WO2002009739A1 - Treatment of ocular disorders with somatostatin analogues - Google Patents

Treatment of ocular disorders with somatostatin analogues Download PDF

Info

Publication number
WO2002009739A1
WO2002009739A1 PCT/EP2001/008620 EP0108620W WO0209739A1 WO 2002009739 A1 WO2002009739 A1 WO 2002009739A1 EP 0108620 W EP0108620 W EP 0108620W WO 0209739 A1 WO0209739 A1 WO 0209739A1
Authority
WO
WIPO (PCT)
Prior art keywords
cys
trp
phe
lys
hydrogen
Prior art date
Application number
PCT/EP2001/008620
Other languages
French (fr)
Inventor
Mario Fsadni
Kathrin Wyss
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H
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 Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H filed Critical Novartis Ag
Priority to AU2001283957A priority Critical patent/AU2001283957A1/en
Publication of WO2002009739A1 publication Critical patent/WO2002009739A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • 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

Definitions

  • the present invention relates to a method of treating ocular disorders, in particular to a method of treating ocular neurodegeneration, comprising the administration of a somatostatin analogue, in particular octreotide, to an individual in need thereof.
  • the somatostatin class is a known class of small peptides comprising the naturally occurring somatostatin-14 and analogues having somatostatin related activity, e.g. as disclosed by A.S. Dutta in Small Peptides, Vol.19, Elsevier (1993).
  • a somatostatin peptide or "a somatostatin analogue” as used herein is meant any straight-chain or cyclic polypeptide having a structure based on that of the naturally occurring somatostatin-14 wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups.
  • the terms a somatostatin and a somatostatin analogue are used within this disclosure as synonyms.
  • the above mentioned somatostatins preferably octreotide, appear to maximize and / or preserve the function of the residual visual functions. Accordingly, the addressed somatostatins are highly useful in the treatment of glaucoma alone or in addition to ocular hypotensive agents or procedures. The benefit of said treatment is not dependant upon an effect on intraocular pressure (IOP).
  • IOP intraocular pressure
  • an addressed somatostatin in particular octreotide, is highly useful in the treatment and / or prevention of ocular disorders, selected from the group consisting of: Vision loss due to progressive retinal and / or optic nerve diseases such as glaucoma, retinitis pigmentosa, diabetic macular edema and age related macular degeneration.
  • treatment and / or prevention means the treatment and the prevention of a disorder, preferably the treatment or the prevention of a disorder, more preferably the treatment and in particular the prevention of a disorder.
  • Cyclic, bridge cyclic and straight-chain somatostatin analogues or derivatives are known and have been described together with processes for their production e.g. in US Patent 4,310,518.
  • Preferred somatostatin analogues are e. g. compounds of formula (I),
  • A is d. ⁇ alkyl, C 7-10 phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen, C h alky!, phenyl or C 7- ⁇ 0 phenylalkyl, or ii) RCO- is
  • A' is hydrogen or C 1-3 alkyl
  • Yi and Y 2 represent together a direct bond or each of Yi and Y 2 is hydrogen
  • B is -Phe- optionally ring-substituted by halogen, NO 2 , NH , OH, C ⁇ -3 alkyl and /or C ⁇ -3 alkoxy (including pentafluoroalanine), naphthylalanine or pyridylalanine
  • C is (L)-Trp- or (D)-Trp- optionally a-N-methylated and optionally benzene- ring-substituted by halogen, NO 2 , NH 2 , OH, C ⁇ -3 alkyl and/or C ⁇ -3 alkoxy,
  • D is Lys, 4-aminocyclohexylAla or 4-aminocyclohexylGly
  • E is Thr, Ser, Val, Tyr, He, Leu or an aminobutyric or aminoisobutyric acid residue
  • G is a group of formula: -COOR 7 , -CH 2 OR 10 , -CONRnR ⁇ 2 or
  • R 7 is hydrogen or C h alky!
  • R 10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester
  • R 11 is hydrogen, C ⁇ -3 alkyl, phenyl or C 7- ⁇ 0 phenyl-alkyl
  • R 12 is hydrogen, C 1-3 alkyl or a group of formula -CH(R ⁇ 3 )-X ⁇
  • R 13 is CH 2 OH, -(CH 2 ) 2 -OH, -(CH 2 ) 3 -OH, or -CH(CH 3 )OH or represents the substituent attached to the a-carbon atom of a natural or synthetic a-amino acid (including hydrogen) and
  • ⁇ is a group of formula -COOR 7 , -CH 2 OR 10 or -CO-NR 14 R 15
  • R 7 and R 10 have the meanings given above,
  • R is hydrogen or C ⁇ - 3 alkyl
  • R15 is hydrogen, C ⁇ -3 alkyl, phenyl or C 7-10 phenylalkyl
  • R 1 6 is hydrogen or hydroxy
  • More preferred compounds of formula (I) are compounds (a) - (k).
  • a highly preferred compound of formula (I) is octreotide.
  • Compounds of formula (I) may exist e.g. in free form, salt form or in the form of complexes thereof.
  • Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates.
  • Complexes are e.g. formed from compounds of the invention on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts, and/or an addition of polymeric organic substances.
  • somatostatin analogues suitable for use in accordance with the present invention are: cyclo [-Asn-Phe-Phe-DTrp-Lys-Thr-Phe-Gaba-j, cyclo(Asu-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser), and (D)Nal-Glu-Tyr-(D)Trp-Lys-Val-Lys-Thr-NH 2
  • a somatostatin analogue is preferably administered in the form of a pharmaceutical composition, by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, emulsions or microemulsion preconcentrates, nasally, pulmonary (by inhalation), parenterally, e.g. in the form of injectable solutions or suspensions, in the form of an implant, such as for example a biodegradable polymer loaded with a somatostatin, or topically.
  • a somatostatin analogue is preferably administered parenterally, typically subcutaneously and intramuscularily, e.g by injection and/or infusion.
  • the somatostatin analogue may also be administered in a slow release form, e.g. as disclosed in UK Patent Specification 2,265,311 B.
  • a somatostatin analogue may be administered, e.g. subcutaneously, in a dosage range of about 100 ⁇ g to 10 mg per day as a single dose or in divided doses.
  • octreotide may be administered at a dose of from 0.2 mg to 10 mg twice or three times daily.
  • such formulation may comprise the somatostatin peptide in a concentration from 2.0 to 10% by weight. The release period of such a formulation may be from 1 week to about 2 months.
  • the invention contemplates that an active ingredient discussed herein may be utilized in combination with pharmaceutically acceptable diluents and carriers.
  • Vehicle Carboxymethylcellulose 0.5 % (by weight)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to a method of treating ocular disorders, comprising the administration of a somatostatin analogue to an individual in need thereof.

Description

TREATMENT OF OCULAR DISORDERS WITH SOMATOSTATIN ANALOGUES
The present invention relates to a method of treating ocular disorders, in particular to a method of treating ocular neurodegeneration, comprising the administration of a somatostatin analogue, in particular octreotide, to an individual in need thereof.
The somatostatin class is a known class of small peptides comprising the naturally occurring somatostatin-14 and analogues having somatostatin related activity, e.g. as disclosed by A.S. Dutta in Small Peptides, Vol.19, Elsevier (1993). By the term "a somatostatin peptide" or "a somatostatin analogue" as used herein is meant any straight-chain or cyclic polypeptide having a structure based on that of the naturally occurring somatostatin-14 wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. The terms a somatostatin and a somatostatin analogue are used within this disclosure as synonyms.
Highly surprisingly it was found that the above mentioned somatostatins, preferably octreotide, appear to maximize and / or preserve the function of the residual visual functions. Accordingly, the addressed somatostatins are highly useful in the treatment of glaucoma alone or in addition to ocular hypotensive agents or procedures. The benefit of said treatment is not dependant upon an effect on intraocular pressure (IOP). In summary, an addressed somatostatin, in particular octreotide, is highly useful in the treatment and / or prevention of ocular disorders, selected from the group consisting of: Vision loss due to progressive retinal and / or optic nerve diseases such as glaucoma, retinitis pigmentosa, diabetic macular edema and age related macular degeneration.
Within the context of the present invention the term treatment and / or prevention means the treatment and the prevention of a disorder, preferably the treatment or the prevention of a disorder, more preferably the treatment and in particular the prevention of a disorder. Cyclic, bridge cyclic and straight-chain somatostatin analogues or derivatives are known and have been described together with processes for their production e.g. in US Patent 4,310,518.
Preferred somatostatin analogues are e. g. compounds of formula (I),
A; I 2 I
N-CH-ij-BCDE-NH-CH-G (I)
A' O
wherein
A is d.^alkyl, C7-10phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen, Chalky!, phenyl or C7-ι0phenylalkyl, or ii) RCO- is
a) a D-phenylalanine residue optionally ring-substituted by halogen, NO2, NH2, OH, C-i-salkyl and/or Cι-3alkoxy; or
b) the residue of a natural or a synthetic α-amino-acid other than defined under a) above, or of a corresponding D-amino acid, or
c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, the oc-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-C1-12alkylated or substituted by Cι-8alkanoyl;
A' is hydrogen or C1-3alkyl,
Yi and Y2 represent together a direct bond or each of Yi and Y2 is hydrogen
B is -Phe- optionally ring-substituted by halogen, NO2, NH , OH, Cι-3alkyl and /or Cι-3alkoxy (including pentafluoroalanine), naphthylalanine or pyridylalanine, C is (L)-Trp- or (D)-Trp- optionally a-N-methylated and optionally benzene- ring-substituted by halogen, NO2, NH2, OH, Cι-3alkyl and/or Cι-3alkoxy,
D is Lys, 4-aminocyclohexylAla or 4-aminocyclohexylGly
E is Thr, Ser, Val, Tyr, He, Leu or an aminobutyric or aminoisobutyric acid residue
G is a group of formula: -COOR7, -CH2OR10, -CONRnRι2or
Figure imgf000004_0001
wherein
R7 is hydrogen or Chalky!,
R10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R11 is hydrogen, Cι-3alkyl, phenyl or C7-ι0phenyl-alkyl, R12 is hydrogen, C1-3alkyl or a group of formula -CH(Rι3)-Xι, R13 is CH2OH, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)OH or represents the substituent attached to the a-carbon atom of a natural or synthetic a-amino acid (including hydrogen) and ^ is a group of formula -COOR7, -CH2OR10 or -CO-NR14R15
wherein
R7 and R10 have the meanings given above,
R is hydrogen or Cι-3alkyl and
R15 is hydrogen, Cι-3alkyl, phenyl or C7-10phenylalkyl, and
R16 is hydrogen or hydroxy,
with the proviso that when R12 is -CH(R13)-X1 then Ru is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position each independently have the (L)- or (D)- configuration,
in free form or in pharmaceutically acceptable salt or complex form.
Individual compounds of formula I suitable in accordance with the present invention are the following somatostatin analogues:
(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol also known as octreotide
b I >
(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2
(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-TrpNH2
also known as vapreotide
I I
(D)Trp-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2
(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2
f- 3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2
also known as lanreotide g- (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-β-Nal-NH2
h.
3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-β-Nal-NH 2
l.
(D)Phe-Cys-β-Nal-(D)Trp-Lys-Val-Cys-Thr-NH2
j' (D)Phe-Cys-Tyr-(D)Trp-Lys-Leu-Cys-Thr-NH2
k.
(D)Phe --CCyyss--TTyyrr--((DD))TTrrpp--LLvyss--CCys-Thr-NH2
More preferred compounds of formula (I) are compounds (a) - (k).
A highly preferred compound of formula (I) is octreotide.
Compounds of formula (I) may exist e.g. in free form, salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. Complexes are e.g. formed from compounds of the invention on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts, and/or an addition of polymeric organic substances.
Further somatostatin analogues suitable for use in accordance with the present invention are: cyclo [-Asn-Phe-Phe-DTrp-Lys-Thr-Phe-Gaba-j, cyclo(Asu-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser), and (D)Nal-Glu-Tyr-(D)Trp-Lys-Val-Lys-Thr-NH2
According to the invention, a somatostatin analogue is preferably administered in the form of a pharmaceutical composition, by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, emulsions or microemulsion preconcentrates, nasally, pulmonary (by inhalation), parenterally, e.g. in the form of injectable solutions or suspensions, in the form of an implant, such as for example a biodegradable polymer loaded with a somatostatin, or topically. A somatostatin analogue is preferably administered parenterally, typically subcutaneously and intramuscularily, e.g by injection and/or infusion. The somatostatin analogue may also be administered in a slow release form, e.g. as disclosed in UK Patent Specification 2,265,311 B.
The amount administered is determined taking into account various factors such as the etiology and severity of the disease, and the patient's condition. A somatostatin analogue may be administered, e.g. subcutaneously, in a dosage range of about 100 μg to 10 mg per day as a single dose or in divided doses. Thus octreotide may be administered at a dose of from 0.2 mg to 10 mg twice or three times daily. When administered as a slow release form, such formulation may comprise the somatostatin peptide in a concentration from 2.0 to 10% by weight. The release period of such a formulation may be from 1 week to about 2 months.
The invention contemplates that an active ingredient discussed herein may be utilized in combination with pharmaceutically acceptable diluents and carriers.
A. Formulation Examples:
1. Ampoules
Octreotide 0.5 mg
Mannitol 45.0 mg
Lactic acid (88%) 3.4 mg
Sodium hydrogencarbonate to pH 4.2
Water (inject.grade) to 1 ml
Carbon dioxide q.s. iodegradable sustained release formulation
Octreotide Acetate 4.65 % (by weight)
Poly(DL-lactide-co-glycolide) 78.35 %
Sterile Mannitol 17 %
Vehicle: Carboxymethylcellulose 0.5 % (by weight)
Mannitol 0.6 %
Water for injection 98.9 %

Claims

1. A method of treating and / or preventing an ocular disorder, comprising the administration of a somatostatin analogue to an individual in need thereof.
2. Method of claim 1 , wherein said ocular disorder is selected from the group consisting of: Vision loss due to progressive retinal and / or optic nerve diseases such as glaucoma, retinitis pigmentosa, diabetic macular edema and age related macular degeneration.
3. Method of claim 1 , wherein said somatostatin analogue is a compound of formula (I),
CH^S-Y, CH2-s-Y2
A' %N-CH-rT-BCDE— NH-CH-G (I)
A' O
wherein
A is C1-12alkyl, C7-ι0phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen, Chalky!, phenyl or C7-ιophenylalkyl, or ii) RCO- is
a) a D-phenylalanine residue optionally ring-substituted by halogen, NO2, NH2, OH, C1-3alkyl and/or C1-3alkoxy; or
b) the residue of a natural or a synthetic α-amino-acid other than defined under a) above, or of a corresponding D-amino acid, or
c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, the α-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-Cι.1 alkylated or substituted by Ci-βalkanoyl; A' is hydrogen or Cι-3alkyl,
Y and Y2 represent together a direct bond or each of Y, and Y2 is hydrogen
B is -Phe- optionally ring-substituted by halogen, NO2, NH2, OH, C1-3alkyl and /or Cι-3alkoxy (including pentafluoroalanine), naphthylalanine or pyridylalanine,
C is (L)-Trp- or (D)-Trp- optionally a-N-methylated and optionally benzene- ring-substituted by halogen, NO2, NH2, OH, Cι-3alkyl and/or Cι.3alkoxy,
D is Lys, 4-aminocyclohexylAla or 4-aminocyclohexyIGIy
E is Thr, Ser, Val, Tyr, lie, Leu or an aminobutyric or aminoisobutyric acid residue
G is a group of formula: -COOR7, -CH2OR10, -CONRnRι2or
Figure imgf000010_0001
wherein
R is hydrogen or Cι.3alkyl,
R10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R11 is hydrogen, Cι-3alkyl, phenyl or C7-10phenyl-alkyl, R12 is hydrogen, Cι-3alkyl or a group of formula -CH(Rι3)-Xι, R13 is CH2OH, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)OH or represents the substituent attached to the a-carbon atom of a natural or synthetic a-amino acid (including hydrogen) and Xi is a group of formula -COOR7, -CH2OR10 or -CO-NR14R15
wherein
R and Rι0 have the meanings given above,
Ru is hydrogen or C1-3alkyl and
R15 is hydrogen, Cι-3alkyl, phenyl or C7-ι0phenylalkyl, and R 6 is hydrogen or hydroxy,
with the proviso that when R12 is -CH(Rι3)-Xι then Ru is hydrogen or methyl,
wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position each independently have the (L)- or (D)- configuration,
in free form or in pharmaceutically acceptable salt or complex form.
4. Method of claim 3, wherein said somatostatin analogue is selected from the group consisting of:
a (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol also known as octreotide
(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2
(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-TrpNH2
also known as vapreotide
j I I
(D)Trp-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2
(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2
3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2 also known as lanreotide
(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-β-Nal-NH2
I I
3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-β-Nal-NH2
(D)Phe-Cys-β-Nal-(D)Trp-Lys-Val-Cys-Thr-NH2
Figure imgf000012_0001
k.
(D)Phe-Cys-Tyr-(D)Trp-Lys-Cys-Thr-NH2
5. Method of claim 4, wherein said somatostatin analogue is
(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol also known as octreotide.
6. Method of claim 1 , wherein said administration is subcutaneously and intramuscularily.
7. Method of claim 1 , wherein said somatostatin is formulated in a slow release form.
8. Use of a somatostatin analogue, in free form or in pharmaceutically acceptable salt or complex form, for manufacturing a pharmaceutical composition for treating an ocular disorder.
9. Use of claim 8, wherein said ocular disorder is selected from the group consisting of: Vision loss due to progressive retinal and / or optic nerve diseases such as glaucoma, retinitis pigmentosa, diabetic macular edema and age related macular degeneration.
10. Use of claim 8, wherein said somatostatin analogue is a compound of formula (I),
Figure imgf000013_0001
wherein
A is Cι-ι2alkyl, C7-ι0phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen, Chalky!, phenyl or C7.10phenylalkyl, or ii) RCO- is
a) a D-phenylalanine residue optionally ring-substituted by halogen, NO2, NH2) OH, Cι.3alkyl and/or Cι-3alkoxy; or
b) the residue of a natural or a synthetic α-amino-acid other than defined under a) above, or of a corresponding D-amino acid, or
c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, the α-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-Cι-ι2alkylated or substituted by Cι-8alkanoyl;
A' is hydrogen or C1-3alkyl,
Yi and Y2 represent together a direct bond or each of Yi and Y2 is hydrogen
B is -Phe- optionally ring-substituted by halogen, NO2, NH2, OH, Cι.3alkyl and /or Cι-3alkoxy (including pentafluoroalanine), naphthylalanine or pyridylalanine, C is (L)-Trp- or (D)-Trp- optionally a-N-methylated and optionally benzene- ring-substituted by halogen, NO2, NH2, OH, C1-3alkyl and/or Cι-3alkoxy,
D is Lys, 4-aminocycIohexylAla or 4-aminocyclohexylGly
E is Thr, Ser, Val, Tyr, He, Leu or an aminobutyric or aminoisobutyric acid residue
G is a group of formula: -COOR7, -CH2OR10, -CONRnRι2or
Figure imgf000014_0001
wherein
R7 is hydrogen or Cι.3alkyl,
R10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, Ru is hydrogen, Cι-3alkyl, phenyl or C7-ι0phenyl-alkyl, R 2 is hydrogen, Cι-3alkyl or a group of formula -CH(R 3)-Xι, R13 is CH2OH, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)OH or represents the substituent attached to the a-carbon atom of a natural or synthetic a-amino acid (including hydrogen) and Xi is a group of formula -COOR7, -CH2ORι0 or -CO-NRι4Ri5
wherein
R7 and Rι0 have the meanings given above,
Rι4 is hydrogen or C1-3atkyl and
R15 is hydrogen, Cι-3alkyl, phenyl or C7-ι0phenylalkyl, and
R16 is hydrogen or hydroxy,
with the proviso that when R12 is -CH(R 3)-X then Ru is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position each independently have the (L)- or (D)- configuration,
in free form or in pharmaceutically acceptable salt or complex form.
11. Use of claim 10, wherein said somatostatin analogue is selected from the group consisting of:
a- (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol also known as octreotide
b I I
(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2
c.
(D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-TrpNH2
also known as vapreotide
(D)Trp-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2
e- (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH2
f- 3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2
also known as lanreotide
α > ' y" (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-β-Nal-NH2 h I I
3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-β-Nal-NH2
(D)P e-Cys-β-Nal-(D)Trp-Lys-Val-Cys-Thr-NH2
/ (mD)DPhhαe- ICys-Tyr-(D)Trp-Lys-Leu-Cys-Thr-NH2
(D)Phe --CCyyss--TTyyrr--((DD))TTrrpp--LLyyss--CC'ys-Thr-NH2
12. Use of claim 10, wherein said somatostatin analogue analogue is
(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol also known as octreotide.
PCT/EP2001/008620 2000-07-27 2001-07-25 Treatment of ocular disorders with somatostatin analogues WO2002009739A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001283957A AU2001283957A1 (en) 2000-07-27 2001-07-25 Treatment of ocular disorders with somatostatin analogues

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP00116068 2000-07-27
EP00116068.8 2000-07-27

Publications (1)

Publication Number Publication Date
WO2002009739A1 true WO2002009739A1 (en) 2002-02-07

Family

ID=8169349

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/008620 WO2002009739A1 (en) 2000-07-27 2001-07-25 Treatment of ocular disorders with somatostatin analogues

Country Status (2)

Country Link
AU (1) AU2001283957A1 (en)
WO (1) WO2002009739A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189856B2 (en) 2001-12-28 2007-03-13 Gideon Shapiro Non-peptide somatostatin receptor ligands
EP1787658A1 (en) 2005-11-10 2007-05-23 South Shore Properties Inc. Sustained release formulations of somatostatin analogue inhibitors of growth hormone
WO2011076368A2 (en) 2009-12-22 2011-06-30 Bcn Peptides, S.A. Topical ophthalmic peptide formulation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006185A2 (en) * 1998-07-30 2000-02-10 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Methods of using lanreotide, a somatostatin analogue
CA2263042A1 (en) * 1999-02-25 2000-08-25 Robert W.A. Kuijpers Treatment of edema

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006185A2 (en) * 1998-07-30 2000-02-10 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Methods of using lanreotide, a somatostatin analogue
CA2263042A1 (en) * 1999-02-25 2000-08-25 Robert W.A. Kuijpers Treatment of edema

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
A.C. LAMBOOIJ ET AL.: "Somatostatin receptor 2A expression in choroidal neovascularization secondary to age-related macular degeneration.", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 41, no. 8, July 2000 (2000-07-01), St. Louis, US, pages 2329 - 2335, XP000990309 *
A.C. LAMBOOIJ ET AL.: "Somatostatin receptor 2A expression in choroidal neovascularization secondary to AMD.", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 41, no. 4 Suppl., 15 March 2000 (2000-03-15), St. Louis, US, pages S 836, XP002163800 *
C.W. SPRAUL ET AL.: "Effect of thalidomide, octreotide, and decortine on the migration and proliferation of RPE cells in vitro", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 40, no. 4 Suppl., 15 March 1999 (1999-03-15), St. Louis, US, pages S 224, XP000990318 *
JAFFRAIN-REA M -L ET AL: "VISUAL IMPROVEMENT DURING OCTREOTIDE THERAPY IN A CASE OF EPISELLAR MENINGIOMA", CLINICAL NEUROLOGY AND NEUROSURGERY,NL,ELSEVIER, AMSTERDAM, vol. 100, no. 1, March 1998 (1998-03-01), pages 40 - 43, XP000907228, ISSN: 0303-8467 *
P.M. VAN HAGEN ET AL.: "Somatostatin and somatostatin receptors in retinal diseases.", EUROPEAN JOURNAL OF ENDOCRINOLOGY, vol. 143, no. Suppl. 1, October 2000 (2000-10-01), pages S 43 - S 51, XP000990364 *
R. KUYPERS ET AL.: "Somatostatin receptors in the human retina. A new target in the treatment of cystoid macular edema.", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 40, no. 4 Suppl., 15 March 1999 (1999-03-15), St. Louis, US, pages S 795, XP000990319 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189856B2 (en) 2001-12-28 2007-03-13 Gideon Shapiro Non-peptide somatostatin receptor ligands
EP1787658A1 (en) 2005-11-10 2007-05-23 South Shore Properties Inc. Sustained release formulations of somatostatin analogue inhibitors of growth hormone
WO2011076368A2 (en) 2009-12-22 2011-06-30 Bcn Peptides, S.A. Topical ophthalmic peptide formulation
US20130210728A1 (en) * 2009-12-22 2013-08-15 Bcn Peptides, S.A. Topical ophthalmic peptide formulation
AU2010335595B2 (en) * 2009-12-22 2015-08-27 Bcn Peptides, S.A. Topical ophthalmic peptide formulation
US9216208B2 (en) 2009-12-22 2015-12-22 Bcn Peptides, S.A. Topical ophthalmic peptide formulation

Also Published As

Publication number Publication date
AU2001283957A1 (en) 2002-02-13

Similar Documents

Publication Publication Date Title
US7485620B2 (en) Pharmaceutical compositions comprising unacylated ghrelin and therapeutical uses thereof
US5939387A (en) Method of treating insulin resistance
HU203480B (en) Process for producing parenteral pharmaceutical compositions containing somatostatin analogues as active components
US6362164B1 (en) Combination of a somatostatin analogue and a rapamycin
AU631547B2 (en) Treatment of arthritis
AU2007218297A1 (en) Combination of Somatostatin-analogs with different selectivity for human Somatostatin receptor subtypes
NL8203315A (en) PHARMACEUTICAL PREPARATIONS CONTAINING HUMAN INSULIN AND HUMAN C-PEPTIDE.
KR20040065212A (en) Remedies for dry eye and diseases associated with dry eye
WO2002009739A1 (en) Treatment of ocular disorders with somatostatin analogues
IE920941A1 (en) Small peptidic compounds useful for the treatment of¹glaucoma
CA2470235C (en) Pharmaceutical compositions comprising unacylated ghrelin and therapeutical uses thereof
EP1040837A2 (en) Medicaments for the treatment of a choroidal neovascularization (CNV) related disorder
CA2263042A1 (en) Treatment of edema
EP1583555A1 (en) Use of somatostatin analogs in sleep apnea
AU2008203708B2 (en) Use of somatostatin analogs in cluster headache
JP2764041B6 (en) Improvements on somatostatins
Haddock et al. The effect of the somatostatin analogue SMS 201-995 on experimental pancreatic carcinogenesis in the Syrian golden hamster
JPS6072824A (en) Medicine for metabolism dysfunction treatment
Usadel et al. Cytoprotection by somatostatins
CA2142394A1 (en) Organic compounds
MX2008010141A (en) Combination of somatostatin-analogs with different selectivity for human somatostatin receptor subtypes
JPH07316071A (en) Therapeutic agent for muscular dystrophy

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP