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
  • C07K5/0802—Tripeptides with the first amino acid being neutral
• • 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
  • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
  • C07K14/695—Corticotropin [ACTH]
• • 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
  • C07K5/06—Dipeptides
  • C07K5/06104—Dipeptides with the first amino acid being acidic
• • 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
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
  • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• A represents: H.DMet, H-L-Met O), HDMet O), H-LMet 02), H-DMet 0 desamino-Met, desamino- Met O), desamino-Met 0 or the moiety H NBCO-, in which B stands for a branched or unbranched alkylene group with 1-6 carbon atoms, and in which X represents a hydroxy group, a (N-phenylalkyl)amino group or the group LPheY, in which Y represents a hydroxy group, a (N-aminoalkyl)amino group or the group LLysZ or L-ArgZ, in which Z means a Y PZSX .eteua.-. the r u LL. B.., LTrpG1yOH or a (N3-indoly1alkyl) amino group,
• the peptide with the amino acid sequence 4-10 of ACTH does not only exert the psychopharmacological property, mentioned above, but also a slight MSH activity, as usual in this type of fragments of ACTH.
• MSH activity as usual in this type of fragments of ACTH.
• the peptide HLMet-LGlu-LHis-OH proved to be the shortest peptide inhibiting the extinction of the conditioned avoidance response at practically the same level as the known 4-10 ACTH, while the tri-peptide does not possess a demonstrable MSH activity.
• Alk represents a branched or unbranched alkylene group with 1-6 carbon atoms
• R hydrogen, halogen or hydroxy, or an alkyl or alkoxy group with 1-4 carbon atoms.
• Alk represents a branched or unbranched alkylene group with 2-6 carbon atoms, R hydrogen or a lower alkyl group, and R hydrogen, a lower alkyl group or an amidine group.
• Trp in the hexapeptide 4-9 ACTH (Met-Glu-His-Phe-Lys (or Arg)Trp) could be replaced byv a (N-3- indolylalkyl)amino group of the general formula:
• Alk represents a branched or unbranched alkylene group with l-6 carbon atoms.
• N- terminal amino acid (L-Met) in the above-mentioned peptides and peptide derivatives that was thought to be essential for psychopharmacological activity, can be replaced by various other groups, which groups do not affect the biological activity of the peptides in question, but even cause in certain cases a considerable increase of activity.
• D-methionyl, L- or D-methionylsulfoxide(Met O), L- or D-methionylsulfone(Met 0 desaminomethionyl or the corresponding sulfoxide or sulfone thereof or the moiety encompasses amino acid residues as well as aminosubstituted carboxylic acid residues, such as Gly, Val,
• the peptides in which L-Met has been replaced by one of the above-mentioned groupings, that have no asymetric .centre, such as desamino-methionyl, desamino-methionyl-sulfone, Gly or B-Ala, are preferred because these peptides can be prepared more conveniently.
• R stands for hydrogen, halogen, hydroxy, alkyl (1-4 C) or alkoxy (1-4 C) and Alk" means a branched or unbranched alkylene group with 1-6 carbon atoms
• the group LPheY in which Y represents a hydroxyl group, a (N-aminoalkyl) amino group with the general formula: NHAlkNR R (in which Alk stands for a branched or unbranched alkylene group with 2-6 carbon atoms, R for hydrogen or a lower alkyl group (1-6 C) and R for hydrogen, a lower alkyl 1-6 C) or an amidine group) or the group L-Lys-Z or LArgZ, in which 2 represents a hydroxyl group, the group L-TrpOH, L-Trp-- GlyOl-l or a (N-3-indolylalkyl)amino group, the alkyl group of which contains 1-6 carbon atoms,
• peptides and peptide derivatives according to the invention are prepared by a process commonly used in peptid-chemistry.
• the processes that are employed usually for the manufacture of the present compounds can be summarized as follows:
• Activation of the carboxyl group can be effected, for example, by converting the carboxyl group into an acid halide, an azide, anhydride, imidazolide, or an activated ester such as the N-hydroxy-succinimide ester, or the p-nitro-phenyl ester.
• the reactive groups that are not allowed to participate in the condensation reaction are protected effectiveiy by the socalled protecting groups, which can be easily removed again, for example, by hydrolysis or reduction.
• a carboxyl group can be protected effectively by esterification with methanol, ethanol, tertiary butanol, benzylalcohol or pnitrobenzylalcohol, or by conversion into an amide.
• This latter protecting group is very hard to remove, however, so that it is recommendable to use this group only to protect the carboxyl group of the C-terminal amino acid in the ultimate peptide or the Y-carboxyl group of glutamic acid.
• the peptide synthesis leads direct to the amide of a peptide according to formula 1.
• Groups that are capable of protecting an amino group effectively are usually acid groups.
• benzene-sulfonyl or p-toluene-sulfonyl but also other groups can be employed, such as substituted or unsubstituted aryl or aralkyl groups, for example benzyl and triphenylmethyl, or groups such as ortho-nitro-phenyl-sulfenyl and Z-benzoyll methylvinyl.
• the protecting groups can be split off by various conventional methods, depending upon the nature of the group in question, for example with trifluoro acetic acid, or by mild reduction, for example with hydrogen and a catalyst, such as palladium, or with HBr in glacial acetic acid.
• Peptides according to the present invention having as the N-terminal moiety a methionylsulfoxide or desaminomethionylsulfoxide group may be prepared from the corresponding Metor Desamino-Met peptide by means of a mild oxidation known per se, for example with dilute hydrogenperoxide or a peracid. Such an oxidation yields a mixture of the S- and R-sulfoxide 1- or d-sulfoxide), which mixture may be split off into the separate diastereomeric compounds in a conventional manner.
• the peptides according to the invention having as the N-terminal residue a methionylsulfone (Met 0 or desaminomethionylsulfone (desamino-Met 0 group may be prepared most conveniently by an oxida tion known per se of the corresponding Metor Desamino-Met peptide, for example with H 0 or a peracid.
• peptides or peptide derivatives in which one or more free amino groups have been substituted by an acyl group derived from an aliphatic carboxylic acid with 1-6 carbon atoms, such as an acetyl group,
• esters of the present peptides derived from aliphatic or araliphatic alcohols with 1-18 carbon atoms such as methanol, ethanol, pentanol, hexanol, cyclohexanol, octylalcohol, undecylalcohol, hexadecylalcohol, oleylalcohol, octadecylalcohol, benzylalcohol, phenylethylalcohol, phenyl propylalcohol, or cinnamylalcohol,
• the acid addition salts are obtained by reacting the present compounds with a pharmaceutically acceptable organic or inorganic acid, such as l-lCl, phosphoric acid, acetic acid, maleic acid, tartaric acid or citric acid.
• a pharmaceutically acceptable organic or inorganic acid such as l-lCl, phosphoric acid, acetic acid, maleic acid, tartaric acid or citric acid.
• the present peptides and peptide derivatives as well as their functional derivatives defined above have valuable psychopharmacological activities.
• the present compounds inhibit the extinction of conditioned avoidance response, that means that they can be used, in general, as antidepressant agents. More particularly they can be used for the treatment of certain mental disorders whereby a stimulation of the mental performance is desired, such as in certain types of neurosis and in old-age infirmities (senilit Tli e peptides according to the invention and the functional derivatives defined above can be administered orally, parenterally or intranasally.
• the peptides are employed as an injection preparation, for
• peptides can also be administered in the form of suppositories or sprays.
• the peptides or peptide derivatives according to the invention are preferably administered in daily dosages of from 0.001 to 1 mg per kg body weight, dependent upon the peptids activity level and theform in which they are administered.
• These metal complexes can be obtained by contacting the peptides with sparingly soluble metal salts, metal hydroxides or metal oxides.
• sparingly soluble metal salts the metal phosphates, metal pyrophosphates and metal polyphosphates are commonly used.
• Metals than can be used in this process are the metals belonging to the b-groups of the periodic system, for example cobalt, nickel, copper, iron, and preferably zinc, as well as the metals belonging to the main groups of the periodic system and capable of fonning complexes, such as magnesium and'aluminium.
• the preparation of the said metal complexes takes place in the conventional manner.
• a metal complex can be obtained by adding the peptide and a poorly soluble metal salt, metal hydroxide or metal oxide to an aqueous medium.
• the metal complex can also be obtained by adding an alkaline medium to an aqueous solution of the peptide and an insoluble metal salt to form the insoluble peptide/metal hydroxide complex.
• the metal complex can be obtained by adding the peptide, a soluble metal salt and a soluble salt to an aqueous, preferably alkaline medium to form an insoluble peptide/metal salt complex in situ.
• the metal complexes can be employed at once as suspensions, or for example be lyophilized and afterwards suspended again.
• Biological activity Extinction of the conditioned avoidance response.
• HMet( O)(iluHis-Ol-l i di z flg lf id 25 mg of the tripeptide l-l-Met-Glu-l-lm-OH are THF l'qtmhydrofuwn dissolved in 2.5 ml of acetic acid, after which 15 .Ll of gggfifif$f 30 percent hydrogen peroxide are added. After stirring TAA tri-ethylamine for 1 hour at 20 C, a suspension of 20 mg of platinum TFA trifluoro acetic acid black in 2.5 ml of glacial acetic acid is added and the mixture is stirred for 30 minutes. Then the mixture is filtered and the solvent distilled off in vacuum.
• reaction mixture is neutralised to pH 7, after which it is evaporated to dryness in vacuum.
• residue is taken up in 40 ml of ethyl acetate, acidified with 1.4 ml of 2 N HCl to pH 4 and washed with a little water, after which the layers are separated.
• BocV al-Glu(OtBu)-His OMe Boc-VaI-OH (3.26 g; 15 mmol) is dissolved'in 20 ml of methylene chloride, after which 1.73 g of N- 7 hydroxy succinimide are added. The solution is cooled down to 20 C, after which 3.09 g of DCCl, dissolved in 20 ml of cooled methylene chloride are added and the resulting solution is stirred for 1 hour at 20 C and then for 20 hours at +20C.
• the resulting DCHU is filtered, after which the filtrate is evaporated to dryness and the residue dissolved in 30 ml of DMF, whereupon 7.33 g of Z-G1u(Ot- Bu)-His- -OMe (prepared in accordance with Kappler Helv. 44, 1991, 1961) and 1.4 g of 10 percent pal ladium/carbon are added. Then hydrogen is bubbled through for 5 hours, after which the mixture is stirred for 1 night and filtered, and the filtrate evaporated to dryness. The residue is dissolved in aqueous ethyl ace tate and washed with citric acid, water, sodium bicarbonate and water. The organic phase is dried, after which the ethyl acetate is evaporated in vacuum.
• BocAla--Glu(OtBu)l-lisOMe Boc-AlaOl-l (3.78 g) is converted into the active ester with 2.3 g of N-hydroxy-succinimide and 4.12 g of DCCI.
• the active ester dissolved in 40 ml of DMF, is condensed with H-Glu(OtBu)--His-Ol ⁇ le, obtained from 9.77 g of ZGlu(OtBu)HisOMe as described in example [H.A. Yield: 5.56 g; melting point: 97.5-101 C.
• Rf in Bz:EtOl-l (8:2) 0.36 (SiO D.
• Boc-(o:Me)AlaGlu( OtBu)HisOl ⁇ /le (0.7 g; example 111.13) is dissolved in a cooled solution of dry ammonia gas in 20 ml of methanol. The mixture is stirred for 20 hours, after which the ammonia is evaporated, the residue taken up again in methanol and the solution diluted with ether. The precipitate formed is filtered off (0.41 g); m.p. 93-95 C. The precipitate is then dissolved in 20 ml of percent TFA. The solution is left to stand for 1 hour. after which the solvent is distilled off in vacuum, the residue obtained stirred into ether and dried over KOH tablets.
• the organic phase is washed with bicarbonate and water, after which the organic phase is dried and the solvent distilled off in vacuum.
• Boc-D-Met-Glu(OtBu)-His-Phe-OMe 0.42 2. Boc-D-Met-Glu(OtBu)-His-Phe-OH 0.14 2. Boc-D-Met-G1u(OtBu)-l-lis-Phe-NH 0.20 0.40
• Boc-D-Met-Glu(OtBu)-His-( N phenylethyl amide G Condensation of desamino-Met with the peptides prepared in E In the same manner as described in F, desaminomethionylhydrazide (5 'mmol) is converted 'into the corresponding azide by means of isoamylnitrite, after which the azide formed is coupled to one of H.
• BocMet-Glu(OtBu)-His- Phe-OH prepared in E2
• 0.25 g is dissolved in 1.4 ml
• Example Vl Synthesis of ValGlu-I-lis-Phe derivatives A. BocVal-Glu(OtBu)-HisPhe-NH Boc-Val-Ol-l (0.33 g) is dissolved in ml of DMF, after which 0.81 g of HGlu(OtBu)I-iis PheNl-l (example V.E.3) is added and the pH adjusted to 7.2. After the addition of 0.31 g of DCCI, the mixture is stirred for 5 hours at 0 C and for 20 hours at 20 C. The resulting DCHU is filtered off, after which the filtrate is poured into 100 ml of 0.1 N sodium bicarbonate and the precipitate stirred for 1 hour at 0 C.
• reaction mixture is stirred for 70 hours at 0 C, after which it is evaporated to dryness in vacuum and the residue dissolved in aqueous ethyl acetate.
• the organic phase is washed with water, bicarbonate and water, and dried.
• Boc-Val-Glu(OtBu)-His-Phe-Arg-Trp-OH 0.49.
• ZPhe-ONP ester (2.1 g) is coupled to 2.24 g of H-Lys(Boc)Trp-OMe as described in example XIILC.
• the oily ester is isolated and then saponified with 1.1 equivalent of sodium hydroxide in 10 ml of methanol.
• the tripeptide acid precipitates, which is recrystallised from methanol/water. Yield: 2.61 g.
• Rf in Bz:EtO1-l (8.2) 0.23 (SiO B. HPheLys(Boc)-TrpO1-l Hydrogenation of the tripeptide derivative of A gives a foam in quantitative yield. Crystallisation from water/methanol gives the tripeptide in 71 percent yield.
• Rf in BzzEtOl-l (8:2) 0.05 (SiO C.
• RGlu(OtBu)His-PheLys(Boc)Trp--OH R Desamino-Met or Boc-DMet
• RGlu(Ot- Bu)-HisN 1-1 in which R means: Desamino-Met or Boc-'-D-Met is coupled to the tripeptide prepared in B by means of the azide method.
• the DMF solution is poured into a tenfold quantity of water containing acetic acid (pH 3-4) to obtain a precipitate. After filtration and stirring with water the peptide is isolated as an amorphous substance in 55-60 percent yield.
• reaction mixture is stirred for 3 hours at 0C, 70 hours at room temperature and then evaporated.
• residue is stirred with 40 ml of ethyl acetate and 10 ml of water, filtered, washed with petroleum ether and dried.
• HLMet HDMet O2 desamino-Met, desarninoMet O), desamino-Met 0 and the moiety H NBCO-, in which B is alkylene having l-6 carbon atoms, and in which X is selected from the group consisting of hydroxy, (N-
• R is selected from the group consisting of hydrogen and hydroxy and Alk is alkylene with l-6 carbon atoms
• group LPheY in which Y is selected from the group consisting of hydroxy and (N- aminoalkyl)-amino selected from the group consisting of descarboxy-lysyl and descarboxy-arginyl, the groups LLys-Z and LArg-Z, in which Z is selected from the group consisting of hydroxy, the group LTrp-OH, the group L- Trp-GlyOH, and a (N3- indolylethyl) amino group, and functional derivatives of said peptide selected from the group consisting of pharmaceutically acceptable acid addition salts, derivatives in which one or more free amino groups are substituted by acyl derived from an aliphatic carboxylic acid with l-6 carbon atoms, unsubstituted amides or 26 lower alkyl (l
• A is selected from a sulfoxide and a sulfone of H-Met and X has the meanings indicated in claim 1.

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  • BE BE795788D patent/BE795788A/xx unknown
• 1972
  • 1972-02-22 NL NL7202278A patent/NL7202278A/xx unknown
• 1973
  • 1973-02-06 ZA ZA730839A patent/ZA73839B/xx unknown
  • 1973-02-08 AU AU51979/73A patent/AU471298B2/en not_active Expired
  • 1973-02-08 GB GB621973A patent/GB1416271A/en not_active Expired
  • 1973-02-12 US US00331945A patent/US3853836A/en not_active Expired - Lifetime
  • 1973-02-20 DE DE19732308362 patent/DE2308362A1/de active Pending
  • 1973-02-20 HU HUAO351A patent/HU168890B/hu unknown
  • 1973-02-21 CH CH245873A patent/CH585192A5/xx not_active IP Right Cessation
  • 1973-02-21 CA CA164,274A patent/CA1030953A/en not_active Expired
  • 1973-02-21 JP JP48021120A patent/JPS4896586A/ja active Pending
  • 1973-02-22 FR FR7306338A patent/FR2181759B1/fr not_active Expired

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