds with MW types of less than about 1500 mg / kg are primarily usable either in the form of the free acid or in the form of a salt as oral holecystographic agents

The respective quantitative determination of the toxicity and the

909847/1236

Röntgenstrahlundurchlässigkeitsgrade can be determined by standard test method by the skilled in the art easily, without extensive experimentation are required.

The compounds according to the invention were examined with regard to their intravenous oholecystographic activity according to the following standard method:

The (solid compound was in form of an aqueous solution of the sodium or N-Methylglucosaminsalzes cats intravenously domestic Jiziex'to Each cat was x-rayed at hourly intervals and the Röntgenogrammö were examined and evaluated the density of the shadow gallbladder was evaluated on a numerical scale points = , which was designated as the cholecystographic index (CI) and was a measure of the effectiveness of the test compound, in which the stoners had the following meanings: 0 (ineffective) _? 1 (weakly effective) _t 2 (moderately v / ineffective), 3 ( good effective / effective), 4 (excellent effective) CVgI ₀ J ₀ O ₃ Hoppe, J. Am. Pharm. Assoc, Sci = Edo 48, 268-379 (1959)] c

During the oraX-ehoiecystographic examination, the! Fixed connection Orally in capsules to each of 5 cats About Ί8 hours later, each cat was x-rayed and the Höntgenogrammnie were examined T) he density of the TeBt = - connection in each cable of the gallbladder shadow was determined according to the above numerical point scale and it became the average cholecyatographic index (ACI) determined-

When studying the cholecystographic effectiveness of the Compounds according to the invention of formulas A and B in cats at a dose of 100 mg / kg have been found to be effective in oral or, when administered intravenously, produced gallbladder shadows with a cholecystographic index from 3 * 0 to 4.0 »

The preliminary bindings according to the invention become eholecystographic Use prepared by placing it in the form of a pharmaceutically acceptable salt in an for intravenous injection

909847/1236

suitable sterile aqueous medium dissolves or in capsule or Tablet form with common carriers for oral administration manufactures "

The following examples are intended to explain the invention without, however, restricting it to "

example 1

a) 3.5-bis (glutaTimido) 2.4 «6-tri.1odbengoeeäure [Formula C: H« (CH ₃ ) χ (° 0) ^ t ^y "OHgCHgCHg]

The title compound was prepared by reacting 265 g 3T5-diamino-2 _t 4 _t 6-triiodobenzoic acid _t 400 g glutaric anhydride and 18 ml of concentrated sulfuric acid under stirring for 17 hours heated. The product was recrystallized from dimethyl sulfoxide,

Water

to initiate the precipitation / was added and a light gray solid with 1 mol of crystallization dimethyl sulfoxide, F ₀ above 300 ° C., was obtained. A sample of the acid was converted to its Natriumsais which melts after recrystallization from water at 288-291 ⁰ C t.Zers.).

b) N. N '- (2.4. 6-Tri.1 od-m-pheavlen) dislutarimide [Formula A: R · (CH ₂ ) J (CO) ₂ N, Y - CHgCHgCHg]

A mixture of 89.10 g of sodium-3T5-bis (glutarimido) 2 _t 4,6-triiodobenzoate and 400 ml of dimethylformamide was heated to prepare a solution for 20 minutes at 85 ⁰ C and then for 4 hours at the reflux temperature of I30 to 135 ⁰ C heated. The solution was cooled and the solid product was collected, washed with dimethylformamide and acetone and to constant weight gefess'o'knet (35.18 g) _n By diluting the filtrate with water Further _y 41.75 g of product were obtained. The combined product was recrystallized from acetic acid using activated charcoal to decolorize, and N _$ N '- (2,4,6-triiodo-m-phenylene) diglutarimide was obtained in the form of colorless prisms, F ₀ above 300 ° C

The N, R'-f '^^. G-TrijJocl-m-phenyle ^ diglütarimid can also be through

909847/1238

BATH ORIGINAL

Conversion of 3-amino-2,4,6-tri; iodoaniline (formula Ks R ⁰ ■ QH), 3-amino-2 _f 4,6-triiodoacetanilide (formula K: H ° Q «COOH ₅ ) or 3-acetaraido -2.4 _i 6-tri; iodoacetanilide (formula K: R ⁰ m OH-COIlH, j Q «COCH ₅ ) with glutaric anhydride according to the method of Example 1 a).

Example 2

a) 3-Glutarimido ~ 5 ~ (N-methylacetamido) 2 «». 6 «» tri.1odobenzoic acid [Formula G: R «CH ₅ COlT (CH,), Y» CH ₂ CH ₂ CH ₂ ]

A mixture of 117.2 g of 3-amino-5- (N-methylacetamido) 2,4 _f 6-tri, iodobenzoic acid and 182 g of giutaric anhydride was heated on a steam bath with stirring. 10 ml of concentrated sulfuric acid was added and heating and stirring were continued for 7 hours. The reaction mixture was poured into 700 ml of water and the solid product was poured by filtration and crystallized from acetic acid. The 5 "glutarimido-5 ~ (N-methylacetamido) 2,4,6-triiodobenzoic acid obtained was converted into its sodium salt by the following process:

The free acid was slurried in 40 ml of methanol and a 1 η solution of sodium hydroxide in methanol was added and triturated until the solid had dissolved. The sodium salt was precipitated with ether, the resin obtained was triturated with Ither and dissolved in methanol. This solution was decolored with activated charcoal and the product was reprecipitated with ether . The product was dissolved in water and the solution was filtered and concentrated in vacuo dried in vacuo and gave the sodium salt of 3-glutarimido-5- (N ~ methylacetaiaido) 2 _t 4 _t 6-tri ^ odben2oic acid in the form of a pale pink solid, Ε-. 200 to 204 ⁰ C (

b) N-C2,4.e-3? ri _t 1od-3- (y ~ methylacetamido) phenyl3glutarimide (formula A: R »CH ₅ COJi (CH ₃ ), Y - CH ₂ CH ₂ CH ₂ ]

The title compound can by decarboxylation of sodium 3-glutarimido-5- (N «-methylacetamido) 2 _t 4 _t 6-triiodobenzoate by the method of Example 1 b) or by decarboxylation of

909847/1236

3-Acetamido-5- (N-methylacetamido) 2,4,6-triiodobenzoic acid and subsequent reaction of the 5- (N-methylaoetamido) -2,4,6-tridodaeetanilide [formula K: R ° · CH ₅ COIT (OH ₅ ), 4 - COCH ₅ ] can be produced with glutaric anhydride ·

By replacing the 3-amino-! I ^ (N-methylacetamido) 2,4,6-tri; iodobenzoic acid in the above production process by 1 molar equivalent 3-Amino-5- (N-butylaeetamido) 2, 4 ·, 6 «-triiodobenzoic acid, 3 ~ amino ~ 5- (N-methylpropionamido) 2,4,6-tri3odbenzoic acid, 3-amino 5- (N-methylcaproylamino) 2,4-, 6-triiodobenzoic acid, 3-aniino «-5-

(N, N-dimethylcarbamoyl) 2,4,6-triiodobenzoic acid or 3-amino-5 ~ (N-methyl «=« 2-methoxyacetamido) 2 _f 4 _f 6-triiodobenzoic acid can be the 3-glutarimido-5- (tf- butylacetajiido) 2,4-, 6-tri ^ odbenzoic acid] [Formula C: R · CH ^ SONCC ^ HOjY »CH ₂ CH ₂ CH ₂ ], 3-glutarimido-5- (N-methylpropionamido) 2,4 _e 6- tridodbenzoic acid C Formula C: H »CH ₃ CH ₂ CONCdH,), Y - CHgCHgCHgü, 3-glutarimido-5- (N-methylcaproylamido) 2 _f 4,6-triiodobenzoic acid [Formula C: R - CH ₅ (CH ₂ ) /, CON- (CH ₅ ), Y-CH ₂ CH ₂ CH ₂ ], 3 ™ glutarimido-5- (N, N-dimethylcarbamoyl) -2,4,6-tri-odbenzoic acid C Formula C: R - (CHa) ₂ HCO , Y · or the 3-Gl ^ tarimido-5- (N-methyl-2-methoxyacetamido) 2,4,6-triiodobenzoic acid (formula Cs R - CH ₅ OCH ₂ COH (CH ₅ ), Y »are obtained, which in turn can be decarboxylated to form the H- [2,4 _t 6-tridod ~ 3- (N-butylacetamido) phenyl] glutarimide C Formula A: R »CH ₅ CON (C ^ Hq), Y - CH ₂ CH ₂ CH ₂ ], N- [2,4,6-l ¹ riiodo-3 ^e »(N ~ methylpropionamido) phenyl3-glutarimide [Formula A: R ₈ = CH ₅ CH ₂ CON (CH ₅ ), Y - C H ₂ CH ₂ CH ₂ ], N- [2,4,6-0? Rii} od -3- (H-methylcaproylamino) phenyl] glutarimide [Formula A: R «CHx (CH ₂ ) ^ CON (CHx) Y - CH ₂ CH ₂ CH ₂ ], N -. [2,4,6-Tridod-3- (H, N-dimethylcarbamoyl) phenyl] glutarimide [Formula A: R «(GH ₅ ) ^ CO, Y - CH ₂ CH ₂ CH ₂ ] or N- [2 _β 4,6-Tr ij od-3 - (N-methyl methoxyac et amido) phenyl] glutarimids C Formula A: R - CH ₅ OCH ₂ CON (CH ₅ ) , Y - CH ₂ CH ₂ CH ₂ ].

Example 3

a) 3-SucQinimidQ ° ^ - (H-metnylacetamido) 2.4 _t 6-tri.1odobenzoic acid

C formula C: R »CH ₅ CON (CH ₅ ), Y - CH ₂ CH ₂ ] M <-j Xitelverbindungen was from 87.9 g of 3-amino-5- (N-methylacetami-

9098A7 / 1236

BATH ORIGINAL

do) 2.4 _{t-trijodbenssoeeäure} 6, 120 g of succinic anhydride and 6 ml of sulfuric acid produced by DTA method of Examples 2, except that a reaction temperature was applied from 130 to 140 ⁰ C. The Itasetzung * was essentially complete after 30 minutes Heat · compound was in the form of its sodium salt, a pale yellow solid, isolated, Fo 220-222 ⁰ C (dec.).

b) N ~ C2,4 «6-gri, 1od-3- (N» meth.Ylacetamido) phenyl3auccinimide [Formula A: R - OH ₅ CON (CH ₃ ), Y «CH ₃ CH ₂ ]

The title compound can be prepared by heating sodium 3-euccinimido-5- (N ° methylacetamido) 2 _t 4,5-triiodobenzoate in dimethylformamide according to the method described in Example 1b) »

Beis pi el 4

^a) 2-t-jS Moth.ylKlut arimido) -5- (N-methyIac et amido) 2 '4, 6-tri "1 or beqsb oesäure

formula C: H «GH ₅ GOIi (GH ₅ ), Y * CH ₂ CH (CH ₅ ) OHp]

The title compound was prepared from 3-amino-5- (N-methylacetamido) 2 _i 4,6-tri ^ odbeneoic acid ^ -K -ethylglutaric anhydride and sulfuric acid by the method of Example 2. The product was isolated in the form of the free acid and had a melting point of J01 to 302 ° C. after recrystallization from acetic acid

b) N-C2 _t 4,6-Q? ri _t iod ° 3- (N- »methylace tamido) phen.yl] -3-methyl-Klutar imide

[Formula A: H »CH, GON (CH,), Y» OHoCH (CHa) CHp] The title compound can be obtained by heating sodium -3 ° succinimido-5- (N-methyl acetamido) 2.4 _t 6-triiodobenzoate in dimethylformamide werdoiio prepared by the method described in Example 1 b)

Following the procedure of Example 1, the appropriate 3 «amino-5 =" R ~ 2 _i 4,6-tri ^ odbenzoic acid and the appropriate acid

909847/1236

BATH ORIGINAL

anhydride made the following compounds:

Example 5

B- ( 3 .3-Dimethylglut arimido) -5- (N-methylacetamido) 2.4 «6-tr i.1 od-

benzoic acid

[Formula Ot E «OH ₅ COlT (OH ₅ ), I» CHgCCCH ^ OHg]

Dae product? was a pale dark yellow solid _t P. 274 to 278 ⁰ C

o, from acetic acid); the sodium corn was a pale yellow solid, Fc 235 to 245 ⁰ C (decomp.) o

Example 6

! ft-Glut arimido ^ j ^ N-äthy acetamido) 2 Λ «6-tri.iodbenzoeaäure CFormel C: R" CH ₅ CON (O ₂ H _5), Y 'CHgCHgCHg]

The sodium salt dos Products * had a melting point of about 220 ⁰ C

Example 7

? ~ (Meth ylauccinimido) ~ 5 »(H ~ niethylacetamido) 2.4» 6-tri.1odbenzoic acid

[Formula C: E - CH ₅ CON (CH ₃ ), Y - CH (CH ₅ ) CH ₂ CH ₂ ] The product had a melting point of 285 to 287 ^° C (from acetic acid), the sodium as a melting point of over

Example 8

3 ° ('IUgIyJg climido) - )? · - * t. N ~ meth, ylac et amido) 2,4 ^ 6-tri.i-odbenzoic acid [Formula C: R »CH ₃ -CON (CH,). Y · "CH ₀ OCH ₀ ] The sodium salt" of the product had a melting point of up to 255 ^C C ... No sulfuric acid was used in this production *

Example 9

909847/1236 _BAD ORIGINAL

The liatriumsalz this product was a beige solid, mp _0250-260 ⁰ O (dec _o) c Bai this preparation was not _ö S hwefelsäure used

The compounds of Examples 5, 6 and 7 can be decarboxylated by the method of Example Λ b) to form £? ~ [2,4- τ6 ^ ⁱ I'r.i ^ od-3 ° * (ö-metliylacetaniido) phenyl ] -3? 3-dimethylglutav'imide [.Formal A: R - OH _x GOH (OH,), Y »CHpC (GH ₃ J) ₀ GH ₀ ] J N-C2, .4r6- ^r J? Ri.iod -5 «ÜT-ethylacetamido; phenyl] glutarimide [Formula A: R - OH-OOn (C ₂ H ₅ ), T - GH ₂ CH ₂ GH ₂ J or, N-C2,4- ₉ 6-0? Riiiod- . 3- (N-jiif-tlrjrlacetamido'JfplienyllmethyXßuacinimid [formula A: R "CH, CON- _CH,:" T - GH (CH ₅₎ CH ₂ CH ₂ K

The compounds of Examples 8 and 9 were prepared by 90 minutes of heating eggs ?? reien acid boi eggs Huec-dimethyl-lcflußtemperatur in .forji-amide deearboxyliert <, there was obtained the N ~ C2, Λ ,, 6 = Ί ·! Γ1 iodine -3'-ij ".} - rflethylacetamido) phe 'yl] digl; 7iiolimid [formula Aj · R" ΟΗ, ΟΟΙΤ _5-OH), Y _"o CH 0CH" _t 3 F. 26A' · ⁰ to 266 C (from dimethylformamide) b «\ 7c das ^ - C2, ^ - 5 6« Ti * i, jcd -5 - ί JSf-methylac et amido) phenyl] -3? 5-thiasiorpholindione [F-ori5eI Λ: Ii «* OH ₃ GOIi (CH ₅ ), Y «GH ₂ SOH ₂ ], a beige. Solid, P _e 283 bit fl 285 ° (from acetic acid) _o The two latter compounds were also obtained by the same common Erhitfien GewiohttTiiengen 2 ^, 6

amidoίaniline and DiglyKoisäureanhydrid or- {Dhiodiacetic anhydride to 120 to 150 ^e C produced

The 5 - (3% 5-BioxOtbiomorpliolino) ~ 5 ~ (N ~ methylacetamido) 2 _f ^ _S 6 "kami triiodobenzoic acid with m-Ohlorperbenzoesäure in a dimethylformamide be oxidized to give 3- (3τ5-S _S-i iPetraoxothiomorpho. lino) -5- (N-methylacetamido) 2 _i ^, 6-tridodbenaoic acid [Formula C: E »GH, GON (CH,), Y« CH ₂ SO ₂ CH ₂ ], which is then prepared according to the method of Example 1 b ) can be decarboxylated to form ^ -C2 ₁ 4,6-0? riiodo-3- (Ii »methylacetamido) -phenyl] -3,5-S, S-tetraoxothiomorpholine [Formula A: R ■ CH ₅ CON-) , Y «CHSOCH]

9098 47/1236

B .g i ... B ₁₁ -P- ie -1 10

i; k> d-I ^

[Formula Os R "GH ₅ HOO, Y" ₂₂₂ The sodium saline wax obtained is a light dark yellow solid, mp 250 to 20 ° C (decomposition in the recrystallization from aqueous methanol with the addition of ether) -,

t; rl;} od "

mn f hu ι I

^ Formula (J: E - CiI _x HHCO, Y *

Odd

The! Product hai; ·: «a Bchmelspimkt of over 300 0 * the sodium · = QßX ?. huh? i-iiu pale pink ^ esi-su-off, F _c 258 to 261 ^Q Co

5? Example © 10 and 11 can, after the arrangement,! Hih :: '^ n Ι. "," Example "-1 b ^ dscai'boxyliart with formation

i'i'canal Ai R - OH ^ iJHCU j Γ - OH ₀ OHgCH ^] _s © in colorless solid I. ; ^^ to 23β ° ϋ (from JEssigsäu * "

l: jucitj- ^r njj.iid -! Formula Λ: R »CH, HHCO

(Ponasl Bs fi - OH ₅ COHiOH ₅ ), R ¹ and H "* H, Y ¹ Si?}. O '/ i3chüiig aiii) £ 8» S ^ p = iiiiino-5 ^ö (S' ^t "Eie't7 'biy.lacetamido) 2 _? 4,, 6 "ti'iiodobonisoic acidQ, '/ 4 3 irlutaric anhydride and 8 ml of consent ^ r.ej.-tiir sulfuric acid was poured into water for 5 hours on a steam" bul wi'hitato oils and the reaction mixture was poured into water void the solid Product was collected by filtration

(Example '■>) existing product · was dissolved in excess dilute aqueous sodium hydroxide' and the solution became

9098A7 / 1236 BAD ORIGINAL

-18- 1815198

Heated for 30 minutes, then cooled and 3 η hydrochloric acid was slowly added until the precipitation was complete. The solid product was collected and first added to acetone? then recrystallized from acetic acid and finally from water and yielded 3 ^! "öarbox7-5 ^l - (N-methylacetamido) -2 ^l , 4 ', 6'" triiodiubaraiilic acid in the form of colorless prisms F, 188 _? 8 bis

^k: 2 't ^j fj · y 6'_ u- ~: c:' y, 1 Qd ^ g ₁ '- (IT ~ methyJ} acetamido do glu t ar ani3s CDCR e.

[Formula B: H = · OH ^ OQiT (CH ₅ ), R ¹ and H "* H" Y '^ CH ₂ G ₂₂ ' ΰ} & 'C'itelvsrbinAung can by "heating the disodium salt of the 3 ⁵ ~ Garbo> : _< ; r "!? '-» (N »raethylacetaniido) ~ 2' _? 4 ^f , 6'-trijodglutar => anilsäurö in" Oimeth / iforinainid according to the procedure of example 1 h )

³ · ί 2-1 • --v ^: arboxy ". ^> 3 '° · (H-methylac st amido)" 2 *, 4', 6 ^a -tri.j od-suc

CForiiiel JJ: H «CH ₇ CO, R 'and R" «Η, Υ ¹ = t'ie' Xiteiverbinduu ^ 7 / urds from 3 ^? 3 S 3-Aüi: Lno-5- \ H-methylaaet * aBiido) -2 _T 4,, ß = trioodberiaoesäurö, 82 g succinic anhydride and 5 lüi. Konsentri ^ rtax ¹ Schwfsf fe "eäur-ü and subsequent alkaline ii-vtirolyse de.i arhalten-sn 3» ßacoir.tiruido-5 - (^ "'™aiethylac3i;aiaidQ> 2 _t 4 _i 6-tr.i ₍ joib "inzoQßäurö according to the experience described in Example 12 - the product was made from dilute ethanol and from a mixture of M & thanci. / Artsiro.nitri.l recrystallized and further purified, - by converting it into daa diaüomoniurasaia with the help of ammonium hydroxide in methanol and then acidifying an aqueous solution of the iUmaoniuniiialz euz ¹ regeneration of the free acid _o This gave 3'-carbon dioxide: y ~ 5 ' ^ra (N- = methylaöotamido) ^ ¹ "4 ¹ , e'-triiodosuccinaniic acid, P ₀ 275? 0 276.0 ⁰ C (Zersoj

ϊΛ§ ^ 'ΐλ ^ ββ' ^ Μ ^ ο ) 3U CCinanilaätire

[Formula B: H * OH ₃ CO, E ^ä and R "" H ₅ Y ¹ ^ GH GH _{2 2} J JThe in the form of colorless prisms ,. J _o 209 to 211 ⁰ C, obtained Pro?

909847/1236

product was made from 37 »8 * 1 g Dinatriura-3'-carboxy- !? * - (N-methylacetamido) ^ ¹ , 4 ¹ , e'-tri ^ odsuccinanilate in 100 ml of dimethylformamide by refluxing for 40 minutes. The mixture was acidified with hydrochloric acid and the product collected and recrystallized from acetone.

Similarly, the 3- lutariinido ^G-5- (N-butylacetamido) -2,4 can _t 6-triiodobenzoic acid _t 3- & lutarimido-5- (N-mettiylpropionamido) -2 / _l? 6-t3? Ioodben55oe8 acid _? 3 "Glutarimido ~ 5- (NHoiethylcaproylamino) -2 ₉ 4 _s 6-triiodo-benzoic acid or the 3-glutarimido-5- (N-methyl-2-methoxyacetainido) 2 _? 4,6 - tri: iodobene: 3oic acid by heating in dilute aqueous sodium hydroxide to 3 '"-carboxyl' - (N-butylac et amido) -2 ' _v ' + ', 6'" = trij odglutaranilaäure C Formula D: R "CH, CO.N (G _{Z (} H _Q ), R 'and R "* H. Y» = CHpCH ^ GHp], 3'-Carboxy-5 ^s - (N-methylpropionamido) ~ 2' _f 4 ' _t 6 ^! -Tt * aj odglut aranilic acid [iOrmel D: R - CE ₇ -CH ₀ COBrCCH,), R ¹ and R "- H, I '» CBL ₅ CH ₀ CaLJj 3 ¹ -Carboxy-5' • "(N-metliylcapi ^< oylaitiino) -2 ^t ^ l ', 6 ⁵ -trioodglutaranilic acid [Formula D: R * OH ₅ (CHp) ₄ COW (CH ^) ₁ R ¹ and R "- H _e Y ^f « CH ₂ -ΟΗρΟΗ,>] bzv / - 3 "-Carboxy-5 ^f "(N-methyl ~ 2-methoxyacetamido) ~ 2V · 4 \ 6 '~ trij ^! odglutaraiiilaäure C Formula I): E - OIUOCH ₂ CON (CH ₅ ) J R ^! and R "- n _t Y ¹ » OH ₂ CH ₂ GH ₂ ] are hydrolyzed and this in turn can be decarboxylated to form 3 ^{e =} CN-butylacetamido) -? ¹ _T 4 ' _? 6 ^c -tr.i ^ odglutaranilic acid LFormula B: R '■■ CJT ₅ CON (C ₄ H ₉ ), R ^: - and R ". · H _t Y ¹ - GHpCHgCHg] _f 3' - (N - jV.e> thylpi- ^> opionamido) - 2 ^l , ^ ' _T 6 ^f -trijoäg.lutaranilic acid [formula Bi R · - * CH ₃ GH ₂ COn (CH ₃ ), R ¹ and R "- H, Y ^c « CH ₂ CHpCH ₂ ], 3' - ( Nr.ethylc € iproyl.amino) -2 _'t 4''e' trijodglutaranilsäure [formula B: ^<- (JH ₅ (CH _{2) 4} CON ( "CH _5), R 'and R""is H, Y ^E - CH ₂ CH ₂ CH ₂ J or 2 ' -. I'? ~ Methyl «2-methoxyacetamido) -2 ', 4-', e'-trioodgJ-utaranilic acid LForxnel B: R - CH ₇ OGH ₂ CON (CH ₅ ) JR ^f and R "« H _f Y ^! - CH ₂ CH ₂ CH ₂ ] ο

The 3'-Oarboxy-5 ⁵ - (H-methylacetamido) -2 ' ^ M-' , ö'-triiodoglutaranilic acid can also be obtained by heating 3 ~ Afln-: ao ~ 5- (N ~ methylacetamido) 2,4 _; 6-triiodobenzoic acid with 4-oarbomethoxybutyryl chloride (CH ₅ , OCOCK ₂ CH ₂ Ch ₂ COCI) in a dioxane solution and subsequent hydrolysis of the methyl-3 ^lo carboxy-5 '~ (N- ·. -I: h -'- ■ / .vc-micio ^! -2 'Λ' _? 6 ' ^: -t: cijodglutaranilats are produced.

9098A7 / 1236

BATH

by mixing this with potassium carbonate in methanolic lorning heated

In the same way one can get the 3-amino-5- (N-methylacetamido) -2 _? 4,6-tri; joabenzoic acid with Cl-COCHgOHgOHgCHgCOOCHj _f 01-COCH ₂ -CH ₂ OCh ₂ CH ₂ COOCH ₃ or Cl- COCH ₂ SCH ₂ CH ₂ CH ₂ CH ₂ SCH ₂ COOCh _{5 to} form the following compounds: a Compound of the formula B _f in which R · «CH ₅ CON (CH ₅ ), E ¹ « H, R "- CH ₅ , Y» * CH ₃ -CH ₂ CH ₂ CH ₂ , a compound of the formula D in which R - CH ₅ CON (CH ₅ ), R '»H _{ R" «CH ₅ , Ϊ ¹ « CH ₂ CH ₂ OCH ₂ CH ₂ or a compound of the formula D _f in which R «CH ₅ CON (CH ₅ ) , R ¹ «H, R" - CH ₅ , T ¹ CH ₂ SCH ₂ CH ₂ CH ₂ CH ₂ SCh ₂ , These can be hydrolyzed and decarboxylated to the corresponding dibaeißchen acids in which R "" is hydrogen, with formation of the following Compounds: a compound of the formula B in which R * CH ₅ CON (CH ₅ ), R ¹ and R "« H, Y ^f a CH ₂ CH ₂ CH ₂ CH ₂ , a compound of the formula B in which. R * CH ₅ CON (CH ₅ ), R ¹ and R "* H, Y ¹ « CH ₂ CH ₂ OCH ₂ CH ₂ or «, a compound of the formula B in which R - CH ₅ CON (CH ₅ ), R ¹ and R "* H ₉ Y * « CH ₂ SCH ₂ CH ₂ CH ₂ Ch ₂ SCH ₂ .

In the same way, the 3 _t 5-biamino-2,4,6-tri; iodobenzoic acid can be reacted with CI-COCH ₂ CH ₂ GH ₂ CH ₂ COOCh ₅ to form a compound of the formula D in which R «OH ₅ OCOCH ₂ Oh ₂ CH ₂ -CH ₂ CONH, TV «H _t R" «CH ₅ , Y ¹ - CH ₂ OH ₂ CH ₂ CH ₂ , which can be hydrolyzed to form a compound of the formula D in which R. HOCOCH ₂ CH ₂ CH ₂ CH ₂ COKh, R ¹ and R "« H, Y '«GHpCH ₂ OH ₂ CH ₂ , and the latter compound can be decarboxylated to form a compound of the formula B in which R« HOCOCH ₂ CH ₂ CH ₂ CH ₂ CONII, R ¹ and R "- H ₁ Y ¹ « CH ₂ CH ₂ OH ₂ CH ₂ O

Example 14

a) 3- [2 ° (Carbo3cymethylsulfonyl) acetamido] 2 _t 4 ₁ 6-tridod-5 ~ (N °° methylacetamido) benzoic acid

[Formula D: R «CH ₅ CON (CH ₅ ), R ¹ and R" - H, Y ¹ «OH ₂ SO ₂ CH ₂ ] A solution of 26.1 g of 3-amino-5- (N-methylacetamido) 2,4- _t 6-tritiodobenzoic acid in 300 ml of dioxane was distilled to about

909847/1236

60 ml of dioxane had been removed in order to remove possible traces of water. 5.85 g of sulfonyldiacetyl chloride (ClCOCHgSOg-CHgCOCl) were then added and the mixture was stirred and refluxed for about 5 days. For the removal of the solvent, the reaction mixture was concentrated in vacuo and the residue was dissolved in dilute sodium hydroxide to form a solution of the sodium salt of the product "The basic solution was made weakly acidic, the acid form of the product did not precipitate, treated at 60 ⁰ C with activated carbon and filtered. "The piltrate was acidified with 3 η hydrochloric acid and the precipitated product was collected. The acid product was purified by dissolving it in an ammonium hydroxide solution and re-acidifying the ammonium salt solution obtained. o The acid product was recrystallized from aqueous dimethylformamide to give 3-C2- (Carboxymethylsulfonyl) acetamido] 2,4-j6-triiodo-5- (N-methylaoetamidobenzoic acid, Po over

methylsu.lfony3 | -es3igsäure

[Formula B: R » CH ₅ COH (CH,), R ¹ and R" »H, Y ¹ « CHgSOgCHg] The title compound can be obtained by decarboxylation of 3-C2- (0arboxymethylsulfonyl) acetamido] 2, ^ e- triiodo-J-iN-methylacetamido) benzoic acid prepared according to the method of Example 1b). The product was the same as that described in Example 23 below.

By replacing the sulfonyl diacetyl chloride in the above manufacturing process with sulfoxydiacetyl chloride (ClCOCHg-SO-CH ₂ GOCl), the 3-C2 »(carboxymsthylsulfoxy) acetamido] 2, ^ l-, 6-triiodo-5 ^ct> (M - methylacetamido) benzoic acid [Formula Ds R · 'CE.CON- (GH ₅ ), R' unä R " m H, T ¹ - CHgSOCHg] can be obtained, which can be decarbo2rylie2? T with the formation of JRT-C2,4 ^ 6-TrIjOd- 3 - (H-ma uhji ac et amido) pfrenyl 0 arbamoylmethylsulf © x * -e β acetic acid [Formula Bs Ε »CH ₅ CON (CH ₅ ), R ¹ and R" »H, Y ¹ - GHgSOCHg] O .

By mildly alkaline hydrolysis of the corresponding cyclic

^909847/1236

iir 1 y * * *

1916196

Imides or directly from the appropriate J-amino - ^ - R ^, 4,6-tripod- * benzoic acid without isolation of the cyclic imide intermediate and subsequent decarboxylation of the aniloic acid obtained, the following compounds can be obtained by the method described in Examples 10 and 13 getting produced"

Example 15

a) 3 ^! -Oarboxy-2 ¹ , 4 ».6 '-triiodo ^ -methyl ^' - (N ~ methylacetamido) - glutaric acid

C Formtl D: R «CH ₅ OOIi (OH,), R ¹ and R« H, I ¹ »CiI ₂ CH (OH ₅ The product consisted of colorless crystals, V ₀ 256 to 259 ° C

b) 2 ' " 4 * _t 6' ~ Jri.iod-3-methyl ~ 3 '- (N-methylaQetamidoJRlutaranilic acid C Formula B: R * CH ₅ OON (CH ₃ ) _t R ^! and R" * H, Y ¹ = OH ₂ CH (OH ₅ ) GH ₂ ] The product was obtained from aqueous acetic acid in the form of pale dark yellow crystals, P ₀ 189 to 193 ⁰ C, the sodium salt was a beige powder, mp 202 to 204 ⁰ C (from methanol / lther)

Example 16

a) 3 _? 5-Bi8 (4-carboxybutyramido) 2 _t 4 _< 6-tri.1odbenzoic acid C Formula D: R «HOOO (CH ₂ ) ₅ CONH, R 'and R" »H, Y ¹ »

The product was a colorless solid, F ₀ 25I to 253 ⁰ C (from acetic acid) ₉

b) N, N '- (2,4 «6-Tri.1od-m-phenylene) diglutaramic acid 8

[Formula B: R «HOOO (OHg) ₃ COIiH, R ¹ and R" - H, Y ¹ »CH ₂ CH ₂ OH ₂ ] The product consisted of colorless prisms, F, 278 to 279 ° C (from acetic acid)} it was prepared by hydrolysis for 2 hours under reflux of K _i N '- (2,4-, 6-a? rijod-m-phenylene) diglutarimide (Example 1 b) with sodium hydroxide in acetone solution »

Example 17

a) 3'-0arbO3qr ~ 2'Λ ', 6'-tri.iodo-3 «3-dimethyl-5' - ( N-methylacetamido) ~ Klut aranic acid
[Formula D: R «OH ₃ OON (OH ₅ ), R ¹ and R ^as =» H ₉ T '* CH ₂ C (CH ₃

.909847 / 1236 _BAD

The product consisted of colorless crystals, F ₀ 258 to 262 ⁰ C

b) 2 '.4', 6'-a? ri, 1od ~ 3.3-diethyl> 3 '~ CK-methylacetamido) glutaranilic acid

[Formula B: R - CH, CON (CH,), R ¹ and R "- H, Y ¹ - CH ₉ C (CH,), CHI PP * O

₂
The product was a dark yellow powder, m.p. 132 bis

Example 18

a) ff /.- parboxy-S ' -CN-athylacetamido) - ^' .4 '«6'-tri.1odKlutaranil acid

[Formula D: R - CH ₅ CON (CH ₂ H _5), R ¹ and R "- H, Y '" CH ₂ I ¹ Dan TOdUlCbwar a colorless solid, F "25O ⁰ C (dec")

^D ) 2 ' A' « 6'-Tri.1od> 3 '" ( N «-äthylaoetamido)« lutaranilic acid C Formula B: R »CH ₅ CON (C ₂ H ₅ ), R ¹ and R" «H, Y' «

Example 19

a) 3 '"Carboxy-2' A ¹ , e '" tri.1od-3 "methyl-5' ~ (K-methylacetamido) auocinanilic acid s

CFormel D: R "CH ₃ CoII (CH _3), R ¹ and R" - H, Y ¹ - ₃

The product was a hellöranger solid F · 262-264 ⁰ C

b) 2 * , 4 ' _t 6 ^t "Tri _t 1od'« 3-'methyl »3 '» (N «» methylacetamido) 8UCcinanilic acid ["Formula B: R» 011, COH (CH ₃ ), R ¹ and R "« H, Y ¹ - CH (CH ₃ ) CH ₂ ].

Example 20

a) 3'-Carbo xy- ^ ', 4 * _T 6 ^t ~ triiodo-5 ^> ~ (N »methylacetamido) diglycol anilic acid

CFormel D: _(? Dec) R - - CH ₃ CON (CH _3), R ¹ and R "is H, Y '* The product was obtained in the form of Dinatriumaalzes, a light yellow solid, F _c 245-260 ⁰ C _c

S098 / i7 / 1236

BATH ORIGINAL

b) 2 ', 4' _t 6'-tri; 1od-3 '- (N-methylacetamiao) di-glycolanilic acid [Formula B: R «CH ₅ CON (OH ₅ ), R ¹ and R" - H _f Y ¹ »CH ₂ OCH _2] The product was a colorless solid, F _e 125-133 ° C °

■ Example 21 a) 3'-Carboxy-2 '.4 *, e'-

s aur e

[Formula D: R «CH ₅ NHCO, R ¹ and R" «H, Y ¹ ι Pro«
(Decomp.)

The product consisted of pale pink prisms, F "249-252C

, b) 2 ', 4 * .6' -Tri.iodo-3 '- (H-t-ethylcarbamoyDiKlutaranilBäure [Formula B: R «CH ₅ NHCO, R ¹ and R" * H, Y ¹ «CH ₂ CH ₂ CH ₂ ] The product consisted of colorless needles, F. 268 to 270 ⁰ C (from acetic acid) ο

Example 22

a) 5-C2- (0ftTboxyinethylthio) acetamido] 2 Λ, 6-tri.iod «» 5- (N-methylacetamido benzoic acid

[Formula D: R «CH ₅ CON (CH ₅ ), R ¹ and R" «H, Y ¹ » CH ₂ SCH ₂ ] The product was a beige solid, F ₀ 265 "to 17O ⁰ C,

b); N ~ [2,4 _<l 6 - l? Ri _f '| od-3 ~ (N ~ methylacetamido) phenyl] carbamoylmethyl-

[Formula B; R - CH ₅ OON (CH ₅ ), R ¹ and R "» H, Y ¹ * CH Example 23

p- [2,4 «6 ~ ri.1od ~ 5 ~ (N-» meth ^ lacetamido) phenyl] carbamoylmethyl sulfonyyessiflic acid

[Formula B: R - CH ₅ CON (CH ₅ ), R ¹ and R "» H, Y ¹ «CH ₂ SO ₂ CH ₂ ] tN ~ [2,4,6-triiodo-3- (N-methylacetamido) phenyl] carbamoylmethylthicj-acetic acid (prepared by hydrolysis of 25.0 g of 4-E2,4,6 = triiodo-3- (N-methylacetamido) phenyl] 3,5-thiamorpholindion) was dissolved at 40 ⁰ C in 150 ml of glacial acetic acid " There were 72 ml of 30%

909847/1236

Hydrogen peroxide added. After 5 minutes the mixture was concentrated to a volume of 75 ml and 400 ml of water was added. The precipitated product was crystallized by stirring the mixture-in ice and it was collected and dried to give {N- £ 2,4,6 -! Tri; iodine 3- (N-methylacetamido) phenyl3carbamoylmethylsulfonyl acetic acid _$ 148 to 150 ⁰ C (decomp.).

Example 24

a) ff-8uccinim ido ~ 5-nifrrQb enzoic acid
[Formula F: Y «CEgCHg]

The title compound was prepared by heating 3-AmiO-o-5-nitrobenzoic acid with succinic anhydride in the presence of sulfuric acid. After recrystallization from aqueous dimethylformamide, it had a melting point of 262 to 268 ⁰ O ₀

b), 3, "-Carboxy" -5 '-nitrosueci nani! acid
[Formula II: I - CH ₃ CH ₂ ]

The title compound was prepared by treating 3-succinimido-5 "nitrobenaoic acid with warm dilute aqueous sodium hydroxide and had a melting point of 220 to 221 ⁰ C ₀

c) 3'- Carboxy- aminoauccinaniic acid
[Formula J: Y- CHgCHg.!

83 ₁ 5 g of 3'-Carbo>: y-5'-nitrosuccinanilsäure and 50 ml of concentrated Ammoniiuuhydroxyd in 100 ml of water were added to a heated solution of 5 g ⁴ SO iron (II) sulfate heptahydrate were added in 900 ml of water. Then within 15 minutes. 100 ml of concentrated ammonium hydroxide were added in 5 ml portions. After heating on a steam bath for 50 minutes, the reaction mixture was filtered and acidified to pH 3 »5. The product was collected and dried under vacuum over Fhosphorpentoxyd to give 57s5 S 3 ^l -Garb03ey "> 5 ^l -aminoBuccinani! Acid, F, 194 ⁰ C (dec.).

d) ^ ₁₁ I-Oarbo xy -S'-ami no- ¹ A * , e'-tridodauccinanilic acid

[Formula BsB =. IAI ₂ , R ¹ and R " * H, Y ¹ · CH ₂ CH ₂ ] 'Au of a stirred suspension of 57 * 3 g of 3'-carboxy ~ 5'-aniino-

909847/1238 bad original

suecinanilic acid in 435 ml of water was added to 335 ml of a 2 _t 23 η Ealiumdodiddichloridlösung in water over a period of 40 minutes. Bas solid product? was collected by filtration and recrystallized from water and aqueous dimethylformamide. The product was purified by converting it to the diammonium salt and then to the disodium salt, P ₀ 222 to 225 ° C (dec.). The latter was acidified to form the free acid of 3'-carboxy ^ '- amiao-2 ¹ , 4' _t 6'-triiodosuccinanilic acid, a cream-colored solid, F, 156.2 to 172.2 ⁰ C (Zerse) o

The 3 ^l ~ -carboxy ^{5'-amino-2-liter,} 4 ', e'-trijodsuccinanilsäure can with acetic anhydride using a few drops of perchloric acid as a catalyst can be acylated to form the 3-carb oxy-5'-acetamido ^ ^1, 4 ·, 6 * -tri ^ iodosuccinanilic acid [formula D; R »CH ₅ CONH, E ¹ and R" «H, Y ¹ « CH ₂ CH ₂ ], which can be decarboxylated according to the method of Example 1b) to form 2 ' , 4', e'-triiodo-j ' -acetamidosuccinanilic acid [Formula B: R * CH, -CONH ₁ R 'and R "- H, Y» »

Example 25

a) ^ -Glutarimido- ^ nitrobenzoic acid
[Formula F: Y - CH ₂ CH ₂ CH ₂ ]

The title compound was prepared by heating a mixture of 18.2 g of 3-amino-5-nitrobenzoic acid, 45.6 g of oleic anhydride and 0.5 ml of concentrated sulfuric acid on a steam bath for 2 hours. The product was isolated and recrystallized from aqueous dimethylformamide and gave 3-GHutarimido-5 = · nitrobenzoic acid as pale yellow prisms, mp 300 ⁰ C _n

[Formula G: Y * ₂₂₂
The title compound can nitrobenzoic be prepared by reduction of 3-glutarimido-5 ·. The reduction can be carried out catalytically (with a platinum or nickel catalyst) under neutral or acidic conditions "

909847/1236

BATH ORIGINAL

c) 5 <-Glutarimido »5-ajaino -?. 4i6» tri.1odbenzoic acid t Formula C: R ·· H ₂ N, T - CHgCHgOHg]

The title compound can be obtained by iodination of 3-glutarimido-5-aminobenzoic acid with potassium iodide dichloride according to the example 24 d) described processes are produced.

d) 3-Grlutarimido-5-acetaiBido-2 «4,6-tri.iodobenzoic acid [Formula C: R« OfUCONH, Y - CH ₂ CH ₂ CH ₂ ]

The title compound can be obtained by acetylating 3-glutarimido-5-amino-2,4,6-tridodbenzoic acid made with acetic anhydride using a few drops of perchloric acid as a catalyst be o

e) 2 * .4 «« 6'- ^f fr i.1 od-3 '- »acetamidoglutaranilic acid

Formula B: R - OH ^ COHH, R ¹ and R "- H, Ϊ '- CH ₂ CH ₂ CH ₂ I' The title compound can be obtained by hydrolysis and decarboxylation of 3-crlutarimide () - 5-acetamido-2 _t 4 _t 6-tri ^ odbenzoic acid can be produced.

Example 26

fi) ^ '- Carboxy-S * -amino-' Λ * .e'-tri.iod-H-methylglutajanillaure

C Formula D: R «H ₃ H ₁ R ¹ - CH ₅ , R" ~ H, Y ¹ «CH ₂ CH ₂ CH ₂ ] To a solution of 26.0 g of 3 * -carboxy-5-amino, cooled in a bis-bath -2 ^f , 4 ·, 6'-triiodoglutaranilic acid [prepared by hydrolysis of 3-glutarimido-5-amino-2 _t 4,6-triiodobenzoic acid (Example 25o) 3 in 100 ml of 10% aqueous sodium hydroxide were 8 ml of dimethyl sulfate in Acetone added * After stirring for 3 hours, another 15 ml of the 10 # sodium hydroxide and 2 ml of dimethyl sulfate were added and the mixture was stirred for an additional 3 hours, the reaction mixture was acidified and the product was collected and recrystallized from acetic acid to give 3 ^liters -carboxy-5-amino-2 ^{i l,} 4 ^1, 6'-tridod-H ~ methylßlutaranilsäure pale gray in the form of crystals, P. 218-220 ° C (dec _o) o

909847 / 123S bad ORIGINAL

b) ^ '- Carboxy - ^' - Klutarimido-S ' _t 4'.6' ~ tri:! od-N-methyl - Klutaranilic acid

[Formula C: R «HOOC (CH ₂ ^ CON (CH ₅ ), Y - CH ₂ CH ₂ CH ₂ ] The title compound was obtained by following the procedure of Example 1 from 3 ^f -Carboxy-5 ^I -amino-2 ^l , 4 ', 6'-tri; iodine-N-methylgutaranilic acid and glutaric anhydride produced * The free acid was obtained in the form of a colorless pesticide, Fo 160 to Ί61 ° 0 (recrystallized from acetic acid) and the disodium salt was a beige solid, F. . 252 to ⁰

c) 3 * -Glutarimido-2 ' _T 4 * _t 6'-tri; iodo-N-methylftlutaranilic acid

(Formula A: R «HOOO (CH ₃ ), CON (GH ₃ ), Y - CH ₂ CH ₂ CH ₂ ] The title compound was obtained by refluxing 29» 65 g of the disodium salt of the 3 '"carboxy -5 '~ glutarimido-2 ^1, 4 _"t 6''~ H-triiodo methylglutaranilsäure in 70 ml of dimethylformamide prepared the free acid was obtained in the form' of a violet powder, F _e 256-257 ° 0, which was a violet Natriumsala Powder, Fo 241 to 245 ° C _O

Example 27

a) 3 '~ Carboxy-5 ^< -' (N ~ meth.ylacetamido) -2 ^< .4 · '«e'-tri.iodo-N-methylglutaranilic acid

[Formula D: R * CH ₅ CON (CH ₅ ), R ¹ = CH ₅ , R "· H _f Y ¹ - CH ₂ CH The title compound was obtained by following the procedure of the example from 49.0 g of J'-carboxy ^ ' -iN-methylacetamido) ^ ¹ , 4 ', 6'-triiodoglutaranilic acid (Example 12) and 15 ml of dimethyl sulfate in 175 10% sodium hydroxide. The product was recrystallized from acetic acid using ethyl acetate to precipitate the compound from solution «, was obtained as 3 ^{l -carboxy-l} 5 - (N-methylacetamido) -2 ^l, 4 _'6'-t tridod-N-methylglutaranilsäure in the form of colorless prisms, F "284-287 ⁰ C (dec.).

b) 2 ', 4'"6 ^t ~ Tri.1od ~ 3 ^t - (N ~ meth.vlacetamido) ~ N-methYlclutaranilic acid

C Formula B: R «CH ₅ CON (CH ₅ ), E '= CH ₅ , R" = H, Y ¹ »The title compound was obtained by boiling under reflux for 30 minutes.

909847/1236

BATH ORIGINAL

flow from 16.42 g of the disodium salt of 3'-carboxyl '- (N-methylacetamido) ™ 2 ¹ , 4', e'-triiodo-N-methylglutaranilic acid in
Produced 40 ml of dimethylformamide »The free acid was luakristallisiert from aqueous acetic acid and obtained as pale cream-colored crystals" Po 90 to 10O ⁰ O. The sodium salt had a F ₀ τοη 173-1

Example 28
(lT-methylaceta mido) ~ 2 ¹ _<I 4 ¹ , 6 '~ tri.1od ~ IT-eth, yl · »

[Formula Jj; R »UH ₅ COH (OII ₅ ), R ¹ * OgH ₅₁ R" »H ₁ Y
The pitel compound was obtained by the method of Example 26 from 56.3 s 3 ⁵ "Garbo2t.y" 5 '- (N-methylacetamido) "2', 4 ·, δ'-triiodoglutaranileic acid (Example 12) and 40 ml of diethyl sulfate prepared in a 10% sodium hydroxide solution. The product was prepared from acetic acid and from an acetic acid / ethyl acetate mixture
umkeistallisiert to give 3 ^'ro carboxy-5' -. _^"!? (N-methylacetamido}" 2 4S6 ^l ".triood-N" ethyl ~ _$ glutaranilsäure F. 259-261 ⁰ C (Ζθγβ)

b) 2 ' \ 4'"6'-iri;iodo-3'"=> CN-methylacetamido) "- H-ethylclutaranilic acid [Formula B: R - GH ₅ CON (GH ₃ ), R ^f - O ₂ H ₅ , R "= H, Y ¹ - CH ₂ CH ₂ CH ₂ ] Dio titol compound was heated under for 45 minutes
Reflux from 44.1 g of the dinabrium salt of the 5 ^l -öaJ? BQxy «5 ^l - (N-methylacetamido) -2 ^! , 4 ^f , e '-' triood-N-ethylglutaranilic acid in ml of di-eth-jrlformamide produced _a The product had near the
Umkristallisatioa to the aqueous acetic acid has a melting point of 112 Isis 112.5 ⁰ Go

On gleislia V / eis © Irami the 3 ^l ~ carboxy-5 ⁱ - (N «mefchylacetamido) -2 ⁸ _S 4 ^S , e ^ -tri-iodoglutaranilic acid © with ii-butyl ^ oaiä or 2-hydroxyätfoy Bildusg Ύ®η 3 ^l ° »öaa? Boxy-» 5 ^l ~ CN-Eiethylaise'uamicio) -2 ⁸ , 4 *, 6 ⁸ -tai _t 1 od-N-butylglutaranileic acid
CForm ©! Bs R - GH ₃ CJOlCoH ₅ ), R ¹ * O ₄ H ^, H "» H, T ⁸ »
or- 3 ¹ -öarboxy-5 "" (^ - methyiaeetamido) -2 · _a 4 ⁵ _t 6 ⁵
hydroxyätiiyljelutaranilsäura [Formula Bi R »CH ₅ CON (CH ₅ ), R '»

9098A7 / 1236

BATH ORIGINAL

HOCH ₂ OH ₂ , R "* H, Y *« CH ₂ OH ₂ OH ₂ I, which in turn can be decarboxylated to form 2 ', 4-' _i 6 ^t- tri; iodo-3 ^l - (N-methylacetamido ) -ir-butylglutaranilic acid (formula Bi R »CH ₃ CON (OH ₃ ), R ^f « C ₄ H ₉ , R "« H, Y * * CH ₂ GH ₂ OH ₂ ] "or, 2 ', 4', G'-Trijöd *? ¹ - (N-methylacetamido) -! I- (2-hydro3qyäthyl) glutaranilic acid [Formula B: R - CH ₃ CON (CH ₃ ), R ¹ »HOCH ₂ CH ₂ , R" * H, Y ¹ «CHgCH ^ CHg].

Example 29

a) 3 '- * 0arboxy-2 ^f .4 *, e ^t -tri _t 1od ~ 5 ^l ~ (N- »methylacetamido)» 3> 3 »N- tri methyl ^ lutaranilic acid

[Formula D: R - CH ₃ OON (CH ₃ ), R ¹ = OH ₃ , R "H, Y CH ₃ C (OH ₃ ) ₂ CH ₂ 3

The title compound was obtained by methylating 3'-carboxy-2 ', 4, 6 -triiodo-3,3-dimethyl-5' - (N-methylacetamido) glutaranilic acid (Example 17 a) following the procedure of Example 26 a) made} F ₀ 183 to ⁰

b) 2 'Λ' * 6 '-q? ri, 1od-3' - (N ~ methylacetaiaido) ~ 3,3, N-trimethylslutaranilic acid

[Formula B: R «CH ₃ CON (CH ₃ ), R '» CH ₃ , R «« H, Y' »(CH) CH3

₃₂₂

The title compound was prepared by decarboxylating 3'-carboxy 2 ¹ , 4 ', 6 ^l -triiiodine-5 ^l - (N-methylacetamido) -3,3, N-trimethylglutaranilic acid according to the method of Example 1 b), it was a beige powder, F ₀ II9 to 122 ⁰ C ₀

Following the methylation process of Example 26 a), the the following connections established 1

Example 30

! Formula B: R »HOOpCH ₂ CHgCON (CHx) _x , R ' * CH ,, R" - H, I «a OH ₂ CH ₂ CH ₂ ]

By methylation of N, N '- (2,4,6-triiodo-m-ph8nylene) glutaramic acid (Example 16 b) the disodium salt was obtained

909847/1236

BATH ORIGINAL

Furniture connection in the form of colorless prisms, F ₀ 243 bis

Example 31

2 '.4' .6 ^t »Tri.1od« -5 '~ (N-meth.ylaoetaniao) »y-attOoinanileäiire C Formula E: R» OH ₅ OON (CH ₅ ), R ¹ * OH ₅ , R "- H, Y ¹ - OH ₂ CH ₂ ] By methylating the 2 * , 4 ', e'-tridod ^' - iN-methylacetamido) succinanilic acid (Example 13b), the title compound was obtained, F "199 to 200 ⁰ ( from aqueous acetic acid); the sodium salt had a F. from 10 0 to 190 ⁰ O (from methanol / ether) ο

Example 32

2 * Λ '.6 ^t -Tri, 1od »3 ^< - (K-methylacetamido)» 3 «y" dimethylglutarai? .Tl ~ acid ·.

C Formula B: R «OH ₅ COK (OH ₅ ), R ¹ - GH ₅ , R ¹¹ - H, Y ⁽ « = CH ₂ CH (OH ₅ ) -CH ₂ ]

Methylation of 2 ', 4 * , 6 · -Tri ^ od-3 * - (N-methylacetamido) -3-methylglutaranilic acid (Example 15b) gave the title compound in the form of a colorless powder, mp 101-107-5 ⁰ C.

Example 33

| g-Methyl-N- [2,4 "6-t i d.iod-3- (N-methylaoetamldophenyl3 carbamoal · · methylthio | * acetic acid Q.

C Formula B: R «CH ₅ OOH (CH ₅ ), R ¹ » OH ₅₁ R "- H, Y ¹ * OH ₂ SCH ₂ ] The titanium compound was obtained by hydrolysis of 4-C2,4,6-triciodo-3- ( N »methylacetamido) phenyl3-3» 5-thiamorpholinedione and methylation of the resulting {h-C2,4,6-triiodo-3- (N-methylacetamido) -phenyl] carbamoylmethylthioj-esbig acid and obtained in the form of a dark yellow solid, F. 124 to 129 ⁰ Oe

Bei p iel 34

2 '.4' .6 ^f -0? Ri.iod ~ 3 '- (N-methylacetamido) -N-methyldiKlycolanilic acid C Formula B: R = GH ₅ OON (GH ₅ ), R ¹ «OH ₅ , R" - H , Y ¹ - CH ^ OCHg] The title compound was prepared by hydrolysis of

^909847/1236 BADOBiG ₁ NAl.

N-C2 _t 4 _t 6-triiodo-3- (N-methylacetamido) phenyl] diglycolimide and methylation of the 2 ¹ , 4 ',, e'-triiodo-J'-CN-methylacetamido) diglycolanilic acid obtained; a colorless plague was obtained, Fo 141 to 14-3 ⁰ Cc

BjJj Ti IeI 35

^a ) 3-amino-2Λ. 6-tri f qd »N _t N" diäthylbenzamid A mixture of 26.6 g of 3 ~ amino-2,4,6-triiodo-benzoyl chloride, 515 ml of diethylamine and 250 ml of benzene was stirred under reflux for 20 minutes The reaction mixture was for 2 days at! room temperature gehalben _T then filtered and the filtrate was concentrated to remove the solvent and the Diäthylaminübersehussss to give _28? 7 g of 3-amino ~ triiodo _6-2? 4 _i * = F _t l! ifdiätliylbenzamid in the form of a amber-colored glass "

^) H-r3 "(H _T N» diethylcarbamoyl) 2 _t 4 _c 6-tri _< iodophenyl] 8uccinimide [Formula A: R- (OpH ^) ₂ NOO, Y »GH ₂ CH ₂ ]

A mixture of 28 ^ 7 S 3-Amino-2 _t 4 _? 6 ° tri3od-N _$ N-diäthylbenzarnid and 51 "6 g of succinic anhydride .wurde to 115 ⁰ C heated» ^J; , 15 2 _{tons of} 5 ml of concentrated sulfuric acid were added, the mixture was stirred for 2 to 3 minutes and then poured into 300 to 400 ml of cold water with stirring. The mixture was diluted with 300 ml of 10 tigern Ifatriumhydroxyd treated and the solid product was collected to give li = C3 ~ (N, Li: ') i.8thyicarbamoyl) 2 ₇ ^/ l _t 6-triiodophenyl] succinimide _t F _c 211 to 218 ⁰ C ₀

Eg spie 1 36

^ '- (KJI-diethyl carba aoyl) ~ 2 ^f , 4' , e '-' tri.-iodosuc cin anilic acid a'ormula B: R «(OpH ^) ₂ ITCO, R ¹ and R" »H, Y ¹ = CH ₂ CH ₂ ] The title compound was prepared by treating a

Solution of N ~ C3-CN _f W "J ^:) iä.thylcarbamoyl) 2.4 _t 6-triiodophenyl] succinitfide in acetone with an excess of 10% aqueous sodium hydrosyde. The solution was stirred _{for 1 hour at room temperature%} to remove the Concentrated solvent and acidified with dilute hydrochloric acid., The product was

909847/1236

BATH ORIGINAL

collected, purified by conversion into the sodium salt and renewed acidification and recrystallized from ethyl acetate and gave 3 '~ (ft _t : tT-: diethylcarbamoyl) ~ 2 " ¹ , 4 *, e'-triöödsuccinänilic acid in the form of colorless prisms, F ₀ 202 bis 2O5 ° C (decomposition) .->

Example 3? 3 '- {I ^ N-diethylaarbamoyl) -2' Λ '«6' -tri.iod-N-methylsuccinanil-

[Formula B: R - (C ^ I ^ BCO, R ¹ «OH ,, R" -H, Y ¹ »The table compound was prepared by the method of the example by methylating 3 ^l « - (H _t If ~ I & ethylearbamoyl) - -2 ^l, 4 * _t 6'-trijodsuccinanilsäurs with potassium hydroxide in Biinethylsulfat manufactured * The product was Onea colorless amorphous solid "also obtained in the form of both a free acid and as ETatriumsalz.

B e i s ρ i e 1 38

3 '"{H.li-diethTlcarbamoyl)" * 2' Λ ' * 6'"-triiodo -N-ethylsucinanilic acid [Ponriel B: H« (0 ₂ H _f p _p NG0 _t Η · «C ₂ H ₅ , R "* H, Y ¹ = 0Η ₂ σΗ ₂ 3 The Äitslverbindungen was prepared by alkylation of 3 '~ (N _; J; i-diethylcarbaiiioyl)"2', 4 ', G'-triiodosuccinanilic acid with diethyl sulfate and potassium hydroxide in aca Tonic solution _o The product was obtained from methanol / ether in the form of the sodium salt as a colorless amorphous pesticide.

Example 39

io mixture of 69? 88 g 3 ~ amino ~ 2 _? 4 _J 6-triiodobenzoyl 'and 3 ^ 0 ml Diiaethylamin was stirred for 15 minutes "It wurfl (jii 50 ml 35? Oige.-s Hatriumhydi'oxyd and 50 ml of water was added uul the Reakfcionamiac.liung was stirred for i hour ₀ The Γ-3'rbt product was collected and by conversion into the ilatriuiusals uad reconversion cleaned in the free acid "Oi · ^LC: s ti - 'C0 æ'-tc-de nsikristallisiert from ethanol to give..!.

909847/123 6 ORIGINAL BATHROOM

3 "Amino-23 * 6-triiodo-IT, N-dimethylbenzamide in the form of a pale yellow solid, mp 165 to 167 ° 0 _β

t>) V-CN .N-Dim et h.vlcgrbainoyl) - ^ ' Λ' »e'-triiodoglutaranilic acid

[Formula B: R »COHx) ₂ HCO ₁ R ¹ and R" * H, T ¹ «CHgCHgCHg] The title compound was prepared by reacting 3 ~ aniino-2 ₉ 43 6-triiodo-IT _> N- = dimethylbenzamide with glutaric anhydride according to the method of Example 35 b) and hydrolysis of the F-C3- (N, N-dimethylcarbamoyl) 2,4 _Y 6-tri, iodophenyl] glutaric acid [formula A: R »(CHj) ₂ HCO, T« CH ₂ CH ₂ CH ₂ ]. The 3 ⁵ - (Nf Ιϊ-dimethylearbamoyl) -2 ', 4', 6 '-tri ^ iodo-glutaranilic acid was obtained in the form of a colorless solid, F ₀ 189 bis

Example 40

3 '-f H , H-Dlmeth .Ylcarbamo.Tl) -2'.4'. 6 '-tri.iod ~ N-ethylglutarani 1- saura

Formula B: R = (CH ₃ ^ HCO, R '* C ₃ H ₅ , R "- H _4. Ϊ ⁵ = CH ₂ CH ₂ CH ₂ ] The title link was made by reacting 3' - (N, IT Dimethyisarbamoyl) -2 ', 4 ·, ö'-trijodglutaranilsäure (example 39 b) with Diäthy! sulfate according to the procedure of example 26 and according to the Uinkristallisation from ethyl acetate as colorless crystals, F _c 180-182 ⁰ C. ,

B ₁ PICTURE 41

3 '~ {H, L "Dime th.ylcarbamoyl) -2', _-4% * 6 '' tri _t io d-N" meth.ylplutaranil "- acid

CForaiel B: - (? N _i e-Diniethylcai bamoyl) R = (CHj) ₂ HCO, R ¹ = CH _7, R "= H, Y 'The title compound was prepared by reacting 3 ¹ ~ 2 ^l, 4 ¹ ₅ 6'-trijodglutaranilsäure (example 39 b) with dimethyl sulfate according to the procedure of example 26 and according to the Ssikristallisation from ethyl acetate to give the product in form of colorless crystals, F _0205-208 ⁰ C _n the Hatriumsalz had a P ₃ 191-200 ⁰ G ₀

909847/1236 ORIGINAL BATHROOM

Example 42

5 '~ (N ~ methylcarbamoyl) ~ 2', 4 ', e'-tri.iodo-N-methylftlutaranilic acid ! Formula B: R «CH ₃ HHO, R ¹ = CH ₃ , R" - H, Y ¹ - OH ₂ CH ₂ CH ₂ ] The title compound was prepared by reacting 3'- (N-methylcarbamoyl) -2 ·, 4 ', G'-tri ^ odglutaranilic acid (Example 21b) with dimethyl sulfate according to the method of Example 26 and according to recrystallization from ethyl acetate gave the product as a colorless solid, F _0164-168 ° C.

At. play 45

a) oc ~ acetamido-2 ', 4' _t 6'-tri, 1od-m »acetotoluidide C formula: R ⁰ * CH ₃ CONHCH ₂ , Q - COCH ₃ ]

The title compound was prepared by decarboxylation of J-Acetamiao - ^ - acetamidomethyl ^^ fG-triiodobenzoic acid according to the procedure of Example 1b) and after recrystallization from acetic acid to give the product as a colorless solid, F.- 287-288 ⁰ C. _e

b) N- [2 _< 4 _< , 6 '»T ri, 1od- | 3" ( acety la minomethyl) phenyl] ftlutarimide C Formula Λ: R = * CH ₃ CONHCH ₂₉ Y «CH ₂ CH ₂ CH ₂ ]

The title compound was prepared by reacting α-acetamido-2 '«4 ¹ _t 6'-triiodo-m-acetotoluidide with glutaric anhydride according to the procedure of Example 2 a) and after recrystallization from isopropyl alcohol the product was obtained in the form of a colorless one Solids * F ₆ 128 to 134 ⁰ C

B _- e is ρ ie 1 44

^a) N '- [2 _f 4,6 "Tri _t 1od - $ - (acetylamino laminomethyl) -5 ~ carboxyphenyl] imide glutar7

C formula C: R «CH ₃ CONHCH ₂ , Y - CH ₂ CH ₂ CH ₂ ]

The title compound was prepared by reacting 3 -.? 'Lcetamiao-5 "S.cetamidomethyl-2,4,6-triiodobenzoic acid with GlutarsHurefinhydrid nHcii the method of Example 2 a) and after ^j iC-l' Umkristfiiiii ation from acetic acid to give the product in

909847/1236

BATH ORIGINAL

Form of a colorless solid, mp 256-258 ° C.

b) N-C2 .6- Λ »Tri.1oa-3 '(aeetylaminomethyl) ~ 5 ~ carboxyphenyl3-Klutaranilsäure

[Formula D: R. «CH ₅ CONHCH ₂ , R ¹ and R" «H, Y ¹ » CHgCHgCHg] The title compound was prepared by hydrolysis of N-C2,4,6-! Pri ^ od-3- (acetylaminomethyl) -5 * "carboxyphenyl] glutarimide with dilute Natriumbydroxyd and recrystallized from acetic acid to give the product as a colorless solid, F _0234-239 ⁰ Oo

c) K ~ C2 ₁ 4 _t 6 '"Tri.1od« -3 ~ (acetylaminomethyl) phenyl3glutaranilic acid [Formula B: R »GH ₅ COIIHGH ₂ , R ¹ and R« »H, Y ¹ = CH ₂ GH ₂ CH ₂ ]

The title compound was prepared by decarboxylation of N- £ 2,4,6-triiodo-3- (acetylaminomethyl) -5 ~ carboxyphenyl] -glutaranilic acid by the method of Example 1 b) and after recrystallization from aqueous dimethylformamide the product was obtained in Form of a colorless solid, F ₀ 254 · to 259 ⁰ G. The same substance can be prepared by hydrolysis of N-C2,4,6-triiodo-3- (acetylaminomethyl) phenyl] glutarimide (Example 43 b) with warm, dilute sodium hydroxide

Example 45

N-C2 _T 4 _t 6-Tri, 1od - ^ - (acetylaminometh, yl) phenyl] -N-methylglutaranilic acid

[Formula B: R »CH ₃ COIiHCH ₂ , R '- GH ,, R""H, Y ¹ - CH ₂ CH ₂ GH ₂ ] The title compound was prepared by reacting N- [2 _t 4,6-triiodo« -3 '= (acetylaminomethyl) phenyl] glutaranilsäure (example 44 c) with dimethyl sulfate according to the procedure of example 26 and recrystallized from ethyl acetate to a colorless solid, F "gave the product in the form of 167-175 ⁰ Co

90984 7/1236

B el a V i β 1 46

a) Methyl 3 * -carboxy- ^ ', 4' .6 * -tri.fod-5 '- (N-methylacetamido) azelanilate

[Formula D: R = OH ₅ COIr (CH,), R ¹ - H, R "» OH ₅ , Υ »A mixture of 100 g of azelaic acid monomethyl ester and 500 ml of thionyl chloride was refluxed for 1 hour» The excess thionyl chloride was removed by distillation and the last traces were removed by addition of benzene and evaporation of the solvent "Then to the obtained Säureciilorid of Azelainsäuremonomethylssters was added a solution of 260 g of 3-" Ajttino-5-acetamido-2 _t 4 _i 6-triiodobenzoic acid in 3500 ml dioxane was added and the mixture was boiled for 6 hours under reflux. the dioxane was then removed by distillation and the residual product was recrystallized from acetic acid to give methy1 = 3'-carboxy-2 _·? 4 _'t 6 ^l -trijod-5 '- (N-methylacetamido) ash lanilate in the form of colorless needles, F ₀ 198 to 203 ° C.

By substituting the azelaic acid monomethyl ester with a molar equivalent of oxalic acid monomethyl ester or malonic acid monomethyl ester, the methyl 3 '-carbosy-2', 4 ', 6'-trij'öd-5'- (N-methylacetaiaido) oxanila1; [Formula D: H> OH ₅ CONCGH-), R * ■ H, R "· OH ,, Y '* single bond ' J \> - δη, 'the methyl-3'« carboxy ^ 2 ', 4 *, 6 '-tri-iodine-5' - (N-met; hylacetBi: i.io) ittalonanilat CForiael D: R = * CH, GON-R '«H _t R ^;) - (JH ₃ , Y'-" GH ₂ -] can be obtained

b) 3 * - "Ci arboxy - ^ '.4'" 6 '"f; ri, iQd ~ 5' ~ {H'-methylaceta mido) azelanils acid

;; orn .el _Is?:? H - UH ₃ OOJIyTT _5), H ¹ and R "" H ₉ Y * = - (CHg) _7-J A mixture of 136 g Metliyl-3'-carboxy ~ 2 ' _S 4 · ₉ 6'-triiodine ~ ^' • "(^« riithylacetaifliüo) azelanilat and 180 ml of water were mixed with • ;; wfj'I'i-O ml hi'opf env / eise augegsbenem 10 '/ oigeia watery liatrinnih; / dr-oj ^ vJ. will be fully liquidated by April ¹ . The f! .Lao) u '"iig is heated for 10 minutes on a steam bath, it' viir-ctßjf '. 18 viii v / ei'uöx-es Ί0% igös sodium hydroxide is added and

e Ί heated for another hour _o The reaction ■ ^ ifgekühlt _s la.i 1; 3? "I-ger hydrochloric acid an"

9 09847/1236

acidified and the solid product was collected, washed with water * dried and recrystallized from acetic acid to give 3 ^! -Garboxy «-2 *, 4 ' _i 6 ^f -tridod-5' - (N'-methylacetamido) a25elanilic acid in the form of a colorless solid j P. 205 to 208 ⁰ C.

By replacing the methy1-3'-carboxy - ^ ', 4 ¹ , e'-acetamido) azelanilate by a molar equivalent of methyl-3'-carboxy-2 ¹ »4 ¹ _i 6 ^l -triiodo-5 ^l " (N-iaethylacetamido) oxanilate or methyl-3'-carboxy-2 ¹ , 4 · _i 6'-triiodo »5 ^l - (N-methylacetamido) malonanilate can be the 3 ^l -ö & .: L ^v boxy-2 ^l , 4 ' _i 6 ^l ~ triiodo-5 ^l ° (N-methylacetamido) ~ oxanilic acid LFormula D: R »CH ₃ CON (CH ₅ ), R ¹ and R" «H, Y '= single bond] or the 3'-carboxy-2 ^l , 4 · _T 6 ^l -tridod-5 ^l - (N-meth3rlacetamido) malonanilic acid-8 [formula D: R »OH ₃ CON (CH,), R ¹ and R" = H ₅ , Y ¹ = -OH ₂ -] will "

°) 2 ¹ j ^ 'teV-Tri; | qd-5 \ - /' N-meth ^

Formula B: R * CH ₅ CON (CH,), R 'and R "- Ή, Y ¹ » - (CH ₂ ) »-] The TiteJ compound was prepared by decarboxylation of 3'-carboxy ~ 2' Λ ' , 6 ^! -Triiodo-5 ^l - (N-methylacetamido) azelanil = acid according to the method of Example 1b) and the product was obtained in the form of a colorless solid _t F ₀ 153 to 160 ^° C.

By EraatB der J'-Garboxy ^ ¹ , .4 ¹ _t 6 ^r -triiodine-5 ^a »(N-methylacet = - amido) aaelanilsäui ³ i3 by a molar equivalent of 3'-Garboxy-2 ³ , 4 ' ₉ 6

triiodo-5 ^{lf =} - (^ "- * niethylacetamido) oxanilic acid and 3 ^I -carboxy-2 'j4' _? 6 '" tri, iodine- = 5 ^lcj (Ii «iii-3thyiacetamldo) malonanilic acid can be the 2 ¹ _t 4 ^{ _i 6 '«tri; iodine <=» 3' - (ir-methylacötamido) oxanilic acid C formula Bi R ^ GH ₃ OOHH (OH ₃ J ₅ RV u, id R "« H, T ¹ · single bond] or, the 2 ^! _f 4 ' _? 6 ⁱ -TriJöd-'j5 ^l - = (N-methylacQtamido) maionanilic acid [Formula B R = C-Pi ^ JOHH (OH ₃ ) ZH ¹ and R "= H ₉ Y ¹ - -OH ₂ -J obtained will _o

Alternatively, the 2 ¹ , 4 * * 6'-triiodo-3 '~ (N-methylacetamido) azel · = anilic acid © by reaction of 3-amino-2 _s , 4 _e 6-fcri-j "od-N-methylacet 'anilide [Formula Ks R ⁰ ^ CH ^ GON (CH ₃ )., Q «H] with the acid chloride of aselaic acid monomethyl ester and mild alkaline hydrolysis d & e obtained mebhyl-2 ¹ _t 4' _s 6 '~ tridod ~ 5 ^? - (N = .methylacetamido) «azelanilats fForraal Bs R-« 'AUUOH (OH ₃ ) ^ R ¹ ■ «H, R" »GH ₃₅ Y ³ ()« -] ₀

^909847/1236 BADOHQlNM.

Example 47

3-glutarimido-2, 4,6-tri.iodobenzamide
C Formula A: R «HgNCO, T - CH ₂ CH ₂ CH ₂ ].

A mixture of 100 g of 3-glutarimido-2,4,6-triiodobenzoic acid and 200 ml of thionyl chloride was refluxed for 90 minutes. The excess thionyl chloride was removed in vacuo and the last traces were removed by boiling with benzene. The acid chloride residue was treated with 200 ml of concentrated ammonium hydroxide and 200 ml of water = the reaction mixture was stirred for 2 hours. The solid product was collected, dried and recrystallized from dimethylformamide with the addition of a small amount of acetic acid and then from dioxane to give 3-glutarimido- 2 _t 4- _t 6-triiodobenzamide in the form of a colorless solid »P ₀ 268 to ⁰

[Formula K: R ⁰ = CH ₅₅ JIHOOj Q, - CCOH ₇ ]

The title connection was established; by decarboxylation of 3- (N-methylLcarbamyl) ~ 5 * "8 ^l cet; araido-2.4 _t 6" trijodbenzoesäui ^% e according to the method of Example 1 b) and the product was obtained in the form of a colorless solid, F, 290 to 292 ⁰ C _c

^) 2 j4 _% 6-Tr 1.1 οd-H-aiethy 1 - ^ -. (Sueciniciidp) benzamide [Formula A: R «CE ₇ NHGO, Y» CHpGH ₂ ]

The title compound was produced by reacting 3-A-33t-amido-2 _s ^ _-1 β-tri ] or "K-methylbenzamide" with succinic anhydride according to the procedure of Example 2 a) and after crystallization TJM aui.>I.'eohanol received the product is colorless in the form Krista.lU _T V. ^277-0

B ei s ρ i e 1

; · Ο, · ί ..;,. 1 K: 9 ° · OH -.- OONCOF.-,), Q - COCH, 3 ' ih :: ■ i ^ eJrex'Dir.cuuig wiarde herg.-ssrhellt through Deoarboxylation

909847/1236

BATH ORIGINAL

of 3-acetamido-5- (N ~ methylacetamido) -2,4 _f 6-triiodobenzoic acid according to the procedure of Example 1b) to give the product as a colorless solid, mp 160 ⁰ Co

b) ^ "Maleimi do ^^. e-triiodo-N-methylacetanilide [Formula A: R - OH ₃ OOIi (GH ₅ ), Y - -OH-GH-]

The tital compound can be obtained by reacting 2,4,6-triiodo-II-methyl-m-benzene diacetamide with maleic anhydride according to the method of Example 2 a) ..

909847/1236

BADORiGIHAL

Claims (1)

Pat entana brew Coded aniline derivatives, characterized by the general Formulas (A) and -H-OO-T-OQOR » in which Y is a lower alkylene group in which 2 or 3 carbon atoms separate the carbonyl groups from one another »a vinylene or a 1 _¥ 3W? ropyiengruppe in which the 2-carbon atom is replaced by O ₄ S _? SO or SOg is replaced, Y ⁸ is a Binfaclibindung or an alkylene bridge having 1 to 8 carbon atoms, or a so lohe group that is interrupted by 1 to members from the group 0, S ₁ SO and SO ", wherein these terms, when more than one is present _$. are separated from each other by at least 2 carbon atoms, E (ffiedrigalkanoyl) HH, (ITiedrigalkanoyl) NHGH _2, (Kiedrigalkanoyl) N (lower alkyl), (lower alkoxy-lower alkanoyl) NH _i (Niedrigalko-fy-niedrigalkanoyDNCniedrigalkyl), H ₂ NCO ₈ (Niedrigalkyl.iilHCO-! (JCiiedrisalkyl) ₂ NGO ₉ Y <^ o ^ ^T »HOOG-Y ¹ ^ CO-M or HOOCJ-Ϊ '-CÜ-Hi-lower alkyl), ^ IV hydrogen, iiiedrigalk ^ I or hydroxy-lower alkyl and II " mean hydrogen or lower alkyl? As well as their salts =, 2. "Compound naoli claim 1, characterized in that in the formula B R (lower alkanoyl) N (lower alkyl) and R" Was »serst off bödout en ο 5 c Yorbj.3idu.ng according to claim 1 _? characterized in that in aej: Formula BH (lower alkyl) _o NG0 and R- "denotes hydrogen , 9098A7 / 1236 _BAD ORiGiNAU 4 ·. The compound of claim 1 _t wherein In the formula AR (NiedrigalkanoyX) NHGH ₂₁ (NiedrigalkanQyX) N (ni: edrigalkyX), (NiedrigaXkoxy-niedrigaXkanoyX) li (niedrigaXkyX), H ₂ NCO, (NiedrigalkyX) NHCO, (Niecb? igaXkyX) ₂ NC0, I ^ Ccq ^ ^or HOOC-Y-CO-NCLoweralkyX) means. 5o N _i N ^ä -. (2 _i 4 _l 6-0? _{Ri t} iodine-in-phenylene) digXutaraiiiidsäurec 6 ₀ 2 ', 4 ·', 6 '"triiodo-5' - (li-methyXacetamido) -N-methylgXutaraniX-acid ₀ . 7. 2 ', * ·, 6 ^l -Triiodo-3 ^l - (N-methyXacetamido) -Ii-methyXsuccinaniX-acid _o 8 ο 2, 4, 6 ~ T _r iiodo-3 '- (N-methyXacetamido) -N-ethyXglutaranilic acid ₀ 9 o 2 ' _t 4, 6'-triiodo-3 - (N-methyXacetamido) -3,3, N-trimethyX-glutaranilic acid o 1Oo 3 '- (N _i N-DimethyXcarbamoyX) -2 ^l , 4- ^' - triiodo-N-methyXgXutaranilic acid, 11 Procedure for establishing the connections according to one of the preceding claims, characterized in that a compound of the general formula C or D COOH -N = OO-X · -COOR " in the _Ι ς I ^1, R _s, R ¹ and R _"t besifcsen the meanings given in claim 1 is heated in an organic solvent ^909847/1236 BADORlS ₁ NAt ■ _; ΡΣ ■; ■: "- 43- 12. The method according to claim 11 for the preparation of a compound according to claim 4 ·, characterized in that one Compound of the general formula K -NHQ j
(K) in which R ⁰ H ₃ N, (lower alkanoyl) NH, (lower alkanoyl) NHCH ₂ , (lower alkanoyl) N (lower alkyl) H ₂ NCO, (lower alkyl) NHCO, (lower alkyl) ₂ N00, Y ^ q§> N or HOOC- Y-CO-NC-lower alkyl), where Y has the meaning given in claim 1 and Q is hydrogen or lower alkanoyl, with a compound of the formula Ot ^ Q ^ äT, in which Y has the meaning given in claim 1, is reacted. 13. Process according to claim 12, characterized in that a compound of the formula A is hydrolyzed under alkaline conditions to form a compound of the formula B in which R ¹ and R "are hydrogen 14-. Process according to claim 13 »characterized in that a compound of the formula B in which R ¹ and R" denote hydrogen is then treated with a lower alkyl or hydroxy lower alkyl halide, sulfate or sulfonate under alkaline conditions to form a compound of the formula B , in which R ^{1 is} lower alkyl or hydroxy-lower alkyl and R "is hydrogen. 15 'Process for the preparation of a compound of the formula B in which R ¹ denotes hydrogen and R "denotes lower alkyl, characterized in that a compound of the formula K in which Q denotes H with a compound of the formula Gl-OO-Y ¹ -CÖOR ", in which Y ^{1 has} the meanings given in claim 1 and R" means lower alkyl, is implemented. 909847/123 6 BATH ORIGINAL 16 · The method according to claim 15t, characterized in that the resulting compound is then hydrolyzed under mild alkaline conditions to form a compound of formula B, in which H "means hydrogen 17. Use of the compounds according to claim 1 in eholeeysto » graphic agents for oral or intravenous administration. 909847/1236 BATH