CA2166374A1 - Acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane - Google Patents
Acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctaneInfo
- Publication number
- CA2166374A1 CA2166374A1 CA002166374A CA2166374A CA2166374A1 CA 2166374 A1 CA2166374 A1 CA 2166374A1 CA 002166374 A CA002166374 A CA 002166374A CA 2166374 A CA2166374 A CA 2166374A CA 2166374 A1 CA2166374 A1 CA 2166374A1
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- compound
- formula
- carbon atoms
- chain
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Genetics & Genomics (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to new acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane, of the general formula (I)
Description
216637~
BAYER AK~IIEN(~I ~ .~CHAI~T 51368 Il.~;en Patente Ki)mem Bufby-SP
New acylated pseu~~ ;des co~aini~ a ~ifluom.~ subsfftuted S ~ibi.~loc~4~
Ihe present invention relates to new acylated pse~l~lopepti~l~ c~ ;"g a triflu~ yl-~ 12-a~bicyclooctane,aprocessfortheir~ 1ionandtheir use as ~~ h~ agents.
Ihe public~ion EP 594 540 A1 discloses ~~ h~ iral acyl compounds.
Ihe present invention relates to new acylated pseudopeptides c~ a trifluol~nl~lyl-~,lb~ail.l~l 2-azabicyclooctane, ofthe general forrn~
R1-CO-NH CO--NH~ (I) o~ oR2 CF3 in which R' ~ a radical of ~e fQnm T ~ A 30 gl~Forei~ ;cs ~16637 i , DA~ L~
A, D, E, L and T are i~i~ntir~l or di~ t and denote hydrogen, halogen, s~i~ht-chain or 1..~ alkyl having up to 4 carbon atoms, molpholinyl, phenyl~io or cycloalkyl having 3 to 6 carbon atoms, R2 lel)lcs~ straight-chain or bl~ 1 acyl having up to 20 ca~on atoms, which is optionally ~lb~ ~ by carboxyl, by straight-chain or l)l~lcl~ed alk~yc&bonyl having up to 6 carbon atoms or by a group of the formula wll~lcill R3 and R4 are id~nti~l or di~ llt and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, r~presents a radical of the form~ -Co-NR5R6 or P(o)(oR7)(oR8), wll~l~lll R5 and R6 have the m~ning of R3 and R4 indicated above and are identical to or di~c;lll from this, R7 and R8 are i~l~ntil ~1 or di~ and denote hydrogen or s~raigh~-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or l~ clled alkoxy having up to 6 carbon atoms, Le A 30 814-ForeiPn colmtries - 2 -Z166~7 1 which is optionally ~ ;1 by din~lolo~ yl, din~ol~ -xy, trifluol~ xy or L
or l~l~ a radical of the r~.. "",1 -co -C-Nl~ 3 ~ ~ -CO-N~N
and their salts.
S The c~ po~ulds of the general formula a) according to the invention have several æ~ let.;c carbon atoms.
Ihe radical of the general f~rrnnl~ (A) ~4 N~CO--NHJ~ ~\ H (A) hæ 6 æylll~ ;c carbon atoms (*), ~ich are present indepen~ntly of one another in~e R- or S~nfigl~ation. Ihe cnnfi~lrations l(R), 2(R), 3(S), 4(S), 5(S) and 6(S) are 10 pl~r~,l~
Physiologically a~t~le salts of the acylated pseudopeptides c~ g a trifluol~ lllyl-sl~ iLI~l~ 2-a~bicyclooctane can be salts ofthe s~lkst~nces according Le A 30 81~Forei~ coll.l1.;cs - 3 -` 216637~
to the invention with min~l acids, carboxylic acids or slllrhnni~ acids. Particularly pl~f~l~ salts are e.g those with hydrochloric acid, hy~hv~lul~ic acid sl~lrhllric acid rhosrhl ric acid ,.,~h~ nll;c acid, ~h;~ r";c acid, tolll~ rhnnic acid -;c acid "~ h~ n";c acid, acetic acid propionic acid, lactic 5 acid, tartaric acid citric acid finn~Tic acid, maleic acid or benzoic acid Salts which may be mentioned are salts with u l~loll l;l. y bæes, such æ, for example, allcali metal salts (e.g sodium or ~~ 11 salts), ~lk~lin~ ear~ metal salts (e.g c~lrillm or m~&~ , salts) or ~ " salts, derived from ~ or organic amines such æ, for ~ , die~ylamine, trie~ylamine, ethyldiisopropylamine, 10 procaine, dibenzylamine, N-methyllllul~ olin~, dih~ ,~ietylamine, 1 e~ ~h;..~"~
or me~yl-piperidine.
l compounds of the general fcrrml~ ) are those in which R~ æt;llt~ a radical of the formlll~
A~ ~N~
wherein A, D, E, L and T are idrntir~l or di~ t and denote hydrogen, flllorin~"
chlorine, bromine, straight-chain or 1~ 1led alkyl having up to 3 carbon atoms, morpholinyl, phenylthio, cyclopentyl or cyclohexyl, 20 R2 represents s~aight-chain or br~nrll~1 acyl having up to 17 carbon atoms, which is optionally s~lbstitllt~l by carboxyl, straight-chain or b~ ,rl-~1 alko~yc~l,onyl Le A 30 814-ForeiQn collntries - 4 -having up to 4 carbon atorns or by a group of the form~ N R3R4, R3 and R4 are id~-ntic~l or dilr~ t and denote hydrogen, phenyl or straight-chain or l~ clled alkyl having up to 4 carbon atoms, S l~ a radical of the formlll~ ~o-NR5R6 or P(o)(oR7)(oR8), R5 and R6 have the m~nin~ of R3 and R4 indicated above and are identic-al to or di~ lt from this, R' and R8 are identi~l or di~ lL and denote hydrogen or straight-chain or l,lzul~lled alkyl having up to 3 carbon atoms, or represents s~aight-chain or b~;1"~ 1 alkoxy having up to 4 carbon atorns, which is optionally ~ iL~ d by difluoLoll~lyl, difluol..."~lhoxy, triflu~ xy ortrifluo~ hyl, or le~ ll~ a radical of the formlll~
-co -CO-N~ H,CxCH3 ~[b -CO-N~N
15 and their salts.
Particularly ~1~ f~,led cornpounds of the general formula (I) are those Le A 30 814-Forei~ colmtries - S -- _ 2166~7 1 in which R~ a radical of the form D~
wl A, D, E, L and T are i(l~tic~l or di~lGll~ and denote hydrogen, flll-ninr., chlorine, bromine, methyl, ~llcllylll~io, cyclopentyl or cyclohexyl, R2 lc~le3ellt~ str~i~ht-chain or l,.i~ ]~1 acyl having up to 15 carbon atoms, which is optionally s~ ~l by carboxyl, str~i~ht~ain or l~ d alk~y~l~llyl having up to 6 ca~on atoms or by a group of the f~rmlll~ -NR3R4, wherein R3 and R4 are i~lrntic~l or di~ lt and denote hydrogen, phenyl or straight-chain or branched allcyl having up to 3 carbon atoms, lC~lCS~ a radical of the fnrrmll~ -Co-NR5R6 or P(oXoR7)(oRg)~
wherem R5 and R6 have the m~ning of R3 and R4 indicated above and are i~l~ntir~l to or di~ om this, R7 and R8 are i;irntir~l or di~ t and denote hydrogen, methyl or ethyl, T ~ A 30 81~ForeiPn colmtries - 6 -_ or ~ straight-chain or l~ 1 alkoxy having up to 3 carbon atoms, which is optionally s lbsti~lt~l by difluo~ llyl, difluol~.",~ y, uolo~ h--xy or llillu~
orlepl~ a radicalofthef~rm -co -Co-N~3 H3CxCH3 b~ -CO-N~ N
H3C \J
S or and their salts.
A process for the ~le~ion of the com~ounds of the general formlll~ (T) according to the invention has additionally been found, char~ l in that first 10 carboxylic acids of the general ft)rmlll~ O
Rl-CO2-H (II) in which Rl has the m~ning indicated above, are converted by reaction with the com~ound of the form Le A 30 81~ForeiPn c~lmtries - 7 --,b~, H H
H2N~,CO--NH \~
into the compounds of the general formula (IV) ~\J ~
. . H H
R'-CO-NH~,CO--NH ~
in which R' has the mP~ning indicated above, if a~lo~ e with prior activation of the carboxylic acid, in inert solvents and in the 5 presence of a base andlor of an auxiliaIy, and in a second step an a~ylation is carried out in inert solvents, if a~lu~ e in the presence of a base and/or of an auxiliary.
The process accol-ling to the invention can be illu~ d by way of ~ le by the following reaction scl~
T P A 30 81~Forei~n c~ ics - 8 -216û37~
.
C,H, ~ ~ , H2N_,CO NH~N~) H,C ~ O~ OH CF, C,H, Morpho CDI ~N~ I H l ~ , H
~N~co--NH~co--NH ~ NrJ
o ~ H CF, C,H, H,C o TEJ~ H,C CO--NH~cO - NH
O~CH, CF
NH, Suitable solvents for all process steps are the w~ y inert solvents uhich do notchange under the reaction ct)n-iition~. Ihese ~ ~ly include organic solvents such as ethers, e.g. diethyl ether, glycol m-nomPtllyl or dimethyl ether, dioxane or tetrahydrof~an, or hydrocarbons such æ bPn7~nP, toluene, xylene, cycl hPY~ne or 5 petroleum fractions, or halogenohydrocarbons such æ methylene rlll(nide, chl~lofulln, carbon tetrachloride, or dimethyl sulphoxide, dimethylformamide, Il~,~lcthylrho~ o~ P~, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mix~ures of the solvents mentioned. Dichlo~ ' dimethylr.""i1",i-1e and tetrahy~orul~l are particularly ~lcf~llcd.
10 Suitable bases, ~ ntling on the individual process steps, are the ~ ;tcllll;lly ill~r~alfiC
or organic bæes. Ihese plcr~l~ly include allcali metal hydroxide such æ, for example, sodium orpot~ lm hydroxide, or allcali-metal c~l~l~L~s such æ sodiurn or pot~cillm Ca~ ;, or allcali metal alkoxides such as, for ~ul~l~, sodium or polæsi~lm methoxide, or sodium or po~ i""~ et~ ide~ or organic amines such as 15 ethyldiisopropylamine, triethylamine, picoline, pyridine, dimethylaminopyridine or N-methylpi~ri~linP, or amides such æ sorlillm amide or lithium diisopropylamide or lithium N-silylalkyl~midP-~, such æ, for cx~l~le, lithium N~bis)lrirhpnylsilylamide or Le A 30 81~Forei~ countries - 9 -.
lithium alkyls such æ n-butyllithillm-The base is employed in an ~m~lmt fiom 1 mol to 10 mol, ~lcr~l~ly from 1 mol to 3 mol, relative to 1 mol of the compounds of the general f~ la (II).
Suitable alTxili~ri~e are ~l~f~"~ly c~-n~ ;"g agents which can also be bases, inS particular if the c~l~yl group is present in activated form as an anhydride. The ;"~to~ .y c~ n-l~n.eing agents are lx~f~l~d here, such ae carb~liimid~, e.g N,NI-diethyl-, N,NI-diisopopyl-, N,NI~icyclohexylcarbo~1iimide~ N{3 dimethyl~minoi.~o-propyl}NI-ethyl carbo-liimide hydro~ e~ N-cyclohexyl-N'{2-morpholinoethyl}
carbo~liimide metho-p-tol~ rh- n~te (CMCT or morpho-CDI), or carbonyl ~1l4,oullds such æ c~boll~ iimitl~7r1~ or i,2~7l~1illm compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-slllrh~te or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such æ 2-ethoxy-l~thoxyc~l,ullyl-1,2 dihydroquinoline, or o~ n~llu-";c anhydride, or isobutyl chlol~f(" " ,~le, or 1~. 1~ 7~1yloxy-tri(dimethylamino)~ os~ h~flll-.u~ e, 1-hydroxy-b~ nle or 15 dimethyl~l~il~o~yridine.
The reactiorls can be carried out either at normal ~UIC or at elevated or reduced pressure (for ~l~le 0.5 to 5 bar), ~l~f.la~ly at normal ~lC~
The reaction is in general carried out in a te~ re range from -20C to +40C, ~L~r~l~ly from 0C to room ~ll~l~~
20 The acylation is in general carried out in one of the al~elllcll~ioned ethers or halogenohydroc~l~ns, ~l~r~l~ly tetrahyd~rul~l or methylene chloride, in a lell~ul~, range from -30C to +50C, ~lef~l~ibly from -10C to room t~ re.
Suitable bæes and/or auxiliaries for the acylation are in general the abovementioned organic amines and pyridines. Triethylamine and din~ .";l,u~,~ridine are ~ler~
25 The bæe is employed in an ~mOlnlt from 1 mol to 10 mol, ~ler~l~ly from 1 mol to 3 mol, relative to 1 mol of the ~s~i~e alcohol.
T ~ A 30 81~Forei~n countries - 10 -216~374 In the case of the ~lin~lin~, pl~c~yls, pyridyls and biphenyls, ~e c~l~A~/lic acids of the general fi~ I) are known per se. Ihe 4uill(~1ine carboxylic acids are known in some cases or are new and can then be ~ ~, for ~1~1~, by reaction of ~e c~ ol~ding phenyl~ l;5 ..;..~ with the osone of ~L~ose - lxc~alcd in situ by S reaction of the ~llcllylh~.h~ with NaNO2 and h~h~llloric acid - and sl.bs~~ .noxidation using H2O2 solution [cf. for ~is G. ~ elrP, Che~ Ber. 91, 1958, 1605-11 and DE 24 10 852].
Ihe compound of ~e gcneral f~ m) is new and can be ~ed, for example, by converting 10 co~pounds of ~e general formula (V) C6Hs W-NH~CO--NH
Oq~
in which W le~lc~llt~ an amino protective group, pl~f~ bly tert-butoxycall~llyl, f~t using an epoxidation reaction~ if ~lu~li~e wi~ ~e aid of a base or a phase-L.~r~, cat~lyst, into ~e corn~ounds of ~e general fûrmula (VI) W-NH CO--NH~7 (VI) Oq~ ' Le A 30 81~ForeiQn colm~ies - 11 -2166~74 ~
in which W has the m~n;~ intlir~t~d above, and then reactingwith 3-triflu~,o~ 1-2-azabicyclo[3.3.0]octane ofthe formlll~ ~) H H
HN~
in solvents and l~ll ~ving the ~ re group acco~ g to ~ 0lll5~. y m~h~l~
S Suitable solvents are the al~ "~y organic solvents which do not change under the reaction c~ mlitiQn~. These ~ r~ ~ly include organic solvents such as alcohols, e.g m~th~nt l, ethanol or n-propanol, ethers, e.g diethyl ether, glycol ~ hyl or dimethyl ether, (lioY~n~ or l~ rul~, or hydroc~bons such as bell7fn., toluene, xylene, cycloh~ or petroleum fi~ctions, or halogenohydroc~l~l~s such as 10 methylene rhl~ri~e, dichloroethane ([)CE), chlo.~r(J.---, carbon tetrachloride, or dimethyl slllphoxitle; din~hylro""~"-;de, h~x1",~ lpl-osl~l-nrarnide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use ll~ixlul~s of the solvents mentioned. Dichlol~",~ , dichlol~lhalle, dimeth~lr."..~--itle and n-propanol areparticularly ~ r~..~
Suitable reagents for the epoxidation are the compounds known from the litera~ure, such as, for ~ , m-chlol~l~.~ic acid, m~es;~ monoperoxyrhth~l~t~, dimethyldioxirane or me~yl(trifluolu.~ yl)dioxirane. m-Chlol~.l,e ~ic acid and m~ium "lol~ yphth~l~te are ~ f~-~d [cf. P. Brcn~h~rn et al., Synthesis (1987), 10is; W. Adam et al., J. Org Chem. 52, 2800 (1987) and R Curci et al., J.
Org Chem. ~, 3890 (1988)].
If the epoxidation is carried out with the aid of the phase-~ r~,l ca~alyst, the Le A 30 81~Forei~ WltliCS - 12 -216637~
.
allxili~riesusedare,for~ organic~ ."...;~ c~ sorbromidessuchas,for le, benzyl~ie~hyl~,-"~ ", chloride or br~mide, ltldllylll;octyl~
chloride, t~b.4yl~rn,.,. ";~" bromide or ~ica~ ln~l~ ""-";ll", chloride (Aliquat336). B~yl~ llyl~ k)n~le and bromide are yl~f~
S Ihe ep-)xi-i~ti~ n is carried out in a (~ll4~ , range from -10C to +90C, ple~l~ly from 0C to ~60C.
Ihe r~r.tion.~ can be carried out ei~er at normal pl~UI~ or at elevated or reduced UlC (for ~x~l4,1e 0.5 to 5 bar), ~lc~ldl)ly at normal ~l~U~
lhe compounds of ~e gene~l formula aV) are kno~ and can be lxepal~d, for 10 cX~14J1e~ as described above.
Ihe compounds of the general fc)nn~ e (V) and (VI) are in the main known [c EP 528 242].
Ihe compound of the general fc)" "~ ~) is new and can be ~lC~ d, for example, by flnlnnn~ti~ n of 2-azabicyclo[3.3.0]octane-3~1,u~ylic acid in the l~;ii~e 15 c--nfi~n~tion using HF and SF4.
It has surrri~in~ly been found that the coll4~u,lds of the general fQnmll~ (I) have an ~Allclnely strong action against re~oviruses. Ihis is cc.ll~.,ll~l using an H[V-specific protease enz~ne test.
Ihe results of the examples shown below were ~ "lil~l according to the HlV tcst 20 system ~ in the following litera~ure lcfelcllc~s [cf. Hansen, J., Billich, S., S~1n~17P; T., Sukrow, S. and Molling, K (1988), EMBO Journal, Vol. 7, No. 6, pp.1785 - 1791]: purified HlV p~)tease was in~lb~ted with ~lllllc1ic peptide ~ich ~ a cleavage site in the Gag prec~sor protein and is an in vivo cleavage site ofHIV ~lcase. Ihe r~lllting cleavage products of the synthetic peptide were analysed 25 by means of reverse phase high ~ . ~o" "~l~ce liquid cl.~ graphy (RP-HPLC). Ihe IC50 values indicated relate to the ~ .,ce col~ .~ion w~ich, under the Le A 30 81~Forei~ collntties - 13 -216637~
-abovementioned test cnn-lihnn~, causes a 50% inhibition of ~tease activity.
Fn7~n~ ~,v, ~V-l Table I
HlV-l-p~te~e ir~ibiffon EsampaeNo. IC~ [moVI] IC~5 Imo~]
1 3.2x104 n.t.
BAYER AK~IIEN(~I ~ .~CHAI~T 51368 Il.~;en Patente Ki)mem Bufby-SP
New acylated pseu~~ ;des co~aini~ a ~ifluom.~ subsfftuted S ~ibi.~loc~4~
Ihe present invention relates to new acylated pse~l~lopepti~l~ c~ ;"g a triflu~ yl-~ 12-a~bicyclooctane,aprocessfortheir~ 1ionandtheir use as ~~ h~ agents.
Ihe public~ion EP 594 540 A1 discloses ~~ h~ iral acyl compounds.
Ihe present invention relates to new acylated pseudopeptides c~ a trifluol~nl~lyl-~,lb~ail.l~l 2-azabicyclooctane, ofthe general forrn~
R1-CO-NH CO--NH~ (I) o~ oR2 CF3 in which R' ~ a radical of ~e fQnm T ~ A 30 gl~Forei~ ;cs ~16637 i , DA~ L~
A, D, E, L and T are i~i~ntir~l or di~ t and denote hydrogen, halogen, s~i~ht-chain or 1..~ alkyl having up to 4 carbon atoms, molpholinyl, phenyl~io or cycloalkyl having 3 to 6 carbon atoms, R2 lel)lcs~ straight-chain or bl~ 1 acyl having up to 20 ca~on atoms, which is optionally ~lb~ ~ by carboxyl, by straight-chain or l)l~lcl~ed alk~yc&bonyl having up to 6 carbon atoms or by a group of the formula wll~lcill R3 and R4 are id~nti~l or di~ llt and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, r~presents a radical of the form~ -Co-NR5R6 or P(o)(oR7)(oR8), wll~l~lll R5 and R6 have the m~ning of R3 and R4 indicated above and are identical to or di~c;lll from this, R7 and R8 are i~l~ntil ~1 or di~ and denote hydrogen or s~raigh~-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or l~ clled alkoxy having up to 6 carbon atoms, Le A 30 814-ForeiPn colmtries - 2 -Z166~7 1 which is optionally ~ ;1 by din~lolo~ yl, din~ol~ -xy, trifluol~ xy or L
or l~l~ a radical of the r~.. "",1 -co -C-Nl~ 3 ~ ~ -CO-N~N
and their salts.
S The c~ po~ulds of the general formula a) according to the invention have several æ~ let.;c carbon atoms.
Ihe radical of the general f~rrnnl~ (A) ~4 N~CO--NHJ~ ~\ H (A) hæ 6 æylll~ ;c carbon atoms (*), ~ich are present indepen~ntly of one another in~e R- or S~nfigl~ation. Ihe cnnfi~lrations l(R), 2(R), 3(S), 4(S), 5(S) and 6(S) are 10 pl~r~,l~
Physiologically a~t~le salts of the acylated pseudopeptides c~ g a trifluol~ lllyl-sl~ iLI~l~ 2-a~bicyclooctane can be salts ofthe s~lkst~nces according Le A 30 81~Forei~ coll.l1.;cs - 3 -` 216637~
to the invention with min~l acids, carboxylic acids or slllrhnni~ acids. Particularly pl~f~l~ salts are e.g those with hydrochloric acid, hy~hv~lul~ic acid sl~lrhllric acid rhosrhl ric acid ,.,~h~ nll;c acid, ~h;~ r";c acid, tolll~ rhnnic acid -;c acid "~ h~ n";c acid, acetic acid propionic acid, lactic 5 acid, tartaric acid citric acid finn~Tic acid, maleic acid or benzoic acid Salts which may be mentioned are salts with u l~loll l;l. y bæes, such æ, for example, allcali metal salts (e.g sodium or ~~ 11 salts), ~lk~lin~ ear~ metal salts (e.g c~lrillm or m~&~ , salts) or ~ " salts, derived from ~ or organic amines such æ, for ~ , die~ylamine, trie~ylamine, ethyldiisopropylamine, 10 procaine, dibenzylamine, N-methyllllul~ olin~, dih~ ,~ietylamine, 1 e~ ~h;..~"~
or me~yl-piperidine.
l compounds of the general fcrrml~ ) are those in which R~ æt;llt~ a radical of the formlll~
A~ ~N~
wherein A, D, E, L and T are idrntir~l or di~ t and denote hydrogen, flllorin~"
chlorine, bromine, straight-chain or 1~ 1led alkyl having up to 3 carbon atoms, morpholinyl, phenylthio, cyclopentyl or cyclohexyl, 20 R2 represents s~aight-chain or br~nrll~1 acyl having up to 17 carbon atoms, which is optionally s~lbstitllt~l by carboxyl, straight-chain or b~ ,rl-~1 alko~yc~l,onyl Le A 30 814-ForeiQn collntries - 4 -having up to 4 carbon atorns or by a group of the form~ N R3R4, R3 and R4 are id~-ntic~l or dilr~ t and denote hydrogen, phenyl or straight-chain or l~ clled alkyl having up to 4 carbon atoms, S l~ a radical of the formlll~ ~o-NR5R6 or P(o)(oR7)(oR8), R5 and R6 have the m~nin~ of R3 and R4 indicated above and are identic-al to or di~ lt from this, R' and R8 are identi~l or di~ lL and denote hydrogen or straight-chain or l,lzul~lled alkyl having up to 3 carbon atoms, or represents s~aight-chain or b~;1"~ 1 alkoxy having up to 4 carbon atorns, which is optionally ~ iL~ d by difluoLoll~lyl, difluol..."~lhoxy, triflu~ xy ortrifluo~ hyl, or le~ ll~ a radical of the formlll~
-co -CO-N~ H,CxCH3 ~[b -CO-N~N
15 and their salts.
Particularly ~1~ f~,led cornpounds of the general formula (I) are those Le A 30 814-Forei~ colmtries - S -- _ 2166~7 1 in which R~ a radical of the form D~
wl A, D, E, L and T are i(l~tic~l or di~lGll~ and denote hydrogen, flll-ninr., chlorine, bromine, methyl, ~llcllylll~io, cyclopentyl or cyclohexyl, R2 lc~le3ellt~ str~i~ht-chain or l,.i~ ]~1 acyl having up to 15 carbon atoms, which is optionally s~ ~l by carboxyl, str~i~ht~ain or l~ d alk~y~l~llyl having up to 6 ca~on atoms or by a group of the f~rmlll~ -NR3R4, wherein R3 and R4 are i~lrntic~l or di~ lt and denote hydrogen, phenyl or straight-chain or branched allcyl having up to 3 carbon atoms, lC~lCS~ a radical of the fnrrmll~ -Co-NR5R6 or P(oXoR7)(oRg)~
wherem R5 and R6 have the m~ning of R3 and R4 indicated above and are i~l~ntir~l to or di~ om this, R7 and R8 are i;irntir~l or di~ t and denote hydrogen, methyl or ethyl, T ~ A 30 81~ForeiPn colmtries - 6 -_ or ~ straight-chain or l~ 1 alkoxy having up to 3 carbon atoms, which is optionally s lbsti~lt~l by difluo~ llyl, difluol~.",~ y, uolo~ h--xy or llillu~
orlepl~ a radicalofthef~rm -co -Co-N~3 H3CxCH3 b~ -CO-N~ N
H3C \J
S or and their salts.
A process for the ~le~ion of the com~ounds of the general formlll~ (T) according to the invention has additionally been found, char~ l in that first 10 carboxylic acids of the general ft)rmlll~ O
Rl-CO2-H (II) in which Rl has the m~ning indicated above, are converted by reaction with the com~ound of the form Le A 30 81~ForeiPn c~lmtries - 7 --,b~, H H
H2N~,CO--NH \~
into the compounds of the general formula (IV) ~\J ~
. . H H
R'-CO-NH~,CO--NH ~
in which R' has the mP~ning indicated above, if a~lo~ e with prior activation of the carboxylic acid, in inert solvents and in the 5 presence of a base andlor of an auxiliaIy, and in a second step an a~ylation is carried out in inert solvents, if a~lu~ e in the presence of a base and/or of an auxiliary.
The process accol-ling to the invention can be illu~ d by way of ~ le by the following reaction scl~
T P A 30 81~Forei~n c~ ics - 8 -216û37~
.
C,H, ~ ~ , H2N_,CO NH~N~) H,C ~ O~ OH CF, C,H, Morpho CDI ~N~ I H l ~ , H
~N~co--NH~co--NH ~ NrJ
o ~ H CF, C,H, H,C o TEJ~ H,C CO--NH~cO - NH
O~CH, CF
NH, Suitable solvents for all process steps are the w~ y inert solvents uhich do notchange under the reaction ct)n-iition~. Ihese ~ ~ly include organic solvents such as ethers, e.g. diethyl ether, glycol m-nomPtllyl or dimethyl ether, dioxane or tetrahydrof~an, or hydrocarbons such æ bPn7~nP, toluene, xylene, cycl hPY~ne or 5 petroleum fractions, or halogenohydrocarbons such æ methylene rlll(nide, chl~lofulln, carbon tetrachloride, or dimethyl sulphoxide, dimethylformamide, Il~,~lcthylrho~ o~ P~, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mix~ures of the solvents mentioned. Dichlo~ ' dimethylr.""i1",i-1e and tetrahy~orul~l are particularly ~lcf~llcd.
10 Suitable bases, ~ ntling on the individual process steps, are the ~ ;tcllll;lly ill~r~alfiC
or organic bæes. Ihese plcr~l~ly include allcali metal hydroxide such æ, for example, sodium orpot~ lm hydroxide, or allcali-metal c~l~l~L~s such æ sodiurn or pot~cillm Ca~ ;, or allcali metal alkoxides such as, for ~ul~l~, sodium or polæsi~lm methoxide, or sodium or po~ i""~ et~ ide~ or organic amines such as 15 ethyldiisopropylamine, triethylamine, picoline, pyridine, dimethylaminopyridine or N-methylpi~ri~linP, or amides such æ sorlillm amide or lithium diisopropylamide or lithium N-silylalkyl~midP-~, such æ, for cx~l~le, lithium N~bis)lrirhpnylsilylamide or Le A 30 81~Forei~ countries - 9 -.
lithium alkyls such æ n-butyllithillm-The base is employed in an ~m~lmt fiom 1 mol to 10 mol, ~lcr~l~ly from 1 mol to 3 mol, relative to 1 mol of the compounds of the general f~ la (II).
Suitable alTxili~ri~e are ~l~f~"~ly c~-n~ ;"g agents which can also be bases, inS particular if the c~l~yl group is present in activated form as an anhydride. The ;"~to~ .y c~ n-l~n.eing agents are lx~f~l~d here, such ae carb~liimid~, e.g N,NI-diethyl-, N,NI-diisopopyl-, N,NI~icyclohexylcarbo~1iimide~ N{3 dimethyl~minoi.~o-propyl}NI-ethyl carbo-liimide hydro~ e~ N-cyclohexyl-N'{2-morpholinoethyl}
carbo~liimide metho-p-tol~ rh- n~te (CMCT or morpho-CDI), or carbonyl ~1l4,oullds such æ c~boll~ iimitl~7r1~ or i,2~7l~1illm compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-slllrh~te or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such æ 2-ethoxy-l~thoxyc~l,ullyl-1,2 dihydroquinoline, or o~ n~llu-";c anhydride, or isobutyl chlol~f(" " ,~le, or 1~. 1~ 7~1yloxy-tri(dimethylamino)~ os~ h~flll-.u~ e, 1-hydroxy-b~ nle or 15 dimethyl~l~il~o~yridine.
The reactiorls can be carried out either at normal ~UIC or at elevated or reduced pressure (for ~l~le 0.5 to 5 bar), ~l~f.la~ly at normal ~lC~
The reaction is in general carried out in a te~ re range from -20C to +40C, ~L~r~l~ly from 0C to room ~ll~l~~
20 The acylation is in general carried out in one of the al~elllcll~ioned ethers or halogenohydroc~l~ns, ~l~r~l~ly tetrahyd~rul~l or methylene chloride, in a lell~ul~, range from -30C to +50C, ~lef~l~ibly from -10C to room t~ re.
Suitable bæes and/or auxiliaries for the acylation are in general the abovementioned organic amines and pyridines. Triethylamine and din~ .";l,u~,~ridine are ~ler~
25 The bæe is employed in an ~mOlnlt from 1 mol to 10 mol, ~ler~l~ly from 1 mol to 3 mol, relative to 1 mol of the ~s~i~e alcohol.
T ~ A 30 81~Forei~n countries - 10 -216~374 In the case of the ~lin~lin~, pl~c~yls, pyridyls and biphenyls, ~e c~l~A~/lic acids of the general fi~ I) are known per se. Ihe 4uill(~1ine carboxylic acids are known in some cases or are new and can then be ~ ~, for ~1~1~, by reaction of ~e c~ ol~ding phenyl~ l;5 ..;..~ with the osone of ~L~ose - lxc~alcd in situ by S reaction of the ~llcllylh~.h~ with NaNO2 and h~h~llloric acid - and sl.bs~~ .noxidation using H2O2 solution [cf. for ~is G. ~ elrP, Che~ Ber. 91, 1958, 1605-11 and DE 24 10 852].
Ihe compound of ~e gcneral f~ m) is new and can be ~ed, for example, by converting 10 co~pounds of ~e general formula (V) C6Hs W-NH~CO--NH
Oq~
in which W le~lc~llt~ an amino protective group, pl~f~ bly tert-butoxycall~llyl, f~t using an epoxidation reaction~ if ~lu~li~e wi~ ~e aid of a base or a phase-L.~r~, cat~lyst, into ~e corn~ounds of ~e general fûrmula (VI) W-NH CO--NH~7 (VI) Oq~ ' Le A 30 81~ForeiQn colm~ies - 11 -2166~74 ~
in which W has the m~n;~ intlir~t~d above, and then reactingwith 3-triflu~,o~ 1-2-azabicyclo[3.3.0]octane ofthe formlll~ ~) H H
HN~
in solvents and l~ll ~ving the ~ re group acco~ g to ~ 0lll5~. y m~h~l~
S Suitable solvents are the al~ "~y organic solvents which do not change under the reaction c~ mlitiQn~. These ~ r~ ~ly include organic solvents such as alcohols, e.g m~th~nt l, ethanol or n-propanol, ethers, e.g diethyl ether, glycol ~ hyl or dimethyl ether, (lioY~n~ or l~ rul~, or hydroc~bons such as bell7fn., toluene, xylene, cycloh~ or petroleum fi~ctions, or halogenohydroc~l~l~s such as 10 methylene rhl~ri~e, dichloroethane ([)CE), chlo.~r(J.---, carbon tetrachloride, or dimethyl slllphoxitle; din~hylro""~"-;de, h~x1",~ lpl-osl~l-nrarnide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use ll~ixlul~s of the solvents mentioned. Dichlol~",~ , dichlol~lhalle, dimeth~lr."..~--itle and n-propanol areparticularly ~ r~..~
Suitable reagents for the epoxidation are the compounds known from the litera~ure, such as, for ~ , m-chlol~l~.~ic acid, m~es;~ monoperoxyrhth~l~t~, dimethyldioxirane or me~yl(trifluolu.~ yl)dioxirane. m-Chlol~.l,e ~ic acid and m~ium "lol~ yphth~l~te are ~ f~-~d [cf. P. Brcn~h~rn et al., Synthesis (1987), 10is; W. Adam et al., J. Org Chem. 52, 2800 (1987) and R Curci et al., J.
Org Chem. ~, 3890 (1988)].
If the epoxidation is carried out with the aid of the phase-~ r~,l ca~alyst, the Le A 30 81~Forei~ WltliCS - 12 -216637~
.
allxili~riesusedare,for~ organic~ ."...;~ c~ sorbromidessuchas,for le, benzyl~ie~hyl~,-"~ ", chloride or br~mide, ltldllylll;octyl~
chloride, t~b.4yl~rn,.,. ";~" bromide or ~ica~ ln~l~ ""-";ll", chloride (Aliquat336). B~yl~ llyl~ k)n~le and bromide are yl~f~
S Ihe ep-)xi-i~ti~ n is carried out in a (~ll4~ , range from -10C to +90C, ple~l~ly from 0C to ~60C.
Ihe r~r.tion.~ can be carried out ei~er at normal pl~UI~ or at elevated or reduced UlC (for ~x~l4,1e 0.5 to 5 bar), ~lc~ldl)ly at normal ~l~U~
lhe compounds of ~e gene~l formula aV) are kno~ and can be lxepal~d, for 10 cX~14J1e~ as described above.
Ihe compounds of the general fc)nn~ e (V) and (VI) are in the main known [c EP 528 242].
Ihe compound of the general fc)" "~ ~) is new and can be ~lC~ d, for example, by flnlnnn~ti~ n of 2-azabicyclo[3.3.0]octane-3~1,u~ylic acid in the l~;ii~e 15 c--nfi~n~tion using HF and SF4.
It has surrri~in~ly been found that the coll4~u,lds of the general fQnmll~ (I) have an ~Allclnely strong action against re~oviruses. Ihis is cc.ll~.,ll~l using an H[V-specific protease enz~ne test.
Ihe results of the examples shown below were ~ "lil~l according to the HlV tcst 20 system ~ in the following litera~ure lcfelcllc~s [cf. Hansen, J., Billich, S., S~1n~17P; T., Sukrow, S. and Molling, K (1988), EMBO Journal, Vol. 7, No. 6, pp.1785 - 1791]: purified HlV p~)tease was in~lb~ted with ~lllllc1ic peptide ~ich ~ a cleavage site in the Gag prec~sor protein and is an in vivo cleavage site ofHIV ~lcase. Ihe r~lllting cleavage products of the synthetic peptide were analysed 25 by means of reverse phase high ~ . ~o" "~l~ce liquid cl.~ graphy (RP-HPLC). Ihe IC50 values indicated relate to the ~ .,ce col~ .~ion w~ich, under the Le A 30 81~Forei~ collntties - 13 -216637~
-abovementioned test cnn-lihnn~, causes a 50% inhibition of ~tease activity.
Fn7~n~ ~,v, ~V-l Table I
HlV-l-p~te~e ir~ibiffon EsampaeNo. IC~ [moVI] IC~5 Imo~]
1 3.2x104 n.t.
2 l.lxlO~ 3.3xlOs 3 1.5 x 10~ 2.5 x 10~
The compounds according to the invention additionally showed action in lentivirus-illr~d cell cult~es. It was possible to show this as exemplified by the HIV virus.
10 HIV infectinn in ~Pll ~llhne The HlV test was carried out wi~ slight modifications accoldillg to the me~od ofPauwels et al. [cf. Journal of ~Irological Methods ~Q, (1988), 309-321].
Normal human blood lymphocytes (PBLs) were enri~ed by means of Ficoll-Hypaque and stim~ te~l in RPM~ 1640 and 20% foetal calf serum with phy~ )h~na~llltinin (90 ~g/ml) and interleul~n-2 (40 U/ml). For infection with the infectious HlV, PBLs were pelleted and the cell pellet was then slle~n~ in 1 ml of H[V virus adsorption solution and in~bat~1 at 37C for 1 hour.
Ihe vin~ adso~ption solution was c~nt~ifil~l and ~e infætecl cell pellet was taken u~
in grow~ m~illm such that a c~ .~ion of 1 x 105 cells per ml was establishe~
20 The cells infsct~ in ~is way were pi~d into ~e wells of 96-well microtitre plates at 1 x 104 cells/well.
Le A 30 814-Forei~ colmtries - 14 -216637~
-Ihe first vertical row of the micl~ plate co.l~;..~ only growth "~in.ll and cells which were not illr~t~d, but had o~e~wise been treated exactly as cles~ih~l above (cell control). Ihe second vertical row of the microtitre plate c~ 1 only HlV-il~d cells (virus c~ol) in grow~h m~lil-m lhe other wells c~ ;..~l t-he S COl~)Ull~JS accol~lg to the invention at di~ t c~ lions, st~rting from the wells of the 3rd vertical row of the microtitre plate, from which the test sul~
were diluted 2' times in steps of 2.
The test bat~hes were in~l~t~ at 37C until, in the ~ltlc~d virus control, the syncytia fo~nation typical of HrV occ~red (b~twæll days 3 and 6 a~er infection),10 which was then microscopically ~ 1 In the ullt~ed virus control about 20 syncytia ~ t;d under these test cnn~litinn~ while the Illltlc~d cell control showed no syncytia Ihe IC50 values were ~ 1 as the cnn~ntration of the treated and infected cells at which 50% (about lO syncytia) of the virus-il-.1u.~1 syncytia were suppressed by 15 the L~ with the compound accol~d.llg to the invention.
It has now been found that the CC~ S acco~lillg to the invention protect H[V-infected cells from virus-inr~ cell des~uction.
T ~ A 30 8l~ForeiQn co1-ntries - lS -2166~ 1 Cell cultl re ~.ees~y, P~3r Table IL
I~B. L
E~ple No. IC50 [molll]
1.08 x lO-~
2 6.12x1~7 3 . 1.2xlO-' The c~ u.ds ~ccoldillg to the invention are useful active compounds in h unan and ~ ,il~y m~ in~ for the l~ and prophylaxis of diso~ produced by retroviruses.
10 E~mrl-e of in-lic-~tion areas in human medicine which can be mentioned are:
1.) Ihe l~ 1 and prophylaxis of human ~ vilus infections.
2.) For the llc;ll",~l1 or prophylaxis of disorders (AIDS) caused by H[V I (human immlml)deficiency virus; earlier called HlLV III/LAV) and HlV II and the stages associated ~ lcwilh such as ARC (AIDS-related complex) and LAS
(lymph~ u p~ly syndrome) as well as the immlm-~deficiency and f~ lopathy caused by this vims.
3.) For the L~ or the ~lo~llylaxis of an HTLV-I or HTLV-II infection.
The compounds according to the invention additionally showed action in lentivirus-illr~d cell cult~es. It was possible to show this as exemplified by the HIV virus.
10 HIV infectinn in ~Pll ~llhne The HlV test was carried out wi~ slight modifications accoldillg to the me~od ofPauwels et al. [cf. Journal of ~Irological Methods ~Q, (1988), 309-321].
Normal human blood lymphocytes (PBLs) were enri~ed by means of Ficoll-Hypaque and stim~ te~l in RPM~ 1640 and 20% foetal calf serum with phy~ )h~na~llltinin (90 ~g/ml) and interleul~n-2 (40 U/ml). For infection with the infectious HlV, PBLs were pelleted and the cell pellet was then slle~n~ in 1 ml of H[V virus adsorption solution and in~bat~1 at 37C for 1 hour.
Ihe vin~ adso~ption solution was c~nt~ifil~l and ~e infætecl cell pellet was taken u~
in grow~ m~illm such that a c~ .~ion of 1 x 105 cells per ml was establishe~
20 The cells infsct~ in ~is way were pi~d into ~e wells of 96-well microtitre plates at 1 x 104 cells/well.
Le A 30 814-Forei~ colmtries - 14 -216637~
-Ihe first vertical row of the micl~ plate co.l~;..~ only growth "~in.ll and cells which were not illr~t~d, but had o~e~wise been treated exactly as cles~ih~l above (cell control). Ihe second vertical row of the microtitre plate c~ 1 only HlV-il~d cells (virus c~ol) in grow~h m~lil-m lhe other wells c~ ;..~l t-he S COl~)Ull~JS accol~lg to the invention at di~ t c~ lions, st~rting from the wells of the 3rd vertical row of the microtitre plate, from which the test sul~
were diluted 2' times in steps of 2.
The test bat~hes were in~l~t~ at 37C until, in the ~ltlc~d virus control, the syncytia fo~nation typical of HrV occ~red (b~twæll days 3 and 6 a~er infection),10 which was then microscopically ~ 1 In the ullt~ed virus control about 20 syncytia ~ t;d under these test cnn~litinn~ while the Illltlc~d cell control showed no syncytia Ihe IC50 values were ~ 1 as the cnn~ntration of the treated and infected cells at which 50% (about lO syncytia) of the virus-il-.1u.~1 syncytia were suppressed by 15 the L~ with the compound accol~d.llg to the invention.
It has now been found that the CC~ S acco~lillg to the invention protect H[V-infected cells from virus-inr~ cell des~uction.
T ~ A 30 8l~ForeiQn co1-ntries - lS -2166~ 1 Cell cultl re ~.ees~y, P~3r Table IL
I~B. L
E~ple No. IC50 [molll]
1.08 x lO-~
2 6.12x1~7 3 . 1.2xlO-' The c~ u.ds ~ccoldillg to the invention are useful active compounds in h unan and ~ ,il~y m~ in~ for the l~ and prophylaxis of diso~ produced by retroviruses.
10 E~mrl-e of in-lic-~tion areas in human medicine which can be mentioned are:
1.) Ihe l~ 1 and prophylaxis of human ~ vilus infections.
2.) For the llc;ll",~l1 or prophylaxis of disorders (AIDS) caused by H[V I (human immlml)deficiency virus; earlier called HlLV III/LAV) and HlV II and the stages associated ~ lcwilh such as ARC (AIDS-related complex) and LAS
(lymph~ u p~ly syndrome) as well as the immlm-~deficiency and f~ lopathy caused by this vims.
3.) For the L~ or the ~lo~llylaxis of an HTLV-I or HTLV-II infection.
4.) For the l~c~ l1 or the prophylaxis of ~e AIDS~rier st~te (Al~S-Lli1...ci.~.i state).
Le A 30 81~Foreig~l col-ntries - 16 --Examples of in-lir~tirn~ in vt~ ~,y ~ e which may be m~ntir,n~rl are:
inf~.til n~ with a) maedi-visna (in sheep and g~ats) b) progressive lJ~r,~ virus (PPV) (in sheep and goats) 5 c) caprine ~llilis ~-,r ~ liti~ virus (in sheep and goats) d) zwoe~7ir~te virus (in sheep) e) infectious ~n~rni~ virus (equine) f) infections caused by feline leukaemia virus g) infections caused by feline immlmn(leficiency virus (~;IV) 10 h) infections caused by simian immlmod~ficiency virus (SIV) From the indication area in human m~irin.? the abovementioned items 2, 3 and 4 are ;r~l~
The present invention inrlu(l~ pl~ r~l.~ical ~le~alalions which, in addition to non-toxic, inertpl~ cally suitable ~ACi~.~ts, contain one or more compounds ofthe 15 formula (I) or which consist of one or more active ~ll~O~Ul~ of the formula (I), and processes for the production of these ~ ~ions.
The active colll~ullJs of the formlll~ (I) should be present in the abovementioned pl.A....~rR~ltical ~lG~ions in a ~..~ n~ion of ap~lox;.~ ely 0.1 to 99.5% by weight, ~lcr~,l~ly of a~ruxill~ly 0.5 to 95% by weight of the total l~clul~.
20 Apart from the compounds of the f~ (I), the abovementioned ph~rm~ltical LeA 30 81~ForeiQn colmhies - 17 -^` 2166374 preparatlons can also contain other pharmaceutlcal actlve compounds .
The abovementloned pharmaceutlcal preparatlons are prepared ln a customary manner by known methods, e.g. by mlxlng the actlve compound(s) wlth the exclplent(s).
The lnventlon also extends to a commerclal package contalnlng a compound of formula-I, together wlth lnstructlons for lts use as an antlretrovlral agent.
In general, lt has proved advantageous both ln human and ln veterlnary medlclne to admlnlster the actlve compound(s) accordlng to the lnventlon ln total amounts of approxlmately 0.5 to approxlmately 500, preferably 1 to 100, mg/kg of body welght every 24 hours, lf approprlate ln the form of several lndlvidual doses, to achleve the deslred results. An lndlvldual dose preferably contalns the actlve compound(s) ln amounts of from approxlmately 1 to approxlmately 80, ln partlcular 1 to 30, mg/kg of body welght. However, lt may be necessary to depart from the doses mentloned, namely dependlng on the type and the body welght of the sub~ect to be treated, the nature and the severlty of the dlsorder, the type of preparatlon and admlnlstratlon of the medlcament, and the perlod or lnterval wlthln whlch admlnlstration takes place.
The compounds accordlng to the lnventlon are enzyme lnhlbltors and can be employed as such for all purposes for whlch enzyme lnhlbltors are utlllzable. ~y wày of example, use as a label for afflnlty chromatG~.a~hy, use as an auxlllary for the elucldatlon of enzyme structures and -reactlon mechanlsms and also use as a reagent for dlagnostlcs can be mentloned here.
18a ~,~
E~ample I
Le A 30 81~Foreig~l col-ntries - 16 --Examples of in-lir~tirn~ in vt~ ~,y ~ e which may be m~ntir,n~rl are:
inf~.til n~ with a) maedi-visna (in sheep and g~ats) b) progressive lJ~r,~ virus (PPV) (in sheep and goats) 5 c) caprine ~llilis ~-,r ~ liti~ virus (in sheep and goats) d) zwoe~7ir~te virus (in sheep) e) infectious ~n~rni~ virus (equine) f) infections caused by feline leukaemia virus g) infections caused by feline immlmn(leficiency virus (~;IV) 10 h) infections caused by simian immlmod~ficiency virus (SIV) From the indication area in human m~irin.? the abovementioned items 2, 3 and 4 are ;r~l~
The present invention inrlu(l~ pl~ r~l.~ical ~le~alalions which, in addition to non-toxic, inertpl~ cally suitable ~ACi~.~ts, contain one or more compounds ofthe 15 formula (I) or which consist of one or more active ~ll~O~Ul~ of the formula (I), and processes for the production of these ~ ~ions.
The active colll~ullJs of the formlll~ (I) should be present in the abovementioned pl.A....~rR~ltical ~lG~ions in a ~..~ n~ion of ap~lox;.~ ely 0.1 to 99.5% by weight, ~lcr~,l~ly of a~ruxill~ly 0.5 to 95% by weight of the total l~clul~.
20 Apart from the compounds of the f~ (I), the abovementioned ph~rm~ltical LeA 30 81~ForeiQn colmhies - 17 -^` 2166374 preparatlons can also contain other pharmaceutlcal actlve compounds .
The abovementloned pharmaceutlcal preparatlons are prepared ln a customary manner by known methods, e.g. by mlxlng the actlve compound(s) wlth the exclplent(s).
The lnventlon also extends to a commerclal package contalnlng a compound of formula-I, together wlth lnstructlons for lts use as an antlretrovlral agent.
In general, lt has proved advantageous both ln human and ln veterlnary medlclne to admlnlster the actlve compound(s) accordlng to the lnventlon ln total amounts of approxlmately 0.5 to approxlmately 500, preferably 1 to 100, mg/kg of body welght every 24 hours, lf approprlate ln the form of several lndlvidual doses, to achleve the deslred results. An lndlvldual dose preferably contalns the actlve compound(s) ln amounts of from approxlmately 1 to approxlmately 80, ln partlcular 1 to 30, mg/kg of body welght. However, lt may be necessary to depart from the doses mentloned, namely dependlng on the type and the body welght of the sub~ect to be treated, the nature and the severlty of the dlsorder, the type of preparatlon and admlnlstratlon of the medlcament, and the perlod or lnterval wlthln whlch admlnlstration takes place.
The compounds accordlng to the lnventlon are enzyme lnhlbltors and can be employed as such for all purposes for whlch enzyme lnhlbltors are utlllzable. ~y wày of example, use as a label for afflnlty chromatG~.a~hy, use as an auxlllary for the elucldatlon of enzyme structures and -reactlon mechanlsms and also use as a reagent for dlagnostlcs can be mentloned here.
18a ~,~
E~ample I
6,7-Dirnethyl-2-[l}arabo-t~ y-butyl]quinoxaline N~CH3 HO-HC~N~--CH3 HC-OH
HC-OH
2.0 g (5.58 mmol) of ~fructose phenylo~ ."ç (l~le~ acc(~l~ing to C.L. Butler, J.A~ Chem. Soc. 51, 1929, 3163) are suspended in 12 ml of water, 12 ml of ethanol and 1.4 ml of conc. hydrochloric acid~ w~lll~d to 45C and ~eated dropwise with a solution of 0.8 g (11.2 mmol) of NaNO2 in 2.5 ml of water. A dar~-red, clear solution is obtained, which is buffered at room I~ re with sodium a(`~ate Everything is ~;x~d by stirring with 15 ml of ethyl acetate, the darl~-red organic phase is separated off, and the yellow, aqueous phase is u n~ .~d son~wl~ andtreatedwith 0.5 g (3.67 mmol) of 4~s~imethylphenyl~n~ minç Ihe mi~e is heated on a boiling water bath for 20 ~ s and the yellow p~æipi~e is then filtered off. It is subse~ ntly washed by stirring in some ~ ol, filtered again and dried.
Yield: 0.3 g (29.4% of theory) of yellow crystals Mp.: 190C (dec.) TLC: Rf (sllbst~nr~ is very poorly soluble) = 0.4 (dichlor~ : m~t~nol = 9:1) Le A 30 81~ForeiPn collntries - 19 -. --E~e 11 6,7-Dimethylquinoxaline-2~1,u~lic acid ,~N~CH3 0.3 g (1.08 mmol) of the co~ d from E~ul~le I are sll~n~ l in 10 ml of 10%
streng~ H2O2 solution. Ihe ll~ is tre~ed with 0.6 g (15 mmol) of NaOH (solid) 5 with stin in~ During the course of this f~tnir~ is observed A~er stirring for about one hour, a clear solution is ol)ti~l~d On acidifying with conc. hydrochloric acid, a colourless ~leci~ iS de~osit~d It is filtered, washed with water and dri-ed.
Yleld: 160 mg (73.3% of theory) of colourless aystals Mp.: 203C (dec.) TLC: Rf = 0.5 (dichlo~ h~n~Jglacial acetic acid/.~,~h~ 1 = 90:10:2) Examp~e m (S,S,S}3-Trifluolol~ lyl-2-a~abicyclo[3.3.0]octane H ~ H
HN
55 g (0.355 mmol) of (S,S,S~2-azabicyclo[3.3.0]octane-3 carboxy1ic acid are flllol;lli11~1 using HF and SF4. The dark-brown, ~lk~line sus~ension (about 200 ml) is 15 filtered, c~ . ~ed to about 50 rnl in vacuo and ~ ~d three times with 50 ml of dichl~ h~-e. The organic phase is dried, ccn~ ~ed to a small volume in vacuo (dark-brown oil) and se~ed by column ~ r~ll~ography (silica gel 60, dichlol~ h~ 3.
T ~ A 30 81~Forei~ coun~ies - 20 -. ~
Yleld: 28.8 g (45.3% of ~eory) of slightly l~l~ wl~i~ll oil Mp.: around 0C, GC: 99/O
Rf= 0.4 (dichlo~ lh~
E~a~e IV
5 (2R,3S)-3-(N-Benzyloxycarbonyl)amino-l-{(S,S,S)-3-trifluoromethyl-2-æabicyclo[3 .3 .O]octan-2-yl}-2-hydroxy~phenylbutane ,~1 [~f H OH g~
0.3 g (1 mmol) of (2R}[l{N-benzyloxycaIbonyl)amino-2-phenyl{lS}e~yl]oxirane and 0.15 g (0.84 mmol) of the compound from E~14,1c m are dissolved in 2 ml of 2-propanol and stirred for 12 h in a closed vessel in an oil bath heated to 130C. A~er 10 cooling, the coTlt~nt~ are c~ ~d to a small volume and sep~ i by column cl~ ~ography (silica gel 60, toluene/e~yl acetate 100:5).
Yleld: 72 mg (18% of theory) of colourless foam Rf = 0.2 (toluene/ethyl acetate = 100:5) LeA 30 81~Forei~n colmtries - 21 -2166~74 - E~ e v (2R,3S)-3-Amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy~phenylbutane ~, H2N ~
112 mg (0.235 mmol) of the c~ ld from E~ l1~)1E IV are dissolved in 15 ml of 5 ,.,~ "o~ (1:1), treated with some Pd/C (10% strength) and hydro~n~t~ at room lel~ re for two hours. After filt~ing off the catalyst and evaporating ~e solvent, a slightly yellow oil is ol)t~
Yleld: 80 mg (~ e) Rf = 0.6 (dichlol~,lll~h~ m~th~nol = 100:5) lo ~ e VI
(2R,3S)-3~ Benzyloxycarbonyl-l,æparaginyl)amino-l-t(S,S,S)-3-trifluo~ tllyl-2-azabicyclo[3 .3 .O]octan-2-yl}-2-hydroxy~phenylbutane N~
O =<~ CF3 0.074 g (0.28 mmol) of Z~Asn-OH and 0.038 g (0.28 mmol) of HOBT
~ydroxyl~ i~le) are dissolved in S ml of DMF under an argon ~tnnn~ e, Le A 30 814-Forei~ colmtries - 22 -,, cooled to 0C in an ice bath and tre~ed with 0.119 g (0.28 mmol) of morpho~DI
with stirnn~ The nlixLu-e is stirred at 0C for 3 hours and then trea~ed with 0.08 g (0.234 mmol) of the cllq~~ from F~ )le V, dissolved in 3 ml of DMF. The lrll~ is allowed to rise to RT and s~iITing is col~ ud overnight. A~er ~ itiQn S of water, a colo lrl~ ~l~ipit~ is o~ 1 It is filtered, washed with water and dried Yleld: 87 mg (63.0% of the~y) of cQlollrl~ crystals Mp.: 162C
HPLC: 97.53%
~e Vll (2R,3S}3{L,~ginyl)arnino-1-7(S,S,S~3-trifluo~ eth~1-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy~phenylbutane I ,~H~
,~ H OH H
~< CF3 0.008 g (0.135 mmol) of the com~ound from Exan~le VI are dissolved in 10 ml of m~t~nol/rHF (1:1), treated with some Pd/C (10% streng~) and hydr~t~l at RT
for 2 hours. A~er filt~ring off the catalyst and ~V~l~illg the solvent in vacuo, a 15 colourless oil is obtained.
Yleld: 58 mg (95% of theay) Rf = 0.2 (dichlol~ oJ.,.~ ()l = 100:5) (spraying with ninhydrin) Le A 30 81~Fore~ cQllntlies - 23 -216637~
Eka~e VII~
(2R,3S)-3-(Quinoxalin-2-yl-L-asparaginyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-~;~;y~,1O[3.3.0]octan-2-yl}-2-lly~ r~phenylbutane ~CO--NHyCO--NH~N~?H
0.095 g (6.7 mmol) of HOBT and 0.071 g (0.7 mmol) of triethylamine are dissolved5 in 2 ml of DMF under an argon ~tmos~hPre, cooled to 40C and treated dropwise with stirring with 0.14 g (0.7 mmol) of ~ n~Y~linP-2 carbonyl chloride in 3 ml of DMF. Ihe ll~~ is allowed to react in an ice ba~ for 2 hours and is ~en treated with 0.3 g (0.657 mmol) of ~e co~ ld from Ex~ul4,1~ VII. Ihe n~ixlul~, is s~red ovP~night the t~ re rising to room tell4~1re. Ihe desired product is ~en 10 ~ d wi~ water and purified by column cl~ll~ography (silica gel 60, eluent:
dichlolc,~ m~th~nol = 100:5).
Yleld: 130 mg (~ 32.3% of ~eory) of colourless foam Rf = 0.5 (dichlorom~th~nP~ h~u)l = 100:5) ~mple 1~
(2R,3S)-3-(Quinolin-2-yl-L-asparaginyl)amino-1-[(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.O]octan-2-yl}-2-lly~ y~phenylbutane Le A 30 814-Forei~n collntties - 24 -- 216637~
. ~
~CO--NH CO--NH~
OH
Oq~ CF3 0.014 g (0.08 mol) of ~1in~lin~-2-carboxylic acid and 0.011 g (0.08 mmol) of HOBT
are dissolved in S ml of DMF under argon, cooled to 0C in an ice bath and ~eated with 0.034 g (0.08 mol) of m~h~CDI. Mer stirring at 0C for 3 hours, 0.03 g (0.657 mol) of the compound from Example VII, dissolved in 1 ml of DMF, are added 5 and the nl,xlule is stirred ovemight, the te~ re rising to room tel~ re. The desired product is then ~ il~d by addition of water, filtered, dried and purified by .i~ion with m~th~n~ l and diisopropyl edler.
Yleld: 270 mg (67.2% of theory) of colourless glass Rf = 0.5 (dichlo~ "~h~ -A~ 01 = 100:5) 10 In analogy to the above ~ l~., the following new pseudo~Aides ~)lllsl;"i,-g a ~ifluol~ lbsti~ 1 2-azabicyclooctane are ~le~ed, Table I:
T ~ A 30 814-Fore~ countries - 25 -216~37 l ~ o~
Z ~o ~Z p~ ~ o O
p~ I I
T e A 30 81~For~iQn co~ 26 -epalaffon E~cs Esample 1 (2R,3S)-3-(Quinolin-2-yl-L-asparaginyl)-amino-1-[(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.O]octan-2-yl}-2~3-ethoxyc~bu~ l)propionyl~phenylbutane ~ ' [~CO--NH~CO NH~N~H
- ~G CF3 0~
0.6 g (0.981 mmol) of the c~ d from Exa~ 1e IX is stilred ovemight at room , with 0.4 g (3.93 mmol A 0.54 ml) of triethylamine (d = 0.73), 0.32 g (1.96 mmol ^ 0.278 ml) of ethyl succinyl chloride (d - 1.15) and 0.6 g (4.92 mmol) of dimethylaminopyridine (~)MAP) in 15 ml of dried THF under argon. The ll~ixlule is treated with water, the yl~iyi~ is s~,yi~ 1 off, washed with water and dissolved in 10 toluene, and the solution is dried and c~ .~d.
Yleld: 0.58 g (~ 80% of theory) of colourless crystals Mp.: 138C
Rf ~ 0.6 (dichlo~ h~ ",~ ;..,ol = 100:5) HPLC: 92.5%
15 recryst~lli7P~l from dichlolv".~lw-~diiso~opyl ether => HPLC: 94.2%
In analogy to the procedure of Exa,l4:1~ 1, the compounds shown in Table 1 are ~r~a~
T ~ A 30 81~Forei~n countries - 27 -~_ 216637~
Table 1:
H~
R'--CO--NH~s~CO NH~-- ~H
oq~r C 3 E~ Rl 1~ Mp.(C~/Rf**Yield No. (% of ~o~y) 2 -C~CH3 colourless 93.6 I foam ~ ~N~ ~ 0.7*
3 H,C N~ -C~CH3 colourless 93.9 ~ ~ , ~ foam H,C~ ~V ~N~ 0.3*
4 ~ -C~C(CH3)3 colourless 26.5 0.5*
,~ -CO (CH2h-CH3 colourless 89 W~N1 0.5**
6 ~ -C~CH(CH3)2 colourless 89 I foam ~ ~N~ ~ 0.5**
HC-OH
2.0 g (5.58 mmol) of ~fructose phenylo~ ."ç (l~le~ acc(~l~ing to C.L. Butler, J.A~ Chem. Soc. 51, 1929, 3163) are suspended in 12 ml of water, 12 ml of ethanol and 1.4 ml of conc. hydrochloric acid~ w~lll~d to 45C and ~eated dropwise with a solution of 0.8 g (11.2 mmol) of NaNO2 in 2.5 ml of water. A dar~-red, clear solution is obtained, which is buffered at room I~ re with sodium a(`~ate Everything is ~;x~d by stirring with 15 ml of ethyl acetate, the darl~-red organic phase is separated off, and the yellow, aqueous phase is u n~ .~d son~wl~ andtreatedwith 0.5 g (3.67 mmol) of 4~s~imethylphenyl~n~ minç Ihe mi~e is heated on a boiling water bath for 20 ~ s and the yellow p~æipi~e is then filtered off. It is subse~ ntly washed by stirring in some ~ ol, filtered again and dried.
Yield: 0.3 g (29.4% of theory) of yellow crystals Mp.: 190C (dec.) TLC: Rf (sllbst~nr~ is very poorly soluble) = 0.4 (dichlor~ : m~t~nol = 9:1) Le A 30 81~ForeiPn collntries - 19 -. --E~e 11 6,7-Dimethylquinoxaline-2~1,u~lic acid ,~N~CH3 0.3 g (1.08 mmol) of the co~ d from E~ul~le I are sll~n~ l in 10 ml of 10%
streng~ H2O2 solution. Ihe ll~ is tre~ed with 0.6 g (15 mmol) of NaOH (solid) 5 with stin in~ During the course of this f~tnir~ is observed A~er stirring for about one hour, a clear solution is ol)ti~l~d On acidifying with conc. hydrochloric acid, a colourless ~leci~ iS de~osit~d It is filtered, washed with water and dri-ed.
Yleld: 160 mg (73.3% of theory) of colourless aystals Mp.: 203C (dec.) TLC: Rf = 0.5 (dichlo~ h~n~Jglacial acetic acid/.~,~h~ 1 = 90:10:2) Examp~e m (S,S,S}3-Trifluolol~ lyl-2-a~abicyclo[3.3.0]octane H ~ H
HN
55 g (0.355 mmol) of (S,S,S~2-azabicyclo[3.3.0]octane-3 carboxy1ic acid are flllol;lli11~1 using HF and SF4. The dark-brown, ~lk~line sus~ension (about 200 ml) is 15 filtered, c~ . ~ed to about 50 rnl in vacuo and ~ ~d three times with 50 ml of dichl~ h~-e. The organic phase is dried, ccn~ ~ed to a small volume in vacuo (dark-brown oil) and se~ed by column ~ r~ll~ography (silica gel 60, dichlol~ h~ 3.
T ~ A 30 81~Forei~ coun~ies - 20 -. ~
Yleld: 28.8 g (45.3% of ~eory) of slightly l~l~ wl~i~ll oil Mp.: around 0C, GC: 99/O
Rf= 0.4 (dichlo~ lh~
E~a~e IV
5 (2R,3S)-3-(N-Benzyloxycarbonyl)amino-l-{(S,S,S)-3-trifluoromethyl-2-æabicyclo[3 .3 .O]octan-2-yl}-2-hydroxy~phenylbutane ,~1 [~f H OH g~
0.3 g (1 mmol) of (2R}[l{N-benzyloxycaIbonyl)amino-2-phenyl{lS}e~yl]oxirane and 0.15 g (0.84 mmol) of the compound from E~14,1c m are dissolved in 2 ml of 2-propanol and stirred for 12 h in a closed vessel in an oil bath heated to 130C. A~er 10 cooling, the coTlt~nt~ are c~ ~d to a small volume and sep~ i by column cl~ ~ography (silica gel 60, toluene/e~yl acetate 100:5).
Yleld: 72 mg (18% of theory) of colourless foam Rf = 0.2 (toluene/ethyl acetate = 100:5) LeA 30 81~Forei~n colmtries - 21 -2166~74 - E~ e v (2R,3S)-3-Amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy~phenylbutane ~, H2N ~
112 mg (0.235 mmol) of the c~ ld from E~ l1~)1E IV are dissolved in 15 ml of 5 ,.,~ "o~ (1:1), treated with some Pd/C (10% strength) and hydro~n~t~ at room lel~ re for two hours. After filt~ing off the catalyst and evaporating ~e solvent, a slightly yellow oil is ol)t~
Yleld: 80 mg (~ e) Rf = 0.6 (dichlol~,lll~h~ m~th~nol = 100:5) lo ~ e VI
(2R,3S)-3~ Benzyloxycarbonyl-l,æparaginyl)amino-l-t(S,S,S)-3-trifluo~ tllyl-2-azabicyclo[3 .3 .O]octan-2-yl}-2-hydroxy~phenylbutane N~
O =<~ CF3 0.074 g (0.28 mmol) of Z~Asn-OH and 0.038 g (0.28 mmol) of HOBT
~ydroxyl~ i~le) are dissolved in S ml of DMF under an argon ~tnnn~ e, Le A 30 814-Forei~ colmtries - 22 -,, cooled to 0C in an ice bath and tre~ed with 0.119 g (0.28 mmol) of morpho~DI
with stirnn~ The nlixLu-e is stirred at 0C for 3 hours and then trea~ed with 0.08 g (0.234 mmol) of the cllq~~ from F~ )le V, dissolved in 3 ml of DMF. The lrll~ is allowed to rise to RT and s~iITing is col~ ud overnight. A~er ~ itiQn S of water, a colo lrl~ ~l~ipit~ is o~ 1 It is filtered, washed with water and dried Yleld: 87 mg (63.0% of the~y) of cQlollrl~ crystals Mp.: 162C
HPLC: 97.53%
~e Vll (2R,3S}3{L,~ginyl)arnino-1-7(S,S,S~3-trifluo~ eth~1-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy~phenylbutane I ,~H~
,~ H OH H
~< CF3 0.008 g (0.135 mmol) of the com~ound from Exan~le VI are dissolved in 10 ml of m~t~nol/rHF (1:1), treated with some Pd/C (10% streng~) and hydr~t~l at RT
for 2 hours. A~er filt~ring off the catalyst and ~V~l~illg the solvent in vacuo, a 15 colourless oil is obtained.
Yleld: 58 mg (95% of theay) Rf = 0.2 (dichlol~ oJ.,.~ ()l = 100:5) (spraying with ninhydrin) Le A 30 81~Fore~ cQllntlies - 23 -216637~
Eka~e VII~
(2R,3S)-3-(Quinoxalin-2-yl-L-asparaginyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-~;~;y~,1O[3.3.0]octan-2-yl}-2-lly~ r~phenylbutane ~CO--NHyCO--NH~N~?H
0.095 g (6.7 mmol) of HOBT and 0.071 g (0.7 mmol) of triethylamine are dissolved5 in 2 ml of DMF under an argon ~tmos~hPre, cooled to 40C and treated dropwise with stirring with 0.14 g (0.7 mmol) of ~ n~Y~linP-2 carbonyl chloride in 3 ml of DMF. Ihe ll~~ is allowed to react in an ice ba~ for 2 hours and is ~en treated with 0.3 g (0.657 mmol) of ~e co~ ld from Ex~ul4,1~ VII. Ihe n~ixlul~, is s~red ovP~night the t~ re rising to room tell4~1re. Ihe desired product is ~en 10 ~ d wi~ water and purified by column cl~ll~ography (silica gel 60, eluent:
dichlolc,~ m~th~nol = 100:5).
Yleld: 130 mg (~ 32.3% of ~eory) of colourless foam Rf = 0.5 (dichlorom~th~nP~ h~u)l = 100:5) ~mple 1~
(2R,3S)-3-(Quinolin-2-yl-L-asparaginyl)amino-1-[(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.O]octan-2-yl}-2-lly~ y~phenylbutane Le A 30 814-Forei~n collntties - 24 -- 216637~
. ~
~CO--NH CO--NH~
OH
Oq~ CF3 0.014 g (0.08 mol) of ~1in~lin~-2-carboxylic acid and 0.011 g (0.08 mmol) of HOBT
are dissolved in S ml of DMF under argon, cooled to 0C in an ice bath and ~eated with 0.034 g (0.08 mol) of m~h~CDI. Mer stirring at 0C for 3 hours, 0.03 g (0.657 mol) of the compound from Example VII, dissolved in 1 ml of DMF, are added 5 and the nl,xlule is stirred ovemight, the te~ re rising to room tel~ re. The desired product is then ~ il~d by addition of water, filtered, dried and purified by .i~ion with m~th~n~ l and diisopropyl edler.
Yleld: 270 mg (67.2% of theory) of colourless glass Rf = 0.5 (dichlo~ "~h~ -A~ 01 = 100:5) 10 In analogy to the above ~ l~., the following new pseudo~Aides ~)lllsl;"i,-g a ~ifluol~ lbsti~ 1 2-azabicyclooctane are ~le~ed, Table I:
T ~ A 30 814-Fore~ countries - 25 -216~37 l ~ o~
Z ~o ~Z p~ ~ o O
p~ I I
T e A 30 81~For~iQn co~ 26 -epalaffon E~cs Esample 1 (2R,3S)-3-(Quinolin-2-yl-L-asparaginyl)-amino-1-[(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.O]octan-2-yl}-2~3-ethoxyc~bu~ l)propionyl~phenylbutane ~ ' [~CO--NH~CO NH~N~H
- ~G CF3 0~
0.6 g (0.981 mmol) of the c~ d from Exa~ 1e IX is stilred ovemight at room , with 0.4 g (3.93 mmol A 0.54 ml) of triethylamine (d = 0.73), 0.32 g (1.96 mmol ^ 0.278 ml) of ethyl succinyl chloride (d - 1.15) and 0.6 g (4.92 mmol) of dimethylaminopyridine (~)MAP) in 15 ml of dried THF under argon. The ll~ixlule is treated with water, the yl~iyi~ is s~,yi~ 1 off, washed with water and dissolved in 10 toluene, and the solution is dried and c~ .~d.
Yleld: 0.58 g (~ 80% of theory) of colourless crystals Mp.: 138C
Rf ~ 0.6 (dichlo~ h~ ",~ ;..,ol = 100:5) HPLC: 92.5%
15 recryst~lli7P~l from dichlolv".~lw-~diiso~opyl ether => HPLC: 94.2%
In analogy to the procedure of Exa,l4:1~ 1, the compounds shown in Table 1 are ~r~a~
T ~ A 30 81~Forei~n countries - 27 -~_ 216637~
Table 1:
H~
R'--CO--NH~s~CO NH~-- ~H
oq~r C 3 E~ Rl 1~ Mp.(C~/Rf**Yield No. (% of ~o~y) 2 -C~CH3 colourless 93.6 I foam ~ ~N~ ~ 0.7*
3 H,C N~ -C~CH3 colourless 93.9 ~ ~ , ~ foam H,C~ ~V ~N~ 0.3*
4 ~ -C~C(CH3)3 colourless 26.5 0.5*
,~ -CO (CH2h-CH3 colourless 89 W~N1 0.5**
6 ~ -C~CH(CH3)2 colourless 89 I foam ~ ~N~ ~ 0.5**
7 ,~ -C~(CH2)l4CH3 colourless 79 ~Nl 0.5**
8 ,~ -C~ yl colourless 25 I I - foam ~ ~N~ 0.6**
* (dichlo~ .Pl~ .ol= 100:4) ** dichloro~ P~e~yl a~e= 1:
T ~ A 30 814-Forei,~ c~lntlies - 28 -
* (dichlo~ .Pl~ .ol= 100:4) ** dichloro~ P~e~yl a~e= 1:
T ~ A 30 814-Forei,~ c~lntlies - 28 -
Claims (21)
1. A pseudopeptide containing a trifluoromethyl-substituted 2-azabilcyclooctane, of the general formula (I) (I) in which R1 represents a radical of the formula or wherein A, D, E, L and T are identical or different and denote hydrogen, halogen, straight-chain or branched alkyl having up to 4 carbon atoms, morpholinyl, phenylthio or cycloalkyl having 3 to 6 carbon atoms, R represents straight-chain or branched acyl having up to 20 carbon atoms, whlch 18 optlonally substltuted by carboxyl, by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, represents a radical of the formula -CO-NR5R6 or P(O)(OR7)(OR8), wherein R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched alkoxy having up to 6 carbon atoms, which is optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or represents a radical of the formula , , or or a salt thereof.
2. A compound of the general formula (I), according to Claim 1 in which R1 represents a radical of the formula or wherein A, D, E, L and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, straight-chain or branched alkyl having up to 3 carbon atoms, morpholinyl, phenylthio, cyclopentyl or cyclohexyl, R2 represents straight-chain or branched acyl having up to 17 carbon atoms, which is optionally substituted by carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, represents a radical of the formula -CO-NR5R6 or P(O)(OR7)(OR8), wherein R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, R7 and R8 are identical and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or represents straight-chain or branched alkoxy having up to 4 carbon atoms, which is optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or represents a radical of the formula or or a salt thereof.
3. A compound of the general formula (I) according to Claim 1 in which R1 represents a radical of the formula or wherein A, D, E, L and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, methyl, phenylthio, cycopentyl or cyclohexyl, R2 represents straight-chain or branched acyl having up to 15 carbon atoms, which is optionally substituted by carboxyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, represents a radical of the formula -CO-NR5R6 or P(O)(OR7)(OR8), wherein R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, R7 and R8 are identical or different and denote hydrogen, methyl or ethyl, or represents straight-chain or branched alkoxy having up to 3 carbon atoms, which is optionally substituted by difluoromethyl, difluoromehtoxy, trifluoromethoxy or trlfluoromethyl, or represents a radical of the formula , , or or a salt thereof.
4. A compound of the general formula (I), according to claim 1 in which R1 represents OR and R2 represents -CO-CH3, -CO-C(CH3)3, -CO-(CH2)2-CH3, -CO-CH(CH3)2, -CO-(CH2)14CH3 or -CO-adamantyl or a salt thereof.
5. A process for the preparation of a compound of the general formula (I) according to Claim 1, characterized in that first a carboxylic acid of the general formula (II) R1-CO2-H (II) in which R1 has the meaning indicated in Claim 1, is converted by reaction with a compound of the formula (III) (III) into a compound of the general formula (IV) (IV) in which R1 has the meaning indicated in Claim 1, and in a second step an acylation is carried out.
6. A process for the preparation of a compound of the general formula (I) according to Claim 2, characterized in that first a carboxylic acid of the general formula (II) R1-CO2-H (II) in which R1 has the meaning indicated in Claim 2, is converted by reaction with a compound of the formula (III) (III) into a compound of the general formula (IV) (IV) in which R1 has the meaning indicated in Claim 2, and in a second step an acylation is carried out.
7. A process for the preparation of a compound of the general formula (I) according to Claim 3, characterized in that first a carboxylic acid of the general formula (II) R1-CO2-H (II) in which R1 has the meaning indicated in Claim 3, is converted by reaction with a compound of the formula (III) (III) into a compound of the general formula (IV) (IV) in which R1 has the meaning indicated in Claim 3, and in a second step an acylation is carried out.
8. A process for the preparation of a compound of the general formula (I) according to Claim 4, chsracterized in that first a carboxylic acid of the general formula (II) R1-CO2-H (II) in which R1 has the meaning indicated in Claim 4, is converted by reaction with a compound of the formula (III) (III) into a compound of the general formula (IV) (IV) in which R1 has the meaning indicated in Claim 4, and in a second step an acylation is carried out.
9. A compound of the general formula in which R1 represents OR
and R2 represents -CO-CH3, -CO-C(CH3)3, -CO-(CH2)2-CH3, -CO-CH(CH3)2, -CO-(CH2)14CH3 or -CO-adamantyl or a salt thereof.
and R2 represents -CO-CH3, -CO-C(CH3)3, -CO-(CH2)2-CH3, -CO-CH(CH3)2, -CO-(CH2)14CH3 or -CO-adamantyl or a salt thereof.
10. A compound of the general formula in which R1 represents and R2 represents -CO-CH3.
11. A use of a compound of the general formula I as defined in Claim 1, 2, 3, 4, 9 or 10, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of a disorder caused by a human immunodeficiency virus, a lymphadenopathy syndrome or an immunodeficiency or an encephalopathy caused by a human immunodeficiency virus.
12. A use of a compound of the general formula as defined in claim 1, 2, 3, 4, 9 or 10, or a pharmaceutically acceptable salt thereof, for the treatment or the prophylaxis of an HTLV-I or HTLV-II infection.
13. A use of a compound of the general formula as defined in claim 1, 2, 3, 4, 9 or 10, or a pharmaceutically acceptable salt thereof, for the treatment or the prophylaxis of an AIDS-carrier state.
14. A use of a compound of the general formula as defined in claim 1, 2, 3, 4, 9 or 10, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of human retrovirus infections.
15. A use of a compound of the general formula I as defined in Claim 1, 2, 3, 4, 9 or 10, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of maedi-visna in sheep or goats, progressive pneumonia virus in sheep or goats, caprine arthritis encephalitis virus in sheep or goats, zwoegerziekte virus in sheep, infectious anaemia virus in an equine animal, an infection caused by feline leukaemia virus, an infection caused by feline immunodeficiency virus or an infection caused by simian immunodeficiency virus.
16. A commercial package containing a compound of the general formula I as defined in Claim 1, 2, 3, 4, 9 or 10, or a pharmaceutically acceptable salt thereof, together with instructions for the use thereof for the treatment or prophylaxis of a disorder caused by human immunodeficiency virus, a lymphadenopathy syndrome or an immunodeficiency or an encephalopathy caused by a human immunodeficiency virus, the treatment or the prophylaxis of an HTLV-I or HTLV-II
infection or the treatment or the prophylaxis of the AIDS-carrier state.
infection or the treatment or the prophylaxis of the AIDS-carrier state.
17. A pharmaceutical composition comprising a compound as defined in Claim 1, 2, 3, 4, 9 or 10, together with a suitable diluent or carrier, for the treatment or prophylaxis of disorders caused by the human immunodeficiency virus.
18. A process according to Claim 5, 6, 7 or 8 wherein the second step acylation is carried out by treatment with an acid, acid anhydride, or acid chloride of the general formula OR
in which R2 has the meaning indicated in Claim 1.
in which R2 has the meaning indicated in Claim 1.
19. A process according to Claim 5, 6, 7 or 8 wherein the second step acylation is carried out by treatment with an acid, acid anhydride, or acid chloride of the general formula , OR in which R2 has the meaning indicated in Claim 2.
20. A process according to Claim 5, 6, 7 or 8 wherein the second step acylation is carried out by treatment with an acid, acid anhydride, or acid chloride of the general formula , OR in which R2 has the meaning indicated in Claim 3.
21. A process according to Claim 5, 6, 7 or 8 wherein the second step acylation is carried out by treatment with an acid, acid anhydride, or acid chloride of the general formula , OR
in which R2 has the meaning indicated in Claim 4.
in which R2 has the meaning indicated in Claim 4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19500120A DE19500120A1 (en) | 1995-01-04 | 1995-01-04 | New acylated pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane |
| DE19500120.6 | 1995-01-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2166374A1 true CA2166374A1 (en) | 1996-07-05 |
Family
ID=7750986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002166374A Abandoned CA2166374A1 (en) | 1995-01-04 | 1995-12-29 | Acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0720987A1 (en) |
| JP (1) | JPH08259594A (en) |
| KR (1) | KR960029345A (en) |
| CN (1) | CN1134940A (en) |
| AU (1) | AU4067895A (en) |
| CA (1) | CA2166374A1 (en) |
| CZ (1) | CZ1296A3 (en) |
| DE (1) | DE19500120A1 (en) |
| FI (1) | FI960015A (en) |
| HU (1) | HUT74805A (en) |
| IL (1) | IL116622A0 (en) |
| NO (1) | NO960016L (en) |
| NZ (1) | NZ280729A (en) |
| PL (1) | PL312146A1 (en) |
| SK (1) | SK1296A3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8138146B2 (en) | 2006-02-28 | 2012-03-20 | Toagosei Co., Ltd | Antiviral peptide and antiviral agent |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20001420A1 (en) * | 1998-12-23 | 2000-12-18 | Pfizer | CCR5 MODULATORS |
| US6448245B1 (en) | 2000-05-04 | 2002-09-10 | The United States Of America As Represented By The Department Of Health And Human Services | Methods of and compounds for inhibiting calpains |
| CA2547518A1 (en) | 2003-12-12 | 2005-06-30 | Wyeth | Quinolines useful in treating cardiovascular disease |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1408675A (en) | 1973-03-16 | 1975-10-01 | Allen & Hanburys Ltd | Amides derived from quinoxaline |
| CA1340588C (en) * | 1988-06-13 | 1999-06-08 | Balraj Krishan Handa | Amino acid derivatives |
| DE4126485A1 (en) | 1991-08-10 | 1993-02-11 | Bayer Ag | TRIFLUOROMETHYL-CONTAINING PSEUDOPEPTIDE |
| TW372972B (en) | 1992-10-23 | 1999-11-01 | Novartis Ag | Antiretroviral acyl compounds |
-
1995
- 1995-01-04 DE DE19500120A patent/DE19500120A1/en not_active Withdrawn
- 1995-01-04 SK SK12-96A patent/SK1296A3/en unknown
- 1995-12-21 NZ NZ280729A patent/NZ280729A/en unknown
- 1995-12-22 EP EP95120369A patent/EP0720987A1/en not_active Withdrawn
- 1995-12-27 JP JP7351205A patent/JPH08259594A/en active Pending
- 1995-12-28 AU AU40678/95A patent/AU4067895A/en not_active Abandoned
- 1995-12-29 CA CA002166374A patent/CA2166374A1/en not_active Abandoned
- 1995-12-29 IL IL11662295A patent/IL116622A0/en unknown
- 1995-12-29 HU HU9503927A patent/HUT74805A/en unknown
-
1996
- 1996-01-02 PL PL96312146A patent/PL312146A1/en unknown
- 1996-01-02 FI FI960015A patent/FI960015A/en unknown
- 1996-01-03 KR KR1019960000008A patent/KR960029345A/en not_active Application Discontinuation
- 1996-01-03 CZ CZ9612A patent/CZ1296A3/en unknown
- 1996-01-03 NO NO960016A patent/NO960016L/en unknown
- 1996-01-04 CN CN96100927A patent/CN1134940A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8138146B2 (en) | 2006-02-28 | 2012-03-20 | Toagosei Co., Ltd | Antiviral peptide and antiviral agent |
Also Published As
| Publication number | Publication date |
|---|---|
| FI960015A (en) | 1996-07-05 |
| EP0720987A1 (en) | 1996-07-10 |
| PL312146A1 (en) | 1996-07-08 |
| NO960016D0 (en) | 1996-01-03 |
| IL116622A0 (en) | 1996-03-31 |
| KR960029345A (en) | 1996-08-17 |
| HUT74805A (en) | 1997-02-28 |
| HU9503927D0 (en) | 1996-03-28 |
| CN1134940A (en) | 1996-11-06 |
| AU4067895A (en) | 1996-07-11 |
| CZ1296A3 (en) | 1997-05-14 |
| FI960015A0 (en) | 1996-01-02 |
| SK1296A3 (en) | 1996-08-07 |
| NO960016L (en) | 1996-07-05 |
| DE19500120A1 (en) | 1996-07-11 |
| NZ280729A (en) | 1996-08-27 |
| JPH08259594A (en) | 1996-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2002303929B9 (en) | Cytotoxins, prodrugs, linkers and stabilizers useful therefor | |
| EP0810208B1 (en) | N-substituted Hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors | |
| US6403585B1 (en) | α-and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors | |
| CA2263198A1 (en) | Novel acetamide derivatives and protease inhibitors | |
| CN101133060A (en) | Enzyme inhibitors | |
| CA2143191A1 (en) | Sulfonylalkanoylamino hydroxyethylamino sulfamic acids useful as retroviral protease inhibitors | |
| SK279706B6 (en) | Hydrazine derivatives, pharmaceutical compositions them containing, their use, methods of their preparation, as well as intermediates for their preparation | |
| JPH07258287A (en) | Antithrombotic agent | |
| CA2092414A1 (en) | N-(2-alkyl-3-mercaptoglutaryl)-amino-diaza cycloalkanone derivatives and their use as collagenase inhibitors | |
| CA2098165A1 (en) | Inhibitors of hiv protease useful for the treatment of aids | |
| US20040024000A1 (en) | Dihydropyrimidine derivatives as cysteine protease inhibitors | |
| CA2166374A1 (en) | Acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane | |
| US6184241B1 (en) | Aspartic protease inhibitors | |
| US5281717A (en) | Epoxysuccinamic acid derivatives | |
| JPH05194366A (en) | Glycine derivative-monosodium salt-tetrahydrate, its production, medicine containing the same and production of intermediate for the same derivative | |
| JP2000502997A (en) | Retroviral protease inhibitor compound | |
| WO1992015319A1 (en) | Hiv protease inhibitors | |
| JPH08259532A (en) | Peptide-like compound or its pharmacologically acceptable salt | |
| SK110996A3 (en) | Heterocyclicly substituted pseudo-peptides, producing method thereof and drugs containing these substances | |
| JPH08259534A (en) | Novel pseudopeptide containing trifluoromethylated 2-azabicyclooctane | |
| CA2356966A1 (en) | Amidomalonamides and their use as inhibitors of matrix metalloproteinase | |
| JPH09328428A (en) | Medicine comprising tripeptide derivative containing ahpba as active ingredient |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |