WO2002009739A1 - Treatment of ocular disorders with somatostatin analogues - Google Patents
Treatment of ocular disorders with somatostatin analogues Download PDFInfo
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- 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
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- cys
- trp
- phe
- lys
- hydrogen
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- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 title claims abstract description 28
- 229940075620 somatostatin analogue Drugs 0.000 title claims abstract description 22
- 208000022873 Ocular disease Diseases 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 claims description 12
- 108010016076 Octreotide Proteins 0.000 claims description 12
- 229960002700 octreotide Drugs 0.000 claims description 11
- -1 Chalky! Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 108010056088 Somatostatin Proteins 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 102000005157 Somatostatin Human genes 0.000 claims description 7
- 108010016626 Dipeptides Proteins 0.000 claims description 6
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 229960000553 somatostatin Drugs 0.000 claims description 5
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical group CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- UWPXWOJLMYFRGY-VKHMYHEASA-N (2s)-2-(difluoroamino)-2,3,3-trifluoropropanoic acid Chemical compound OC(=O)[C@](F)(C(F)F)N(F)F UWPXWOJLMYFRGY-VKHMYHEASA-N 0.000 claims description 3
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 claims description 3
- CNMAQBJBWQQZFZ-LURJTMIESA-N (2s)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 claims description 3
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 claims description 3
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 claims description 3
- 201000004569 Blindness Diseases 0.000 claims description 3
- 150000008574 D-amino acids Chemical class 0.000 claims description 3
- 125000001711 D-phenylalanine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 3
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims description 3
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 3
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 3
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 201000011190 diabetic macular edema Diseases 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
- 108010021336 lanreotide Proteins 0.000 claims description 3
- 229960002437 lanreotide Drugs 0.000 claims description 3
- 208000002780 macular degeneration Diseases 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 208000020911 optic nerve disease Diseases 0.000 claims description 3
- 230000000750 progressive effect Effects 0.000 claims description 3
- 230000002207 retinal effect Effects 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 229960002730 vapreotide Drugs 0.000 claims description 3
- 108700029852 vapreotide Proteins 0.000 claims description 3
- 230000004393 visual impairment Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 230000002265 prevention Effects 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 229960001494 octreotide acetate Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
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)
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (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
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
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
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),
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
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.
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)
| 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)
| 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 |
-
2001
- 2001-07-25 WO PCT/EP2001/008620 patent/WO2002009739A1/en active Application Filing
- 2001-07-25 AU AU2001283957A patent/AU2001283957A1/en not_active Abandoned
Patent Citations (2)
| 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 |
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| 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)
| 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 |
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