US2819997A - Quaternary salt derivatives of harman - Google Patents

Quaternary salt derivatives of harman Download PDF

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US2819997A
US2819997A US2819997DA US2819997A US 2819997 A US2819997 A US 2819997A US 2819997D A US2819997D A US 2819997DA US 2819997 A US2819997 A US 2819997A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • This invention is concerned with a unique group of substituted ammonium salts useful as therapeutic agents.
  • they are monosalts and are derivatives of barman and 1,2,3,4-tetrahydroharman. They have the unique property of causing a therapeutically useful lowering of the blood pressure of an animal when administered thereto.
  • R is either a lower hydrocarbonoxy group containing up to about six carbon atoms or it is the --NHCH CH NL group wherein L is a lower alkyl group containing up to about three carbon atoms such as methyl, ethyl or propyl.
  • L is a lower alkyl group containing up to about three carbon atoms such as methyl, ethyl or propyl.
  • lower hydrocarbonoxy group is meant groups such as the methoxy group, the ethoxy group, the butoxy group, the isobutoxy group and the hexoxy group.
  • hydrocarbonoxy groups are substantially saturated but they may contain some unsaturated linkages such as in the allyloxy group.
  • R is either a hydrogen atom or a lower aliphatic hydrocarbon group containing up to about six carbon atoms.
  • the lower aliphatic hydrocarbon groups are such groups as methyl, ethyl, allyl, butyl and hexyl again substantially saturated but which may contain a minor proportion of unsaturated linkages.
  • At least two to four of the substituents R R R R and R attached to the nucleus of the benzyl group in Formulas I and III are hydrogens, and the remainder are selected from the group consisting of a halogen atom, that is a fluorine, a chlorine, a bromine or an iodine atom and a lower hydrocarbonoxy group containing up to about six carbon atoms as defined above. In other words, at least one and not more than three of these groups are substituents other than hydrogen.
  • R is a hydrogen atom or a lower hydrocarbonoxy group containing up to about six carbon atoms. Some examples of such groups appear above.
  • X is a pharmacologically acceptable anion. By pharmacologically acceptable anion is meant an anion which is well tolerated in the dosages employed with the products of this invention. Examples of pharmacologically acceptable anions are chloride,'
  • quaternizing agents include aliphatic hydrocarbon halides, sulfates, and sulfonates in which the organic portion of the molecule corresponds to in the above structural formulas.
  • useful quaternizing agents include methyl iodide, dimethylsulfate, ethyl bromide, diethyl sulfate, m-methoxybenzyl bromide, 3,4-dichlorobenzyl bromide, 3,4.-dimethoxybenzyl p-toluene sulfonate, p-rnethoxybenzyl chloride, p-ethoxybenzyl methanesulfonate, etc.
  • NGHaCO2C a H Harman the nitrogen compounds employed in preparing this mono-quaternary is prepared synthetically by the cyclodehydration, decarboxylation, and dehydrogenation of N-acetyl-dl-tryptophan by methods well known in the art employing various dehydrating agents such as phosphoryl chloride, polyphosphoric acid, etc. This process is illustrated by the following equation CH2CHGO2H NHCOCH: N N H H (I) Similar processes are known which employ tryptophan or tryptamine and acetaldehyde as starting materials.
  • R R R R R and R have the same meanings as above. treated with Z-diethylaminoethyl amine which resulted in the formation of the desired amide as is illustrated in the following equation.
  • the anion X is usually either a halogen anion such as chloride, bromide or iodide or an organic sulfate or sulfonate anion such as methosulfate, ethosulfate, benzenesulfonate, or paratoluenesulfonate.
  • halogen anion such as chloride, bromide or iodide
  • organic sulfate or sulfonate anion such as methosulfate, ethosulfate, benzenesulfonate, or paratoluenesulfonate.
  • These anions may be replaced by other pharmaceutically acceptable anions such as the phosphate, succinate, citrate, or tartrate by various processes well known in the art.
  • the salt may be converted to the quaternary ammonium hydroxide by treatment with silver oxide or'by passage through a column of a strongly basic anion exchange resin on the hydroxide cycle.
  • Examples of useful ion exchange resins are Dowex 1, Dowex 2, Amberlite IRA-400 and Amberiite IRA-410. These resins are polyquaternary ammonium compounds in which the quaternary ammonium groups are attached to a styrene-divinylbenzene copolymer. Such resins are prepared for example, by chloromethylating the copolymer and then treating it with an alkyl halide such as trimethylamine or dimethylethanolamine. The soobtained solution of the substituted ammonium hydroxide corresponding to one of the salts of this invention is then neutralized with the acid corresponding to the desired anion. Alternatively, one of the above substituted mono-ammonium halides of this invention may be treated directly with the silver salt of the acid corresponding to the desired anion in an aqueous alcoholic solution. The silver halide precipitates and can be separated from the product.
  • the ability of these compounds to bring about a therapeutically useful reduction in blood pressure was determined in cats anesthetized with chloralose by canulating the carotid artery and recording the blood pressure on a kymograph after subjecting the cat to various stimuli.
  • the ganglionic blocking activity was determined by measuring the ability of these materials to abolish or decrease the response of the nictitating membrance to a standard preganglionic electrical stimulation in the superior cervical ganglion preparation of the cat as well as their ability to block the stimulating effect on the ganglia of the tetramethylammonium ion.
  • Stimulation of the ganglia in the latter fashion is manifested by a rise in blood pressure and a contraction of the nictitating membrance as well as other pharmacodynamic effects. All of the above compounds were found in these tests to be highly etfective in reducing the blood pressure. That is each was found to possess ganglionic blocking activity, or direct vasodilator activity or a combination thereof which elfected a significant reduction in the animals blood pressure.
  • Neuro-muscular blocking or curariform activity was measured in the gastrocnemius preparation of the guinea pig. The activity of these compounds was compared with that of d-tubocurarine. None was found to possess more than 4% of the activity of d-tubocurarine.
  • the valuable hypotensive agents of this invention may be administered by various routes. In the animal experiments described above, however, intravenous administration was found to be the most convenient. These valuable agents are relatively toxic materials exhibiting acute intravenous toxicities in the range of about 10-40 mg./ kg. However, very small doses of these substances are required. Intravenous doses in the range 0.5-4.0 mg./kg. were found to be effective. Doses of the order of 1 mg./kg. or less were commonly used. Thus the therapeutic index is sufiiciently high to make these materials safe to use.
  • Example I Substituted ammonium salts
  • the bulk of the substituted ammonium salts referred to herein Were prepared by refluxing the base with the quaterresults obtained for each of the compounds prepared by this type of procedure are summarized in the accompanying table.
  • the bases employed in preparing these quarternary salts were harman, 1,2-dimethy1-1,2,3,4-tetrahydro- 8-carboline, and 1,2 dimethyl-7-methoxy-l,2,3,4-tetrahydro-p-carboline.
  • Example IV.1-methyl-2-(Z-diethylaminoethylcarbamylmethyl)-fi-carb0linium bromide Z-Carbomethyloxymethyl harmanium bromide (Example l-compound No. 2 in the table), 2.01 g. was refluxed with 3.48 g. of dry diethylaminoethylamine in 30 ml. of anhydrous methanol for 4 hours. The solution was concentrated and the product precipitated by treatment of the concentrate with benzene. It was a light yellow solid which was collected, washed with benzene and ether and recrystallized from acetone and methanol. Its melting point was 189-l90 C.
  • R is selected from the group consisting of a lower hydrocarbonoxy group containing up to six carbon atoms and the -NHCH CH NL group wherein L is a lower alkyl group containing up to three carbon atoms; and X is a pharmacologically acceptable anion.
  • a therapeutic composition comprising a compound as claimed in claim 1 and a pharmaceutical carrier therefor.
  • a method for reducing the blood pressure comprising the step of administering to the host a compound as claimed in claim 1.

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Description

United States Patent O QUATERNARY SALT DERIVATIVES F HARMAN William M. McLamore, Kew Gardens, N. Y., assignor to Chas. Pfizer & Co., Brooklyn, N. Y., a corporation of Delaware No Drawing. Original application January 30, 1956, Serial No. 562,026. Divided and this application March 1, 1957, Serial No. 643,244
Claims. (Cl. 167-65) This invention is concerned with a unique group of substituted ammonium salts useful as therapeutic agents. In particular, they are monosalts and are derivatives of barman and 1,2,3,4-tetrahydroharman. They have the unique property of causing a therapeutically useful lowering of the blood pressure of an animal when administered thereto.
Various compounds have been suggested from time to time, in the past, for use in the therapy of hypertension. Some of these useful compounds are quaternary ammo nium salts. However, these hypotensive quaternary ammonium salts known to the art are distinguished from the valuable substituted mono-ammonium salts of this invention in that they are bis-quaternary ammonium salts such as hexamethonium chloride which is the bisquaternary ammonium salt, N,N,N',N'-tetra.methyl- 1,6-hexanediamine dimethochloride. Heretofore, substituted mono-ammonium salts have not been found useful in the therapy of hypertension. In fact, attempts to find useful agents among the mono-ammonium salts in the past have met with disappointment. It is therefore surprising that it has now been found that certain substituted mono-ammonium salts have a particularly valuable com-a bination of pharmacohynamic properties which makes vasodilator activity which makes them particularly useful as hypotensive agents. In addition, they have a remarkably low degree of troublesome side effects including the cardiac effects referred to above.
The valuable mono-ammonium salts of this type have the following structural formulas R: Qxe
N-CH R4 2,8193%! Patented Jan. 14, 1953 rue This application is a divisional application of copending application Serial Number 562,026 filed January 30, 1956 in which the salts of Formula III are claimed. Those materials represented by Formula II are claimed in the present application. In the foregoing structural formulas R is either a lower hydrocarbonoxy group containing up to about six carbon atoms or it is the --NHCH CH NL group wherein L is a lower alkyl group containing up to about three carbon atoms such as methyl, ethyl or propyl. By lower hydrocarbonoxy group is meant groups such as the methoxy group, the ethoxy group, the butoxy group, the isobutoxy group and the hexoxy group. These hydrocarbonoxy groups are substantially saturated but they may contain some unsaturated linkages such as in the allyloxy group. R is either a hydrogen atom or a lower aliphatic hydrocarbon group containing up to about six carbon atoms. The lower aliphatic hydrocarbon groupsare such groups as methyl, ethyl, allyl, butyl and hexyl again substantially saturated but which may contain a minor proportion of unsaturated linkages. At least two to four of the substituents R R R R and R attached to the nucleus of the benzyl group in Formulas I and III are hydrogens, and the remainder are selected from the group consisting of a halogen atom, that is a fluorine, a chlorine, a bromine or an iodine atom and a lower hydrocarbonoxy group containing up to about six carbon atoms as defined above. In other words, at least one and not more than three of these groups are substituents other than hydrogen. R is a hydrogen atom or a lower hydrocarbonoxy group containing up to about six carbon atoms. Some examples of such groups appear above. X is a pharmacologically acceptable anion. By pharmacologically acceptable anion is meant an anion which is well tolerated in the dosages employed with the products of this invention. Examples of pharmacologically acceptable anions are chloride,'
bromide, sulfate, methosulfate, phosphate, citrate, tartrate gluconate, succinate, etc.
These compounds are readily prepared by treating the parent nitrogenous base with the appropriate quaternizing agent. Appropriate quaternizing agents include aliphatic hydrocarbon halides, sulfates, and sulfonates in which the organic portion of the molecule corresponds to in the above structural formulas. Examples of useful quaternizing agents include methyl iodide, dimethylsulfate, ethyl bromide, diethyl sulfate, m-methoxybenzyl bromide, 3,4-dichlorobenzyl bromide, 3,4.-dimethoxybenzyl p-toluene sulfonate, p-rnethoxybenzyl chloride, p-ethoxybenzyl methanesulfonate, etc.
The treatment of barman with methyl bromoacetate to yield one of these valuable substituted mono-ammonium salts is represented in the accompanying equation which illustrates the quaternization process.
(1 i N BICHzCOzCH;
NGHaCO2C a H Harman, the nitrogen compounds employed in preparing this mono-quaternary is prepared synthetically by the cyclodehydration, decarboxylation, and dehydrogenation of N-acetyl-dl-tryptophan by methods well known in the art employing various dehydrating agents such as phosphoryl chloride, polyphosphoric acid, etc. This process is illustrated by the following equation CH2CHGO2H NHCOCH: N N H H (I) Similar processes are known which employ tryptophan or tryptamine and acetaldehyde as starting materials. In the tetrahydroharman series Formula III wherein R is 70 compound of Formula II wherein a hydrogen atom, py-N-methylal,2,3,4-tetrahydroharman (1,Z-di-rnethyl-l,2,3,4-tetrahydr-B-carboliue) was treated with a series of substituted benzyl halides, sulfates, and sulfonates according to they following'equation wherein Py-N-methyl-l,2,3,4-tetrahydroharman was prepared by the reduction of harman methobromide or the anhydronium base py-Nmethylharman by a standard known procedure. With the anhydronium base, catalytic hydrogenation employing a platinum catalyst was the most satisfactory method forcarrying out the reduction while sodium borohydride was the most satisfactory agent for reducing the methobromide salt. These processes are illustrated below.
The parent bases in the tetrahydro series (Formula 111) wherein R is a lower hydrocarbonoxy group are readily prepared by analogous procedures from the O-alkylated harmalol derivatives which are known compounds. Harmalol is obtained by demethylation of harmaline, one of the Harmala alkaloids. This series is illustrated below wherein R stands for the lower hydrocarbonoxy group of F of Formula 111.
Two of the compounds were prepared by special procedures. In the harman series, for the preparation of the the monoquaternary ammonium salt derived from her man and methyl bromoacetate, described above, was
R R R R and R have the same meanings as above. treated with Z-diethylaminoethyl amine which resulted in the formation of the desired amide as is illustrated in the following equation.
In the tetrahydroharman series, Formula III, the compound wherein R =OCH and the remaining R groups are hydrogens was prepared by treating harman with m-methoxybenzyl bromide and reducing the so-obtained material with sodium borohydride. This process is illustrated by the following equation.
OCH:
In the above quaternization processes the anion X is usually either a halogen anion such as chloride, bromide or iodide or an organic sulfate or sulfonate anion such as methosulfate, ethosulfate, benzenesulfonate, or paratoluenesulfonate. These anions may be replaced by other pharmaceutically acceptable anions such as the phosphate, succinate, citrate, or tartrate by various processes well known in the art. For example, with the quaternary salts, the salt may be converted to the quaternary ammonium hydroxide by treatment with silver oxide or'by passage through a column of a strongly basic anion exchange resin on the hydroxide cycle. Examples of useful ion exchange resins are Dowex 1, Dowex 2, Amberlite IRA-400 and Amberiite IRA-410. These resins are polyquaternary ammonium compounds in which the quaternary ammonium groups are attached to a styrene-divinylbenzene copolymer. Such resins are prepared for example, by chloromethylating the copolymer and then treating it with an alkyl halide such as trimethylamine or dimethylethanolamine. The soobtained solution of the substituted ammonium hydroxide corresponding to one of the salts of this invention is then neutralized with the acid corresponding to the desired anion. Alternatively, one of the above substituted mono-ammonium halides of this invention may be treated directly with the silver salt of the acid corresponding to the desired anion in an aqueous alcoholic solution. The silver halide precipitates and can be separated from the product.
The ability of these compounds to bring about a therapeutically useful reduction in blood pressure was determined in cats anesthetized with chloralose by canulating the carotid artery and recording the blood pressure on a kymograph after subjecting the cat to various stimuli. The ganglionic blocking activity was determined by measuring the ability of these materials to abolish or decrease the response of the nictitating membrance to a standard preganglionic electrical stimulation in the superior cervical ganglion preparation of the cat as well as their ability to block the stimulating effect on the ganglia of the tetramethylammonium ion. Stimulation of the ganglia in the latter fashion is manifested by a rise in blood pressure and a contraction of the nictitating membrance as well as other pharmacodynamic effects. All of the above compounds were found in these tests to be highly etfective in reducing the blood pressure. That is each was found to possess ganglionic blocking activity, or direct vasodilator activity or a combination thereof which elfected a significant reduction in the animals blood pressure.
With regard to possible side effects of these materials afiecting either the heart or the neuro-muscular transmission, further tests were carried out. The cardiac effects were measured in the isolated perfused cats heart according to the Langendorf method. The coronary inflow was measured with a fiowmeter, and the contractile force and rate were recorded with the inkwriting recorder. In a hypotensive drug, a decrease in any of these activities is undesirable since it reflects cardio-toxicity of the drug. While an increase in coronary inflow is desirable, it is not a necessary prerequisite for a useful drug. None of the valuable mono-ammonium salts of the present invention was found to elicit the above manifestations of cardiotoxicity to a harmful degree. Some actually had a favorable type of action. Neuro-muscular blocking or curariform activity was measured in the gastrocnemius preparation of the guinea pig. The activity of these compounds was compared with that of d-tubocurarine. None was found to possess more than 4% of the activity of d-tubocurarine.
The valuable hypotensive agents of this invention may be administered by various routes. In the animal experiments described above, however, intravenous administration was found to be the most convenient. These valuable agents are relatively toxic materials exhibiting acute intravenous toxicities in the range of about 10-40 mg./ kg. However, very small doses of these substances are required. Intravenous doses in the range 0.5-4.0 mg./kg. were found to be effective. Doses of the order of 1 mg./kg. or less were commonly used. Thus the therapeutic index is sufiiciently high to make these materials safe to use.
These compounds may be combined with various pharmaceutical carries the choice of which depends upon the properties of the particular compounds and upon the route of administration. For intravenous administration, it is convenient to employ the compounds in the form of dilute solutions either in water or in aqueous solutions isotonic in glucose or sodium chloride.
The following examples are given to illustrate the preparation of specific compounds of this invention. They are presented for illustrative purposes only and are not to be considered as limiting the invention in any way.
Example I.Substituted ammonium salts The bulk of the substituted ammonium salts referred to herein Were prepared by refluxing the base with the quaterresults obtained for each of the compounds prepared by this type of procedure are summarized in the accompanying table. In this particular series of compounds, the bases employed in preparing these quarternary salts were harman, 1,2-dimethy1-1,2,3,4-tetrahydro- 8-carboline, and 1,2 dimethyl-7-methoxy-l,2,3,4-tetrahydro-p-carboline.
SUBSTITUTED AMMONIUM SALTS PREPARED BY THE PROCEDURE OF EXAMPLE I Analysis No. Compound M.P.,C. Reeryst. solvent Calculated Found H N X 0 H N X NR x -CH: OCH; Br assumes M on 62.67 5.00 1.31 62 .56 5.18 6.97
2 CHzGOaCH| Br 209-210 MeOH 53.74 4.51 8.36 23.84 53.47 4.50 8.38 23.79
Compound G9 0H. N\ x N H R R R X CH OCH; H Br 180-181 MeOH-MeaGO-.- 62.84 6.28 6.98 62.65 6.60 6.68
4 OH. H (31 199-201 MeOH-MezOO-.- 70.67 7.06 7.85 9.94 70.64 7.47 7.47 10.00
OCH:
OCH: l
-cm@ H m 188-189 Not recryst 62.84 6.28 6.98 62.25 6.21 6.84
6---- -OH H Br 179-180 .....(10 54.57 4.81 6.36 54.94 5.24 6.15
7.--- --CHUOCH= OOH; Br 177-178.5 61,25 6.31 6.49 61.85 6.33 6.27
Example II.1,2-dimethyZ-7-meth xy-1 ,2,3,4-tetrahydro- S-carboline Harmaline methosulfate, 6.77 g., dissolved in 120 ml. of methanol was added to a solution of 3.78 g. of sodium borohydride and 1.33 g. of sodium hydroxide dissolved in ml. of methanol. The mixture was refluxed for 2 hours and a further 1.99 g. of sodium borohydride and 20 ml. of methanol was added. The solution was refluxed for an additional three hours after which time the yellow color had faded. The solvent was removed and ether and Water were added to the residue. The layers were separated and the water layer extracted several times with additional portions of ether. The comchloride solution, dried over magnesium sulfate and concentrated until crystals separated. The product weighed 6.32 g. and had a melting point of 177-l79 C. It was a white crystalline solid which could be recrystallized from ethanol and acetone. An analytical sample so prepared had a melting point of 1775-1785.
Analysis.-Calculated for C H ON C, 73.01; H, 7.88; N, 12.17. Found: C, 72.99; H, 7.98; N. 12.19.
Example III.1-methyl 2 (m-merhoxybenzyl)-1,2,3,4-
tetrahydrO-fi-carbqline hydrocr'iloride A solution of 12.1 grams of sodium borohydridein 100 ml. of methanol was slowly added to a slurry of 16 bined ether extracts were washed with an aqueous sodium g. of" the m-methoxybenzyl bromide salt of barman (Example Icompound No. 1 in the table) in 200 m1. of methanol. The mixture was refiuxed with stirring for six hours, the methanol evaporated, and the residue treated with water and ether. The layers were separated and the ether and the water layer extracted with several additional portions of ether. The extracts were dried over magnesium sulfate and the solvent removed yielding 13.6 g. of crude 1-methyl-2-(m-methoxybenzyl)-1,2,3,4-tetrahydro-p-carboline. This material was dissolved in dry ether and treated with an excess of methanolic hydrogen chloride. The hydrochloride salt of the base was precipitated by treating the solution with acetone. The crude product was recrystallized from a mixture of methanol and acetone yielding white needles, melting point 226--226.5 C.
Analysis-Calculated for C H ON Cl: C, 70.06; H, 6.47; N, 8.17. Found: C, 69.85; H, 6.60; N, 8.19.
Example IV.1-methyl-2-(Z-diethylaminoethylcarbamylmethyl)-fi-carb0linium bromide Z-Carbomethyloxymethyl harmanium bromide (Example l-compound No. 2 in the table), 2.01 g. was refluxed with 3.48 g. of dry diethylaminoethylamine in 30 ml. of anhydrous methanol for 4 hours. The solution was concentrated and the product precipitated by treatment of the concentrate with benzene. It was a light yellow solid which was collected, washed with benzene and ether and recrystallized from acetone and methanol. Its melting point was 189-l90 C.
10 Analysis-Calculated for C H ON Br: C, 57.28; H, 6.49; N, 13.36. Found: C, 56.83; H, 6.37; N, 13.19.
What is claimed is: 1. A compound having the formula wherein R is selected from the group consisting of a lower hydrocarbonoxy group containing up to six carbon atoms and the -NHCH CH NL group wherein L is a lower alkyl group containing up to three carbon atoms; and X is a pharmacologically acceptable anion.
2. A therapeutic composition comprising a compound as claimed in claim 1 and a pharmaceutical carrier therefor.
3. A method for reducing the blood pressure comprising the step of administering to the host a compound as claimed in claim 1.
4. 1 Methyl 2 (2 diethylaminoethylcarbamylmethyD-fl-carbolinium bromide.
5. 1 Methyl 2 (carbomethoxymethyl) 9 carbolinium bromide.
No references cited.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3077476A (en) * 1959-04-28 1963-02-12 Jr Brennie E Hackley Bis quaternary oximes
US3345376A (en) * 1963-11-06 1967-10-03 Upjohn Co Polyhydro-6-methoxy-1-(3, 4, 5-trimethoxyphenyl)-9h-pyrido[3, 4-b]indoles
US4451655A (en) * 1982-05-17 1984-05-29 Pfizer Inc. Process for preparing carboline derivatives and compounds used in their preparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2143590A (en) * 1936-09-26 1939-01-10 Univ Alberta Insulin preparation and process of producing crystals of insulin
US2648622A (en) * 1950-11-29 1953-08-11 Research Corp Purifying insulin by seeding with unclumped fibrils of insulin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2143590A (en) * 1936-09-26 1939-01-10 Univ Alberta Insulin preparation and process of producing crystals of insulin
US2648622A (en) * 1950-11-29 1953-08-11 Research Corp Purifying insulin by seeding with unclumped fibrils of insulin

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3077476A (en) * 1959-04-28 1963-02-12 Jr Brennie E Hackley Bis quaternary oximes
US3345376A (en) * 1963-11-06 1967-10-03 Upjohn Co Polyhydro-6-methoxy-1-(3, 4, 5-trimethoxyphenyl)-9h-pyrido[3, 4-b]indoles
US4451655A (en) * 1982-05-17 1984-05-29 Pfizer Inc. Process for preparing carboline derivatives and compounds used in their preparation

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