IL31862A - Cyclic amides and anilic acids of aniline derivatives - Google Patents
Cyclic amides and anilic acids of aniline derivativesInfo
- Publication number
- IL31862A IL31862A IL31862A IL3186269A IL31862A IL 31862 A IL31862 A IL 31862A IL 31862 A IL31862 A IL 31862A IL 3186269 A IL3186269 A IL 3186269A IL 31862 A IL31862 A IL 31862A
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- methylacetamido
- carboxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
- C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
- C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
- C07D265/33—Two oxygen atoms, in positions 3 and 5
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- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Detergent Compositions (AREA)
- Indole Compounds (AREA)
- Pyrrole Compounds (AREA)
Description
© »tK»irrt Q'^ ^S D'TO)* Cyclic amides and anillo cds of aniline derivatives This invention relates to iodinated aniline derivatives, and more particularly is related to cyclic imides \and anilic acids of 2,1+,6-triiodoanilines bearing a substituted amino group or substituted carbamyl group in the 3-position, and with methods for the preparation of these compounds · An aspect of the invention resides in oompounds of the formulas: wherein Z is wherein Y is a lower-alkylene group wherein 2 or 3 oarbon atoms separate the oarbonyl groups, vinylene, or a 1,3- propylene group wherein the 2-carbon atom is replaced by 0, S, SO or S02j Y' is a single bond or an alkylene bridge having from one to eight oarbon atoms or such a group interrupted by from one to three members selected from 0, S, SO and S02, said members, when more than one, being separated by at least two carbon atoms; R is ( lower-alkanoyl)- NHCH2, (lower-alkanoyl)N(lower-alkyl) , H2NC0, ( lower-alkyl)- NHCO, (lower-alkyl) NCO, Y HOOC-Y»-CO-NH, or HOOC-Y'-CO-N(lower-alkyl)j R' is hydrogen, lower-alkyl, or hydroxy«»lower~alkyli and R" is hydrogen or lower-alkyl, or a salt form thereof* For convenience, the oompounds of Formula I can be rewritten as Formulas A and B, below.
(A) (B) In the above Formula A, Y stands for a lower-alkylene group wherein 2 or 3 oarbon atoms separate the oarbonyl groups and thus can be an ethylene or propylene group optionally substituted by lower-alkyl. The group Y oan have from two to six oarbon atoms and inoludes such groups as *0H CH2-, -GH2CHCH2-, -CHiCH^CHg-, --CH2CH(GH3)CH2-# -CHiCl^GHiC^)-, -CH2GH(C2I¾)GH2-, -0fi(CH3)CH2CH2-, -ΟΗ(ΟΗ3)σΗ(σΗ3)σΗ(σΗ3)-# -0Η20(σΗ3)20Η2-, and the like. Y also stands for a 2-oxa- or 2-thia-l,3-propylene group having from 2 to k oarbon atoms, for example, -GH20CH2-, -GH2SCH2-, -CH2S0CH2-, CH2S02CH2-, -CH(CH3)0CH2-, -CH(CH3)OCH(aH3)-, and the like. The group Y1 in Formula B represents a single bond or a divalent bridge having from one to eight oarbone separating the oarbony1 and oarboxyl groups.
When R in the above Formula stands for (lower-alkanoyl)NHCH2, or ( lower-alkanoyl)N(lower-alkyl) , the lower-alkanoyl group has from one to six oarbon atoms thus inoludlng, for example, formyl, aoetyl, propionyl, butyryl, isobutyryl, valeryl, oaproyl, and the like.
When R stands for (lower-alkanoyl)N( lower-alkyl) , ( lower-alkyl)NHC0, (lo er-alkyl)2NC0, or HOOC-Y'-CO-N-( lower-alkyl) , and/or R' stands for lower-alkyl, and/or R" stands for lower-alkyl, the lower-alkyl group has from one to four oarbon atoms, thus inoluding, for example, methyl, ethyl, propyl, isopropyl, and butyl.
A preferred oompound of this invention is one of Formula I wherein Z is -N-CO-Y' -C00R" , R is (lower- R' alkanoyl)N)( lower alkyl) and R" is hydrogen.
Another preferred oompound of this invention is one of Formula I wherein Z is -N-00-Y»-000R" , R R' is ( lower-alkyl)2N00 and R" is hydrogen.
Particularly preferred oompounds of this invention are N,N 2,^,6-triiodo-m-phenylene)diglutaramio aoid, 2' ,6'-triiodo-3'-(N-methylaoetamido)-N-methylglutaranilio aoid, 2* Λ' ,6' -triiodo-3 N-methylaoetamido )-N-methyl-suooinanilio aoid, 2» , ,6»-triiodo-3f-( -methylaoetamido )-N-ethylglutaranilio aoid, 2' , ,6' -triiodo-3 '-(N-methylaoetamido)-3,3-N-trimethylglutaranilio aoid and 3f-(N,N-dimethyloarbamoyl)-2f , ,6'-triiodo-N-methylglutaranilio aoid.
The compounds of the invention of Formula I above are prepared by decarboxylation of a oompound of the Formula as ollows : II wherein R and Z have the same meanings given hereinabove.
For convenience, the oompounds of Formula II can be rewritten as Formulas C and D, below, (0) (D) The decarboxylation is oarried out by heating a oompound of Formula C or D, either in the free aoid or salt form, in an organic solvent. A preferred method is heating the free acid or salt form, for example, the sodium salt, in dimethylformamide at a temperature between about 85 and 1^.0 °C, The structures of the oompounds of the invention were determined by the modes of synthesis, by elementary analysis and by neutral equivalent determination. The course of the reactions was followed by thin-layer chromato raphy.
The compounds of Formula B, being carboxylio acids, can be obtained in the form of salts derived from inorganic bases or organic amines. Preferred salts are those whioh are pharmaceutically acceptable, for example, the sodium, magnesium, calcium and N-methylgluo amine salts; although all salts are useful either as characterizing derivatives or as intermediates in the purification of the acids. The salt forms of the compounds of the invention are considered the full equivalents of the free acids claimed herein, and thus are part of the same inventive concept.
The compounds of the invention having the formulas A and B are useful as X-ray contrast media for visualization of the gallbladder (cholecystography). The compounds have intravenous toxicity (approximate LD^0 values) in the range between 600 and 700 mg./kg. in mice. The compounds of lesser toxicity, LD50 = 15OO mg./kg. or greater, are primarily useful, in the form of their water-soluble, pharmaceutlally acceptable salts, as intravenous cholecystrographic agents. The compounds having LD^Q values less than about 1500 mg./kg. are primarily useful, either in the free acid or salt form,, as oral cholecystographic agents.
The actual quantitative determination of toxicity and radiopaque effectiveness for a particular compound is readily determined by standard test procedures by tech-nicians trained in pharmacological test procedures, without the need for any extensive experimentation.
The compounds were tested for their intravenous cholecystographic efficacy by standard procedure as follows: The test compound was injected intravenously in the form of an aqueous solution of the sodium or N-methylglucamlne salt to cats. Each cat was X-rayed at hourly intervals and the roentgenograms examined and evaluated. The density of the gallbladder shadows was interpreted in accordance with a numerical scoring plan designated as the Cholecysto-graphic Index (CI), a measure of the efficiency of the test compound, viz.: 0 (none), 1 (poor), 2 (fair), 3 (good), 4 (excellent) /see J. 0. Hoppe, J. Am. Pharm. Assoc., Sci.
In testing for oral cholecystography, the test compound was administered orally in capsules to each of five cats. About eighteen hours later, each cat was X-rayed and the roentgenograms were examined. The density of the gallbladder shadow evoked by the test compound in each cat was Interpreted in accordance with the above numerical scoring plan and the Average Cholecystographic Index (ACI) determined.
A and B above, upon testing for cholecystographic effectiveness in cats at a dose of 100 mg./kg. > were found to produce gallbladder shadows having a Cholecystographic Index of 3.0-4.0 either by oral or by intravenous administration.
The compounds of the invention are prepared for cholecystographic use by dissolving a pharmaceutically acceptable salt form in sterile aqueous medium suitable for intravenous injection; or in capsule or in tablet form with conventional exciplents for oral administration.
The following examples will further illustrate the invention without the latter being limited thereby.
Example 1 a) 3, 5-bis( Glutarlmido)-2,4 ,6-trllodobenzolc Acid /C; R is (CH2) 3(C0)2 , Y is GH2CH2CH2_7 was prepared from 265 g. of 3 , 5-diamino-2,4 ,6-triiodobenzoic acid, 400 g. of glutaric anhydride and 18 ml. of concentrated sulfuric acid, heated and stirred for seventeen hours. The product was recrystal-lized from dimethyl sulfoxide, adding water to induce precipitation, and was obtained as a light gray solid with one mole of dimethyl sulfoxide of crystallization, m.pa above 300°c . A sample of the acid was converted to its sodium salt form, m,p. 288-291°C. (dec ) when recrystallized from water. b) Ν,Ν' -(2, 4 , 6-Trliodo-jB-phenylene)diglutarimide /A; R is (CH2)3(C0)2N, Y is CH20H2CH2_7.
A mixture of 89»10 g. of sodium 3 , 5-bis(glutar-imido)2,4 ,6-triiodobenzoate and 400 ml. of dlmethylformamide was warmed at 85°C. for 20 minutes to effect solution, and then heated at reflux temperature ( 130-135°C.) for four hours. The solution was cooled, and the solid product collected, washed with dimethylformamide and acetone, and dried to constant weight (35.18 g.). An additional 41.75 g. of product was obtained by diluting the filtrate with water. The combined product was recrystallized from acetic acid, using activated charcoal for decolorizing purposes, to give Ν,Ν' -(2,4,6-trliodo-m-phenylene)diglutarimide, colorless prisms, m.p. above 300°C.
N,N* -(2,4,6-Triiodo-m-phenylene)diglutarimide can also be prepared by reacting 3-amino-2,4,6-triiodoanillne ( ; R° is H2N, Q is H), 3-amino-2,4,6-triiodoacetanilide (K; R° is H2N, Q is COCH3), or 3-acetamido-2,4,6-triiodoacet-anilide ( ; R° is CH3CONH, <¾ is COCH3) with glutaric anhydride according to the procedure of Example 1, part (a).
Example 2 a) 3-Glutarimldo-5-(N-methylacetamldo)-2,4,6-trllodobenzoic Acid /C; R is CH3CON( CH3) , Y is CH2CH2CH27.
A mixture of 117.2 g. of 3-amlno-5-(N-methylacet-amido)2,4,6-trliodobenzoic acid and 182 g. of glutaric anhydride was heated with stirring on a steam bath. Con-centrated sulfuric acid (10 ml.) was added, and heating and stirring were continued for seven hours. The reaction mixture was added to 700 ml. of water, and the solid product was collected by filtration and recrystallized from acetic acid. The resulting 3-glutarimido-5-(N-methylacetamido) -2,4,6-triiodobenzoic acid was converted to its sodium salt form as follows: the free acid was slurried with 40 ml. of methanol and a IN solution of sodium hydroxide in methanol was added with trituration until the solid had dissolved.
The sodium salt was precipitated out with ether, and the resulting gum was triturated with ether and dissolved in methanol. The latter solution was decolorized with activated charcoal and the product reprecipitated with ether. The product was dissolved in water and the solution filtered and concentrated in vacuo. The residue was dried ln_ vacuo to give the sodium salt of 3-glutarimido-5-(N-methyl-acetamido) -2,4,6-triiodobenzoic acid as a pale pink solid, m.p. 200-204°C.(dec. ). b) N-/2~,4,6-Triiodo-3--( N-methylacetamldo)phenyl7glutarimlde /A; R is Y is CH2CH2CH2_7' can be prepared by decarboxylation of sodium 3-glutarimido-5-( N-methylacet-amido) -2,4,6-triiodobenzoate according to the procedure of Example 1(b); or by decarboxylation of 3-acetamldo-5-(N-methylacetamido) -2,4,6-trliodobenzoic acid followed by reacting the resulting 3-( -methylacetamido) -2,4,6-triiodo-acetanilide ij R° Is CH3) , Q is C0CH3_7 with glutaric anhydride.
By replacing the 3-amino-5-( -methylacetamido) -2,4,6-triiodobenzoic acid in the foregoing preparation by a molar equivalent amount of 3-amino-5-(N-butylacetamido ) -2,4,6-trliodobenzoic acid, 3-amino-5-(N-methylpropionamido) -2,4,6-triiodobenzoic acid, 3-amino-5-(N-methylcaproylamino)-2,4,6-triiodobenzoic acid, 3-amlno-5-(N,N-dimethylcarbamoyl) -2,4,6-triiodobenzoic acid, or 3-amino-5-( N-methyl^-methoxy-acetamido) -2,4,6-trliodobenzoic acid, there can be obtained, respectively, 3-glutarimido-5-(N-butylacetamido) -2,4,6-triiodobenzoic acid /G; R is CI^CON^Hg) , Y is CH2CH2CH2_ ", 3-glutarimido-5-(N-methylpropionamido) -2,4,6-triiodobenzoic acid /C; R is CH3CH2CO (CH3), Y is CH2CH2CH2/, 3-glutarimido-5-( N-methylcaproylamino ) -2,4,6-triiodobenzoic acid /C; R is CH^CHg^COl^C.^), Y is CH2CH2CH2_7", 3-glutarimido- -(N,N-dimethylcarbamoyl)-2,4,6-triiodobenzoic acid /C; R is (CH3)2NC0, Y is CH2CH CH2_7, or 3-glutarimido-5-( N-methyl-2-raethoxyacetamido) -2,4,6-triiodobenzoic acid /C; R is σΗ3οοΗ2σθΝ(σΗ3) , Υ is CH2CH2CH2_7'; whicn in tux>n can be de_ carboxylated to give, respectively, N-/2~,4,6-triiodo-3- (N-butylacetamido)phenyl7glutarimlde /A; R is CH^CON( C4H ) , Y is CH2CH2CH2_7", N-/2,4,6-triiodo-3-(N-methylpropionamido)-phenyl/glutarimide /A; R is CH^CI^COl^ CH3) Y is CH2CH2CH2_7, N-/2,4,6-triiodo-3-( -methylcaproylamino )phenyl/glutarimide /A; R is CH3(CH2) C0 (CH3) , Y is CH2CH2CH2_7, N-/2,4,6-tri-iodo-3-(N,N-dimethylcarbamoyl) phenyl/glutarimide /A; R is (σΗ3)2Νσθ, Y is CH2CH CH _7", or N-,/2,4,6-triiodo-3-(N-methyl-methoxyacetamido)phenyl7glutarimide ^A R is CH30CH2C0N( CH3) , Example 3 a) 3-Succinimido-5-( -methylacetamido) -2,4,6-triiodobenzolc 3id ,' R is CH3CO (CH3), Y is CH2CH2_7" was prepared from 87.9 g of 3-amino-5-(N-methylacetamido) -2,4,6-triiodoben-zoic acid, 120 g. of succinic anhydride and 6 ml. of sulfuric acid according to the procedure of Example 2, except that a reaction temperature of 130-l40°C. was used. The reaction was essentially complete after 30 minutes heating time. The compound was isolated in the form of its sodium salt, pale yellow solid, m.p. 220-222°C. (dec). b) N-/2,4,6-Triiodo-3-( -methylacetamldo)phenyl7succlnlmlde /A; R is CH3CON(CH"3), Y is CH2CH2_7 can be prepared by heating sodium 3-succinimldo-5-(N-methylacetamido)-2,4,6-tri-iodobenzoate in dimethylformamide by the method described in Example 1 (b).
Example 4 a) 3-( 3- ethylglutarimldo ) -5 -( N-methylacetamldo ) -2 ,4 ,6-trllodobenzoic Acid /C; R is CH3CO (CH3), Y is CH2CH(CH3)-CH2_7 was prepared from 3-amino-5-(N-methylacetamido) -2,4 ,6-triiodobenzoic acid, 3-methylglutaric anhydride and sulfuric acid according to the procedure of Example 2. The product was isolated in the free acid form, m.p. 301 -302°C. (dec . ) when recrystallized from acetic acid. b) N-/2 , 4 , 6-Triiodo -3-( N-methylacetamido )phenyl "- 3-methyl-glutarimide /A; R is CH3CON(CH3), Y is CH2CH( CH3) CH2_7" can be prepared by heating sodium 3-succinimido-5-(N-methyl-acetamido) -2 ,4,6-triiodobenzoate in dimethylformamide by the method described in Example 1(b).
The following compounds were prepared following the procedure of Example 1 from the appropriate 3-amino -5-R-2, 4, 6-triiodobenzoic acid and acid anhydride: Example 5 : 3-( 3, 3-Diniethylglutarlmido) ^-(N-methylacetamldo) -2 , 4 , 6-triiodobenzoic Acid /C; R is CH3C0N(CH3), Y is CH C(CH3)2CH2_7", pale tan solid, m.p. 274-278°C. ( dec . ) (from acetic acid); sodium salt form, pale yellow solid, m.p. 235-245°C.(dec. ).
Example 6 ; 3-Glutarimldo -5-(N-ethylacetamido ) -2 , 4 , 6-triiodo benzoic Acid /C; R is CH3C0N( C2H5 ) , Y is CH2CH2CH2_7, sodium salt form, m.p. above 220°C.
Example 7 : 3-( Methylsucclnlmldo) -5-(N-methylacetamido) -2,4 ,6-triiodobenzolc Acid /C; R is CH3CON(CH3), Y is CH(CH3)CH2CH2_", m.p. 285-287°C. (from acetic acid); sodium salt form, m.p. above 245°C. (dec. ) .
Example 8 : 3-( Diglycollmldo ) -5-( -methylacetamido ) -2 , 4, 6 -triiodobenzoic Acid /C; R is CH3CON(CH3), Y is CH20CH2_7", sodium salt form, m.p. 250-255°C. No sulfuric acid was used in this preparation,, Example 9 : 3-( 3j 5-Dioxothiomorphollno) -5-( N-methylacet-lmido) -2 ,4 ,6-trllodobenzoic Acid /C; Ris CH3CON(CH3), Y is CH2SCH2_7", sodium salt form, beige solid, m.p. 250-260°C. (dec.). No sulfuric acid was used in this preparation.
The compounds of Examples 5 * 6 and 7 can be de-carboxylated by the method of Example 1(b) to produce, respectively, N-/2 , , 6-triiodo -3-(N-methylacetamido)phenyl7-3, 3-dimethylglutarlmide /A; R is CH3C0N(CH"3), Y is CHgC- ( CH3)2<¾_7, N-/2", 4 , 6-triiodo -3-( N-ethylacetamido )phenyl7*-glutari ide /A; R is CH3C0 ( C2H5) , Y is CH2CH2CH2_7, and N-/~2 , 4 , 6-triiodo -3-( N-methylacetamido)phenyl7"methylsuccin-imide /A; R is CH3CO (CH3), Y is CH( CH^CHgCH^T".
The compounds of Examples 8 and 9 were decarboxyl-ated by heating the free acid forms in dimethylformamide, 90 minutes at reflux temperature. There was obtained, respectively, N-^5",4,6-triiodo-3-(N-methylacetamido)phenyl7"-diglycolimide K; R is CH3CON(CH"3), Y is CH20CH2_7*, m.,p. 264-266°C. (from dimethylformamide; and 4-/2", 4, 6-triiodo-3-( N-methylacetamido )phenyl/"- 3 , 5-thiamorpholinedione /A; R is CH3C0N(CH3), Y is CH2SCH2_7, beige solid, m.p. 283-285°C. (from acetic acid). The latter two compounds were also prepared by heating together at 120-150°C. equal weights of 2 , 4 , 6-triiodo-3-(N-methylacetamido) -aniline and diglycolic anhydride or thiodiacetic anhydride, respectively. 3~( 3* 5-Dioxothiomorpholino) -5-(N-methylacetamido)-2,4 ,6-triiodobenzoic acid can be oxidized with m-chloroper-benzoic acid in dimethylformamide solution to give 3-( 3, 5 , - S,S-tetraoxothiomorpholino ) -5-( N-methylacetamido ) -2,4,6-triiodobenzoic acid /C; R is ) , Y is CH2S02CH2_7"> which can be decarboxylated according to the procedure of Example 1(b) to give 4-/2,4,6-trliodo-3-(N-methylacetamido)-phenyl7"-3>5,S,S-tetraoxothlomorpholine /A; R is ) * Example 10: 3-Glut rimido-2,4,6-triiodo-N-methylisophthal-amic Acid /C; R is CH3NHCO, Y is CR^CHgC^^, sodium salt form, light tan solid, m.p. 250-270°C. ( dec. ) when recrystal-lized from aqueous methanol with addition of ether.
Example 11: 3-Suecinimido-2,4,6-triiodo-N-methylisophthal-amic Acid /C; R is CI^NHCO, Y is CH2CH2J7', m.p. above 300°C. ; sodium salt form, pale pink solid, m.p. 258-26l°C.
The compounds of Examples 10 and 11 can be de-carboxylated by the method of Example 1(b) to produce, respectively, N-/2,4,6-triiodo-3-( N-methylcarbamoyl) phenyl^ glutarimide /A; R is CH3NHCO, Y is CH2CH2CH2_7', colorless solid, m.p. 23^-236°C. (from acetic acid), and N-/2,4,6-triiodo-3-(N-methylcarbamoyl)phenyl7"succinimide /A; R is Example 12 a) 3' -Carboxy-5' -(N-methylacetamido) -2' ,4' ,6' -trllodo-glutaranllic Acid /Dj R is CH3CON(CH3), R' and R" are H, A mixture of 58.6 g. of 3-amino-5-(N-methylacetamido) -2,4,6-triiodobenzoic acid, 74 g. of glutaric anhydride and 8 ml. of concentrated sulfuric acid was heated on a steam bath for five hours. The reaction mixture was poured into water and the solid product collected by fil-tration. The product, consisting of 3-glutarimido-5-( N- dissolved in excess dilute aqueous sodium hydroxide, and the solution warmed for thirty minutes, then cooled and 3N hydrochloric acid added slowly until precipitation was complete. The solid product was collected and recrystal-lized first from acetone, then from acetic acid, and finally from water to give 3 ' -carboxy-5 ' -(N-methylacetamido) -2 ' ,4 1 , 6 ' -trliodoglutaranilic acid, colorless prisms, m.p. 188.8-196.0°C. b) 2 ' ,4 ' , 6 ' -Trliodo -3 '-( -methylacetamido )glutaranillc Acid /Bj R is CH3CON(CH3), R' and R" are H, Y' is CH2CH2CH2_r can be prepared by heating the disodium salt form of 3 ' -carboxy-5 ' -(N-methylacetamido) -2 ' ,4 ' ,6 ' -trliodoglutaranilic acid in dimethylformamide according to the procedure of Example 1(b).
Example 13 a) 3 ' -Carboxy-5 ' -(N-methylacetamido) -2' ,4 ' , 6 ' -triiodosuc-cinanilic Acid 5; R is CH3CO, R' and R" are H, Y' is CH2CH2_r was prepared from 3^.3 g. of 3-amino - -(N-methylacetamido) -2 ,4, 6-triiodobenzoic acid, 82 g. of succinic anhydride and 5 nil. of concentrated sulfuric acid, followed by alkaline hydrolysis of the resulting 3-succinimido-5-( -methylacetamldo) -2, 4 , 6-triiodobenzoic acid, according to the method described in Example 12. The product was recrystallized from dilute ethanol and from a methanol-acetonitrile mixture and further purified by converting it to the diammonium salt by means of ammonium hydroxide in methanol, and then acidifying an aqueous solution of the ammonium salt to regernate the free acid. There was thus obtained 3 ' -carboxy-5 ' -(N-methylacetamldo) -2 · , 4 ' , 6 * -tri-iodosuccinanilic acid, m.p„ 275 _ 0-276.0°C. (dec. ) . b) 2' , ' ,β' -Trllodo-31 -(N-methylacetamldo)3ucclnanlllc Acid /Bj R is CH^CO, R« and R" are H, Y' is CH2CH2_r, colorless prisms, m.p. 209-211°C, was prepared from 37.81 g. of dlsodium 3' -carboxy-51 -( N-methylacetamido ) -21 ,4' ,61 -triiodosuccinanilate in 100 ml. of dimethylformamide, 40 minutes at reflux. The mixture was acidified with hydrochloric acid and the product collected and recrystallized from acetone.
Similarly, by warming in dilute aqueous sodium hydroxide, 3-glutarimido-5-(N-butylacetamido) -2,4,6-triiodo-benzoic acid, 3-glutarimldo-5-(N-methylpropionamido) -2,4,6-triiodobenzoic acid, 3-glutarimido-5-(N-methylcaproylamino) -2,4,6-triiodobenzoic acid, or 3-gl tarimido-5-(N-methyl-2-methoxyacetamido) -2,4,6-triiodobenzoic acid can be hydro-lyzed, respectively, to 3' -carboxy-5 ' -(N-butylacetamido) -2· ,4' ,6' -triiodoglutaranilic acid /D; R is CH3C0N( C H9) , R' and R" are H, Y' is C"H2CH2CH_7, 3' -carboxy- 1 -( -methyl-proplonamido ) -2' ,4' ,6' -triiodoglutaranilic acid /Dj R is CH3CH2CON(CH"3), R1 and R" are H, Y1 is CH2GH2CH2_7", 3'-carboxy- 1 -(N-methylcaproylamlno)^' ,4' ,6' -triiodoglutaranilic acid /p; R is CH~3( CH"3) , R1 and R" are H, Y' is or 3' -carboxy-5' -( -methyl-2-methoxy-acetamido) -2 ',4' >6' -triiodoglutaranilic acid /Dj R is 0Η3Ο0Η20ΟΝ(0Η3), R' and R" are H, Y' is Cn2™2C}i2-?>' and in turn decarboxylated to give, respectively, 3'-(N-butyl-acetamldo) -2' ,4" ,6' -triiodoglutaranilic acid /B; R is CH3C0 (C H9), R' and R" are H, Y' is CH2CH2CH2Jr, 3'-(N-methylpropionamido) -2' ,4' ,6' -triiodoglutaranilic acid /B; R is CH3CH2C0N(CH3), R1 and R" are H, Y» is CH2CH2CH2_r, 3' -( -methylcaproylamino) -2* ,4' ,6' -triiodoglutaranilic acid /Έ\ R is CH3(CH2) CON(CH3), R« and R" are H, Y« is CH2-CH2CH2_7, or 3' -( N-methyl-2-methoxyacetamido) -2',4'6' -triiodoglutaranilic acid /B; R is CH3) , R' and R" are H, Y" . is CH2CH2CH2_7. 3' -Carboxy-5' -( -methylacetamido) -2 ' .4' ,6' -triiodoglutaranilic acid can also be prepared by heating 3-araino-5-( N-methylacetamido) -2,4,6-triiodobenzoic acid with 4-carbomethoxybutyryl chloride ( CH 0C0CH2CH2CH2C0C1 ) in dioxane solution, followed by hydrolysis of the result-ing methyl 3' -carboxy-51 -(N-methylacetamido) -2" ,4' ,6' -triiodoglutaranilate by heating it with potassium carbonate in methanol solution.
Similarly, 3-amino-5-(N-methylacetamido ) -2,4,6-triiodobenzoic acid can be caused to react with C1-C0CH2CH2CH2CH2C00CH3, Cl-COCHgCH^OCH^CH^COOCH^ or C1-C0CH2SCH2CH2CH2CH2SCH2C00CH3 to give, respectively, the following compounds: /D; R is R' is H, R" is CH3, Y' is 0Η2σΗ2σΗ2σΗ2_7; /β,' R is CH3CO (CH3), R" is H, R" is CH3, Y' is CH2CH20CH2CH2_7; or Έ; R is CH3C0N( CH3) , R' is H, R" is CH3, Y' is These can be hydrolyzed to the corresponding dibasic acids where R" is hydrogen and decarboxylated to give, respectively, the following R' and R" are H, Y! is 3) , R' and R" are H, Y' is σΗ2σΗ20σΗ20Η2_7ί or /I; R is CH3CO (CH3), In the same manner, 3>5-ciiamino-2,4,6-triiodo-benzoic acid can be caused to react with COOGH3 to give /D; R is C^OCOCI^Ci^CHgCi^CONH, R.' is H, R" is CH3, Y' is CH2CH2CH2CH2_7, which can be hydrolyzed to give /D; R is ROC0CH2CH2CH2CH2C0NH, R" and R" are H, Y1 is CH2CH2CH2CH2_7"i and the latter decarboxylated to give /B; R is H0C0CH2CH CH2CH2C0NH, R« and R" are H, Y1 is CH2CH2CH2CH2_^.
Example 14 a) 3-/ -( Carboxymethylsulfonyl )acetamido/-2,4,6-trilodo-5-(N-methylacetamldo)benzolc Acid / ; R is R' and R" are H, Y' is CH2S02CH2_7.
A solution of 26.1 g. of 3-amino-5-(N-methyl-acetamido) -2,4,6-triiodobenzoic acid in 300 ml. of dioxane was distilled until about 60 ml. of dioxane was removed in order to eliminate possible traces of water. Sulfonyl-diacetyl chloride ( C1C0CH2S02CH2C0C1) (5 85 g. ) was then added, and the mixture was stirred and refluxed for about five days. The reaction mixture was concentrated in vacuo to remove the solvent, and the residue was dissolved in dilute sodium hydroxide to give a solution of the sodium salt of the product. The basic solution was made weakly acid, which did not cause precipitation of the acid form of the product, treated with activated charcoal at 60°C. and filtered. The filtrate was acidified with 3N hydrochloric acid and the precipitated product collected. The acid product was purified by dissolving it in ammonium hydroxide solution and reacidifying the resulting ammonium salt solution. The acid product was recrystallized from aqueous dimethylformamide to give 3-/2-( carboxymethyl-sulfonyl)acetamidor-2,4,6-triiodo-5-( N-methylacetamldo ) -benzoic acid, m.p. above 300°C. b) {N-/2",4,6-Triiodo-3-(N-methylacetamido)phenyl7carbamoyl methylsulfonyl] acetic Acid /Bj R is R' and are H, Y' is CH2S02CH"2_7" can be prepared by decarboxylation of 3-/2-( carboxymethylsulfonyl)acetamido7'-2,4,6-triiodo-5-( N-methylacetamido )benzoic acid according to the procedure of Example 1(b). The product is the same as that described in Example 23 below.
By replacing the sulfonyldiacetyl chloride in the foregoing preparation by sulfoxydiacetyl chloride (C1C0CH2-S0-CH2C0C1) there can be obtained 3-^ -( carboxy-methylsulfoxy)acetamidc -2,4,6-trliodo-5-( N-methylacetamido)-benzoic acid /D; R is ) , R1 and R" are H , Y1 is CH2S0CH2_7"J which can be decarboxylated to give { -/ ,4 , 6-triiodo -3-( -methylacetamido )phenyl/carbamoylmethylsulfoxy] - ) , R1 and R" are H, Y' is The following compounds can be prepared either by mild alkaline hydrolysis of the corresponding cyclic imides, or directly from the appropriate 3-amino -5-R-2,4,6 -triiodobenzoic acid without isolation of the intermediate cyclic imide, followed by decarboxylation of the resulting anillc acid, as described above in Examples 12 and 13.
Example 15: (a) 3 ' -Carboxy-2' ,4' ,6 ' -trilodo-3-methyl- ' -( N-methylacetamldo)glutaranlllc Acid /D; R is CH3) , R* and R" are H, Y* is CHgCHC CH"3)CH2_7, colorless crystals, m.p. 256-259°C.(dec. ). (b) 2' ,4 ' ,6 ' -Trliodo-3-methyl-3 ' -( N-methylacetamido )glutaranilic Acid /B; R is CH3) , R' and R" are H, Y' is CH2CH( CH3)GH2_ i pale tan crystals from aqueous acetic acid, m.p,, 189-193°C; sodium salt form, beige powder from methanol-ether, m.p. 202-204°C.
Example l6; (a) 3 , -bis( 4-Carboxybutyramldo ) -2 ,4, 6-trl- Y is CH2CH2CH2_7", colorless solid, m.p. 251-253°C (from acetic acid). (b) Ν,Ν' -( 2, ,6-Trilodo-m-phenylene )diglutar-amic Acid / ; R is HOOC( CH2)3CONH, R' and R" are H, Y1 is CH2CH"2CH2_7", colorless prisms from acetic acid, m.p. 278-279°C. /prepared by hydrolysis of Ν,Ν' -(2,4,6-triiodo-m-phenylene)diglutarimide (Example lb) with sodium hydroxide in acetone solution two hours at refluxJ".
Example 17: (a) 3' -Carboxy-2' ,4' ,6' -triiodo-3,3-dimethyl-5' -(N-methylacetamido)glutaranilic Acid ^D; R is CH^CON-(CH3), R' and R" are H, Y' is CH2C( colorless crystals, m.p. 258-262°σ. (dec.), (b) 2' ,4' ,6' -Triiodo-S^-dlmethyl-S1 -(N-methyl-acetamido)glutaranilic Acid /B R is CH3CO (CH ), R' and R" are H, Y' is CH2C( CH3)2CH2_7, tan powder, m.p. 132-13 °C. Example 18: (a) 3' -Carboxy-5' · (N-ethylacetamldo ) -2 ' ,4' ,6' -trliodoglutaranlllc Acid /D; R is C2H"5) , R' and R" are H, Y* is CH2CH2CH2_7", colorless solid, m.p. 250°C. (dec . ) . (t>) ≥' A' ,6' -Trllodo-3' -(N-ethylacetamldo) -glutaranillc Acid /_β; R is CH3C0N( C2H5 ) , R' and R" are H, Y is 0Η20Η20Η2^.
Example 19; (a) 3* -Carboxy-21 ,4' ,61 -trllodo-3-methyl-5 ' -( N-methylacetamido )succinanilic Acid (Έ; R is CH3) , R' and R" are H, Y' is CH( 0Ή3)0Ή2_7", light orange solid, m.p. 262-264°C.(dec. ). (b) 2' ,4' ,6' -Triiodo-3-methyl-3' -(N-methylacetamido) succinanilic Acid /B; R is CH3CO (CH ), R' and Example 20: (a) 3' -Carboxy-2' ,4' ,6' -trilodo-51 -(N-methyl-acetamldo)dlglycolanillc Acid /DJ R is CH3C0 (CH3), R' and R" are H, Y' is CHgOCHg^ disodium salt form, light tan solid, m.p. 245-260°C. (dec. ) . (b) 2' ,4' ,6' -Trliodo-3' -( -methylacetamldo) - diglycolanlllc Acid /Bj R is R1 and R" are H, Y' is CH20CH2_7, colorless solid, m.p. 125-133°C.
Example 21; (a) 3' -Carboxy-2' ,4' ,6' -trilodo-5' -(N-methyl- carbamoyl)glutaranilic Acid /Dj R is CH3NHCO, R1 and R" are H, Y' is CH2CH2CH2_7, pale pink prisms, m.p. 249-252°C. (dec. ) . (b) 2' ,4' ,6' -Trliodo-3' -(N-methylcarbamoyl)- glutaranilic Acid B∑ R is CH3NHCO, R1 and R" are H, Y' is CH2CH2CH2_/*, colorless needles, m.p. 268-270°C. (from acetic acid).
Example 22: (a) 3-/2-( Carboxymethylthlo )acetamidoT"-2,4,6- triiodo-5-(N-methylacetamido)benzoic Acid /D; R is CH3- C0N(CH3), R' and R" are H, Y' is CH2SCH2_ , beige solid, m.p. l65-170°Ce (b) (N-/2",4,6-Trliodo-3-( -methylacetamido )- phenyl7carbamoylmethylthio3 acetic Acid /B>; R is R' and R" are H, Y' is CH2SCH2_7.
Example 23 methylsulfonyl acetic Acid /§; R is R' and R" are H, Y' is CH2S02CH2_7.
(N-/2~,4,6-Triiodo-3-( N-methylacetamido )phenyl7- carbamoylmethylthio} acetic acid (derived by hydrolysis of 25.Ο g. of 4-/2",4,6-triiodo-3-(N-methylacetamido)phenyl7- 3,5-thiamorpholinedlone) was dissolved in 150 ml. of glacial acetic acid at 40°C. Hydrogen peroxide (72 ml. $) was added. After five minutes the mixture was concen- trated to a volume of 75 nil. and 400 ml. of water added. The product which separated was crystallized by stirring the mixture in ice, and was collected and dried to give [N-/2~,4,6-triiodo -3-( N-methylacetamido )phenyl/earbamoyl-methylsulfonyl j acetic acid, m0p. l48-150°C. (dec. ) .
Example 24 a) 3-Succlnlmldo-5-nitrobenzoic Acid Ψ; Y is C 2Cii2_^ was prepared by heating 3-amino-5-nltrobenzoic acid with succinic anhydride in the presence of sulfuric acid. It had the m. p. 262-268°C. when recrystallized from aqueous dimethylformamide . b) 3 ' -Carboxy-5 ' -nltrosuccinanlllc Acid /Hj Y is CH2CH2_7 was prepared by treating 3-succinimido-5-nitrobenzolc acid with warm dilute aqueous sodium hydroxide, and had the m.p. 220-221°C. c) 3 ' -Carboxy-5 ' -aminosucclnanillc Acid /J; γ is CH2CH2_". 3 ' -Garboxy-5 ' -nitrosucclnanilic acid ( 83.5 g.) and 50 ml. of concentrated ammonium hydroxide in 100 ml. of water were added to a heated solution of 5^0 g. of ferrous sulfate heptahydrate in 900 ml. of water. Concentrated ammonium hydroxide (100 ml.) was then added during fifteen minutes in 50 ml. portions. After thirty minutes of heating on a steam bath, the reaction mixture was filtered and made acid to pH 3.5. The product was collected and dried in_ vacuo over phosphorus pentoxide to give 57.5 g. of 3 ' -carboxy-5 ' -aminosuccinanilic acid, m.p. 194°C. (dec. ). d ) 3 ' -Carboxy-5 ' -amlno-21 ,4' ,6 ' -triiodosucclnanilic Acid /p; R is NH2, R' and R" are H, Y' is CH2CH2_7.
Potassium iododichloride( 335 ml. 2.23N in water), was added over a period of forty minutes to a stirred suspension of 57 o 3 g. of 3 ' -carboxy-5 " -aminosuccinanilic acid in 35 ml. of water. The solid product was collected by filtration and recrystalllzed from water and from aqueous dimethylformamide. The product was purified by converting it to the diammonium salt and then to the disodium salt, m.p. 222-225°c. ( dec . ) . The latter was acidified to produce the free acid form of 3 ' -carboxy-5 ' -amlno-2 ' ,4 ' ,6 » -tri-iodosuccinanilic acid, cream colored solid, m.p. I56.2-172.2°C.(dec. ). 31 -Carboxy-5 ' -amino-2 " ,4 ' ,6 · -triiodosuccinanilic acid can be acylated with acetic anhydride, using a few drops of perchloric acid as a catalyst to obtain 3'-carboxy-5 ' -acetamido-21 , 4 ' ,6 ' -triiodosuccinanilic acid /~D; R is CH3CONH, R' and R." are H, Y1 is CH2CH2_7", which can be decarboxylated according to the method of Example 1(b) to give 2 ' ,4 ' ,6 ' -triiodo-3 ' -acetamidosucclnanilic acid /B; R is CH3C0NH, R' and R" are H, Y' is CH2CH2_7*.
Example 2 a) 3-Glutarlmldo - -nitrobenzoic Acid /F; Y is CH2CH2CH2_7 was prepared by heating a mixture of 18.2 g. of 3-amino-5-nitrobenzoic acid, 45.6 g.. of glutaric anhydride and 0.5 ml. of concentrated sulfuric acid on a steam bath for two hours. The product was Isolated and recrystalllzed from aqueous dimethylformamide to give 3-glutarimido -5-nitrobenzoic acid, pale yellow prisms, m.p. above 300°c. b) 3-Glutarlmido-5-amlnobenzoic Acid /G; Y is CH2CH2CH2_7 can be prepared by reduction of 3-glutarlmido -5-nitrobenzoic acid. The reduction can be carried out catalytically (platinum or nickel catalyst) under neutral or acidic conditions , c) 3-Glutarimldo-5-amino-2 , ,6-trllodobenzoic AcId ^C R is H2N, Y is CH2CH2CH2_7' can be prepared by iodination of 3-glutarimido-5-aminobenzoic acid with potassium iododi-chloride according to the procedure described in Example 24, part (d)„ d) 3-Glutarimldo-5-acetamido -2,4,6-triiodobenzoic Acid /C; R is CH3CONH, Y is CH2CH2CH2_ can be prepared by acetylation of 3-glutarimido-5-amino-2,4,6-triiodobenzoie acid with acetic anhydride, using a few drops of perchloric acid as a catalyst, e) 2' ,4' ,6' -Trilodo-3' -acetamldoglutaranilic Acid /§; R is CH3C0NH, R' and R" are H, Y is CI^CHgCH^Z can be prepared by hydrolysis and decarboxylation of 3-glutarimido-5-acetamido-2,4,6-triiodobenzoic acid.
Example 26 a) 3' -carboxy-5' -amlno-21 ,4' ,6' -trllodo-N-methylglutar-anlllc Acid /Ό; R is H2N, R' is CH3, R" is H, Y" is CH2-CH CH _7".
To a solution of 26.0 g. of 31 -carboxy-51 -amino- 21 ,4' ,6' -triiodoglutaranilic acid ^prepared by hydrolysis of 3-glutatimido-5-amino-2,4,6-triiodobenzoic acid (Example 25c) " in 100 ml. of 10% aqueous sodium hydroxide cooled in an ice bath was added 8 ml. of dimethyl sulfate in acetone. After three hours of stirring an additional ml. of 10 sodium hydroxide and 2 ml. of dimethyl sulfate were added and the mixture stirred three hours longer. The reaction mixture was acidified, and the product collected and recrystallized from acetic, acid to give 3'-carboxy-5' -amino-2' ,4· ,6' -triiodo-N-methylglutaranilic acid, pale gray crystals, m.p. 2l8-220°C (dec . ) . b) 3 * -Carboxy-51 -glutarlmido-2' ,4' ,6 ' -trliodo-N-methyl-glutaranlllc Acid /C; R Is H00C(CH2)3C0N(CH3) , Y Is CH2CH2CH2_7" was prepared from 3 ' -carboxy-51 -amlno-2 ' , ' ,61 -trllodo-N-methylglutaranlllc acid and glutaric anhydride according to the procedure of Example 1. The free acid was obtained as a colorless solid, m.p. l60-l6l°C. when recrystallized from acetic acid, and the disodium salt form as a beige solid, m0p„ 252-255°c. c) 3 ' -Glutarimido-2' ,4' ,6 ' -triiodo-N-methylglutaranlllc Acid /A"; R is H00C( CH2)3C0 ( CH3) , Y is was prepared from 29.65 g. of the disodium salt of 3'-carboxy-5 ' -glutarlmido-2 · ,4 ! ,6 " -triiodo-N-methylglutaranillc acid in 70 ml. of dimethylformamide, 30 minutes at reflux. The free acid product was obtained in the form of a mauve powder, m.p. 256-257°c. ; sodium salt form, mauve powder, m.p. 24l-245°C.
Example 27 a) 3' -Carboxy-5 ' -( -methylacetamido) -2' ,4 ' ,6 ' -trilodo-N-methylglutaranillc Acid /p; R is CH"3C0N(CH3), R' is CR"3, R" is H, Y' is CH2CH2CH2_7 was prepared from 49.0 g. of 3 ' -carboxy-5 ' -( N-methylacetamldo) -21 ,4 ' ,6 ' -triiodoglutar-anilic acid (Example 12) and 15 ml. of dimethyl sulfate in 175 ml. of 10$ sodium hydroxide according to the procedure of Example 26. The product was recrystallized from acetic acid, using ethyl acetate to bring the compound out of solution. There was thus obtained 3' -carboxy-5 ' -(N-methylacetamido) -2' ,4 ' ,6 ' -trliodo-N-methylglutaranilic acid, colorless prisms, m.p. 284-287°C. (dec . ) . b) 2' ,4 ' ,6 ' -Trllodo-3 ' -( -methylacetamido)-N-methylglutar- is 0Η20Η20Η2_Γ was prepared from 16.42 g„ of the di3odium salt of 3' -carboxy-5' -(N-methylacetamido) -2! ,4' ,6' -triiodo-N-methylglutaranilic acid in 40 ml. of dimethylformamide, 30 minutes at reflux. The free acid product was recrystal-lized from aqueous acetic acid and obtained as pale cream-colored crystals, m.p„ 90-100°C; sodium salt form, m.p. 173-175°C Example 28 a) 3' -Carboxy-51 -(N-methylacetamido) -2' ,4' ,6' -triiodo-N-ethylglutaranllic Acid /D? R is CH3CON(CH3), R' is C2H5, R" is H, Y1 is CH2CH2CH2_7 was prepared from 56.3 g. of 3' -carboxy-51 -(N-methylacetamido) -2' ,4' ,6' -triiodoglutar-anilic acid (Example 12) and 40 ml. of diethyl sulfate in 10 sodium hydroxide solution according to the procedure of Example 26. The product was recrystallized from acetic acid and from an acetic acid-ethyl acetate mixture to give 3' -carboxy-5' -(N-methylacetamido) -2· ,4' ,6' -triiodo-N-ethyl-glutaranilic acid, m.p. 259-26l°C. (dec . ) . b) 2' ,4' ,6' -Triiodo-3' -(N-methylacetamido ) -N-ethylglutar-anilic Acid β; R is CH3CON(CH3), R' is G2H5, R" is H, y* is CH CH2CH2_7" was prepared from 44.1 g. of the disodium salt of 3' -carboxy-5' -( N-methylacetamido) -2',4' ,6' -triiodo-N-ethylglutaranilic acid in 107 ml. of dimethylformamide, 45 minutes at reflux. The product had the m.p. 112-112.5°CU when recrystallized from aqueous acetic acid. 3' -Carboxy-5' -( N-methylacetamido) -2 ■ ,4» ,6' -tri-iodoglutaranilic acid can similarly be alkylated with n-butyl iodide or 2-hydroxyethyl bromide to give 3'-carboxy-5' -(N-methylacetamido) -2' ,4' ,6' -triiodo-N-butylglutaranilic acid /Dj R is CH3CO (CH ), R' is C^H , R" is H, Y' is CH2CH2CH2_7'i or 3' -carboxy-5 « -(N-methylacetamldo) -2' ,4· -6' -triiodo-N-(2-hydroxyethyl)glutaranillc acid /Dj R Is CH3CON(CH3), R' Is HOCH2CH2, R" is H, Y1 is CH2CH2CH2_" which in turn can be decarboxylated to give, respectively, 2» ,4' ,6' -trliodo-3' -( -methylacetamido )-N-butylglutaranilic acid /Bj R is CH^CON{CR^) , R« is C H9, R" is H, Y' is CH2CH2CH2_7, or 2' ,4' ,6' -triiodo-3» -( N-methylacetamido ) -N-(2-hydroxyethyl)glutaranillc acid /B; R is CH^CONC CH^) . R' is H0CH2CH2, R" is H, Y is Example 29 a) 3' -Carboxy-2' ,4' ,6' -trilodo-5' -( -methylacetamido )-3,3 , N-trlmethylglutaranilic Acid /D; R is CH3CON(CH"3), R' is CH3, R" is H, Y is ΟΗ20(ΟΗ3)2ΟΗ2_ m.p. l83-l84.5°C. was prepared by methylation of 3' -carboxy-21 ,4' ,6' -triiodo-3, 3-dimethy1-5' -( -methylacetamido)glutaranilic acid (Example 17a) according to the method of Example 26(a). b) 2' ,4' ,6' -Trllodo-3' -(N-methylacetamido)-3,3,N-trlmethyl-glutaranilic Acid /Έ,' R is CH"3CO (CH3), R" is CEy R" is H, Y is 0Η2σ(0Η3)20Η2_7 beige powder, m.p. 119-122°C, was prepared by decarboxylation of 3' -carboxy-2' ,4' ,6' -trliodo-5' -(N-methylacetamido )-3>3*N-trimethylglutaranilic acid acccording to. the method of Example 1(b).
The following compounds were prepared by the methylation procedure of Example 26(a): Example 30; Ν,Ν' -(2,4,6-Trllodo-m-phenylene)bls(N-methyl-glutaramlc acid) /β; R is H00CCH2CH2C0N( CH3) , R* is CH3, R" is H, Y is CH2CH2CH2_7, dlsodium salt form, colorless prisms, m.p. 24l-245°C, by methylation of Ν,Ν' -(2,4,6-triiodo-m-phenylene)diglutaramic acid (Example l6b).
' ' ' - - ' - - - - H, Y is m.p. 199-200°C. from aqueous acetic acidj sodium salt form, m.pe 170-190OC from methanol-ether, by methylation of 2' ,4» ,6' -triiodo-3' -(N-methylacetamido) -succinanilic acid (Example 13b) „ Example 32: 2' ,4' ,6' -Triiodo-3' -( N-methylacetamido) -3,N-dimethylglutaranilic Acid /B; R is R" is H, γ' is 0Η2σΗ(σΗ3)σΗ2_*, colorless powder, m.p. 101-107.5°C, by methylation of 2' ,4» ,6' -triiodo-3' -(N-methylacetamido) -3-methylglutaranilic acid (Example 15b) „ Example 33: fN-Methyl-N-/2", , 6-triiodo -3-( N-methylacetamldo-phenyj/carbamoylmethylthioj acetic Acid /B; R is CH3CO (σί-3), R' is CH3, R" is H, y'is GE2SCE2_7't tan solid, m.p. 124-129°C, prepared by hydrolysis of 4-/2,4, 6-triiodo-3-(N-methylacetamido )phenyl_7-3* 5-thiamorpholinedione and methyla-tion of the resulting N-/2, 4, 6-triiodo -3-( -methylacetamido)-phenyl/r carbamoylmethylthioj acetic acid.
Example 3 : 2' ,4* ,6' -Trllodo-31 -( N-methylacetamldo ) -N-methyldiglycolanilic Acid ^Bj R is CH3CO (CH3) R' is CH^, R" is H, Y'is GK20CK2_~> colorless solid, m.p. l4l-l43°C, prepared by hydrolysis of N-/2~,4,6-triiodo-3-( N-methylacetamido )phenyl7"-diglycolimide, and methylation of the resulting 2' ,4' ,6' -triiodo-3' -(N-methylacetamido )diglycolanilic acid.
Example 35 a) 3-Amino -2,4,6-triiodo-N, -dlethylbenzamide .
A mixture of 26.6 g. of 3-amlno-2,4,6-triiodo-benzoyl chloride, 515 ml. of dlethylamine and 250 ml. of benzene was stirred at reflux for 20 minutes. The reaction mixture was kept at room temperature for two days, then filtered and the filtrate concentrated to remove solvent and excess diethylamine to give 28.7 g. o 3-amino-2,4,6-triiodo-N,N-diethylbenzamide as an amber glass, b) N-/ -(N,N-Dlethylcarbamoyl) -2, ,6-triiodophenyl73uccln-imide / ; R is (σΗ"5)2Νσθ, γ is 0Η20Ή2_7.
A mixture of 28.7 go of 3-amino-2,4 ,6-trliodo- Ν,Ν-diethylbenzamide and 51.6 g. of succinic anhydride was heated to 115°C. Concentrated sulfuric acid (2.5 ml.) was added, the mixture stirred for two to three minutes and then poured into 300-400 ml. of cold water with stirring. The mixture was treated with 300 ml. of 10$ sodium hydroxide and the solid product collected to give N-/J-(N,N-diethyl-carbamoyl)-2,4 ,6-triiodophenyl7succinlmide, m.p. 211-2l8°C.
Example 36 3 ' -(N,N-Dlethylcarbamoyl)-2' , 4 ' ,6 ' -trliodosucclnanillc Acid /β; R is (G2H5)2 C0, R' and R" are H, Y;is CH2CH2_7 was prepared by treating a solution of N-, 3-( N,N-diethylcarbam-oyl)-2,4 ,6-trliodophenyl "succinimide in acetone with an excess of 10$ aqueous sodium hydroxide. The solution was stirred for one hour at room temperature, concentrated to remove the solvent and acidified with dilute hydrochloric acid. The product was collected, purified by conversion to its sodium salt and reacidification, and re'crystallized from ethyl acetate to give 3 ' -(N,N-diethylcarbamoyl)-2' , 4 ' ,6 ' -triiodosuccinanilic acid, colorless prisms, m.p. 202-205°C. (dec).
Example 37 3 ' -(N,N-Diethylcarbamoyl)-2' ,4 ' ,6 ' -trliodo-N-methylsuccln-anlllc Acid /B; R is (C2H"5)2NC0, R' is CH3, R" is H, Y1 is CH2CH2_7 was prepared by methylation of 3 ' -( N,N-diethyl-carbamoyl) -2' ,4 ' , 6 ' -triiodosuccinanilic acid with dimethyl sulfate In potassium hydroxide according to the procedure of Example 26. The product was obtained as a colorless amorphous solid both in the free acid and sodium salt forms.
Example 38 3' -(N,N-Diethylcarbamoyl)-2' ,4' ,6' -triiodo-N-ethylsuccln-anlllc Acid /B; R is (C2H5)2NC0, R1 is C2H5, R" is H, Y* is CH2CH2_7 was prepared by alkylation of 3' -( N,N-diethyl-carbamoyl ) -2 ' ,4' ,6 · -trliodosucclnanilic acid with diethyl sulfate and potassium hydroxide in acetone solution. The product was obtained in the sodium salt form as a colorless amorphous solid from. methanol -ether.
Example 39 a ) 3-Amino-2,4,6-trllodo -N,N-dimethylbenzamlde .
A mixture of 69.88 g. of 3-amino-2,4,6-triiodo-benzoyl chloride and 300 ml. of dimethylamlne was stirred for 15 minutes. Sodium hydroxide (50 ml. 35$) and 50 ml. of water was added, and the reaction mixture was stirred for one hour. The solid product was collected and purified by conversion to its sodium salt form and reconversion to the free acid. The latter was recrystallized from ethanol to give 3-amino-2,4,6-trilodo-N,N-dimethylbenzamide, pale yellow solid, m.p. l65-l67°c. b) 31 -(N,N-Dimethylcarbamoyl) -2' ,4' ,6' -trliodoglutaranlllc Acid /B; R is (CH3)2NC0, R' and R" are H, Y IS CH2CH2CH"2_7" was prepared by reacting 3-amino-2,4,6-triiodo-N,N-dimethyl-benzamide with glutaric anhydride, according to the procedure of Example 35b> and hydrolyzing the resulting N-/3-(N,N-dimethylcarbamoyl ) -2,4,6-triiodophenyl7"glutarimide /A"; R is (CH3)2NC0, Y is CHgd^CHg^. The 3' -( N,N-dimethyl-carbamoyl) -2' ,4' ,6' -triiodo-glutaranilic acid was obtained as a colorless solid, m.p. 189-192°C.
Example 40 3 ' -(N,N-Dimethylcarbamoyl)-2' ,4' ,6' -triiodo-N-ethylglutar-anilic acid /B; R is (CH3)2NC0, R« is ^K^, R" is H, Υ' is CH2CH2CH2_r was prepared by interacting 3'-(N,N-dimethylcarbamoyl ) -2' ,4' ,6' -triiodoglutaranilic acid (Example 39b ) with diethyl sulfate according to the procedure of Example 26 , and was obtained in the form of colorless crystals, m.p. l80-l82°c. when recrystallized from ethyl acetate.
Example 4l glutaranilic acid /B; R is (CH^ CO, R' is CH3, R" is H, Y'IS CH2CH2CH2_" was prepared by interacting 3'-(N,N-dimethylcarbamoyl)-2' , 4 ' ,6 ' -triiodoglutaranilic acid (Example 39b ) with dimethyl sulfate according to the procedure of Example 26, and was obtained in the form of colorless crystals, m.p. 205-208°C. when recrystallized from ethyl acetate. The sodium salt form had m.p. I91 -200°C.
Example 42 3 ' -(N- ethylcarbamoyl)-2' ,4 ' ,6 ' -triiodo-N-methylglutar-anlllc acid /B; R is CH3 HC0, R' is CH3, R" is H, Y* is CH2CH CH2_7" was prepared by interacting 3 ' -(N-methyl-carbamoyl ) -2 ' , 4 ' , 6 ' -triiodoglutaranilic acid (Example 21b) with dimethyl sulfate according to the procedure of Example 26, and was obtained in the form of a colorless solid, m.p. l64-l68°C. when recrystallized from ethyl acetate.
CH3CONHCH2i Q is CYi^_7 was prepared by decarboxylation of 3-acetamido-5-acetamidomethyl-2,4,6-triiodo-benzoic acid according to the method of Example 1(b), and was obtained in the form of a colorless solid, m.p. 287-288°Co when recrystallized from acetic acid, b) N-/2~, ,6-Triiodo-3-(acetylaminomethyl)phenylr-glutarlmlde /Aj R is CH3CONHCH2, Y is CH2CH2CH _7" was prepared by interacting iX-acetamido-21 ,4' ,6' -triiodo-m-acetotoluidide with glutaric anhydride according to the method of Example 2(a), and was obtained in the form of a colorless solid, m.p. 128-134°C. when recrystallized from isopropyl alcohol.
Example 44 a) N-/2",4,6-Triiodo-3-( acetylaminomethyl ) - -carboxy-phenyl/glutarimlde ^C; R is CH3C0NHCH2, Y is CH2CH2CH2Jr was prepared by interacting 3-acetamldo-5-acetamldomethyl-2,4,6-triiodobenzoic acid with glutaric anhydride according to the method of Example 2(a), and was obtained in the form of a colorless solid, m.p. 256-258°c. when re-crystallized from acetic acid. b) N-/2^,4,6-Trllodo-3-( acetylamlnomethyl) -5-carboxy-phenylZglutaranllic acid /D; R is CH^CONHCH-p, R» and R" are H, Y1 is CH2CH2CH2_7" was prepared by hydrolysis of N-/2,4,6-triiodo-3-( acetylamlnomethyl) -5-carboxyphenyl7-glutarimide with dilute sodium hydroxide, and was obtained in the form of a colorless solid, m.p. 234-239°C. when recrystallized from acetic acid. c ) N-^2",4,6-Trllodo-3-( acetylamlnomethyl )phenyl/glutar-anlllc acid /B; R is CH3C0NHCH2, R' and R" are H, Y'is CH2CH2CH2./was prepared by decarboxylation of N-/2~,4,6- trliodo-3-( acetylaminomethyl) -5 -carboxyphenyl/glutar-anllic acid according to the method of Example 1 (b), and was obtained in the form of a colorless solid, m.p. 254 -259°C. when recrystallized from aqueous dimethyl -formamide. The same substance can be prepared by hydrolysis of acetylaminomethyl ) -phenylglutarimide (Example 43b ) with warm dilute sodium hydroxide.
Example 45 N-/2 , 4 , 6-Trilodo -3-( acetylaminomethyl ) phenylZ-N-methyl -glutaranilic acid ¾ R is CH3C0NHCH2, R' is CH3, R" is H, Y' is CH2CH2GH2_" was prepared by interacting N-/2 ,4 , 6-triiodo-3-( acetylaminomethyl )phenyl7glutaranilic acid (Example 44c ) with dimethyl sulfate according to the procedure of Example 26, and was obtained in the form of a colorless solid, m.p. l67 -175°c„ when recrystallized from ethyl acetate.
Example 46 a) Methyl 3 ' -carboxy-2 1 , 4 ' ,6' -triiodo- ' -( N-methylacet-atnldo)-azelanllate /D,« R is CH3CO (CH"3), R1 is H, R" A mixture of 100 g. of azelalc acid monomethyl ester and 500 ml. of thionyl chloride was refluxed for one hour. The excess thionyl chloride was removed by distillation and the last traces removed by adding benzene and evaporating the solvent. A solution of 260 g. of 3-amino-5-acetamido-2 , 4,6-triiodobenzoic acid in 35 Ο ml. of dioxane was then added to the resulting acid chloride of azelaic acid monomethyl ester, and then removed by distillation and the residual product recrystallized from acetic acid to give methyl 3 ' -carboxy-2 · , ' ,6 · -triiodo- ' -( N-methylacetamido )azel-anilate, as colorless needles, m.p. 198-203°C By replacing the azelaic acid monomethyl ester by a molar equivalent amount of oxalic acid monomethyl ester or malonic acid monomethyl ester, there can be obtained, respectively, methyl 3 ' -carboxy-2' ,4 ' ,6 ' -triiodo-5 ' -( N-methylacetamido )oxanilate / "; R is CH^CON-(CH3), R' is H, R" is CH3, Y» is single bond/, or methyl 3 ' -carboxy-2' , 4 ' ,6 ' -triiodo-51 -( N-methylacetamido )-malonanilate /D R is CH3CO (CH3), R' is H, R" is CE^, Y' is -CH2-7". b) 3 ' -Carboxy-2 ' ,4 ' ,6 ' -trllodo-5 ' -(N-methylacetamldo)-azelanlllc acid /D; R is CH3CON(CH3), R' and R" are H, Y' is -(CH2 )7 7.
A mixture of 136.5 g. of methyl 3'-carboxy-2' ,4 ' ,6 ' -trllodo-51 -( N-methylacetamido )azelanilate and l80 ml. of water was treated with 10$ aqueous sodium hydroxide (about l40 ml.), added dropwise until solution was complete. The mixture was heated on a steam bath for ten minutes, 18 ml. more of 10$ sodium hydroxide was added, and the mixture heated one hour longer. The reaction mixture was cooled, acidified with 3$ hydro-chloric acid, and the solid product collected, washed with water, dried and recrystallized from acetic acid to give 3 ' -carboxy-2' ,4' , 6 ' -triiodo-5 ·-( -methylacetamido )azelanilic acid as a colorless solid, m.p. 205-208°C.
By replacing the methyl 3 ' -carbox -2 ' , ' , 6 1 - triiodo-5 ' -(N-methylacetamido)azelanilate by a molar equivalent amount of methyl 3' -carboxy-21 , ' ,6' -tri-iodo-51 -(N-methylacetamido)oxanilate or methyl 3'-carboxy-2' ,4' ,6' -triiodo-5' -( -methylacetamido)malon-anilate there can be obtained, respectively, 3'-carboxy-2' ,4' ,6' -triiodo-51 -(N-methylacetamido)oxanillc acid /D; R is CH3CON(CH3), R1 and R". are H, Y' is single bond/" or 3' -carboxy-2' ,4' ,6" -triiodo-5' -(N-methylacet-amido)malonanilic acid /Dj R is R' and R" are H, Y' is -CH2-7. c ) 2' ,4' ,6' -Trllodo-31 -(N-methylacetamldo)azelanillc acid /B; R is CH3CON(CH3), R1 and R" are H, Y1 is -(0Κ2)γζΖ was prepared by decarboxylation of 3'-carboxy-2' ,4' ,6' -triiodo-5' -(N-methylacetamido)azelanilic acid according to the method of Example 1 (b), and was obtained in the form of a colorless solid, m.p„ 153-l60°C.
By replacing the 3' -carboxy-21 ,4' ,6' -triiodo-5' -(N-methylacetamido)azelanilic acid by a molar equivalent amount of 3' -carboxy-2' ,4' ,6' -trliodo-5* -(N-methyl-acetamido)oxanilic acid and 3' -carboxy-2' ,4' ,6' -trliodo- ' -(N-methylacetamido)malonanilic acid there can be obtained, respectively, 2' ,4' ,6' -triiodo-31 -(N-methyl-acetamido)oxanilic acid /Bj R is , R' and R" are H, Y' is single bond or 2' ,4' ,6' -triiodo-3' -(N-methylacetamido)malonanllic acid /Bj R is CH^CONR^ CH3) , R« and R" are H, Y' is -CE2^Z.
Alternatively, 2' ,4 » ,6 · -triiodo-3' -(N-methyl-acetamido)azelanilic acid can be prepared by interacting 3-amino-2,4,6-triiodo-N-methylacetanilide /K; R° is acid raonomethyl ester, and subjecting to mild alkaline hydrolysis the resulting methyl 2' , * ,6' -triiodo-51 - (N-methylacetamldo)azelanilate /B; R is R' is H, R" is CH3, Y» is -(0Η2)7- Example 7 3-Glutarlmldo-2,4,6-trliodobenzamlde /A; R is HgNCO, y is ΟΉ^Οϋ^Οϋ^^^Ί, 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 removed by boiling down with benzene. The residue of acid chloride was treated with 200 ml. of concentrated ammonium hydroxide and 200 ml. of water. The reaction mixture was stirred for two hours. The solid product was collected, dried and recrystallized from dimethylformamide with addition of a little acetic acid, and then from dioxane to give 3-glutarlmido-2,4,6-trliodobenzamlde, colorless solid, m.p. 268-275°C Example 48 a) 3-Acetamido-2,4,6-1rliodo-N-methy1benzamide /iC; R° is CR3NHCO, Q is was prepared by decarboxylation of 3-(N-methylcarbamyl)-5-acetamido-2,4,6-triiodobenzoic acid according to the method of Example 1 (b), and was obtained in the form of a colorless solid, m.p. 290-292°C. b) ,4,6-Trilodo-N-methyl-3-( succinimido)benzamide /A; R is CH3NHCO, Y is CH2CH2_7 was prepared by interacting 3-acetamido-2,4,6-trilodo-N-methylbenzamide with succinic anhydride according to the procedure of Example 2(a), and was ob aine 277-28 °C. when recrystallized from methanol.
Example 49 a) 2,4,6-Triiodo-N-methyl-m-benzenediacetamide ^ft; R°.is was prepared by decarboxylation of 3-acetamido-5-(N-methylacetamido) -2,4,6-triiodobenzolc acid according to the procedure of Example 1(b), and was obtained in the form of a colorless solid, m.p. l60°C. b) 3- aleimido-2,4,6-trllodo-N-methylacetanlllde /A; R is can be prepared by interacting 2,4,6-triiodo-N-methyl-m-benzenediacetamide with malelc anhydride according to the procedure of Example 2(a).
Claims (1)
1. Compounds of formula wherein Z is wherein Y is a wherein 2 or 3 carbon atoms separate the carbonyl or a propylene group wherein the atom is replaced by SO or is a single bond or an alkylene bridge having from one to eight carbon atoms or such a group interrupted by from one to three members selected from SO and said when more than being separated by at least two carbon R is or is or and is hydrogen or or a salt form A compound according to claim 1 of Formula I wherein Z is R is 31 862 and is A compound according to claim 1 of Formula I wherein Z is R is and is glutaranilic succinanilic lacetamido glutaranilic A process of preparing a compound of Formula I as defined in claim characterized by decarboxylating a compound of the formula wherein R and Z are as defined in claim 1 or a salt form for oral or intravenous containing compounds of the Formula I as defined For Applicants AND insufficientOCRQuality
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71558368A | 1968-03-25 | 1968-03-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL31862A0 IL31862A0 (en) | 1969-05-28 |
| IL31862A true IL31862A (en) | 1973-08-29 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL31862A IL31862A (en) | 1968-03-25 | 1969-03-20 | Cyclic amides and anilic acids of aniline derivatives |
Country Status (11)
| Country | Link |
|---|---|
| BE (1) | BE730385A (en) |
| BR (1) | BR6907386D0 (en) |
| CA (1) | CA946846A (en) |
| CH (1) | CH504412A (en) |
| DE (1) | DE1915196A1 (en) |
| FR (1) | FR2004680A1 (en) |
| GB (1) | GB1228521A (en) |
| IL (1) | IL31862A (en) |
| IT (1) | IT974525B (en) |
| NL (1) | NL6904602A (en) |
| NO (1) | NO124252B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0391847A1 (en) * | 1989-04-04 | 1990-10-10 | Ciba-Geigy Ag | 1-Phenyl-piperidine-2,4-dione with herbicidal activity |
-
1969
- 1969-03-18 CA CA046,086A patent/CA946846A/en not_active Expired
- 1969-03-19 GB GB1228521D patent/GB1228521A/en not_active Expired
- 1969-03-20 IL IL31862A patent/IL31862A/en unknown
- 1969-03-20 NO NO691170A patent/NO124252B/no unknown
- 1969-03-21 BR BR207386/69A patent/BR6907386D0/en unknown
- 1969-03-24 IT IT35931/69A patent/IT974525B/en active
- 1969-03-25 BE BE730385D patent/BE730385A/xx unknown
- 1969-03-25 CH CH452369A patent/CH504412A/en not_active IP Right Cessation
- 1969-03-25 FR FR6908707A patent/FR2004680A1/fr not_active Withdrawn
- 1969-03-25 DE DE19691915196 patent/DE1915196A1/en active Pending
- 1969-03-25 NL NL6904602A patent/NL6904602A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA946846A (en) | 1974-05-07 |
| CH504412A (en) | 1971-03-15 |
| NL6904602A (en) | 1969-09-29 |
| GB1228521A (en) | 1971-04-15 |
| FR2004680A1 (en) | 1969-11-28 |
| IL31862A0 (en) | 1969-05-28 |
| BR6907386D0 (en) | 1973-05-31 |
| BE730385A (en) | 1969-09-25 |
| NO124252B (en) | 1972-03-27 |
| DE1915196A1 (en) | 1969-11-20 |
| IT974525B (en) | 1974-07-10 |
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