[go: up one dir, main page]

WO1992016550A1 - Composes d'organosoufre utiles pour traiter le glaucome - Google Patents

Composes d'organosoufre utiles pour traiter le glaucome Download PDF

Info

Publication number
WO1992016550A1
WO1992016550A1 PCT/DK1992/000094 DK9200094W WO9216550A1 WO 1992016550 A1 WO1992016550 A1 WO 1992016550A1 DK 9200094 W DK9200094 W DK 9200094W WO 9216550 A1 WO9216550 A1 WO 9216550A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
acm
cys
derivative
salt
Prior art date
Application number
PCT/DK1992/000094
Other languages
English (en)
Inventor
Kailash Kumar Gauri
Stig Aasmul-Olsen
Fred Widmer
Original Assignee
Carlbiotech Ltd. A/S
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
Application filed by Carlbiotech Ltd. A/S filed Critical Carlbiotech Ltd. A/S
Priority to JP4507120A priority Critical patent/JPH06505988A/ja
Publication of WO1992016550A1 publication Critical patent/WO1992016550A1/fr

Links

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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Organosulphur compounds useful for the treatment of glaucoma are:
  • the present invention relates to organosulphur compounds, pharmaceutical preparations containing such compounds and a method for treating glaucoma.
  • Glaucoma is a very common eye disease affecting millions of people in the later stages of their life. Glaucoma is characterized by abnormally high intraocular pressure and, if untreated, damage to the optic nerves which may cause narrowing of the visual field, and eventually irreversible blindness.
  • the intraocular pressure is determined by the rates of inflow and outflow, i.e. the dynamics of the aqueous humour.
  • the aqueous humour enters into the posterior chamber of the eye, and then flows through the pupil to the anterior chamber, from where it eventually leaves the eye through the trabecular meshwork.
  • the aqueous humour supplies nutrients to the lens and cornea, and its proper supply is thus of the utmost importance for maintaining healthy eyes.
  • Glaucoma drugs are thus all hypotensive agents.
  • antiglaucoma agents are adrenergic antagonists; many of them are 0-blockers (the most widely used of this type is timolol), adrenergic agonists, dopaminergic agents, cholinergic agents (the most widely used of this type is pilocarpine), or several other classes of compounds.
  • adrenergic antagonists many of them are 0-blockers (the most widely used of this type is timolol), adrenergic agonists, dopaminergic agents, cholinergic agents (the most widely used of this type is pilocarpine), or several other classes of compounds.
  • one of the characteristics of glaucoma therapy is the fact that an enormous variety of chemical structural types can be used to reduce excessively high intraocular pressure.
  • Examples are carboxyalkyl dipeptides (European Patent No. 0088350) and the atrial natriuretic factor, a long peptide of 29 amino acids in length (Fort Whitneye der Ophthalmologie, Volume 89, pp. 89/91 (1989)).
  • compositions comprising carboxyalkyl dipeptides joined through a sulfonamido group to a benzothiadiazinyl sulfonylphenyl moiety and to a method for using said composition in the treatment of glaucoma.
  • the compositions contain as active agent cyclic, proline-type amino acids, which differ substantially from the compounds according to the invention.
  • the peptide moiety present differs substantially from amino acid like compounds claimed in this invention and also the sulphur atoms obligatorily present are in SO,,-oxidized state and substituted with nitrogen to form sulfonamido groups.
  • the sulfonamido group is also present in the older antiglaucoma drug acetazolamide which is a carbonic anhydrase inhibitor and where the other sulphur atom is bound in a heterocyclic aromatic thiadiazole ring.
  • Danish Patent Application No. 1315/85 discloses a process for treatment of glaucoma and/or intraocular hypertension by using ACE inhibitors.
  • the ACE inhibitors mentioned were said to be useful also for lower- ing high blood pressure of different genesis.
  • the proposed ACE inhibitors are not of the type proposed in the present invention. Further it is not rendered possible that the compounds have the claimed effect.
  • hydrolysates of milk proteins were also described as having antiglaucoma activity (WO 86/04217 and EP 210204).
  • the peptide compositions described therein are not well defined chemical compounds as are the compounds of the present invention, rather they are mixtures which resulted from the hydrolysis of milk proteins.
  • A is absent or is a non-hydrophobic, uncharged amino acid or a derivative thereof
  • B is absent or is an uncharged amino acid or an uncharged N-methylated amino acid
  • C is an uncharged amino acid or an uncharged N-methylated amino acid
  • D is an uncharged amino acid with a non-hydrophilic "or absent side chain
  • E is cysteine or a cysteine homologue, the sulphhydryl group being free or substituted,
  • R 2 is optionally substituted NH 2 , optionally substituted OH,
  • the present invention relates to organosulphur compounds, which lower the intraocular pressure, IOP, in relevant animal models.
  • the compounds of the invention are of the general formula
  • R- is H, straight or branched alkyl or cycloalkyl up to C 20 , optionally containing double bonds and/or substituted with halogen, nitro, amino, sulpho, phospho or carboxy, or aralkyl or aryl optionally mono- or polysubstituted with halogen, hydroxy, nitro, amino, sulfo, phospho, carboxy or alkyl, or R 1 is glycosyl, nucleosyl or an L- or O-a amino acid or a peptide moiety of 2 to 8 residues connected by bonds of type [P],
  • a 0, 1, 2 or 3
  • C is a tetrahedral carbon atom (SP3 hybridized) having R or S configuration
  • C is a triplanar carbon atom (SP2 hybridized) and D is absent or C is a tetrahedral carbon atom and D is H ⁇ ,
  • [A] is absent, a decarboxy amino acid residue or NHR ', wherein R. ' is as defined for R. , and is absent when the compound is an N-C cyclic form,
  • [P] is absent or is a peptide bond CO-NH
  • [B] is absent or C.-C, optionally branched alkyl or cycloalkyl,
  • [E] is absent when the compound is in disulfide bridged form, or E is (CR 3 R. ) -NHCOR-., wherein R 3 and R. independently are H, CH 3 or halogen, and R-. is H, straight, branched alkyl or cycloalkyl, aralkyl or aryl, all of which are optionally mono- or polysubstituted with halogen, hydroxy, carboxy, sulfo, phospho, amino or nitro, or a decarboxy amino acid or a decarboxy peptide moiety, and c is 1, 2 or 3,
  • R g R g , R caution and R caution are independently H, halogen, straight, branched alkyl or cycloalkyl, aralkyl or aryl, all of which are optionally mono- or polysubstituted as indicated for R 5 ,
  • CR g R ⁇ n R ⁇ are independently H, alkyl, aralkyl or aryl, all of which are optionally mono- or polysubstituted as indicated for R..,
  • R- 2 is C 1 -C 10 aralkyl or heteroaralkyl
  • R_ 2 wherein R 12 is as defined above,
  • R 13 and R... are independently H, straight, branched alkyl or cycloalkyl, aralkyl or aryl optionally substituted as defined for R..,
  • R- r- is H, straight, branched alkyl or cycloalkyl, aralkyl or aryl, optionally substituted as defined for R--, O-glycosyl, or
  • R 2 is absent, when E is a decarboxy derivative of cysteine or a homologue thereof or the compound is an N-C cyclic form,
  • b is 1, 2, 3, 4 or 5
  • R 1 , R 2 and R-. together comprise no more than 10 amino acid residues
  • hydrogen atoms may be replaced by fluorine.
  • Preferred compounds of the invention are of the general formula
  • G -CxH is a desamino-Cy ⁇ *s or -Pen or sidechain
  • [E] is a sulphur substitution group chosen among
  • R %. 1 _ 3 which is C -C-- alkyl, such as methyl, ethyl, isopropyl, n-butyl, isobutyl, and tert.butyl, n-pentyl, isopentyl, tert.pentyl, 1,2-dimethylpropyl and 2,2- dimethylpropyl or
  • R.. which is C---C Intel homo- or heteroaralkyl, such as phenyl, benzyl, toluyl and pyridyl, or
  • [E] is absent and the compound is an S-S-dimer
  • R, , [A], [P], Cy, D, Rz and b are as defined in claim 1.
  • More preferred compounds of the invention are of the general formula I' , wherein
  • G is desamino-Cys, -Pen or -homocystein or 3-Mercaptopropionic acid
  • active compounds are H-Cys-(Acm)-Met-NH 2 , H-Ile-Gln-Cys(Acm)-NH 2 , (H-Ile-Gln) 2 ⁇ Cystine-(OMe) 2 , H-Ile-Gln-Cys(BAM)-NH 2 , 3-Mercaptopropionic acid-(Acm)-Tyr-OH
  • a number of small peptides which contain some of the basic substructures belonging to the class of compounds defined in the present invention are known, see e.g. EP 0278787, EP 0359399, EP 0179412, WO 88/03535, EP 0399656, Patent Abstract of Japan, 13, 238, US 4968696, CH 0658661, EP 0183245, EP 0161017, Patent Abstract of Japan, 7_, 171, DE 2261926, C.A. 103, 100572b, US 3959519 and US 4024286. None of the compounds disclosed are said to have antiglaucoma effect.
  • the invention relates to a pharmaceutical composition containing a compound acc ⁇ rding to the invention in an amount effective to treat glaucoma or intraocular hypertension and a pharmaceutically acceptable diluent or excipient. Additionally, the invention relates to a method for treating glaucoma or intraocular hypertension, comprising administering to a mammal an effective antiglaucoma or intraocular pressure lowering amount of a compound according to the invention.
  • the compounds of this invention are preferably used in topically applicable aqueous isotonic and sterile solutions or in sterile solutions or dispersions in an oil as used for the topical treatment of the eye.
  • a typical oil for ocular treatment is sterile castor oil.
  • These topical solutions or dispersions contain 0.01 - 10%, in particular 0.1 - 5%, preferably 0.25 - 1% (percent by weight) of at least one of the organosulphur compounds of this invention.
  • the normal dosage of these solutions is 1 to 5 drops administered to the conjunctival sac of the eye. This dosage is normally administered 2 to 6 times per day. [20 drops of a DAB-9 dropper (Tropfenbaumer gemSss "Deutsches Arzneibuch 9”) will give about 1 ml] .
  • organosulphur structures are part of peptidic compounds containing amino acids.
  • amino acid is to be understood to not only cover the 20 natural amino acids, but also to embrace amino acid replacements and substituents as recognized in the art.
  • alkyl is to be understood to cover all saturated hydrocarbons as exemplified in e.g. IUPAC. As examples are mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert.-butyl for C--C. alkyl.
  • cycloalkyl and aryl are as defined in e.g. IUPAC, and halogen means chlor, brom, iod or fluor.
  • peptide is to be understood to embrace peptide bond replacements and/or peptide mimics, i.e. pseudopeptides, as recognized in the art (see for example: Proceedings of the 20th European Peptide Symposium, edt. G. Jung, E. Bayer, pp. 289-336, and references therein), as well as salts and pharmaceutical preparations and/or formulations which render the bioactive peptide(s) particularly suitable for topical application as drops, or for oral delivery.
  • Such salts, formulations, amino acid replacements and pseudopeptide structures may be necessary and desirable to enhance the stability, formulation, deliverability, or to improve the economy of production, and they are acceptable, provided they do not negatively affect the required biological activity of the peptide as a hypotensive agent suitable for lowering of elevated intraocular pressure and glaucoma.
  • the actual pharmacological activity effects are envisaged as mediated through binding of the structurally active centre(s) of the molecules to one or more hitherto unestablished and perhaps unknown receptors in the eye.
  • the compound HAsnLeuGlyValCys(Acm)NH 2 a potent compound according to PCT DK90/00322
  • PCT DK90/00322 has been able to demonstrate any a- adrenergic agonistic or 0-adrenergic antagonistic effects, cholinergic effects or carbonic anhydrase inhibitory effects.
  • the pharmacological efficacy, potency and duration of effect may be modulated through additional structural features, such as chain elongation, optical isomerism, the substitution of peptide bond isosters, or substitution with one or more groups, which in case of susceptibility to enzymatic or spontaneous chemical conversion under the pharmacological conditions may also constitute prodrug forms.
  • Different additives and vehicles may also affect pharmacokinetic and therapeutic effects.
  • the modulation may in some cases lead to significant improvement of performance because of enhanced stability, eye penetration, transport to the receptor, or controlled release.
  • An example of the use of amino acid and N-terminal substitutions to enhance stability is given in "Enzyme resistant immunomodulatory peptides" U.S. patent 4,505,583 (1985), Goldstein, G. et al.
  • the compounds of the invention can be synthesized by various methods which are known in principle, namely by chemical coupling methods (cf. Wunsch, E. : “Methoden der organischen Chemie", Volume 15, Band 1 + 2, Synthese von Peptiden, Thieme Verlag, Stuttgart (1974), and Barrany, G.; Merrifield, R.B.: “The Peptides”, eds. E. Gross, J. Meienhofer., Volume 2, Chapter 1, pp. 1-284, Academic Press (1980)), or by enzymatic coupling methods (cf. Widmer, F., Johansen, J.T., Carlsberg Res. Commun., Volume 44, pp. 37- 46 (1979), and Kullmann, W.
  • the compounds of the invention can be produced by the above listed general synthetic methods, or by an advantageous combination thereof.
  • the compounds according to the invention can be used for the treatment of glaucoma in pharmaceutical preparations, possibly in combination with pharmaceutical carriers and delivery systems and/or other useful and pharmaceutically acceptable additives.
  • the animal model on which the IOP lowering effect of the antiglaucoma compound(s) was first established is a clinically relevant model which was developed in the laboratory of one of the inventors who has positively shown in this model the pressure lowering effect of many 5- blockers (such as timolol) and adrenergic agonists, and thus has demonstrated the clinical relevance of the model on known and putative glaucoma drugs.
  • the main feature of this clinical model is a stress induced elevation of the IOP in the rabbit eye above the initial and normal value.
  • the stress is exerted, i.e. applied, in the form of measuring the pressure (at 12 hour intervals) with the help of a SHIOTZ-Tonometer, which is loaded with 7.5 grams.
  • the pressure first begins to rise after 5 measurements, i.e. after 2 1/2 days, and reaches a maximum after 10 measurements, i.e. after 5 days.
  • the IOP activity of the compounds of the present invention has likewise been demonstrated on this model as shown in the examples. These organosulphur compounds are thus likely candidates for the treatment of glaucoma.
  • the compounds according to the invention are of low molecular weight ( ⁇ 800), and thus topically applicable, unlike the atrial natriuretic factor described in Fort Whitneye der Ophthalmologie, Volume 86, p. 89-91 (1989), which has a molecular weight of ⁇ 3000, and needs to be administered by injection to achieve an antiglaucoma effect.
  • the atrial natriuretic factor is a cardiovascular hormone and thus not suited to be used for treatment of glaucoma over prolonged periods of time.
  • both the peptidic protein hydrolysate mixtures (which are not necessarily strictly peptidic in chemical structural terms) and the atrial natriuretic factor are of a size which may give rise to an immune response followed by the production of antibodies. Such a response is unlikely to occur with the low molecular weight compounds according to the invention.
  • the mechanism, or mechanisms, by way of which the organosulphur compounds according to the invention work, is so far not known in detail and may be of hitherto unknown types or related to some known mechanisms. With the apparent lack of b-blocking effects, ⁇ -agonistic effects, cholinergic effects and inhibitory effects on the enzyme carbonic anhydrase other effects on aqueous humour outflow could be working. Some indications of mechanisms of the latter type have been found in in vitro studies. Thus, an in vitro study conducted at an early stage demonstrated that the parent compound HAsnGlyGlyValCys(Acm)NH 2 induced a marked and significant decrease of uptake of glycosamines in cultured bovine trabecular meshwork cells. From this decrease in the synthesis of glucosamineglycanes of importance in the outflow resistance was inferred.
  • the compound lowers the experimentally increased IOP in the rabbit animal model, or it antagonizes, i.e. prevents the increase in pressure when it is applied simultaneously with the treatment which inflicts the increase in the pressure.
  • the compound was a freeze-dried powder, and was applied to the rabbit eye as a powder, or as drops, dissolved in 0.9% NaCl aqueous solution. Negative control was 0.9% NaCl solution in water.
  • the studies utilized a "water load” animal model.
  • rabbits were injected intraperitonally with 60 ml/kg of sterile distilled water for injection (30 °C) spiked with an antibiotic mixture (Sigma P9032).
  • Peptides were tested for the intraocular pressure lowering or antagonising effects in the water load model or the stress induced antagonising model respectively, in groups of four to ten rabbits, as described above. The tests were performed on homogeneous groups of random sexed rabbits, weight 2.5-3.0 kg, but of different breeds in various laboratories several places in the world. Thus, in some cases intergroup variations were found in the absolute starting pressure of the rabbits' eyes.
  • each rabbit served as its own reference control for the duration of the experiment, and in the case of the stress induced antagonistic model, each group of rabbits served as reference control, at the beginning of end of 10 stress units.
  • the peptides were dissolved in plain isotonic saline, but in two cases in the waterload model, a TRIS-buffer at physiological pH was included.
  • fig. 1 shows the change in the intraocular pressure, ⁇ IOP, in mm Hg as a function of the time in minutes for the compound Peptide No. 119 [H-Cys(Acm)] 2 Cystine0Me 2 ,
  • fig. 2 shows the change in the intraocular pressure, ⁇ IOP, in mm Hg as a function of the time in minutes for the compound Peptide No. 125, H-[Pen(Acm)] 2 ⁇ NH 2 ,
  • fig. 3 shows the change in the intraocular pressure, ⁇ IOP, in mm Hg as a function of the time in minutes for the compound Peptide No. 1 VI, 1%, HIleGlnCys(Acm)NH 2 ,
  • fig. 4 shows the change in the intraocular pressure, ⁇ IOP, in mm Hg as a function of the time in minutes for the positive reference control, 2,6% pilocarpine, and
  • fig. 5 shows the mass spectrum for Peptide No. 125, H-[Pen(Acm)] 2 - NH 2 •
  • the peptides were applied topically as a 1% solution in 0.9% aqueous NaCl in aliquots of 60 ul three times daily over a period of 5 days.
  • the peptide was applied topically as a 1% solution in 0.9% aqueous NaCl in aliquots of 60 ⁇ l three times daily over a period of 5 days.
  • Val-ONSu was added and the reaction mixture stirred for one day at 4-5 °C and for one day at room temperature.
  • Boc-Ile-ONSu was dissolved in 30 ml acetonitrile and poured into a solution of 7.7 g (52.5 mmoles) L-glutamine in a mixture of 100 ml H 2 0 and 50 ml acetonitrile which had been adjusted to alkaline pH by addition of 30 ml 2 M aqueous sodium hydroxide. The mixture was stirred for 40 minutes at room temperature to completion of reaction, and pH was lowered to 6 using 10 M aqueous HC1.
  • reaction was stirred overnight at 4 °C.
  • reaction mixture was then filtered for DCU, applied to a Waters Preppak 500 C 18 column and purified using aqueous ethanol/acetic acid/water buffers. Fractions containing pure product were combined and taken to dryness under reduced pressure to give the product as a white powder.
  • Boc-Ile-Gln-Cys(BAM)-NH 2 was added 5 ml TFA. The mixture was stirred for 15 minutes. Following repeated additions of toluene and evaporation to dryness under reduced pressure, Ile-Gln-Cys(BAM)-NH 2 was then dissolved in 10 ml of 50 mM NH.Ac, filtered and applied to a C.,,, reverse phase HPLC column eqvilibrated in H 2 0, and partially purified by elution.
  • Fractions containing purified product were combined and lyophilized. The purification procedure was repeated. The product was eluted with 5% ethanol/water and lyophilized from combined fractions of pure product.
  • reaction was stirred overnight at room temperature, and pH was adjusted to 3 with HC1.
  • the reaction mixture was then filtered, applied to a Waters 20 liter reverse phase C l ⁇ column and purified using ethanol/water/acetic acid buffers.
  • Boc-Pen(Acm)-0H and 1.35 g HONSu were dissolved in 50 ml acetonitrile, and following cooling to 0°C, 1.7 g of DCC was added. Following the chemical activation, NH_ gas was bubbled though. The mixture was taken to dryness under reduced pressure, redissolved in DMF and purified by reverse phase HPLC using water/ethanol/acetic acid buffers, and combined fractions of product were taken to dryness by evaporation under reduced pressure to yield 0.8 g of Boc- Pen(Acm)-NH 2 . This was then deboced by trifluoracetic acid catalysis to yield TFA, H-Pen(Acm)-NH 2 .
  • Boc-Pen(Acm)-OH and 0.6 of HONSu were dissolved in 20 ml of DMF and cooled to 0°C, after which 0.7 g of DCC was added.
  • the TFA,H-Pen(Acm)-NH 2 prepared as above was added in 20 ml of DMF containing some TEA to neutralize the TFA.
  • the formed Boc-Pen(Acm)- Pen(Acm)-NH 2 was deboced in 20% TFA in methylene chloride, after which it was taken to dryness under reduced pressure, redissolved and purified by reverse phase HPLC using water/ethanol/acetic acid mixtures.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention concerne des composés d'organosoufre, des compositions pharmaceutiques contenant au moins un composé de ce type qui est actif contre le glaucome et l'hypertension intra-oculaire, ainsi qu'un procédé de traitement relatif au glaucome et à l'hypertension intra-oculaire.
PCT/DK1992/000094 1991-03-25 1992-03-25 Composes d'organosoufre utiles pour traiter le glaucome WO1992016550A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4507120A JPH06505988A (ja) 1991-03-25 1992-03-25 緑内症の治療に有用な有機硫黄化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0531/91 1991-03-25
DK91531A DK53191D0 (da) 1991-03-25 1991-03-25 Organosvovlforbindelse og farmaceutisk praeparat indeholdende en saadan forbindelse

Publications (1)

Publication Number Publication Date
WO1992016550A1 true WO1992016550A1 (fr) 1992-10-01

Family

ID=8094601

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1992/000094 WO1992016550A1 (fr) 1991-03-25 1992-03-25 Composes d'organosoufre utiles pour traiter le glaucome

Country Status (7)

Country Link
EP (1) EP0577690A1 (fr)
JP (1) JPH06505988A (fr)
AU (1) AU1455992A (fr)
CA (1) CA2106860A1 (fr)
DK (1) DK53191D0 (fr)
IE (1) IE920940A1 (fr)
WO (1) WO1992016550A1 (fr)

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2261926A1 (de) * 1972-12-18 1974-06-27 Degussa Dl-methionyl-dl-methionin
US4024286A (en) * 1976-05-17 1977-05-17 Miles Laboratories, Inc. Fortification of foodstuffs with C-terminal amino acid substituted methionine dipeptides
EP0161017A1 (fr) * 1984-04-13 1985-11-13 Akzo N.V. Peptides
EP0179412A2 (fr) * 1984-10-19 1986-04-30 Northwestern University Composés peptidiques antigènes
EP0183245A2 (fr) * 1984-11-30 1986-06-04 FARMITALIA CARLO ERBA S.r.l. Promoteur de croissance animal
CH658661A5 (de) * 1982-11-10 1986-11-28 Erba Farmitalia Peptidverbindungen.
WO1988003535A1 (fr) * 1986-11-06 1988-05-19 Nycomed As Composes peptidiques
EP0278787A1 (fr) * 1987-02-13 1988-08-17 Carlbiotech Ltd. A/S Procédé de production enzymatique de dipeptides
US4885293A (en) * 1984-09-24 1989-12-05 Schering Corporation Antiglaucoma agents
EP0359399A1 (fr) * 1988-08-12 1990-03-21 Carlbiotech Ltd. A/S Procédé de production enzymatique des dipeptides
US4968696A (en) * 1986-10-24 1990-11-06 Pfrimmer + Co. Pharmazeutische Werke Erlangen Gmbh + Co. Kg N,N'-bis-L-amino acid-L-cystine-peptide containing amino acid preparations for oral parenteral nutrition
EP0399656A1 (fr) * 1989-04-24 1990-11-28 Kyowa Hakko Kogyo Kabushiki Kaisha Compositions nutritives pour le supplément d'acide aminé pour mammifères!
WO1991009053A1 (fr) * 1989-12-07 1991-06-27 Carlbiotech Ltd. A/S Derive peptidique, son procede de preparation, preparation pharmaceutique le contenant et procede du traitement du glaucome
EP0474456A2 (fr) * 1990-09-03 1992-03-11 Richter Gedeon Vegyeszeti Gyar R.T. Oligopeptides ayant une activité sélective d'inhibition de la prolifération des cellules hémopoiétiques

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2261926A1 (de) * 1972-12-18 1974-06-27 Degussa Dl-methionyl-dl-methionin
US4024286A (en) * 1976-05-17 1977-05-17 Miles Laboratories, Inc. Fortification of foodstuffs with C-terminal amino acid substituted methionine dipeptides
CH658661A5 (de) * 1982-11-10 1986-11-28 Erba Farmitalia Peptidverbindungen.
EP0161017A1 (fr) * 1984-04-13 1985-11-13 Akzo N.V. Peptides
US4885293A (en) * 1984-09-24 1989-12-05 Schering Corporation Antiglaucoma agents
EP0179412A2 (fr) * 1984-10-19 1986-04-30 Northwestern University Composés peptidiques antigènes
EP0183245A2 (fr) * 1984-11-30 1986-06-04 FARMITALIA CARLO ERBA S.r.l. Promoteur de croissance animal
US4968696A (en) * 1986-10-24 1990-11-06 Pfrimmer + Co. Pharmazeutische Werke Erlangen Gmbh + Co. Kg N,N'-bis-L-amino acid-L-cystine-peptide containing amino acid preparations for oral parenteral nutrition
WO1988003535A1 (fr) * 1986-11-06 1988-05-19 Nycomed As Composes peptidiques
EP0278787A1 (fr) * 1987-02-13 1988-08-17 Carlbiotech Ltd. A/S Procédé de production enzymatique de dipeptides
EP0359399A1 (fr) * 1988-08-12 1990-03-21 Carlbiotech Ltd. A/S Procédé de production enzymatique des dipeptides
EP0399656A1 (fr) * 1989-04-24 1990-11-28 Kyowa Hakko Kogyo Kabushiki Kaisha Compositions nutritives pour le supplément d'acide aminé pour mammifères!
WO1991009053A1 (fr) * 1989-12-07 1991-06-27 Carlbiotech Ltd. A/S Derive peptidique, son procede de preparation, preparation pharmaceutique le contenant et procede du traitement du glaucome
EP0474456A2 (fr) * 1990-09-03 1992-03-11 Richter Gedeon Vegyeszeti Gyar R.T. Oligopeptides ayant une activité sélective d'inhibition de la prolifération des cellules hémopoiétiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, Vol. 13, No. 238, C603; & JP,A,01 050 897 publ 1989-02-27 (SANSHIN KAGAKU KOGYO K.K.). *

Also Published As

Publication number Publication date
JPH06505988A (ja) 1994-07-07
IE920940A1 (en) 1992-10-07
DK53191D0 (da) 1991-03-25
CA2106860A1 (fr) 1992-09-26
AU1455992A (en) 1992-10-21
EP0577690A1 (fr) 1994-01-12

Similar Documents

Publication Publication Date Title
US5411942A (en) Peptide derivative, pharmaceutical preparation containing it and method for treatment of glaucoma
US6147051A (en) Methods and compositions for the prophylactic and/or therapeutic treatment of organ hypofunction
JP4310588B2 (ja) 新規ペプチドおよびその医薬用途
JP5701375B2 (ja) 血管新生促進用ペプチド及びその使用
WO1995030687A1 (fr) Antagonistes de la neurokinine (tachykinine)
CA2613464A1 (fr) Traitement de la keratoconjonctivite seche
US5464821A (en) Small peptidic compounds useful for the treatment of glaucoma
AU679913B2 (en) Stable polypeptide composition
AU677324B2 (en) Motilin-like polypeptides with gastrointestinal motor stimulating activity
JP2013523719A (ja) 血管新生促進用ペプチド及びその使用
WO1992016550A1 (fr) Composes d'organosoufre utiles pour traiter le glaucome
JP2003231695A (ja) 新規ペプチドおよびその医薬用途
AU636427C (en) Peptide derivative, process for the preparation thereof, pharmaceutical preparation containing it and method for treatment of glaucoma
HUT62012A (en) Process for producing acid amides and peptides
HUT62915A (en) Process for producing amino acid derivatives and pharmaceutical compositions comprising same as active ingredient

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CA CH CS DE DK ES FI GB HU JP KP KR LK LU MG MN MW NL NO PL RO RU SD SE US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE BF BJ CF CG CH CI CM DE DK ES FR GA GB GN GR IT LU MC ML MR NL SE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
EX32 Extension under rule 32 effected after completion of technical preparation for international publication
WWE Wipo information: entry into national phase

Ref document number: 1992907708

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2106860

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 1993 122512

Country of ref document: US

Date of ref document: 19930924

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 1992907708

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1992907708

Country of ref document: EP