DE4016994A1 - New anhydro-statin-phosphono:pyrrolidine(s) and -piperidine(s) - useful as antiviral cpds. in human and animal medicine, active against e.g. HIV - Google Patents

Abstract

Pyrrolidine and piperidine-substd. pseudopeptide derivs. of formula (I) and their physiologically acceptable salts are new. W = H, or a typical amino protecting gp., opt. branched 1-6C alkyl or alkenyl (each opt. substd. by 6-10C aryl), R3CO-, R5R4NCO- or R6SO2-; R3 = H, CF3, opt. branched 1-8C alkoxy, 1-18C alkyl (opt. substd. with 6-10C aryl or pyridyl), 6-10C aryl (opt. substd. by halogen, CF3, CF3O or opt. branched 1-8C alkyl), 3-7C cycloalkyl, indolyl, pyridyl, morpholino, piperazinyl, R8YCH2CH(R7)-, R9COOCH(R7)-, R10S(O)mNHCH(R7)-, T-NH(CH2)p-, (v), (R7CH2)2 or (R11)2PO(CH2)sCH(R7)-; R7 = Ph or naphthyl; R8, R10 and R10 = each opt. branched 1-17C alkyl (opt. substd. with Ph or naphthyl) or 6-10C aryl (opt. substd. with 1-4C alkyl); m = 0, 1 or 2; T = morpholino or cyclohexyl; p = 1, 2 or 3; Y and Y' = each CO or SO2; t = 0-1; R11 = opt. different OH or 1-8C alkoxy; s = 1 or 2; R4 and R5 = each H, 6-10C aryl (opt. substd. by opt. branched 1-6C alkyl or halogen), 3-7C cycloalkyl or opt. branched 1-18C alkyl (opt. substd. by pyridyl; R6 = opt. branched 1-8C alkyl; A, B (and D) = a bond or a gp. of formula (i)-(iv) n and n1 = each 1 or 2; r = 0 or 1; z = 0 or 1; R12 = H or opt. branched 1-8 alkyl; R13 = 3-8C cycloalkyl, 6-10C aryl, H or opt. branched 1-8C alkyl, 5-6 membered heterocycle or indolyl in which the corresp. NH functions are opt. protected by 1-6C alkyl); R15 and R15 = each H, opt. branched 1-8C alkyl or Ph; R16 = OH, benzyloxy, 1-6C alkoxy or -NR14R15; R1 = 3-8C cycloalkyl, opt. branched 1-10C alkyl or alkenyl n = 1-2; R2 = -PO(R11)z1-COR17 or -CONR4R5; R17 = opt. branched 1-8C alkoxy opt. substd. by Ph. USE/ADVANTAGE - (I) can be used as antiviral agents in human and animal medicine. (I) are esp. effective against retroviruses. (34pp Dwg.No.0/0)

Description

The invention relates to novel anhydro-statin-phosphonopyrrolidines and -piperidines, process for their preparation and their use as medicines, in particular as antiviral agents in human and veterinary medicine.

It has already been tried, pseudopeptides that partially are also effective in controlling renininhibitor of AIDS [cf. GB A 12 03 740; EP 3 37 714; EP 3 42 541; EP 3 46 847 and EP 3 52 000].

The present invention relates to novel pyrrolidine and piperidine-substituted pseudopeptides of the general Formula (I)

in which
W is hydrogen or a typical amino protecting group, or
- represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which are optionally substituted by aryl having 6 to 10 carbon atoms, or
- represents a group of the formula R³-CO-, R⁵R⁴N-CO- or R⁶-SO₂-,
wherein
R³ is hydrogen, trifluoromethyl or straight-chain or branched alkoxy having up to 8 carbon atoms or alkyl having up to 18 carbon atoms, which are optionally substituted by aryl having 6 to 10 carbon atoms or pyridyl, or
- aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl having up to 8 carbon atoms,
- Cycloalkyl having 3 to 7 carbon atoms, or
- Indolyl, pyridyl, morpholino or piperazinyl means, or
- a remainder of the formula

or (R⁷CH₂) ₂-CH-
means
wherein
R⁷ is phenyl or naphthyl,
R⁸, R⁹ and R¹⁰ are the same or different and are straight-chain or branched alkyl having up to 17 carbon atoms, which is optionally substituted by phenyl or naphthyl, or aryl having 6 to 10 carbon atoms, which in turn is substituted by alkyl having up to 4 carbon atoms is
m is a number 0, 1 or 2,
T - morpholino or cyclohexyl means
p is a number 1, 2 or 3,
Y and Y 'are the same or different and denote the CO or SO₂ group,
t - a number 0 or 1 means
R¹¹ and R¹¹ 'are the same or different and are hydroxy or alkoxy having up to 8 carbon atoms,
s - a number 1 or 2 means
R⁴ and R⁵ are the same or different and
- hydrogen or
- aryl having 6 to 10 carbon atoms, which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms or halogen, or
- cycloalkyl having 3 to 7 carbon atoms, or
straight-chain or branched alkyl having up to 18 carbon atoms, which is optionally substituted by pyridyl,
R⁶ represents straight-chain or branched alkyl having up to 8 carbon atoms,
A, B and D are the same or different and
- for a direct bond or
- for a remainder of the formula

stand,
wherein
x and x 'are the same or different and denote the number 1 or 2
and
r - the number 0 or 1 means
or
- for a group of the formula

stand,
wherein
z - the number 0 or 1 means
R¹² is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
R¹³ is cycloalkyl of 3 to 8 carbon atoms or aryl of 6 to 10 carbon atoms or hydrogen, or
- represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by alkylthio having up to 6 carbon atoms, hydroxy, mercapto, guanidyl or by a group of the formula -NR¹⁴R¹⁵ or R¹⁶-OC-,
wherein
R¹⁴ and R¹⁵ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl
and
R¹⁶ represents hydroxy, benzyloxy, alkoxy having up to 6 carbon atoms or the above-mentioned group -NR¹⁴R¹⁵,
or which is optionally substituted by cycloalkyl of 3 to 8 carbon atoms or by aryl of 6 to 10 carbon atoms, which in turn is substituted by hydroxy, halogen, nitro, alkoxy of up to 8 carbon atoms or by the group -NR¹⁴R¹⁵,
wherein
R¹⁴ and R¹⁵ have the abovementioned meaning,
or optionally substituted by a 5- or 6-membered nitrogen-containing heterocycle or indolyl, wherein the corresponding -NH functions are optionally protected by alkyl of up to 6 carbon atoms or by an amino-protecting group,
R¹ - represents cycloalkyl having 3 to 8 carbon atoms,
- represents straight-chain or branched alkyl or alkenyl having up to 10 carbon atoms, which are optionally substituted by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn by halogen, nitro, hydroxy, amino or straight-chain or branched alkoxy with up to 6 carbon atoms,
n - stands for the number 1 or 2,
R² - for a radical of the formula

-CO-R¹⁷ or -CO-NR⁴R⁵ stands,
wherein
R⁴, R⁵, R¹¹ and R¹¹ 'are as defined above,
R¹⁷ - straight-chain or branched alkoxy having up to 8 carbon atoms, which is optionally substituted by phenyl
and their physiologically acceptable salts.

The compounds of the general formula according to the invention (I), have several asymmetric carbon atoms. They can be used independently in the D- or L- Form present. The invention includes the optical antipodes as well as the isomer mixtures or racemates. Prefers the groups A, B and D are independent of each other in the optically pure, preferably in the L-form in front.

The rest of the general formula (VIII)

has 2 asymmetric carbon atoms (1, 2), which independently in the R or S configuration may be present.

The geometry of the double bond can be both trans (E) as well as cis (Z).

Amino protecting groups in the context of the invention are the common amino protecting groups used in peptide chemistry.

These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5- Trimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl, tert-butoxycarbonyl, Cyclohexoxycarbonyl, 1,1-dimethyloxycarbonyl, adamantylcarbonyl, Phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, Phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-  Bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene.

The compounds of the general Formula (I) may be in the form of their salts. This may salts with inorganic or organic acids or bases.

Preference is given to compounds of the general formula (I)
in which
W - for hydrogen, tert. Butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Z), or
represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, which are optionally substituted by phenyl, or
- represents a group of the formula R³-CO- or R⁵R⁴N-CO-,
wherein
R³ - hydrogen, trifluoromethyl or straight-chain or branched alkoxy having up to 4 carbon atoms or alkyl having up to 16 carbon atoms, which are optionally substituted by phenyl, naphthyl or pyridyl, or
Phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl having up to 6 carbon atoms,
- cyclopropyl, cyclopentyl, cyclohexyl, indolyl, pyridyl, morpholino or piperazinyl, or
- a remainder of the formula

means
wherein
Y - the CO or SO₂ group means
R⁷ is phenyl or naphthyl,
R⁸, R⁹ and R¹⁰ are identical or different and denote straight-chain or branched alkyl having up to 15 carbon atoms, tolyl, phenyl or naphthyl,
m - a number 1 or 2 means
R⁴ and R⁵ are the same or different and
- hydrogen or
Phenyl or naphthyl, which is optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, fluorine or chlorine,
- cyclopropyl, cyclopentyl or cyclohexyl, or
straight-chain or branched alkyl having up to 16 carbon atoms, which is optionally substituted by pyridyl,
A, B and D are the same or different and
- for a direct bond or
- stand for proline, or
- for a remainder of the formula

stand,
wherein
r is the number 0 or 1
and
x 'is the number 1 or 2,
- for a group of the formula

stand,
wherein
z - the number 0 or 1 means
R¹² represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R¹³ is cyclopentyl, cyclohexyl, phenyl or hydrogen,
- or straight-chain or branched alkyl having up to 6 carbon atoms, which may optionally be substituted by hydroxyl, carboxyl or H₂N-CO-,
or is substituted by cyclohexyl, naphthyl or phenyl, which in turn may be substituted by fluorine, hydroxy, nitro or alkoxy having up to 4 carbon atoms,
or is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, where the corresponding -NH functions are optionally protected by alkyl having up to 4 carbon atoms or by an amino-protecting group,
R¹ - represents cyclopropyl, cyclopentyl or cyclohexyl,
represents straight-chain or branched alkyl or alkenyl having up to 8 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, which in turn is substituted by fluorine, chlorine, bromine, nitro, hydroxy or amino,
n - stands for the number 1 or 2,
R² - for a radical of the formula

-CO-R¹⁷ or -CO-NR⁴R⁵ stands,
wherein
R⁴ and R⁵ are the same or different and have the meaning given above,
R¹¹ and R¹¹ 'are identical or different and denote hydroxy or straight-chain or branched alkoxy having up to 6 carbon atoms,
R¹⁷ - straight-chain or branched alkoxy having in each case up to 6 carbon atoms, which is optionally substituted by phenyl
and their physiologically acceptable salts.

Particular preference is given to compounds of the general formula (I)
in which
W - for hydrogen, tert. Butyloxycarbonyl (BOC) or benzyloxycarbonyl (Z), or
- represents allyl or benzyl,
- represents a group of the formula R³-CO- or R⁵R⁴N-CO-,
wherein
R³ - hydrogen, trifluoromethyl or straight-chain or branched alkyl having up to 14 carbon atoms, which are optionally substituted by phenyl, naphthyl or pyridyl, or
Is phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl having up to 1 carbon atoms,
- cyclopropyl, cyclopentyl, cyclohexyl, indolyl, pyridyl, morpholino or piperazinyl, or
- a remainder of the formula

means
wherein
Y - the CO or SO₂ group means
R⁷ is phenyl or naphthyl,
R⁸, R⁹ and R¹⁰ are the same or different and denote straight-chain or branched alkyl having up to 14 carbon atoms, tolyl, phenyl or naphthyl,
m - a number 1 or 2 means
R⁴ and R⁵ are the same or different and
- hydrogen or
Phenyl or naphthyl, which is optionally substituted by methyl, fluorine or chlorine,
- cyclopropyl, cyclopentyl or cyclohexyl, or
straight-chain or branched alkyl having up to 14 carbon atoms, which is optionally substituted by pyridyl,
A, B and D are the same or different and
- stand for a direct bond, or
- stand for proline, or
- for a group of the formula

stand,
wherein
z - the number 0 or 1 means
R¹² is hydrogen or methyl,
R¹³ is cyclopentyl or cyclohexyl,
- or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or H₂N-CO-,
or is substituted by cyclohexyl, naphthyl or phenyl, which in turn may be substituted by fluorine, chlorine or alkoxy having up to 4 carbon atoms, or
is substituted by imidazolyl, triazolyl, pyridyl or pyrazolyl, where the NH function is optionally protected by methyl, benzyloxymethylene or t-butyloxycarbonyl (Boc),
R¹ - represents cyclopentyl or cyclohexyl, or
represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which in turn may be substituted by hydroxyl,
n - stands for the number 1 or 2,
R² - for a radical of the formula

-CO-R¹⁷ or -CO-NR⁴R⁵ stands,
wherein
R⁴ and R⁵ are the same or different and have the meaning given above,
R¹¹ and R¹¹ 'are the same or different and denote hydroxy or straight-chain or branched alkoxy having up to 4 carbon atoms,
R¹⁷ - straight-chain or branched alkoxy having in each case up to 4 carbon atoms, which is optionally substituted by phenyl
and their physiologically acceptable salts.

In addition, a method for producing the Compounds of the general formula according to the invention (I)

in which
W, A, B, D, R¹, R² and n are as defined above,
found, characterized in that one

• [A] Compounds of general formula (Ia) in which
  R¹, R² and n have the abovementioned meaning,
  via the corresponding salts, preferably via the trifluoroacetates,
  either with compounds of the general formula (II) WABD-OH (II) in which
  W, A, B and D are as defined above,
  with activation of the carboxylic acid,
  or with compounds of the general formulas (III) or (IV) WX (III) (W '') ₂O (IV) in which
  W has the meaning given above
  X is halogen, preferably chlorine,
  and
  W '' is the group CF₃CO or CH₃CO,
  condensed according to the conditions customary in peptide chemistry, in inert solvents, if appropriate in the presence of an adjuvant,

or

• [B] Compounds of the general formulas (V) or (VI) in which
  R¹, W, A, B and D have the abovementioned meaning
  and
  W 'is an amino protecting group, preferably BOC,
  with compounds of the general formula (VII) in which
  R 2 and n have the abovementioned meaning, with activation of the carboxylic acids, optionally in the presence of a base and an auxiliary and in the case of the compounds of general formula (V) the protecting group W 'then cleaved by a conventional method and optionally with the compounds of the general Formulas (II), (III) or (IV) according to the method described in method [A] further.

The methods of the invention can be achieved by the following Formula scheme are explained by way of example:

Suitable solvents are suitable for all process steps the usual inert solvents that are among the Do not change reaction conditions. These include preferably organic solvents such as ethers z. B. diethyl ether, Glycol mono or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, Xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, Hexamethylphosphoric triamide, ethyl acetate, Pyridine, triethylamine or picolines. It is also possible Use mixtures of the solvents mentioned. Particularly preferred are dichloromethane, chloroform, Dimethylformamide or tetrahydrofuran.  

As adjuvants for the respective peptide couplings preferably condensing agent used, which also Bases may be, especially if the carboxyl group activated as anhydride. Preference will be here the usual condensing agents such as carbodiimides z. B. N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'- Dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) - N'-ethylcarbodiimide hydrochloride, N-cyclohexyl-N '- (2- morpholinoethyl) carbodiimide metho-p-toluenesulfonate, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2- oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2- Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or Propanephosphonic anhydride, or isobutylchloroformate, or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or 1-hydroxybenzotriazole.

In addition, for example, alkali metal carbonates z. B. Sodium or potassium carbonate or bicarbonate, or organic bases such as trialkylamines z. Triethylamine, N-ethylmorpholine, N-methylpiperidine or N-methylmorpholine be used. Preference is given to N-methylmorpholine.

The excipients and bases are in an amount of 1.0 Mol to 3.0 mol, preferably 1.0 to 1.2 mol, based on in each case 1 mol of the compounds of the general formula (V) or (VI) used.  

The peptide clutches are in a temperature range from 0 ° C to 100 ° C, preferably at 0 ° C to 30 ° C and carried out at atmospheric pressure.

The reactions can be carried out both at atmospheric pressure as well at elevated or reduced pressure (for example 0.5 to 5 bar), preferably at atmospheric pressure become.

The compounds of general formula (Ia) are also new and can after the above listed Method [B] are produced.

The compounds of the general formulas (II), (III) and (IV) are known or can by the usual method getting produced.

The compounds of the general formulas (V) and (VI) are partly known or new and may be in the latter Case starting from the corresponding esters Saponification can be prepared by conventional method [see US 47 25 584; EP 2 09 897; EP 1 63 237; J. Med. Chem. 31, 1377 (1988), 29, 104 (1968); THL, 43, 4297 (1987)].

The compounds of general formula (VII) are also known [n = 1 cf. US 41 86 268; Y. Nomura et al., Chem. Lett., 693 (1977); n = 2 cf. V.A. Solodenko et al., Zh. Obshch. Khim. 57, 2392 (1987)].

It has surprisingly been found that the compounds of general formula (I) is extremely strong  Possess activity against retroviruses. This will come with a HIV-specific protease enzyme test demonstrated.

The results of the examples below were after the in the following references [vgl. Hansen, J., Billich, S., Schulze, T., Sukrow, S. and Mölling, K. (1988), EMBO Journal, Vol, 7, no. 6, pp. 1785-1791] HIV test system detects: purified HIV Protease was mixed with synthetic peptide containing a Interface imitated in gag precursor protein and a in vivo cleavage site of the HIV protease, incubated. The resulting fission products of the synthetic Peptides were via Reverse Phase High Performance Liquid Chromatography (RP-HPLC) analyzed. The specified IC₅₀ values refer to the substance concentration, under the test conditions listed above causes a 50% inhibition of protease activity.

Example no. IC₅₀ (RP-HPLC) (M) 3 <10 ^-5 7 <10 ^-5 27 <10 ^-5 33 10 ^-8 60 <10 ^-5 62 <10 ^-5

In addition, the compounds of the invention showed activity in the infected cell culture. This could be exemplified of the visnavirus and the HIV virus [cf. Kühnel, H.  et al., Proc. Natl. Acad. Sci, USA Vol. 86, p. 2382 (1989); Popovic, M. et al., Science 224, p. 497 (1984)] to be shown.

The Visna virus and the HIV virus (virus of the human Immunodeficiency) both belong to the retrovirus subfamily the lentiviruses. Both viruses have a similar one Genome organization and one over the other Retroviruses complex transcription pattern on.

Known inhibitors of HIV also inhibit the Visna virus in vitro in comparable concentrations, d. h., this one Model is suitable for the examination and detection of Inhibitors of HIV.

In cell cultures infected with Visna virus, Significant 5 to 10 days after infection virus-induced, cytopathic effects on. By treatment the infected cell cultures with the inventive Connections could be the occurrence of these Cytopathic effects are prevented.

The Visna virus test was performed by the O method. Narayan et al., Journal of Infectious Diseases 135, 5, 1977, 800-806. For this purpose, the inventive Compounds in the culture medium in non-cytotoxic Concentrations in 96-well microtiter plates diluted. Subsequently, fibroblast cells from the Sheep (5 x 10⁴ cells per well) in production medium supplied to each cup. Each cup was then received 50 μl of a Visna virus solution with a titer of approx.  2.5 × 10⁴ TCID₅₀ (TCID = tissue culture infections dose). This virus dose corresponds to an MOI (multiplicity the infection) of about 0.05.

Under these infection conditions resulted between Day 5 and day 10 in an infection control without substance a virus-induced, cytopathic effect. The infected and treated cells and the control cells were incubated for 7 days at 37 ° C 5% CO₂.

When the virus-induced cytopathogenic effect occurs with the untreated virus control were cultures fixed with formalin and then with a Colored Giemsa solution. The inhibitory concentration (IC₅₀) was determined microscopically as the concentration in which the cytopathic effect is inhibited by 50% was compared to the untreated virus control, which had 100% cell destruction.

It has been found that the compounds of the invention virus-infected cells infected with Visna virus Protect cell destruction.

Example no. IC₅₀ (μM) 46 (nonpolar isomer) 4.1 46 (polar isomer) 6.1 61 5.2 62 48.9 63 16 64 16

The compounds of the invention are suitable as Active ingredients for the treatment and prophylaxis of diseases, caused by retroviruses, in the Human and veterinary medicine.

As indications in human medicine, for example to be named:

• 1. The treatment or prophylaxis of human Retrovirus infections.
• 2. For the treatment or prophylaxis of HIV I (virus human immunodeficiency; formerly HTLV III / LAV called) and HIV II related diseases (AIDS) and associated stages such as ARC (AIDS related complex) and LAS (Lymphadenopathy Syndrome) as well as the immunodeficiency caused by this virus and encephalopathy.
• 3. For the treatment or prophylaxis of HTLV I or HTLV II infection.
• 4. For the treatment or prophylaxis of the AIDS carrier Condition (AIDS transmitter condition).

Examples of indications in veterinary medicine include:
Infections with

• a) Maedivisna (in sheep and goats)
• b) progressive pneumonia virus (PPV) (in sheep and goats)  
• c) caprine arthritis encephalitis virus (in sheep and goats)
• d) Zwoegerziekte virus (in sheep)
• e) infectious anemia (horse) virus
• f) infections caused by the Feline leukemia virus
• g) Infections caused by the virus Feline immunodeficiency.

Preference is given to the field of indication in human medicine the above points 2, 3 and 4.

The present invention includes pharmaceutical preparations, In addition to non-toxic, inert pharmaceutical suitable carriers one or more compounds of the formula (I) or from one or several active compounds of the formula (I) exist, and methods for the preparation of these preparations.

The active compounds of the formula (I) are described in the above pharmaceutical preparations, preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture his.

The above-listed pharmaceutical preparations may, in addition to the compounds of formula (I) also contain further pharmaceutical active ingredients.

The preparation of the pharmaceuticals listed above Preparations are carried out in the usual way according to known Methods, eg. B. by mixing the active substance or with the one or more excipients.  

In general, it has become both in the human and proven in veterinary medicine, the or the active compounds of the formula (I) in total amounts of from about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight every 24 hours, possibly in the form of several Single doses to achieve the desired results to administer. A single gift contains the one or more Active ingredients preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg of body weight. It can however, be required by the doses mentioned to deviate, depending on the species and the body weight of the object to be treated, the type and the severity of the disease, the way of preparation and the application of the medicine and the period or interval within which the administration takes place.  

Appendix to the experimental part I. List of the solvent mixtures used for chromatography

I dichloromethane: methanol
II toluene: ethyl acetate
III acetonitrile: water
IV dichloromethane: methanol: ammonia 9: 1: 0.1

II. Amino acids

In general, the name of the configuration is made by prefixing an L or D before the amino acid abbreviation, in the case of the racemate by a D, L- where for convenience in L-amino acids the configuration name can be omitted and then only in the case the D-form or the D, L mixture Explicit designation is carried out.

Ala L-alanine
Arg L-arginine
Asn L-asparagine
Asp L-aspartic acid
Cys L-cysteine
Gln L-glutamine
Glu L-glutamic acid
Gly L-glycine
His L-histidine
Ile L-isoleucine
Leu L-Leucine
Lys L-lysine
Met L-methionine
Pro L-proline
Phe L-phenylalanine
Ser L-serine
Thr L-threonine
Trp L-tryptophan
Tyr L-Tyrosine
Val L-valine

III. Abbreviations

BOC tert. butoxycarbonyl
CMCT 1-Cyclohexyl-3- (2-morpholino-ethyl) carbodiimide-metho-p-toluenesulfonate
DCC dicyclohexylcarbodiimide
DMF dimethylformamide
HOBT 1-hydroxybenzotriazole
Me Miristoyl
Ph phenyl
THF tetrahydrofuran

starting compounds example I (4S) -4 - [(tert -butoxycarbonyl) amino] -5-phenyl-2-pentenoic acid

9.26 g (30.3 mmol) of (4S) -4 - [(tert-butoxycarbonyl) amino] -5-phenyl-2-pentenoic acid methyl ester [cf. DHR Barton et al., Tetrahedron 43, 4297, (1987); Thompson, Th., Et al., J. Med. Chem. 29, 104 (1986)] and 2.54 g (60.6 mmol) of lithium hydroxide hydrate were refluxed in a mixture of 16 ml of tetrahydrofuran and 7 ml of water for 15 minutes , Thereafter, it was stirred in a mixture of 200 ml of ethyl acetate and 200 ml of water. The water phase (about pH 10) was separated, treated with 100 g of ice and 200 ml of ethyl acetate and adjusted to pH 3.0 with 1 N hydrochloric acid. The organic phase was separated and the water phase extracted again with 50 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate. Evaporation of the solvent and trituration of the residue with a little diethyl ether gave 7.07 g (80% of theory) of the title compound as colorless crystals.
Mp .: 160 ° C
R _f = 0.59 (acetonitrile: water = 9: 1)
MS (FAB): m / z = 292 (M + H) ⁺, 314 (M + Na) ⁺, 335 (M + 2Na-H) ⁺

example II (4S) -4 - [(tert -butoxycarbonyl) amino] -5-cyclohexyl-2- pentenoic

As described for Example I, 123 g of 159 g (511 mmol) of (4S) -4 [(tert-butoxycarbonyl) -amino] -5-cyclohexyl-2-pentenoic acid methyl ester (JR Luly et al., US Pat. No. 4,725,584) were obtained (81% of theory) of the title compound as colorless crystals.
M.p .: 140 ° C
R _f = 0.34 (dichloromethane: methanol = 95: 5)
MS (DCI, NH₃): m / z = 298 (M + H) ⁺, 315 (M + NH₄) ⁺

example III N- (tert-butoxycarbonyl) -N- [2- (2-pyridinyl) ethyl-L- prolinamide

A stirred solution of 15.06 g (70.0 mmol) BOC-L-proline in 100 ml dichloromethane was added at 0 ° C with 9.2 ml (77.0 mmol) 2- (2-aminoethyl) -pyridine, 13 , 4 g (87.5 mmol) of 1-hydroxybenzotriazole (HOBT) and 16.61 g (80.5 mmol) of dicyclohexylcarbodiimide (DCC). The mixture was stirred for 15 h at room temperature, the precipitated urea was separated by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in 200 ml of ethyl acetate, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. Chromatography of the crude product on silica gel (dichloromethane: methanol = 10: 1) gave 20.6 g (92% of theory) of the title compound.
R _f = 0.50 (dichloromethane: methanol = 10: 1)
MS (EI, 70 eV): m / z = 319 (M) ⁺

example IV N- [2- (2-pyridinylethyl)] - L-prolinamide

A solution of 20.6 g (65 mmol) of the compound from Example III in 150 ml of a 4 N solution of gaseous hydrogen chloride in dioxane was stirred in the presence of 30 ml of anhydrous methanol for 8 h at 0 ° C. It was then concentrated under reduced pressure and the residue was dissolved in 10% aqueous sodium carbonate solution (pH 10). This solution was concentrated to dryness and the residue was extracted with warm dichloromethane. Drying of the organic phase over sodium sulfate and evaporation of the solvent in vacuo gave 12.4 g (87% of theory) of the title compound.
R _f = 0.34 (dichloromethane: methanol: ammonia = 9: 1: 0.1)

example V Me-Phe-Phe-Val-OCH₃

A stirred, cooled to 0 ° C solution of 3.94 g (10.5 mmol) of N-Miristoyl-L-phenylalanine [cp. US 43 96 543; GB 21 20 257; AV Prabhudesai et al., Chem. Phys. Lipids 22, 71 (1978)] and 1.49 g (11.0 mmol) of HOBT in 30 ml of anhydrous dimethylformamide were added 2.17 g (10.5 mmol) of DCC and stirred at 0 ° C for 2 h. To this mixture was added dropwise a solution of 3.14 g (10.0 mmol) of HCl-Phe-Val-OCH₃ and 3.30 ml (30.0 mmol) of N-methylmorpholine in 15 ml of dimethylformamide and stirred in a thawing ice bath for 15 h to. The resulting precipitate was separated by filtration and washed with 50 ml of toluene. The filtrate was concentrated in vacuo with 50 ml of toluene and concentrated again. The residue was dissolved in 200 ml of ethyl acetate, a little insoluble material was separated by filtration, the organic phase was washed with 100 ml of water and dried over magnesium sulfate. After evaporation of the solvent in vacuo and chromatography of the residue on 350 g of silica gel (toluene: ethyl acetate 1: 1) gave 1.9 g (30% of theory) of the title compound as a colorless powder.
M.p .: 140 ° C
R _f = 0.42 (toluene: ethyl acetate 1: 1)
MS (FAB) m / z = 636 (M + H) ⁺, 658 (M + Na) ⁺

example VI Me-Phe-Phe-Val-OH

A solution of 1.27 g (20 mmol) of the compound from Example V in 15 ml of tetrahydrofuran was treated with a solution of 170 mg (4.0 mmol) of lithium hydroxide in 4 ml of water and stirred for 3 h at room temperature. Thereafter, the reaction mixture was poured into a mixture of 50 ml of water, 10 g of ice and 50 ml of ethyl acetate and adjusted by addition of 1 N hydrochloric acid pH 3. The organic phase was separated, the water phase extracted with 50 ml of ethyl acetate and the combined organic extracts were dried over magnesium sulfate. After evaporation of the solvent in vacuo and treating the residue with 5 ml of ether and 30 ml of n-pentane gave 1.03 g (83% of theory) of the title compound as colorless crystals.
M.p .: 173 ° C
HPLC purity: <96%
R _f = 0.41 (acetonitrile: water = 9: 1)
MS (FAB): m / z 622 (M + H) ⁺, 644 (M + Na) ⁺

example VII Me-Val-Phe-Val-OCH₃

As described for Example V, 3.44 g (10.5 mmol) of N-miristoyl-L-valine [cf. Iyer et al., J. Indian Chem. Soc. 59, 856 (1982); DE 22 34 399; Fri 21 92 795] and 3.14 g (10.0 mmol) of HCl · Phe-Val-OCH₃ 1.70 g (29% of theory) of the title compound as colorless crystals.
M.p .: 170 ° C
R _f = 0.36 (toluene: ethyl acetate 1: 1)
MS (FAB): m / z = 588 (M + H) ⁺, 600 (M + Na) ⁺

example VIII Me-Val-Phe-Val-OH

We described for Example VI was obtained from 1.06 g (1.8 mmol) of Mir-Val-Phe-Val-OCH₃ 780 mg (79% of theory) of the title compound as colorless crystals.
M .: 233 ° C
HPLC purity: <94%
R _f = 0.36 (acetonitrile: water 9: 1)
MW (FAB): m / z = 580 (M + Li) ⁺, 596 (M + Na) ⁺

Preparation Examples (general formula I) Example 1 1 - {(4s) -4 - [(tert-butoxycarbonyl) amino] -5-phenyl-2- pentenoyl} - (2R, S) -2 - ((pyrrolidinyl) -phosphonic acid diethyl ester

A solution of 6.18 g (21.2 mmol) of the compound of Example I in 50 ml of anhydrous dimethylformamide was added at 0.degree. C. to 3.15 g (23.32 mmol) of HOBT and 4.59 g (22.3 mmol ) DCC offset. The cooling bath was removed and stirred for 1 h at room temperature. It was then cooled again to 0 ° C and it was added dropwise a solution of 4.83 g (23.32 mmol) of diethyl 2 (R, S) -2- (pyrrolidinyl) phosphonic acid [see. EW Petrillo et al., Tetrahedron Lett. 51, 4929 (1979); No. 4,186,268] in 50 ml of dimethylformamide and 5.1 ml (46.64 mmol) of N-methylmorpholine. The cooling bath was removed and stirred for 2 h at room temperature. The resulting precipitate was separated by filtration, the filtrate was treated with 50 ml of toluene and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate, washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvent in vacuo and chromatography of the crude product on 600 g of silica gel (dichloromethane: methanol = 95.5) gave 8.10 g (80% of theory) of the title compound as a viscous oil.
R _f = 0.29 (dichloromethane: methanol 95: 5)
MS (FAB) m / z = 481 (M + H) ⁺, 503 (M + Na) ⁺

example 2 1 - {(4S) -4- [tert. Butoxycarbonyl) amino] -5-phenyl-2- pentenoyl} -N- [2- (2-pyridinylether)] - L-prolinamide

To a cooled to 0 ° C, stirred solution of 5.01 g (17.2 mmol) of the compound from Example I, 3.42 g (15.6 mmol) of the compound of Example IV and 2.99 g (19, 5 mmol) of HOBT in 50 ml of anhydrous dichloromethane were added portionwise over 15 min 3.86 g (18.7 mmol) of DCC. The reaction mixture was stirred for 16 h in a thawing ice bath, then the resulting precipitate was separated by filtration. The filtrate was washed twice each with 50 ml of saturated sodium bicarbonate solution and NaCl solution and dried over sodium sulfate. After evaporation of the solvent in vacuo and chromatography of the crude product on 500 g of silica gel (dichloromethane: methanol: ammonia = 9: 1: 0.1) gave 5.78 g (75% of theory) of the title compound as a rigid foam.
R _f = 0.47 (dichloromethane: methanol: ammonia = 9: 1: 0.1)
MS (EI, 70eV) m / z = 492 (M) ⁺

example 3 1 - {(4S) -4 - [(tert-butoxycarbonyl) amino] -5-cyclohexyl-2-one pentenoyl} - (2R, S) -2- (pyrrolidinyl) -phosphonic acid diethyl ester

A solution of 180 g (0.61 mmol) of the compound of Example II in 900 ml of anhydrous dimethylformamide was treated at 0 ° C with 90 g (0.66 mol) of HOBT and after its dissolution with 269 g (0.64 mol) of 1 -Cyclohexyl-3- (2-morpholinoethyl) - carbodiimide-metho-p-toluenesulfonate (CMCT). The cooling bath was removed and stirred for 2 h at room temperature. It was then cooled again to 0 ° C and a solution of 138 g (0.66 mol) of diethyl 2 (R, S) -2- (pyrrolidinyl) phosphonic acid in 300 ml of dimethylformamide and 161 ml (2.23 mol) N was added dropwise Methylmorpholine too. The cooling bath was removed and stirred for 15 h at room temperature. Thereafter, the reaction mixture was concentrated in vacuo and the residue was partitioned between 1 liter of water and 1 liter of ethyl acetate. The water phase was extracted with 500 ml of ethyl acetate, the combined organic extracts were washed with 500 ml of water and dried over sodium sulfate. Evaporation of the solvent in vacuo and chromatography of the crude product on 8 kg of silica gel (dichloromethane: methanol 94: 6) gave 236 g (80% of theory) of the title compound as a viscous oil.
R _f = 0.24 (dichloromethane: methanol 95: 5)
MS (FAB): m / z = 487 (M + H) ⁺, 509 (M + Na) ⁺
Diastereomer ratio: 1: 1.16 (HPLC)

example 4 1 - {(4S) -4 - [(tert-butoxycarbonyl) amino] -5-cyclohexyl-2-one pentenoyl-L-proline benzyl ester

As described for Example 3, 1.00 g (3.37 mmol) of the compound from Example II and 0.82 g (3.37 mmol) of L-proline benzyl ester hydrochloride are obtained after chromatography of the crude product over 94 g of silica gel (toluene: ethyl acetate = 15:85) 1.10 g (67% of theory) of the title compound as an oil.
R _f = 0.48 (toluene: ethyl acetate 1: 9)
MS (FAB): m / z = 485 (M + H) ⁺

example 5 1 - {(4S-4 - [(tert-butoxycarbonyl) amino] -5-cyclohexyl-2-one pentenoyl} -L-proline

As described for Example 3, 1.00 g (3.37 mmol) of the compound from Example II and 0.61 g (3.71 mmol) of L-proline methyl ester hydrochloride were obtained after chromatography of the crude product on 73 g of silica gel (dichloromethane: methanol 95: 5) 866 mg (63% of theory) of the title compound as a foam.
R _f = 0.32 (dichloromethane: methanol = 95: 5)
MS (DCI, NH₃): m / z = 409 (M + H) ⁺

example 6 1 - [(4S) -4-amino-5-phenyl-2-pentenoyl] - (2R, S) -2- (pyrrolidinyl) phosphonic acid diethyl ester trifluoroacetate

A cooled to 0 ° C solution of 465 mg (0.96 mmol) of the compound from Example 1 and 104 .mu.l (0.96 mmol) of anisole in 1 ml of anhydrous dichloromethane was treated with 2.0 ml of trifluoroacetic acid. The cooling bath was removed and stirred for 20 minutes at room temperature. 2 ml of toluene were added and concentrated in vacuo. The residue was treated with 2 ml of toluene and concentrated again in vacuo. This process was repeated twice more. Drying under high vacuum gave 551 mg (94% of theory) of the title compound as an oil.
R _f = 0.31 (dichloromethane: methanol 9: 1)
MS (FAB): m / z = 381 (M + H) ⁺, 403 (M + Na) ⁺, 419 (M + K) ⁺

example 7 1 - [(4S) -4-amino-5-cyclohexyl-2-pentenoyl] - (2R, S) -2- (pyrrolidinyl) phosphonic acid diethyl ester trifluoroacetate

As described for Example 6, from 10.10 g (20.76 mmol) of the compound from Example 2 in the presence of 6.30 ml of anisole, 12.62 g (99% of theory) of the title compound were obtained as an oil.
R _f = 0.30 (dichloromethane: methanol 9: 1)
MS (FAB): m / z = 387 (M + H) ⁺, 409 (M + Na) ⁺

example 8 1 - [(4S) -4-amino-5-cyclohexyl-2-pentenoyl] -L-proline benzyl ester trifluoroacetate

As described for Example 6, from 927 mg (1.91 mmol) of the compound of Example 4 in the presence of 0.4 ml of anisole and trituration of the crude product in ether, 947 mg (81% of theory) of the title compound were obtained as colorless crystals.
Mp .: 128 ° C
R _f = 0.58 (dichloromethane: methanol 4: 1)
MS (DCI, NH₃): m / z = 385 (M + H) ⁺

example 9 1 - [(4S) -4-amino-5-cyclohexyl-2-pentanoyl] -2-proline methyl ester trifluoroacetate

As described for Example 8, 601 mg (1.47 mmol) of the compound from Example 5 gave 568 mg (72% of theory) of the title compound as colorless crystals.
M.p .: 193 ° C
R _f = 0.24 (dichloromethane: methanol 9: 1)
MS (FAB): m / z = 309 (M + H) ⁺

example 10 1 - [(4S) -4-acetylamino-5-cyclohexyl-2-pentenoyl] -L- proline

To a cooled to 0 ° C solution of 134 mg (0.25 mmol) of the compound of Example 9 in 1 ml of anhydrous dimethylformamide and 110 ul (0.99 mmol) N-methylmorpholine were added dropwise 29 ul (0.31 mmol) of acetic anhydride , After 15 min at 0 ° C was poured into a mixture of 20 ml of ice-cold sodium bicarbonate solution and 10 ml of ethyl acetate and stirred well. The organic phase was separated, the water phase extracted with 10 ml of ethyl acetate and the combined organic extracts dried over magnesium sulfate. Evaporation of the solvent in vacuo and repeated dissolution and concentration again with toluene and dichloromethane gave 87 mg (99% of theory) of the title compound as a colorless foam.
R _f = 0.44 (dichloromethane: methanol 9: 1)
MS (DCI, NH₃): m / z = 351 (M + H) ⁺

As described for Example 10 starting from the compounds of Example 7 [R² = P (O) (OC₂H₅) ₂], Example 8 (R² = COO-CH₂-Ph) or Example 9 (R² = COOCH₃) by reaction with an acylating agent (W'COX) after chromatography on silica gel in the stated solvent mixture, the following products (Table 1).

example 30 1 - [(4S) -5-cyclohexyl-4- (2-indolylcarbonyl) amino] - (2R) and (2S) -2- (pyrrolidinyl) phosphonic acid diethyl ester

A stirred solution of 125 mg (0.77 mmol) indole-2-carboxylic acid in 1.5 ml dimethylformamide was treated at 0 ° C with 115 mg (0.85 mmol) HOBT and 342 mg (0.80 mmol) CMCT. The cooling bath was removed and stirred for 2 h at room temperature. It was then cooled again to 0 ° C and a solution of 430 mg (0.70 mg) of the compound from Example 7 and 0.31 ml (2.8 mmol) of N-methylmorpholine in 1.5 ml of dimethylformamide was added dropwise and stirred 16 h in the thawing ice bath. Thereafter, the reaction mixture was concentrated in vacuo and the residue was partitioned between 25 ml of water and 25 ml of ethyl acetate. The water phase was extracted with 20 ml of ethyl acetate and the combined organic extracts were dried over magnesium sulfate. Evaporation of the solvent in vacuo and chromatography of the residue on 90 g of silica gel (dichloromethane: methanol 95: 5) gave 118 mg (29% of theory) of the nonpolar diastereomer as a foam.
R _f = 0.29 (dichloromethane: methanol 95: 5)
MS (FAB): m / z = 530 (M + H) ⁺
and also 159 mg (43% of theory) of the polar diastereomer as a foam.
R _f = 0.24 (dichloromethane: methanol 95: 5)
MS (FAB): m / z = 530 (M + H) ⁺

As described for Example 30, the following products of the general formula (I) were obtained by reacting the indicated trifluoroacetates with the corresponding carboxylic acids (Table 2):

As described for Example 6 was obtained by treating the corresponding tert. Butoxycarbonyl-protected compounds with trifluoroacetic acid and treating with ether following products as trifluoroacetates (Table 3).

example 59 1 - {(4S) -4 - [(tert-butoxycarbonyl) amino] -5-phenyl-2-pentenoyl} - (2R, S) -2- (pyrrolidinyl) phosphonsäuremonoethylester lithium salt

To a stirred solution of 78 mg (0.16 mmol) of the compound of Example 1 in 2 mL of anhydrous acetonitrile was added 74 mg (0.36 mmol) of anhydrous lithium iodide and 30 μL (0.36 mmol) of pyridine and dried for 2.5 h heated to reflux. It was then allowed to cool, treated with 5 ml of toluene and concentrated to dryness in vacuo. This procedure was repeated twice before the crude product was filtered on 1.2 g of silica gel (dichloromethane: methanol 4: 1). The product-containing fractions were concentrated, dissolved in 1 ml of water and adjusted to pH 7.5 by addition of aqueous 1N LiOH solution. Chromatography of this aqueous solution on a Merck-Lobar LiChroprep RP-8 finished column, size A (water with increasing acetonitrile content) and freeze-drying of the product fractions gave 24 mg (32% of theory) of the title compound as a colorless lyophilizate.
R _f = 0.24 (dichloromethane: methanol 4: 1)
MS (FAB): m / z = 459 (M + H) ⁺, 465 (M + Li) ⁺

example 60 1 - [(4S) -4-amino-5-phenyl-2-pentenoyl] - (2R, S) -2- (Pyrrolidinyl) phosphonic acid monoethyl ester sodium salt

To a cooled to 0 ° C, stirred solution of 961 mg (2.0 mmol) of the compound of Example 1 in 4 ml of anhydrous dichloromethane was slowly added dropwise 0.60 ml (4.4 mmol - 2.2 equivalents) of trimethyliodosilane. The mixture was stirred for 1.5 h at 0 ° C and gently concentrated in vacuo. The residue was partitioned between 20 ml of ethyl acetate and 20 ml of water. The cold water phase was adjusted to pH 8 with 1 N NaOH. The organic phase was separated and discarded. The water phase was concentrated in vacuo to a volume of 5 ml and chromatographed on a Merck-Lobar LiChroprep RP-8 finished column, size B (water with increasing acetonitrile content). After freeze-drying of the product fractions, 355 mg (51% of theory) of the title compound were obtained as lyophilizate.
R _f = 0.18 (dichloromethane: methanol 4: 1)
MS (FAB): m / z = 375 (M + H) ⁺

example 61 1 - {(4S) -4 - [(tert-butylaminocarbonyl) amino-5-cyclohexyl 2-pentenoyl} - (2R, S) -2- (pyrrolidinyl) -phosphonic acid diethyl ester

To a stirred solution of 330 mg (0.54 mmol) of the compound of Example 7 and 150 μl (1.07 mmol) of triethylamine in 3 ml of anhydrous dichloromethane was added 70 μl (0.59 mmol) of tert. Butyl isocyanate is added dropwise. After 30 min at room temperature, the mixture was concentrated in vacuo. Chromatography of the residue on 41 g of silica gel (dichloromethane: methanol 93: 7) gave 144 mg (55% of theory) of the title compound as a colorless rigid foam.
R _f = 0.36, 0.34 (dichloromethane: methanol 93: 7)
MS (FAB): m / z = 486 (M + H) ⁺, 508 (M + Na) ⁺

As described for Example 61, the following products were obtained by reacting the compound from Example 7 with various isocyanates (Table 4):

Claims (8)

1. Pyrrolidine and piperidine-substituted pseudopeptides of the general formula (I) in which
W is hydrogen or a typical amino protecting group, or
- represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which are optionally substituted by aryl having 6 to 10 carbon atoms, or
- for a group of the formula R³-CO-; R⁵R⁴N-CO- or R⁶-SO₂- stands,
wherein
R³ is hydrogen, trifluoromethyl or straight-chain or branched alkoxy having up to 8 carbon atoms or alkyl having up to 18 carbon atoms, which are optionally substituted by aryl having 6 to 10 carbon atoms or pyridyl, or
- aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl having up to 8 carbon atoms,
- Cycloalkyl having 3 to 7 carbon atoms, or
- Indolyl, pyridyl, morpholino or piperazinyl means, or
- a remainder of the formula means
wherein
R⁷ is phenyl or naphthyl,
R⁸, R⁹ and R¹⁰ are the same or different and are straight-chain or branched alkyl having up to 17 carbon atoms, which is optionally substituted by phenyl or naphthyl, or aryl having 6 to 10 carbon atoms, which in turn is substituted by alkyl having up to 4 carbon atoms .
m is a number 0, 1 or 2,
T - morpholino or cyclohexyl means
p is a number 1, 2 or 3,
Y and Y 'are the same or different and denote the CO or SO₂ group,
t - a number 0 or 1 means
R¹¹ and R¹¹ 'are the same or different and are hydroxy or alkoxy having up to 8 carbon atoms,
s - a number 1 or 2 means
R⁴ and R⁵ are the same or different and
- hydrogen or
- aryl having 6 to 10 carbon atoms, which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms or halogen, or
- cycloalkyl having 3 to 7 carbon atoms, or
straight-chain or branched alkyl having up to 18 carbon atoms, which is optionally substituted by pyridyl,
to 8 carbon atoms means
A, B for a direct bond or
- for a remainder of the formula stand,
wherein
x and x 'are the same or different and denote the number 1 or 2
and
r - the number 0 or 1 means
or
- for a group of the formula stand,
wherein
z - the number 0 or 1 means
R¹² is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
R¹³ is cycloalkyl of 3 to 8 carbon atoms or aryl of 6 to 10 carbon atoms or hydrogen, or
is straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by alkylthio having up to 6 carbon atoms, hydroxy, mercapto, guanidyl or by a group of the formula -NR¹⁴R¹⁵ or R¹⁶-OC-substituted,
wherein
R¹⁴ and R¹⁵ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl
and
R¹⁶ hydroxy, benzyloxy, alkoxy with up to
6 carbon atoms or the above-mentioned group -NR¹⁴R¹⁵ means
or which is optionally substituted by cycloalkyl of 3 to 8 carbon atoms or by aryl of 6 to 10 carbon atoms, which in turn is substituted by hydroxy, halogen, nitro, alkoxy of up to 8 carbon atoms or by the group -NR¹⁴R¹⁵,
wherein
R¹⁴ and R¹⁵ have the abovementioned meaning,
or optionally substituted by a 5- or 6-membered nitrogen-containing heterocycle or indolyl, wherein the corresponding -NH functions are optionally protected by alkyl of up to 6 carbon atoms or by an amino-protecting group,
R¹ - represents cycloalkyl having 3 to 8 carbon atoms,
- represents straight-chain or branched alkyl or alkenyl having up to 10 carbon atoms, which are optionally substituted by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn by halogen, nitro, hydroxy, amino or straight-chain or branched alkoxy with up to 6 carbon atoms,
n - stands for the number 1 or 2,
R² - for a radical of the formula -CO-R¹⁷ or -CO-NR⁴R⁵ stands,
wherein
R⁴, R⁵, R¹¹ and R¹¹ 'are as defined above,
R¹⁷ - straight-chain or branched alkoxy having up to 8 carbon atoms, which is optionally substituted by phenyl and their physiologically acceptable salts. 2. According to claim 1 compounds of general formula (I),
in which
W - for hydrogen, tert. Butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Z), or
represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, which are optionally substituted by phenyl, or
- represents a group of the formula R³-CO- or R⁵R⁴N-CO-,
wherein
R³ - hydrogen, trifluoromethyl or straight-chain or branched alkoxy having up to 4 carbon atoms or alkyl having up to 16 carbon atoms, which are optionally substituted by phenyl, naphthyl or pyridyl, or
Phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl having up to 6 carbon atoms,
- cyclopropyl, cyclopentyl, cyclohexyl, indolyl, pyridyl, morpholino or piperazinyl, or
- a remainder of the formula means
wherein
Y - the CO or SO₂ group means
R⁷ is phenyl or naphthyl,
R⁸, R⁹ and R¹⁰ are identical or different and denote straight-chain or branched alkyl having up to 15 carbon atoms, tolyl, phenyl or naphthyl,
m - a number 1 or 2 means
R⁴ and R⁵ are the same or different and
- hydrogen or
Phenyl or naphthyl, which is optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, fluorine or chlorine,
- cyclopropyl, cyclopentyl or cyclohexyl, or
straight-chain or branched alkyl having up to 16 carbon atoms, which is optionally substituted by pyridyl,
A, B and D are the same or different and
- for a direct bond or
- stand for proline, or
- for a remainder of the formula stand,
wherein
r is the number 0 or 1
and
x 'is the number 1 or 2,
- for a group of the formula stand,
wherein
z - the number 0 or 1 means
R¹² represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R¹³ is cyclopentyl, cyclohexyl, phenyl or hydrogen,
- or straight-chain or branched alkyl having up to 6 carbon atoms, which may optionally be substituted by hydroxyl, carboxyl or H₂N-CO-,
or is substituted by cyclohexyl, naphthyl or phenyl, which in turn may be substituted by fluorine, hydroxy, nitro or alkoxy having up to 4 carbon atoms,
or is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, where the corresponding -NH functions are optionally protected by alkyl having up to 4 carbon atoms or by an amino-protecting group,
R¹ - represents cyclopropyl, cyclopentyl or cyclohexyl,
represents straight-chain or branched alkyl or alkenyl having up to 8 carbon atoms, which are optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, which in turn is substituted by fluorine, chlorine, bromine, nitro, hydroxy or amino,
n - stands for the number 1 or 2,
R² - for a radical of the formula -CO-R¹⁷ or -CO-NR⁴R⁵ stands,
wherein
R⁴ and R⁵ are the same or different and have the meaning given above,
R¹¹ and R¹¹ 'are identical or different and denote hydroxy or straight-chain or branched alkoxy having up to 6 carbon atoms,
R¹⁷ - straight-chain or branched alkoxy having in each case up to 6 carbon atoms, which is optionally substituted by phenyl
and their physiologically acceptable salts. 3. Compounds of general formula (I), according to claim 1
in which
W - for hydrogen, tert. Butyloxycarbonyl (BOC) or Benzyloycarbonyl (Z), or
- represents allyl or benzyl,
- represents a group of the formula R³-CO- or R⁵R⁴N-CO-,
wherein
R³ - hydrogen, trifluoromethyl or straight-chain or branched alkyl having up to 14 carbon atoms, which are optionally substituted by phenyl, naphthyl or pyridyl, or
Phenyl or naphthyl, which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl having up to 4 carbon atoms,
- cyclopropyl, cyclopentyl, cyclohexyl, indolyl, pyridyl, morpholino or piperazinyl, or
- a remainder of the formula means
wherein
Y - the CO or SO₂ group means
R⁷ is phenyl or naphthyl,
R⁸, R⁹ and R¹⁰ are the same or different and denote straight-chain or branched alkyl having up to 14 carbon atoms, tolyl, phenyl or naphthyl,
m - a number 1 or 2 means
R⁴ and R⁵ are the same or different and
- hydrogen or
Phenyl or naphthyl, which is optionally substituted by methyl, fluorine or chlorine,
- cyclopropyl, cyclopentyl or cyclohexyl, or
straight-chain or branched alkyl having up to 14 carbon atoms, which is optionally substituted by pyridyl,
A, B and D are the same or different and
- stand for a direct bond, or
- stand for proline, or
- for a group of the formula stand,
wherein
z - the number 0 or 1 means
R¹² is hydrogen or methyl,
R¹³ is cyclopentyl or cyclohexyl,
- or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or H₂N-CO-,
or is substituted by cyclohexyl, naphthyl or phenyl, which in turn may be substituted by fluorine, chlorine or alkoxy having up to 4 carbon atoms, or
is substituted by imidazolyl, triazolyl, pyridyl or pyrozolyl, where the NH function is optionally protected by methyl, benzyloxymethylene or t-butyloxycarbonyl (Boc),
R¹ - represents cyclopentyl or cyclohexyl, or
represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which in turn may be substituted by hydroxyl,
n - stands for the number 1 or 2,
R² - for a radical of the formula -CO-R¹⁷ or -CO-NR⁴R⁵ stands,
wherein
R⁴ and R⁵ are the same or different and have the meaning given above,
R¹¹ and R¹¹ 'are the same or different and denote hydroxy or straight-chain or branched alkoxy having up to 4 carbon atoms,
R¹⁷ - straight-chain or branched alkoxy having in each case up to 4 carbon atoms, which is optionally substituted by phenyl
and their physiologically acceptable salts. 4. Process for the preparation of the compounds of general formula (I), in which
W, A, B, D, R¹, R² and n are as defined above,
found, characterized in that one

• [A] Compounds of general formula (Ia) in which
  R¹, R² and n have the abovementioned meaning,
  via the corresponding salts, preferably via the trifluoroacetates,
  either with compounds of the general formula (II) WABD-OH (II) in which
  W, A, B and D are as defined above,
  with activation of the carboxylic acid,
  or with compounds of the general formulas (III) or (IV) WX (III) (W '') ₂O (IV) in which
  W has the meaning given above
  X is halogen, preferably chlorine,
  and
  W '' is the group CF₃CO or CH₃CO,
  condensed according to the conditions customary in peptide chemistry, in inert solvents, if appropriate in the presence of an adjuvant,

or

• [B] Compounds of the general formulas (V) or (VI) in which
  R¹, W, A, B and D have the abovementioned meaning
  and
  W 'is an amino protecting group, preferably B,
  with compounds of the general formula (VII) in which
  R 2 and n have the abovementioned meaning, with activation of the carboxylic acids, optionally in the presence of a base and an auxiliary and in the case of the compounds of general formula (V) the protecting group W 'then cleaved by a conventional method and optionally with the compounds of the general Formulas (II), (III) or (IV) according to the method described in method [A] further.

5. Medicaments containing one or more Compounds of claims 1 to 3. 6. Antiviral agents containing one or more Compounds of claims 1 to 3. 7. Use of the compounds of claims 1 to 3 for the preparation of antiviral medicines.