CA2016355A1 - Cyclopeptides - Google Patents
CyclopeptidesInfo
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- CA2016355A1 CA2016355A1 CA002016355A CA2016355A CA2016355A1 CA 2016355 A1 CA2016355 A1 CA 2016355A1 CA 002016355 A CA002016355 A CA 002016355A CA 2016355 A CA2016355 A CA 2016355A CA 2016355 A1 CA2016355 A1 CA 2016355A1
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- alkyl
- phe
- gly
- leu
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/22—Tachykinins, e.g. Eledoisins, Substance P; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Proteomics, Peptides & Aminoacids (AREA)
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- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Cyclopeptides A B S T R A C T
The invention relates to novel cyclopeptides of the formula I
I
in which R1 to R9 and n have the meanings indicated in Claim 1. These substances have, inter alia, vasodilatory and/or analgesic activity.
The invention relates to novel cyclopeptides of the formula I
I
in which R1 to R9 and n have the meanings indicated in Claim 1. These substances have, inter alia, vasodilatory and/or analgesic activity.
Description
MercX Patent Gesellschaft mit beschr~nkter Haftung 6100 D a r m ~ t a d t Cyclopeptides S The invention relates to no~l cyclopeptides of the formula I
. .
~(NR -CHRl-co-NR8-cHR2-co-NN-cxR3-co-NH-cHR4-co-NH-cHRS-co-NR9-CHR6-C0)~ I
__ in whi~h n is 1 or 2, Rl And R7 in o~ch c~-e ~re H, A, ~lk nyl or alkynyl in each c~se h~ving up to 4 C atoms, Ar-~lkyl, Het-~lkyl, cyclo~lkyl h~ving 3-7 C atom~, or cyclo~lkyl~lkyl having 4-11 C ato~, Rl and R7 together ~re ~180 alkylQne or alkenylQne in each c~se h~ving 2-6 C ~tom~, which ~re unsub-stituted or ~ubstltuted by A, Ar, Ar-~lkyl, OH, OA or Het-~lkyl, ;~ R2 is A, :~ R~ i- A, A-8(0).-alkyl, A-O-~lkyl, Ar-alkyl or carb~oyl-~lkyl, R~ l- H, A,~4N-alkyl, HAN-alkyl, A~N-al~yl or, lf ir dlff r-nt fro H ~nd~or ~t lea~t on of th radlcal- FP, R~, R~ aDd~or R~ h~s the R-conflgur~lon, 1~ al~o carba~oyl-aikyl, R l- ar-a~kyl or H t-alkyl, R~ 1~ A or Ar-alkyI, R' and R~ ar~ in each ca~e H or A, A is al~yl havlng 1-8 C ato~, Ar i- phenyl whlch lc unJub-tltuted, monosub~tl-tuted or poly~ub-tltut~d by A, aA, ~al, CF~, OH
and~or NH2, or un~ubstltuted naphthyl, Het i- a saturated or unsaturated 5- or 6-mffmbered heterocycllc radlcal havlng 1-4 N, O and/or S
Atoes, which can be fused to a benzene ring or 20~3~
. .
~(NR -CHRl-co-NR8-cHR2-co-NN-cxR3-co-NH-cHR4-co-NH-cHRS-co-NR9-CHR6-C0)~ I
__ in whi~h n is 1 or 2, Rl And R7 in o~ch c~-e ~re H, A, ~lk nyl or alkynyl in each c~se h~ving up to 4 C atoms, Ar-~lkyl, Het-~lkyl, cyclo~lkyl h~ving 3-7 C atom~, or cyclo~lkyl~lkyl having 4-11 C ato~, Rl and R7 together ~re ~180 alkylQne or alkenylQne in each c~se h~ving 2-6 C ~tom~, which ~re unsub-stituted or ~ubstltuted by A, Ar, Ar-~lkyl, OH, OA or Het-~lkyl, ;~ R2 is A, :~ R~ i- A, A-8(0).-alkyl, A-O-~lkyl, Ar-alkyl or carb~oyl-~lkyl, R~ l- H, A,~4N-alkyl, HAN-alkyl, A~N-al~yl or, lf ir dlff r-nt fro H ~nd~or ~t lea~t on of th radlcal- FP, R~, R~ aDd~or R~ h~s the R-conflgur~lon, 1~ al~o carba~oyl-aikyl, R l- ar-a~kyl or H t-alkyl, R~ 1~ A or Ar-alkyI, R' and R~ ar~ in each ca~e H or A, A is al~yl havlng 1-8 C ato~, Ar i- phenyl whlch lc unJub-tltuted, monosub~tl-tuted or poly~ub-tltut~d by A, aA, ~al, CF~, OH
and~or NH2, or un~ubstltuted naphthyl, Het i- a saturated or unsaturated 5- or 6-mffmbered heterocycllc radlcal havlng 1-4 N, O and/or S
Atoes, which can be fused to a benzene ring or 20~3~
~ pyridine ring and/or mono~ub~tituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, COOA, CN, CONH2, CONHA, CONA2, CONHAr, CONH-alkyl-Ar, SO2NHl, NHSO~A, Ar, As-al~yl, Ar-alkenyl, hydroxy-alkyl snd/or amino-alkyl in aach case having 1-8 C atoms ~nd/or whose N
and/or S heteroatom~ can al80 be ox~dized, -alkyl- 18 an alkyl~ne chnin having 1-4 C atoms, -alkenyl- is an alkenylene chain having 2-4 C atoms, Hal is F, Cl, Br or I, m 18 0, 1 or 2 and Ac iJ H-CO-, A-CO-, Ar-CO-, A-NH-CO- or Ar-NH-CO-, and their salts.
Sim$1ar compounds ~re known fro~ Phar~azie 40 (8), 532-5~ (1985).
The ob~ct of the lnventlon was t.o find novel compound~ h~ving usoful properties, ~n partlcul~r those wh~ch can be used for the preparntion of m~dica~ents.
It ha~ b~en found th~t th~ compounds of the formul~ I ~nd the$r s~lt~ have very u~eful properties. In p~r*$cular, they h~ve A tachykln$n ~gonist (e.g. va~o-dll~t$ng) and/or t~chykinin ant~gonist (e.g. an~lge~$c) effect. The~e eff-¢t~ c~n be detected, Q.g. ~y the m-thod~ ~hlch ~r- gi~en ln U8-A~ 72,305, the ~odll~t-lng -ffect .g. al~o ~y the ~ethod of F. L~r~ec~ et al., 81Oche~. R~. Co~e. ~Q~, 1318-1321 (1981), and the analgeJ$c ffe¢t e.g. in the wr~thing te-t on r~tJ or iq--~for ~ethod ¢onpare C. Vander Nende and S. Hargolin, Fed. Pro¢. ~ 9~ ff. (1956)t ~. Sieg und et al., Proc.
Soc. e~p. 8iol. (NY) ~, 729-731 (1957)s L.L. Hendqr~hot and J. Fors~lth, J. Phar a¢ol, e~p. Ther. 125, 237-240 (1959)). In the ca~e of the agoni8t~, ~xclt~tlon~ of the motor sy~tQ~ and blood pre-~ure redu¢tion~ further~ore o¢cur, and in the ca~e of th~ antagoni-t~, ~ntl-infla~matory and/or spasmolytic effectJ. Furthermore, stimulating effects on l~crimal secretlon, in particular on local ~ministr~tion, are shown in the c~se of the compounds of the formul~ I. The compounds of the ~1';.'; ~ ~
IA~` `
20~.!33~3 formula I are additionally dist~nguished by high selec-tivity and a good stability to proteases.
The compounds can be employed as pharmaceutical active compounds in human and veterinary med~cine, in particular for the prophylaxis and the treatment of cardiovascular disorders, spastic disorders, states of pain, inflammations, di~orders of the central nervous system and/or the circulation, and/or for ~timulating lacrimal secretion.
The abbreviations of amino acid radicals shown above and below ~tand for the radicals -NR-CR'R''-C0- (in which R, R~ and R'' have the specific meaning~ known for each amino acid) of the following amino acidss Ala alanine Gln glutamine Gly glycine His histidine Leu leucine Net methionin~
~et(0) methionine-S-oxide Net(02) methionine-S,S-dioxide N-Me-Phe N-methyl-phenyl~lanine Phe phenyl~l~nine Pro proline Trp tryptoph~n V~l v~lln~.
In ~ddit~on~ the following h~ve the ~e~nings belOWt BOC tert.-buto yc~rbony Ba~ b n~yloxy~ethyl 30 i~i-Bo~ bensyloxy~ethyl ln the- 1-po~ltlon of the imid~zole ring C~8. benzyloxyc~rbonyl DCCI dicyclohexylc~rbodlim$de D~F dimethylfor 4 ide DNP 2,4-dlnltrophenyl i~i-DNP 2,4-dinltrophenyl ln the l-positlon of the imid~zole ring EDCI N-ethyl-N'-(}-di~ethyl~minopropyl)-carbodi-imidehydrochloride : .
: ~.:, .:, i: '' ! ' . . ' . ~ : ' ' ~ "
FMOC 9-fluorenylmethoxycarbonyl HOBt l-hydroxybenzotriazole Me methyl OMe methyl ester S OEt ethyl e~ter POA phenoxyacetyl TFA . trifluoroAcetic acid If the amino acids mentioned above can occur in 3everal enantiomeric ~orms, then all these form~ and also their mixtures (e.g. the DL-forms) are included above and below, e.g. a~ constituents of the compounds of the formula I. The L-forms are preferred. If individual compounds are mentioned below, then the abbreviations of these amino acid~ in each ca-e rel~te to the L-form, if not expressly stated otherwise.
The invention further relates to ~ process for the preparation of ~ cyclopeptide of the formula I, char~cterized in th~t it i~ liberAted from one of its function~l deriv~tives by tre~ting ~lth ~ solvolyzing or hydrogenolyzing agent, or in th~t a peptide of the formula II
( )n ~ . II
in which n i- 1 or 2 ~nd 25~ NR7-C~YI-cC-NR3-C~-Co-NH-CHR3-Co-NH-cHR~-Co-NH
,~ CHR~-Co-NR9-CHR~-Co-, . . . -N~3-C}F~-Co-iC-C8R3 ~ NH-CER~-oo-NH-CHR~Co-NR~-CHR3-CO-NR7~1Rl-CO-, ; ~ -NII~IR3~_~NR~3~NR~IRl Co-NR3-cHR2-co-~
-N}l-CIIR~-CO-NII-C~R~-CO-NR~-CHR~-CO-NR7-CHRl-CO-NR3-CHR~-Co-NH-CHR3-Co-, -Nll-C~lR~-CO-NR~-CHR3-CO-NR7-CHRl-CO-NR3-CHR~-CO-NH-CHR3-CO-NH-CHR~-CO-or -NR~-CHR3-Co-NR7-CHRl-Co-NR3-CHR2-Co-NH-CHR3-Co-NH
CHR~-CO-NH-CHR~-CO-, ,~; ~ .
i . . .
; ' ~ . . .
s or a reactive derivative of such a peptide i~ treated with a cycliz~ng agent, and in that, if appropriate in a compound of the formula I, a thioether group i~ oxidized to a sulfoxide group or to a sulfone group and/or a 8ul-foxide group i8 reduced to a thioether group and/or a compound of the formula I i8 converted into one of it3 8alt8 by tr~ating with an acid The radicals and parameter~ n, Rl to R~, A, Ar, Het, Hal, m, Ac and Z above and below have the meanings 10 given in the formulae I or II, if not expressly stated otherwise In the above formulae, A has 1 - 8, preferably 1, 2, 3 or 4 C atoms A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl or 15 tert -butyl, and in ~ddition also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethyl-propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethyl-butyl, l-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 20 1,1,2- or 1,2,2-trimethylpropyl, heptyl or octyl Cyclo~lkyl i8 preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but al80 e g 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclo-he y l Corre-pon~gly, cycloalkyl-~l~yl i~ prefer~bly cyclopropylmothyl, 2-cyclopropyl thyl, cyclobutyl ethyl, 2-cyclobutyl-thyl,cyclop~ntyl~e~hrl,2-cyclopentyl-thyl, cyclohexyloethyl, 2-cyclohe yl'ethyl, but al~o e g 1-,'2-' or 3-methylcycIopentyl~ethyl, or 1-, 2-, 3- or ''4-30 '~ethylcyclohe y l~ethyl H~ preferably F, Cl or Br, but ~180 I
AC i8 preferably ~-C0- or A-C0- such ~8 acetyl, propionyl or butyryl, Ar-COL ~uch ~8 benroyl, o-, m- or p-methoxybenroyl or 3,4-d~etho~yben~oyl, A-NH-C0- such 35 a~ N-methyl- or N-ethylc~rb~moyl or Ar-NH-C0- such as N-phenylcar~amoyl ' Ar i8 preferably phenyl, ~nd ~n ~ddition prefer~
ably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or . . .
;;a~
p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- sr 3,5-dLmethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m- or p-S aminophenyl, or 1- or 2-naphthyl Correspondingly, Ar-alkyl i8 preferably benzyl, 1- or 2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, -m- or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1-or 2-o-, -m- or -p-et~ylphenyl~thyl, o-, m- or p-m~thoxy-benzyl, 1- or 2-o-, -m- or -p-methoxyphenylethyl, o-, m-or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenyl-ethyl, o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chlorophenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, o-, m- or p-iodobenzyl, 1- or lS 2-o-, -m- or -p-iodophenylethyl, o-, m- or p-trifluoro-methylbenzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trime-thoxybenzyl, o-, m- or p_a~- nobenzyl, or 1- or 2-naphthylmethyl Het i8 preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imid~zolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-i~othi~zo-lyl, 2-, 3- or ~-pyridyl, 2-, ~-, 5- or 6-pyrimidyl, and further or pr ferably 1,2,3-tria-ol-1-, -4- or -5-yl, 1,2,~-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-ox~diazol-3- or -S-yl, 1,3,~-thiadiazol-2- or -5-yl, 1,2,~-thiadiazol-3- or -5-yl, 2,1,5-thi~dlazol-3- or -4-yl, 2-, 3-, 4-, 5- ~r 6-2~-thiopyranylj, ?-, 3- or 4-~H-thiopyr~nyl, 3- or 4-pyrida-~inyl, pyr~zinyl, 2-, 3-, 4-, S-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-lndolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-i~oindolyl, 1-, 2-, 4- or 5-bens~-~dazolyl, 1-, 3-, 4-, 5-, 6- or 7-b nzopyr~zolyl, 2-, 4-, 5-, 6- or 7-benzo~azolyl, 3-, 4-, 5-, 6- or 7-benzi~oxazolyl, 2-, 4-, 5-, 6- or 7-benso-thlazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadi~zolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-i~oquinolyl, 1-, .~
201~rj 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, ~-, 4-, 5-, 6-, 7- or 8-cinnolyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolyl The heterocyclic radicals can also be partially S or completely hydrogenated Het can thus also be e g 2,3-dihydro-2-, -3-, -4- or -5-fury~, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, tetra-hydro-2- or -3-thienyl, 2,3-dihydro~ 2-, -3-, -4- or -5-pyrryl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrryl, 1-, 2- or ~-pyrrolidinyl, tetrahydro-l-, -2- or -4-imida-zolyl, 2,3-dihydro-1-, -2-, -3-, -4- or 5-pyrazolyl, 2,5-dihydro-l-, -2-, -3-, -4 or 5-pyrazolyl, tetrahydro-l-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetr~hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetr~hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpho-linyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -S-yl, hexahydro-l-, -3- or -4-pyrid~zinyl, hex~hydro-l-, -2-, -4- or -5-pyrimidyl, 1-, 2- or 3-piper~inyl, 1,2,3,4-tetr~hydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or 8-i~oquinolyl ~~he heterocyclic r~dical~ c~n ~l~o be substitut~d ~ -~ st~ted Het c~n thuz ~l~o prefer~bly be~ 2-~ ino-4-thiarolyl, 4-~arbo y-2-thi~zol~ -c~rb~oyl-2~ o-lyl, ~-(2-a-~nethyl)-2-thi~zolyl, 2-~ ino-5,6-di~ethyl-3-pyr~zinyl, 4-carb~ooylplperidino, ~nd in ~dd1t~on e g 3~ or 5-m~thyl-2-furyl, 2-j ~- or 5-methyl-3-furyl, 2,4-d~ethyl-3-furyl! 5-nitro-2-furyl, 5-~tyryl-2-furyl, 3-, 4- or 5- -thyl-2-thlenyl, 2-, ~- or 5-~ethyl-3-thienyl, 3-~ethyl-5-tort -butyl-2-thlenyl, 5-chloro-2-thienyl, 5-phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-~ethyl-2-pyrrolyl, 1-~ethyl-4- or -5-nltro-2-pyrrolyl, 3,5-dimethyi-4-ethyl-2-pyrrolyl,4-methyl-5-pyr~zolyl,4-or 5-methyl-2-thi~zolyl, 2- or 5-methyl-4-thi~zolyl, 2-or 4-methyl-5-thi~zolyl, 2,4-dimethyl-5-thi~zolyl, 3-, 4-, 5- or 6-methyl-2-pyrldyl, 2-, 4-, 5- or 6-methyl-3- ~`~
pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-,~ 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or :~:
3-chloro-4-pyridyl, 2,6-d~chloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (~ lH-2-pyridon-3-, -4-, -5- or -6-yl),5-phenyl-lH-2-pyridon-3-yl,5-p-mathoxyph~nyl-1~-2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N~-methylureido-lH-4-pyridon-5-yl, 5- or 6-methyl-4-pyr~mid-yl, ?,6-dihydroxy-4-pyrimidyl, 5-chloro-2-methyl-4-pyrimidyl, 2-methyl-4-amino-5-pyrimidyl, 3-methyl-2-benzofuryl, 2-ethyl 3-benzofuryl, 7-methyl-2-benzothi-enyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, l-methyl-5- or -6-benzimldazo}yl, 1-ethyl-5- or -6-benzimid~Azolyl or 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl.
Rl and R7 are preferably in each case H or A or, together, an alkylene chain having 2-6, in particular 3 C atoms.
Ra is preferably propyl, isobutyl or sec.-butyl.
R3 is preferably A-S(0),-alkyl, in part~cular CH3-S(0),-CH2CH2-, where m is preferably 0.
R ~ is preferably H or ~if Rl ia different from H
and/or at least one of the radicals R2 to R~ has the R-configur~Ation) H2N-C0-CH2CH2-.
R~ is preferably Ar-alkyl or Het-alkyl, in par-ticul~r b~n~yl or 3-indolyl- ethyl, and in addition p-hydroxyben7yl or p- ethoxyben~yl.
R~ 1~ prefer~bly Ar-~lkyl, in particular ben~yl, and in ~dditlon p-hydroxyben~yl or p-xethoxyben~yl.
-NR7-CHRl-co- i- preferablys Gly, Pro or D-Pro~
-NR~-CHR~-C0- i~ pr f-r~blys I~u, ~nd ~n addltion D-Leu, , Ile or D-Ile;
: . . .
30 -NH-CHR~-C0- i~ preferablys Net, D-Het, Met~0), D-Met(0), ~et~02) or D-Met(02), and in addition Leu or D-~eus -NH-CHR~-C0-- i~ preferablys Gly or Gln, and in addition 3S Ala or D-Ala;
-NH-CHR5-Co-s 1~ preferablys Phe or Trp;
-NR~-CHR~-C0-s i~ preferablys Phe, D-Phe, N-Ne-Phe or D-N-Ne-Phe, and in addition Val or D-Val.
. ' ~ ~ .
:, The parameter n is preferably 1 Accordingly, the invention in particular relates to those compound~ of the formula I in which at least one of the said radicals and/or parameters has one of the S preferred meanings given above Some preferred groups of compounds can be expressed by the part formula Ia, which otherwise corresponds to the formula I, but in which R1 is H, or, together with R7, -(CH2)3-, RZ i8 isobutyl, R3 i8 CH3-S(O)~-CR2CH2-~
R~ is H or, if Rl i8 different from H and/or at least one of the radicals R2, R3, R', ~5 and/or R6 have the R-configuration, is also H2N-CO-CR2CH2-, R5 i8 benzyl or 3-indolyl-methyl, RB i8 benzyl, R7 i8 H or, together with R1, -(CH2) 3-, Ra i8 H and R is H or Me Particul~rly preferred compounds of the formulae I and Ia are those in wh$ch n i8 additionally 1 The compounds of the formula I and also the starting material~ for the$r preparation ~re oth~rwise prepared by thod- which are known per ~e, a8 are - de-cribed $n the liter~ture (e g in the standard works such ~- Hbub n-Weyl, ~ethoden der org~ni-chen Che~$e, (~ethod~ o~ Orga~ic Che~i~try) Gsorg-Th$ _ -Verlag, Stuttg~rt), $n particular under reaction cond~tions which ~ i ar known and ~uitable for the sa$d reaction~ In this cont xt, uJ- can al-o be ~ade of variant~ which are known per ~e and ~re not entloned in ~ore detall here The ~tart~ng sub-tancs- can al~o be formed in -~
situ, if de~ired, uch that they ~r~ not i~olated from th reaction lxture, but i~ edi~tely reacted further to give the co~pound- of the ormula I
The co~pounds of the for~ula I can be obtained by liberatlng thQm from thelr functlonal derlvatives by solvolysi~, in particular hydrolysis, or by hydrogenolysis Preferred starting materials for the solvolysis : ., ' : '- .. i ... . '. . .
or hydrogenoly~is are those which contain appropriate protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl group~, preferably those which carry an amino protecting group instead of an H
S atom which i9 bonded to an N atom, e g those which correspond to the formula I, but contain an N(im)-R~-His group (in which R~ i8 an amino protecting group, e g BOM
or DNP) instead of an His group In addition, starting materials are preferred which carry a hydroxyl protecting group instead of the H
atom of a hydroxyl group, e g those which correspond to the formula I, but contain an R''O-phenyl group (in which R~ is a hydroxyl protecting group) instead-of a hydroxy-phenyl group Several - identical or different - protected amino and/or hydroxyl groups can be pre~ent in the molecule of the starting material If the protective groups present are different from one another, in many cases they can be removed selectively The expression ~amino protecting group~ i8 generally known and relates to groups which are suitable for protecting (or blocking) an am$no group from ch d -cal reactlon , but which are eas~ly removab~e, after the de-ired ch d cal reaction ha- b~en carrled out on other po-ltion~ of the ~ol-cule Typical group~ of this typo are, in particular, w ub tituted or sub~tltuted acyl, ~ryl (- g DNP), ar~lkoxy ethyl (e g BQ~) or aralkyl group- (e g b n~yl, ~-nitroben~yl or triphenylmethyl) A~ the a ino protecting group are re~oved a~ter the de-ired reaction (or react$on -equence), their n~ture and si~e is otherwi-e not critical~ but those having 1-20, in partlcular 1-8, C ato~ are preferr~d~ The expre~-lon ~cyl group~ $- to be taken in its w$de-t sen~e $n connection with the pre-ent process It include~ acyl groups derived fro~ al$phat$c, araliphat$c, ~romat$c or heterocyclic carboxylic acids or sulfonic ac$ds ~nd in part$cul~r alkoxycarbonyl, ~ryloxycarbonyl and, above all, aralkoxycarbonyl groups 2x~mples of acyl groups of th$s type are alkanoyl such as acetyl, propionyl or .
.' . ~
. . . :
.... . .
,. ,-: , .. . .. ..
3 ~ ~
butyryl; aralkanoyl such a3 phenylacetyl; aroyl ~uch a~
benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxy-carbonyl ~uch as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl;
S aralkylo~ycarbonyl sueh as CBZ ("carbobenzoxy~), 4-methoxybenzyloxycarbonyl and FMOC. Preferred amino protecting groups are DNP and BOM, and in addition CBZ, FMOC, benzyl and aeetyl.
The expression "hydroxy protecting qroup~ i~ also generally known and relates to groups whieh are suitable for proteeting a hydroxyl group from ehemieal reaetions, but whieh are easily removable, after the desired ehemi-eal reaetion has been earried out on other positions of the moleeule. Typie~l groups of this type are the ~bove-mentioned unsubstituted or substituted aryl, aralkyl or aeyl groups, and in ~ddition also alkyl groups. The nature and size of the hydroxy proteeting groups is not eritieal, as they are removed ag~in after the desired ehemie~l re~etion or re~etion sequeneQ; preferred groups are those h~Ying 1-20, in p~rtieular 1-10 C ato~s.
~x~mples of hydroxyl proteeting groups are, inter ali~
benzyl, p-nitroben~oyl, p-toluenesulfonyl and ~cetyl, benzyl ~nd ~cetyl being p~rticul~rly preferred.
The functional deriv~t$ves of the compounds of the for ul~ I to b u-ed ~ tartlng w~t~ri~l~ c~n be prep~red by cu~to~ry ~ethod~ of a~lno ~c$d and peptide ynthe~$~, uch ~- ~re de~cribe~ e.g. in the st~nd~rd wor~ ~nd p~t nt ~pplic~t$on- mentioned, ~nd e.g. ~l~o by the ~errifield ol~d ph~e ~ethod. , The liber~tion of the co~pounds of the ~oruul~
fro~ their function~l deriv~tlve~ $8 c~rried out -depending on the protecting group u~ed - e.g. with strong ~cids, prefer~bly with TFA or perchloric ~cid, but ~l~o with other ~trong inorg~nic ~clds such ~8 hydrochloria ~cid or sulfuric ~cid, or ~trong org~nic c~rboxylic ~c$ds such ~8 trichloro~cetic ~cid or sulfon~c ~cids ~uch ~8 ben~ene- or p-toluenesulfonic ~cid. The presence of ~n addition~l inert solvent is pos~ible, but not ~lw~ys necess~ry. Suit~ble inert solvents are prefer~bly 2 ~
organic, for example carboxylic acids such as acetic acid, ether~ such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbon~ such as dichloro-methane, and in addition also alcohols such as methanol, ethanol or isopropanol and also water.
In addition, mixtures of the abovementioned solvents are suitable. TFA is preferably used in an excess without addition of a further solvent, perchloric acid in the form of~a mixture of acetic acid and 70 %
perchloric acid in the ratio 9:1. The reaction temper-atures for the cleavage are preferably betwe~n about 0 and about 50, preferably between 15 and 30- (room temperature).
The BOC group c~n be removed e.g. preferably using 40 % TFA ~n dichloromethane or with about 3 to 5 N
HCl in dioxane at 15-30-,-the F W group using an about 5- to 20 % solution of dimethylamine, diethylamine or piperidine in DMF at 15-30-. ~emoval of the DNP group is carried out e.g. al80 using an about 3 to 10 % ~olution 1 20 of 2-mercaptoethanol in DNF/w~ter st 15-30-.
Protecting groups which can ba removed by hydro-genolys~s (e.g. B0~, CB~ or ben~yl) can be removed, e.g.
by treating with hydrogon in the presence of ~ catalyst (e.g. a noble ~etal catalyst ~uch as palladium, proferab-ly on ~ c~rri r uch a- carbon). Suit~ble ~olventJ in thi~ ca~e ar tho~e entioned abov-, in p~rticular e.g.
alcohol~ uch a- oth~nol or ethanol or amide~ ~uch as D~F. Tho hydrogenoly~ carried ~ut, as a rule, at t~perature~ botw~en about 0 and 100- ~nd pre~ures botwe~n about 1 and 200 b~r, preferably at 20-30- ~nd 1-10 bar. Hydrogenoly~l- of the CBS group i~ ea~ily carrled out e.g. on 5 to 10 ~ Pd-C in meth~nol or uslng a~onlum form~te (iN te~d of H~) on Pd-C in methanol/DN~ ~t 20-30-.
Co~pounds of the formul~ I ean ~180 be obtalned by eyeli~atlon of eo~pounds of the for ula II under the eondition~ of a p~ptide synthesi~. In this e~se, the re w tion $J preferably earried out by custom~ry methods of peptide synthesls, ~8 are deserlb~d e.g. ln Houben-Weyl, loe cit. volume 15/II, p~ges 1 to 806 (1974).
2`'i . ~ ~
.'` ~' "' :
'`.: :.. ., :~
2~ 3~
The reaction i8 preferably carried out in the presence of ~ dehydrating agent, e.g. a carbodiimide such as DCCI or EDCI, and in addition propanepho~phonic anhydride (compare Angew. Chem. 92, 129 (1980)), diphen-s ylpho~phoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-di-hydroquinoline, in an inert solvent, e.g. ~ halogen~ted hydrocarbon such as dichloromethane, an ether such as tetr~hydrofuran or dioxane, an ~mide such as DMF or dimethyl~cet~ide, a nitrile such ~8 acetonitrile, or in mixtures of these solvent~, at temperatures between about -10 and 40, prefer&bly between O and 30-. In order to promote intramolecular cycliz~tion before intermolecul~r peptide bonding, it is preferable to woxk in dilute solut~ons (dilution prlnciple).
Inste~d of II, suit~ble react~ve deriv~tives of these substances can also be employed in the reactlon, e.g. those in which re~ctive groups ~re ~ntermedl~tely blocked by protect$ng groups. The ~mlno ~cid deriv-atives II c~n be used e.g. ln the form of their ~ctiv~ted 1 20 esters which ~re prefer~bly formed in situ, e.g. by ~ddition of HOBt or N-hydroxysuccinimide.
Tha at~rting m~teri~lo of the for~ul~ II are, ~
~ rule, novel. They c~n be prep~red by ~nown ~ethods, e.g. the ~bove~entioned ~ethoda of peptide ynthesis ~nd of remov~l of`prot ctive group~
A~ ~ rul-, prot~¢ted hex~peptid 0-t ra of the for~ul~ R'-Z-OR'', e.g. BOC-~-ONe or BOC-g-OBt ~re ini-ti~lly oynthe-i~ed, which ~re firat hydroly~ed to gl~e ~¢idJ of th formul~ R'-S-OH, -.g. BOC-Z-OH~ the protec-ti~o group R' ia remo~ed fro these, by ~e~n~ of which the free peptidea of the formula H-Z-OR (II; n ~ re obt~ined. The dodecapeptide~ of the for ula H-(Z)~-OH are prof-rably pr p~red by re~ction of acida of the formula R'-Z-OH with a~ino e~ter~ of the for~ula H-~-OR'' to give protected dodecapeptidea of the formula R'(Z)~-O-R'' and subsequent re~oval of the protecting group~ R' and R''.
It is al80 possible to oxidize a thioether group to a sulfoxide group or sulfone group, ~n particular a group -NH-CHR3-Co- - ~et to a group -NH-CHR3-Co-~.~ . . . . .
~ J~
, = Met(0) or ~et(oz)~ e.g. by passing air into a solution of the compound of the formula I (-NH-CHR3-Co- = Met) in acetonitxile/water at temperatures between 0 and 30-. The thioether can also be oxidized with H202. The sulfoxide is thus predominantly obtained at 20~ in methanol using the calculated amount of oxidizing agent, and the sulfone is predominantly obtained at 50-, on the other hand, using an excess of the oxidizing agent.
Conversely, a sulfoxide group (e.g. in I, -NH-CHR3-Co- = Met(0)) can be reduced to give a thioether group (e.g. in I, -NH-CHR3-Co- = Met), e.g. usin~ NH,I in aqueous ~A at temperatures between -10 and 25-.
A base of the formula I can be converted into the appropriate acid addition salt using an acid. Suitable acids for this reaction are in particul~r those which yield physiologically accep Wble salts. Inorganic acids can thus be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such a8 orthophosphoric acid and sulfamic acid, and in addition organic acids, in par-ticular aliphatic, alicyelic, araliphstic, aro~tic or heterocycllc mono- or polybasie carbo ylie, sulfonie or sulfurie aeld~, e.g. for ie aeid, acetie aeld, propionle aeid, pivallc aoid, diethrlacetic acid, malonic acid, succinic ~cid, pin~lic acid, fum~ric ~cid, ~aleic acid, lactic-acid, t~rt~ric acid, ~alic acid, benzoic acid, salicylic ~cid, 2- or 3-phffnylpropionic acld, citr~c aeid, glueonie aeid, a~eorbie aeid, nieotinie ~eid, i~onieotinie aeid, methane- or eth~ne-ulfonic acid, eth~nedlsulfonic aeid, 2-hydroxyeth~nesulfonlc acid, benzenesulfonie aeid, p-toluene~ulfonie aeid, naphthal-ene-mono- and -di~ulfoni~ aeid~, and laurylsulfurie aeid.
Salt~ with phy~iologieally unaeceptable acid~, e.g.
picrates, can be u~ed for the i~olation and/or purifica-tion of the eompounds of the formul~ I.
The novel eompounds of the formula I and theirphysiologic~lly accept~ble salt~ can be used for the production of ph~roaceuticAl preparations by bringing them into a suitable dosage form together with at least ~ ~ ,~ ,... . .
... . . ~ .
. . . ... . .
2 ~
one excipient or auxiliary and, if de~ired, together w$th one or more other active compound(~). The preparations thus obtained can be employed as pharmaceuticals in human or veterinary medicine. Suitable excipient ~ubstance~ are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal), parenteral or local (e.g.
topicAl) adminiEtration or for administration in the form of an inhalant spray and which do not react with the novel compounds, foF example water, lower alcohols, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates ~uch as lactose or starch, magnesium stearate, talc, cellulose and vaseline.
Tablet~, coated tablets, capsules, syrups, liquids or drops, in particular, are used for oral ad~inistration;
film tablets and capsules having gastric ~uice-resistant coatings or capsule shells are especially of interest.
Suppositor$es are used for rectal ~dministration, and solutions, prefer~bly oily or agueous solutions, and in addition suspensions, emulsions or implants, are used for parenter~l admini~tration. Solutions, e.g., which can be used in the for~ of eye drop~, and in addltion, e.g.
suspension~, e~ul~ion~, creams, oint~ent~ or co~presses are ~uitabl- for topical appllcation. Sprays c~n be u~ed which cont in th~ activ co~pound e$ther dl~olved or su-pended in a propellant ga~ ~tUrQ (e.g. chlorofluoro-hydrocarbonJ~ for ad lni~trat$o~ a~ inhalant spr~ys. The activ- co pound here i~ prefer~bly usQd in micronized for~, ~t being po -ible for one or re ~dditlonal physlologically tolerable solvents to be present, e.g.
; ethanol. Inhalant ~olution~ can be adminl~ter~d with the aid of customary inh~ler~. The novel co pounds can also be lyophyli~ed and the lyophyli~ates obtained used e.g.
for the production of in~ection preparations. The prepar-ations indicated can be sterilized ~nd/or can contain au~iliarie~ such a8 preservati~e~, stabilizers and/or wetting agents, e~ulsifiers, salts for influencing osmotic pressure, buffer substances, colorants and/or fl~vourings. If desired, they can al80 cont~in one or .. ... . .. ~.. . .. "-.. ",.. ,~... .
.: - , .
2 ~
more other active compounds, e.g. one or more vitam$ns.
The substances according to the invention are as a rule administered in analogy to other known commercial-ly available peptides, but in particular in analogy to the compounds described in US-A-4,472,305, preferably in dosages between about 0.05 and 500, in particular between 0.5 a~d 100 mg per dosage unit. The daily dose i8 prefer-ably between about 0.01 and 2 mg~kg of body weight. ~he specific dose for each intended patient depends, however, on many different factors, for example the activity of the specific compound employed, the age, body weight, general state of health, sex, the cost, the time and route of administration, and the rate of excretion, pharmaceutical comb~nation and severity of the part$cular disorder to which the therapy applies. Parenteral admini-stration i8 preferred.
All te~per~tures above ~fid below are st~ted in C. In the following ex~mples, ~customary working up~
mean8 5 water i8 ~dded, if necessary, the mixture i8 neutralized and e~tr~ted with ether or dichlorometh~ne, the organic ph~se is separ~ted off, dr$ed over sodium sulf~te, filtered ~nd ev~por~ted ~d the re~idue is purified by chrom~togr~phy on ilic~ gel ~nd/or cryst~l-lir~tion. RT - ret ntion ti~e (~inute~) for ~PLC on ~n RP 18 250-~ colu-n, if not t~t d otherwi~e; eluent~
w~ter, b - 0.3 % TFA in water, c ~ ~cetonitrile.
Rf - Rf v~lue by thin-layer chro~togr~phy on ~ilic~ gel;
eluent~ chlorofor~eth~nol/~cetic ~cid 85-10-5. FAB-NS -- ~f~t ~to~ bo b-rdm-nt~ m~- spectrum.
Example 1 A ixture of 900 mg of cyclot-glycyl-L-phenyl-~l~nyl-L-phenyl~l~nyl-L-~N-imi-2,4-dinitrophenyl-his-tidyl)-L-leucyl-L- ethionine-l tcyclo(Gly-phe-phe-(~m~-DNP-Hi~)-Leu-Met-); obt~in~ble by cycli~tion of H-Gly-Phe-Phe-(imi-DNP-Hls)-Leu-Het-0~ ~n~logously to ~mple 3, see below], 2 g of 2-merc~ptoeth~nol, 20 ml of DMF ~nd 20 ml of w~ter is ~d~usted to pH 8 with ~queous N~2C03 ~olution while stirring ~t 20- and is stirred for :,','`: .' ' ' .. . . . .
, . . . . .
!. ~ . . ' 2 hour~ at 20 Cu~tomary working up give~ cyclo(-glycyl-L-phenylalanyl-L-phenylalanyl-L-histidyl-L-leucyl-L-methionine-)tcyclo(-Gly-Phe-Phe-Hi~-Leu-Met-)]
Example 2 1 g ofcyclo[-Gly-phe-phe-(imi-BoM-His)-Leu-Met-]
[obtainable from H-Gly-phe-phe-(imi-BoM-Hi8)-Leu-Met-oH
analogously to Example 3, see below] i8 dissolved in 25 ml of methanol, hy~rogenated for 3 hours on 0 5 % Pd-C
at 20 and 1 bar, and the mixture is filtered and evapor-ated and, after customary working up, gives cyclo(-Gly~
Phe-Phe-His-Leu-Met-) Example 3 1 8 g (2 mmol) of BOC-Leu-D-Met-Gln-Trp-Phe-Gly-OMe are dissolved in 50 ml of methanol, 1 5 ml of 2 N
aqueous sodium hydroxide solution are added and the mixture is ~tirred for 3 hours ~t 20 It i~ evaporated, ~nd the residue i~ taken up in water, acidified to pH 3 with HCl ~nd e~tr~cted with ethyl acetate The extr~ct is dried over N~SO~ ~nd ev~por~ted The BOC-Leu-D-Met-Gln-Trp-Phe-Gly-OH thu~ obt~ined i8 ~tirred ~t 20 for 2 hours with 20 ~1 of 2 N HCl in diox~ne The mlxture i~
ev~por~ted, the H-Leu-D-~et-Gln-Trp-Phe-Gly-OH obt~lned i- di--ol~ d in a ~xtur of 1800 ~1 of dichloro ethane ~nd 200 ~1 of Dh~ ~n~ ¢ool~d to 0-! Q 5 g of DCCI, 0 3 g of BOPt nd 0~23 d of N _ thyl~orphollne ~re ~dded ~ucc--~ively with ~tirring, and the mixture .i8 stirred for 2~ hour~ at 0 and 48 hour ~t 20 The olution i~
concentrated and ~tirred wlth a ~ixed bed lon e~ch~nger to re~o~e ~lt- ~hi~ filtered off, the -olution i~
ev~por~ted ~nd the re~idue i8 purified by chro ~togr~phy Cyclo(-Gln-Trp-Phe-Gly-Leu-D-~t-) i~ obt~inediS RT 11 37 (b/c 6s4) The following ~re obt~ined ~n~lo~ously from the corresponding linear hex~peptlde~
Cyclo(-Al~-Phe-Phe-Pro-Leu-Met-), m p 134 - 140 Cyclol-Ala-Phe-Phe-Pro-Leu-Met(O)-1 Cyclo~-Ala-Phe-Phe-Pro-Leu-Met( 2 ) - ]
- 18- 20~ pr,,~
Cyclo(-Ala-Phe-Phe-Pro-Leu-D-Met-), m.p. 133 - 138 Cyclo(-Gly-Phe-N-Me-Phe-Gly-Leu-Met-), RT 15 09 (a/c 6 4) Cyclo~-Gly-Phe-N-Me-Phe-Gly-Leu-Met(0)-), Cyclo(-Gly-Phe-N-Me-Phe-Gly-L~ -Net(02)-), Cyclo(-Gly-Phe-D-N-Me-Phe-Gly-Leu-Met-), RT 12 30 (a/c 6 4) Cyclot-Gly-Phe-D-N-Me-Phe-Gly-Leu-Met(0)-]
Cyclo[-Gly-Phe-~-N-Me-Ph~-Gly-LQu-Met( 2 ) - ]
I Cyclo(-Gly-Phe-Phe-Pro-Leu-Leu-) Cyclot-Gly-Phe-Phe-Pro-Leu-~et-), FAB-NSs (M+H)~ 694 Cyclo[-Gly-Phe-Phe-Pro-Leu-Met(0)-], FAB-MSs (M+H)' 710 Cyclot-Gly-Phe-Phe-Pro-Leu-Met( 2 ) - ], m p 157-162 Cyclo(-Gly-Phe-D-Phe-Pro-Leu-Met-) Cyclot-Gly-Phe-D-Phe-Pro-Leu-Met(0)-]
Cyclot-Gly-Phe-D-Phe-Pro-Leu-M~t(02)-], m.p. 128 - 135 Cyclol-Gly-Phe-Phe-D-Pro-Leu-Met-), RF O 63 Cyclot-Gly-Phe-Phe-D-Pro-Leu-Met(0)-~, RF ~ 42 Cyclot-Gly-Phe-Phe-D-Pro-Leu-Nbt( 2) - ]
cyclot-Gly-phe-ph~-pro-Leu-D-~et-)~ m p 13~ - 140 Cyclol-Gly-Phe-Phe-Pro-Leu-D-NQt(0)-]
Cyclo[-Gly-Phe-Phe-Pro-Leu-D-Met (2) - 1 Cyclo(-Gly-Phe-V~l-Gly-Leu-Net-), RF 051 Cyclol-6ly-Phe-V~l-Gly-Leu-~t(O)-]
Cyclot-Gly-Phe-V~l-Gly-~eu-~bt(0~)-]
Cy~lo(-Gly-Trp-Ph -Pro-L~u-~t-) Cyclol-Gly-Trp-Ph -Pro-Leu-~t(O)-]
CycloI-Gly- ~ Ph -Pro-Leu-15-t(0~)-]
Cyclol-GlyTrp-Ph -D-Pro-Leu-~et-) Cyciot-Gly- ~ -Phe-D-Pro-leu-~et(O)- I
Cyclol--Glr-Trp-Phe-D--P~o-Leu-Nbt(2 ) - ] .
Esample 4 Cycio(-Gly-Phe-Phe-Pro-Leu-Net-)2, m.p. 216-218-is obt~ined ~nalogou~ly to Es~mple 3 by cyclizatlon of H-(Gly-Phe-Phe-Pro-Leu-~et)2-OH tobtainable by reaction of BOC-Gly-Phe-Phe-Pro_Leu-Met_O~ w~th H-Gly-Phe-Phe-Pro-Leu-~et-OM~ to give BOC-~Gly-Phe-Phe-Pro-Leu-~et)2-O~e and subsequent remov~l of the protecting groupl.
The following are obtained ~nalogously from the ,, ~ . . .~
... . ~
corre~ponding linear dodecapeptides:
Cyclo-(Ala-Phe-Phe-Pro-Leu-Met-)2, m.p. 137 - 144 Cyclo-(Ala-Phe-Phe-Pro-Leu-D-Met)21 RF 0.74 Cyclo[-Gly-Phe-Phe-Pro-Leu-Met(O)-] 2 S Cyclo[-Gly-Phe-Phe-Pro-Leu-Met( 2 ) - ] 2 ~ :
Cyclo[-Gly-Trp-Phe-Pro-Leu-Met-) 2 Cyclo[-Gly-Trp-Phe-Pro-Leu-Met(0)-~2 Cyclo[-Gly-Trp-Phe-Pro-Leu-Met-( 2 ) - ] 2 Cyclo[-Gly-Trp-Phe-D-Pro-Leu-Met-) 2 Cyclo[-Gly-Trp-Phe-D-Pro-Leu-Met-(O)-] 2 Cyclo[-Gly-Trp-Phe-D-Pro-Leu-Met-( 2 ) - ] 2 .
Exampl~ 5 1.7 g (2 mmol) of BOC-Gly-Phe-Phe-Pro-Leu-Met-OMe (m.p. 92-99-) ~re dissolved in 50 ml of methanol, 2 ml of hydrazine hydrate are added, and the mixture i8 stirred for 16 hours and evaporated. The BOC-Gly-Phe-Phe-Pro-Leu-Met-NHNH2 thus obtained i~ stirred at 20- for 2 hours with 20 ml of 2 N RCl in dioxane. The mixture is evaporated, the H-Gly-Phe-Phe-Pro-Leu-Met-NHNH2 dihydrochloride obtained i8 dissolved in 50 ml of DHF and cooled to -lS-wlth ~tirring, and 0.83 ~1 of 35 % hydrochloric acld and 1.5 ml of ~ 1~ % aqueou~ NaNO2 solutlon are ~dded succes-slvoly. The ~l~ture 1- stirr~d ~t -15- for 1 hour and poured lnto 2 1 of cooled D~F. 1.1 ml of N- thylmor-phollne ~r~ add d, and th ~ixture 18 ~tirred for 24 hour at--lS- ~nd ~llo~sd to stand for 2 d~y~ at 20-. The : solution i- concentrated, a Jixed b~d ion exchAnger is ~dded to r~ ove ~alt~, the m~xture is filtered, the fiitrate 1~ vapor~ted, ~nd the re~ldue 18 purif~ed by chromatography to give cyclo(-Gly-Phe-Phe-Pro-Leu-~et-);
FAB-MS (M+H)~ 694.
Example 6 A ~olution of 100 mg of cyclo(-Gly-Phe-Phe-Pro-.Leu-Met-) and 1 equivalent of 30 % aqueous H2O2 in SO ml of meth~nol is stirred ~t 20- for 2 hours. ~vaporation and custom~ry worklng up gives cyclol-Gly-Phe-Phe-Pro-Leu-Met(O)-]; FAB-~Ss (~+H)~ 710.
Example 7 A solution of 100 mg of cyclo(-Gly-Phe-Phe-Pro-~ .. , ~ , :
.. . .
. .
~Q~ ~13~j -Leu-Met-) and 10 equiv~lents of 30 % aqueous Hz02 in 50 ml of methanol is warmed to 50 for 2 hours Evaporation and, cu~tomary working up gives cyclot-Gly-Phe-Phe-Pro-LQu-Met( 2)-]; m p 157-162 Example 8 ~ir i8 pa~sed through a solution of 1 g of cyclo[-Gly-Phe-Phe-Pro-Leu-Met-) in 50 ml of acetonitrile a~d 50 ml of w~ter until reaction is complete Customary working up gives the corresponding sulfoxide cyclot-Gly-Phe-Phe-Pro-Leu-Met(0)-]; FAB-MSs (M+H)~ 710 Example 9 20 ~1 of a 2 M NH~I solu~ion is added at 0 to a solution of 1 g of cyclot-Gly-Phe-Phe-Pro-Leu-Met(O)-I in 50 ml of TFA After stirring at 0 for 1 hour, the resulting iodine i8 reduced by adding thio~lycolic acid, and the mixture i8 worked up as is customary to give cyclot-Gly-Phe-Phe-Pro-Leu-Met-); FAB-MS~ (~+H)~ 694 The ex~ples below relate to pharmaceutical preparation-~x~ple At In~ectlon ~$al-A olutlon of 100 g of cyclot-Gly-Phe-Phe-Pro-Leu-~et-) ~nd 5 g of d$-od$um hydrogenpho~phate $n 31 of doubly d$-till d wat-r i- ad~u-ted to p~ 6 5 with 2 N
hydrochloric acid, terllo filtered, filled into in~ec-t~o~ vi~ nd lyophili~ed under terile con~ition~, and the vial~ ~re clos~sd in a terilo manner ~,ach in~ection '~ vlal contain- 5 mg of active compound E~4mple B~ Su,ppo~itorles A DiXture of 20 g of cyclot-Gln-~rp-Phe-Gly-Leu-D-Met-) i~ fuJed with 100 g of oya lecithin and 1400 g , of cocoa butter, and the mi~ture is poured into ~oulds and allowed to cool Each suppository contain~ 20 mg of active compound ~;, " ~
3 ~
-~ - 21 -Example C: Solution ~r- A solution of 1 g of cyclot-Gly-Phe-Phe-Pro-Leu-Met(O)-], 9.38 g of NaH2PO~.2H20, 28.48 g of Na2HPO~.12H20 and 0.1 g of benzalkonium chloride i8 prepared in 940 ml of doubly distilled water. The solution is ad~usted to pH 6.8, made up to 1 1 and sterilized by irradiation.
This solution can be used in the form of eye drops.
Example Ds Ointment 500 mg of cyclol-Gly-Phe-Phe-Pro-Leu-Met-)2 i8 mixed with 99.5 g of petroleum ~elly under asoptic conditions.
' ~
and/or S heteroatom~ can al80 be ox~dized, -alkyl- 18 an alkyl~ne chnin having 1-4 C atoms, -alkenyl- is an alkenylene chain having 2-4 C atoms, Hal is F, Cl, Br or I, m 18 0, 1 or 2 and Ac iJ H-CO-, A-CO-, Ar-CO-, A-NH-CO- or Ar-NH-CO-, and their salts.
Sim$1ar compounds ~re known fro~ Phar~azie 40 (8), 532-5~ (1985).
The ob~ct of the lnventlon was t.o find novel compound~ h~ving usoful properties, ~n partlcul~r those wh~ch can be used for the preparntion of m~dica~ents.
It ha~ b~en found th~t th~ compounds of the formul~ I ~nd the$r s~lt~ have very u~eful properties. In p~r*$cular, they h~ve A tachykln$n ~gonist (e.g. va~o-dll~t$ng) and/or t~chykinin ant~gonist (e.g. an~lge~$c) effect. The~e eff-¢t~ c~n be detected, Q.g. ~y the m-thod~ ~hlch ~r- gi~en ln U8-A~ 72,305, the ~odll~t-lng -ffect .g. al~o ~y the ~ethod of F. L~r~ec~ et al., 81Oche~. R~. Co~e. ~Q~, 1318-1321 (1981), and the analgeJ$c ffe¢t e.g. in the wr~thing te-t on r~tJ or iq--~for ~ethod ¢onpare C. Vander Nende and S. Hargolin, Fed. Pro¢. ~ 9~ ff. (1956)t ~. Sieg und et al., Proc.
Soc. e~p. 8iol. (NY) ~, 729-731 (1957)s L.L. Hendqr~hot and J. Fors~lth, J. Phar a¢ol, e~p. Ther. 125, 237-240 (1959)). In the ca~e of the agoni8t~, ~xclt~tlon~ of the motor sy~tQ~ and blood pre-~ure redu¢tion~ further~ore o¢cur, and in the ca~e of th~ antagoni-t~, ~ntl-infla~matory and/or spasmolytic effectJ. Furthermore, stimulating effects on l~crimal secretlon, in particular on local ~ministr~tion, are shown in the c~se of the compounds of the formul~ I. The compounds of the ~1';.'; ~ ~
IA~` `
20~.!33~3 formula I are additionally dist~nguished by high selec-tivity and a good stability to proteases.
The compounds can be employed as pharmaceutical active compounds in human and veterinary med~cine, in particular for the prophylaxis and the treatment of cardiovascular disorders, spastic disorders, states of pain, inflammations, di~orders of the central nervous system and/or the circulation, and/or for ~timulating lacrimal secretion.
The abbreviations of amino acid radicals shown above and below ~tand for the radicals -NR-CR'R''-C0- (in which R, R~ and R'' have the specific meaning~ known for each amino acid) of the following amino acidss Ala alanine Gln glutamine Gly glycine His histidine Leu leucine Net methionin~
~et(0) methionine-S-oxide Net(02) methionine-S,S-dioxide N-Me-Phe N-methyl-phenyl~lanine Phe phenyl~l~nine Pro proline Trp tryptoph~n V~l v~lln~.
In ~ddit~on~ the following h~ve the ~e~nings belOWt BOC tert.-buto yc~rbony Ba~ b n~yloxy~ethyl 30 i~i-Bo~ bensyloxy~ethyl ln the- 1-po~ltlon of the imid~zole ring C~8. benzyloxyc~rbonyl DCCI dicyclohexylc~rbodlim$de D~F dimethylfor 4 ide DNP 2,4-dlnltrophenyl i~i-DNP 2,4-dinltrophenyl ln the l-positlon of the imid~zole ring EDCI N-ethyl-N'-(}-di~ethyl~minopropyl)-carbodi-imidehydrochloride : .
: ~.:, .:, i: '' ! ' . . ' . ~ : ' ' ~ "
FMOC 9-fluorenylmethoxycarbonyl HOBt l-hydroxybenzotriazole Me methyl OMe methyl ester S OEt ethyl e~ter POA phenoxyacetyl TFA . trifluoroAcetic acid If the amino acids mentioned above can occur in 3everal enantiomeric ~orms, then all these form~ and also their mixtures (e.g. the DL-forms) are included above and below, e.g. a~ constituents of the compounds of the formula I. The L-forms are preferred. If individual compounds are mentioned below, then the abbreviations of these amino acid~ in each ca-e rel~te to the L-form, if not expressly stated otherwise.
The invention further relates to ~ process for the preparation of ~ cyclopeptide of the formula I, char~cterized in th~t it i~ liberAted from one of its function~l deriv~tives by tre~ting ~lth ~ solvolyzing or hydrogenolyzing agent, or in th~t a peptide of the formula II
( )n ~ . II
in which n i- 1 or 2 ~nd 25~ NR7-C~YI-cC-NR3-C~-Co-NH-CHR3-Co-NH-cHR~-Co-NH
,~ CHR~-Co-NR9-CHR~-Co-, . . . -N~3-C}F~-Co-iC-C8R3 ~ NH-CER~-oo-NH-CHR~Co-NR~-CHR3-CO-NR7~1Rl-CO-, ; ~ -NII~IR3~_~NR~3~NR~IRl Co-NR3-cHR2-co-~
-N}l-CIIR~-CO-NII-C~R~-CO-NR~-CHR~-CO-NR7-CHRl-CO-NR3-CHR~-Co-NH-CHR3-Co-, -Nll-C~lR~-CO-NR~-CHR3-CO-NR7-CHRl-CO-NR3-CHR~-CO-NH-CHR3-CO-NH-CHR~-CO-or -NR~-CHR3-Co-NR7-CHRl-Co-NR3-CHR2-Co-NH-CHR3-Co-NH
CHR~-CO-NH-CHR~-CO-, ,~; ~ .
i . . .
; ' ~ . . .
s or a reactive derivative of such a peptide i~ treated with a cycliz~ng agent, and in that, if appropriate in a compound of the formula I, a thioether group i~ oxidized to a sulfoxide group or to a sulfone group and/or a 8ul-foxide group i8 reduced to a thioether group and/or a compound of the formula I i8 converted into one of it3 8alt8 by tr~ating with an acid The radicals and parameter~ n, Rl to R~, A, Ar, Het, Hal, m, Ac and Z above and below have the meanings 10 given in the formulae I or II, if not expressly stated otherwise In the above formulae, A has 1 - 8, preferably 1, 2, 3 or 4 C atoms A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl or 15 tert -butyl, and in ~ddition also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethyl-propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethyl-butyl, l-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 20 1,1,2- or 1,2,2-trimethylpropyl, heptyl or octyl Cyclo~lkyl i8 preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but al80 e g 1-, 2- or 3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclo-he y l Corre-pon~gly, cycloalkyl-~l~yl i~ prefer~bly cyclopropylmothyl, 2-cyclopropyl thyl, cyclobutyl ethyl, 2-cyclobutyl-thyl,cyclop~ntyl~e~hrl,2-cyclopentyl-thyl, cyclohexyloethyl, 2-cyclohe yl'ethyl, but al~o e g 1-,'2-' or 3-methylcycIopentyl~ethyl, or 1-, 2-, 3- or ''4-30 '~ethylcyclohe y l~ethyl H~ preferably F, Cl or Br, but ~180 I
AC i8 preferably ~-C0- or A-C0- such ~8 acetyl, propionyl or butyryl, Ar-COL ~uch ~8 benroyl, o-, m- or p-methoxybenroyl or 3,4-d~etho~yben~oyl, A-NH-C0- such 35 a~ N-methyl- or N-ethylc~rb~moyl or Ar-NH-C0- such as N-phenylcar~amoyl ' Ar i8 preferably phenyl, ~nd ~n ~ddition prefer~
ably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or . . .
;;a~
p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- sr 3,5-dLmethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m- or p-S aminophenyl, or 1- or 2-naphthyl Correspondingly, Ar-alkyl i8 preferably benzyl, 1- or 2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, -m- or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1-or 2-o-, -m- or -p-et~ylphenyl~thyl, o-, m- or p-m~thoxy-benzyl, 1- or 2-o-, -m- or -p-methoxyphenylethyl, o-, m-or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenyl-ethyl, o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chlorophenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, o-, m- or p-iodobenzyl, 1- or lS 2-o-, -m- or -p-iodophenylethyl, o-, m- or p-trifluoro-methylbenzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trime-thoxybenzyl, o-, m- or p_a~- nobenzyl, or 1- or 2-naphthylmethyl Het i8 preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imid~zolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-i~othi~zo-lyl, 2-, 3- or ~-pyridyl, 2-, ~-, 5- or 6-pyrimidyl, and further or pr ferably 1,2,3-tria-ol-1-, -4- or -5-yl, 1,2,~-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-ox~diazol-3- or -S-yl, 1,3,~-thiadiazol-2- or -5-yl, 1,2,~-thiadiazol-3- or -5-yl, 2,1,5-thi~dlazol-3- or -4-yl, 2-, 3-, 4-, 5- ~r 6-2~-thiopyranylj, ?-, 3- or 4-~H-thiopyr~nyl, 3- or 4-pyrida-~inyl, pyr~zinyl, 2-, 3-, 4-, S-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-lndolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-i~oindolyl, 1-, 2-, 4- or 5-bens~-~dazolyl, 1-, 3-, 4-, 5-, 6- or 7-b nzopyr~zolyl, 2-, 4-, 5-, 6- or 7-benzo~azolyl, 3-, 4-, 5-, 6- or 7-benzi~oxazolyl, 2-, 4-, 5-, 6- or 7-benso-thlazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadi~zolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-i~oquinolyl, 1-, .~
201~rj 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, ~-, 4-, 5-, 6-, 7- or 8-cinnolyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolyl The heterocyclic radicals can also be partially S or completely hydrogenated Het can thus also be e g 2,3-dihydro-2-, -3-, -4- or -5-fury~, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, tetra-hydro-2- or -3-thienyl, 2,3-dihydro~ 2-, -3-, -4- or -5-pyrryl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrryl, 1-, 2- or ~-pyrrolidinyl, tetrahydro-l-, -2- or -4-imida-zolyl, 2,3-dihydro-1-, -2-, -3-, -4- or 5-pyrazolyl, 2,5-dihydro-l-, -2-, -3-, -4 or 5-pyrazolyl, tetrahydro-l-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetr~hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetr~hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpho-linyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -S-yl, hexahydro-l-, -3- or -4-pyrid~zinyl, hex~hydro-l-, -2-, -4- or -5-pyrimidyl, 1-, 2- or 3-piper~inyl, 1,2,3,4-tetr~hydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or 8-i~oquinolyl ~~he heterocyclic r~dical~ c~n ~l~o be substitut~d ~ -~ st~ted Het c~n thuz ~l~o prefer~bly be~ 2-~ ino-4-thiarolyl, 4-~arbo y-2-thi~zol~ -c~rb~oyl-2~ o-lyl, ~-(2-a-~nethyl)-2-thi~zolyl, 2-~ ino-5,6-di~ethyl-3-pyr~zinyl, 4-carb~ooylplperidino, ~nd in ~dd1t~on e g 3~ or 5-m~thyl-2-furyl, 2-j ~- or 5-methyl-3-furyl, 2,4-d~ethyl-3-furyl! 5-nitro-2-furyl, 5-~tyryl-2-furyl, 3-, 4- or 5- -thyl-2-thlenyl, 2-, ~- or 5-~ethyl-3-thienyl, 3-~ethyl-5-tort -butyl-2-thlenyl, 5-chloro-2-thienyl, 5-phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-~ethyl-2-pyrrolyl, 1-~ethyl-4- or -5-nltro-2-pyrrolyl, 3,5-dimethyi-4-ethyl-2-pyrrolyl,4-methyl-5-pyr~zolyl,4-or 5-methyl-2-thi~zolyl, 2- or 5-methyl-4-thi~zolyl, 2-or 4-methyl-5-thi~zolyl, 2,4-dimethyl-5-thi~zolyl, 3-, 4-, 5- or 6-methyl-2-pyrldyl, 2-, 4-, 5- or 6-methyl-3- ~`~
pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-,~ 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or :~:
3-chloro-4-pyridyl, 2,6-d~chloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (~ lH-2-pyridon-3-, -4-, -5- or -6-yl),5-phenyl-lH-2-pyridon-3-yl,5-p-mathoxyph~nyl-1~-2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N~-methylureido-lH-4-pyridon-5-yl, 5- or 6-methyl-4-pyr~mid-yl, ?,6-dihydroxy-4-pyrimidyl, 5-chloro-2-methyl-4-pyrimidyl, 2-methyl-4-amino-5-pyrimidyl, 3-methyl-2-benzofuryl, 2-ethyl 3-benzofuryl, 7-methyl-2-benzothi-enyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, l-methyl-5- or -6-benzimldazo}yl, 1-ethyl-5- or -6-benzimid~Azolyl or 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl.
Rl and R7 are preferably in each case H or A or, together, an alkylene chain having 2-6, in particular 3 C atoms.
Ra is preferably propyl, isobutyl or sec.-butyl.
R3 is preferably A-S(0),-alkyl, in part~cular CH3-S(0),-CH2CH2-, where m is preferably 0.
R ~ is preferably H or ~if Rl ia different from H
and/or at least one of the radicals R2 to R~ has the R-configur~Ation) H2N-C0-CH2CH2-.
R~ is preferably Ar-alkyl or Het-alkyl, in par-ticul~r b~n~yl or 3-indolyl- ethyl, and in addition p-hydroxyben7yl or p- ethoxyben~yl.
R~ 1~ prefer~bly Ar-~lkyl, in particular ben~yl, and in ~dditlon p-hydroxyben~yl or p-xethoxyben~yl.
-NR7-CHRl-co- i- preferablys Gly, Pro or D-Pro~
-NR~-CHR~-C0- i~ pr f-r~blys I~u, ~nd ~n addltion D-Leu, , Ile or D-Ile;
: . . .
30 -NH-CHR~-C0- i~ preferablys Net, D-Het, Met~0), D-Met(0), ~et~02) or D-Met(02), and in addition Leu or D-~eus -NH-CHR~-C0-- i~ preferablys Gly or Gln, and in addition 3S Ala or D-Ala;
-NH-CHR5-Co-s 1~ preferablys Phe or Trp;
-NR~-CHR~-C0-s i~ preferablys Phe, D-Phe, N-Ne-Phe or D-N-Ne-Phe, and in addition Val or D-Val.
. ' ~ ~ .
:, The parameter n is preferably 1 Accordingly, the invention in particular relates to those compound~ of the formula I in which at least one of the said radicals and/or parameters has one of the S preferred meanings given above Some preferred groups of compounds can be expressed by the part formula Ia, which otherwise corresponds to the formula I, but in which R1 is H, or, together with R7, -(CH2)3-, RZ i8 isobutyl, R3 i8 CH3-S(O)~-CR2CH2-~
R~ is H or, if Rl i8 different from H and/or at least one of the radicals R2, R3, R', ~5 and/or R6 have the R-configuration, is also H2N-CO-CR2CH2-, R5 i8 benzyl or 3-indolyl-methyl, RB i8 benzyl, R7 i8 H or, together with R1, -(CH2) 3-, Ra i8 H and R is H or Me Particul~rly preferred compounds of the formulae I and Ia are those in wh$ch n i8 additionally 1 The compounds of the formula I and also the starting material~ for the$r preparation ~re oth~rwise prepared by thod- which are known per ~e, a8 are - de-cribed $n the liter~ture (e g in the standard works such ~- Hbub n-Weyl, ~ethoden der org~ni-chen Che~$e, (~ethod~ o~ Orga~ic Che~i~try) Gsorg-Th$ _ -Verlag, Stuttg~rt), $n particular under reaction cond~tions which ~ i ar known and ~uitable for the sa$d reaction~ In this cont xt, uJ- can al-o be ~ade of variant~ which are known per ~e and ~re not entloned in ~ore detall here The ~tart~ng sub-tancs- can al~o be formed in -~
situ, if de~ired, uch that they ~r~ not i~olated from th reaction lxture, but i~ edi~tely reacted further to give the co~pound- of the ormula I
The co~pounds of the for~ula I can be obtained by liberatlng thQm from thelr functlonal derlvatives by solvolysi~, in particular hydrolysis, or by hydrogenolysis Preferred starting materials for the solvolysis : ., ' : '- .. i ... . '. . .
or hydrogenoly~is are those which contain appropriate protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl group~, preferably those which carry an amino protecting group instead of an H
S atom which i9 bonded to an N atom, e g those which correspond to the formula I, but contain an N(im)-R~-His group (in which R~ i8 an amino protecting group, e g BOM
or DNP) instead of an His group In addition, starting materials are preferred which carry a hydroxyl protecting group instead of the H
atom of a hydroxyl group, e g those which correspond to the formula I, but contain an R''O-phenyl group (in which R~ is a hydroxyl protecting group) instead-of a hydroxy-phenyl group Several - identical or different - protected amino and/or hydroxyl groups can be pre~ent in the molecule of the starting material If the protective groups present are different from one another, in many cases they can be removed selectively The expression ~amino protecting group~ i8 generally known and relates to groups which are suitable for protecting (or blocking) an am$no group from ch d -cal reactlon , but which are eas~ly removab~e, after the de-ired ch d cal reaction ha- b~en carrled out on other po-ltion~ of the ~ol-cule Typical group~ of this typo are, in particular, w ub tituted or sub~tltuted acyl, ~ryl (- g DNP), ar~lkoxy ethyl (e g BQ~) or aralkyl group- (e g b n~yl, ~-nitroben~yl or triphenylmethyl) A~ the a ino protecting group are re~oved a~ter the de-ired reaction (or react$on -equence), their n~ture and si~e is otherwi-e not critical~ but those having 1-20, in partlcular 1-8, C ato~ are preferr~d~ The expre~-lon ~cyl group~ $- to be taken in its w$de-t sen~e $n connection with the pre-ent process It include~ acyl groups derived fro~ al$phat$c, araliphat$c, ~romat$c or heterocyclic carboxylic acids or sulfonic ac$ds ~nd in part$cul~r alkoxycarbonyl, ~ryloxycarbonyl and, above all, aralkoxycarbonyl groups 2x~mples of acyl groups of th$s type are alkanoyl such as acetyl, propionyl or .
.' . ~
. . . :
.... . .
,. ,-: , .. . .. ..
3 ~ ~
butyryl; aralkanoyl such a3 phenylacetyl; aroyl ~uch a~
benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxy-carbonyl ~uch as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl;
S aralkylo~ycarbonyl sueh as CBZ ("carbobenzoxy~), 4-methoxybenzyloxycarbonyl and FMOC. Preferred amino protecting groups are DNP and BOM, and in addition CBZ, FMOC, benzyl and aeetyl.
The expression "hydroxy protecting qroup~ i~ also generally known and relates to groups whieh are suitable for proteeting a hydroxyl group from ehemieal reaetions, but whieh are easily removable, after the desired ehemi-eal reaetion has been earried out on other positions of the moleeule. Typie~l groups of this type are the ~bove-mentioned unsubstituted or substituted aryl, aralkyl or aeyl groups, and in ~ddition also alkyl groups. The nature and size of the hydroxy proteeting groups is not eritieal, as they are removed ag~in after the desired ehemie~l re~etion or re~etion sequeneQ; preferred groups are those h~Ying 1-20, in p~rtieular 1-10 C ato~s.
~x~mples of hydroxyl proteeting groups are, inter ali~
benzyl, p-nitroben~oyl, p-toluenesulfonyl and ~cetyl, benzyl ~nd ~cetyl being p~rticul~rly preferred.
The functional deriv~t$ves of the compounds of the for ul~ I to b u-ed ~ tartlng w~t~ri~l~ c~n be prep~red by cu~to~ry ~ethod~ of a~lno ~c$d and peptide ynthe~$~, uch ~- ~re de~cribe~ e.g. in the st~nd~rd wor~ ~nd p~t nt ~pplic~t$on- mentioned, ~nd e.g. ~l~o by the ~errifield ol~d ph~e ~ethod. , The liber~tion of the co~pounds of the ~oruul~
fro~ their function~l deriv~tlve~ $8 c~rried out -depending on the protecting group u~ed - e.g. with strong ~cids, prefer~bly with TFA or perchloric ~cid, but ~l~o with other ~trong inorg~nic ~clds such ~8 hydrochloria ~cid or sulfuric ~cid, or ~trong org~nic c~rboxylic ~c$ds such ~8 trichloro~cetic ~cid or sulfon~c ~cids ~uch ~8 ben~ene- or p-toluenesulfonic ~cid. The presence of ~n addition~l inert solvent is pos~ible, but not ~lw~ys necess~ry. Suit~ble inert solvents are prefer~bly 2 ~
organic, for example carboxylic acids such as acetic acid, ether~ such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbon~ such as dichloro-methane, and in addition also alcohols such as methanol, ethanol or isopropanol and also water.
In addition, mixtures of the abovementioned solvents are suitable. TFA is preferably used in an excess without addition of a further solvent, perchloric acid in the form of~a mixture of acetic acid and 70 %
perchloric acid in the ratio 9:1. The reaction temper-atures for the cleavage are preferably betwe~n about 0 and about 50, preferably between 15 and 30- (room temperature).
The BOC group c~n be removed e.g. preferably using 40 % TFA ~n dichloromethane or with about 3 to 5 N
HCl in dioxane at 15-30-,-the F W group using an about 5- to 20 % solution of dimethylamine, diethylamine or piperidine in DMF at 15-30-. ~emoval of the DNP group is carried out e.g. al80 using an about 3 to 10 % ~olution 1 20 of 2-mercaptoethanol in DNF/w~ter st 15-30-.
Protecting groups which can ba removed by hydro-genolys~s (e.g. B0~, CB~ or ben~yl) can be removed, e.g.
by treating with hydrogon in the presence of ~ catalyst (e.g. a noble ~etal catalyst ~uch as palladium, proferab-ly on ~ c~rri r uch a- carbon). Suit~ble ~olventJ in thi~ ca~e ar tho~e entioned abov-, in p~rticular e.g.
alcohol~ uch a- oth~nol or ethanol or amide~ ~uch as D~F. Tho hydrogenoly~ carried ~ut, as a rule, at t~perature~ botw~en about 0 and 100- ~nd pre~ures botwe~n about 1 and 200 b~r, preferably at 20-30- ~nd 1-10 bar. Hydrogenoly~l- of the CBS group i~ ea~ily carrled out e.g. on 5 to 10 ~ Pd-C in meth~nol or uslng a~onlum form~te (iN te~d of H~) on Pd-C in methanol/DN~ ~t 20-30-.
Co~pounds of the formul~ I ean ~180 be obtalned by eyeli~atlon of eo~pounds of the for ula II under the eondition~ of a p~ptide synthesi~. In this e~se, the re w tion $J preferably earried out by custom~ry methods of peptide synthesls, ~8 are deserlb~d e.g. ln Houben-Weyl, loe cit. volume 15/II, p~ges 1 to 806 (1974).
2`'i . ~ ~
.'` ~' "' :
'`.: :.. ., :~
2~ 3~
The reaction i8 preferably carried out in the presence of ~ dehydrating agent, e.g. a carbodiimide such as DCCI or EDCI, and in addition propanepho~phonic anhydride (compare Angew. Chem. 92, 129 (1980)), diphen-s ylpho~phoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-di-hydroquinoline, in an inert solvent, e.g. ~ halogen~ted hydrocarbon such as dichloromethane, an ether such as tetr~hydrofuran or dioxane, an ~mide such as DMF or dimethyl~cet~ide, a nitrile such ~8 acetonitrile, or in mixtures of these solvent~, at temperatures between about -10 and 40, prefer&bly between O and 30-. In order to promote intramolecular cycliz~tion before intermolecul~r peptide bonding, it is preferable to woxk in dilute solut~ons (dilution prlnciple).
Inste~d of II, suit~ble react~ve deriv~tives of these substances can also be employed in the reactlon, e.g. those in which re~ctive groups ~re ~ntermedl~tely blocked by protect$ng groups. The ~mlno ~cid deriv-atives II c~n be used e.g. ln the form of their ~ctiv~ted 1 20 esters which ~re prefer~bly formed in situ, e.g. by ~ddition of HOBt or N-hydroxysuccinimide.
Tha at~rting m~teri~lo of the for~ul~ II are, ~
~ rule, novel. They c~n be prep~red by ~nown ~ethods, e.g. the ~bove~entioned ~ethoda of peptide ynthesis ~nd of remov~l of`prot ctive group~
A~ ~ rul-, prot~¢ted hex~peptid 0-t ra of the for~ul~ R'-Z-OR'', e.g. BOC-~-ONe or BOC-g-OBt ~re ini-ti~lly oynthe-i~ed, which ~re firat hydroly~ed to gl~e ~¢idJ of th formul~ R'-S-OH, -.g. BOC-Z-OH~ the protec-ti~o group R' ia remo~ed fro these, by ~e~n~ of which the free peptidea of the formula H-Z-OR (II; n ~ re obt~ined. The dodecapeptide~ of the for ula H-(Z)~-OH are prof-rably pr p~red by re~ction of acida of the formula R'-Z-OH with a~ino e~ter~ of the for~ula H-~-OR'' to give protected dodecapeptidea of the formula R'(Z)~-O-R'' and subsequent re~oval of the protecting group~ R' and R''.
It is al80 possible to oxidize a thioether group to a sulfoxide group or sulfone group, ~n particular a group -NH-CHR3-Co- - ~et to a group -NH-CHR3-Co-~.~ . . . . .
~ J~
, = Met(0) or ~et(oz)~ e.g. by passing air into a solution of the compound of the formula I (-NH-CHR3-Co- = Met) in acetonitxile/water at temperatures between 0 and 30-. The thioether can also be oxidized with H202. The sulfoxide is thus predominantly obtained at 20~ in methanol using the calculated amount of oxidizing agent, and the sulfone is predominantly obtained at 50-, on the other hand, using an excess of the oxidizing agent.
Conversely, a sulfoxide group (e.g. in I, -NH-CHR3-Co- = Met(0)) can be reduced to give a thioether group (e.g. in I, -NH-CHR3-Co- = Met), e.g. usin~ NH,I in aqueous ~A at temperatures between -10 and 25-.
A base of the formula I can be converted into the appropriate acid addition salt using an acid. Suitable acids for this reaction are in particul~r those which yield physiologically accep Wble salts. Inorganic acids can thus be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such a8 orthophosphoric acid and sulfamic acid, and in addition organic acids, in par-ticular aliphatic, alicyelic, araliphstic, aro~tic or heterocycllc mono- or polybasie carbo ylie, sulfonie or sulfurie aeld~, e.g. for ie aeid, acetie aeld, propionle aeid, pivallc aoid, diethrlacetic acid, malonic acid, succinic ~cid, pin~lic acid, fum~ric ~cid, ~aleic acid, lactic-acid, t~rt~ric acid, ~alic acid, benzoic acid, salicylic ~cid, 2- or 3-phffnylpropionic acld, citr~c aeid, glueonie aeid, a~eorbie aeid, nieotinie ~eid, i~onieotinie aeid, methane- or eth~ne-ulfonic acid, eth~nedlsulfonic aeid, 2-hydroxyeth~nesulfonlc acid, benzenesulfonie aeid, p-toluene~ulfonie aeid, naphthal-ene-mono- and -di~ulfoni~ aeid~, and laurylsulfurie aeid.
Salt~ with phy~iologieally unaeceptable acid~, e.g.
picrates, can be u~ed for the i~olation and/or purifica-tion of the eompounds of the formul~ I.
The novel eompounds of the formula I and theirphysiologic~lly accept~ble salt~ can be used for the production of ph~roaceuticAl preparations by bringing them into a suitable dosage form together with at least ~ ~ ,~ ,... . .
... . . ~ .
. . . ... . .
2 ~
one excipient or auxiliary and, if de~ired, together w$th one or more other active compound(~). The preparations thus obtained can be employed as pharmaceuticals in human or veterinary medicine. Suitable excipient ~ubstance~ are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal), parenteral or local (e.g.
topicAl) adminiEtration or for administration in the form of an inhalant spray and which do not react with the novel compounds, foF example water, lower alcohols, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates ~uch as lactose or starch, magnesium stearate, talc, cellulose and vaseline.
Tablet~, coated tablets, capsules, syrups, liquids or drops, in particular, are used for oral ad~inistration;
film tablets and capsules having gastric ~uice-resistant coatings or capsule shells are especially of interest.
Suppositor$es are used for rectal ~dministration, and solutions, prefer~bly oily or agueous solutions, and in addition suspensions, emulsions or implants, are used for parenter~l admini~tration. Solutions, e.g., which can be used in the for~ of eye drop~, and in addltion, e.g.
suspension~, e~ul~ion~, creams, oint~ent~ or co~presses are ~uitabl- for topical appllcation. Sprays c~n be u~ed which cont in th~ activ co~pound e$ther dl~olved or su-pended in a propellant ga~ ~tUrQ (e.g. chlorofluoro-hydrocarbonJ~ for ad lni~trat$o~ a~ inhalant spr~ys. The activ- co pound here i~ prefer~bly usQd in micronized for~, ~t being po -ible for one or re ~dditlonal physlologically tolerable solvents to be present, e.g.
; ethanol. Inhalant ~olution~ can be adminl~ter~d with the aid of customary inh~ler~. The novel co pounds can also be lyophyli~ed and the lyophyli~ates obtained used e.g.
for the production of in~ection preparations. The prepar-ations indicated can be sterilized ~nd/or can contain au~iliarie~ such a8 preservati~e~, stabilizers and/or wetting agents, e~ulsifiers, salts for influencing osmotic pressure, buffer substances, colorants and/or fl~vourings. If desired, they can al80 cont~in one or .. ... . .. ~.. . .. "-.. ",.. ,~... .
.: - , .
2 ~
more other active compounds, e.g. one or more vitam$ns.
The substances according to the invention are as a rule administered in analogy to other known commercial-ly available peptides, but in particular in analogy to the compounds described in US-A-4,472,305, preferably in dosages between about 0.05 and 500, in particular between 0.5 a~d 100 mg per dosage unit. The daily dose i8 prefer-ably between about 0.01 and 2 mg~kg of body weight. ~he specific dose for each intended patient depends, however, on many different factors, for example the activity of the specific compound employed, the age, body weight, general state of health, sex, the cost, the time and route of administration, and the rate of excretion, pharmaceutical comb~nation and severity of the part$cular disorder to which the therapy applies. Parenteral admini-stration i8 preferred.
All te~per~tures above ~fid below are st~ted in C. In the following ex~mples, ~customary working up~
mean8 5 water i8 ~dded, if necessary, the mixture i8 neutralized and e~tr~ted with ether or dichlorometh~ne, the organic ph~se is separ~ted off, dr$ed over sodium sulf~te, filtered ~nd ev~por~ted ~d the re~idue is purified by chrom~togr~phy on ilic~ gel ~nd/or cryst~l-lir~tion. RT - ret ntion ti~e (~inute~) for ~PLC on ~n RP 18 250-~ colu-n, if not t~t d otherwi~e; eluent~
w~ter, b - 0.3 % TFA in water, c ~ ~cetonitrile.
Rf - Rf v~lue by thin-layer chro~togr~phy on ~ilic~ gel;
eluent~ chlorofor~eth~nol/~cetic ~cid 85-10-5. FAB-NS -- ~f~t ~to~ bo b-rdm-nt~ m~- spectrum.
Example 1 A ixture of 900 mg of cyclot-glycyl-L-phenyl-~l~nyl-L-phenyl~l~nyl-L-~N-imi-2,4-dinitrophenyl-his-tidyl)-L-leucyl-L- ethionine-l tcyclo(Gly-phe-phe-(~m~-DNP-Hi~)-Leu-Met-); obt~in~ble by cycli~tion of H-Gly-Phe-Phe-(imi-DNP-Hls)-Leu-Het-0~ ~n~logously to ~mple 3, see below], 2 g of 2-merc~ptoeth~nol, 20 ml of DMF ~nd 20 ml of w~ter is ~d~usted to pH 8 with ~queous N~2C03 ~olution while stirring ~t 20- and is stirred for :,','`: .' ' ' .. . . . .
, . . . . .
!. ~ . . ' 2 hour~ at 20 Cu~tomary working up give~ cyclo(-glycyl-L-phenylalanyl-L-phenylalanyl-L-histidyl-L-leucyl-L-methionine-)tcyclo(-Gly-Phe-Phe-Hi~-Leu-Met-)]
Example 2 1 g ofcyclo[-Gly-phe-phe-(imi-BoM-His)-Leu-Met-]
[obtainable from H-Gly-phe-phe-(imi-BoM-Hi8)-Leu-Met-oH
analogously to Example 3, see below] i8 dissolved in 25 ml of methanol, hy~rogenated for 3 hours on 0 5 % Pd-C
at 20 and 1 bar, and the mixture is filtered and evapor-ated and, after customary working up, gives cyclo(-Gly~
Phe-Phe-His-Leu-Met-) Example 3 1 8 g (2 mmol) of BOC-Leu-D-Met-Gln-Trp-Phe-Gly-OMe are dissolved in 50 ml of methanol, 1 5 ml of 2 N
aqueous sodium hydroxide solution are added and the mixture is ~tirred for 3 hours ~t 20 It i~ evaporated, ~nd the residue i~ taken up in water, acidified to pH 3 with HCl ~nd e~tr~cted with ethyl acetate The extr~ct is dried over N~SO~ ~nd ev~por~ted The BOC-Leu-D-Met-Gln-Trp-Phe-Gly-OH thu~ obt~ined i8 ~tirred ~t 20 for 2 hours with 20 ~1 of 2 N HCl in diox~ne The mlxture i~
ev~por~ted, the H-Leu-D-~et-Gln-Trp-Phe-Gly-OH obt~lned i- di--ol~ d in a ~xtur of 1800 ~1 of dichloro ethane ~nd 200 ~1 of Dh~ ~n~ ¢ool~d to 0-! Q 5 g of DCCI, 0 3 g of BOPt nd 0~23 d of N _ thyl~orphollne ~re ~dded ~ucc--~ively with ~tirring, and the mixture .i8 stirred for 2~ hour~ at 0 and 48 hour ~t 20 The olution i~
concentrated and ~tirred wlth a ~ixed bed lon e~ch~nger to re~o~e ~lt- ~hi~ filtered off, the -olution i~
ev~por~ted ~nd the re~idue i8 purified by chro ~togr~phy Cyclo(-Gln-Trp-Phe-Gly-Leu-D-~t-) i~ obt~inediS RT 11 37 (b/c 6s4) The following ~re obt~ined ~n~lo~ously from the corresponding linear hex~peptlde~
Cyclo(-Al~-Phe-Phe-Pro-Leu-Met-), m p 134 - 140 Cyclol-Ala-Phe-Phe-Pro-Leu-Met(O)-1 Cyclo~-Ala-Phe-Phe-Pro-Leu-Met( 2 ) - ]
- 18- 20~ pr,,~
Cyclo(-Ala-Phe-Phe-Pro-Leu-D-Met-), m.p. 133 - 138 Cyclo(-Gly-Phe-N-Me-Phe-Gly-Leu-Met-), RT 15 09 (a/c 6 4) Cyclo~-Gly-Phe-N-Me-Phe-Gly-Leu-Met(0)-), Cyclo(-Gly-Phe-N-Me-Phe-Gly-L~ -Net(02)-), Cyclo(-Gly-Phe-D-N-Me-Phe-Gly-Leu-Met-), RT 12 30 (a/c 6 4) Cyclot-Gly-Phe-D-N-Me-Phe-Gly-Leu-Met(0)-]
Cyclo[-Gly-Phe-~-N-Me-Ph~-Gly-LQu-Met( 2 ) - ]
I Cyclo(-Gly-Phe-Phe-Pro-Leu-Leu-) Cyclot-Gly-Phe-Phe-Pro-Leu-~et-), FAB-NSs (M+H)~ 694 Cyclo[-Gly-Phe-Phe-Pro-Leu-Met(0)-], FAB-MSs (M+H)' 710 Cyclot-Gly-Phe-Phe-Pro-Leu-Met( 2 ) - ], m p 157-162 Cyclo(-Gly-Phe-D-Phe-Pro-Leu-Met-) Cyclot-Gly-Phe-D-Phe-Pro-Leu-Met(0)-]
Cyclot-Gly-Phe-D-Phe-Pro-Leu-M~t(02)-], m.p. 128 - 135 Cyclol-Gly-Phe-Phe-D-Pro-Leu-Met-), RF O 63 Cyclot-Gly-Phe-Phe-D-Pro-Leu-Met(0)-~, RF ~ 42 Cyclot-Gly-Phe-Phe-D-Pro-Leu-Nbt( 2) - ]
cyclot-Gly-phe-ph~-pro-Leu-D-~et-)~ m p 13~ - 140 Cyclol-Gly-Phe-Phe-Pro-Leu-D-NQt(0)-]
Cyclo[-Gly-Phe-Phe-Pro-Leu-D-Met (2) - 1 Cyclo(-Gly-Phe-V~l-Gly-Leu-Net-), RF 051 Cyclol-6ly-Phe-V~l-Gly-Leu-~t(O)-]
Cyclot-Gly-Phe-V~l-Gly-~eu-~bt(0~)-]
Cy~lo(-Gly-Trp-Ph -Pro-L~u-~t-) Cyclol-Gly-Trp-Ph -Pro-Leu-~t(O)-]
CycloI-Gly- ~ Ph -Pro-Leu-15-t(0~)-]
Cyclol-GlyTrp-Ph -D-Pro-Leu-~et-) Cyciot-Gly- ~ -Phe-D-Pro-leu-~et(O)- I
Cyclol--Glr-Trp-Phe-D--P~o-Leu-Nbt(2 ) - ] .
Esample 4 Cycio(-Gly-Phe-Phe-Pro-Leu-Net-)2, m.p. 216-218-is obt~ined ~nalogou~ly to Es~mple 3 by cyclizatlon of H-(Gly-Phe-Phe-Pro-Leu-~et)2-OH tobtainable by reaction of BOC-Gly-Phe-Phe-Pro_Leu-Met_O~ w~th H-Gly-Phe-Phe-Pro-Leu-~et-OM~ to give BOC-~Gly-Phe-Phe-Pro-Leu-~et)2-O~e and subsequent remov~l of the protecting groupl.
The following are obtained ~nalogously from the ,, ~ . . .~
... . ~
corre~ponding linear dodecapeptides:
Cyclo-(Ala-Phe-Phe-Pro-Leu-Met-)2, m.p. 137 - 144 Cyclo-(Ala-Phe-Phe-Pro-Leu-D-Met)21 RF 0.74 Cyclo[-Gly-Phe-Phe-Pro-Leu-Met(O)-] 2 S Cyclo[-Gly-Phe-Phe-Pro-Leu-Met( 2 ) - ] 2 ~ :
Cyclo[-Gly-Trp-Phe-Pro-Leu-Met-) 2 Cyclo[-Gly-Trp-Phe-Pro-Leu-Met(0)-~2 Cyclo[-Gly-Trp-Phe-Pro-Leu-Met-( 2 ) - ] 2 Cyclo[-Gly-Trp-Phe-D-Pro-Leu-Met-) 2 Cyclo[-Gly-Trp-Phe-D-Pro-Leu-Met-(O)-] 2 Cyclo[-Gly-Trp-Phe-D-Pro-Leu-Met-( 2 ) - ] 2 .
Exampl~ 5 1.7 g (2 mmol) of BOC-Gly-Phe-Phe-Pro-Leu-Met-OMe (m.p. 92-99-) ~re dissolved in 50 ml of methanol, 2 ml of hydrazine hydrate are added, and the mixture i8 stirred for 16 hours and evaporated. The BOC-Gly-Phe-Phe-Pro-Leu-Met-NHNH2 thus obtained i~ stirred at 20- for 2 hours with 20 ml of 2 N RCl in dioxane. The mixture is evaporated, the H-Gly-Phe-Phe-Pro-Leu-Met-NHNH2 dihydrochloride obtained i8 dissolved in 50 ml of DHF and cooled to -lS-wlth ~tirring, and 0.83 ~1 of 35 % hydrochloric acld and 1.5 ml of ~ 1~ % aqueou~ NaNO2 solutlon are ~dded succes-slvoly. The ~l~ture 1- stirr~d ~t -15- for 1 hour and poured lnto 2 1 of cooled D~F. 1.1 ml of N- thylmor-phollne ~r~ add d, and th ~ixture 18 ~tirred for 24 hour at--lS- ~nd ~llo~sd to stand for 2 d~y~ at 20-. The : solution i- concentrated, a Jixed b~d ion exchAnger is ~dded to r~ ove ~alt~, the m~xture is filtered, the fiitrate 1~ vapor~ted, ~nd the re~ldue 18 purif~ed by chromatography to give cyclo(-Gly-Phe-Phe-Pro-Leu-~et-);
FAB-MS (M+H)~ 694.
Example 6 A ~olution of 100 mg of cyclo(-Gly-Phe-Phe-Pro-.Leu-Met-) and 1 equivalent of 30 % aqueous H2O2 in SO ml of meth~nol is stirred ~t 20- for 2 hours. ~vaporation and custom~ry worklng up gives cyclol-Gly-Phe-Phe-Pro-Leu-Met(O)-]; FAB-~Ss (~+H)~ 710.
Example 7 A solution of 100 mg of cyclo(-Gly-Phe-Phe-Pro-~ .. , ~ , :
.. . .
. .
~Q~ ~13~j -Leu-Met-) and 10 equiv~lents of 30 % aqueous Hz02 in 50 ml of methanol is warmed to 50 for 2 hours Evaporation and, cu~tomary working up gives cyclot-Gly-Phe-Phe-Pro-LQu-Met( 2)-]; m p 157-162 Example 8 ~ir i8 pa~sed through a solution of 1 g of cyclo[-Gly-Phe-Phe-Pro-Leu-Met-) in 50 ml of acetonitrile a~d 50 ml of w~ter until reaction is complete Customary working up gives the corresponding sulfoxide cyclot-Gly-Phe-Phe-Pro-Leu-Met(0)-]; FAB-MSs (M+H)~ 710 Example 9 20 ~1 of a 2 M NH~I solu~ion is added at 0 to a solution of 1 g of cyclot-Gly-Phe-Phe-Pro-Leu-Met(O)-I in 50 ml of TFA After stirring at 0 for 1 hour, the resulting iodine i8 reduced by adding thio~lycolic acid, and the mixture i8 worked up as is customary to give cyclot-Gly-Phe-Phe-Pro-Leu-Met-); FAB-MS~ (~+H)~ 694 The ex~ples below relate to pharmaceutical preparation-~x~ple At In~ectlon ~$al-A olutlon of 100 g of cyclot-Gly-Phe-Phe-Pro-Leu-~et-) ~nd 5 g of d$-od$um hydrogenpho~phate $n 31 of doubly d$-till d wat-r i- ad~u-ted to p~ 6 5 with 2 N
hydrochloric acid, terllo filtered, filled into in~ec-t~o~ vi~ nd lyophili~ed under terile con~ition~, and the vial~ ~re clos~sd in a terilo manner ~,ach in~ection '~ vlal contain- 5 mg of active compound E~4mple B~ Su,ppo~itorles A DiXture of 20 g of cyclot-Gln-~rp-Phe-Gly-Leu-D-Met-) i~ fuJed with 100 g of oya lecithin and 1400 g , of cocoa butter, and the mi~ture is poured into ~oulds and allowed to cool Each suppository contain~ 20 mg of active compound ~;, " ~
3 ~
-~ - 21 -Example C: Solution ~r- A solution of 1 g of cyclot-Gly-Phe-Phe-Pro-Leu-Met(O)-], 9.38 g of NaH2PO~.2H20, 28.48 g of Na2HPO~.12H20 and 0.1 g of benzalkonium chloride i8 prepared in 940 ml of doubly distilled water. The solution is ad~usted to pH 6.8, made up to 1 1 and sterilized by irradiation.
This solution can be used in the form of eye drops.
Example Ds Ointment 500 mg of cyclol-Gly-Phe-Phe-Pro-Leu-Met-)2 i8 mixed with 99.5 g of petroleum ~elly under asoptic conditions.
' ~
Claims (7)
1. Cyclopeptides of the formula I
I
in which n is 1 or 2, R1 and R7 in each case are H, A, alkenyl or alkynyl in each case having up to 4 C atoms, Ar-alkyl, Het-alkyl, cycloalkyl having 3-7 C atoms, or cycloalkylalkyl having 4-11 C atoms, R1 and R7 together are also alkylene or alkenylene in each case having 2-6 C atoms, which are unsub-stituted or substituted by A, Ar, Ar-alkyl, OH, OA or Het-alkyl, R2 is A, R3 is A, A-S(O)?-alkyl, A-O-alkyl, Ar-alkyl or carbamoyl-alkyl, R4 is H, A, H2N-alkyl, HAN-alkyl, A2N-alkyl or, if R1 is different from H and/or at least one of the radicals R2, R3, R5 and/or R6 has the R-configuration, is also carbamoyl-alkyl, R5 is Ar-alkyl or Het-alkyl, R6 is A or Ar-alkyl, R? and R? are in each case H or A, A is alkyl having 1-8 C atoms, Ar is phenyl which is unsubstituted, monosubsti-tuted or polysubstituted by A, OA, Hal, CF3, OH
and/or NH2, or unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O and/or S
atoms, which can be fused to a benzene ring or a pyridine ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, COOA, CN, CONH2, CONHA, CONA2, CONHAr, CONH-alkyl-Ar, SO2NH2, NHSO2A, Ar, Ar-alkyl, Ar-alkenyl, hydroxy-alkyl and/or amino-alkyl in each case having 1-8 C atoms and/or whose N
and/or S heteroatoms can also be oxidized, -alkyl- is an alkylene chain having 1-4 C atoms, -alkenyl- is an alkenylene chain having 2-4 C atoms, Hal is F, Cl, Br or I, m is O, 1 or 2 and Ac is H-CO-, A-CO-, Ar-CO-, A-NH-CO- or Ar-NH-CO-, and their salts.
I
in which n is 1 or 2, R1 and R7 in each case are H, A, alkenyl or alkynyl in each case having up to 4 C atoms, Ar-alkyl, Het-alkyl, cycloalkyl having 3-7 C atoms, or cycloalkylalkyl having 4-11 C atoms, R1 and R7 together are also alkylene or alkenylene in each case having 2-6 C atoms, which are unsub-stituted or substituted by A, Ar, Ar-alkyl, OH, OA or Het-alkyl, R2 is A, R3 is A, A-S(O)?-alkyl, A-O-alkyl, Ar-alkyl or carbamoyl-alkyl, R4 is H, A, H2N-alkyl, HAN-alkyl, A2N-alkyl or, if R1 is different from H and/or at least one of the radicals R2, R3, R5 and/or R6 has the R-configuration, is also carbamoyl-alkyl, R5 is Ar-alkyl or Het-alkyl, R6 is A or Ar-alkyl, R? and R? are in each case H or A, A is alkyl having 1-8 C atoms, Ar is phenyl which is unsubstituted, monosubsti-tuted or polysubstituted by A, OA, Hal, CF3, OH
and/or NH2, or unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O and/or S
atoms, which can be fused to a benzene ring or a pyridine ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, SA, SO-A, SO2-A, COOA, CN, CONH2, CONHA, CONA2, CONHAr, CONH-alkyl-Ar, SO2NH2, NHSO2A, Ar, Ar-alkyl, Ar-alkenyl, hydroxy-alkyl and/or amino-alkyl in each case having 1-8 C atoms and/or whose N
and/or S heteroatoms can also be oxidized, -alkyl- is an alkylene chain having 1-4 C atoms, -alkenyl- is an alkenylene chain having 2-4 C atoms, Hal is F, Cl, Br or I, m is O, 1 or 2 and Ac is H-CO-, A-CO-, Ar-CO-, A-NH-CO- or Ar-NH-CO-, and their salts.
2. a) Cyclo(-Gly-Phe-Phe-Pro-Leu-Met-);
b) Cyclo(-Gly-Phe-Phe-Pro-Leu-Met(O)-];
c) Cyclo(-Gly-Phe-Phe-Pro-Leu-Met-)2.
b) Cyclo(-Gly-Phe-Phe-Pro-Leu-Met(O)-];
c) Cyclo(-Gly-Phe-Phe-Pro-Leu-Met-)2.
3. Process for the preparation of a cyclopeptide of the formula I according to Claim 1, characterized in that it is liberated from one of its functional derivatives by treating with a solvolyzing or hydrogenolyzing agent, or in that a peptide of the formula II
H-(Z)n-OH
in which n is 1 or 2 and Z is -NR7-CHR1-CO-NR?-CHR2-CO-NH-CHR3-CO-NH-CHR4-CO-NH-CHR5-CO-NR9-CHR6-CO-, -NR?-CHR2-CO-NH-CHR3-CO-NH-CHR4-CO-NH-CHR5-CO-NR?-CHR6-CO-NR7-CHR1-CO-, CO-NR?-CHR2-CO-, -NH-CHR4-CO-NH-CHR5-CO-NR9-CHR6-CO-NR7-CHR1-CO-NR?-CHR2-CO-NH-CHR3-CO-, -NH-CHR5-CO-NR?-CHR6-CO-NR7-CHR1-CO-NR6-CHR2-CO-NH-or -NR?-CHR6-CO-NR7-CHR1-CO-NR8-CHR2-CO-NH-CHR3-CO-NH-CHR4-CO-NH-CHR5-CO-, or a reactive derivative of such a peptide with a cyclizing agent, and in that, if appropriate in a com-pound of the formula I, a thioether group is oxidized to a sulfoxide group or to a sulfone group and/or a sulf-oxide group is reduced to a thioether group and/or a compound of the formula I is converted into one of its salts by treating with an acid.
H-(Z)n-OH
in which n is 1 or 2 and Z is -NR7-CHR1-CO-NR?-CHR2-CO-NH-CHR3-CO-NH-CHR4-CO-NH-CHR5-CO-NR9-CHR6-CO-, -NR?-CHR2-CO-NH-CHR3-CO-NH-CHR4-CO-NH-CHR5-CO-NR?-CHR6-CO-NR7-CHR1-CO-, CO-NR?-CHR2-CO-, -NH-CHR4-CO-NH-CHR5-CO-NR9-CHR6-CO-NR7-CHR1-CO-NR?-CHR2-CO-NH-CHR3-CO-, -NH-CHR5-CO-NR?-CHR6-CO-NR7-CHR1-CO-NR6-CHR2-CO-NH-or -NR?-CHR6-CO-NR7-CHR1-CO-NR8-CHR2-CO-NH-CHR3-CO-NH-CHR4-CO-NH-CHR5-CO-, or a reactive derivative of such a peptide with a cyclizing agent, and in that, if appropriate in a com-pound of the formula I, a thioether group is oxidized to a sulfoxide group or to a sulfone group and/or a sulf-oxide group is reduced to a thioether group and/or a compound of the formula I is converted into one of its salts by treating with an acid.
4. Method for the production of pharmaceutical preparations, characterized in that a compound of the formula I and/or one of its physiologically acceptable salts are brought into a suitable dosage form together with at least one solid, liquid or semisolid excipient or auxiliary and, if appropriate, in combination with one or more other active compound(s).
5. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.
6. Use of compounds of the formula I or their physiologically acceptable salts for the production of a medicament.
7. Use of compounds of the formula I or their physiologically acceptable salts in the control of cardiovascular disorders, spastic disorders, states of pain, inflammations, disorders of the central nervous system and/or the circulation and/or in the stimulation of lacrimal secretion.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3915361.4 | 1989-05-11 | ||
| DE3915361A DE3915361A1 (en) | 1989-05-11 | 1989-05-11 | CYCLO PEPTIDE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2016355A1 true CA2016355A1 (en) | 1990-11-11 |
Family
ID=6380432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002016355A Abandoned CA2016355A1 (en) | 1989-05-11 | 1990-05-09 | Cyclopeptides |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0401507A1 (en) |
| JP (1) | JPH032197A (en) |
| KR (1) | KR900018141A (en) |
| AU (1) | AU5480890A (en) |
| CA (1) | CA2016355A1 (en) |
| DE (1) | DE3915361A1 (en) |
| HU (1) | HUT56382A (en) |
| ZA (1) | ZA903627B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5635379A (en) * | 1990-05-11 | 1997-06-03 | Romano Deghenghi | D-2-alkyl-tryptophan and peptides containing same |
| US5795957A (en) * | 1994-09-27 | 1998-08-18 | Deghenghi; Romano | Polypeptide compounds containing D-2-alkyltryptophan capable of promoting the release of growth hormone |
| US5872100A (en) * | 1990-05-11 | 1999-02-16 | Deghenghi; Romano | Peptides containing D-2-Alkyl-Tryptophan |
| US6218364B1 (en) | 1988-06-20 | 2001-04-17 | Scott L. Harbeson | Fluorinated neurokinin A antagonists |
| US11021514B2 (en) | 2016-06-01 | 2021-06-01 | Athira Pharma, Inc. | Compounds |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5830863A (en) * | 1988-06-20 | 1998-11-03 | Merrell Pharmaceuticals Inc. | Neurokinin A antagonists |
| WO1993003059A1 (en) * | 1991-08-08 | 1993-02-18 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Cyclic hexapeptides as tachyquinin antagonists, their preparation and pharmaceutical compositions thereof |
| IT1262902B (en) * | 1992-04-15 | 1996-07-22 | Menarini Farma Ind | TRICYCLIC COMPOUNDS ANTAGONISTS OF TACHYCHININS, THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL COMPOSITIONS. |
| DE4415310A1 (en) * | 1994-04-30 | 1995-11-02 | Merck Patent Gmbh | Cyclopeptides |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8807246D0 (en) * | 1988-03-25 | 1988-04-27 | Merck Sharp & Dohme | Therapeutic agents |
-
1989
- 1989-05-11 DE DE3915361A patent/DE3915361A1/en not_active Withdrawn
-
1990
- 1990-04-30 EP EP90108261A patent/EP0401507A1/en not_active Withdrawn
- 1990-05-07 AU AU54808/90A patent/AU5480890A/en not_active Abandoned
- 1990-05-09 CA CA002016355A patent/CA2016355A1/en not_active Abandoned
- 1990-05-10 KR KR1019900006580A patent/KR900018141A/en not_active Withdrawn
- 1990-05-11 JP JP2120193A patent/JPH032197A/en active Pending
- 1990-05-11 HU HU903011A patent/HUT56382A/en unknown
- 1990-05-11 ZA ZA903627A patent/ZA903627B/en unknown
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6218364B1 (en) | 1988-06-20 | 2001-04-17 | Scott L. Harbeson | Fluorinated neurokinin A antagonists |
| US5635379A (en) * | 1990-05-11 | 1997-06-03 | Romano Deghenghi | D-2-alkyl-tryptophan and peptides containing same |
| US5646301A (en) * | 1990-05-11 | 1997-07-08 | Romano Deghenghi | D-2-alkyl tryptophan compounds |
| US5872100A (en) * | 1990-05-11 | 1999-02-16 | Deghenghi; Romano | Peptides containing D-2-Alkyl-Tryptophan |
| US5955421A (en) * | 1990-05-11 | 1999-09-21 | Deghenghi; Romano | Peptides containing D-2-alkyl-Tryptophan |
| US5795957A (en) * | 1994-09-27 | 1998-08-18 | Deghenghi; Romano | Polypeptide compounds containing D-2-alkyltryptophan capable of promoting the release of growth hormone |
| US11021514B2 (en) | 2016-06-01 | 2021-06-01 | Athira Pharma, Inc. | Compounds |
| US12421276B2 (en) | 2016-06-01 | 2025-09-23 | Athira Pharma, Inc. | Methods of treating neurodegenerative disease with substituted n-hexanoic-l-tyrosine-l-isoleucine-(6)-aminohexanoic amide analogues |
Also Published As
| Publication number | Publication date |
|---|---|
| KR900018141A (en) | 1990-12-20 |
| ZA903627B (en) | 1991-02-27 |
| EP0401507A1 (en) | 1990-12-12 |
| AU5480890A (en) | 1990-11-15 |
| HUT56382A (en) | 1991-08-28 |
| JPH032197A (en) | 1991-01-08 |
| HU903011D0 (en) | 1990-09-28 |
| DE3915361A1 (en) | 1990-11-15 |
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| Date | Code | Title | Description |
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