EP0090798A1 - A drug based on a substance p antagonist - Google Patents
A drug based on a substance p antagonistInfo
- Publication number
- EP0090798A1 EP0090798A1 EP81902811A EP81902811A EP0090798A1 EP 0090798 A1 EP0090798 A1 EP 0090798A1 EP 81902811 A EP81902811 A EP 81902811A EP 81902811 A EP81902811 A EP 81902811A EP 0090798 A1 EP0090798 A1 EP 0090798A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substance
- trp
- pro
- prophylactically
- antagonist
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
Links
- 239000003890 substance P antagonist Substances 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title claims abstract description 14
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims abstract description 35
- 101800003906 Substance P Proteins 0.000 claims abstract description 35
- 206010061218 Inflammation Diseases 0.000 claims abstract description 16
- 230000004054 inflammatory process Effects 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 9
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 9
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 claims abstract description 7
- 102100024304 Protachykinin-1 Human genes 0.000 claims abstract 12
- 239000013543 active substance Substances 0.000 claims abstract 3
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims description 19
- 230000000699 topical effect Effects 0.000 claims description 7
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000005557 antagonist Substances 0.000 abstract description 9
- 230000001960 triggered effect Effects 0.000 abstract 2
- 102400000096 Substance P Human genes 0.000 description 23
- 239000000126 substance Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-Phenylalanine Chemical group OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000005036 nerve Anatomy 0.000 description 6
- 239000012530 fluid Substances 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000001179 pupillary effect Effects 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 210000000554 iris Anatomy 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 230000001800 adrenalinergic effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 230000000763 evoking effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- -1 t-butyloxycarbonyl Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- OIXLLKLZKCBCPS-RZVRUWJTSA-N (2s)-2-azanyl-5-[bis(azanyl)methylideneamino]pentanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.OC(=O)[C@@H](N)CCCNC(N)=N OIXLLKLZKCBCPS-RZVRUWJTSA-N 0.000 description 1
- WBIIPXYJAMICNU-AWEZNQCLSA-N (2s)-5-[amino-[(4-methylphenyl)sulfonylamino]methylidene]azaniumyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate Chemical compound CC1=CC=C(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(O)=O)C=C1 WBIIPXYJAMICNU-AWEZNQCLSA-N 0.000 description 1
- HJMMCTZLXOVMFB-LBPRGKRZSA-N (4-nitrophenyl) (2s)-5-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoate Chemical compound CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)OC1=CC=C([N+]([O-])=O)C=C1 HJMMCTZLXOVMFB-LBPRGKRZSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 229930182820 D-proline Natural products 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010027646 Miosis Diseases 0.000 description 1
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- UEKYKRQIAQHOOZ-KBPBESRZSA-N Pro-Trp Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)[O-])C(=O)[C@@H]1CCC[NH2+]1 UEKYKRQIAQHOOZ-KBPBESRZSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000775 effect on neurotransmitter Effects 0.000 description 1
- 210000003372 endocrine gland Anatomy 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000003547 miosis Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 101150006061 neur gene Proteins 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Definitions
- the present invention relates to a Substance P antagonist for use in drugs for the prophylactic or therapeutic treatment of diseases released by Substance P, to a method of prophylactically or therapeutically treat ing such a disease, and to a drug for prophylactically. or therapeutically treating inflammations. More specifically, the invention relates to a Substance P antagonist which, in relation to Substance P, has a structure in which L-proline in position 2 has been replaced by D-proline, and L-phenylalanine in position 7 and
- the Substance P antagonist according to this inven tion thus is (D-Pro 2 , D-Trp 7 ' 9 ) Substance P having the formula
- transmitter substances or transmitters consist not only of substances related to adrenaline and acetyl choline (adrenergic and cholinergic nerves, respectively), but also of chemical compounds made up of a series of amino acids joined by peptide bonds, i.e. polypeptides or oligopeptides. In most cases, peptides alone can serve as such neur ⁇ transmitters. A whole series of peptides having this function are already known (see for example the papers published in the New England Journal of Medicine, Vol. 304, pp. 876-885 and 944-951).
- Substance P may be classed among transmitter substances because it has been shown to occur both in nerves transmitting impulses from peripheral parts of the body to the brain (afferents) and nerves extending from the brain (or peripheral ganglia) to different peripheral organs (efferents).
- Substance P is deemed to play an important part in the transmission of pain stimuli from the periphery to the brain.
- the efferent nerves which contain Substance P are apparently capable of stimulating secretion from endocrine glands and causing vasodilation and. contraction of smooth muscle.
- Substance P as synthetized by us has an inhibiting effect on inflammatory conditions in the body, especially the skin, the upper airpassages, the intestine and the eye.
- the present invention therefore relates to the Substance P antagonist (D-Pro 2 , D-Trp 7,9 ) Substance P for use in drugs for the prophylactic or therapeutic treatment of diseases released by substance P.
- the invention concerns a drug for the prophylactic or therapeutic treatment of inflammations, in particular inflammations in the eye.
- the invention relates to a method of prophylatically or therapeutically treating diseases released by Substance P, in particular such diseases as inflammations in the skin, the upper air-passages, the intestine and/or the eye.
- a suitable form for administration of the drug according to this invention is by topical application. Preparation of the Substance P antagonist according to the invention
- L-Arg-D-Pro-L-Lys-L-Pro-L-Gln-L-Gln-D-Trp-L-Phe-D-Trp-L-Leu-L-Met-NH 2 is prepared in a manner that is conventional in this particular field, viz. by the solid phase method described by R.B. Merrifield (J. Am. Chem. Soc., 85, (1963), 2149-2154).
- the solid phase employed is the benzhydrylamine resin described by Monahan et al. (Biochem. Biophys. Res. Com. 48, 1100-1105, (1972)).
- the starting materials employed in the preparation were Boc-Arg-Tos, Boc-Gln-ONp and Boc-Leu from Ferring AB, Malmö, Sweden; D-Pro, Pro, D-Trp and Phe from Merck Darmstadt, Federal Republic of Germany; and the benzhydrylamine resin from Beckman Inc.
- the synthesis was conducted by stages, starting from 5 g BHA resin, 0.51 meq. NH 2 /g, and the amino acids in the compound according to the invention were coupled according to the following schedule
- the peptide content of the material was 86.7%, based on the triacetate.
- the Substance P antagonist used for the present invention was shown to inhibit or cure inflammation by the following experiment.
- a similar inflammatory reaction can be evoked by infrared radiation of a restricted area on the iris.
- the Substance P antagonist according to this invention 90 nmol of the Substance P antagonist according to this invention were injected into the corpus vitrium of the left eye (3 rabbits).
- the right eye was used for control purposes and was given 0.9% saline.
- the irises of both eyes were exposed to infrared radiation.
- the amount of protein in the chamber fluid was measured, and it was found that the so-called light path in the left, treated eye was substantially unchanged, whereas it had been trebled in the right control eye.
- the experiments carried out to induce inflammation by infrared radiation also comprised experiments which showed that the minimum amount of recordable effects was 0.9 nmol of the Substance P antagonist in saline, while the minimum dose for maximum effect was 90 nmol in saline.
- the effect of the antagonist was found to be dose-dependent and rather linear.
- the Substance P antagonist according to the invention was used dissolved in saline for injection and eye drops, but other forms of administration for topical application by spraying, inhalation, instillation, insufflation and injection are also possible. Furthermore, salves, creams, suppositories, tablets, capsules and granulates can be prepared in which the active constituent consists of the Substance P antagonist according to this invention and the remaining ingredients are conventional inert carriers, diluents, excipients etc.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Un antagoniste de substance P est utilisé dans des médicaments pour le traitement prophylactique ou thérapeutique de maladies déclenchées par la substance P. L'antagoniste consiste en (D-Pro2, D-Trp7,9) Substance P ayant la formule$(6,)$. Un médicament pour le traitement prophylactique ou thérapeutique d'inflammations, spécialement dans l'oeil, est également décrit, ce médicament contenant comme substance active l'antagoniste de la substance P mentionné ci-dessus. De plus, un procédé de traitement prophylactique ou thérapeutique d'une maladie déclenchée par la substance P, ou des inflammations, spécialement dans l'oeil, est également décrit. Dans ce procédé, on utilise une quantité thérapeutiquement active de (D-Pro2, B-Trp7,9) Substance P, spécialement sous une forme appropriée à une application locale.A substance P antagonist is used in medicines for the prophylactic or therapeutic treatment of diseases triggered by substance P. The antagonist consists of (D-Pro2, D-Trp7,9) Substance P having the formula $(6,) $. A medicament for the prophylactic or therapeutic treatment of inflammations, especially in the eye, is also described, this medicament containing as active substance the substance P antagonist mentioned above. Additionally, a method of prophylactic or therapeutic treatment of disease triggered by substance P, or inflammations, especially in the eye, is also described. In this process, a therapeutically active amount of (D-Pro2, B-Trp7,9) Substance P is used, especially in a form suitable for local application.
Description
A DRUG BASED ON A SUBSTANCE P ANTAGONIST
The present invention relates to a Substance P antagonist for use in drugs for the prophylactic or therapeutic treatment of diseases released by Substance P, to a method of prophylactically or therapeutically treat ing such a disease, and to a drug for prophylactically. or therapeutically treating inflammations. More specifically, the invention relates to a Substance P antagonist which, in relation to Substance P, has a structure in which L-proline in position 2 has been replaced by D-proline, and L-phenylalanine in position 7 and
L-glycocoll in position 9 have been replaced by D-tryp tophan.
The Substance P antagonist according to this inven tion thus is (D-Pro 2, D-Trp7'9) Substance P having the formula
L-Arg-D-Pro-L-Lys-L-Pro-L-Gln-L-Gln-D-Trp-L-Phe-D-Trp-L-Leu-L-Met-NH2
Background
In recent years, it has been shown that substances which transmit signals to the nervous system, so-called transmitter substances or transmitters, consist not only of substances related to adrenaline and acetyl choline (adrenergic and cholinergic nerves, respectively), but also of chemical compounds made up of a series of amino acids joined by peptide bonds, i.e. polypeptides or oligopeptides. In most cases, peptides alone can serve as such neur©transmitters. A whole series of peptides having this function are already known (see for example the papers published in the New England Journal of Medicine, Vol. 304, pp. 876-885 and 944-951).
Nowadays a polypeptide called Substance P may be classed among transmitter substances because it has been shown to occur both in nerves transmitting impulses from peripheral parts of the body to the brain (afferents)
and nerves extending from the brain (or peripheral ganglia) to different peripheral organs (efferents).
Substance P is deemed to play an important part in the transmission of pain stimuli from the periphery to the brain. The efferent nerves which contain Substance P are apparently capable of stimulating secretion from endocrine glands and causing vasodilation and. contraction of smooth muscle.
Although Substance P was discovered already in 1931 by von Euler and Gaddum, J. Physiol. 72, 74 (1931), the structure of Substance P
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 was not discovered until 1971 by Chang et al, Nature New Biol. 232, 86 (1971).
It has long been known that stimulating effects produced by neurotransmitters can be reduced or suspended. Such blocking of the nervous impulse or its effect can be achieved by substances which are in close chemical relation to the transmitter itself and which therefore react with the sensors (receptors) via which the transmitter substances transmit impulses in the nerve synapses or act upon their targets. A great number of substances are known which have such a blocking (antagonistic) effect on neurotransmitters, although most of them refer to the neurotransmitters in the adrenergic or cholinergic nerves. Prior Art
It is only in the last few years that one has tried to find antagonists against Substance P. Recently published results of examinations of some antagonists against Substance P have shown that these antagonists have an inhibiting effect on Substance P-induced salivation and on smooth muscle stimulated by Substance P. (See K Folkers et al, Acta Physiol, Scand 1981, 111, 505-506).
It has been suggested that a compound having the structure (D-Pro2, D-Trp7,9) Substance P as referred
to in the present application, is an antagonist against Substance P. The compound in question was shown speci fically to block in vivo the Substance P-induced excitation of locus coerulens neurons and was therefore con- sidered to be a CNS antagonist against Substance P.
The works which have so far been published on antagonists against Substance P have solely aimed at finding antagonists, thereby to be able to establish which physiological functions in the body are controlled or affected by Substance P, but any effective drugs have not been developed. The Invention
It has now been found, very surprisingly, that the substance (D-Pro 2-D-Trp7,9) Substance P as synthetized by us has an inhibiting effect on inflammatory conditions in the body, especially the skin, the upper airpassages, the intestine and the eye.
The present invention therefore relates to the Substance P antagonist (D-Pro 2, D-Trp7,9) Substance P for use in drugs for the prophylactic or therapeutic treatment of diseases released by substance P. In addition, the invention concerns a drug for the prophylactic or therapeutic treatment of inflammations, in particular inflammations in the eye. Furthermore, the invention relates to a method of prophylatically or therapeutically treating diseases released by Substance P, in particular such diseases as inflammations in the skin, the upper air-passages, the intestine and/or the eye. A suitable form for administration of the drug according to this invention is by topical application.
Preparation of the Substance P antagonist according to the invention
The following abbreviations are used:
Met Methionine Leu Leucine
Trp Tryptophan
Phe Phenylalanine
Gin Glutamine
Pro Proline Lys Lysine
Arg Arginine
DCC Dicyclohexyl carbodiimide
AC2O Acetic anhydride
Py Pyridine HONp p-nitrophenol
Np Nitrophenyl
Boc t-butyloxycarbonyl
TFA Trifluoroacetic acid
DMF Dimethylformamide BHA Benzhydrylamine
(D-Pro2, D-Trp7,9) Substance P having the formula
L-Arg-D-Pro-L-Lys-L-Pro-L-Gln-L-Gln-D-Trp-L-Phe-D-Trp-L-Leu-L-Met-NH2 is prepared in a manner that is conventional in this particular field, viz. by the solid phase method described by R.B. Merrifield (J. Am. Chem. Soc., 85, (1963), 2149-2154). The solid phase employed is the benzhydrylamine resin described by Monahan et al. (Biochem. Biophys. Res. Com. 48, 1100-1105, (1972)).
The starting materials employed in the preparation were Boc-Arg-Tos, Boc-Gln-ONp and Boc-Leu from Ferring AB, Malmö, Sweden; D-Pro, Pro, D-Trp and Phe from Merck Darmstadt, Federal Republic of Germany; and the benzhydrylamine resin from Beckman Inc.
The t-butyloxycarbonyl protective group (Boc) was coupled to D-Pro, Pro, Phe and D-Trp by means of 2-(tbutyloxycarbonyl oxyimino)-2-ρhenylacetonitrile (Boc-ON).
(M. Itoh, D. Hagiwara, T. Kamiya, Tetrahedron Letters 4393 (1975)).
The synthesis was conducted by stages, starting from 5 g BHA resin, 0.51 meq. NH2/g, and the amino acids in the compound according to the invention were coupled according to the following schedule
1 Boc-Het-NH-BHA
2 Boc-Leo-Het-NH-BHA 3 Boc-D-Trp-leu-Het-NH-BHA
4 Boc-Phe-D-Trp-Leu-Het-NH-BHA
5 Boc-D-Trp-Phe-D-Trp-Leu-Het-NH-BHA
6 Boc-Gln-D-Trp-Phβ-D-Trp-Leu-Het-NH-BHA
7 Boc-Gln-Gln-D-Trp-Phe-D-Trp-leu-Het-NH-BHA
8 Boc-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Het-NH-BHA
9 Boc-Lys(Z}-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Het-NH-BHA 10 Boc-D-Pro-Lys(Z)-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Het-NH-BHA 11 Boc-Arg (ToS)D-Pro-Lys(Z)-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Met-NH-BHA
After the coupling stages, the peptide was split off from the resin, and after purification of the peptide by gel filtration and column chromatography as well as lyophilization, the required product was obtained which was then analyzed. HPLC Column: μ-Bondapak C 18, (Waters), 2.4x300 mm Mobile phase: 32% CH.CN, 68% K-phosphate buffer
0.1 M, ph 3.0 Flow rate: 1.5 ml/min Detection: 210 nm In this system, the substance had a retention time of
8.14 min. It gave a single symmetrical shoulderless peak, with an integral of 98.1 area percent. Thin-layer chromatography
Thin-layer chromatography was run on Merck HPTLC plates (Silica gel 60). Distance run: 15 cm. The substance was uniform in the following solvent system:
Amino acid analysis
For the analysis , the substance (1 mg) was hydro lized in 1 ml 4 M methane sulphonic acid containing 0.2% tryptamme for 24 h in a sealed tube at 120°C. The amino acid analysis was carried out on a Biotronik-LC-2000 amino acid analyser. For the individual amino acids, the following results were obtained:
Glu: 2.08; Pro: 2.00; Met: 1.05; Leu: 0.99; Phe: 1.01; Arg: 1.06; Trp: 1.9.
The peptide content of the material was 86.7%, based on the triacetate. Optical rotation
Measuring was effected with a Perkin-Elmer polari meter. For the measuring, 10 mg of the substance were dissolved in 1 ml methanol, and measuring was carried out at a layer thickness of 10 cm. Temp. = 25°C. Thus, there was obtained
= —40.'1o. The effect of (D-Pro2, D-Trp7,9) Substance P on inflammation
The Substance P antagonist used for the present invention was shown to inhibit or cure inflammation by the following experiment.
Injection of Substance P into the corpus vitrium of a rabbit's eye evokes inflammatory reaction. The inflammatory effects were recorded on the basis of the ensuing miosis and the increase in the amount of protein within the chamber fluid. The change in the pupillary diameter was measured with a ruler, and the amount of protein in the chamber fluid was estimated by measur
ing the so-called "light path" which is determined by admitting a luminous ray into the eye and recording the Tyndall phenomenon in the eye chamber which is a consequence of the light-reflecting ability of the protein in the chamber fluid. This reflection phenomenon may be quantized and related to a standard according to a method previously described by Anjou and Krakau (Acta Ophthalmol. 39, 1, 1961).
A similar inflammatory reaction can be evoked by infrared radiation of a restricted area on the iris.
Three rabbits were injected with 30 nmol Substance P antagonist according to the invention in the corpus vitrium of the left eye, and with 0.9% saline in the corpus vitrium of the right eye. After three hours, 3 nmol Substance P were injected in the same localities. One hour later the differences between the pupillary diameters of both eyes were measured, and it was found that the pupillary diameter of the left eye had been reduced by about 0.5 mm, while the pupillary diameter of the right eye had been reduced by about 2.7 mm, and the amount of protein in the chamber fluid in the right eye had increased twice as much as in the left eye. By these experiments, it could be established that the Substance P antagonist according to this invention in itself had but an insignificant effect on the eye.
90 nmol of the Substance P antagonist according to this invention were injected into the corpus vitrium of the left eye (3 rabbits). The right eye was used for control purposes and was given 0.9% saline. After three hours, the irises of both eyes were exposed to infrared radiation. One hour after radiation, the amount of protein in the chamber fluid was measured, and it was found that the so-called light path in the left, treated eye was substantially unchanged, whereas it had been trebled in the right control eye.
Analogous experiments were carried out by administering the Substance P antagonist and the saline in eye
drops, and it was found that the so-called light path was more than twice as large in the control eye than in the treated eye.
The experiments carried out to induce inflammation by infrared radiation also comprised experiments which showed that the minimum amount of recordable effects was 0.9 nmol of the Substance P antagonist in saline, while the minimum dose for maximum effect was 90 nmol in saline. The effect of the antagonist was found to be dose-dependent and rather linear.
To sum up, it can be established that inflammation of the eye, evoked by injection of Substance P into the corpus vitrium or by infrared radiation of the iris, was inhibited or cured by the Substance P antagonist according to this invention which was injected into the corpus vitrium or administered in the form of eye drops.
Preparation of a solution for topical application The purified substance (D-Pro2, D-Trp7,9) Substance
P which had been kept in lyophilized form, was dissolved in saline to suitable concentration. The solution was filtered under sterile conditions and filled into sterile bottles, whereupon it was used for the experiments described above.
In the above experiments, the Substance P antagonist according to the invention was used dissolved in saline for injection and eye drops, but other forms of administration for topical application by spraying, inhalation, instillation, insufflation and injection are also possible. Furthermore, salves, creams, suppositories, tablets, capsules and granulates can be prepared in which the active constituent consists of the Substance P antagonist according to this invention and the remaining ingredients are conventional inert carriers, diluents, excipients etc.
Claims
1. A Substance P antagonist for use in drugs for the prophylactic or therapeutic treatment of diseases released by Substance P, c h a r a c t e r i s e d in that it consists of (D-Pro2, D-Trp7,9) Substance P hav ing the formula
L-Arg-D-Pro-L-Lys-L-Pro-L-Gln-L-Gln-D-Trp-L-Phe-D-Trp-L-Leu-L-Met-NH2
2. A drug for the prophylactic or therapeutic treatment of inflammations, c h a r a c t e r i s e d in that it comprises, as the active substance, (D-Pro2, D-Trp 7,9) Substance P together with an inert carrier or excipient.
3. A drug for the prophylactic or therapeutic treatment of inflammations in the eye, c h a r a c t e r i s e d in that it comprises, as the active substance, (D-Pro2, D-Trp7,9) Substance P together with an inert carrier or excipient.
4. A drug as claimed in claim 2 or 3, c h a r a c t e r i s e d in that it is available in a form suitable for topical application.
5. A method of prophylactically or therapeutically treating a disease released by Substance P, c h a r a c t e r i s e d by administering a prophylactically or therapeutically active amount of (D-Pro2, D-Trp7,9) Substance P.
6. A method as claimed in claim 5, c h a r a c t e r i s e d by administering the prophylactically or therapeutically active amount of (D-Pro 2, D-Trp7,9)
Substance P by topical application.
7. A method of prophylactically or therapeutically treating inflammations, c h a r a c e r i s e d by administering a prophylactically or therapeutically active amount of (D-Pro2, D-Trp7,9) Substance P.
8. A method as claimed in claim 7, c h a r a c t e r i s e d by administering the prophylactically or therapeutically active amount of (D-Pro7, D-Trp7,9)
Substance P by topical application.
9. A method of prophylactically or therapeutically treating inflammations in the eye, c h a r a c t e r i s e d by administering a prophylactically or therapeu- tically active amount of (D-Pro2, D-Trp7,9) Substance P.
10. A method as claimed in claim 9, c h a r a c t e r i s e d by administering the prophylactically or therapeutically active amount of (D-Pro2, D-Trp7,9)
Substance P by topical application.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/SE1981/000292 WO1983001252A1 (en) | 1981-10-09 | 1981-10-09 | A drug based on a substance p antagonist |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0090798A1 true EP0090798A1 (en) | 1983-10-12 |
Family
ID=20342922
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP81902811A Ceased EP0090798A1 (en) | 1981-10-09 | 1981-10-09 | A drug based on a substance p antagonist |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0090798A1 (en) |
| JP (1) | JPS58501675A (en) |
| BE (1) | BE894602A (en) |
| IT (1) | IT1191028B (en) |
| WO (1) | WO1983001252A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0391909B1 (en) * | 1987-09-03 | 1994-08-17 | The University Of Georgia Research Foundation, Inc. | Ocular cyclosporin composition |
| US6203803B1 (en) | 1994-12-14 | 2001-03-20 | Societe L'oreal S.A. | Use of a substance P antagonist in a cosmetic composition, and the composition thus obtained |
| FR2719474B1 (en) * | 1994-05-05 | 1996-05-31 | Oreal | Use of a substance P antagonist in a cosmetic composition and composition obtained. |
| FR2719476B1 (en) * | 1994-05-05 | 1997-05-23 | Oreal | Use of a substance P antagonist in a cosmetic composition and composition obtained. |
| FR2728265A1 (en) * | 1994-12-19 | 1996-06-21 | Oreal | USE OF A SUBSTANCE P ANTAGONIST IN A PHARMACEUTICAL COMPOSITION |
| FR2732598B1 (en) | 1995-04-10 | 1997-05-09 | Oreal | USE OF ALKALINE EARTH METAL SALT FOR THE TREATMENT OF PRURITUS AND EYE OR PALPEBRAL DYSESTHESIA |
| EP0737471A3 (en) * | 1995-04-10 | 2000-12-06 | L'oreal | Use of alkaline earth metal salts as TNF-alpha inhibitor in a topical composition and composition obtained therefrom |
| FR2737408B1 (en) * | 1995-07-31 | 1997-09-05 | Oreal | USE OF A BRADYKININE ANTAGONIST IN A COSMETIC, PHARMACEUTICAL OR DERMATOLOGICAL COMPOSITION AND COMPOSITION OBTAINED |
| FR2738741B1 (en) * | 1995-09-19 | 1997-12-05 | Oreal | COMPOSITION FOR DYEING KERATINIC FIBERS, CONTAINING AN ANTAGONIST OF SUBSTANCE P |
| FR2740335B1 (en) * | 1995-10-26 | 1997-12-19 | Oreal | USE OF LANTHANIDE, LITHIUM, TIN, ZINC, MANGANESE OR YTTRIUM SALT AS A SUBSTANCE P ANTAGONIST |
| FR2740341B1 (en) * | 1995-10-26 | 1997-12-19 | Oreal | USE OF LANTHANIDE SALT, TIN, ZINC, MANGANESE, YTTRIUM, COBALT, BARIUM, STRONTIUM IN A SKIN COMPOSITION |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3954640A (en) * | 1973-06-27 | 1976-05-04 | Xerox Corporation | Electrostatic printing inks |
| US4052325A (en) * | 1974-12-23 | 1977-10-04 | Eastman Kodak Company | Liquid electrographic developer composition containing redispersible polyester toner and process |
| JPS5425833A (en) * | 1977-07-29 | 1979-02-27 | Canon Inc | Electrophotography |
| US4202785A (en) * | 1978-05-15 | 1980-05-13 | Eastman Kodak Company | Polyesterionomers having utility in liquid electrographic developer compositions |
| JPS5725832A (en) * | 1980-07-23 | 1982-02-10 | Olympus Optical Co | Light source apparatus for endoscope |
-
1981
- 1981-10-09 JP JP50331281A patent/JPS58501675A/en active Pending
- 1981-10-09 WO PCT/SE1981/000292 patent/WO1983001252A1/en not_active Application Discontinuation
- 1981-10-09 EP EP81902811A patent/EP0090798A1/en not_active Ceased
-
1982
- 1982-10-05 BE BE0/209172A patent/BE894602A/en not_active IP Right Cessation
- 1982-10-08 IT IT23678/82A patent/IT1191028B/en active
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8301252A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| IT8223678A0 (en) | 1982-10-08 |
| BE894602A (en) | 1983-01-31 |
| JPS58501675A (en) | 1983-10-06 |
| WO1983001252A1 (en) | 1983-04-14 |
| IT1191028B (en) | 1988-02-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0275748B1 (en) | Peptide derivatives and their therapeutical use | |
| US5902790A (en) | Pharmaceutical angiostatic dipeptide compositions and method of use thereof | |
| US6235716B1 (en) | Multivalent ligands which modulate angiogenesis | |
| RU2060998C1 (en) | Method of synthesis of peptides, peptides, immunomodulating composition and a method of regulation of insufficient or excessive function of t-cells in patient | |
| CA2153789C (en) | Biologically active tgf-.beta.1 and tgf-.beta.2 peptides | |
| EP2552470B1 (en) | Peptides for promoting angiogenesis and an use thereof | |
| EP0298820A1 (en) | Peptide derivatives and their therapeutic application | |
| AU657723B2 (en) | Nonapeptide bombesin antagonists | |
| EP0090798A1 (en) | A drug based on a substance p antagonist | |
| EP0546068A1 (en) | Bioactive egf peptides for promotion of tissue regeneration and cancer therapy | |
| EP1309613B1 (en) | Pharmaceutical composition comprising an analgesic peptide | |
| US5411943A (en) | Hepatoma treatment with somatostatin analogs | |
| NZ219764A (en) | Heterocyclic compounds and pharmaceutical compositions | |
| JPH04305535A (en) | Combination of therapeutic active substances having cell proliferation inhibiting action or cytotoxicic action | |
| AU2017261638A1 (en) | Aromatic-cationic peptides and uses of same | |
| WO1995003067A1 (en) | Pharmaceutical with immunomodulating activity | |
| EP0588873B1 (en) | Treatment of liver cancer | |
| FR2608160A1 (en) | New peptide derivatives and their application especially in therapy. | |
| WO2011119008A2 (en) | Peptides for promoting angiogenesis and an use thereof | |
| EP2198878A1 (en) | Polypeptide bombesin antagonists | |
| LV10109B (en) | New oligopeptides selectively inhibiting haemopoietic stem cells, pharmaceutical composition on their base and method for preparing thereof | |
| EP1937710A1 (en) | Kinin b1 receptor peptide agonists and uses thereof | |
| JPS59130259A (en) | Novel peptide derivatives, manufacture and pharmaceutical use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19830526 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT CH DE FR GB LI NL SE |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
| 18R | Application refused |
Effective date: 19851102 |
|
| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: HAKANSON, ROLF Inventor name: HOERIG, JOACHIM |