EP2299995A1 - Combination of amidine derivates with cyclic depsipeptides - Google Patents
Combination of amidine derivates with cyclic depsipeptidesInfo
- Publication number
- EP2299995A1 EP2299995A1 EP09768920A EP09768920A EP2299995A1 EP 2299995 A1 EP2299995 A1 EP 2299995A1 EP 09768920 A EP09768920 A EP 09768920A EP 09768920 A EP09768920 A EP 09768920A EP 2299995 A1 EP2299995 A1 EP 2299995A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- spp
- alkyl
- products according
- aminophenylamidine
- sec
- 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.)
- Withdrawn
Links
- 108010002156 Depsipeptides Proteins 0.000 title claims abstract description 22
- 150000001409 amidines Chemical class 0.000 title description 4
- 241001465754 Metazoa Species 0.000 claims abstract description 9
- 244000079386 endoparasite Species 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 32
- XOIOGKHKNQYULW-HTNNXBMUSA-N tribendimidine Chemical compound C1=CC(/N=C(\C)N(C)C)=CC=C1\N=C\C(C=C1)=CC=C1\C=N\C1=CC=C(\N=C(/C)N(C)C)C=C1 XOIOGKHKNQYULW-HTNNXBMUSA-N 0.000 claims description 18
- YJNUXGPXJFAUQJ-LYWANRAQSA-N PF1022A Chemical group C([C@@H]1C(=O)N(C)[C@H](C(O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](CC=2C=CC=CC=2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O1)=O)CC(C)C)C1=CC=CC=C1 YJNUXGPXJFAUQJ-LYWANRAQSA-N 0.000 claims description 17
- ZMQMTKVVAMWKNY-YSXLEBCMSA-N emodepside Chemical group C([C@@H]1C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@H](C(O[C@H](CC=2C=CC(=CC=2)N2CCOCC2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O1)=O)CC(C)C)C(C=C1)=CC=C1N1CCOCC1 ZMQMTKVVAMWKNY-YSXLEBCMSA-N 0.000 claims description 17
- 108010056417 emodepside Proteins 0.000 claims description 16
- 229960001575 emodepside Drugs 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 150000001408 amides Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 230000000507 anthelmentic effect Effects 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- JUUCSAKZQUXQQB-UHFFFAOYSA-N n'-(4-aminophenyl)-n,n-dimethylethanimidamide Chemical compound CN(C)C(C)=NC1=CC=C(N)C=C1 JUUCSAKZQUXQQB-UHFFFAOYSA-N 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- -1 compound amide Chemical class 0.000 description 92
- 125000000217 alkyl group Chemical group 0.000 description 17
- 239000004480 active ingredient Substances 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 239000013543 active substance Substances 0.000 description 8
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 6
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 241000244206 Nematoda Species 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 241001494479 Pecora Species 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000006622 cycloheptylmethyl group Chemical group 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 244000144972 livestock Species 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 3
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 241001147657 Ancylostoma Species 0.000 description 3
- 241000243976 Haemonchus Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 241000243795 Ostertagia Species 0.000 description 3
- 241000282849 Ruminantia Species 0.000 description 3
- 241001489151 Trichuris Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000007598 dipping method Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 244000038280 herbivores Species 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 102000012440 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 241000204727 Ascaridia Species 0.000 description 2
- 241000244186 Ascaris Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- 241000283086 Equidae Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
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- MKFMTNNOZQXQBP-UVTDQMKNSA-N chembl2105966 Chemical compound COCC(=O)NC1=CC=C(\N=C(\C)N(C)C)C=C1 MKFMTNNOZQXQBP-UVTDQMKNSA-N 0.000 description 2
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- WTYUZZZCRIRLJQ-UHFFFAOYSA-N 2-(4-aminophenyl)-n,n'-dimethylethanimidamide Chemical compound CNC(=NC)CC1=CC=C(N)C=C1 WTYUZZZCRIRLJQ-UHFFFAOYSA-N 0.000 description 1
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- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/15—Depsipeptides; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the combination of Aminophenylamidin derivatives with cyclic depsipeptides, products containing this combination and the use of these agents in combination for the control of endoparasites in humans and in animals.
- Anthelmintisch effective aminophenylamidines and related compounds have long been known, see, for.
- An important member of this class is the amidantel, which is known to be a potent anthelmintic for dogs (Wollweber H et al. Arzneistoffforschung / Drug Research 29 (1) 31-32; DE-OS-20 29 298). Human use against Ancylostoma duodenale is described in Rim HJ. et al. The Korean Journal of Parasitology 18 (1) 24-36.
- Tribendimidine a symmetrical diamine derivative of amidine sheath
- Tribendimidine a symmetrical diamine derivative of amidine sheath
- the control of endoparasites in livestock is the subject of our co-pending patent application DE-Akz. 10 2007 061262.
- PF 1022 and emodepside and their action against endoparasites are also already known, see e.g. EP-A 382 173, EP-A 634 408.
- the subject of the present invention are:
- Anthelmintisch effective aminophenylamidine derivatives are preferably compounds of formula (I), wherein
- R, 1 is hydrogen or C i. 4- alkyl
- R is preferably hydrogen, -COCH 2 (C 1-4 alkoxy) or, together with R, the radical
- the anthelmintically effective Arninophenylamidin- derivative is the compound amide shell of the formula
- the anthelmintic aminophenylamidine derivative is the compound Bay d 9216 of the formula
- Tribendimidine and its synthesis are known.
- a production method is described, for example, in Yao RH, Chen YQ (1986) "Synthesis of Tribendimidine and its substituted analogues as new anthelmintic agents.” Annual Report of Institute of Parasitic Diseases, Chinese Academy of Preventive Medicine, 1986, pp. 199-202 ,
- Depsipeptides are similar to peptides and differ from them in that one or more ⁇ -amino acid building blocks are replaced by ⁇ -hydroxycarboxylic acid building blocks.
- Preferably used according to the invention are cyclic depsipeptides having 18 to 24 ring atoms, in particular having 24 ring atoms (octadepsipeptides).
- depsipeptides with 18 ring atoms include compounds of the general formula (IT):
- R 2 , R 4 and R 6 independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl , Dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl optionally substituted aryl or arylalkyl wherein as substituents may be mentioned halogen, hydroxy, alkyl, alkoxy, and their optical isomers and racemates.
- R 2 , R 4 and R 6 independently of one another represent straight-chain or branched C 1 -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec Pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, 1 hydroxyethyl, C 1 -C 4 -Al- kanoyloxy-C ⁇ C ö alkyl, in particular acetoxymethyl, 1-acetoxyethyl, C 1 -C 4 -alkoxy-C 1
- R ', R 3 and R 5 independently of one another represent straight-chain or branched C 1 -C 3 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl , sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, hydroxy-CrC ö alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C 4 -AIkanoyIoxy-dC 6 - alkyl, in particular acetoxymethyl, 1-acetoxyethyl, C 1 -C 4 -alkoxy C 1 -C 6 -alkyl, in particular Methoxymethyl, 1-methoxyethyl
- R 2 , R 4 and R 6 independently of one another represent straight-chain or branched Q-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec - pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, aryl-ci G t alkyloxy-Ci-Ce-alkyl, in particular benzyloxymethyl, 1-benzyloxyethyl, carboxy-Ci-C ß alkyl, in particular carboxymethyl, carboxyethyl
- R 1 , R 3 and R 5 independently of one another represent straight-chain or branched C 1 -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl , sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C 2 -C 8 -alkenyl, especially allyl, C 3 -C 7 -cycloalkyl-Ci-C 4 -alkyl, in particular Cyclohexylmethyl, phenyl-C r C 4 -alkyl, in particular phenylmethyl,
- R ', R 2 , R 3 , R 4 independently of one another represent hydrogen, Q-Cio-alkyl or aryl, in particular
- Phenyl which are optionally substituted by hydroxy, C] -C ] 0 -alkoxy or halogen.
- R a, R 2a, R l la and R 12a independently of one another
- Ci -8 - alkyl, C ,. 8 -haloalkyl, C 3-6 -cycloalkyl, aralkyl, aryl, R 3a , R 5a , R 7a , R 9a independently of one another represent hydrogen or straight-chain or branched C 1-8 -
- R 3a, R 5a, R 7a, R 9a is hydrogen, straight or branched Ci -8 alkyl, especially methyl, ethyl, propyl, i-propyl, n-, s-, t-butyl, optionally substituted by Ci ⁇ - Alkoxy, especially methoxy,
- R 4a , R 6a , R 8a , R 10a independently of one another represent hydrogen, methyl, ethyl, n-propyl, n-butyl,
- the compounds of the formula (IIId) can also be prepared according to the methods described in EP-A-382 173, DE-A 4 317432, DE-A 4 317457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872481, EP-A-685 469, EP-A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, Obtained by EP-A-903 347.
- Very particularly preferred depilatory puffs according to the invention are PF 1022 A (see formula (IIIa) and emodepside (PF 1022-221, compound of the formula (IIIb) in which both Z radicals are the morpholinyl radical.)
- the INN emodepside stands for the compound with systematic name: Cyclo [(R) -lactoyl-N-methyl-L-leucyl- (R) -3- (p-monopholinophenyl) lactoyl-N-methyl-L-leucyl (i) -lactoyl-N-methyl -L-leucyl- (i?) - 3- (p-mo ⁇ hohnophenyl) lactoyl-N-methyl-L-leucyl.
- active compounds can be present in stereoisomeric forms or as stereoisomer mixtures, e.g. as enantiomers or racemates. Both the stereoisomer mixtures and the pure stereoisomers can be used according to the invention.
- salts of the active compounds with pharmaceutically acceptable acids or bases and also solvates, in particular hydrates, of the active substances or their salts.
- the present invention also encompasses the use of the tautomeric forms.
- the active compounds may also be used in the form of their salts, solvates and solvates of the salts
- salts physiologically acceptable salts of the active ingredients are preferred in the context of the present invention.
- Physiologically acceptable salts of the active compounds comprise, depending on the structure of the active substance, acid addition salts of maleic acids, carboxylic acids and sulfonic acids, for example salts of chlorine.
- Physiologically acceptable salts of the active compounds optionally also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
- customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and
- Solvates in the context of the invention are those forms of the active ingredients which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
- the present invention also includes prodrugs of the active ingredients.
- prodrugs includes compounds which may themselves be biologically active or inactive, but are converted to the actual active ingredient during their residence time in the body (for example metabolically or hydrolytically).
- the products according to the invention are suitable in the case of favorable warm-blooded toxicity for controlling pathogenic endoparasites which occur in humans and in animal husbandry and animal breeding in productive, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species.
- pathogenic endoparasites it is intended to reduce disease, fatalities and impairments (for example in the production of meat, milk, wool, hides, eggs, honey, etc.) so that the use of the active substances makes it possible to achieve more economical and easier animal husbandry.
- the pathogenic endoparasites include cestodes, trematodes, nematodes, acantocephalen in particular:
- Cyclophyllidea eg: Mesocestoides spp., Anoplocephala spp., Paranoplocuspala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
- Echinochasmus spp. Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp, Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis
- Strongylus spp. Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp.
- Stephanurus spp. Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus Spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Paraflaroids spp., Trichostrongylus spp., Haemonchus spp.
- Oxyuris spp. Enterobius spp., Passaluras spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
- Ascaridia for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.
- Spirurida Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
- tapeworms e.g. Taenia spp.
- nematodes such. B .:
- Spirurida for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
- the livestock include in particular mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, Chinchilla, Raccoon.
- cattle are preferably sheep and pigs.
- non-mammal species but which are also livestock: birds, e.g. Chickens, geese, turkeys, ducks; Freshwater and saltwater fish such as Trout, carp, eels, reptiles; Insects such as e.g. Honeybee and silkworm.
- Hobby animals include dogs and cats.
- preferred are Toxoscaris spp., Toxocara spp., Trichuris spp., Trichinella spp. and the hookworms Ancylostoma spp. and Uncinaria spp. fought.
- the products can also be used in humans.
- Ascaris spp. Ancylostoma spp, Necator spp., Trichuris spp., Strongyloides spp. and Enterobius spp. fought.
- herbivores are preferred for the application of the abovementioned combinations, ie animals which mainly feed on plants.
- ruminants such as sheep, goats, cattle.
- Strongyhda in particular Haemonchus spp., T ⁇ chostrongylus spp., Coope ⁇ a spp. and Ostertagia spp. be fought.
- sheep are particularly preferably treated.
- cattle are treated according to the invention.
- the application can be both prophylactic and therapeutic.
- the application of the active ingredient is carried out directly or in the form of suitable preparations enteral, parenteral, dermal, nasal, by treatment of the environment or with the aid of active ingredient-containing moldings such.
- suitable preparations enteral, parenteral, dermal, nasal, by treatment of the environment or with the aid of active ingredient-containing moldings such.
- active ingredient-containing moldings such as strips, plates, ligaments, collars, ear tags, limb bands, marking devices.
- Enteral administration of the active ingredient is e.g. oral form of powder, suppositories, tablets, capsules, fasting, potions, granules, drenches, boii, medicated feed or drinking water.
- the dermal application is e.g. in the form of dipping, spraying, bathing, washing, pour-on and spot-on, and empowering.
- Parenteral administration is, for example, in the form of injection (mtramuscular, subcutaneous, intravenous, intrape ⁇ toneal) or by implants.
- Suitable preparations are:
- Solutions such as injection solutions, other solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels; Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
- Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, tablets, capsules; Aerosols and inhalants, active substance-containing moldings.
- Injection solutions are administered intravenously, intramuscularly and subcutaneously.
- Concentrates are applied directly. Concentrates are administered orally after prior dilution to the concentration of use.
- Solutions for use on the skin are dripped, brushed, rubbed, sprayed on, sprayed on or applied by dipping (dipping, bathing or washing).
- Gels are applied to the skin or brushed or incorporated into body cavities.
- Pour-on formulations are infused or sprayed onto limited areas of the skin, whereby the active ingredient either penetrates the skin and acts systemically or spreads on the body surface.
- Emulsions can be administered orally, dermally or as an injection. Emulsions are either water-in-oil type or oil-in-water type.
- Suspensions may be administered orally, dermally or as an injection.
- Semi-solid preparations may be administered orally or dermally.
- the active compound is mixed with suitable excipients, if appropriate with the addition of auxiliaries, and brought into the desired form.
- the products according to the invention may optionally contain further active ingredients.
- the use in combination means either that the anthelmintic aminophenylamidine derivatives and the cyclic depsipeptides in a common preparation formulated and applied together accordingly.
- the products may also comprise separate preparations for each active substance. If more than two active substances can be used, corresponding to all active ingredients in a common preparation, all active ingredients are formulated in separate formulations, conceivable are also mixed forms in which a part of the active ingredients together and a part of the active ingredients is formulated separately.
- the products contain the active ingredients in each case in concentrations of 10 ppm to 90 weight percent, preferably 0.1 to 50 weight percent.
- Ready-to-use preparations usually contain the active compounds in concentrations of 10 ppm to 20 percent by weight, preferably from 0.1 to 10 percent by weight.
- Preparations which are diluted before use contain the active compounds in concentrations of 0.5-90 wt .-%, preferably from 5 to 50 weight percent.
- the weight ratio of aminophenylamidine to cyclodepsipeptide in the products according to the invention depends on various factors, but is generally in the range of 10:90 to 50:50, preferably 20:80 to 30:70.
- Usual dosages of Aminophenylamidine per day are 1 to 100 mg / kg body weight, preferably 2 to 60 mg / kg body weight.
- Usual dosages of depsipeptides per day are 0.1 to 100 mg / kg, preferably 0.5 to 50 mg / kg, more preferably 1 to 50 mg / kg of body weight per day.
- the active ingredients are filled in the amounts given below as a powder in a gelatin capsules:
- the compounds were dissolved in DMSO and added to the incubation medium so that final concentrations of 100, 10, 1, 0.1, 0.01, 0.001 and 0.0001 ⁇ g / ml were present.
- the controls contained only DMSO.
- the acetylcholinesterase activity was determined according to the above publication.
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Abstract
The present invention relates to a combination of aminophenylamidine derivates with cyclic depsipeptides, to products comprising said combination, and to the use of said agents in combinations for combating endoparasites in humans and animals.
Description
Kombination von Amidin-Derivaten mit cyclischen Depsipeptiden Combination of amidine derivatives with cyclic depsipeptides
Die vorliegende Erfindung betrifft die Kombination von Aminophenylamidin-Derivaten mit cyclischen Depsipeptiden, Erzeugnisse enthaltend diese Kombination sowie die Verwendung dieser Wirkstoffe in Kombination zur Bekämpfung von Endoparasiten beim Menschen und bei Tieren.The present invention relates to the combination of Aminophenylamidin derivatives with cyclic depsipeptides, products containing this combination and the use of these agents in combination for the control of endoparasites in humans and in animals.
Anthelmintisch wirksame Aminophenylamidine und verwandte Verbindungen sind seit langem bekannt, siehe z. B. DE OS 2 029 297, DE OS 2 029 298, DE OS 2 029 299 und DE OS 2 145 807. Ein wichtiger Vertreter dieser Klasse ist das Amidantel, das als ein potentes Anthelminthikum für Hunde bekannt ist (Wollweber H et al. Arzneimittelforschung/Drug Research 29 (1) 31-32; DE- OS-20 29 298). Die Anwendung beim Menschen gegen Ancylostoma duodenale ist beschrieben bei Rim HJ. et al. The Korean Journal of Parasitology 18 (1) 24-36.Anthelmintisch effective aminophenylamidines and related compounds have long been known, see, for. For example, DE OS 2 029 297, DE OS 2 029 298, DE OS 2 029 299 and DE OS 2 145 807. An important member of this class is the amidantel, which is known to be a potent anthelmintic for dogs (Wollweber H et al. Arzneimittelforschung / Drug Research 29 (1) 31-32; DE-OS-20 29 298). Human use against Ancylostoma duodenale is described in Rim HJ. et al. The Korean Journal of Parasitology 18 (1) 24-36.
Amidantel wird in vivo recht schnell zum entsprechenden freien Amin (Bay d 9216) deacyliert, das ebenfalls anthelmintisch wirksam ist (Thomlinson et al., European Journal of Pharmacology, 113 (1985) 255-262).Amide shell is rapidly deacylated in vivo to the corresponding free amine (Bay d 9216), which is also anthelmintically active (Thomlinson et al., European Journal of Pharmacology, 113 (1985) 255-262).
Tribendimidin, ein symmetrisches Diamidin-Derivat von Amindantel, ist seit etwa 20 Jahren bekannt und wird in China als Breitband-Anthelmintikum für die Anwendung beim Menschen ent- wickelt (siehe z. B: Ren, H. N. et al. Chin. J. Parasitol. Parasit. Dis. 5 (1987) 262-264; Keiser, J. et al. Antimicrob. Agents Chemother. 51 (2007) 1096-1098). Die Bekämpfung von Endoparasiten bei Nutztieren ist Gegenstand unserer parallel anhängigen Patentanmeldung DE-Akz. 10 2007 061262.Tribendimidine, a symmetrical diamine derivative of amidine sheath, has been known for about 20 years and is being developed in China as a broad-spectrum anthelmintic for human use (see, for example: Ren, HN et al., Chin. J. Parasitol. Parasite, Dis., 5 (1987) 262-264; Keizer, J. et al., Antimicrob. Agents Chemother. 51 (2007) 1096-1098). The control of endoparasites in livestock is the subject of our co-pending patent application DE-Akz. 10 2007 061262.
Cyclische Depsipeptide und ihre endoparasitizide Wirkung sind bekannt: Enniatine und andere 18- gliedrige cyclische Depsipeptide (EP-A 644 883, EP-A 658 551, EP-A 669 343, WO 95/27498);Cyclic depsipeptides and their endoparasiticidal action are known: enniatins and other 18-membered cyclic depsipeptides (EP-A 644 883, EP-A 658 551, EP-A 669 343, WO 95/27498);
24-gliedrige cyclische Depsipeptide (EP-A 626 376, EP-A 626 375, EP 787 141, EP-A 903 347,24-membered cyclic depsipeptides (EP-A 626 376, EP-A 626 375, EP 787 141, EP-A 903 347,
EP-A 973 756, WO 98/55469, WO 99/47506, WO 00/14079, WO 98/37088, WO 99/67281), cyclische Depsipeptide mit 12 Ringatomen (EP-A 664 297). Cyclische Oktadepsipeptide wieEP-A 973 756, WO 98/55469, WO 99/47506, WO 00/14079, WO 98/37088, WO 99/67281), cyclic depsipeptides having 12 ring atoms (EP-A 664 297). Cyclic octadepsipeptides such as
PF 1022 und Emodepsid und ihre Wirkung gegen Endoparasiten (z.B. gegen Darmnematoden und Gewebsnematoden) sind ebenfalls bereits bekannt, siehe z.B. EP-A 382 173, EP-A 634 408.PF 1022 and emodepside and their action against endoparasites (e.g., against intestinal nematodes and tissue nematodes) are also already known, see e.g. EP-A 382 173, EP-A 634 408.
Gegenstand der vorliegenden Erfindung sind:The subject of the present invention are:
Erzeugnisse enthaltend anthelmintisch wirksame Aminophenylamidin-Derivate und cyclische Depsipeptide.Products containing anthelmintic aminophenylamidine derivatives and cyclic depsipeptides.
Anthelmintisch wirksame Aminophenylamidin-Derivate sind vorzugsweise Verbindungen der Formel (I),
worinAnthelmintisch effective aminophenylamidine derivatives are preferably compounds of formula (I), wherein
R , 1 Wasserstoff oder C i .4-Alkyl bedeutet undR, 1 is hydrogen or C i. 4- alkyl and
R2 Wasserstoff, -COO(C1-4-Alkyl), -CO(CM-Alkyl), -COCH2(C1 ^-Alkyl), -COCH2OPhenyl oder -COHetaryl bedeutet, wobei Hetaryl für einen fünf- oder 6-gliedrigen aromatischen Heterocyclus mit einem oder mehreren Heteroringatomen ausgewählt aus O, N und S steht, oder R1 und R2 gemeinsam für den RestR 2 is hydrogen, -COO (C 1-4 alkyl), -CO (C M alkyl), -COCH 2 (C 1 ^ alkyl), -COCH2 OPhenyl or -COHetaryl, wherein hetaryl a five- or 6-membered aromatic heterocycle having one or more hetero ring atoms selected from O, N and S, or R 1 and R 2 together represent the radical
stehen. stand.
R1 steht bevorzugt für Wasserstoff.R 1 is preferably hydrogen.
R steht bevorzugt für Wasserstoff, -COCH2(C ^-Alkoxy) oder zusammen mit R für den RestR is preferably hydrogen, -COCH 2 (C 1-4 alkoxy) or, together with R, the radical
Gemäß einer bevorzugten Ausführungsform ist das anthelmintisch wirksame Arninophenylamidin- Derivat die Verbindung Amidantel der FormelAccording to a preferred embodiment, the anthelmintically effective Arninophenylamidin- derivative is the compound amide shell of the formula
Amidantel und seine Herstellung sind beschrieben in DE-OS 2 029 298. Amide shell and its preparation are described in DE-OS 2 029 298.
Gemäß einer weiteren bevorzugten Ausführungsform ist das anthelmintisch wirksame Aminophenylamidin-Derivat die Verbindung Bay d 9216 der Formel
According to a further preferred embodiment, the anthelmintic aminophenylamidine derivative is the compound Bay d 9216 of the formula
Die Herstellung von N-(4-Aminophenyl-N,N'-dimethylacetamidin (Bay d 9216) als Vorstufe ist ebenfalls beschrieben in DE-OS 2 029 298.The preparation of N- (4-aminophenyl-N, N'-dimethylacetamidine (Bay d 9216) as precursor is likewise described in DE-OS 2 029 298.
Gemäß einer weiteren bevorzugten Ausführungsform ist das anthelmintisch wirksame Aminophenylamidin-Derivat Tribendimidin der FormelAccording to another preferred embodiment, the anthelmintically active aminophenylamidine derivative is tribendimidine of the formula
Tribendimidin und seine Synthese sind bekannt. Ein Herstellungsverfahren ist zum Beispiel beschrieben bei Yao RH, Chen YQ (1986) „Synthesis of Tribendimidine and its substituted analogues as new anthelmintic agents." Annual Report of Institute of Parasitic Diseases, Chinese Academy of Preventive Medicine in 1986, S. 199-202.Tribendimidine and its synthesis are known. A production method is described, for example, in Yao RH, Chen YQ (1986) "Synthesis of Tribendimidine and its substituted analogues as new anthelmintic agents." Annual Report of Institute of Parasitic Diseases, Chinese Academy of Preventive Medicine, 1986, pp. 199-202 ,
Depsipeptide sind den Peptiden ähnlich und unterscheiden sich von diesen darin, dass ein oder mehrere α-Aminosäurebausteine durch α-Hydroxycarbonsäurebausteine ersetzt sind. Erfindungsgemäß bevorzugt eingesetzt werden cyclische Depsipeptide mit 18 bis 24 Ringatomen, insbesondere mit 24 Ringatomen (Octadepsipeptide).Depsipeptides are similar to peptides and differ from them in that one or more α-amino acid building blocks are replaced by α-hydroxycarboxylic acid building blocks. Preferably used according to the invention are cyclic depsipeptides having 18 to 24 ring atoms, in particular having 24 ring atoms (octadepsipeptides).
Zu den Depsipeptiden mit 18 Ringatomen zählen Verbindungen der allgemeinen Formel (IT):The depsipeptides with 18 ring atoms include compounds of the general formula (IT):
in welcher
R1, R3 und R5 unabhängig voneinander für Wasserstoff geradkettiges oder verzweigtes Alkyl mit bis zu 8 Kohlenstoffatomen, Hydroxyalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Aryloxyalkyl, Mercaptoalkyl, Alkylthioalkyl, Alkylsulfinylalkyl, Alkylsulfonylalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Arylalkoxycarbonylalkyl, Carbamoylalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl, Guamdinoalkyl, das gegebenenfalls durch einen oder zwei Benzyloxycarbonylreste oder durch einen, zwei, drei oder vier Alkylreste substituiert sein kann, Alkoxycarbonylaminoalkyl, 9-Fluorenyl- methoxycarbonyl(Fmoc)aminoalkyl, Alkenyl, Cycloalkyl, Cycloalkylalkyl sowie gegebenenfalls substituiertes Arylalkyl, wobei als Substituenten genannt seien Halogen, Hydroxy, Alkyl und Alkoxy, stehen, in which R 1 , R 3 and R 5 independently of one another represent hydrogen straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, Dialkylaminoalkyl, guamdinoalkyl, which may optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four alkyl radicals, alkoxycarbonylaminoalkyl, 9-fluorenyl-methoxycarbonyl (Fmoc) aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted arylalkyl, where as substituents may be mentioned halogen, hydroxy, alkyl and alkoxy,
R2, R4 und R6 unabhängig voneinander für Wasserstoff, geradkettiges oder verzweigtes Alkyl mit bis zu 8 Kohlenstoffatomen, Hydroxyalkyl, Mercaptoalkyl, Alkanoyloxyalkyl, Alkoxyalkyl, Aryloxyalkyl, Alkylthioalkyl, Alkylsulfinylalkyl, Alkylsulfonylalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Arylalkoxycarbonylalkyl, Carbamoylalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl, Alkoxycarbonylaminoalkyl, Alkenyl, Cycloalkyl, Cycloalkylalkyl gegebenenfalls substituiertes Aryl oder Arylalkyl wobei als Substituenten genannt seien Halogen, Hydroxy, Alkyl, Alkoxy, stehen, sowie deren optische Isomere und Racemate.R 2 , R 4 and R 6 independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl , Dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl optionally substituted aryl or arylalkyl wherein as substituents may be mentioned halogen, hydroxy, alkyl, alkoxy, and their optical isomers and racemates.
Bevorzugt sind Verbindungen der Formel (H), in welcherPreference is given to compounds of the formula (H) in which
R1, R3 und R5 unabhängig voneinander für geradkettiges oder verzweigtes C1-C8-AIlCyI, insbesondere Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sec.-Butyl, tert.-Butyl, Pentyl, Isopentyl, sec.-Pentyl, Hexyl, Isohexyl, sec.-Hexyl, Heptyl, Isoheptyl, sec.-Heptyl, tert -Heptyl, Oktyl, Isooktyl, sec. -Oktyl, Hydroxy-Ci-C6-alkyl, insbesondere Hydroxymethyl, 1-Hydroxyethyl, CrC4- Alkanoyloxy-Ci-Cβ-alkyl, insbesondere Acetoxymethyl, 1-Acetoxyethyl, Ci-C4-Alkoxy-Ci-C6-alkyl, insbesondere Methoxymethyl, 1-Methoxyethyl, Aryl-Ci-Gralkyloxy-Ci-Ce-alkyl, insbesondere Benzyloxymethyl, 1-Benzyloxy-ethyl, Mercapto-Ci-Cβ-alkyl, insbesondere Mercaptomethyl, C]-C4- Alky]thio-Ci-C6-alky], insbesondere Methylthioethyl, Ci-Q-Alkylsulfinyl-Ci-Cs-alkyl, insbesondere Methylsulfinylethyl, Ci-C4-Alkylsulfonyl-Ci-C6-alkyl, insbesondere Methylsulfonylethyl, Carboxy- Ci-Cβ-alkyl, insbesondere Carboxymethyl, Carboxyethyl, Ci-C4-Alkoxycarbonyl-CrC6-alkyl, insbesondere Methoxycarbonylmethyl, Ethoxycarbonylethyl, C1-C4-Arylalkoxycarbonyl-Ci-C6-alkyl, insbesondere Benzyloxycarbonylmethyl, Carbamoyl-Ci-Q-alkyl, insbesondere Carbamoylmethyl, Carbamoylethyl, Ammo-CrC6-aikyi, insbesondere Aiiuuopröpyl, Arnmobutyl, CrC4-Alkylarnino-Ci- Cö-alkyl, insbesondere Methylaminopropyl, Methylaminobutyl, Ci-Gt-Dialkylammo-Ci-Cg-alkyl, insbesondere Dimethylammopropyl, Dimethylaminobutyl, Guanido-Ci-C6-alkyl, insbesondere Guamdopropyl, Ci-C4-Alkoxycarbonylamino-Ci-C6-alkyl, insbesondere tert.-Butoxycarbonylamino- propyl, tert.-Butoxycarbonylaminobutyl, 9-Fluorenylmethoxycarbonyl(Fmoc)amino-Ci-C6-alkyl, ms-
besondere 9-Fluorenyl-methoxycarbonyl(Fmoc)aminopropyl, 9-Fluorenylmethoxycarbonyl(Fmoc)- aminobutyl, C2-C8-Alkenyl, insbesondere Vinyl, Allyl, Butenyl, C3-C7-Cycloalkyl, insbesondere Cyclopentyl, Cyclohexyl, Cycloheptyl, C3-C7-Cycloalkyl-Ci-C4-alkyl, insbesondere Cyclopentyl- methyl, Cyclohexylmethyl, Cycloheptylmethyl, Phenyl-Ci-C4-alkyl, insbesondere Phenylmethyl das gegebenenfalls durch Reste aus der Reihe Halogen, insbesondere Fluor, Chlor Brom oder Iod, Hydroxy, CrC4- Alkoxy, insbesondere Methoxy oder Ethoxy, Ci-C4-AIlCyI, insbesondere Methyl, substituiert sein kann,R 1 , R 3 and R 5 independently of one another represent straight-chain or branched C 1 -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec Pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, 1-hydroxyethyl , C r C 4 - alkanoyloxy-Ci-Cβ-alkyl, in particular acetoxymethyl, 1-acetoxyethyl, Ci-C4-alkoxy-Ci-C 6 -alkyl, in particular methoxymethyl, 1-methoxyethyl, aryl-Ci-Ci-Gralkyloxy Ce-alkyl, in particular benzyloxymethyl, 1-benzyloxy-ethyl, mercapto-Ci-Cβ-alkyl, in particular mercaptomethyl, C] -C 4 - alkyl] thio-Ci-C 6 -alky], in particular methylthioethyl, Ci-Q-alkylsulfinyl Ci-Cs-alkyl, in particular methylsulfinylethyl, Ci-C 4 -alkylsulfonyl-Ci-C 6 -alkyl, in particular methylsulfonylethyl, carboxy-Ci-Cβ-alkyl, in particular carboxymethyl, carboxyethyl, Ci-C 4 -alkoxycarbonyl-C r C 6 -alkyl, in particular methox ycarbonylmethyl, ethoxycarbonylethyl, C 1 -C 4 -arylalkoxycarbonyl-C 1 -C 6 -alkyl, in particular benzyloxycarbonylmethyl, carbamoyl-C 1 -Q-alkyl, in particular carbamoylmethyl, carbamoylethyl, ammoC r C 6 -alkyl, in particular aluoprylyl, arnobutyl, C r C 4 -Alkylarnino-Ci- C ö alkyl, in particular methylaminopropyl, methylaminobutyl, Ci-G t -Dialkylammo-Ci-Cg-alkyl, in particular Dimethylammopropyl, dimethylaminobutyl, guanido-C 6 alkyl, particularly Guamdopropyl, Ci- C 4 -alkoxycarbonylamino-C 1 -C 6 -alkyl, in particular tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, 9-fluorenylmethoxycarbonyl (Fmoc) amino C 1 -C 6 -alkyl, ms- particular 9-fluorenyl-methoxycarbonyl (Fmoc) aminopropyl, 9-fluorenylmethoxycarbonyl (Fmoc) -aminobutyl, C 2 -C 8 -alkenyl, in particular vinyl, allyl, butenyl, C 3 -C 7 -cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C 1 -C 4 -alkyl, in particular phenylmethyl which is optionally substituted by radicals from the series halogen, in particular fluorine, chlorine, bromine or iodo, hydroxy, C r C 4 - alkoxy, in particular methoxy or ethoxy, Ci-C 4 -alkyl, in particular methyl may be substituted,
R2, R4 und R6 unabhängig voneinander für geradkettiges oder verzweigtes C)-C8-Alkyl, insbesondere Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sec.-Butyl, tert.-Butyl, Pentyl, Isopentyl, sec.-Pentyl, Hexyl, Isohexyl, sec.-Hexyl, Heptyl, Isoheptyl, sec.-Heptyl, tert.-Heptyl, Oktyl, Isooktyl, sec.-Oktyl, Hydroxy-Ci-C6-alkyl, insbesondere Hydroxymethyl, 1-Hydroxyethyl, C1-C4-Al- kanoyloxy-C^Cö-alkyl, insbesondere Acetoxymethyl, 1-Acetoxyethyl, C1 -C4-AIkOXy-C1 -Cβ-alkyl, insbesondere Methoxymethyl, 1-Methoxyethyl, ATyI-C1 -d-alkyloxy-Q-Ce-alkyl, insbesondere Benzyloxymethyl, 1-Benzyloxy-ethyl, Mercapto-Q-Cö-alkyl, insbesondere Mercaptomethyl, Ci-C4- Alkylthio-CrCö-alkyl, insbesondere Methylthioethyl,
insbesondere Methylsulfinylethyl, Ci-C4-Alkylsulfonyl-Ci-C6-alkyl, insbesondere Methylsulfonylethyl, Carboxy- Ci-C6-alkyl, insbesondere Carboxymethyl, Carboxyethyl, Ci-C4-Alkoxycarbonyl-Ci-C6-alkyl, insbesondere Methoxycarbonylmethyl, Ethoxycarbonylethyl, C1-C4- Arylalkoxycarbonyl-Ci-C6-alkyl, insbesondere Benzyloxycarbonylmethyl, Carbamoyl-Ci-C6-alkyl, insbesondere Carbamoylmethyl, Carbamoylethyl, Amino-Q-Q-alkyl, insbesondere Aminopropyl, Aminobutyl, CrC4-Alkylamino-Ci- C6-alkyl, insbesondere Methylaminopropyl, Methylaminobutyl, Ci-C4-Dialkylamino-C1-C6-alkyl, insbesondere Dimethylaminopropyl, Dimethylaminobutyl, C2-Cg-Alkenyl, insbesondere Vinyl, Allyl, Butenyl, C3-C7-Cycloalkyl, insbesondere Cyclopentyl, Cyclohexyl, Cycloheptyl, C3-C7-CyClOaIlCyI-C1- C4-alkyl, insbesondere Cyclopentylmethyl, Cyclohexylmethyl, Cycloheptylmethyl, Phenyl, Phenyl-d- C4-alkyl, insbesondere Phenylmethyl das gegebenenfalls durch Reste aus der Reihe Halogen, insbesondere Fluor, Chlor Brom oder Iod, Hydroxy, C]-C4- Alkoxy, insbesondere Methoxy oder Ethoxy, Ci-C4-Alkyl, insbesondere Methyl, substituiert sein kann, sowie deren optische Isomere und Racemate.R 2 , R 4 and R 6 independently of one another represent straight-chain or branched C 1 -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec Pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, 1 hydroxyethyl, C 1 -C 4 -Al- kanoyloxy-C ^ C ö alkyl, in particular acetoxymethyl, 1-acetoxyethyl, C 1 -C 4 -alkoxy-C 1 -Cβ alkyl, in particular methoxymethyl, 1-methoxyethyl, ATyI- C 1-d-alkyloxy-Q-Ce-alkyl, in particular benzyloxymethyl, 1-benzyloxy-ethyl, mercapto-Q-COE-alkyl, in particular mercaptomethyl, Ci-C 4 - alkylthio-CrC ö alkyl, in particular methylthioethyl, in particular methylsulfinylethyl, C 1 -C 4 -alkylsulfonyl-C 1 -C 6 -alkyl, in particular methylsulfonylethyl, carboxy-C 1 -C 6 -alkyl, in particular carboxymethyl, carboxyethyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 6 -alkyl, in particular methoxycarbonylmethyl , Ethoxycarbonylethyl, C 1 -C 4 -arylalkoxycarbonyl-C 1 -C 6 -alkyl, in particular benzyloxycarbonylmethyl, carbamoyl-C 1 -C 6 -alkyl, in particular carbamoylmethyl, carbamoylethyl, amino-QQ-alkyl, in particular aminopropyl, aminobutyl, C r C 4 -Alkylamino-Ci- C 6 -alkyl, in particular methylaminopropyl, methylaminobutyl, C 1 -C 4 -dialkylamino-C 1 -C 6 -alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, C 2 -CG-alkenyl, in particular vinyl, allyl, butenyl, C C 3 -C 7 -cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl, phenyl-C 1 -C 4 -alkyl, in particular phenylmethyl optionally substituted by radicals from the series halogen, ins particular fluorine, chlorine, bromine or iodine, hydroxy, C] -C 4 - alkoxy, especially methoxy or ethoxy, Ci-C 4 alkyl, especially methyl, may be substituted, and their optical isomers and racemates.
Besonders bevorzugt sind Verbindungen der Formel (II), in welcherParticular preference is given to compounds of the formula (II) in which
R', R3 und R5 unabhängig voneinander für geradkettiges oder verzweigtes Ci-C3-Alkyl, insbesondere Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sec.-Butyl, Pentyl, Isopentyl, sec- Pentyl, Hexyl, Isohexyl, sec.-Hexyl, Heptyl, Isoheptyl, sec.-Heptyl, Oktyl, Isooktyl, sec.-Oktyl, Hydroxy-CrCö-alkyl, insbesondere Hydroxymethyl, 1-Hydroxyethyl, Ci-C4-AIkanoyIoxy-d-C6- alkyl, insbesondere Acetoxymethyl, 1-Acetoxyethyl, Ci -C4-AIkOXy-C1 -Cβ-alkyl, insbesondere
Methoxymethyl, 1-Methoxyethyl, Aryl-Ci-C4-alkyloxy-Ci-C6-alkyl, insbesondere Benzyloxymethyl, 1-Benzyloxyethyl, Ci-Q-Alkoxycarbonylamino-Ci-Ce-alkyl, insbesondere tert-Butoxycarbonyl- aminopropyl, tert.-Butoxycarbonylaminobutyl, C2-C8-Alkenyl, insbesondere Vinyl, Allyl, C3-C7- Cycloalkyl, insbesondere Cyclopentyl, Cyclohexyl, Cycloheptyl, C3-C7-Cycloalkyl-Ci-C4-alkyl, insbesondere Cyclopentylmethyl, Cyclohexylmethyl, Cycloheptylmethyl, Phenyl-Ci-Q-alkyl, insbesondere Phenylmethyl das gegebenenfalls durch einen oder mehrere gleiche oder verschiedene der oben angegebenen Reste substituiert sein kann,R ', R 3 and R 5 independently of one another represent straight-chain or branched C 1 -C 3 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl , sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, hydroxy-CrC ö alkyl, in particular hydroxymethyl, 1-hydroxyethyl, Ci-C 4 -AIkanoyIoxy-dC 6 - alkyl, in particular acetoxymethyl, 1-acetoxyethyl, C 1 -C 4 -alkoxy C 1 -C 6 -alkyl, in particular Methoxymethyl, 1-methoxyethyl, aryl-C 1 -C 4 -alkyloxy-C 1 -C 6 -alkyl, in particular benzyloxymethyl, 1-benzyloxyethyl, C 1 -C 4 -alkoxycarbonylamino-C 1 -C 6 -alkyl, in particular tert-butoxycarbonylaminopropyl, tert. Butoxycarbonylaminobutyl, C 2 -C 8 -alkenyl, in particular vinyl, allyl, C 3 -C 7 -cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, Cycloheptylmethyl, phenyl-Ci-Q-alkyl, in particular phenylmethyl which may optionally be substituted by one or more identical or different radicals given above,
R2, R4 und R6 unabhängig voneinander für geradkettiges oder verzweigtes Q-Cg-Alkyl, insbeson- dere Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sec.-Butyl, tert.-Butyl, Pentyl, Isopentyl, sec- Pentyl, Hexyl, Isohexyl, sec.-Hexyl, Heptyl, Isoheptyl, sec.-Heptyl, tert.-Heptyl, Oktyl, Isooktyl, sec- Oktyl, Hydroxy-Ci-C6-alkyl, insbesondere Hydroxymethyl, Aryl-Ci-Gt-alkyloxy-Ci-Ce-alkyl, insbesondere Benzyloxymethyl, 1-Benzyloxyethyl, Carboxy-Ci-Cß-alkyl, insbesondere Carboxy- methyl, Carboxyethyl, Ci-C4-Alkoxycarbonyl-Ci-C6-alkyl, insbesondere Methoxycarbonylmethyl, Ethoxycarbonylethyl, Ci-C4-Aryl-alkoxycarbonyl-Ci-C6-alkyl, insbesondere Benzyloxycarbonylme- thyl, Ci-C4-Alkylamino-Ci-C6-alkyl, insbesondere Methylaminopropyl, Methylaminobutyl, CrC4- Dialkylamino-Ci-C6-alkyl, insbesondere Dimethylaminopropyl, Dimethylaminobutyl, C2-C8-Alkenyl, insbesondere Vinyl, Allyl, Butenyl, C3-C7-Cycloalkyl, insbesondere Cyclopentyl, Cyclohexyl, Cycloheptyl, C3-C7-Cycloalkyl-Ci-C4-alkyl, insbesondere Cyclopentylmethyl, Cyclohexylmethyl, Cyclo- heptyl-methyl, Phenyl, Phenyl-C1-C4-alkyl, insbesondere Phenylmethyl das gegebenenfalls durch einen oder mehrere gleiche oder verschiedene der oben angegebenen Reste substituiert sein kann, sowie deren optische Isomere und Racemate.R 2 , R 4 and R 6 independently of one another represent straight-chain or branched Q-Cg-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec - pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-Ci-C 6 -alkyl, in particular hydroxymethyl, aryl-ci G t alkyloxy-Ci-Ce-alkyl, in particular benzyloxymethyl, 1-benzyloxyethyl, carboxy-Ci-C ß alkyl, in particular carboxymethyl, carboxyethyl, Ci-C 4 alkoxycarbonyl-Ci-C 6 -alkyl, in particular methoxycarbonylmethyl , ethoxycarbonylethyl, Ci-C 4 aryl-alkoxycarbonyl-Ci-C6 alkyl, particularly Benzyloxycarbonylme- methyl, Ci-C 4 alkylamino-C 6 -alkyl, in particular methylaminopropyl, methylaminobutyl, C r C 4 - dialkylamino C 1 -C 6 -alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, C 2 -C 8 -alkenyl, in particular vinyl, allyl, butenyl, C 3 -C 7 -cycloalkyl, in particular cyclopentyl, cyclohexyl, cycloheptyl, C 3 -C 7 cycloalkyl-Ci-C4-alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptyl-methyl, phenyl, phenyl-C 1 -C 4 -alkyl, in particular phenylmethyl which is optionally substituted by one or more identical or different The above radicals may be substituted, as well as their optical isomers and racemates.
Ganz besonders bevorzugt sind Verbindungen der Formel (IT), in welcherVery particular preference is given to compounds of the formula (II) in which
R1, R3 und R5 unabhängig voneinander für geradkettiges oder verzweigtes Ci-C8-Alkyl, insbesondere Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sec.-Butyl, Pentyl, Isopentyl, sec- Pentyl, Hexyl, Isohexyl, sec.-Hexyl, Heptyl, Isoheptyl, sec.-Heptyl, Oktyl, Isooktyl, sec.-Oktyl C2-C8- Alkenyl, insbesondere Allyl, C3-C7-Cycloalkyl-Ci-C4-alkyl, insbesondere Cyclohexylmethyl, Phenyl- CrC4-alkyl, insbesondere Phenylmethyl,R 1 , R 3 and R 5 independently of one another represent straight-chain or branched C 1 -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl , sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C 2 -C 8 -alkenyl, especially allyl, C 3 -C 7 -cycloalkyl-Ci-C 4 -alkyl, in particular Cyclohexylmethyl, phenyl-C r C 4 -alkyl, in particular phenylmethyl,
R2, R4 und R6 unabhängig voneinander für geradkettiges oder verzweigtes Ci-C8-Alkyl, insbesondere Methyl, Ethyl, Propyl, Isopropyi, Butyl, Isobutyl, sεc. -Butyl, Pentyl, Isopentyl, sec- Pentyl, Hexyl, Isohexyl, sec.-Hexyl, Heptyl, Isoheptyl, sec.-Heptyl, Oktyl, Isooktyl, sec.-Oktyl, C2-C8- Alkenyl, insbesondere Vinyl, Allyl, C3-C7-Cycloalkyl-CrC4-alkyl, insbesondere Cyclohexylmethyl, Phenyl-Ci-C4-alkyl, insbesondere Phenylmethyl das gegebenenfalls durch einen oder mehrere gleiche
oder verschiedene der oben angegebenen Reste substituiert sein kann, sowie deren optische Isomere und Racemate.R 2 , R 4 and R 6 independently of one another represent straight-chain or branched C 1 -C 8 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s.ec. Butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C 2 -C 8 alkenyl, in particular vinyl, allyl , C 3 -C 7 -cycloalkyl-C r C 4 -alkyl, in particular cyclohexylmethyl, phenyl-Ci-C 4 -alkyl, in particular phenylmethyl optionally substituted by one or more identical or different of the above radicals may be substituted, and their optical isomers and racemates.
Im einzelnen seien folgende Verbindungen der allgemeinen Formel (II) genannt, in welcher die Reste R1 bis R6 die folgende Bedeutung haben:Specifically, the following compounds of the general formula (II) may be mentioned, in which the radicals R 1 to R 6 have the following meaning:
Me = Methyl; Phe = PhenylMe = methyl; Phe = phenyl
Weiterhin sei als Depsipeptid die aus EP-OS 382 173 bekannte Verbindung PF 1022 der folgenden Formel (UIa) genannt:Also to be mentioned as depsipeptide is the compound PF 1022 of the following formula (IIaa) known from EP-OS 382 173:
Außerdem seien als Depsipeptide die aus der PCT-Anmeldung WO 93/19053 bekannten Verbindungen genannt.Also mentioned as depsipeptides are the compounds known from PCT application WO 93/19053.
Insbesondere seien aus WO 93/19053 die Verbindungen der folgenden Formel (HIb) genannt:WO 93/19053, in particular, mentions the compounds of the following formula (IIIb):
in welcher in which
Z für N-Mornholinyl. Amino, Mono- oder Dimethylamino steht.Z for N-mornholinyl. Amino, mono- or dimethylamino stands.
Außerdem seien Verbindungen der folgenden Formel (Die) genannt:
in welcherIn addition, compounds of the following formula (The) may be mentioned: in which
R', R2, R3, R4 unabhängig voneinander für Wasserstoff, Q-Cio-Alkyl oder Aryl, insbesondereR ', R 2 , R 3 , R 4 independently of one another represent hydrogen, Q-Cio-alkyl or aryl, in particular
Phenyl stehen, die gegebenenfalls substituiert sind durch Hydroxy, C]-C]0-Alkoxy oder Halogen.Phenyl which are optionally substituted by hydroxy, C] -C ] 0 -alkoxy or halogen.
Die Verbindungen der allgemeinen Formel (II) sind bekannt und können nach den in EP-A-382 173, DE-A 4 317 432, DE-A 4 317 457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872 481, EP-A-685 469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787 141, EP-A-865498, EP-A- 903 347 beschriebenen Verfahren erhalten werden.The compounds of the general formula (II) are known and can be prepared by the methods described in EP-A-382 173, DE-A 4 317 432, DE-A 4 317 457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872 481, EP-A-685 469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787 141, EP-A- 865498, EP-A-903 347.
Zu den cyclischen Depsipeptiden mit 24 Ringatomen zählen auch Verbindungen der allgemeinen Formel (ffld)The cyclic depsipeptides with 24 ring atoms also include compounds of the general formula (ffld)
in welcher Rla, R2a, Rl la und R12a unabhängig voneinander für Ci-8- Alkyl, C,.8-Halogenalkyl, C3-6-Cycloalkyl, Aralkyl, Aryl stehen,
R3a, R5a, R7a, R9a unabhängig voneinander für Wasserstoff oder geradkettiges oder verzweigtes C1-8- in which R a, R 2a, R l la and R 12a independently of one another Ci -8 - alkyl, C ,. 8 -haloalkyl, C 3-6 -cycloalkyl, aralkyl, aryl, R 3a , R 5a , R 7a , R 9a independently of one another represent hydrogen or straight-chain or branched C 1-8 -
Alkyl steht, das gegebenenfalls durch Hydroxy, > Carboxamid,
Is alkyl optionally substituted by hydroxy, > carboxamide,
(- substituiert sein kann und
ferner für Aryl oder Aralkyl die durch Halogen, Hydroxy, CM-Alkyl, Q-4-AIkOXy substituiert sein können, steht,(- can be substituted and further for aryl or aralkyl which may be substituted by halogen, hydroxy, C M alkyl, Q 4 alkoxy,
R4a, R6a, R8a, R1Oa unabhängig voneinander für Wasserstoff, geradkettiges C].5-Alkyl, C2-6-R 4a , R 6a , R 8a , R 10a independently of one another are hydrogen, straight-chain C]. 5- alkyl, C 2-6 -
Alkenyl, C3.7-Cycloalkyl, die gegebenenfalls durch Hydroxy, Ci-4-AIkOXy, Carboxy, Carboxamid, Imidazolyl, Indolyl, Guanidino, SH oder
substituiert sein können, sowie für Aryl oder Aralkyl die durch Halogen, Hydroxy, Ci-4- Alkyl, Ci-4-AIkOXy substituiert sein können, stehen sowie deren optische Isomere und Racemate.Alkenyl, C. 3 7 cycloalkyl, optionally substituted by hydroxy, Ci -4 -alkoxy, carboxyl, carboxamide, imidazolyl, indolyl, guanidino, SH or can be substituted, as well as by halogen, hydroxy, Ci -4 aryl or aralkyl - may be substituted alkyl, Ci -4 -alkoxy, standing and their optical isomers and racemates.
Bevorzugt werden Verbindungen der Formel (IHd) eingesetzt, in welcherPreference is given to using compounds of the formula (III) in which
Rla, R2a, Rl la und R12a unabhängig voneinander für Methyl, Ethyl, Propyl, Isopropyl, n-, s-, t-Butyl oder Phenyl, das gegebenenfalls substituiert ist durch Halogen, CM-Alkyl, OH, CM-Alkoxy, sowie für Benzyl oder Phenylethyl stehen, die gegebenenfalls durch die bei Phenyl angegebenen Reste substituiert sein können;R 1a , R 2a , R l la and R 12a independently of one another are methyl, ethyl, propyl, isopropyl, n-, s-, t-butyl or phenyl, which is optionally substituted by halogen, C M alkyl, OH, C M is alkoxy, as well as benzyl or phenylethyl, which may optionally be substituted by the radicals indicated for phenyl;
R3a bis R1Oa die oben angegebene Bedeutung haben.R 3a to R 10a have the abovementioned meaning.
Besonders bevorzugt sind Verbindungen der Formel (IHd), in welcherParticular preference is given to compounds of the formula (IHd) in which
Rla, R2a, Rl la und RI2a unabhängig voneinander für Methyl, Ethyl, Propyl, Isopropyl oder n-, s-, t- Butyl stehen,R la, R 2a, R l la and R I2a independently methyl, ethyl, propyl, isopropyl or n-, s-, t-butyl,
R3a, R5a, R7a, R9a für Wasserstoff, geradkettiges oder verzweigtes Ci-8-Alkyl, insbesondere Methyl, Ethyl, Propyl, i-Propyl, n-, s-, t-Butyl, die gegebenenfalls durch Ci ^-Alkoxy, insbesondere Methoxy,R 3a, R 5a, R 7a, R 9a is hydrogen, straight or branched Ci -8 alkyl, especially methyl, ethyl, propyl, i-propyl, n-, s-, t-butyl, optionally substituted by Ci ^ - Alkoxy, especially methoxy,
Ethoxy, Imidazolyl, Indolyl oder
insbesondere Methylthio, Ethylthio substituiert sein können, femer für Pheriyl. Benzyl oder Phenethyl stehen, die gegebenenfalls durch Halogen insbesondere Chlor substituiert sein können.Ethoxy, imidazolyl, indolyl or especially methylthio, ethylthio may be substituted, furthermore for pheriyl. Benzyl or phenethyl, which may optionally be substituted by halogen, in particular chlorine.
R4a, R6a, R8a, R1Oa unabhängig voneinander für Wasserstoff, Methyl, Ethyl, n-Propyl, n-Butyl,R 4a , R 6a , R 8a , R 10a independently of one another represent hydrogen, methyl, ethyl, n-propyl, n-butyl,
Vinyl, Cyclohexyl, die gegebenenfalls durch Methoxy, Ethoxy, Imidazolyl, Indolyl, Methylthio,
Ethylthio substituiert sein können, sowie für Isopropyl, s-Butyl ferner für gegebenenfalls halogensubstituiertes Phenyl, Benzyl oder Phenylethyl stehen.Vinyl, cyclohexyl optionally substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, Ethylthio may be substituted, as well as isopropyl, s-butyl furthermore represents optionally halogen-substituted phenyl, benzyl or phenylethyl.
Die Verbindungen der Formel (HId) können ebenfalls nach den in EP-A-382 173, DE-A 4 317432, DE-A 4 317457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872481, EP-A-685 469, EP- A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, EP-A-903 347 beschriebenen Verfahren erhalten werden.The compounds of the formula (IIId) can also be prepared according to the methods described in EP-A-382 173, DE-A 4 317432, DE-A 4 317457, DE-A 4 317 458, EP-A-634 408, EP-A-718 293, EP-A-872481, EP-A-685 469, EP-A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, Obtained by EP-A-903 347.
Erfindungsgemäß ganz besonders bevorzugte Depsipepüde sind PF 1022 A (siehe Formel (HIa) und Emodepside (PF 1022-221, Verbindung der Formel (HIb) worin beide Reste Z für den Morpholinyl- rest stehen). Der INN Emodepside steht für die Verbindung mit dem systematischen Namen: Cyclo[(R)-lactoyl-N-methyl-L-leucyl-(R)-3-(p-moφholinophenyl)lactoyl-N-methyl-L-leucyl-(i?)- lactoyl-N-methyl-L-leucyl-(i?)-3-(p-moφhohnophenyl)lactoyl-N-methyl-L-leucyl.Very particularly preferred depilatory puffs according to the invention are PF 1022 A (see formula (IIIa) and emodepside (PF 1022-221, compound of the formula (IIIb) in which both Z radicals are the morpholinyl radical.) The INN emodepside stands for the compound with systematic name: Cyclo [(R) -lactoyl-N-methyl-L-leucyl- (R) -3- (p-monopholinophenyl) lactoyl-N-methyl-L-leucyl (i) -lactoyl-N-methyl -L-leucyl- (i?) - 3- (p-moφhohnophenyl) lactoyl-N-methyl-L-leucyl.
Wirkstoffe können je nach Struktur in stereoisomeren Formen oder als Stereoisomerengemische vorliegen, z.B. als Enantiomere oder Racemate. Sowohl die Stereoisomerengemische als auch die reinen Stereoisomeren können erfindungsgemäß verwendet werden.Depending on the structure, active compounds can be present in stereoisomeric forms or as stereoisomer mixtures, e.g. as enantiomers or racemates. Both the stereoisomer mixtures and the pure stereoisomers can be used according to the invention.
Weiterhin können gegebenenfalls verwendet werden: Salze der Wirkstoffe mit pharmazeutisch annehmbaren Säuren oder Basen und auch Solvate, insbesondere Hydrate, der Wirkstoffe oder ihrer Salze.It is also possible to use, where appropriate, salts of the active compounds with pharmaceutically acceptable acids or bases and also solvates, in particular hydrates, of the active substances or their salts.
Die in den erfindungsgemäßen Erzeugnissen verwendeten Wirkstoffe können in Abhängigkeit von ihrer Struktur in stereoisomeren Formen (Enantiomere, Diastereomere) existieren. Erfindungsgemäß könne die Enantiomeren oder Diastereomeren und ihre jeweiligen Mischungen eingesetzt werden.The active substances used in the products according to the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). According to the invention, the enantiomers or diastereomers and their respective mixtures can be used.
Sofern die Wirkstoffe in tautomeren Formen vorkommen können, umfasst die vorliegende Erfindung auch den Einsatz der tautomeren Formen.If the active compounds can occur in tautomeric forms, the present invention also encompasses the use of the tautomeric forms.
Die Wirkstoffe können gegebenenfalls auch m Form ihrer Salze, Solvate und Solvate der Salze eingesetzt werdenIf appropriate, the active compounds may also be used in the form of their salts, solvates and solvates of the salts
Als Salze sind im Rahmen der vorliegenden Erfindung physiologisch unbedenkliche Salze der Wirkstoffe bevorzugt.As salts physiologically acceptable salts of the active ingredients are preferred in the context of the present invention.
Physiologisch unbedenkliche Salze der Wirkstoffe umfassen je nach Struktur des Wirkstoffs Säure- additionssalze von Mmeralsäuren, Carbonsäuren und Sulfonsäuren, z.B. Salze der Chlor-
wasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethan- sulfonsäure, Toluolsulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure, Trifiuor- essigsäure, Propionsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Fumarsäure, Maleinsäure und Benzoesäure.Physiologically acceptable salts of the active compounds comprise, depending on the structure of the active substance, acid addition salts of maleic acids, carboxylic acids and sulfonic acids, for example salts of chlorine. hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic
Physiologisch unbedenkliche Salze der Wirkstoffe umfassen gegebenenfalls auch Salze üblicher Basen, wie beispielhaft und vorzugsweise Alkalimetallsalze (z.B. Natrium- und Kaliumsalze), Erdalkalisalze (z.B. Calcium- und Magnesiumsalze) und Ammoniumsalze, abgeleitet von Ammoniak oder organischen Aminen mit 1 bis 16 C-Atomen, wie beispielhaft und vorzugsweise Ethylamin, Diethylamin, Triethylamin, Ethyldiisopropylamin, Monoethanolamin, Diethanolamin, Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Prokain, Dibenzylamin, N-Methylmoφholin, Arginin, Lysin, Ethylendiamin, N-Methylpiperidin und Cholin.Physiologically acceptable salts of the active compounds optionally also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
Als Solvate werden im Rahmen der Erfindung solche Formen der Wirkstoffe bezeichnet, welche in festem oder flüssigem Zustand durch Koordination mit Lösungsmittelmolekülen einen Komplex bilden. Hydrate sind eine spezielle Form der Solvate, bei denen die Koordination mit Wasser erfolgt. Außerdem umfasst die vorliegende Erfindung auch Prodrugs der Wirkstoffe. Der Begriff „Prodrugs" umfasst Verbindungen, welche selbst biologisch aktiv oder inaktiv sein können, jedoch während ihrer Verweilzeit im Körper zu dem eigentlichen Wirkstoff umgesetzt werden (beispielsweise metabolisch oder hydrolytisch).Solvates in the context of the invention are those forms of the active ingredients which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. In addition, the present invention also includes prodrugs of the active ingredients. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but are converted to the actual active ingredient during their residence time in the body (for example metabolically or hydrolytically).
Die erfindungsgemäßen Erzeugnisse eignen sich bei günstiger Warmblütertoxizität zur Bekämpfung von pathogenen Endoparasiten, die bei Menschen und in der Tierhaltung und Tierzucht bei Nutz-, Zucht-, Zoo-, Labor-, Versuchs- und Hobbytieren vorkommen. Sie sind dabei gegen alle oder einzelne Entwicklungsstadien der Schädlinge sowie gegen resistente und normal sensible Arten wirksam. Durch die Bekämpfung der pathogenen Endoparasiten sollen Krankheit, Todesfälle und Leistungsminderungen (z.B. bei der Produktion von Fleisch, Milch, Wolle, Häuten, Eiern, Honig usw.) vermindert werden, so dass durch den Einsatz der Wirkstoffe eine wirtschaftlichere und einfachere Tierhaltung möglich ist. Zu den pathogenen Endoparasiten zählen Cestoden, Trematoden, Nematoden, Acantocephalen insbesondere:The products according to the invention are suitable in the case of favorable warm-blooded toxicity for controlling pathogenic endoparasites which occur in humans and in animal husbandry and animal breeding in productive, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By controlling pathogenic endoparasites, it is intended to reduce disease, fatalities and impairments (for example in the production of meat, milk, wool, hides, eggs, honey, etc.) so that the use of the active substances makes it possible to achieve more economical and easier animal husbandry. The pathogenic endoparasites include cestodes, trematodes, nematodes, acantocephalen in particular:
Aus der Ordnung der Pseudophyllidea z.B.: Diphyllobothrium spp., Spirometra spp., Schistocepha- lus spp., Ligula spp., Bothridium spp., Diphiogonoporus spp..From the order of Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphiogonoporus spp.
Aus der Ordnung der Cyclophyllidea z.B.: Mesocestoides spp., Anoplocephala spp., Paranoploce- phala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp.,
Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp..From the order of the Cyclophyllidea eg: Mesocestoides spp., Anoplocephala spp., Paranoplocuspala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
Aus der Unterklasse der Monogenea z.B.: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp..From the subclass of Monogenea, for example: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.
Aus der Unterklasse der Digenea z.B.: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp-, Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus spp..From the subclass of Digenea, for example: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp. , Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp, Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus spp.
Aus der Ordnung der Enoplida z.B.: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp..From the order of Enoplida, for example: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp.
Aus der Ordnung des Rhabditia z.B.: Micronema spp., Strongyloides spp..From the order of Rhabditia, for example: Micronema spp., Strongyloides spp.
Aus der Ordnung der Strongylida z.B.: Strongylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafϊlaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp., Cylicocyclus spp., Cylicodontophorus spp..For example, Strongylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp. , Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus Spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Paraflaroids spp., Trichostrongylus spp., Haemonchus spp. , Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp., Cylicocyclus spp., Cylicodontophorus spp.
Aus der Ordnung der Oxyuπda z.B.: Oxyuris spp., Enterobius spp., Passalurαs spp., Syphacia spp., Aspiculuris spp., Heterakis spp..From the order of Oxyuπda, for example: Oxyuris spp., Enterobius spp., Passaluras spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
Aus der Ordnung der Ascaridia z.B.: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp..
Aus der Ordnung der Spirurida z.B.: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp..From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp. For example, from the order of Spirurida: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
Aus der Ordnung der Filariida z.B.: Stephanofilaria spp., Parafϊlaria spp., Setaria spp., Loa spp., Dirofüaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp..From the order of the Filariida, for example: Stephanofilaria spp., Paraflaria spp., Setaria spp., Loa spp., DirofÃÂariaaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.
Aus der Gruppe der Gigantohynchida z.B.: Filicollis spp., Moniliformis spp., Macra- canthorhynchus spp., Prosthenorchis spp..From the group of Gigantohynchida, for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.
Bevorzugt ist die Bekämpfung von Bandwürmern, z.B. Taenia spp. Ebenfalls bevorzugt ist die Bekämpfung von Nematoden, wie z. B.:Preferably, the control of tapeworms, e.g. Taenia spp. Also preferred is the control of nematodes, such. B .:
Aus der Ordnung der Spirurida z.B.: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp..From the order of Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
Besonders bevorzugt ist die Verwendung der erfmdungsgemäßen Erzeugnisse zur Bekämpfung von Strongylida, insbesondere Haemonchus spp., Trichostrongylus spp., Cooperia spp. und Ostertagia spp. sowie von Ascaridida wie z. B. Parascaris spp.Particularly preferred is the use of the inventive products for the control of Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp. Ascaridida such. B. Parascaris spp.
Zu den Nutztieren gehören insbesondere Säugetiere wie z.B. Rinder, Pferde, Schafe, Schweine, Ziegen, Kamele, Wasserbüffel, Esel, Kaninchen, Damwild, Rentiere, Pelztiere wie z.B. Nerze, Chinchilla, Waschbär. Von den Nutztier-Säugetieren bevorzugt sind Rinder Schafe und Schweine Ebenfalls eingeschlossen für die erfindungsgemäße Verwendung sind die folgenden Tierarten, die keine Säugetiere sind, die aber ebenfalls zu den Nutztieren gehören: Vögel, wie z.B. Hühner, Gänse, Puten, Enten; Süß- und Salzwasserfische wie z.B. Forellen, Karpfen, Aale, Reptilien; Insekten wie z.B. Honigbiene und Seidenraupe.The livestock include in particular mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, Chinchilla, Raccoon. Of the livestock mammals, cattle are preferably sheep and pigs. Also included in the use according to the invention are the following non-mammal species, but which are also livestock: birds, e.g. Chickens, geese, turkeys, ducks; Freshwater and saltwater fish such as Trout, carp, eels, reptiles; Insects such as e.g. Honeybee and silkworm.
Zu den Hobbytieren gehören bevorzugt Hunde und Katzen. Bei diesen werden bevorzugt Toxoscaris spp., Toxocara spp., Trichuris spp., Trichinella spp. sowie die Hakenwürmer Ancylostoma spp. und Uncinaria spp. bekämpft.Hobby animals include dogs and cats. Among these, preferred are Toxoscaris spp., Toxocara spp., Trichuris spp., Trichinella spp. and the hookworms Ancylostoma spp. and Uncinaria spp. fought.
Gemäß einer weiteren Ausführungsform können die Erzeugnisse auch beim Menschen eingesetzt werden. Vorzugsweise werden beim Menschen Ascaris spp., Ancylostoma spp, Necator spp., Trichuris spp., Strongyloides spp. und Enterobius spp. bekämpft.
Unter den Saugetieren werden gemäß einer Ausführungsform für die Anwendung von obengenannten Kombinationen die Pflanzenfresser (Herbivoren) bevorzugt, also Tiere, die sich hauptsächlich von Pflanzen ernähren. Besonders bevorzugt ist die Behandlung von Wiederkäuern (wie z. B. Schafe, Ziegen, Rinder).According to another embodiment, the products can also be used in humans. Preferably, Ascaris spp., Ancylostoma spp, Necator spp., Trichuris spp., Strongyloides spp. and Enterobius spp. fought. Among the mammals, according to one embodiment, herbivores (herbivores) are preferred for the application of the abovementioned combinations, ie animals which mainly feed on plants. Particularly preferred is the treatment of ruminants (such as sheep, goats, cattle).
Als nicht wiederkäuende Pflanzenfresser, die Säugetiere sind, seien als bevorzugtes Beispiel die Pferde genannt. Dort können die obengenannten Kombinationen bevorzugt z. B. zur Bekämpfung von Strongyhda oder insbesondere von Spulwürmern (Ascaπdia), wie z. B. Parascaπs equorum, eingesetzt werden.As non-ruminant herbivores, which are mammals, the horses are mentioned as a preferred example. There, the above combinations may be preferred z. B. for combating Strongyhda or in particular roundworms (Ascaπdia), such as. B. Parascaπs equorum used.
Bei den Wiederkäuern können bevorzugt Strongyhda, insbesondere Haemonchus spp., Tπchostrongylus spp., Coopeπa spp. und Ostertagia spp. bekämpft werden.In ruminants, Strongyhda, in particular Haemonchus spp., Tπchostrongylus spp., Coopeπa spp. and Ostertagia spp. be fought.
Besonders bevorzugt werden erfindungsgemäß Schafe behandelt.According to the invention, sheep are particularly preferably treated.
Ebenfalls besonders bevorzugt werden erfmdungsgemäß Rinder behandelt.Likewise particularly preferred, cattle are treated according to the invention.
Die Anwendung kann sowohl prophylaktisch als auch therapeutisch erfolgen.The application can be both prophylactic and therapeutic.
Die Anwendung des Wirkstoffs erfolgt direkt oder in Form von geeigneten Zubereitungen enteral, parenteral, dermal, nasal, durch Behandlung der Umgebung oder mit Hilfe wirkstoffhaltiger Formkörper wie z. B. Streifen, Platten, Bänder, Halsbänder, Ohrmarken, Gliedmaßenbänder, Markierungsvorrichtungen.The application of the active ingredient is carried out directly or in the form of suitable preparations enteral, parenteral, dermal, nasal, by treatment of the environment or with the aid of active ingredient-containing moldings such. As strips, plates, ligaments, collars, ear tags, limb bands, marking devices.
Die enterale Anwendung des Wirkstoffs geschieht z.B. oral m Form von Pulver, Zäpfchen, Tabletten, Kapseln, Fasten, Tränken, Granulaten, Drenchen, BoIi, medikiertem Futter oder Trinkwasser. Die dermale Anwendung geschieht z.B. in Form des Tauchens (Dippen), Sprühens (Sprayen), Badens, Waschens, Aufgießens (pour-on and spot-on) und des Empuderns. Die parenterale Anwendung geschieht z B. in Form der Injektion (mtramusculär, subcutan, intravenös, intrapeπtoneal) oder durch Implantate.Enteral administration of the active ingredient is e.g. oral form of powder, suppositories, tablets, capsules, fasting, potions, granules, drenches, boii, medicated feed or drinking water. The dermal application is e.g. in the form of dipping, spraying, bathing, washing, pour-on and spot-on, and empowering. Parenteral administration is, for example, in the form of injection (mtramuscular, subcutaneous, intravenous, intrapeπtoneal) or by implants.
Geeignete Zubereitungen sind:Suitable preparations are:
Losungen wie Injektionsiösungen, υrdlc Lösungen, Konzentrate zur oralen Verabreichung nach Verdünnung, Lösungen zum Gebrauch auf der Haut oder in Körperhöhlen, Aufgußformulierungen, Gele;
Emulsionen und Suspensionen zur oralen oder dermalen Anwendung sowie zur Injektion; halbfeste Zubereitungen;Solutions such as injection solutions, other solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels; Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
Formulierungen bei denen der Wirkstoff in einer Salbengrundlage oder in einer Öl in Wasser oder Wasser in Öl Emulsionsgrundlage verarbeitet ist;Formulations in which the active substance is processed in an ointment base or in an oil in water or water in oil emulsion base;
Feste Zubereitungen wie Pulver, Premixe oder Konzentrate, Granulate, Pellets, Tabletten, BoIi, Kapseln; Aerosole und Inhalate, wirkstoffhaltige Formkörper.Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, tablets, capsules; Aerosols and inhalants, active substance-containing moldings.
Injektionslösungen werden intravenös, intramusculär und subcutan verabreicht.Injection solutions are administered intravenously, intramuscularly and subcutaneously.
Orale Lösungen werden direkt angewendet. Konzentrate werden nach vorheriger Verdünnung auf die Anwendungskonzentration oral angewendet.Oral solutions are applied directly. Concentrates are administered orally after prior dilution to the concentration of use.
Lösungen zum Gebrauch auf der Haut werden aufgeträufelt, aufgestrichen, eingerieben, aufgespritzt, aufgesprüht oder durch Tauchen (Dippen, Baden oder Waschen) aufgebracht.Solutions for use on the skin are dripped, brushed, rubbed, sprayed on, sprayed on or applied by dipping (dipping, bathing or washing).
Gele werden auf die Haut aufgetragen oder aufgestrichen oder in Körperhöhlen eingebracht.Gels are applied to the skin or brushed or incorporated into body cavities.
Aufgießformulierungen werden auf begrenzte Bereiche der Haut aufgegossen oder aufgespritzt, wobei der Wirkstoff entweder die Haut durchdringt und systemisch wirkt oder sich auf der Körperoberfläche verteilt.Pour-on formulations are infused or sprayed onto limited areas of the skin, whereby the active ingredient either penetrates the skin and acts systemically or spreads on the body surface.
Emulsionen können oral, dermal oder als Injektion angewendet werden. Emulsionen sind entweder vom Typ Wasser in Öl oder vom Typ Öl in Wasser.Emulsions can be administered orally, dermally or as an injection. Emulsions are either water-in-oil type or oil-in-water type.
Suspensionen können oral, dermal oder als Injektion angewendet werden.Suspensions may be administered orally, dermally or as an injection.
Halbfeste Zubereitungen können oral oder dermal verabreicht werden.Semi-solid preparations may be administered orally or dermally.
Zur Herstellung fester Zubereitungen wird der Wirkstoff mit geeigneten Trägerstoffen gegebenenfalls unter Zusatz von Hilfsstoffen vermischt und in die gewünschte Form gebracht.For the preparation of solid preparations, the active compound is mixed with suitable excipients, if appropriate with the addition of auxiliaries, and brought into the desired form.
Die erfindungsgemäßen Erzeugnisse können gegebenenfalls weitere Wirkstoffe enhalten.The products according to the invention may optionally contain further active ingredients.
Die Anwendung in Kombination bedeutet entweder, dass die anthelmintisch wirksamen Aminophenylamidin-Derivate und die cyclischen Depsipeptide in einer gemeinsamen Zubereitung
formuliert und entsprechend gemeinsam appliziert werden. Die Erzeugnisse können aber auch getrennte Zubereitungen für jeden Wirkstoff umfassen. Falls mehr als zwei Wirkstoffe eingesetzt werden sollen können, entsprechend alle Wirkstoffe in einer gemeinsamen Zubereitung, alle Wirkstoffe in getrennten Formulierungen formuliert werden, denkbar sind auch Mischformen, bei denen ein Teil der Wirkstoffe gemeinsam und ein Teil der Wirkstoffe getrennt formuliert wird.The use in combination means either that the anthelmintic aminophenylamidine derivatives and the cyclic depsipeptides in a common preparation formulated and applied together accordingly. However, the products may also comprise separate preparations for each active substance. If more than two active substances can be used, corresponding to all active ingredients in a common preparation, all active ingredients are formulated in separate formulations, conceivable are also mixed forms in which a part of the active ingredients together and a part of the active ingredients is formulated separately.
Getrennte Formulierungen erlauben die getrennte oder zeitlich abgestufte Anwendung der jeweiligen Wirkstoffe.Separate formulations allow separate or sequential use of the respective active ingredients.
Die Erzeugnisse (Zubereitungen) enthalten die Wirkstoffe jeweils in Konzentrationen von 10 ppm bis 90 Gewichtsprozent, bevorzugt 0,1 bis 50 Gewichtsprozent.The products (preparations) contain the active ingredients in each case in concentrations of 10 ppm to 90 weight percent, preferably 0.1 to 50 weight percent.
Anwendungsfertige Zubereitungen enthalten die Wirkstoffe üblicherweise in Konzentrationen von jeweils 10 ppm bis 20 Gewichtsprozent, bevorzugt von 0,1 bis 10 Gewichtsprozent.Ready-to-use preparations usually contain the active compounds in concentrations of 10 ppm to 20 percent by weight, preferably from 0.1 to 10 percent by weight.
Zubereitungen die vor Anwendung verdünnt werden, enthalten die Wirkstoffe in Konzentrationen von 0,5-90 Gew.-%, bevorzugt von 5 bis 50 Gewichtsprozent.Preparations which are diluted before use, contain the active compounds in concentrations of 0.5-90 wt .-%, preferably from 5 to 50 weight percent.
Das Gewichtsverhältnis von Aminophenylamidin zu Cyclodepsipeptid in den erfindungsgemäßen Erzeugnissen hängt von verschiedenen Faktoren ab, liegt aber in der Regel im Bereich 10:90 bis 50: 50, bevorzugt 20:80 bis 30:70.The weight ratio of aminophenylamidine to cyclodepsipeptide in the products according to the invention depends on various factors, but is generally in the range of 10:90 to 50:50, preferably 20:80 to 30:70.
Übliche Dosierungen der Aminophenylamidine pro Tag liegen bei 1 bis 100 mg/kg Körpergewicht, vorzugsweise 2 bis 60 mg/kg Körpergewicht.Usual dosages of Aminophenylamidine per day are 1 to 100 mg / kg body weight, preferably 2 to 60 mg / kg body weight.
Übliche Dosierungen der Depsipeptide liegen pro Tag bei 0,1 bis 100 mg/kg , bevorzugt bei 0,5 bis 50 mg/kg, besonders bevorzugt bei 1 bis 50 mg/kg Körpergewicht pro Tag.
Usual dosages of depsipeptides per day are 0.1 to 100 mg / kg, preferably 0.5 to 50 mg / kg, more preferably 1 to 50 mg / kg of body weight per day.
BeispieleExamples
Beispiel 1 (Flüssigformulierung):Example 1 (liquid formulation):
Suspensionen in 100 ml Glycerinformal/Glycerin-Polyethylenglykolricinoleat (Cremophor® EL)/Wasser im Mischungsverhältnis 1 : 10 mit:Suspensions in 100 ml glycerol formal / glycerol-Polyethylenglykolricinoleat (Cremophor® EL) / water in the mixing ratio 1:10 with:
• 500 mg PF 1022, 1000 mg Tribendimidin• 500 mg PF 1022, 1000 mg tribendimidine
• 500 mg PF 1022, 1500 mg Tribendimidin• 500 mg PF 1022, 1500 mg tribendimidine
• 400 mg Emodepsid, 1000 mg Tribendimidin• 400 mg emodepside, 1000 mg tribendimidine
• 400 mg Emodepsid, 1500 mg Tribendimidin • 500 mg PF 1022, 1000 mg Amidantel• 400 mg emodepside, 1500 mg tribendimidine • 500 mg PF 1022, 1000 mg amide shell
• 500 mg PF 1022, 1500 mg Amidantel• 500 mg PF 1022, 1500 mg amide shell
• 400 mg Emodepsid, 1000 mg Amidantel• 400 mg of emodepside, 1000 mg of amide shell
• 400 mg Emodepsid, 1500 mg Amidantel• 400 mg of emodepside, 1500 mg of amide shell
Beispiel 2 fFlüssigformulierung):Example 2 Liquid Formulation):
Suspensionen in 100 ml Cremophor® EL/Wasser im Mischungsverhältnis 1 : 5 mit:Suspensions in 100 ml Cremophor® EL / water in a mixing ratio of 1: 5 with:
• 500 mg PF 1022, 1000 mg Tribendimidin• 500 mg PF 1022, 1000 mg tribendimidine
• 500 mg PF 1022, 1500 mg Tribendimidin• 500 mg PF 1022, 1500 mg tribendimidine
• 400 mg Emodepsid, 1000 mg Tribendimidin • 400 mg Emodepsid, 1500 mg Tribendimidin• 400 mg emodepside, 1000 mg tribendimidine • 400 mg emodepside, 1500 mg tribendimidine
• 500 mg PF 1022, 1000 mg Amidantel• 500 mg PF 1022, 1000 mg amide shell
• 500 mg PF 1022, 1500 mg Amidantel• 500 mg PF 1022, 1500 mg amide shell
• 400 mg Emodepsid, 1000 mg Amidantel• 400 mg of emodepside, 1000 mg of amide shell
• 400 mg Emodepsid, 1500 mg Amidantel• 400 mg of emodepside, 1500 mg of amide shell
Beispiel 3 CFeststoffformulierung)Example 3 CFsubstate formulation)
Die Wirkstoffe werden in den unten angegebenen Mengen als Pulver in eine Gelatinekapseln gefüllt:The active ingredients are filled in the amounts given below as a powder in a gelatin capsules:
• 100 mg PF 1022, 200 mg Tribendimidin • 100 mg PF 1022, 300 mg Tribendimidin• 100 mg PF 1022, 200 mg tribendimidine • 100 mg PF 1022, 300 mg tribendimidine
• 80 mg Emodepsid, 250 mg Tribendimidin• 80 mg emodepside, 250 mg tribendimidine
• 100 mg Emodepsid, 300 mg Tribendimidin• 100 mg emodepside, 300 mg tribendimidine
• 100 mg PF 1022, 200 mg Amidantel• 100 mg PF 1022, 200 mg amide shell
• 100 mg PF 1022, 300 mg Amidantel • 150 mg Emodepsid, 400 mg Amidantel• 100 mg PF 1022, 300 mg amide shell • 150 mg emodepside, 400 mg amide shell
• 100 mg Emodepsid, 300 mg Amidantel
Biologische Beispiele• 100 mg emodepside, 300 mg amide shell Biological examples
Synergistischer Effekt der Kombination von Amidinen (z.B. Amidantel, Bay d 9216) mit cyclischen Oktadepsipeptiden (z.B. PF1022A)Synergistic Effect of the Combination of Amidines (e.g., Amidantel, Bay d 9216) with Cyclic Octadepsipeptides (e.g., PF1022A)
Testverfahren für in vitro Experimente mit Nippostrongylus brasiliensisTest procedure for in vitro experiments with Nippostrongylus brasiliensis
Adulte Nippostrongylus brasiliensis wurden aus dem Dünndarm weiblicher Wistar-Ratten isoliert, in 0.9% NaCl transferiert, das 20 μg/ml Sisomycin und 2 μg/ml Canesten enthielt. Die Inkubation der Wurmgruppen (beide Geschlechter) wurde in 1.0 ml Medium durchgeführt, das auch für die Bestimmung der Acetylcholinesterase- Aktivität verwendet wurde. Die Inkubation und die Enzymbestimmung wurden in der Arbeit von Rapson et al. (1987) Z. Parasitenkunde 73, 190-191 beschrieben. Die Verbindungen wurden in DMSO gelöst und dem Inkubationsmedium zugefügt, sodass Endkonzentrationen von 100, 10, 1, 0.1, 0.01, 0.001 and 0.0001 μg/ml vorhanden waren. Die Kontrollen enthielten nur DMSO. In dem Inkubationsmedium wurde die Acetylcholinesterase- Aktivität bestimmt entsprechend der obigen Publikation.Adult Nippostrongylus brasiliensis were isolated from the small intestine of female Wistar rats, transferred to 0.9% NaCl containing 20 μg / ml sisomycin and 2 μg / ml Canesten. The incubation of the worm groups (both sexes) was carried out in 1.0 ml of medium which was also used for the determination of acetylcholinesterase activity. Incubation and enzyme determination were performed in the work of Rapson et al. (1987) Z. Parasitenkunde 73, 190-191. The compounds were dissolved in DMSO and added to the incubation medium so that final concentrations of 100, 10, 1, 0.1, 0.01, 0.001 and 0.0001 μg / ml were present. The controls contained only DMSO. In the incubation medium, the acetylcholinesterase activity was determined according to the above publication.
Die Einteilung der Wirksamkeit erfolgte mittels einer Skalierung 0-3, wobei 0 = keine Aktivität (< 50% Enzymhemmung) bedeutet; 1 = schwache Aktivität; 2 = gute Aktivität; 3 = volle AktivitätThe classification of the effectiveness was carried out by means of a scale 0-3, where 0 = no activity (<50% enzyme inhibition) means; 1 = weak activity; 2 = good activity; 3 = full activity
Claims
Patentansprüche claims
1. Erzeugnisse enthaltend anthelmintisch wirksame Aminophenylamidin-Derivate und cyclische Depsipeptide.1. Products containing anthelmintic aminophenylamidine derivatives and cyclic depsipeptides.
2. Erzeugnisse gemäß Anspruch 1, worin das Aminophenylamidin-Derivat eine Verbindung der Formel (I) ist,2. Products according to claim 1, wherein the aminophenylamidine derivative is a compound of the formula (I),
woπnembedded image in which
R1 Wasserstoff oder C1-4-Alkyl bedeutet undR 1 is hydrogen or C 1-4 -alkyl and
R2 Wasserstoff, -COO(C1-4-AIlCyI), -CO(C1-4-Alkyl), -COCH2(C1-4-Alkyl), -COCH2OPhenyl oder -COHetaryl bedeutet, wobei Hetaryl für einen fünf- oder 6- gliedrigen aromatischen Heterocyclus mit einem oder mehreren Heteroringatomen ausgewählt aus O, N und S steht, oderR 2 is hydrogen, -COO (C 1-4 -alkyl), -CO (C 1-4 -alkyl), -COCH 2 (C 1-4 -alkyl), -COCH 2 -OPhenyl or -COHetaryl, where hetaryl is for a five- or six-membered aromatic heterocycle having one or more hetero ring atoms selected from O, N and S, or
R1 und R2 gemeinsam für den RestR 1 and R 2 together for the rest
stehen. stand.
4. Erzeugnisse gemäß einem der vorstehenden Ansprüche, worin das Aminophenylamidin-4. Products according to any one of the preceding claims, wherein the aminophenylamidine
Derivat eine Verbindung der Formel (I) ist, worinDerivative is a compound of formula (I) wherein
R1 für Wasserstoff steht,R 1 is hydrogen,
R2 für Wasserstoff, -COCH2(C1 ^- Alkoxy) oder zusammen mit R1 für den Rest
steht.R 2 is hydrogen, -COCH 2 (C 1 ^ - alkoxy) or together with R 1 is the radical stands.
5. Erzeugnisse gemäß einem der vorstehenden Ansprüche, worin das Aminophenylamidin- Derivat Amidantel, Bay d 9216 oder Tribendimidin ist.5. Products according to any one of the preceding claims, wherein the aminophenylamidine derivative is amide shell, Bay d 9216 or tribendimidine.
6. Erzeugnisse gemäß einem der vorstehenden Ansprüche, worin das Aminophenylamidin- Derivat Tribendimidin ist.Products according to any one of the preceding claims, wherein the aminophenylamidine derivative is tribendimidine.
7. Erzeugnisse gemäß einem der vorstehenden Ansprüche, worin das cyclische Depsipeptid ein 24-gliedriges Octacyclodepsipeptid ist.Products according to any one of the preceding claims, wherein the cyclic depsipeptide is a 24-membered octacyclodepsipeptide.
8. Erzeugnisse gemäß Anspruch 6, worin das cyclische Depsipeptid Emodepsid ist.8. Products according to claim 6, wherein the cyclic depsipeptide is emodepside.
9. Erzeugnisse gemäß Anspruch 6, worin das cyclische Depsipeptid PF 1022 ist.9. Products according to claim 6, wherein the cyclic depsipeptide is PF 1022.
9. Verwendung von anthelmintisch wirksamen Aminophenyiamidin-Derivaten und cyclischen Oktadepsipeptiden zur Herstellung von Arzneimitteln zur Bekämpfung von Endoparasiten bei Menschen oder Tieren.
9. Use of anthelmintic Aminophenyiamidin derivatives and cyclic Oktadepsipeptiden for the preparation of medicaments for the control of endoparasites in humans or animals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102008030764A DE102008030764A1 (en) | 2008-06-28 | 2008-06-28 | Combination of amidine derivatives with cyclic depsipeptides |
| PCT/EP2009/004304 WO2009156071A1 (en) | 2008-06-28 | 2009-06-16 | Combination of amidine derivates with cyclic depsipeptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2299995A1 true EP2299995A1 (en) | 2011-03-30 |
Family
ID=41010493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP09768920A Withdrawn EP2299995A1 (en) | 2008-06-28 | 2009-06-16 | Combination of amidine derivates with cyclic depsipeptides |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US20110201550A1 (en) |
| EP (1) | EP2299995A1 (en) |
| JP (1) | JP2011526262A (en) |
| AR (1) | AR073180A1 (en) |
| AU (1) | AU2009262581A1 (en) |
| BR (1) | BRPI0913996A2 (en) |
| CA (1) | CA2729420A1 (en) |
| DE (1) | DE102008030764A1 (en) |
| MX (1) | MX2010014442A (en) |
| TW (1) | TW201012471A (en) |
| UY (1) | UY31921A (en) |
| WO (1) | WO2009156071A1 (en) |
| ZA (1) | ZA201009064B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102344391B (en) * | 2011-07-28 | 2013-12-25 | 山东新华制药股份有限公司 | Synthesis method for N-(4-acetylaminophenyl)-N', N'-dimethylethanamidine |
| US10081656B2 (en) | 2015-05-20 | 2018-09-25 | Merial, Inc. | Anthelmintic depsipeptide compounds |
| CA3009867C (en) | 2015-12-28 | 2022-05-31 | Merial, Inc. | Anthelmintic cyclic depsipeptide compounds |
| WO2018093920A1 (en) | 2016-11-16 | 2018-05-24 | Merial, Inc. | Anthelmintic depsipeptide compounds |
| WO2020018888A1 (en) | 2018-07-20 | 2020-01-23 | The Board Of Regents Of The University Of Oklahoma | Antimicrobial peptides and methods of use |
| CN114146074B (en) * | 2020-09-08 | 2024-03-01 | 中国疾病预防控制中心寄生虫病预防控制所(国家热带病研究中心) | Antiparasitic pharmaceutical composition, application and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2029299C3 (en) * | 1970-06-13 | 1980-08-21 | Bayer Ag, 5090 Leverkusen | New aminophenylamidines, processes for their preparation and pharmaceuticals containing them |
| DE2029298C3 (en) | 1970-06-13 | 1980-04-17 | Bayer Ag, 5090 Leverkusen | Aminophenylamidines, process for their preparation and medicaments containing them |
| DE2029297A1 (en) * | 1970-06-13 | 1971-12-30 | Farbenfabriken Bayer Ag, 5090 Leverkusen | New aminophenyl-cycloamidines, processes for their production and their use as pharmaceuticals |
| BE788743A (en) * | 1971-09-14 | 1973-03-13 | Bayer Ag | NEW 2- (AMINOPHENYLIMINO) -3- AZA-1-THIA-CYCLOALCANES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS |
| NO176766C (en) | 1989-02-07 | 1995-05-24 | Meiji Seika Kaisha | Process for the preparation of a compound having anthelmintic activity |
| US5270037A (en) * | 1990-07-12 | 1993-12-14 | Boehringer Ingelheim Gmbh | Use of interferon and a substance with an antimalarial activity for the treatment of malaria infections |
| ES2166359T3 (en) * | 1992-03-17 | 2002-04-16 | Fujisawa Pharmaceutical Co | DERIVED FROM DEPSIPEPTIDE, ITS PRODUCTION AND USE. |
| DE4317458A1 (en) * | 1992-06-11 | 1993-12-16 | Bayer Ag | Use of cyclic depsipeptides with 18 ring atoms for the control of endoparasites, new cyclic depsipeptides with 18 ring atoms and process for their preparation |
| WO1994019334A1 (en) * | 1993-02-19 | 1994-09-01 | Meiji Seika Kaisha, Ltd. | Pf1022 derivative, cyclic depsipeptide |
| DE4317457A1 (en) * | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptides with endoparasiticidal activity |
| DE4317432A1 (en) | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptides with endoparasiticidal activity |
| EP0718293B1 (en) * | 1993-09-06 | 2002-03-13 | Fujisawa Pharmaceutical Co., Ltd. | Cyclodepsipeptide compound |
| DE4342907A1 (en) | 1993-12-16 | 1995-06-22 | Bayer Ag | New cyclic depsipeptides with 18 ring atoms and their use for the control of endoparasites |
| DE4401389A1 (en) * | 1994-01-19 | 1995-07-20 | Bayer Ag | Use of cyclic depsipeptides with 12 ring atoms for the control of endoparasites, new cyclic depsipeptides with 12 ring atoms and process for their preparation |
| DE4406025A1 (en) * | 1994-02-24 | 1995-08-31 | Bayer Ag | Lactic acid-containing cyclic depsipeptides with 18 ring atoms as endoparasiticidal agents and process for their preparation |
| DE4412492A1 (en) | 1994-04-12 | 1995-10-19 | Bayer Ag | Use of cyclic depsipeptides with 18 ring atoms |
| DE4437198A1 (en) * | 1994-10-18 | 1996-04-25 | Bayer Ag | Process for sulfonylation, sulfenylation and phosphorylation of cyclic depsipeptides |
| US5856436A (en) * | 1995-06-30 | 1999-01-05 | Fujisawa Pharmaceutical Co., Ltd. | Depsipeptide derivative, process for production thereof, and novel intermediate therefor |
| KR19990063676A (en) | 1995-09-22 | 1999-07-26 | 빌프리더 하이더 | Novel Cyclic Defepeptides PF1022 Derivatives |
| DE19545639A1 (en) * | 1995-12-07 | 1997-06-12 | Bayer Ag | Process for the preparation of substituted aryl lactic acid-containing cyclodepsipeptides with 24 ring atoms |
| WO1998037088A1 (en) | 1997-02-19 | 1998-08-27 | Meiji Seika Kaisha Ltd. | Derivatives of cyclodepsipeptide, pf1022 substance |
| DE19713626A1 (en) | 1997-04-02 | 1998-10-08 | Bayer Ag | New thiodepsipeptides to control endoparasites and a simple process for their preparation |
| JP2002502398A (en) * | 1997-06-04 | 2002-01-22 | バイエル・アクチエンゲゼルシヤフト | Desoxycyclodepsipeptide and its use for controlling endoparasites |
| DE19811559A1 (en) | 1998-03-17 | 1999-09-23 | Bayer Ag | New substituted derivatives of cyclooctadepsipeptide PF1022, useful as parasiticides, especially anthelmintics |
| DE19828047A1 (en) | 1998-06-24 | 1999-12-30 | Bayer Ag | New sulfonyl-substituted cyclooctadepsipeptide derivatives useful for prevention and treatment of helminth infection |
| DE19840320A1 (en) | 1998-09-04 | 2000-03-09 | Bayer Ag | Aza cyclodepsipeptides |
| DE102007061262A1 (en) | 2007-12-19 | 2009-06-25 | Bayer Animal Health Gmbh | New use of tribendimidine |
-
2008
- 2008-06-28 DE DE102008030764A patent/DE102008030764A1/en not_active Withdrawn
-
2009
- 2009-06-16 CA CA2729420A patent/CA2729420A1/en not_active Abandoned
- 2009-06-16 US US13/000,510 patent/US20110201550A1/en not_active Abandoned
- 2009-06-16 EP EP09768920A patent/EP2299995A1/en not_active Withdrawn
- 2009-06-16 BR BRPI0913996A patent/BRPI0913996A2/en not_active IP Right Cessation
- 2009-06-16 AU AU2009262581A patent/AU2009262581A1/en not_active Abandoned
- 2009-06-16 JP JP2011515161A patent/JP2011526262A/en active Pending
- 2009-06-16 WO PCT/EP2009/004304 patent/WO2009156071A1/en not_active Ceased
- 2009-06-16 MX MX2010014442A patent/MX2010014442A/en not_active Application Discontinuation
- 2009-06-18 UY UY0001031921A patent/UY31921A/en not_active Application Discontinuation
- 2009-06-24 AR ARP090102325A patent/AR073180A1/en unknown
- 2009-06-26 TW TW098121497A patent/TW201012471A/en unknown
-
2010
- 2010-12-17 ZA ZA2010/09064A patent/ZA201009064B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2009156071A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009156071A8 (en) | 2010-12-29 |
| TW201012471A (en) | 2010-04-01 |
| AR073180A1 (en) | 2010-10-20 |
| BRPI0913996A2 (en) | 2015-10-20 |
| JP2011526262A (en) | 2011-10-06 |
| WO2009156071A1 (en) | 2009-12-30 |
| CA2729420A1 (en) | 2009-12-30 |
| ZA201009064B (en) | 2012-02-29 |
| US20110201550A1 (en) | 2011-08-18 |
| MX2010014442A (en) | 2011-01-21 |
| AU2009262581A1 (en) | 2009-12-30 |
| UY31921A (en) | 2010-01-29 |
| DE102008030764A1 (en) | 2009-12-31 |
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