CA2184146A1 - Heterocyclically substituted pseudopeptides - Google Patents
Heterocyclically substituted pseudopeptidesInfo
- Publication number
- CA2184146A1 CA2184146A1 CA002184146A CA2184146A CA2184146A1 CA 2184146 A1 CA2184146 A1 CA 2184146A1 CA 002184146 A CA002184146 A CA 002184146A CA 2184146 A CA2184146 A CA 2184146A CA 2184146 A1 CA2184146 A1 CA 2184146A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- trifluoromethyl
- azabicyclo
- amino
- octan
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to new heterocyclically substituted pseudopeptides of the general formula (I) (I)
Description
218`4146 Le A 31290-Forei~ Countries / Bu / AB/S-P
New het~ .lically su~s'd~d ~
Ihe present invention relates to new heterocyclically sllksth~ pseudopeptides, aprocess for their ~ lion and their use as ~ iral agents.
Trifluoromethyl~., ~ il-g pseudopeptides are described as ~~ c~ iral agents in the publication EP 528 242.
The present invention relates to new heterocyclically substituted pseudopeptides of the general formula (I) ~W ^
H H (I) R'-NH--~--N~
in which R' represents a radical of the formula R3-o ~NH 1 CO--CH2 or R4--O CO-0~ NH2 in which R3 and R4 are identical or di~r~ and denote a heterocyclic radical of the 21~4146 - Le A 31290-Foreign Countries - 2 -formula L~, ~ or [~
R2 represents hydrogen or straight-chain or branched acyl having up to 20 carbonatoms, which is optionally substituted by carboxyl, or by straight-chain or 5branched alkoxycarbonyl having up to 6 carbon atoms, and their salts.
The compounds of the general formula (I) according to the invention have a plurality of asymmetric carbon atoms.
The representative radical of the general formula (Ia) --co--NH~ H (Ia) oR2 CF3 10 has 5 asymmetric carbon atoms ( ), which are present independently of one another in the R- or S-configuration. The l(R), 2(R), 3(S), 4(S), 5(S) and 6(S) configurations are preferred.
The amino acids employed in the compounds of the general formula (~) according to the invention can be present either in the L- or in the ~form.
15 Physiologically acceptable salts of the heterocyclically substituted pseudopeptides having a trifluoromethyl-substituted 2-azabicyclooctane can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids.
- Le A 31290-Foreign Countries - 3 -Particularly pl~r~ d salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphc)ric acid, m~th~n~lllph~nic acid, ethanesulphonic acid, tol~ llrh- nic acid, b~n7~n~ rhonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or ben_oic 5 acid.
I~er~ d compounds of the general formula (I) according to the invention are those in which Rl represents a radical of the formula R3-o ,NH ~ co n ~' R4-o co-o CH2 or 0~ NH2 in which R3 and R4 are identical or different and denote a heterocyclic radical of the formula ~, or ~, R2 represents hydrogen or straight-chain or branched acyl having up to 6 carbon atoms, and their salts.
Particularly preferred compounds of the general formula (I) according to the invention are those 21841`~6 ~~ Le A 31290-Foreign Countries - 4 -in which R' represents a radical of the forrnula R3-o ~rNH ~ co--~ R4--O--CO-o CH2 or 0~ NH2 in which S R3 and R4 are identical or diff~l~.. l and denote a heterocyclic radical of the forrnula ~ L~, or [~, R2 represents hydrogen or straight-chain or branched acyl having up to 5 carbon atoms, 10 and their salts.
Very particularly plefelled compounds of the general formula (I) according to the invention are those in which R2 represents hydrogen or straight-chain or branched acyl having up to 4 carbon 15 atoms.
A process for the ~rep~ion of the compounds of the general formula (I) according to the invention has additionally been found, characterized in that 21~4146 Le A 3129~Foreign Countries - 5 -compounds of the formula (II) or (III) ~ ~\
H H
H2N,~----N~/ (Il) H7NCO--NH ~ N~/ (111) ~' OH CF3 are reacted ~,vith compounds of the general formula (IV) R'-OH (~V) in which 5 R' has the meaning indicated above, if appropriate with prior activation of the carboxylic acid~ in inert solvents and in the presence of a base and/or of an auxiliary, and in a second step if R2 ~ H an acylation is carried out in inert solvents, if ap~lol,liate in the presence of a base and/or of an auxiliary.
10 One process according to the invention is illustrated by way of example by the following reaction scheme:
Suitable solveIlts for all process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvent~s such as ethers, e.g. diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, 21~4146 - Le A 3129~Foreign Countries - 6 -o ~ H ~ H
+ H2N CO--NH--~N
O-CO2H ~- OH CF, O--CO--NHyCO--NH~--'N~lH
OH
o _ CF3 or hydrocarbons such as bPn7PnP, toluene, xylene, cyclohexane or petroleum fractions or halogenohydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylforrnamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents S mentioned. Dichloro",~lh~nP dimethylro~ ~ide or tetrahydrofuran are particularly ~l~r~ d.
Depending on the individual process step, suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, 10 or alkali metal alkoxides such as sodium or potassium methoxide, or sodium orpotassium ethoxide, or organic amines such as ethyldiisopropylamine, triethylamine, picoline, pyridines, dimethylaminopyridine or N-methylpiperidine, or amides such as sodium amide or lithium diisopropylamide, or lithium N-silylalkylamides, such aslithium N-(bis)triphenylsilylamide, or lithium alkyls such as n-butyllithium.
15 The base is employed in an amount from 1 mol to 10 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the compounds of the formula (II) or (III).
- Le A 31290-Foreigrl Countries - 7 -Suitable auxiliaries are ~ rel~bly con~n~inE agents, which can also be bases, inparticular if the carboxyl group is present in activated form as an anhydride. Ihe customary con(~ ing agents are pler~lled here, such as carbodiimides, e.g.
N,N'-diethyl-, N,N'-diisopropyl- or N,N'-dicyclohexylcarbodiimide, 5 N{3-diethylaminoisopropyl~N'-ethyl-carbodiimide hydrochloride, N-cyclohexyl-N'-(2-morpholinoethyl)-carbodiimide metho-p-toluenesulphonate (CMCT or morpho-CDI) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or 2-tert-butyl-5-methyl-oxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxyc~ul~llyl-10 1,2-dihydroquinoline, or prop~n~hosI h-)nic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tri(dimethylamino)phosphonium hexafluorophosphate, l-hydroxyl~ iazole or dimethylaminopyridine.
The reactions can be carried out either at ~trnn~ph~ic pressure or at elevated or reduced pressure (for example 0.5 to 5 bar), plcr~l~ly at atmospheric pressure.
15 The reaction is in general carried out in a temperature range from -20C to +40C, pl~r~lably from 0C to room t~nl~l~ re.
The acylation is in general carried out in one of the abovementioned ethers or halogenohydrocarbons, pl~relably tetrahydrofuran or methylene chloride, in a temperature range from -30C to +50C, pl~rel~bly from -10C to room temperature.
20 Suitable bases and/or auxiliaries for the acylation are in general the abovementioned organic amines and pyridines. Triethylamine and dimethylaminopyridine are pl~r~lled.
The base is employed in an amount of from 1 mol to 10 mol, preferably from 1 molto 3 mol, relative to 1 mol of the respective alcohol.
The compound of the general formula (II) is known.
25 The compound of the forrnula (III) is new and can be prepared, for exarnple, by converting `~ Le A 3129~Forei~ Countries - 8 -compounds of the general formula (V) C6Hs W-NH CO--NH
Oq~
in which W represents an amino protective group, pl~rt.~ly tert-butoxycarbonyl, fLrst using an epoxidation reaction, if a~lo~.iate with the aid of a base or of a phase S lLd~rer catalyst, into the compounds of the general formula (VI) ,~
W-NH CO--NH~7 (VI) Oq~
NH2 ,.
in which W has the abovementioned mP~ning, and then reacting with 3-trifluoromethyl-2-azabicyclo[3.3.0]octane of the formula (VII) /\
H H
(VII) HN
21~4146 - Le A 31290-Forei~n Countries - 9 -in solvents and removing the protective group by customary methods.
Suitable solvents are the Cl~O~ organic solvents which do not change under the reaction conditions. Ihese ~ r~l~ly include organic solvents such æ alcohols, e.g m~th~nol, ethanol or n-propanol, ethers, e.g diethyl ether, glycol mono- or dimethyl S ether, dioxane or tetrahydrofuran, or hydrocarbons such æ benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenohydrocarbons such æ methylene chloride, dichloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylro",~ ide, hexarnethylIhosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned.
10 Dichlorom~qth~n~ dichloroethane, dimethylr~n,l~,de or n-propanol are particularly r~ d.
Suitable reagents for the epoxidation are the compounds known from the literature, for examplem-chloroperbenzoicacid,m~gn~sillrnmonoperoxyrhth~l~te dimethyldioxirane or methyl(trifluoromethyl)dioxirane. m-Chloroperbenzoic acid and m~g,n~sium monoperoxyphth~l~te are pl~relled (cf. P. Br n~h~m et al., Synthesis (1987), 1015; W.
Adam et al., J. Org. Chem. ~, 2800 (1987) and R Curci et al., J. Org. Chem. 53, 3890 (1988)].
If the epoxidation is carried out with the aid of a phæe transfer catalyst, the auxiliaries employed are, for example, organic ~mmonium chlorides or bromides, for example 20 benzyltriethylammonium chloride or bromide, methyltrioctylammonium chloride, tetrabutylammonium bromide or tricaprylmethyl~mmcnium chloride (Aliquat 336).
Benzyltriethylammonium chloride and bromide are plefel,ed.
The epoxidation is carried out in a temperature range from -10C to +90C, preferably from 0C to +60C.
25 Ihe reactions can be carried out either at atmospheric pressure or at elevated or reduced pressure (for example 0.5 to 5 bar), pl~r~l~ly at atmospheric pressure.
The compounds of the general formula (IV) are known per se or can be prepared by 21~4146 Le A 31290-Foreign Countries - 10 -customary methods.
The compounds of the general formulae (V) and ~Vl) are in the main known [cf. EP 528 242].
The compound of the general forrnula (VII) is new and can be prepared, for example, 5 by fluorination of 2-azabicyclo[3.3.0]octane-3-carboxylic acid in the respective configuration with ~ and SF4.
It has surprisingly been found that the compounds of the general formula (I) have an extremely strong action against retroviruses. This is co~ A using an H[V-specific protease enzyme test.
10 The results of the exarnples mentioned below were determinPA according to the HIV
test system described in the following reference [cf. Hansen, J., Billich, S., Schulze, T., Sukrow, S. and Molling, K (1988), EMBO Journal, Vol. 7, No. 6, pp. 1785 - 1791]:purified HIV protease was inc~lb~ted with synthetic peptide which imit~tçs a cleavage site in the gag precursor protein and is an in vivo cleavage site of ~V protease. The 15 resulting cleavage products of the synthetic peptide were analyzed by means of reversed phase high p~lrolll~lce liquid cLI~nl~ography (RP-HPLC). The ICso values indicated relate to the substance concentration which, under the abovementioned test conditions, causes a 50 % inhibition of the protease activity.
New het~ .lically su~s'd~d ~
Ihe present invention relates to new heterocyclically sllksth~ pseudopeptides, aprocess for their ~ lion and their use as ~ iral agents.
Trifluoromethyl~., ~ il-g pseudopeptides are described as ~~ c~ iral agents in the publication EP 528 242.
The present invention relates to new heterocyclically substituted pseudopeptides of the general formula (I) ~W ^
H H (I) R'-NH--~--N~
in which R' represents a radical of the formula R3-o ~NH 1 CO--CH2 or R4--O CO-0~ NH2 in which R3 and R4 are identical or di~r~ and denote a heterocyclic radical of the 21~4146 - Le A 31290-Foreign Countries - 2 -formula L~, ~ or [~
R2 represents hydrogen or straight-chain or branched acyl having up to 20 carbonatoms, which is optionally substituted by carboxyl, or by straight-chain or 5branched alkoxycarbonyl having up to 6 carbon atoms, and their salts.
The compounds of the general formula (I) according to the invention have a plurality of asymmetric carbon atoms.
The representative radical of the general formula (Ia) --co--NH~ H (Ia) oR2 CF3 10 has 5 asymmetric carbon atoms ( ), which are present independently of one another in the R- or S-configuration. The l(R), 2(R), 3(S), 4(S), 5(S) and 6(S) configurations are preferred.
The amino acids employed in the compounds of the general formula (~) according to the invention can be present either in the L- or in the ~form.
15 Physiologically acceptable salts of the heterocyclically substituted pseudopeptides having a trifluoromethyl-substituted 2-azabicyclooctane can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids.
- Le A 31290-Foreign Countries - 3 -Particularly pl~r~ d salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphc)ric acid, m~th~n~lllph~nic acid, ethanesulphonic acid, tol~ llrh- nic acid, b~n7~n~ rhonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or ben_oic 5 acid.
I~er~ d compounds of the general formula (I) according to the invention are those in which Rl represents a radical of the formula R3-o ,NH ~ co n ~' R4-o co-o CH2 or 0~ NH2 in which R3 and R4 are identical or different and denote a heterocyclic radical of the formula ~, or ~, R2 represents hydrogen or straight-chain or branched acyl having up to 6 carbon atoms, and their salts.
Particularly preferred compounds of the general formula (I) according to the invention are those 21841`~6 ~~ Le A 31290-Foreign Countries - 4 -in which R' represents a radical of the forrnula R3-o ~rNH ~ co--~ R4--O--CO-o CH2 or 0~ NH2 in which S R3 and R4 are identical or diff~l~.. l and denote a heterocyclic radical of the forrnula ~ L~, or [~, R2 represents hydrogen or straight-chain or branched acyl having up to 5 carbon atoms, 10 and their salts.
Very particularly plefelled compounds of the general formula (I) according to the invention are those in which R2 represents hydrogen or straight-chain or branched acyl having up to 4 carbon 15 atoms.
A process for the ~rep~ion of the compounds of the general formula (I) according to the invention has additionally been found, characterized in that 21~4146 Le A 3129~Foreign Countries - 5 -compounds of the formula (II) or (III) ~ ~\
H H
H2N,~----N~/ (Il) H7NCO--NH ~ N~/ (111) ~' OH CF3 are reacted ~,vith compounds of the general formula (IV) R'-OH (~V) in which 5 R' has the meaning indicated above, if appropriate with prior activation of the carboxylic acid~ in inert solvents and in the presence of a base and/or of an auxiliary, and in a second step if R2 ~ H an acylation is carried out in inert solvents, if ap~lol,liate in the presence of a base and/or of an auxiliary.
10 One process according to the invention is illustrated by way of example by the following reaction scheme:
Suitable solveIlts for all process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvent~s such as ethers, e.g. diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, 21~4146 - Le A 3129~Foreign Countries - 6 -o ~ H ~ H
+ H2N CO--NH--~N
O-CO2H ~- OH CF, O--CO--NHyCO--NH~--'N~lH
OH
o _ CF3 or hydrocarbons such as bPn7PnP, toluene, xylene, cyclohexane or petroleum fractions or halogenohydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylforrnamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents S mentioned. Dichloro",~lh~nP dimethylro~ ~ide or tetrahydrofuran are particularly ~l~r~ d.
Depending on the individual process step, suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, 10 or alkali metal alkoxides such as sodium or potassium methoxide, or sodium orpotassium ethoxide, or organic amines such as ethyldiisopropylamine, triethylamine, picoline, pyridines, dimethylaminopyridine or N-methylpiperidine, or amides such as sodium amide or lithium diisopropylamide, or lithium N-silylalkylamides, such aslithium N-(bis)triphenylsilylamide, or lithium alkyls such as n-butyllithium.
15 The base is employed in an amount from 1 mol to 10 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the compounds of the formula (II) or (III).
- Le A 31290-Foreigrl Countries - 7 -Suitable auxiliaries are ~ rel~bly con~n~inE agents, which can also be bases, inparticular if the carboxyl group is present in activated form as an anhydride. Ihe customary con(~ ing agents are pler~lled here, such as carbodiimides, e.g.
N,N'-diethyl-, N,N'-diisopropyl- or N,N'-dicyclohexylcarbodiimide, 5 N{3-diethylaminoisopropyl~N'-ethyl-carbodiimide hydrochloride, N-cyclohexyl-N'-(2-morpholinoethyl)-carbodiimide metho-p-toluenesulphonate (CMCT or morpho-CDI) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or 2-tert-butyl-5-methyl-oxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxyc~ul~llyl-10 1,2-dihydroquinoline, or prop~n~hosI h-)nic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tri(dimethylamino)phosphonium hexafluorophosphate, l-hydroxyl~ iazole or dimethylaminopyridine.
The reactions can be carried out either at ~trnn~ph~ic pressure or at elevated or reduced pressure (for example 0.5 to 5 bar), plcr~l~ly at atmospheric pressure.
15 The reaction is in general carried out in a temperature range from -20C to +40C, pl~r~lably from 0C to room t~nl~l~ re.
The acylation is in general carried out in one of the abovementioned ethers or halogenohydrocarbons, pl~relably tetrahydrofuran or methylene chloride, in a temperature range from -30C to +50C, pl~rel~bly from -10C to room temperature.
20 Suitable bases and/or auxiliaries for the acylation are in general the abovementioned organic amines and pyridines. Triethylamine and dimethylaminopyridine are pl~r~lled.
The base is employed in an amount of from 1 mol to 10 mol, preferably from 1 molto 3 mol, relative to 1 mol of the respective alcohol.
The compound of the general formula (II) is known.
25 The compound of the forrnula (III) is new and can be prepared, for exarnple, by converting `~ Le A 3129~Forei~ Countries - 8 -compounds of the general formula (V) C6Hs W-NH CO--NH
Oq~
in which W represents an amino protective group, pl~rt.~ly tert-butoxycarbonyl, fLrst using an epoxidation reaction, if a~lo~.iate with the aid of a base or of a phase S lLd~rer catalyst, into the compounds of the general formula (VI) ,~
W-NH CO--NH~7 (VI) Oq~
NH2 ,.
in which W has the abovementioned mP~ning, and then reacting with 3-trifluoromethyl-2-azabicyclo[3.3.0]octane of the formula (VII) /\
H H
(VII) HN
21~4146 - Le A 31290-Forei~n Countries - 9 -in solvents and removing the protective group by customary methods.
Suitable solvents are the Cl~O~ organic solvents which do not change under the reaction conditions. Ihese ~ r~l~ly include organic solvents such æ alcohols, e.g m~th~nol, ethanol or n-propanol, ethers, e.g diethyl ether, glycol mono- or dimethyl S ether, dioxane or tetrahydrofuran, or hydrocarbons such æ benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenohydrocarbons such æ methylene chloride, dichloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylro",~ ide, hexarnethylIhosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned.
10 Dichlorom~qth~n~ dichloroethane, dimethylr~n,l~,de or n-propanol are particularly r~ d.
Suitable reagents for the epoxidation are the compounds known from the literature, for examplem-chloroperbenzoicacid,m~gn~sillrnmonoperoxyrhth~l~te dimethyldioxirane or methyl(trifluoromethyl)dioxirane. m-Chloroperbenzoic acid and m~g,n~sium monoperoxyphth~l~te are pl~relled (cf. P. Br n~h~m et al., Synthesis (1987), 1015; W.
Adam et al., J. Org. Chem. ~, 2800 (1987) and R Curci et al., J. Org. Chem. 53, 3890 (1988)].
If the epoxidation is carried out with the aid of a phæe transfer catalyst, the auxiliaries employed are, for example, organic ~mmonium chlorides or bromides, for example 20 benzyltriethylammonium chloride or bromide, methyltrioctylammonium chloride, tetrabutylammonium bromide or tricaprylmethyl~mmcnium chloride (Aliquat 336).
Benzyltriethylammonium chloride and bromide are plefel,ed.
The epoxidation is carried out in a temperature range from -10C to +90C, preferably from 0C to +60C.
25 Ihe reactions can be carried out either at atmospheric pressure or at elevated or reduced pressure (for example 0.5 to 5 bar), pl~r~l~ly at atmospheric pressure.
The compounds of the general formula (IV) are known per se or can be prepared by 21~4146 Le A 31290-Foreign Countries - 10 -customary methods.
The compounds of the general formulae (V) and ~Vl) are in the main known [cf. EP 528 242].
The compound of the general forrnula (VII) is new and can be prepared, for example, 5 by fluorination of 2-azabicyclo[3.3.0]octane-3-carboxylic acid in the respective configuration with ~ and SF4.
It has surprisingly been found that the compounds of the general formula (I) have an extremely strong action against retroviruses. This is co~ A using an H[V-specific protease enzyme test.
10 The results of the exarnples mentioned below were determinPA according to the HIV
test system described in the following reference [cf. Hansen, J., Billich, S., Schulze, T., Sukrow, S. and Molling, K (1988), EMBO Journal, Vol. 7, No. 6, pp. 1785 - 1791]:purified HIV protease was inc~lb~ted with synthetic peptide which imit~tçs a cleavage site in the gag precursor protein and is an in vivo cleavage site of ~V protease. The 15 resulting cleavage products of the synthetic peptide were analyzed by means of reversed phase high p~lrolll~lce liquid cLI~nl~ography (RP-HPLC). The ICso values indicated relate to the substance concentration which, under the abovementioned test conditions, causes a 50 % inhibition of the protease activity.
~ Le A 31290-Foreif~n Countries - 11 -Lnzyme assay, HrV-1 -Table I
No. ICsOImol/ll IC;,5[mol/l]
No. ICsOImol/ll IC;,5[mol/l]
3.0 x 10-8 3.8 x 10-7 2 2.7 x 10-l 3.6 x 10-9 3 9.5 x 10-9 n.t.
4 2.1 x 10-9 3.9 x 10-9 4.1 x 10-9 4.7 x 10-8 2.5 x 10-8 5.0 x 10-8 7 2.5 x 10-8 n.t.
8 3.2 x 10-9 4.1 x 10-8 Ihe compounds according to the invention additionally showed action in lentivirus-infected cell cultures. It was possible to show this using the HIV virus as an example.
HIV infection in cell culture The HlV test was carried out with slight modifications according to the method of Pauwels et al. [cf. Journal of Virological Methods 20, (1988), 309-321].
Normal human blood Iymphocytes (PBLs) were concentrated by means of Ficoll-Hypaque and stim~ te(l with phytoh~tom~lutinin (90 ~g/ml) and interleukin-2 (40 U/ml) in RPMl 1640, 20 % foetal calf serum. For infection with the infectious HIV, PBLs were pelleted and the cell pellet was then suspended in 1 ml of HlV virus adsorption solution and incub~t~l at 37C for 1 hour.
Le A 31290-Foreign Countries - 12 -The virus adsorption solution was centrifuged and the infected cell pellet taken up in growth mediurn so that a concentration of 1 x 105 cells per ml wæ established. Ihe cells infected in this way were pipetted at 1 x 104 cells/well into the wells of 9~well microtitre plates.
S The first vertical row of the microtitre plate c nt~in~l only growth medium and cells which had not been infected, but otherwise had been treated exactly as described above (cell control). The second vertical row of the microtitre plates cont~in~ only H~V-infected cells (virus control) in growth mediu~ The other wells contained the compounds according to the invention at di~ concentrations, starting from the 10 wells of the 3rd vertical row of the microtiter plate, from which the test sl1bst~nces were diluted 21 tirnes in steps of 2.
The test batches were inalb~tecl at 37C until in the untreated virus control the syncytia formation typical of HlV occurred (between day 3 and 6 after infection), which was then ~se~se~l microscopically. In the untreated virus control about 2015 syncytia resulted under these test conditions, while the untreated cell control showed no syncytia The IC50 values were (let~nnined as the co~ct;~ lion of the treated and infected cells at which 50 % (about 10 syncytia) of the virus-in~-cecl syncytia were suppressed by the tre~tm~nt with the compound according to the invention.
20 It has now been found that the compounds according to the invention protect H~V-infected cells from virus-in~hlc~d cell destruction.
Le A 31290-Foreign Countries - 13 -Cell culture assay, PBL
Table II:
PBL
~le No. ICsO[mol/l] I~,5[moUIl 2.2 x 10 3.5 x 10 2 2.0 x 10 3.5 x 10 3 1.2xlO~ l.9xlO~
4 >1.6 x 10-5 n.t.
1.4 x 10-5 2.2 x 10-5 6 2.8 x 10 1.3 x 10 7 6.2 x 10~ n.t.
8 1.7 x 10-5 >2 x 10-5 The compounds according to the invention are useful active compounds in human and veterinary medicine for the tre~tm~nt and prophylaxis of disorders caused byretroviruses.
Indication areas in human medicine which can be mentioned, for example, are:
1.) The tre~tm~nt and prophylaxis of human retrovirus infections.
2.) The tre~1m~nt or prophylaxis of disorders (AIDS) caused by HIV I (hurnan immlm(ldeficiency virus; formerly called HTLV III/LAV) and HIV II and the stages associated therewith such as ARC (AIDS-related complex) and LAS
(Iymphadenophathy syndrome) and also the immllnodeficiency and encephalopathy caused by this virus.
218ql46 - Le A 31290-Foreign Countries - 14 -3.) The tre~tm~nS or the prophylaxis of an HILV-I or HTLV-II infection.
4.) Ihe tre~tm~nt or the prophylaxis of the AlDS-carrier state (AlDS-ll~ls~ ler state).
Indications in v~ ~y medicine which can be mentioned are, for example:
8 3.2 x 10-9 4.1 x 10-8 Ihe compounds according to the invention additionally showed action in lentivirus-infected cell cultures. It was possible to show this using the HIV virus as an example.
HIV infection in cell culture The HlV test was carried out with slight modifications according to the method of Pauwels et al. [cf. Journal of Virological Methods 20, (1988), 309-321].
Normal human blood Iymphocytes (PBLs) were concentrated by means of Ficoll-Hypaque and stim~ te(l with phytoh~tom~lutinin (90 ~g/ml) and interleukin-2 (40 U/ml) in RPMl 1640, 20 % foetal calf serum. For infection with the infectious HIV, PBLs were pelleted and the cell pellet was then suspended in 1 ml of HlV virus adsorption solution and incub~t~l at 37C for 1 hour.
Le A 31290-Foreign Countries - 12 -The virus adsorption solution was centrifuged and the infected cell pellet taken up in growth mediurn so that a concentration of 1 x 105 cells per ml wæ established. Ihe cells infected in this way were pipetted at 1 x 104 cells/well into the wells of 9~well microtitre plates.
S The first vertical row of the microtitre plate c nt~in~l only growth medium and cells which had not been infected, but otherwise had been treated exactly as described above (cell control). The second vertical row of the microtitre plates cont~in~ only H~V-infected cells (virus control) in growth mediu~ The other wells contained the compounds according to the invention at di~ concentrations, starting from the 10 wells of the 3rd vertical row of the microtiter plate, from which the test sl1bst~nces were diluted 21 tirnes in steps of 2.
The test batches were inalb~tecl at 37C until in the untreated virus control the syncytia formation typical of HlV occurred (between day 3 and 6 after infection), which was then ~se~se~l microscopically. In the untreated virus control about 2015 syncytia resulted under these test conditions, while the untreated cell control showed no syncytia The IC50 values were (let~nnined as the co~ct;~ lion of the treated and infected cells at which 50 % (about 10 syncytia) of the virus-in~-cecl syncytia were suppressed by the tre~tm~nt with the compound according to the invention.
20 It has now been found that the compounds according to the invention protect H~V-infected cells from virus-in~hlc~d cell destruction.
Le A 31290-Foreign Countries - 13 -Cell culture assay, PBL
Table II:
PBL
~le No. ICsO[mol/l] I~,5[moUIl 2.2 x 10 3.5 x 10 2 2.0 x 10 3.5 x 10 3 1.2xlO~ l.9xlO~
4 >1.6 x 10-5 n.t.
1.4 x 10-5 2.2 x 10-5 6 2.8 x 10 1.3 x 10 7 6.2 x 10~ n.t.
8 1.7 x 10-5 >2 x 10-5 The compounds according to the invention are useful active compounds in human and veterinary medicine for the tre~tm~nt and prophylaxis of disorders caused byretroviruses.
Indication areas in human medicine which can be mentioned, for example, are:
1.) The tre~tm~nt and prophylaxis of human retrovirus infections.
2.) The tre~1m~nt or prophylaxis of disorders (AIDS) caused by HIV I (hurnan immlm(ldeficiency virus; formerly called HTLV III/LAV) and HIV II and the stages associated therewith such as ARC (AIDS-related complex) and LAS
(Iymphadenophathy syndrome) and also the immllnodeficiency and encephalopathy caused by this virus.
218ql46 - Le A 31290-Foreign Countries - 14 -3.) The tre~tm~nS or the prophylaxis of an HILV-I or HTLV-II infection.
4.) Ihe tre~tm~nt or the prophylaxis of the AlDS-carrier state (AlDS-ll~ls~ ler state).
Indications in v~ ~y medicine which can be mentioned are, for example:
5 Infections with a) Maedi-visna (in sheep and goats) b) progressive pnYlmoni~ virus (PPV) (in sheep and goats) c) caprine arthritis ~n~h~liti~ virus (in sheep and goats) d) zwoegersiete virus (in sheep) 10 e) infectious ~n~mi~ virus (equine) f) infections caused by the feline le~ virus g) infections caused by the feline irnmunodeficiency virus (FIV) h) infections caused by the sirnian immlmodeficiency virus (SIV) From the indication area in human medicine, the abovementioned iterns 2, 3 and 4 are 15 ~ r~ d.
The present invention includes ph~ ,eutical preparations which, in addition to non-toxic, inert pharm~ ically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more active compounds of the formula (I), and processes for the production of these p~ lions.
Le A 31290-Foreign Countries - 15 -Ihe active compounds of the formula (I) should bc present in the abovementioned ph~ re~ltical plc~al~ions in a concentration of al)ploxill~ely 0.1 to 99.5 % by weight, plcrc~bly of approximately 0.5 to 95 % by weight, of the total rnixture.
In addition to the compounds of the formula (I), the abovementioned ph~rm~ce~tical S ~lc~lions can also contain other ph~rrn~r~ltic~l active compounds.
Ihe abovementioned ph~rm~celltical plc~lions are prepared in a Cl~ilOn~y manner by known methods, e.g. by mixing the active compound or compounds with the excipient or excipients.
In general, it has proved advantageous both in human and in ~/cl~il~y medicine to 10 a~rnini~t~r the active compound or compounds in total amounts of approximately 0.5 to ~uloxi~ cly 500, ~lcrcl~bly 1 to 100, m~kg of body weight every 24 hours, if a~r~liate in the form of a plurality of individual doses, to achieve the desired results.
An individual dose c~nt~in~ the active compound or compounds, plcrcl~ly in amounts of approximately 1 to approximately 80, in particular 1 to 30, mg/kg of body weight.
15 However, it may be n~ss~ry to depart from the doses mentioned, narnely depending on the nature and the body weight of the subject to be treated, the type and the severity of the disorder, the manner of ~lc~ion and ~(lmini~tration of the medir~m~nt andthe time or interval within which ~mini~tration takes place.
The compounds according to the invention are enzyme inhibitors and can be employed 20 as such for all purposes for which enzyme inhibitors can be used. An example to be mentioned here is use as a label for affinity cl~ro~ ography, use as an aid for the elucidation of enzyme structures and reaction m~l~ni~m~, and use as a reagent for diagnostics.
21 ~41 46 Le A 31290-Foreign Countries - 16 -F~mDle 1 (2S,3S)-3-(Tetrahydrofuran-3-yl-oxycarbonyl-L-asparaginyl)amino- 1 - {(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2yl} -2-hydroxy~phenylbutane o ~ ~
C~ 1 H ~ H
O--CO--NH ,CO--NH ~N
- OH
0.1 g (0.22 mmol) of (2R,3S~3-(L-asparaginyl)amino-1-~(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2yl}-2-hydroxy~phenylbutane and 0.11 g (0.44 mmol) of tetrahydrofuran-3-yl 4-lliL~ enyl~l~l.~l~ (analogously to Daniel F. Veber et al., J.
Org. Chem., Vol. 42, No. 20, 1977, pp. 3286-8) are dissolved in 3 ml of THF and stirred overnight at RT under an argon ~tmosph~e. The mixture is then evaporated to dryness, and the residue is separated by column cllroll~lography (silica gel 60,dichlorom~th~n~lm~th~n-)l = 100:5, Rf = 0.4).
Yield: 120 mg (96.0 % of theory) of colourless foam The compounds listed in Table 1 are prepared in analogy to the procedure of Example 1:
- Le A 31290-Foreign Countries - 17 -Table 1:
~W /\
H 1.~ H
R3--O ~=CO--NH~
E~L No. ~ R, /m~ (~) Yield (% of ~lY) 2 o Dichloro~ e/MeOH 89.6 = 100:5 0.4 (colourless foam) 3 so2 Dichlolu~ h~nelMeOH 92.3 4 =100:5 0.2 (colourless foam) 4 so2 Dichlorom~th~n~MeOH 74.0 (~ = 100:7 0.5 (colourless foam) h~ -npe 5 (2R,3S)-3-(Tetrahydrofuran-3-yl-oxycarbonyl)-amino-1-{(S,S,S)-3-trifluoromethyl-2-a~abicyclo[3.3 Ø]octan-2-yl}-2-hydroxy~phenylbutane --Le A 31290-Foreign Countries - 18 -o ,~ H ~ H
--0--CO--NH ~Ny 0.1 g (0.29 mmol) of (2R,3S)-3-amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3Ø]octan-2-yl}-2-hydroxy~phenylbutane and 0.11 g (0.44 mmol) oftetrahydrofuran-3-yl 4-nitrophenylca~ (analogously to Daniel F. Veber et al., J.Org. Chem., Vol. 42, No. 20, pp. 328~8) are dissolved in 3 ml of abs. THF and stirred S overnight at RT under an argon atmosphere. The mi~ure is then evaporated to dryness and the residue is separated by column cl~o,l~lography (silica gel 60;
dichlorometll~n~lethyl acetate = 4:1).
Rf = 0.5 (dichloromethane/ethyl acetate = 1:1) Yleld: 50 mg (37.5 % of theory) of colourless foam 10 The compounds listed in Table 2 are prepared in analogy to the procedure of Example 5.
Le A 31290-Foreign Countries - 19 -Table 2: -~^
H ' ~ H
R4 0--CO--NH~ N~
HO
E~. No. 1~ Rr /m~ (C) Yield (% of ~eoly) 6 0 0.4 (Dichloro- 75.0 C~ methane/ethyl acetate =
9:1) colourless cIystals 7 so2 0.5 (Dichloro- 67.8 4 methane/ethyl acetate =
4 1) colourless foam 8 so2 0.5 (Dichloro- 95.4 methane/ethyl acetate =
4 1) colourless glass ~le 9 (2S,3S)-3-(Tetrahydrofuran-3-yl-oxycarbonyl-L-asparaginyl)amino-1-~(S,S,S)-3-trifluoromethyl-2-azabicyclo[3 .3 .O]octan-2-yl-2-acetoxy~phenylbutane ~~ Le A 3129~Forei~ Countries - 20 -O--CO--NHycO--NH~N~?' H
0~ CO CF3 50 mg (0.0876 mmol) of the compound of Example 1, 25 mg (0.035 ml) of triethylamine and 13 mg (0.13 mmol) of acetic anhydride are dissolved in 2 ml of dry tetrahydrofuran (THF) under an argon ~trnosph~re~ treated with a spatula tipful of dimethylaminopyridine (DMAP) and stirred overnight.
S The mixture is evaporated to dryness in vacuo and stirred with 5 ml of water and 15 ml of ethyl acetate. Ihe organic phase is separated off, dried wi~ sodium slllph~te and separated by column cl~ro~ ography (silica gel 60, eluent: dichlorometll~n~lethyl acetate = 4:1).
Colourless crystals, m.p. = 191C; Rf = 0.4 (dichloromethane/ethyl acetate = 4:1), yield: 35 mg (65.2 % of theory).
~le 10 (2S,3S}3-[Tetrahydrofuran~3S}3-yl-oxycarbonyl]-amino-1-{(S,S,S}3-trifluoromethyl-2-azabicyclo-[3.3.0]octan-2-yl}-2-isobutyroxy-4-phenylbut~ne O-CO-NH'f~, In analogy to the procedure of Example 9, the title compound is prepared from 50 mg (0.11 mmol) of the compound from Example 6, 20 mg (0.027 ml/0.2 mmol) of ` 2184146 Le A 31290-Foreign Countries - 21 -triethylamine and 15 mg (0.14 mmol) of butyric anhydride using a spatula tipful of dimethylaminopyridine.
Colourless foam; Rf = 0.6 (dichloromethane/e~yl acetate 4:1) Yield: 40 mg (69.3 % of theory)
The present invention includes ph~ ,eutical preparations which, in addition to non-toxic, inert pharm~ ically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more active compounds of the formula (I), and processes for the production of these p~ lions.
Le A 31290-Foreign Countries - 15 -Ihe active compounds of the formula (I) should bc present in the abovementioned ph~ re~ltical plc~al~ions in a concentration of al)ploxill~ely 0.1 to 99.5 % by weight, plcrc~bly of approximately 0.5 to 95 % by weight, of the total rnixture.
In addition to the compounds of the formula (I), the abovementioned ph~rm~ce~tical S ~lc~lions can also contain other ph~rrn~r~ltic~l active compounds.
Ihe abovementioned ph~rm~celltical plc~lions are prepared in a Cl~ilOn~y manner by known methods, e.g. by mixing the active compound or compounds with the excipient or excipients.
In general, it has proved advantageous both in human and in ~/cl~il~y medicine to 10 a~rnini~t~r the active compound or compounds in total amounts of approximately 0.5 to ~uloxi~ cly 500, ~lcrcl~bly 1 to 100, m~kg of body weight every 24 hours, if a~r~liate in the form of a plurality of individual doses, to achieve the desired results.
An individual dose c~nt~in~ the active compound or compounds, plcrcl~ly in amounts of approximately 1 to approximately 80, in particular 1 to 30, mg/kg of body weight.
15 However, it may be n~ss~ry to depart from the doses mentioned, narnely depending on the nature and the body weight of the subject to be treated, the type and the severity of the disorder, the manner of ~lc~ion and ~(lmini~tration of the medir~m~nt andthe time or interval within which ~mini~tration takes place.
The compounds according to the invention are enzyme inhibitors and can be employed 20 as such for all purposes for which enzyme inhibitors can be used. An example to be mentioned here is use as a label for affinity cl~ro~ ography, use as an aid for the elucidation of enzyme structures and reaction m~l~ni~m~, and use as a reagent for diagnostics.
21 ~41 46 Le A 31290-Foreign Countries - 16 -F~mDle 1 (2S,3S)-3-(Tetrahydrofuran-3-yl-oxycarbonyl-L-asparaginyl)amino- 1 - {(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2yl} -2-hydroxy~phenylbutane o ~ ~
C~ 1 H ~ H
O--CO--NH ,CO--NH ~N
- OH
0.1 g (0.22 mmol) of (2R,3S~3-(L-asparaginyl)amino-1-~(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2yl}-2-hydroxy~phenylbutane and 0.11 g (0.44 mmol) of tetrahydrofuran-3-yl 4-lliL~ enyl~l~l.~l~ (analogously to Daniel F. Veber et al., J.
Org. Chem., Vol. 42, No. 20, 1977, pp. 3286-8) are dissolved in 3 ml of THF and stirred overnight at RT under an argon ~tmosph~e. The mixture is then evaporated to dryness, and the residue is separated by column cllroll~lography (silica gel 60,dichlorom~th~n~lm~th~n-)l = 100:5, Rf = 0.4).
Yield: 120 mg (96.0 % of theory) of colourless foam The compounds listed in Table 1 are prepared in analogy to the procedure of Example 1:
- Le A 31290-Foreign Countries - 17 -Table 1:
~W /\
H 1.~ H
R3--O ~=CO--NH~
E~L No. ~ R, /m~ (~) Yield (% of ~lY) 2 o Dichloro~ e/MeOH 89.6 = 100:5 0.4 (colourless foam) 3 so2 Dichlolu~ h~nelMeOH 92.3 4 =100:5 0.2 (colourless foam) 4 so2 Dichlorom~th~n~MeOH 74.0 (~ = 100:7 0.5 (colourless foam) h~ -npe 5 (2R,3S)-3-(Tetrahydrofuran-3-yl-oxycarbonyl)-amino-1-{(S,S,S)-3-trifluoromethyl-2-a~abicyclo[3.3 Ø]octan-2-yl}-2-hydroxy~phenylbutane --Le A 31290-Foreign Countries - 18 -o ,~ H ~ H
--0--CO--NH ~Ny 0.1 g (0.29 mmol) of (2R,3S)-3-amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3Ø]octan-2-yl}-2-hydroxy~phenylbutane and 0.11 g (0.44 mmol) oftetrahydrofuran-3-yl 4-nitrophenylca~ (analogously to Daniel F. Veber et al., J.Org. Chem., Vol. 42, No. 20, pp. 328~8) are dissolved in 3 ml of abs. THF and stirred S overnight at RT under an argon atmosphere. The mi~ure is then evaporated to dryness and the residue is separated by column cl~o,l~lography (silica gel 60;
dichlorometll~n~lethyl acetate = 4:1).
Rf = 0.5 (dichloromethane/ethyl acetate = 1:1) Yleld: 50 mg (37.5 % of theory) of colourless foam 10 The compounds listed in Table 2 are prepared in analogy to the procedure of Example 5.
Le A 31290-Foreign Countries - 19 -Table 2: -~^
H ' ~ H
R4 0--CO--NH~ N~
HO
E~. No. 1~ Rr /m~ (C) Yield (% of ~eoly) 6 0 0.4 (Dichloro- 75.0 C~ methane/ethyl acetate =
9:1) colourless cIystals 7 so2 0.5 (Dichloro- 67.8 4 methane/ethyl acetate =
4 1) colourless foam 8 so2 0.5 (Dichloro- 95.4 methane/ethyl acetate =
4 1) colourless glass ~le 9 (2S,3S)-3-(Tetrahydrofuran-3-yl-oxycarbonyl-L-asparaginyl)amino-1-~(S,S,S)-3-trifluoromethyl-2-azabicyclo[3 .3 .O]octan-2-yl-2-acetoxy~phenylbutane ~~ Le A 3129~Forei~ Countries - 20 -O--CO--NHycO--NH~N~?' H
0~ CO CF3 50 mg (0.0876 mmol) of the compound of Example 1, 25 mg (0.035 ml) of triethylamine and 13 mg (0.13 mmol) of acetic anhydride are dissolved in 2 ml of dry tetrahydrofuran (THF) under an argon ~trnosph~re~ treated with a spatula tipful of dimethylaminopyridine (DMAP) and stirred overnight.
S The mixture is evaporated to dryness in vacuo and stirred with 5 ml of water and 15 ml of ethyl acetate. Ihe organic phase is separated off, dried wi~ sodium slllph~te and separated by column cl~ro~ ography (silica gel 60, eluent: dichlorometll~n~lethyl acetate = 4:1).
Colourless crystals, m.p. = 191C; Rf = 0.4 (dichloromethane/ethyl acetate = 4:1), yield: 35 mg (65.2 % of theory).
~le 10 (2S,3S}3-[Tetrahydrofuran~3S}3-yl-oxycarbonyl]-amino-1-{(S,S,S}3-trifluoromethyl-2-azabicyclo-[3.3.0]octan-2-yl}-2-isobutyroxy-4-phenylbut~ne O-CO-NH'f~, In analogy to the procedure of Example 9, the title compound is prepared from 50 mg (0.11 mmol) of the compound from Example 6, 20 mg (0.027 ml/0.2 mmol) of ` 2184146 Le A 31290-Foreign Countries - 21 -triethylamine and 15 mg (0.14 mmol) of butyric anhydride using a spatula tipful of dimethylaminopyridine.
Colourless foam; Rf = 0.6 (dichloromethane/e~yl acetate 4:1) Yield: 40 mg (69.3 % of theory)
Claims (12)
1. A heterocyclically substituted pseudopeptide of the general formula (I) (I) in which R1 represents a radical of the formula or , in which R3 and R4 are identical or different and denote a heterocyclic radical of the formula or , R represents hydrogen or straight-chain or branched acyl having up to 20 carbonatoms, which is optionally substituted by carboxyl, or by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, and its salts.
2. A compound of the general formula (I), according to Claim 1 in which R1 represents a radical of the formula , in which R3 and R4 are identical or different and denote a heterocyclic radical of the formula , or , R represents hydrogen or straight-chain or branched acyl having up to 6 carbon atoms, and its salts.
3. A compound ofthe general formula (I), according to Claim 1 in which R1 represents a radical of the formula or , in which R3 and R4 are identical or different and denote a heterocyclic radical of the formula , or , R represents hydrogen or straight-chain or branched acyl having up to 5 carbon atoms, and its salts.
4. A compound of the general formula (I) according to Claim 1, in which R represents hydrogen or straight-chain or branched acyl having up to 4 carbon atoms.
5. A compound selected from the group consisting of (2S,3S)-3-(tetrahydrofuran-3-yl-oxycarbonyl-L-asparaginyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo-[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane, (2S,3S)-3-[tetrahydrofuran-(3S)-3-yl-oxycarbonyl-L-asparaginyl]amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo-[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane, (2S,3S)-3-(tetrahydrothiophene 1,1-dioxide-3-yl-oxycarbonyl-L-asparaginyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane, (2S,3S)-3-(2,3-dihydrothiophene 1,1-dioxide-3-yl-oxycarbonyl-L-asparaginyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydro-4-phenylbutane, (2R,3S)-3-(tetrahydrofuran-3-yl-oxycarbonyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane, (2R,3S)-3-[tetrahydrofuran-(3S)-3-yl-oxycarbonyl]-amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane, (2R,3S)-3-(tetrahydrothiophene 1,1-dioxide-3-yl-oxycarbonyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo-[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane, (2R,3S)-3-(2,3-dihydrothiophene 1,1-dioxide-3-yl-oxycarbonyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo-[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane, (2S,3S)-3-(tetrahydrofuran-3-yl-oxycarbonyl-L-asparaginyl)amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo-[3.3.0]octan-2-yl}2-acetoxy-4-phenylbutane, and (2S,3S)-3-[tetrahydrofuran-(3S)-3-yl-oxycarbonyl]-amino-1-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-isobutyroxy-4-phenylbutane.
6. A process for the preparation of a compound of the general formula (I) according to Claim 1, characterized in that a) a compound of the formula (II) (II) is reacted with a compound of the general formula (IV) R1-OH (IV) wherein R1 has the meaning indicated in Claim 1; or b) a compound of the formula (III) (III) is reacted with a compound of the general formula (IIIa) R3OCO2H (IIIa) wherein R3 has the meaning indicated in Claim 1;
if appropriate with prior activation of the carboxylic acid, in inert solvents and in the presence of a base and/or of an auxiliary, and in a second step if R ? H an acylation is carried out in inert solvents, if appropriate in the presence of a base and/or of an auxiliary.
if appropriate with prior activation of the carboxylic acid, in inert solvents and in the presence of a base and/or of an auxiliary, and in a second step if R ? H an acylation is carried out in inert solvents, if appropriate in the presence of a base and/or of an auxiliary.
7. A process according to Claim 6, wherein the base is employed in an amount from 1 mole to 10 mole relative to 1 mole of the compound of formula (II) or (III).
8. A medicament containing one or more compounds according to Claims 1 to 5.
9. A medicament according to Claim 8, for the treatment of retroviral infections.
10. Use of one or more compounds according to Claims 1 to 5, for the production of antiretroviral medicaments.
11. Use of one or more compounds according to Claims 1 to 5, for the treatment of retroviral infections.
12. One or more compounds according to Claims 1 to 5, for the treatment of retroviral infections.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19531685.1 | 1995-08-29 | ||
| DE19531685A DE19531685A1 (en) | 1995-08-29 | 1995-08-29 | New heterocyclically substituted pseudopeptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2184146A1 true CA2184146A1 (en) | 1997-03-01 |
Family
ID=7770627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002184146A Abandoned CA2184146A1 (en) | 1995-08-29 | 1996-08-26 | Heterocyclically substituted pseudopeptides |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0761667A1 (en) |
| JP (1) | JPH09124642A (en) |
| KR (1) | KR970010765A (en) |
| CN (1) | CN1148042A (en) |
| AU (1) | AU6421496A (en) |
| CA (1) | CA2184146A1 (en) |
| CZ (1) | CZ253396A3 (en) |
| DE (1) | DE19531685A1 (en) |
| HR (1) | HRP960376A2 (en) |
| HU (1) | HUP9602374A3 (en) |
| IL (1) | IL119136A0 (en) |
| MX (1) | MX9603722A (en) |
| NO (1) | NO963598L (en) |
| PL (1) | PL315851A1 (en) |
| SK (1) | SK110996A3 (en) |
| ZA (1) | ZA967278B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1604662A1 (en) * | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | 1-[(3R)-Amino-4-(2-fluoro-phenyl)-butyl]-pyrrolidine-(2R)-carboxylic acid benzyl amine derivatives and related compounds as dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of type 2 diabetes mellitus |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO1993008184A1 (en) * | 1991-10-23 | 1993-04-29 | Merck & Co., Inc. | Hiv protease inhibitors |
-
1995
- 1995-08-29 DE DE19531685A patent/DE19531685A1/en not_active Withdrawn
-
1996
- 1996-08-13 HR HR19531685.1A patent/HRP960376A2/en not_active Application Discontinuation
- 1996-08-16 EP EP96113160A patent/EP0761667A1/en not_active Withdrawn
- 1996-08-22 JP JP8238618A patent/JPH09124642A/en active Pending
- 1996-08-22 AU AU64214/96A patent/AU6421496A/en not_active Abandoned
- 1996-08-26 IL IL11913696A patent/IL119136A0/en unknown
- 1996-08-26 CA CA002184146A patent/CA2184146A1/en not_active Abandoned
- 1996-08-27 PL PL96315851A patent/PL315851A1/en unknown
- 1996-08-28 ZA ZA967278A patent/ZA967278B/en unknown
- 1996-08-28 MX MX9603722A patent/MX9603722A/en unknown
- 1996-08-28 CZ CZ962533A patent/CZ253396A3/en unknown
- 1996-08-28 NO NO963598A patent/NO963598L/en unknown
- 1996-08-28 KR KR1019960036115A patent/KR970010765A/en not_active Application Discontinuation
- 1996-08-28 SK SK1109-96A patent/SK110996A3/en unknown
- 1996-08-29 CN CN96111429A patent/CN1148042A/en active Pending
- 1996-08-29 HU HU9602374A patent/HUP9602374A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL315851A1 (en) | 1997-03-03 |
| SK110996A3 (en) | 1997-03-05 |
| IL119136A0 (en) | 1996-11-14 |
| HUP9602374A2 (en) | 1997-09-29 |
| CN1148042A (en) | 1997-04-23 |
| AU6421496A (en) | 1997-03-06 |
| MX9603722A (en) | 1997-03-29 |
| KR970010765A (en) | 1997-03-27 |
| HRP960376A2 (en) | 1998-02-28 |
| DE19531685A1 (en) | 1997-03-06 |
| CZ253396A3 (en) | 1997-03-12 |
| EP0761667A1 (en) | 1997-03-12 |
| ZA967278B (en) | 1997-04-16 |
| NO963598D0 (en) | 1996-08-28 |
| NO963598L (en) | 1997-03-03 |
| HU9602374D0 (en) | 1996-10-28 |
| HUP9602374A3 (en) | 1998-01-28 |
| JPH09124642A (en) | 1997-05-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 19990826 |