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WO1992006998A1 - Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel - Google Patents

Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel Download PDF

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Publication number
WO1992006998A1
WO1992006998A1 PCT/EP1991/001934 EP9101934W WO9206998A1 WO 1992006998 A1 WO1992006998 A1 WO 1992006998A1 EP 9101934 W EP9101934 W EP 9101934W WO 9206998 A1 WO9206998 A1 WO 9206998A1
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WO
WIPO (PCT)
Prior art keywords
arg
ile
phe
gly
asp
Prior art date
Application number
PCT/EP1991/001934
Other languages
German (de)
English (en)
French (fr)
Inventor
Gerd Schnorrenberg
Rainer Palluk
Stefan Heinrichs
Original Assignee
Boehringer Ingelheim Kg
Boehringer Ingelheim International Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19904032269 external-priority patent/DE4032269A1/de
Priority claimed from DE19904032271 external-priority patent/DE4032271A1/de
Priority claimed from DE19904032268 external-priority patent/DE4032268A1/de
Priority claimed from DE19914117733 external-priority patent/DE4117733A1/de
Priority to PL91299317A priority Critical patent/PL168456B1/pl
Priority to JP3516845A priority patent/JPH06501950A/ja
Application filed by Boehringer Ingelheim Kg, Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim Kg
Priority to SK32693A priority patent/SK32693A3/sk
Priority to CS93618A priority patent/CZ61893A3/cs
Publication of WO1992006998A1 publication Critical patent/WO1992006998A1/de
Priority to FI931499A priority patent/FI931499A0/fi
Priority to NO931341A priority patent/NO931341D0/no
Priority to KR1019930701088A priority patent/KR930702395A/ko

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • 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
    • C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin
    • C07K14/582—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new cyclopeptides made from natural and unnatural amino acid residues
  • the peptides are built, their manufacture and their use as medicines.
  • the peptides are ANP agonists.
  • the new cyclopeptides represent partial sequences, interlinked discontinuously
  • Atrial natriuretic peptide ANP
  • ANP is mainly found in the muscle cells of the
  • Plasma renin activity and the plasma aldosterone level acts spasmolytically on the smooth muscles of the
  • Intestinal and broncholytic The effect is mediated via specific receptors.
  • the invention relates to cyclopeptides of the general formula I with ANP agonistic activity, An-Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn (I)
  • Cyclopeptides are preferred in which the spacer group An contains an aromatic or cycloaliphatic radical in the part closest to the Bn member.
  • amino acid residues can be in the D or L form.
  • Cyclopeptides in which the members or the majority of the members Bn, Cn, En, Fn, Gn, Hn, In and Kn are in the L-form are preferred.
  • the spacer group An holds the ⁇ -C atoms of the members Bn and Kn at a distance of 5 to 15 angstroms.
  • An does not bind to ANP receptors, but influences the receptor binding ability and thus the pharmacological action of the cyclopeptides of the general formula I.
  • amino acid residues of the ANP are understood to mean amino acid residues or peptide templates (both the L-form and the D-form) which have the effect that the
  • Receptor binding ability of the cyclopeptide is more or less affected and the degree and in some
  • amino acid encompasses natural and unnatural amino acids.
  • Particularly suitable salts are those with physiologically compatible inorganic or organic acids, such as, for example, HCl, HBr, H 2 SO 4 , H 3 PO 4 , maleic acid,
  • the chirality centers in the new peptides can each have R, S or R, S configurations.
  • the elements Bn, Fn and In correspond to the Arg (27), Arg (11) and Arg (14) of ANP or their
  • Bn, Fn and In can independently of one another be ⁇ -amino acid residues with two basic side chains or preferably one basic side chain.
  • the basic group is preferably at the end of the side chain.
  • Cn corresponds to Phe (8) of the ANP or its structural and functional equivalents.
  • Cn can be an a-amino acid residue with two lipophilic
  • Lipophilic side chain at this position means an alkyl side chain with 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, in particular with 1 carbon atom).
  • This alkyl side chain can contain one or two oxy group (s) (-O-), thio group (s) (-S-) or -C (O) O group (s).
  • This alkyl side chain carries one or two residues. These residues are independently cycloaliphatic or aromatic residues.
  • Cycloaliphatic radical (preferably cycloalkyl radical) contains 3 to 10, preferably 4 to 7, carbon atoms.
  • the aromatic radical is preferably phenyl, naphthyl, substituted (e.g. by NO 2 , hydroxy,
  • benzo-fused aromatic heterocycle wherein 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the others
  • Links C are, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl.
  • the elements Dn and En correspond, as mentioned, to Gly (9) and Gly (10) of the ANP or their
  • Dn and En can independently be Gly or an ⁇ -amino acid residue, which is the spatial structure of the native
  • Mimicking amino acid (Gly), or Dn and En together can mean an ⁇ -amino acid residue -NH (CH 2 ) 2-11 -CO- or a peptide template.
  • amino acid residues are preferably suitable, according to the statistical analyzes by Chou and Fasman
  • Positions i + 1 and i + 2 occur with increased frequency, especially those with a frequency from 0.06 (Table 1 of the publication mentioned).
  • Suitable peptide templates include those
  • Gn and Kn correspond, as mentioned above, to Met (12) and Ile (15) of ANP or their spatial and functional structures Equivalents.
  • Gn and Kn can independently of one another be ⁇ -amino acid residues each with two lipophilic side chains or preferably one lipophilic side chain.
  • Lipophilic side chain at these positions is preferably understood to mean an alkyl side chain with 1 to 10 C atoms, preferably 1 to 6 C atoms, in particular those with at least 3 C atoms.
  • This alkyl side chain can additionally 1 or 2 oxy group (s) (-O-) or
  • This side chain can also contain 1 to 2 alkyl radicals.
  • link Hn corresponds to the Asp (13) of ANP or its spatial and functional structure
  • the link acts as a spacer.
  • Hn can be an ⁇ -amino acid residue, namely Gly or a residue which has no functional group in the side chain or -COOH and / or -CONH 2 .
  • the side chain is preferably an alkyl side chain with 1 to 6 (preferably 1-3) carbon atoms, which can also carry a phenyl group and / or HOOC (CH 2 ) 1-4 or H 2 N-CO (CH 2 ) 1-4 -.
  • This group can a) the group -A 1 -A 2 -A 3 - b) the group -A 4 -A 5 - c) an amino acid residue of the formula III
  • a 1 can be Gly or an ⁇ -amino acid residue with two
  • a 2 is a covalent bond or a
  • n is an integer from 1 to 11 (preferably 1 to 6).
  • a 3 can be an ⁇ -amino acid residue with two lipophilic
  • This alkyl side chain can contain one or two oxy group (s) (-O-), thio group (s) (-S-) or -C (O) O group (s).
  • This alkyl side chain carries one or two residues. These residues are independently cycloaliphatic or aromatic residues.
  • the cycloaliphatic radical (preferably cycloalkyl radical) contains 3 to 10, preferably 4 to 7, carbon atoms.
  • the aromatic radical is preferably phenyl, naphthyl, substituted (for example by NO 2 , hydroxy, phenyl (C 1-4 ) alkyloxy or C 1 -C 4 alkoxy) phenyl or a 5- or
  • aromatic heterocycle in which two members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl , Pyrimidinyl, pyridazinyl, indolyl,
  • a 4 can be a peptide template or an ⁇ -amino acid residue of the formula
  • n is an integer from 1 to 11
  • peptide template includes groups such as Clg, Btu, The and Trc.
  • a 5 can be a covalent bond or
  • Alkyl side chain may contain one or two oxy group (s) (-O-), thio group (s) (-S-) or -C (O) O group (s). This alkyl side chain carries one or two residues. These residues are independent
  • the cycloaliphatic radical (preferably cycloalkyl radical) contains 3 to 10, preferably 4 to 7, carbon atoms.
  • the aromatic radical is preferably phenyl, naphthyl, substituted (for example by NO, hydroxy, phenyl (C 1-4 ) alkyloxy or
  • 6-membered optionally benzo-fused aromatic heterocycle in which 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl,
  • Morpholinyl An can also be an amino acid residue of the formula III -NH- (CH 2 ) m -CH (R) -CO- (III), where m is an integer from 1 to 11 and
  • X represents hydrogen, an unsubstituted or substituted benzoyl radical, one
  • Y represents a C1 to C14 alkyl radical or aryl (C1 to C14 alkyl) radical and
  • amino acid residue of the formula is preferred
  • cyclopeptides of the general formula are those in which
  • Bn, Fn and In are independently Arg, D-Arg, Lys, D-Lys, Orn, D-Orn, Homo-Arg, D-Homo-Arg, Dap, D-Dap or 4-Amino-Phe, preferably Arg , D-Arg, Lys, D-Lys or Orn;
  • Dn and En are independently Ala, Gly, Pro, Ser, Asn, Lys, Asp or Thr or their D-form, preferably Dn D-Ala, Gly, Pro, D-Pro, Ser or D-Ser;
  • En is Gly, Asp or Asn; or
  • Dn and En together are an ⁇ -amino acid residue of the formula -NH- (CH 2 ) 2-5 -CO- or a peptide template, preferably Btu, Clg, The or Trc or their
  • Gn and Kn are independently Ile, D-Ile, Met, D-Met, Nle, D-Nle, Leu, D-Leu, Val or D-Val; preferably Ile, Met, Nle or Leu;
  • a 1 is Ala, Gly, Phe, Val, Ile, Leu or Nle or their D-form, preferably Gly, Ala or D-Ala;
  • a 2 is an ⁇ -amino acid residue of formula II, wherein n is 2, 3 or 5;
  • n 2, 3 or 5;
  • Is D-Glu (Bzl), preferably Phe, Tyr, Cha, Nal or (4-NO 2 ) -Phe; or c) an amino acid residue of the formula III, in which m 1,
  • R is as defined in claim 8, wherein X represents hydrogen, an unsubstituted or substituted by chlorine, methoxy or (C1 to C3) alkyl benzoyl radical, cyclohexyloxy or menthyloxycarbonyl radical, one
  • Benzyloxycarbonylrest preferably represents benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- or 4-trifluoromethylbenzylcarbonyl or 4-nitrobenzyloxycarbonyl, in particular benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or 2- or
  • Y represents a C1 to C14 alkyl radical or (C1 to C14 alkyl) phenyl radical, preferably benzyl or phenylethyl;
  • a 1 is Gly
  • a 3 is Phe, Phe (4-NO 2 ), Tyr or Tyr (Bzl); or
  • a 4 ßAla, Aca, The, Aund, Btu or D-Btu is, and
  • a 5 is a covalent bond, Phe, D-Phe,
  • X 2 is one of the following groups
  • Aib or Nle is
  • Aib is
  • a 2 is an ⁇ -aminoalkanoic acid residue of the formula
  • a 3 is Phe, Tyr, Cha, Nal or 4-NO 2 -Phe;
  • Cn is Phe, Cha, Tyr, Nal or Tyr (Bzl);
  • Dn is D-Ala, Gly, Phe or D-Phe;
  • En is Gly or Ala; or
  • Gn and Kn independently of each other Ile, Met, Nle or
  • Hn is Asp, Glu or Gly
  • a 1 is Gly, Ala or D-Ala; especially those in which
  • a 1 is Gly.
  • Preferred compounds according to the invention are:
  • a 4 is an ⁇ -aminoalkanoic acid residue of the formula
  • a 5 is Phe, Tyr, Cha, Nal or 4-NO 2 -Phe; Bn, Fn and In independently of one another Arg, D-Arg,
  • Cn is Phe, Cha, Tyr, Nal or Tyr (Bzl);
  • Dn is D-Ala, Gly, Phe or D-Phe;
  • En is Gly or Ala; or
  • Gn and Kn independently of each other Ile, Met, Nle or
  • Hn is Asp, Glu or Gly; especially those in which
  • Tyr is;
  • Dn is D-Ala; En is Gly; or
  • Preferred compounds according to the invention are:
  • Dn is D-Ala
  • n 1 or 4
  • R is NHX or NXY
  • X is benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2- or 4-trifluoromethylbenzyloxycarbonyl, cyclohexyloxycarbonyl or menthyloxyearbonyl
  • Y is benzyl or phenylethyl
  • Bn, Fn and In are independently Arg, D-Arg, Lys, D-Lys, Orn or Ctr;
  • Cn is Phe, Cha, Tyr, Nal, Tyr (Bzl) or 4-NO 2 -Phe; Dn is D-Ala, Gly, Phe or D-Phe;
  • En is Gly, Ala or Phe; or
  • Dn and En together are D-Btu, L-Clg or D-Clg;
  • Gn and Kn independently of each other Ile, Met, Nle or
  • Hn is Asp, Glu or Gly; especially those in which
  • Bn is Arg, Lys, Orn or Phe
  • Dn is D-Ala
  • Preferred compounds according to the invention are: 1. H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile
  • Dn is D-Ala
  • n 1 or 4
  • Dn is D-Ala, Gly, Phe or D-Phe;
  • En is Gly, Ala or Phe; or
  • Dn and En together are D-Btu, L-Clg or D-Clg; Gn and Kn independently of each other Ile, Met, Nie or
  • Hn is Asp, Glu or Gly; especially those in which
  • R is as defined above and
  • Chain -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- is, with special attention to the examples.
  • the compounds of the invention are ANP agonists. Like natural ANP, they show - specific and affine binding to ANP receptors - diuretic and saluretic properties
  • GMP probably the intracellular messenger (“second messenger”), which can be detected in plasma after ANP administration.
  • Binding to ANP receptors of zona glomerulosa cells from bovine adrenal glands is carried out according to the method of Bürgisser et al. (Biochem. Biophys. Res. Commun. 133, 1201 (1985)), modified after Bürgisser (2nd World Congress on Biologically Active Atrial
  • the examinations are anesthetized
  • the trachea is cannulated. Blood pressure is recorded from the carotid artery via a pressure-voltage converter (Statham) on a recorder (Watanabe multicorder). The heart rate is calculated from the number of pulse waves per unit of time calculated.
  • the substance is administered through a cannulated jugular vein.
  • the bladder is cannulated by a small abdominal incision and the urine is collected. The urine volume is determined gravimetrically.
  • Cyclic GMP is obtained from arterial blood using a commercially available radioimmunoassay (IBL, Hamburg)
  • the glomerular filtration rate is on
  • the vasodilatory effect in analogy to ANP is determined using a modified method by Faison et al. (Eur. J. Pharmacol. 102, 169 (1984)).
  • the rabbit breast aorta is characterized by a
  • Solvent control measured.
  • the EC 50 is determined graphically from several doses. - Broncholytic effect
  • the compounds according to the invention can be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, preferably by
  • Iontophoresis or known enhancers promoted, and take place orally.
  • the doses are a significant reduction in blood pressure (> 20 mmHg) and / or diuresis (+ 300%) or saluresis
  • Zona glomerulosa cells from bovine adrenal glands are carried out with an IC 50 between 1.10 -10 and 1.10 -5 mol / l.
  • Vascular relaxing effects on rabbit aortic rings occur in vitro with an EC 50 between 1.10 -9 and
  • the compounds according to the invention contain no disulfide bridges, which improves their metabolic stability compared to ANP and ANP-like derivatives.
  • Blood circulation (vasodilatory effect), e.g. at
  • Test methods e.g. RIA, ELISA
  • receptor binding tests e.g. radioreceptor assay
  • the invention therefore also relates to the use of the compounds of the general formula I as medicinal products and pharmaceutical preparations which contain these compounds. Use in humans is preferred.
  • the compounds according to the invention may be used with the substances customary for this, such as solubilizers, emulsifiers or others
  • solvents water, physiological saline or alcohols, e.g.
  • sugar solutions such as glucose or mannitol solutions or a mixture of different solvents.
  • the compounds can also be applied by implants, for example made of polylactide, polyglycolide or polyhydroxybutyric acid. Other options for application are intranasal, inhalation
  • the invention also relates to the use of
  • the compounds according to the invention can be prepared by generally known methods in peptide chemistry. Such processes are described in Houben-Weyl, Methods of Organic Chemistry Vol 15/2. Production after solid phase peptide synthesis (e.g.
  • anchor groups which give peptide carboxylic acids during the cleavage. It is particularly advantageous to use anchor groups in which the cleavage takes place under conditions which are so mild that any side chain protection groups which may be present are retained.
  • anchor groups are: the 2-methoxy-4-alkoxybenzyl alcohol group (M. Mergler et. Al., Proceedings of the 10th
  • the amino protecting group is split off in the case of the Boc group with trifluoroacetic acid in dichloromethane or in the case of the Fmoc group preferably with organic bases, especially amines such as piperidine or morpholine in DMF or N-methylpyrrolidone (NMP). Usual concentrations are 20 to 50% of the base in the solvent
  • Solvent is washed. Preferred solvents for these washing steps are DMF, NMP, dichloromethane, trichloromethane, methanol, ethanol, isopropanol, water and tetrahydrofuran. After the piperidine has been completely removed, the Fmoc amino acid required for the next coupling is coupled. This cycle will
  • Diisopropyl carbodiimide, ethyl (3-dimethylaminopropyl) carbodiimide or O-benzotriazol-1-yl-tetramethyl-uronium hexafluorophosphate or tetrafluoroborate R. Knorr et al., THL 30, 1927 (1989)
  • benzotriazol-1-yl-oxy- tris (dimethylamino) phosphonium hexafluorophosphate B. Castro et al., THL 1975, 1219.
  • 3-Hydroxy-4-oxo-3,4-dihydrobenzotriazine can optionally suppress racemization or increase the reaction rate.
  • Amino acids Asn and Gin are preferably coupled in the form of their N-protected p-nitrophenyl esters.
  • the Couplings are usually made with a 2- to 5-fold excess of N-protected amino acid and
  • Coupling reagent in solvents such as dichloromethane, dimethylformamide, N-methylpyrrolidone (NMP) or mixtures of these carried out.
  • solvents such as dichloromethane, dimethylformamide, N-methylpyrrolidone (NMP) or mixtures of these carried out.
  • Coupling reaction is by the Kaiser test (E. Kaiser et al., Anal. Biochem. 34, 595 (1970) or by the
  • the solid phase synthesis can be done manually as well as automatically with the help of a
  • Cyclization reagents that can be used for coupling the amino acids or also pentafluorophenyl esters / DMAP or
  • DPPA Diphenylphosphoryl azide
  • 2-methoxybenzyloxybenzyl ester anchor preferred.
  • the DCC / HOBt, DIC / HOBt or TBTU methods are used as coupling methods to build up the sequences
  • the N-terminal Fmoc group is cleaved as usual, the resin is washed thoroughly with dichloromethane after removal of the piperidine and then with a 1% solution of trifluoroacetic acid in order to cleave the peptide
  • Cyclopeptides implemented. Subsequent side chain protecting groups are then removed by appropriate cleavage reagents. Trifluoroacetic acid / scavenger mixtures are preferred. Substances such as e.g. Anisole, thioanisole, cresol, thiocresol, ethanedithiol, water or the like and mixtures of these scavengers are preferably used. The peptides are then processed and purified using the methods customary in peptide chemistry.
  • the crude products obtained are purified by means of gel chromatography, e.g. on Sephadex G25 (MR ⁇ 1400) or G15 (MR ⁇ 1400) with 1% or 5% acetic acid. If necessary, further purification is carried out using preparative RP-HPLC with methanol or
  • Cation exchangers can also be used for cleaning
  • Sephadex or polystyrene base can be used.
  • the cleaning is preferably carried out by reversed phase HPLC using water / acetonitrile gradients with the addition of
  • the peptide synthesis was carried out with an ACT200 peptide synthesizer from Advanced ChemTech using the Fmoc strategy using a modified one
  • Example 1 described a crude peptide obtained which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.50 min).

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PCT/EP1991/001934 1990-10-11 1991-10-10 Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel WO1992006998A1 (de)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CS93618A CZ61893A3 (en) 1990-10-11 1991-10-10 Cyclopeptides, process of their preparation and their use as medicaments
SK32693A SK32693A3 (en) 1990-10-11 1991-10-10 Cyclopeptides, a method of preparing them and their use as drugs
PL91299317A PL168456B1 (pl) 1990-10-11 1991-10-10 Sposób wytwarzania cyklopeptydów PL PL PL
JP3516845A JPH06501950A (ja) 1990-10-11 1991-10-10 環状ペプチド、その調製法およびその薬理組成物としての使用
FI931499A FI931499A0 (fi) 1990-10-11 1993-04-02 Cyklopeptider, foerfarande foer deras framstaellning och deras anvaendningsaosom laekemedel
NO931341A NO931341D0 (no) 1990-10-11 1993-04-07 Cyklopeptider, fremgangsmaate for fremstilling derav og deres anvendelse som legemiddel
KR1019930701088A KR930702395A (ko) 1990-10-11 1993-04-10 사이클로펩타이드, 이의 제조방법 및 약제로서의 이의 용도

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
DEP4032269.6 1990-10-11
DEP4032268.8 1990-10-11
DEP4032271.8 1990-10-11
DE19904032269 DE4032269A1 (de) 1990-10-11 1990-10-11 Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE19904032268 DE4032268A1 (de) 1990-10-11 1990-10-11 Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE19904032271 DE4032271A1 (de) 1990-10-11 1990-10-11 Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE19914117733 DE4117733A1 (de) 1991-05-30 1991-05-30 Cyclopeptide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DEP4117733.9 1991-05-30

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EP (1) EP0552238A1 (fi)
JP (1) JPH06501950A (fi)
KR (1) KR930702395A (fi)
AU (1) AU8736691A (fi)
CA (1) CA2089747A1 (fi)
CZ (1) CZ61893A3 (fi)
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Cited By (28)

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US5665704A (en) * 1993-11-12 1997-09-09 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5846932A (en) * 1993-11-12 1998-12-08 Genentech, Inc. Receptor specific atrial natriuretic peptides
WO1999067286A2 (en) * 1998-06-24 1999-12-29 The Rockefeller University Novel staphylococcus peptides for bacterial interference
WO2001013114A1 (fr) * 1999-08-16 2001-02-22 Bio-Rad Pasteur Composes synthetiques portant deux epitopes pour immunodosages
WO2001068593A2 (en) * 2000-03-15 2001-09-20 Pharmacor Inc. Amino acid derivatives as hiv aspartyl protease inhibitors
US6337385B1 (en) 1998-06-24 2002-01-08 The Rockefeller University Staphylococcus peptides for bacterial interference
US6525022B1 (en) 1993-11-12 2003-02-25 Genentech, Inc. Receptor specific atrial natriuretic peptides
WO2007115175A2 (en) 2006-03-30 2007-10-11 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
US7361636B2 (en) 2004-10-06 2008-04-22 Amr Technology, Inc. Cyclosporin alkynes and their utility as pharmaceutical agents
US7378391B2 (en) 2004-09-29 2008-05-27 Amr Technology, Inc. Cyclosporin alkyne analogues and their pharmaceutical uses
US7388008B2 (en) 2004-08-02 2008-06-17 Ambrilia Biopharma Inc. Lysine based compounds
US7511013B2 (en) 2004-09-29 2009-03-31 Amr Technology, Inc. Cyclosporin analogues and their pharmaceutical uses
US7538084B2 (en) 2003-03-17 2009-05-26 Amr Technology, Inc. Cyclosporins
US7795221B2 (en) 2006-03-30 2010-09-14 Palatin Technologies, Inc. Linear natriuretic peptide constructs
US8227450B2 (en) 2005-11-30 2012-07-24 Ambrilia Biopharma Inc. Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation
US8410300B2 (en) 2006-09-21 2013-04-02 Taimed Biologics, Inc. Protease inhibitors
US8580746B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Amide linkage cyclic natriuretic peptide constructs
US8859723B2 (en) 2010-08-13 2014-10-14 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8889632B2 (en) 2007-01-31 2014-11-18 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US8927500B2 (en) 2012-02-15 2015-01-06 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8987414B2 (en) 2012-02-15 2015-03-24 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US9096684B2 (en) 2011-10-18 2015-08-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9604919B2 (en) 2012-11-01 2017-03-28 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10023613B2 (en) 2015-09-10 2018-07-17 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of MCL-1
US10253067B2 (en) 2015-03-20 2019-04-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10301351B2 (en) 2007-03-28 2019-05-28 President And Fellows Of Harvard College Stitched polypeptides
US10471120B2 (en) 2014-09-24 2019-11-12 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10905739B2 (en) 2014-09-24 2021-02-02 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof

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WO2015179438A1 (en) * 2014-05-20 2015-11-26 Ohio State Innovation Foundation Small molecule rac or rho inhibitors

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WO1989009611A1 (en) * 1988-03-29 1989-10-19 California Biotechnology Inc. Cyclic analogs of atrial natriuretic peptides
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EP0320967A2 (en) * 1987-12-16 1989-06-21 Bio-Mega/Boehringer Ingelheim Research Inc. ANF derivatives with novel bridging
WO1989009611A1 (en) * 1988-03-29 1989-10-19 California Biotechnology Inc. Cyclic analogs of atrial natriuretic peptides
WO1990000561A1 (en) * 1988-07-07 1990-01-25 Novo Nordisk A/S Novel peptides

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525022B1 (en) 1993-11-12 2003-02-25 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5846932A (en) * 1993-11-12 1998-12-08 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5665704A (en) * 1993-11-12 1997-09-09 Genentech, Inc. Receptor specific atrial natriuretic peptides
WO1999067286A2 (en) * 1998-06-24 1999-12-29 The Rockefeller University Novel staphylococcus peptides for bacterial interference
WO1999067286A3 (en) * 1998-06-24 2000-03-16 Univ Rockefeller Novel staphylococcus peptides for bacterial interference
US6337385B1 (en) 1998-06-24 2002-01-08 The Rockefeller University Staphylococcus peptides for bacterial interference
US6953833B2 (en) 1998-06-24 2005-10-11 The Rockefeller University Staphylococcus peptides for bacterial interference
WO2001013114A1 (fr) * 1999-08-16 2001-02-22 Bio-Rad Pasteur Composes synthetiques portant deux epitopes pour immunodosages
WO2001068593A2 (en) * 2000-03-15 2001-09-20 Pharmacor Inc. Amino acid derivatives as hiv aspartyl protease inhibitors
US6455587B1 (en) * 2000-03-15 2002-09-24 Pharmacor Inc. Amino acid derivatives as HIV aspartyl protease inhibitors
WO2001068593A3 (en) * 2000-03-15 2002-02-28 Pharmacor Inc Amino acid derivatives as hiv aspartyl protease inhibitors
EP1921062A3 (en) * 2000-03-15 2008-07-16 Ambrilia Biopharma Inc. Amino acid derivatives as HIV aspartyl protease inhibitors
US7538084B2 (en) 2003-03-17 2009-05-26 Amr Technology, Inc. Cyclosporins
US7388008B2 (en) 2004-08-02 2008-06-17 Ambrilia Biopharma Inc. Lysine based compounds
US8008297B2 (en) 2004-08-02 2011-08-30 Ambrilia Biopharma Inc. Lysine based compounds
US7378391B2 (en) 2004-09-29 2008-05-27 Amr Technology, Inc. Cyclosporin alkyne analogues and their pharmaceutical uses
US7511013B2 (en) 2004-09-29 2009-03-31 Amr Technology, Inc. Cyclosporin analogues and their pharmaceutical uses
US7361636B2 (en) 2004-10-06 2008-04-22 Amr Technology, Inc. Cyclosporin alkynes and their utility as pharmaceutical agents
US7632807B2 (en) 2004-10-06 2009-12-15 Albany Molecular Research, Inc. Cyclosporin alkynes and their utility as pharmaceutical agents
US8580995B2 (en) 2005-11-30 2013-11-12 Taimed Biologics, Inc. Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation
US8227450B2 (en) 2005-11-30 2012-07-24 Ambrilia Biopharma Inc. Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation
US8580746B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Amide linkage cyclic natriuretic peptide constructs
US7795221B2 (en) 2006-03-30 2010-09-14 Palatin Technologies, Inc. Linear natriuretic peptide constructs
US7622440B2 (en) 2006-03-30 2009-11-24 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
US8580747B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
WO2007115175A2 (en) 2006-03-30 2007-10-11 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
US8410300B2 (en) 2006-09-21 2013-04-02 Taimed Biologics, Inc. Protease inhibitors
US8742158B2 (en) 2006-09-21 2014-06-03 TaiMed Biologies, Inc. Protease inhibitors
US8889632B2 (en) 2007-01-31 2014-11-18 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US9527896B2 (en) 2007-01-31 2016-12-27 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US10301351B2 (en) 2007-03-28 2019-05-28 President And Fellows Of Harvard College Stitched polypeptides
US8859723B2 (en) 2010-08-13 2014-10-14 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9957299B2 (en) 2010-08-13 2018-05-01 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9522947B2 (en) 2011-10-18 2016-12-20 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10308699B2 (en) 2011-10-18 2019-06-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9096684B2 (en) 2011-10-18 2015-08-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8927500B2 (en) 2012-02-15 2015-01-06 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8987414B2 (en) 2012-02-15 2015-03-24 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US10213477B2 (en) 2012-02-15 2019-02-26 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10227380B2 (en) 2012-02-15 2019-03-12 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US9505804B2 (en) 2012-02-15 2016-11-29 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9845287B2 (en) 2012-11-01 2017-12-19 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US9604919B2 (en) 2012-11-01 2017-03-28 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10669230B2 (en) 2012-11-01 2020-06-02 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10471120B2 (en) 2014-09-24 2019-11-12 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10905739B2 (en) 2014-09-24 2021-02-02 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof
US10253067B2 (en) 2015-03-20 2019-04-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10023613B2 (en) 2015-09-10 2018-07-17 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of MCL-1

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CZ61893A3 (en) 1994-01-19
AU8736691A (en) 1992-05-20
FI931499L (fi) 1993-04-02
CA2089747A1 (en) 1992-04-12
SK32693A3 (en) 1993-09-09
KR930702395A (ko) 1993-09-09
HUT63859A (en) 1993-10-28
IE913582A1 (en) 1992-04-22
FI931499A0 (fi) 1993-04-02
JPH06501950A (ja) 1994-03-03
HU9301054D0 (en) 1993-07-28
EP0552238A1 (de) 1993-07-28

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