Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0815—Tripeptides with the first amino acid being basic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1002—Tetrapeptides with the first amino acid being neutral
  • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
  • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1019—Tetrapeptides with the first amino acid being basic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• This invention relates to novel, therapeutically useful polypeptides which exhibit varying degrees of phagocytosis or pinocytosis stimulation or inhibition.
• the gamma globulin fraction of whole mammalian blood is the fraction which contains the antibodies utilized by the body in resisting invasion by antigens. More specifically, the gamma globulin fraction of mammalian blood is the fraction containing substance which the body utilizes in combatting attack by infectious diseases.
• the production of antibodies is a natural defense mechanism of the body stimulated by the presence of antigens in the body. Normally specific antibodies are produced to combat specific antigens and, in many instances the body thereafter maintains an antibody level against the specific antigen or infectious organism so that reinfection is inhibited and often prevented.
• gamma globulin fraction of mammalian blood as a therapetutic agent has therefore attracted considerable medical attention since it would seem possible to utilize this fraction from an individual who has successfully overcome an infection to stimulate resistance to that same infection in another individual.
• a tetrapeptide L-threonyl-L-lysyl-L-prolyl-L-arginine which can be isolated from gamma globulin by procedures to be described hereinafter, but which does not exist as a discrete and free molecule in gamma globulin, has the ability to stimulate phagocytosis and subsequent destruction of bacteria by blood polymorphonuclear leucocytes especially neutrophilic leucocytes in mammals. It also stimulates pinocytosis to the same extent allowing the cells to obtain nourishment from the surrounding medium.
• This application is principally concerned with the class of polypeptides of which this tetrapeptide is one member, with analogs, derivatives and pharmacologically acceptable salts thereof.
• THE INVENTION 1 A new class of therapeutically useful polypeptides has been discovered.
• the members of the class are useful for their phagocytosis or pinocytosis stimulating or inhibiting activity.
• the principal characteristics of the class are that 'Arg-Pro-Arg-Thr its members are non-antigenic, contain at least three and up to about nineteen amino acids, and contain at least one peptide unit in which two basic amino acids are joined together by one or two proline molecules.
• the lowest member of the class therefore is a tripeptide in which two basic amino acids are linked through proline.
• LysineLys Serine-Ser ArginineArg TyrosineTyr Ornithine-Orn Pheny1alaninePhe HistidineI-Iis ProlinePro Threonine-Thr The first four of these acids are the basic amino acids, and they are included within the term basic amino acids as used in this specification and the appended claims.
• the basic unit of the class of polypeptides with which this invention is concerned is a tripeptide in which two basic amino acids are joined through proline.
• Arg-Pro-Lys-Thr Various degrees of inhibition can be achieved by replacing one or more of the D-amino acids with L-amino acids.
• the following compounds therefore are within the scope of the invention: a v Arg-Pro-Lys-Ser Orn-Pro-Arg-Thr Lys-Pro-Lys-Thr Orn-Pro-Lys-Thr His Pro-Lys-Thr Lys-Pro-Arg-Thr His-Pro-Lys-Ser
• the most active stimulators are found amongst those tetrapeptides in which all of the amino acids are in the L-form, and the fourth amino acid joined to the basic tetrapeptide unit is an hydroxyl substituted, aliphatic amino acid joined through its carboxyl group to the alpha amino group of the basic amino acid, the carboxyl group of which is joined to the proline in a peptide bond.
• the reverse position isomers of these compounds in which all of the amino acids are in the D-form are active inhibitors
• the presently preferred compounds are tetrapeptides.
• the compound with the highest order of stimulating activity yet noted is Thr-Lys-Pro- Arg in which all of the amino acids are in the L-form.
• the preferred inhibitor is Arg-Pro-Lys-Thr in which all of the amino acids are in the D-form.
• tuftsin IV the first named compound has been called tuftsin IV and the second named compound is called retrotuftsin IV.
• Tuftsin IV as it exists in the blood of mammals is a part of the larger molecule leukokinin, as is clear from its method of isolation which requires a specific enzyme leukokininase for its cleavage. It appears to stimulate phagocytosis and pinocytosis by a mechanism which involves (a) binding of leukokinin at a specific site on the cell membrane, (b) cleavage from the leukokinin molecule through the action of the membrane enzyme leukokininase which forms an integral part of the binding site, and (c) transport as a complex with the enzyme to the site of its activity where it is apparently destroyed as its discharges its stimulatory action.
• Tuftsin II, HI and IV are obtained from phospocellulose fraction IV (PC IV) by treatment of this fraction with trypsin or the enzyme leukokininase which is prepared from the membranes of blood neutrophilic leucocytes and from rabbit peritoneal exudates by known procedures. They are principally peptides and are separated from the balance of the protein, after the enzyme treatment, by precipitation of the latter with 5% trichloroacetic acid. The supernatant contains the tuftsin compounds.
• Trichloracetic acid is removed by ether extraction and the tuftsins are lyophilized and chromatographed on Sephadex G-10 columns equilibrated with a running eluting fluid composed of 0.1 N acetic acid saturated with chloroform.
• the effluent is collected in 1 ml. samples.
• Samples to contain tuftsin II, and samples to 158 contain tuftsin III and IV.
• the effluent containing tuftsin III and IV is lyophilized and taken up in pyridineacetate buffer at pH 4.
• the mixture is chromatographed on Dowex 50 columns and eluted at pH 4.0 to 6.0 in 1.2 to 2.5 M pyridine concentration (linear gradient technique).
• Tuftsin HI in samples 20 to 35
• tuftsin IV is in samples 65 t0
• Tuftsin IV when subjected to thin layer chromatography utilizing 2:1 propanol-water yielded a single band.
• Dansylation of the peptide with dansyl chloride results in a single fluorescent band on thin layer chromatography with silica gel using 15:4:1 chloroform-methanel-acetic acid.
• Tritium exchange following treatment of the peptide with acetic acid an hydride in pyridine in tritium water established arginine as the only radioactive residue.
• the presence of proline between lysine and arginine is established by the resistance of the peptide to trypsin digestion. After removal of arginine by carboxypeptidase B, refluxing of the remaining peptide with acetic acid anhydride for 45 minutes in tritium water showed proline as the only radioactive residue.
• the structure of tuftsin IV is established as Thr-Lys-Pro-Arg.
• Tuftsin IV can also be isolated from commercially available Cohn fraction II gamma globulin by the process illustrated in the examples, but not in practically useful qualities.
• the phagocytic activity of the products of this invention is established by the following test:
• Buffy (white cell) coats from dog or human blood or peritoneal exudate from rabbit or guinea pigs were prepared, washed three times with Krebs-Ringer medium and suspended in the same medium. A otal of 0.15 ml. of this medium containing 45 10 neutrophilic leucocytes per cubic millimeter were pipetted into a reaction vessel. Next 0.1 ml. of the tuftsin mixture containing 0.2 to 2 were added to the vessel followed by 0.05 ml. of staphylococci opsonized in inactivated opsonin rich serum. This represented 1.5 to 2 bacteria per neutrophile. The final volume was 0.3 ml. This was rotated at eight cycles per minute at 35 C. for /2 hour. Smears were made and stained with Wrights stain. The number of cells containing engulfed bacteria for each 100 cells counted is the index of phagocytosis.
• the stimulatory eifect of tuftsin IV and the related products of this invention is destroyed by incubation for 3 hours at 30 C. with pronase, subtilisin, carboxypeptidase B and leucine aminopeptidase, using 40 ,ug. of protein per ml. under optimum conditions of enzyme action. Similarly it is destroyed by incubation with soluble supernatants of disrupted leucocytes and membrane preparations from human erythrocytes and rat liver at pH 7.0 in phosphate bulfer. In all of these media phagocytosis is at the same level as the controls. Tuftsin 1V is not destroyed by exposure to aeration in the presence or absence of cysteine, heating at 80 C.
• the products of this invention are useful mammalian therapeutic agents and are effective as stimulating or inhibiting agents at extremely low levels.
• the physician or veterinarian will determine the dosage which will be most suitable for a particular application. It may vary from patient to patient depending on the size of the patient, the condition under treatment and other factors which are readily evaluated by those skilled in the art.
• the products will normally be provided in various dosage forms varying from relatively large to build up a prompt blood level to relatively small to maintain an effective level.
• various dosage forms may be provided.
• the products maybe administered at very high levels, even up to two or more grams per day. Normally they will be provided in dosage units containing about 250 mg. of the active ingredient and the number of units appropriate to the condition under treatment can be prescribed per day.
• the products of this invention may be administered alone but will generally be administered with pharmaceutically acceptable, non-toxic carriers, the proportions of which are determined by the suitability and chemical nature of the particular carrier, the chosen route of administration, and standard pharmaceutical practice.
• pharmaceutically acceptable, non-toxic carriers the proportions of which are determined by the suitability and chemical nature of the particular carrier, the chosen route of administration, and standard pharmaceutical practice.
• in combatting various infections or in maintaining therapeutically elfective levels in the blood or tissues may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay, etc. They may be enteric coated so as to be more resistant to the acid With digestive enzymes of the stomach.
• intravenous and intramuscular administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
• the acids which may be used to prepare the pharmacologically acceptable acid addition salts of this invention are those containing non-toxic anions and include, for example, hydrochloric, sulfuric, phosphoric, acetic, lactic, citric, tartaric, oxalic, succinic, maleic, gluconic, saccharic, and the like acids.
• polypeptides of this invention can be synthesized by any of a wide variety of techniques now available for the synthesis of simple and complex polypeptides and even relatively low molecular Weight proteins.
• these techniques involve stepwise synthesis by successive additions of amino acids to produce progressively larger molecules.
• the amino acids are linked together by condensation between the carboxyl group of one amino acid and the amino group of another amino acid to form a peptide bond.
• the blocking groups must be easily removed. The whole series of reactions must take place without causing racemization of the products.
• Certain amino acids have additional functional groups, for example, the hydroxyl group of tyrosine or'of threonine. It is usually necessary to block these additional groups with an easily removed blocking agent so that it does not interfere with the condensation reaction.
• the presently preferred procedures for the synthesis of the polypeptides of this invention are the Merrifield technique and the N-carboxy anhydride technique.
• an amino acid is first bound to a resin particle, as by an ester bond and the peptide is generated in a stepwise manner by successive additions of protected amino acids to the growing chain.
• an N-carboxyl amino acid anhydride is reacted with the amino group of a second amino acid or peptide under conditions such that the only amino group present in appreciable concentration in reactive form during the course of the reaction is the amino group which is to participate in the reaction.
• This control is effected by selection of concentration, temperature, time and hydrogen ion concentration.
• tuftsin IV and retrotuftsin IV are preferred members of the class is their high order of activity. Another is because they lend themselves so readily to slight molecular modifications to produce compounds which have more or less activity than the parent tetrapeptide; or may be more or less readily absorbed into the tissues; or particularly suitable for a selected route of administration.
• tetrapeptides are the preferred members of the class
• the compounds with which this invention is concerned may be generally described as therapeutically useful, non-antigenic polypeptides containing at least three and up to about nineteen amino acids comprising one unit or repeating units, each unit containing three to five amino acids, each repeating unit being joined to an adjacent unit by proline or cystine, each unit containing two basic amino acids linked together by one to two proline molecules.
• the repeating units will normally be identical, it is not essential that they are.
• the invention also includes the pharmacologically acceptable salts and derivatives of these polypeptides. Typical members of the class could include therefore:
• the preferred linking amino acids are proline and cystine. The reason for this is that these amino acids form peptide bonds which are relatively resistant to the enzymes of the digestive tract. Since the high molecular weight products of the invention will normally be used by patients under long term treatment it is preferred that the therapeutic agent be ingested orally. It is essential, therefore, that the oral agent is not one which will be sufiiciently resistant to digestion to permit absorption.
• Tuftsin IV can readily be obtained as an amide.
• the tetrapeptide can be reacted with thionyl chloride to form the acid chloride, and the latter reacted with ammonia under conditions that minimize racemization to form the amide.
• the tetrapeptide can be formed by joining proline, lysine and threonine successively to an arginine ester and then converting the resulting tetrapeptide ester to an amide by ammonolysis.
• the ester may be, for example, any lower alkanol ester containing up to about six carbon atoms.
• Enzymes are available in the body which will hydrolyze both amide and ester groups to regenerate the stimulatory activity of the acid. Both ester and amide derivatives are useful therapeutic agents because of their increased chemical stability compared with the free acids. They have altered rates of absorption or diffusion into the tissues and delayed excretion through the kidneys. They may be used in the form of pharmacologically acceptable salts.
• Other useful derivatives may be obtained by modifying the free functional groups on the polypeptide backbone, for example, free hydroxyl groups or free amino groups.
• One very convenient class of derivatives is the class in which a free hydroxyl group, for example, the free hydroxyl group of threonine or tyrosine is esterified with an alkanoyl or alkenoyl group containing up to eighteen or more carbon atoms.
• an amino group for example, the amino group of threonine or lysine can be acylated with an alkanoyl or alkenoyl group containing up to about eighteen carbon atoms.
• the preferred derivatives are those in which the derivatizing groups contain from eleven to eighteen carbon atoms because the longer hydrocarbon chains impart increased lipid solubility to the molecules and enhance their transport across cell barriers.
• Both types of derivatives may be prepared directly from the polypeptide, but are preferably prepared by incorporating in the peptide during synthesis of an amino acid with the selected group, for example, the alkanoyl group already in place.
• tuftsins and other polypeptides of this invention are, in a sense, natural therapeutic agents and can be used alone for that purpose, they will often be administered together with one or more other therapeutically active materials such as an antibiotic, antifungal or antiviral agent.
• an antibiotic, antifungal or antiviral agent One reason for this is to combat acute, potentially lethal infections with all of the resources available.
• Another is to clean up the toxins, especially the endotoxins of gram negative bacteria and other debris which accumulate in the tissue and the blood as a result of the death of infectious microorganisms. The toxemia resulting from such accumulations is sometimes as dangerous, if not more so, to the health of the patient as the original infection.
• the presence of tuftsin IV or its analogs helps the body eliminate the endotoxins.
• the carboxyl group of penicillin can be used to esterify tuftsin IV through the hydroxyl group of threonine. It can also form an amide linkage through the alphaamino group of threonine or the epsilon amino group of lysine;
• the stimulatory peptides of this invention may also be used to preserve the usefulvalues of whole blood. It has been observed that on standing, even under normal refrigeration, whole blood loses its phagocytic activity and the white cells start to disappear. The addition of small amounts of, for example, tuftsin IV will reverse this trend.
• the first gamma globulin fraction was eluted with 0.05 M acetate buffer (pH 4.8) in 0.15 M NaCl and contained 51 mg. of protein (34%). Elution with the same buffer was continued until the absorbance at 280 m corresponded to that of the buffer. This was routinely achieved with each fraction after 1.3 to 1.7 holdup volumes of the eluting butter had passed through the column, i.e. until 180 to 230 ml. of efiluent was collected.
• the second fraction contained 37 ml. of gamma globulin (25.0%) and was eluted using 0.05 M acetate buifer (pH 5.0) in 0.15 M NaCl; and the third fraction, 29 mg.
• fraction PC IV 100 mg. of fraction PC IV were digested with leukokininase prepared from human, dog or rabbit polymorphonuclear leucocyte membranes. pg. of leukokininase protein were added per mg. of PC IV, in a final volume of 25 ml. of 0.1 M phosphate buffer pH 6.7. This was incubated for two hours at 37 C. The reaction was stopped by adding trichloroacetic acid to a final concentration of 5%. The precipitate was separated out.
• the efiluent containing tuftsin III and IV was lyophilized and taken up into pyridine-acetate buifer pH 4 containing 1.2 M pyridine. This was then chromatographed on aminex columns; height 60 cm.; internal diameter 0.6 cm.; and eluted with a linear gradient at 60 C.
• the starting buffer is pyridineacetate pH 4.0 containing 1.2 M pyridine; and the final butter pyridine acetatepH 6.0 containing 2.5 M pyridine.
• the sequence proved to be Thr-Lys-Pro- Arg, and the amount recovered was about 1,000 g. giving a yield of 1.0 g. per 1,000 g. of fraction PC IV or 1.0 pg. per 10,000 g. of whole gamma globulin.
• Fresh gamma globulin was prepared from 100 ml. of human or dog serum as follows: to 100 ml. of serum were added 100 ml. of 0.15 N sodium chloride and 100 ml. of saturated ammonium sulphate solution. The precipitate was allowed to form at room temperature for two hours. It was centrifuged down and the precipitate dissolved in 20 ml. of 0.15 N sodium chloride. To this were added 10 ml. of saturated ammonium sulphate. After two hours of standing at room temperature it was left at 5 C. overnight. The preparation was then centrifuged down and the supernatant discarded. The gamma globulin precipitate was then dialyzed against 1 liter of 0.15 N sodium chloride for 4 hours. The dialysis was repeated 2 more times.
• EXAMPLE IV Tuftsin IV from freshly prepared gamma globulin Freshly prepared gamma globulin, as in Example III, was fractionated on phosphocellulose columns as in Example I. 100 mg. of fraction IV were then treated with leukokinase and fractionated on Dowex 100 and aminex columns, as in Example I. The isolated tuftsin IV gave identical residues with similar values as in Examples I, II, and IH, threonine 0.92, lysine 1.00, proline 1.04 and arginine 0.97.
• N-t-BOC N carbobenzoxy (CBZ) lysine 1.35 mmoles was coupled to proline, deprotected, neutralized and 1.35 mmoles of N-t-BOC-O-benzyl threonine was then coupled to the deprotected N of lysine.
• steps of deprotection (cleavage of the t-BOC alone) with TFA, washing, neutralization with triethylamine, washing and coupling with DCC was repeated for each amino acid residue in an identical manner.
• tetrapeptide resin 30 mg. were hydrolyzed with 6 N hydrochloric acid in dioxane for 18 hours and the product assayed on the amino acid analyzer. 'It yielded a ratio of Thr 0.9, Lys 1.0, Pro 1.08, Arg 1.0.
• the value for arginine is again the sum of arginine, ornithine and nitroarginine.
• the tetrapeptide was cleaved off the resin with hydrogen bromide in TFA at room temperature for 1 /2 hours. It was then dried in vacuo, washed twice with water and lyophilized. Its weight of 176 mg. represented a 78% yield based on arginine esterified.
• the material was then chromatographed on an aminex column with a linear pH gradient 46 with pyridine 1.2 M to 2.5 M at flow rate of 8 ml. per hour.
• the major peak, the tetrapeptide appeared exactly at the tuftsin IV peak derived from CP fraction 1V gamma globulin, i.e. between 138-150 ml. with a peak with 144 ml. of effiuent.
• the collected material was dried in vacuo, washed twice with 0.1 molar acetic acid, taken up in 0.1 molar acetic acid, and lyophilized. Upon amino acid assay a ratio of Thr 0.96, Lys 1.0, Pro 1.03, Arg 1.0 was observed. All amino acids were in the L-form.
• EXAMPLE VI Synthesis of tuftsin IV t-BOC-nitroarginine is esterified to the chloromethylated resin, deprotected, neutralized and washed as in Example plus an additional wash with dimethylformamide (DMF). 1.2 g. containing 0.25 mmole of arginine is used as starting material. t-BOC pnoline succinimide ester, 1.0 mmoles is added to the resin in DM-F and allowed to react for 24 hours with shaking at room temperature.
• DMF dimethylformamide
• Example V Deblocking, neutralization, and washing as in Example V with a final wash with DMF repeated for each succeeding coupling with 1.0 mmole of N hydroxysuccinimide esters of N-t-BOC N-CBZ lysine and N-t-BOC-O-benzyl threonine.
• the cleavage from the resin, catalytic hydrogenation, column purification are exactly the same as in Example V.
• the aminex column, as in Example V showed a predominantly major peak at the tuftsin IV level.
• the yield based on arginine esterified was 34%. After cleavage from the resin, the ratios were Thr 0.85, Lys 1.0, Pro 0.95, Arg 1.08.
• the nonapeptide is cleaved from the resin with hydrogen bromide intrifluoroaceticacid and the nitro arginine residues reduced by catalyst hydrogenation with palladium or barium sulfate.',,Pu rification is effected on Sephadex vG10 followed by an aminex column. i j
• a paste was separately prepared with 80 g. of corn starch and 350 ml. of distilled water.
• the above mixture waswell kneaded with the paste and the mass was passed through a 4 mesh sieve and the resulting globules were dried at 50 C. for 15 hours.
• the dried globules were then granulated first on a granulating machine and then passed through a 16 mesh sieve.
• the grains were covered with a powdery mixture which had been prepared by blending 30 g. of calcium stearate, 200 g. of cornstarch and g. of talc, and then passed through a 40 mesh sieve.
• Tablets each containing 250 mg. of tuftsin IV were made of the above-obtained granules in accordance with the conventional procedure knownin the art.
• Therapeutically useful non-antigenic polypeptides containing at least fourand up to about nineteen amino acids comprising one unit or repeating units each unit containing four to five amino acids at .least one of the terminal amino acids in each unit being a hydroxyl substituted amino acid, each repeating unit being joined to an adjacent unit by proline or'cystine, each unit containing two basic amino acids linked together by one to two proline molecules and pharmacologically acceptablesalts and derivatives thereof.
• Thr-Lys-Pro-Arg in which the hydroxyl group of the threonine moiety is esterified with an alkanoyl or alkenoyl group containing up to eighteen carbon atoms and pharmacologically acceptable salts and derivatives thereof.
• Thr-Lys-ProArg in which the amino group of the threonine moiety is acylated with an alkanoyl or alkenoyl group containing up to eighteen carbon atoms and pharmacologically acceptable salts and derivatives thereof.

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• 1970
  • 1970-12-16 US US00098890A patent/US3778426A/en not_active Expired - Lifetime
• 1971
  • 1971-05-14 DE DE2124003A patent/DE2124003C2/de not_active Expired
  • 1971-05-14 JP JP46032004A patent/JPS6053040B1/ja active Pending
  • 1971-12-10 CA CA129,894A patent/CA999851A/en not_active Expired
  • 1971-12-15 GB GB5823571A patent/GB1364497A/en not_active Expired
  • 1971-12-16 CH CH1838971A patent/CH605672A5/xx not_active IP Right Cessation
  • 1971-12-16 FR FR7145283A patent/FR2118134B1/fr not_active Expired

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