US3324140A - Pyridoxolyl-hydrocarbon and substituted hydrocarbon disulfides - Google Patents

Pyridoxolyl-hydrocarbon and substituted hydrocarbon disulfides Download PDF

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US3324140A
US3324140A US409950A US40995064A US3324140A US 3324140 A US3324140 A US 3324140A US 409950 A US409950 A US 409950A US 40995064 A US40995064 A US 40995064A US 3324140 A US3324140 A US 3324140A
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disulfide
methyl
pyridoxolyl
acid
hydroxy
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Schorre Gustav
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Merck KGaA
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E Merck AG
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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
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal

Definitions

  • the principal object of this invention is to provide novel pyridyl disulfides and their acid addition salts.
  • Another object is to provide processes for their production, including the discovery of novel intermediates therefor.
  • Still another aspect of this invention is to provide novel pharmaceutical compositions and therapeutic methods, based on the novel compounds of this invention.
  • R represents: alkyl which can, if desired, be substituted; alkenyl; alkynyl; aryl or aralkyl, either of which can, if desired, be substituted.
  • the new compounds are derived from vitamin B and its acyl derivatives, respectively.
  • acyl residues R and R set forth in Formula I are preferably of saturated or unsaturated aliphatic monocarboxylic acids of up to 18 carbon atoms, particularly preferred residues being derived from the following acids: acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic-acid, pelargonic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, acrylic acid, crotonic acid, oleic acid, elaidie acid, undecylenic acid, linoleic acid, and linoleneic acid.
  • R can represent a straight-chain or branched, substituted or unsubstituted alkyl residue having generally no more than 20 carbon atoms.
  • Suitable alkyl residues are particularly the lower alkyls, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, amyl, and isoamyl, and further those having a longer chain, such as hexyl, heptyl, octyl, nonyl, cetyl, undecyl, dodecyl, or lauryl.
  • the alkyl group can be monoor poly-substituted. Preferably, only such alkyl groups are substituted which do not contain more than 6 carbon atoms in the alkyl chain.
  • Preferred substituents are halogens, such as, for example, fluorine, chlorine, or bromine; hydroxyl; lower alkoxy groups of up to about 5 carbon atoms, particularly methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and isobutoxy.
  • amino group wherein one or both hydrogen atoms can likewise be substituted by lower alkyl groups (the alkyl groups being the same or different) having up to about 5 carbon atoms; these latter alkyl groups, in turn, can also be joined with one another, if desired, via a further hetero-atom, particularly a nitrogen or an oxygen atom.
  • impor- .tance are the 2-aminoethyl-, 3-amino-propyl-, 3-amino-2'- methyl-propyl-, and 4-aminobutyl-residues, as well as the corresponding N-methyl-, N-ethyl-, N-propyl-, N-butyl-, N,N-dimethyl-, N,N-diethyl-, N-methyl-N-ethyl-, N,N-dipropyl-, N,N-di-tert.butyl-, and piperidino-derivatives.
  • substituents for the substituted alkyls are, for example, aralk-oxy groups wherein the aryl is preferably a hydrocarbon of 6 to 10 carbon atoms and the alkoxy is a lower alkoxy, particularly the benzyloxy residue, as Well as acyloxy groups of aliphatic or aromatic carboxylic acids of up to 9 carbon atoms, preferably monocarboxylic acids, especially acetoxy, n-propanoyloxy, isopropanoyloxy, n-butanoyloxy, isobutanoyloxy, tert.
  • butanoyloXy and pentanoyloxy, and also benzoyloxy, toluyloxy, carbobenzoxy, or cinnamoyloxy.
  • the alkyl residue R can also be substituted by a free or by an esterified carboxyl group of up to 9 carbon atoms, i.e., for example by carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, also benzyloxycarbonyl, and toloxycarbonyl.
  • the alkyl group can also be substituted by acid amide residues, CONH the hydrogen atoms of the amino group can also be replaced, in this connection, by lower alkyl residues which can also be connected with one another, if desired via another hetero-atom.
  • CONH the amides of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.
  • the substituent' R of Formula I can also represent an alkenyl residue of generally not more than about 12 carbon atoms.
  • This alkenyl residue can contain one or several double bonds, but generally no more than two.
  • Preferred alkenyl residues are, for example, vinyl, allyl, butenyl, heptenyl, undecylene and 'butadienyl, hexadienyl, and heptadienyl.
  • Alkynyl residues (R in Formula I) usually contain not more than 3 carbon atoms, and are preferably ethynyl and propa-rgyl.
  • R can represent an aryl residue of not more than 2 rings with 5 to 6 carbon atoms per ring.
  • Hydrocarbon aryl such as phenyl or naphthyl
  • aryl nuclei can be employed. Particularly suitable are the benzyl and the phenethyl residues. If the aromatic nucleus, particularly the phenyl residue, is mono or poly- (e.g.
  • the substituents are preferably halogens, such as fluorine, chlorine, or bromine; or lower alkyl or alkoxy groups of up to 5 carbon atoms, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl and amyl, and the corresponding alkoxy groups; or hydroxyl, nitro, arnino, monoand dialkylamino, preferably lower alkylamino groups, respectively.
  • halogens such as fluorine, chlorine, or bromine
  • lower alkyl or alkoxy groups of up to 5 carbon atoms especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl and amyl, and the corresponding alkoxy groups; or hydroxyl, nitro, arnino, monoand dialkylamino, preferably lower alkylamin
  • substituted aryl residues are set forth as preferred examples: o-, m-, or p-chlorophenyl; o-, m-, or p-bromophenyl; tolyl; xylyl; p-methoxyphenyl; 0-, rn-, or p-ethoxyphenyl; propoxyphenyl; hydroxyphenyl; nitrophenyl; aminophenyl; aminotolyl; 2-amino-3-hydroxyphenyl; 2-methoXy-3-aminophenyl; N-methyl-aminophenyl; N-ethyl-aminophenyl; N-rnethyl-N-butyl-aminophenyl; N,N-di-tert. butyl-aminophenyl; 2-methyl-4-chlorophenyl; and 2,4-dimethyl-phenyl.
  • n 1 or 2.
  • R represents hydrogen, ammonium, or an equivalent of .a
  • metallic atom preferably an alkali metal such as sodium,
  • Y represents SO R %O R SOR Br, Cl, or
  • R SR (V) wherein: R and R have the previously indicated meanings.
  • a compound of Formula I wherein R and/or R represent hydrogen can be treated with an acylating agent; or a compound of Formula I wherein R and/or R represent acyl can be treated with a saponification agent.
  • a compound of Formula I can be converted, in a conventional manner, to its acid addition salt; or similarly the base compound can be liberated from an acid addition salt if the latter is obtained as a reactio product.
  • the reaction between a 3-mercaptomethyl-pyridine compound of Formula II and such sulfur-containing compounds of Formula III wherein Y represents SO R or SOR is suitably carried out in approximately neutral solution.
  • the yields of the desired end products generally decrease substantially in strongly acidic or strongly alkaline solution.
  • polar solvents particularly alcohols, such as methanol, ethanol, propanol, and isopropanol.
  • the reaction can be conducted in the absolute alcohols, as well as in aqueous alcoholic solution.
  • the reaction temperatures are generally between 0 and about C.; preferably, however, room temperature is employed. Normally, 'it is suflicient to allow the reaction mixture to stand for a few hours.
  • solvents are likewise used, such as ether, dioxane, di
  • reaction mixture be allowed to stand for a longer period of time, for example overnight, at room temperature; however, it is also possible to heat the reaction mixture to increase the rate of reaction.
  • a sulfur-containing pyridine derivative of Formula IV, wherein Z represents SO R is reacted with a mercaptan derivative of Formula V
  • the pH value of the reaction mixture is advantageously held above 7, preferably between 7 and 11.
  • aqueous solutions of sodium, potassium, or ammonium hydroxide are added in order to obtain these pH values.
  • any conventional acylating method can be utilized. Particularly advantageous is the reaction with the corresponding acid anhydrides and/or acid chlorides of the above-mentioned acids in the presence of alkaline agents, particularly pyridine.
  • the acid chlorides are preferably employed.
  • the isolation of the reaction products is also done in a conventional manner, for example, by precipitating with the addition of a miscible non-solvent; by evaporating the solvent; by extraction; or by chromatographic methods.
  • the conversion of the compounds of Formula I into their acid addition salts is likewise conventional, for example, by reaction with the corresponding acid in an inert solvent.
  • all acids can be employed which yield physiologically compatible acid addition salts.
  • the following acids are contemplated: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, and alkylsulfonic acids, such as p-toluenesulfonic acid.
  • the starting compounds of Formula II are known from US. Patent No. 3,010,966 (e.g. claim 2) or they can be produced therefrom by conventional reaction with an acylating agent (R and/r R representing acyl) or with an alkali metal or ammonium hydroxide (R representing an alkali metal or ammonium equivalent).
  • R and/r R representing acyl an acylating agent
  • R representing an alkali metal or ammonium hydroxide R representing an alkali metal or ammonium equivalent
  • the thiosulfinic acid derivatives of Formula III (Y: SOR can be produced, in a known manner, by oxidation of the corresponding disul-fides (-R SSR with perbenzoic acid.
  • the t'hiosulfonic acid derivatives of Formula III (Y: SO R are formed by heating the correspondingly substituted sulfinic acids (R SO H) in water, the thiosulfonates being precipitated by disproportionation according to the following recation:
  • the sulfenyl thiocyanates of Formula 111 which are further compounds usable as starting materials can be obtained, as mentioned above, by reacting rhodanates with. the correspondingly substituted mercaptan derivatives.
  • novel compounds of Formula I and their acid addition slats can be employed as therapeutic drugs and can be particularly utilized in cases wherein vitamin B therapy is indicated, more particularly for the treatment of cerebral malfunctions.
  • the novel compounds exhibit a higher lipoid solubility. For this reason, they penetrate the cellular membranes more readily and thus are better absorbed by the lipoid-rich nerve tissue.
  • Carrier substances can be such organic or inorganic substances which are suitable for parenteral or enteral application and which do not react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, gelatine, lactose, amylose, magnesium sterate, talcum, Vaseline, cholesterol, etc.
  • solutions are especially used, preferably oily or aqueous solutions, as well as suspensions or emulsions which, if desired, are used in sterilized form or mixed with auxiliary agents, such as preservatives, stabilizers, or wetting agents, or with salts for influencing the osmotic pressure, or with buffer substances.
  • auxiliary agents such as preservatives, stabilizers, or wetting agents, or with salts for influencing the osmotic pressure, or with buffer substances.
  • tablets or dragees are particularly suitable.
  • a unit dosage of a compound of this invention comprises on the order of 10 to 500 mg. preferably 50 to mg.
  • Example 1 (a) 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-5- mercaptomethyl-pyridine are dissolved in a mixture of 15 ml. water and 25 ml. of 1 N-sodium hydroxide, and mixed with 3.5 g. butylthiosulfate Buntes salt). The reaction mixture is allowed to stand for 10 minutes at room temperature, and the obtained precipitate is removed by suction. After recrystallization from benzene, the obtained [2-methyl-3-hydroxy-4-hydroxymethyl pyridyl (5)-methyl]-n-butyldisulfide melts at 100 C. Yield: 2.2 g.
  • Example 2 (a) g. 2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-(3)-methyl-bromide are slowly added to 800 ml. acetyl chloride in an ice bath and under vigorous stirring; subsequently, the mixture is refluxed for 2 hours. The precipitated 2-methyl-3-acetoxy-4-acetoxymethylpyridyl (3)-methyl-bromide-hydrochloride is removed by suction, and subsequently dissolved in water; the aqueous solution is adjusted to a pH of 7 by means of dilute sodium hydroxide.
  • Example 3 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridine are dissolved in 40 ml. 0.5 N NaOH and mixed with 4.5 g. lauryl thiosulfate. The reaction mixture is heated for 15 minutes to 50-55 C. The precipitated [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl- 5 methyl]-lauryl-disulfide is removed by suction and re crystallized from benzene. M.P. 114-115 C. Yield: 2.8 g.
  • Example 4 8.7 g. l-propanethiosulfinic acid propyl ester are dissolved in 150 ml. methanol and mixed with a solution of 22.1 g. 2-methyl-3-hydroxy-4 hydroxymethyl-S-mercaptomethyl-pyridine-hydrochloride in 100 ml. methanol. After the mixture has been allowed to stand at room temperature for 6- hours, 50* ml. ether are added. The [2-methyl-3- hydroxy-4-hydroxymethyl-pyridyl-( 5 methyH-n-propyldisulfide-hydrochloride which precipitates is removed by suction and recrystallized from isopropyl alcohol/ether. M.P. 117-118 C. Yield: 19' g.
  • Example 5 11.9 g. isopentanethiosulfonic acid isoamyl ester are dissolved in 30 ml. absolute alcohol and mixed with a solution of 9 g. 2-methyl-3-hydroxy-4-hydroxymethyl-S- mercaptornethyl-pyridine in 50 ml. absolute alchol. After the mixture has been allowed to stand for 12 hours at room temperature, it is evaporated to dryness under vacuurn. The residue is mixed with 2 N-aqueous solution of sodium bicarbonate. The [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl- (5 -methyl] -isoamyl-disulfide which separates is removed by suction and recrystallized from benzene. M.P. 114-115 C. Yield: 7.4 g.
  • Example 6 22.5 g. lead rhodanate are suspended in 150 ml. ab solute ether and mixed with 3 ml. bromine at 5-10 C. Once the mixture loses its color, the precipitated lead bromide is removed by suction. A solution of 5.5 g. thiophenol in 100 ml. dimethyl formamide is slowly added,
  • Example 7 9.2 g. 2-methyl-3-hydroxy-4-hydroxymethyI-S-mercaptomethyl-pyridine are dissolved in 100 ml. dimethyl formamide. The solution is mixed with 4.8 g. o-nitrobenzene sulfenylchloride in 50 ml. dimethyl formamide. The reaction mixture is stirred for 2 hours at room temperature and is then allowed to stand overnight. The obtained precipitate is removed by suction, and the filtrate is concentrated to about /s its volume and mixed with 500 ml. water. The precipitating substance is removed by suction, washed with 20ml. 1 N-hydrohloric acid, and recrystallized from methanol/ether. The obtained [2-methyl-3-hydroxy-4-hydroxymethyl pyridyl-(5)-methyl]-onitrophenyl-disulfide melts at 163 C. Yield: 1.3 g.
  • Example 8 Analogously to Example 1, the following compoundsare obtained by reaction of 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridine with the corresponding alkylthio sulfates (a) [2-methyl-3 -hydroxy-4-hydroxyme thyl-pyridyl- (5 hydrochloride: M.P. 97 C. (isopropanol/ether).
  • Example 9 Analogously to the method described in Example 1,
  • Example 10 Analogously to the method set forth in Example 1, 2.75 g. 2-methyl-3-hydroxy 4 hydroxymethyl-S-mercaptornethyl-pyridine are reacted with phenylthiosulfate to form [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl- (5)-methyl]-phenyl-disulfide.
  • Example 11 Analogously to the method described in Example 1, 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-5-rnercaptomethyl-pyridine are reacted with 4'-acetoxy-butylthiosulfate to yield [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-(5)-methyl]-4'-acetoxybutyl-disulfide.
  • Example 12 Analogously to the method mentioned in Example 1, 2.75 g. 2-methyl-3-hydroxy-4-hydroxymethyl-S-mercaptomethyl-pyridine are reacted with fl-et'hoxy-carbonylethylthiosulfate to yield [2 methyl 3.- hydroxy-4-hydroxymethyl pyridyl (5 methyl] J8 ethoxy-carbonylethyldisulfide.
  • Example 13 Analogously to the method described in Example 1, 5.4 g. 2-methyl-3-hydroxy 4 hydroxymethyl-S-mercaptomethylpyridine are reacted. with 11.6 g. p-chlorophenoxyethylthiosulfate to form ['2-methyl-3-hydroxy-4-hydroxymethylpyridyl (5) methyl] p chlorophenoxyethyldisulfide. M.P. 145-146" C. (methanol).
  • Example 14 Analogously to the method set forth in Example 1, 5. 4 g. 2-methyl 3 hydroxy 4 hydroxymethyl-S-mercaptomethylpyridine are reacted with 8.78 g. benzoyl-methylt-hiosulfate to produce [2-methyl-3-hydroxy-4-hydroxymethyl pyridyl (5) methyl]-benzoylmethyl-disulfide. M.P. 142 C. (190 C. decomposition)-(methanol).
  • M.P. 156 -157" C. (methanol).
  • Example 16 Analogously to the method set forth in Example 1, 5.4 g. 2 methyl 3 hydroxy 4-hydroxymethyl- 5- mercaptomethylpyridine are reacted with 9.6 g. p-xylylt-hiosulfate toproduce [2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-(5)-methyl]-p-xylyl-disulfide. M.P. 135- 136 C. (methanol).
  • Example 17 Analogously to the method mentioned in Example 1, 5.4 g. 2 methyl 3 hydroxy 4 hydroxymethyl-S- mercaptomethylpyridine are reacted with 8 g. B-naphthylmethyl-thiosulfate to form [2 methyl 3 hydroxy-4- hydroxymethyl pyridyl (5)-methyl]-B-naphthylmethyldisulfide.
  • Example 18 Analogously to Example 1, the following compounds are obtained by reaction, of 2 methyl-3 -hydroxy-4- hydroxymethyl-5-mercaptomethyl-pyridine with the corresponding thiosulfates:
  • Pyridoxolyl-methyl-disulfide Pyridoxolyl-vinyl-disulfide Pyridoxolyl-crotyl-disulfide Pyridoxolyl-undecylenyl-disulfide Pyridoxolyl-ethynyl-disulfide Pyridoxolyl-propargyl-disulfide Pyridoxolyl-naphthyl-disulfide Pyridoxolyl-phenethyl-disulfide Pyridoxolyl-4-methoxybutyl-disulfide Pyrid0xolyl-4-ethoxybutyl-disulfide Pyridoxolyl-4-butoxybutyl-disulfide Pyridoxolyl-4-benzyloxybutyl-disulfide Pyridoxolyl-4-propoxybutyl-disulfide
  • composition of this invention For a specific preferred embodiment of a pharmaceutical composition of this invention, the following is presented:
  • Each tablet contains- Mg. Pyridoxolyl-allyl-disulfide Lactose 200 Corn-starch 35 Magnesium stearate S Talc 20 II.
  • Coated tablets The core contains Pyridoxolylether-disulfide 150 Lactose 100 Potato starch 50 Gelatine 4 The core is coated according to standard techniques with a mixture of sugar and arabic gum to make up a coated tablet with a total weight of 500 mg.
  • Hard gelatine capsules A mixture of- Mg. Pyridoxolyl 2 methyl 3,6 dichlorophenyldisulfide Lactose 50 Talc 15 Vanillin 1 is filled into hard gelatine capsules having 3 mm. in diameter.
  • R and R are each selected from the group consisting of hydrogen and acyl of an aliphatic hydrocarbon carboxylic acid of not more than 18 carbon atoms, and
  • R is selected from the group consisting of (a) unsubstituted alkyl of not more than 20 carbon atoms; (b) alkyl of not more than 20 carbon atoms substituted by at least one member selected from the group consisting of halogen, hydroxyl, lower alkoxy, amino, mono-(lower a1kyl)-amiuo, di-(lower alkyl)-amino, piperidino, morpholino, piperazino and piperazino substituted by lower alkyl, aralkoxy wherein the aryl portion is a hydrocarbon of 6 to carbon atoms and the alkoxy portion is a lower alkoxy, acyloxy of a hydrocarbon monocarboxylic acid of not more than 9 carbon atoms, carbobenzoxy, carboxyl, esterified carboXyl of not more than 9 carbon atoms wherein the alcohol portion is a hydrocarbon alcohol of not more than 8 carbon atoms, unsubstituted -CONH CONH

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US409950A 1963-11-09 1964-11-09 Pyridoxolyl-hydrocarbon and substituted hydrocarbon disulfides Expired - Lifetime US3324140A (en)

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BE (1) BE655454A (fr)
BR (1) BR6464084D0 (fr)
CH (1) CH463502A (fr)
DE (1) DE1470054A1 (fr)
DK (1) DK111750B (fr)
ES (1) ES305791A1 (fr)
FR (1) FR4036M (fr)
GB (1) GB1032377A (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5137877A (en) * 1990-05-14 1992-08-11 Bristol-Myers Squibb Bifunctional linking compounds, conjugates and methods for their production
US20050232928A1 (en) * 2004-02-12 2005-10-20 Iwao Ojima Drug conjugates

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US3010966A (en) * 1958-03-21 1961-11-28 Merck Ag E Derivatives of vitamin b6
US3039930A (en) * 1960-04-06 1962-06-19 Irwin Neisler And Co Pyridyl carbamyl lower alkane derivatives: analgesic process

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US3010966A (en) * 1958-03-21 1961-11-28 Merck Ag E Derivatives of vitamin b6
US3039930A (en) * 1960-04-06 1962-06-19 Irwin Neisler And Co Pyridyl carbamyl lower alkane derivatives: analgesic process

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5137877A (en) * 1990-05-14 1992-08-11 Bristol-Myers Squibb Bifunctional linking compounds, conjugates and methods for their production
US20050232928A1 (en) * 2004-02-12 2005-10-20 Iwao Ojima Drug conjugates
US7282590B2 (en) 2004-02-12 2007-10-16 The Research Foundation Of State University Of New York Drug conjugates
US20080139815A1 (en) * 2004-02-12 2008-06-12 Iwao Ojima Drug conjugates
US7847119B2 (en) 2004-02-12 2010-12-07 The Research Foundation Of State University Of New York Drug conjugates

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CH463502A (de) 1968-10-15
SE315894B (fr) 1969-10-13
NL146159B (nl) 1975-06-16
IL22280A (en) 1968-12-26
BE655454A (fr) 1965-05-10
BR6464084D0 (pt) 1973-07-26
FR4036M (fr) 1966-03-28
DE1470054A1 (de) 1969-05-29
ES305791A1 (es) 1965-04-16
NL6412891A (fr) 1965-05-10
DK111750B (da) 1968-10-07

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