AU628392B2 - Medicament for the treatment of diseases caused by retroviruses - Google Patents

Medicament for the treatment of diseases caused by retroviruses Download PDF

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AU628392B2
AU628392B2 AU42461/89A AU4246189A AU628392B2 AU 628392 B2 AU628392 B2 AU 628392B2 AU 42461/89 A AU42461/89 A AU 42461/89A AU 4246189 A AU4246189 A AU 4246189A AU 628392 B2 AU628392 B2 AU 628392B2
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phe
boc
leu
ampa
amino acid
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AU4246189A (en
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Peter Dr. Radatz
Claus Dr. Schmitges
Klaus E. Dr. von der Helm
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Merck Patent GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

I _1_11_ Our Ref: 288487
AUSTRALIA
Patents Act COMPLETE SPECIFICATION FORM
(ORIGINAL)
Application Number: Lodged: Complete Specification Lodged: Accepted: Published: 62 592 4.,C *44 Priority: Related Art: Applicant(s): Merck Patent Gesellschaft Mit Beschrankter Haftung S Address for Service: So D-6100 Darmstadt FEDERAL REPUBLIC OF GERMANY ARTHUR S. CAVE CO.
Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000 Complete specification for the invention entitled "Medicament for the treatment of diseases caused by retroviruses".
.4 0 4 a The following statement is a full description of this invention, including the best method of performing it known to me:- 1- 5020 1 la- Medicament for the treatment of diseases caused by retroviruses I, ~CFC 0 9 0l 1 099* 0990 9#o 9 09 9 0 I 0 #0 to Ii 0696 0 0 9 0 6' 0 t 4 e The invention relates to a medicament for the treatment of diseases caused by retroviruses, containing 5 amino acid derivatives which are capable of inhibiting the activity of retrovirus proteases, or containing pharmacologically acceptable salts of these compounds.
Retroviruses are responsible for a number of serious and often fatal diseases in animals and humans.
10 Retroviruses which may be mentioned in particular are HTLV-III/LAV (HIV-1), and further HTLV-I and HTLV-II, Rous sarcoma virus, Friend virus and Rauscher leukaemia virus, and diseases which may be mentioned are correspondingly above all AIDS (acquired immunodeficiency syn- 15 drome) and-its precursors.
The treatment of corresponding diseases can be successful and permanent only if the virus or its multiplication is combated directly and specifically in the host cell. There are still few suitable medicaments known. Thus, for example, replication of the HTLV-III/LAV virus can be inhibited in vitro and in vivo by D-penicillamine (compare Chandra and Sarin, Arzneimittelforschung (Drug. Res.) 36 (1986) 184-186; Schulof et al., ibid. 36 (II) (1986) 1531-34). However, the agent, which is commercially available under the name Retrovir, can be used to only a limited degree since it often causes considerable side effects, such as anaemia, leucopenia, etc.
The invention was thus based on the object of providing a medicament which can be used successfully, and also without relatively serious side effects, for combating retroviruses and for the treatment of diseases caused by them.
Surprisingly, it has now been found that amino acid derivatives which are active as aspartyl protease inhibitors and contain the structural element of the formula I -NR -CHR-CR3- (CHR) -CO- 2 wherein R, R S and R 6 are each H or alkyl,
R
2 is H, alkyl or in each case substituted or unsubstituted aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, het or het-alkyl,
R
3 is OH), NR'R 6 or O, Het is a 5- or 6-membered S- or Ocontaining saturated or unsaturated heterocyclic radical and n is 1 or 2, or physiologically acceptable salts thereof, also effectively inhibit the activity of a virus-encoded and thus virus-specific protease essential for retrovirus multiplication.
Amino acid compounds which contain the structural element of the formula I and at the same time can function as aspartyl protease inhibitor are known, for example, from the published patents listed below: S 20 EP 0,155,809, EP 0,156,319, EP 0,161,588, EP 0,179,352, EP 0,184,855, EP 0,188,271, EP 0,212,903, EP 0,220,665, EP 0,222,283, EP 0,229,667, EP 0,244,083, EP 0,249,096, EP 0,262,318, EP 0,264,795 and EP 0,272,444.
The invention thus relates to amino acid derivatives which inhibit the activity of retrovirus proteases and contain the structural element of the formula I, or of physiologically acceptable salts thereof, for the preparation of a medicament for the treatment of diseases caused by retroviruses.
The invention particularly relates to the use of i"i 'such compounds for the preparation of a medicament for the treatment of AIDS.
Suitable pharmaceutically acceptable salts of the compounds containing the structural element of the formula I are those which can be derived from mineral acids or organic acids, for example from sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid f or hydrobromic acid, and furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic -0 LU L TO 3 or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, or isonicotinic acid, methane- or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and disulfonic acids or lauryl-sulphuric acid.
Particularly suitable compounds which can be employed according to the invention are, for example, all those which are included in the abovementioned patent publications. Those compounds from EP-A-0,161,588, EP-A-0,179,352, EP-A-0,249,096, EP-A-0,262,318, EP-A-0,264,795, EP-A-0,272,444, and furthermore from DE 3,707,879, DE 3,717,631 and DE 3,817,449, are particularly preferred for combating retroviruses and for the treatment of diseases caused by them, in particular AIDS. Of these, those compounds which are mentioned in EP-A-O,161,588, EP-A-0,249,096 o and DE 3,817,499 are in turn particularly suitable.
The preparation and properties of the compounds which are employed .according to the invention are explained in detail in the patent publications cited.
The inhibition of the activity of retrovirus protease can be demonstrated and tested, for example, in accordance with a method by Katoh et al., Nature 329, 30 654-656 (1987) or Von der Helm et al.,Proc. Natl.Acad.
Sci... USA Vol. 85 p 6612-16 (1988).
The amino acid derivatives containing the structural element of the formula I or salts thereof can be used orally, parenterally, by spray inhalation or rectally in suitable formulations, which contain customary nontoxic pharmaceutically acceptable excipients, adjuvants and diluents. The term "parenteral" used here includes subcutaneous injections and also intravenous, intramus- RiAi cular and intrasternal injections and infusions. The formulations thus obtained can. b.employed as medicaments r_ 4 in human or veterinary medicine. Possible excipient substances are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or administration in the form of an inhalation spray and do not react with the compounds, for example water, vegetable oils, benzyl alcoe hols, polyethylene glycols, glycerol triacetate and other S' fatty acid glycerides, gelatine, soya lecithin, carbohydrates, such as lactose or starch, magnesiumstearate, 10 talc and cellulose. Tablets, coated tablets, capsules, syrups, elixirs or drops are particularly appropriate for f" oral use; lacquered tablets and capsules with coatings or capsule shells which are resistant to gastric juice are specifically of interest. Corresponding oral formulations can also contain, for example, sweeteners, such as glycerol, sorbitol or sucrose, or else demulcents, Sq preservatives, agents for improving flavour and/or dyestuffs. Suppositories are appropriate for rectal use, and solutions, preferably oily or aqueous solutions, and a t furthermore suspensions, emulsions or implants are appropriate for parenteral administration. Sprays which contain the active compound either dissolved or suspended Sr in a propellant gas mixture (for example fluorochlorohydrocarbons) can be used for administration as an inhalation spray. The active compound is advantageously used here in micronized form, it being possible for one or more additional physiologically tolerated solvents, for example ethanol, to be present. Inhalation solutions can be administered with the aid of customary inhalers.
The compounds can also be lyophilized and the resulting lyophilisates used, for example, for obtaining injection preparations. If appropriate, the formulations mentioned can contain suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum traga canth and gum arabic, and/or dispersing or moistening agents, such as lecithin. The formulations can also be sterilized and/or contain auxiliaries, such as preservatives, stabilizers -and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs and/or aroma substances.
If desired, they can also contain one or more other active compounds, for example one or more vitamins or biological immunomodulators, such as interferon or interleukines.
The compounds which are employed in accordance with the invention are as a rule administered analogously to other known amino acid derivatives or peptides which are commercially available, preferably in dosages between about 10 mg and 10 g, in particular between 50 mg and g, per dosage unit. The daily dosage is preferably between 0.1 and 500 mg, in particular between 0.5 and 100 mg/kg of body weight in the case of enteral administration and between 0.1 and 100 mg, in particular between 0.3 and 30 mg/kg of body weight in the case of parenteral administration. The specific dose for each particular patient depends, however, on the most diverse factors, for example on the activity of the specific 20 compound employed, on the age, body weight, general state I: of health and sex, on the diet, on the time and route of administration, and on the rate of excretion, medicament combination and severity of the particular disease to which the therapy applies. Parenteral administration is 25 preferred.
If desired, the medicaments can also contain one or more other active compounds, for example biological immunomodulators, such as interferon or interleukins.
The amino acid radical abbreviations given in the following examples represent the radicals as a rule -NH-CHR-CO-, (wherein R, R' and R" have the specific meaning known for each amino acid) of the following amino acids:
I
_a -6- Abu 2-aminobutyric acid Ada 3-(1-adamantyl)-alanine 3AHCP 48-amino-3S--hydroxy--5-cyc1ohexy-peltalolc acid AHPP 4S-amino-3S-hydroxy-5-phenyl-peltanoi c acid AHMO 5S-amino-4S-hydroxy---methyl--octanoic acid AHPH 5S-amino-4S-hydroxy-6-pheflyl-hexanoic acid AHCH 5S-amino-4S-hydroxy-6-cyclohexyl-hexanoic acid AHIM 5S-amino-4S-hydroxy-2--isopropyl-7-methyl-octanoic acid AHIP 5S-amino-4S-hydroxy-2-isopropyl-6-phelyl-hexaloic acid AHIC 5S-amino-4S-hydroxy-2-isopropyl-6-Cyclohexyl-hexaloic acid AHDM 5S-amino-4S-hydroxy-2,7-dimlethyl-octanoic acid AHMP 5S-amino-4S-hydroxy-2-methyl--6-phenyl-hexanoic acid AHMC 5S-amino-4S-hydroxy-2-methyl-6-cyclohexyl -hexanoic acid 1!15 Ala alanine I3Ala beta-alanine Arg arginine Cal 3-cyclohexylalanine DACP 3S,4S-diamino-5-cyclohexyl-pentanoic acid DAMH- 3S, 4S-Diamino-6-niethyl-heptanoic acid DAPP 3S,4S-Diamino-5-phenyl-pentanoic acid Gly glycine Gln glutamine His histidine Ile Isoleucine Leu Leucine Mal 3-(p-Methoxyphenyl )-alanine Met methionine Wie norleucine hNva norvaline phenylalanine Ser serine Sta statine Thr threonine ITrp tryptophane Val valine Furthermore, the meanings of abbreviations below are: LI ADPA N-2-amino-5, 6-dimethyl--3-pyrazinyl-methy--amide AMPA N-4-amino-2-methyl-5-pyrimidinyl-methyl-amide 180C tert.-butoxycarbonyl benzyloxycarbonyl ethoxycarbonyl IPOC i sopropoxycarbonyl Omle methyl ester QEt ethyl ester Examples: 1. Injection vials A solution of 100 g of BOC-Pro-Phe-His-DAMH-Ile- Phe-OMe and 5 g of disodium hydrogen phosphate in 3 1 of double distilled water is brought to pH 6.5 with 2 N hydrochloric acid, subjected to o sterile filtration, bottled in injection vials and lyophilized under sterile conditions and the vials are subjected to sterile sealing. Each ~1o injection vial contains 500 mg of active corno pound.
Injection vials containing the following active compounds are prepared analogously: o BOC-Phe-His-DAMH-lle-Sta-OMe 14p 0 C2 BOC-Phe-Abu-DAMEH-le-N-(2-phenylethylamidp) 195 BOC-Phe-Asn-DAMH-lle-Phe-QMe 197-8 BOC-Phe-Abu-DAMH-fle-Val-OEt BOC-Phe-Abu-DAMH-Abu-Phe-QH 00BOC-Abu-DAMH-lle-Phe-NH 2 186 BOC-Asn-DAMIH-lle-Phe-OMe 180 130C-Phe-BAM-DAPP-lle-AMPA 225-7 BOC-Phe-Ala -DAPP-lle-AMPA 163-5 BOC-Phe-Val -DAPP-lle-AMPA 232-4 BOC-Leu-BAla-DAPP-Ile-AM1'A 226-7 25 BOC-Gln-Asn -DAPP-fl1e-Val-Me 192-3 BOC-Phe-Asn -DAPP-Gln-Val-OMe 165-7 BOC-Leu-Asn -DAPP-lle-Ser-OMe 185-7 BOC-Leu-Asn -DAPP-lle-Gly-OMe 186-8 BOC-Leu-Abu -DAPP-fle-Val-QMe 175-6 BOC-Leu-Ala -DAPP-lle-Val-OMe 179-80 CBZ-Phe-Abu -DAPP-Abu-Phe-O- IPOC-Phe-BA1a-DACP-lle-AMPA BOC-Abu -Sta-fle-DAMH-OMe 126-7.
BOC-Phe-Abu -Sta-fle-DAM--Me 190 BOC-Asn -Sta-lle-DAMH-OMe 178-9 BOC-Phe-Asn -Sta-ile-DAMI-OMe 181 BOC-Leu-Abu -Sta-le-DAMH-OMe 197 BOC-Gln-Abu -Sta-fle-DAMH-Me 182-3 CBZ-Phe-Asn -Sta-ile-Val-OMe CBZ-Leu-Asn -Sta-ile-Ser-OMe BOC-Phe-f3Ala-Sta-Ille-AMPA CBZ-His-DAPP-Ile-Phe-OMe BOC-Phe-His-DAPP- Ile-Phe-OMe BOC-Phe-Abu-DAM{- Ile-Phe-NH 2 BOC-Ada--His-DAMH-Ile-N- (2-phenylethylamide) BOC-Phe-Nle-DACP- Ile-DAMH-OMe BOC-Phe-Nle-DACP-Sta-OMe L -8- 0000 00 0 4 9 00 00 0 0000 0000 0 0910 00 00 01 0 0 0000 00)0 0 00 00 0 0 00 0 0 0 0 00 00 0 0 00 00 I 0001 0 II I 0 01
I~
BOC-Leu-Ala-AHPP-fle-Gly-OMe BOC-Leu-Ala-AIIPP-Ile-Ser-QMe BOC-Leu-Asn-AI-PP-lle-Ser-OMe BQC-Phe-Asn-AHPP-Gln-Val-QMe BOC-Gln-Asn-AHPP-lle-Val-OMe BOC.-Phe-l3AIa-AHPP-lle-Val-OH BOC-Phe-B3A~a-AH-PP-lle-AMPA CBZ-Phe-Gly -AHPP-lle-Val-QEt ETOC-Phe-BAla-AHCP-fle-AMPA 10 BOC-Phe-His -AHMO-fle-Phe-OMe BOC-Leu-Asn -AHMO-Lle-Ser-OMe BOC-Phe-Asn -ANMO-Gin-Val-OMe BQC-Gln-Asn -AHMO-flle-Val-OH BOC-Phe-13A~a-AHMO-lle-Ser-OMe BQC-Phe-BAla-AHMQ-lle-Val-OMe BOC-Phe-B3A~a-AHMO-lle-AMPA BOC-.Phe-B3A~a-AHMO-lle-N-(3-pyridyhnethylaxuide) BOC-Phe-B3Ala-AHMO-lle-N-benzylaxnid e 20 BOC-Phe-BAla-AHMO-lle-NH 2 (3-Thia-4-BOC-Phe-butyryl)-AHMO-Ile-AMPA (3-BQC-Phe-propionyl)-AHMO-lle-AMPA BOC-Phe-BAla-AHIMO-Gln-Val-OMe BOC-Phe-Asn-AHMO-fle-AMPA BOC-Leu-Asn-AHMO-lle-AMPA BOC-Leu-Abu-AHMO-lle-AMPA Acetyl-Phe-BAla-AHMO-lle-ADPA BOC-Leu-Ala-AHMO0-Ala-Leu-N1{ 2 Acetyl-Phe-Val-AHMO-Val-Phe-NI{ 2 30 BOC-Phe-Asn-AHIMO-Asn-Phe-NH 2 (4-BOC-amiino-1-piperidinocarbonyl)-Leu-BAla- AIHMO-lle-AMPA Morpholinocarbonyl-Phe-BAla-AH-MO-fle-AMPA Acetyl-Phe-BAla-AHPH-Ile-AMPA Acetyl-Leu-BAla-AHPH-lle-AMPA BOC-Phe-BAla-AHPH-lle-AMPA BOC-Leu-Val -AHIPH-l~le-AMPA BOC-Phe-Asn -AHPH-Gln-Val-OMe BOC-Leu-Asn -AHPH-lle-Gly-OMe BOC-Leu-Val -AHPH-lle-Val-OMe BOC-BAla-AHPH-lle-AMPA BOC-Phe-Asn -AHPH-lle-AMPA BOC-Leu-Abu -ALIPH-ile-AMPA BOC-Leu-Asn -AHPH-llie-AMPA BOC-Gln-Asn -AHPH-lle-AMPA BOC-Phe-8Ala-AHPH-lle-Val-NH 2 BOC-AHPH-AHPH-lle-AMPA AHPH-AHPH-IEc-AMPA 'MP 0
C
186-7 192-3 220 219 182 197-8 239-41 208-9 211-2 205-6 194-5 204-5 173-4 219-20 170-1 209-210 213-5 227-8 206-8 223-4 198-9.
213-4 232-3 223-4 236-8 216-8 205-6 183-4 -9- 2) Suppositories a. A mixture of 500 g of 3S-amino-4S-(BOC-Phe- His) -amino-pentanoyl-Ile-Phe-OMe with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool.
Each suppository contains 500 mg of active compound.
Suppositories containing the following active compounds are prepared analogously: Mp 0
C
Morpholinocarbonyl.-Leu-BAla-AI{PH-lle-AMPA Morpholinocarbonyl-Phe-BAla-AHPH-fle-AMPA Morpholinocarbonyl-Phe-BAla-AHPH-le-Val-N'H 2 Morpholinocarbonyl-Phe-BAla-AHCH-lae-VaI-OMe BOC-Phe-Gly -AHIM-]Eie-AMPA 206 BOC-Phe-BA4da-AHIM-lle-AMPA 237 (3-Thia-4-BOC-Phe-butyryl)-AHIM-Ile-AMPA 196 (3-B OC-Phe-propionyl)-AHIM-lle-AMPA 202 (N-Benzyl-N-isopentyl-carbamoyl)-Gly-AHIMAl02 le-3-pyridylrnethyl-amnide 172 (N-Benzyl-N-isopentyl-carbamoyl)-Gly-AHIM- Ile-AMPA 090-1 (N-Benzyl-N-isopentyl-carbamnoyl)-BAla-AHIM- Ile-AMPA 99 193 t2 (4-BOC-amino-1-piperidinocarbony)-Lu-BAlatAHIM-Ile-AMPA 219-20 t BOC-Phe-BAla-AHIM-Ile-Ser-OMe 205-6 BOC-Phe-BAla-AHIM-fle-Val-OMe 228-9 BOC-Phe-D-Ala-AHIM-fle-AMPA 217-8 BOC-Phe-Ala -AHIM4-ie-AMPA 255-6 BOC-Gln-Asn-AHIM-fle-AMPA 214-5 (4-Aino- I-piperidinocarbonyl)-Leu-BAla- AHIM-fle-AMPA 103-5 (4-BOC-am-ino-1-piperidinocarbonyl)-Phe-3Ala- AHIM-fle-AMPA 199-200 (4-Amino-1-piperidinocarbonyl)-Phe-BAla- ALUM-fle-AMPA 18 2-3 Morpholinocarbonyl-Phe-BAla-AHiI-le-AMPA Morpholinocarbonyl-Leu-BAla-AHIM-lle-AMPA Morpholinocarbonyl-Leu-BAla-AHIM-Leu-AMPA octanoyl- Ile-Phe-OMe 2 -benzyl-4 -phenyl-butyryl-Ala-AHCP-I le-DAMH-OMe 3S-hydroxy-4S- (BOC-Phe-His )-aminooctanoic acid CBZ-His-Sta-Ile-Phe-OH 3) Tablets a. A mixture of 1 kg of CBZ-Leu-Sta-Leu-Phe-OH, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate is pressed to tablets in the customary manner so that each tablet contains 200 mg of active compound.
Tablets containing the following active compounds are prepared analogously: MP .C BOC-Leu-BAa-AHIM-BAla-Leu-N1 2 BOC-Leu-BAla-AHIM-Ala-AMPA Acetyl-Phe-BAla-AHIM-BAla-Phe-N{ 2 Morpholinocarbonyl-Leu-BAla-AHIM-BAla-Val-OMe 0 BOC-Leu-BAla-AHJM-Gly-AMPA Acetyl-Leu-BMia-AHIM-Gly-AMPA 1,5 CBZ-BAIa-AJHM-fle-AMPA o0 BOC-Lcu-3Ala-AHIM-le-N1 2 BOC-Leu-BAla-AHI-lle-N-i.Butylamide 8 8Leu-BAM-AHIM-lle-AMPA CBZ-BAla-AHTM-fle-N-(2--phenethylaiid e) Acetyl-Leu-BAla-AHIM-Leu-N-(3-pyridylmethyl-amide) BOC-Phe-Asn-AHIM-lle-AMPA 25 6-7 BOC-Leu-Asn-AHIM-lle-AMPA 261-2 BOC-Phe-Abu-ABIM-lle-AMPA 260-3 8 (2-Benzyl-4-oxo-5,5-dimethylhexanoyl)-BAla- ABIM-fle-AMPA 145 IPOC-Leu-BAMa-ABIIM-fle-AMPA ETOC-Leu-BMia-AIM-lle-Val-NH 2 IPOC-Leu-BAla-A1HJM-fle-N-(3-pyridylmethyl-amide) BOC-Mal-BAla-ALIM-ile-AMPA Morpholinocarbonyl-Leu-BAla-AHIM-fle-Val-OMe (4-Amiino-l-piperidinocarbonyl)-Leu-BAla- AHIM4-lle-Val-NH 2 (4-Amiino-i -piperidinocarbonyl)-Leu-BAia- AHIM-Ala-Val-N11 2 (4-Amino-i -piperidinocarbonyl)-Leu-BAla- ABIM4-Val-Val-NH 2 (4-Anmino-l-piperidinocarbonyl)-Leu-BAla- AHIM-BAla-Val-N11 2 LI (4-Anmino-1-piperidinocarbonyl)-Lu-BAla- AHIM-Leu-Val-NI{ 2 Morpholinocarbonyl-Leu,-Asn-AHTM-Ile-Val-OMe -BOC-AHPH-AHI-M-Ille-AMIPA 3-phenylpropionyl-His -Sta-Leu-p-chlorbenzylamide BOC-Phe-His-DACP-Ile-N- (2-phenylethylamide) BOC-Phe-Gly-AHCP-Ile-N- (3-pyridyl-methyl-amide) BOC-Phe-SAla-ALLP-Ile-AMPA BOC-Leu-f3Ala-AHIP-U1e-Val-NH 2 *#get:(4-Amino-1-piperidinocarbonyl)-Phe-BAla-AHIP- Ile-AMPA (4-Amino-l-piperidinocarbonyl)-Leu-BAla-AHIPfle-AMPA 4 4 0 (4-Am-ino-l-piperidinocarbony)-Leu-BAla-AHIP- Leu-AMPA Morphoiinocarbonyl-Leu-BAla-AIHP-Leu-Vai-OMe '0 (4-Amino-l-piperidinocarbonyl)-Leu-BAla-AIP- LePu-VaI-NH 2 (4-Am-ino-I -piperidinocarbonyl)-Le.Pu-BAla-AHIP- Ala-Val-NH 2 (4-Amidno-i -piperidinocarbonyl)-Leu-BAla-AHLP- Val-Val-NH 2 (4-Amiino-i -piperidinocarbonyl)-Le-u-BAla-AHIP- BA~a-Val-NH 2 4) Coated tablets Tablets are pressed analogously to Example 3 and are then coated in the customa'ry manner with a coating of sucrose, maize starch, talc, tragacanth and dyestuff.
Capsules Hard gelatine capsules are filled with 500 g of BOC- Phe-His-AHCP-Leu-OH in the customary manner, so that each capsule contains 500 mg of active compound.

Claims (4)

1. Amino acid derivatives of the formula I X-Z-NH-CH (CH2RI) -CR2-CH 2 -CHR 3 -CO-E-G-Y I, wherein X is H, R2- (CH 2 -CO- Rl- (CH 2 -CH (CH 2 R 1 R3-CO--, R3-O-CO--, 4- (R 3 -O-CO-NH) -piperidino-carbonyl, mor- pholino-carbonyl, 4-amino-piperidino-carbonyl, R 3 -O- CO-NH-CHRI -CR2 (CH 2 a-CO-, H 2 N-CHR'-CR 2 (CH 2 )n-CO-, RlR 3 N-CO-, R 3 -CO-CH 2 -CHR1-CO- or another useful amino- protecting group, Z is 0-2 amino acid radicals, linked by a peptide bond to each other, selected from a group consisting of Abu, Ada, Ala, fl-Ala, Asn, Gin, Giy, His, Leu, Mal, Nie, Phe and Val, with the proviso that in the case of a dipep- tide radical the C-terminal amino acid residue can be replaced by -CH 2 -S-CH 2 -CO- or -CH 2 -CH 2 -CO-, E is 1-2 amino acid radicals, linked by a peptide bond to each other, selected from a group consisting of Abu, Ala, f-Ala, Gin, Gly, Ile, Phe, Ser and Val, G is missing or is -NH-CHR'-CR 2 -CH 2 -CO-, Y is -OH, -H -NHR3 or -NH- (CH2)fl-R4, RI is aly ih1-6 C-tmbenzyi, cyciohexyl, phenyl or p-chiorophenyi, R3 isalkylwith1-6 Caos whereby, R1, R 2 and R 3 if they occur several times, can be equal or different and n is 1or 2 4132T:mmb 13 or of physiologically acceptable salts thereof which inhibit the activity of retrovirus proteases, when used for the preparation of a medicament for the treatment of diseases caused by retroviruses.
2. Amino acid derivatives which inhibit the activity of retrovirus and proteases and contain the structural element of the formula I, or of physiologically acceptable salts thereof, when used in combating retroviruses.
3. Amino acid derivatives according to Claim 1 when used for the preparation of a medicament for the treatment of AIDS.
4. Amino acid derivatives according to claim 2 when used in combating AIDS. DATED this 29th day of May, 1992. MERCK PATENT GESELLSHCAFT MIT BESCHRANKTER HAFTUNG "By Its Patent Attorneys DAVIES COLLISON CAVE 0 64 4 4 *o a 0 *o r a ti t 1 t
AU42461/89A 1988-10-05 1989-09-29 Medicament for the treatment of diseases caused by retroviruses Ceased AU628392B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3833764A DE3833764A1 (en) 1988-10-05 1988-10-05 MEDICINAL PRODUCTS FOR THE TREATMENT OF RETROVIRUS DISEASES
DE3833764 1988-10-05

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AU628392B2 true AU628392B2 (en) 1992-09-17

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JP (1) JPH02145515A (en)
AU (1) AU628392B2 (en)
DE (1) DE3833764A1 (en)
HU (1) HU204709B (en)
ZA (1) ZA897549B (en)

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DE4126485A1 (en) * 1991-08-10 1993-02-11 Bayer Ag TRIFLUOROMETHYL-CONTAINING PSEUDOPEPTIDE

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3964489A (en) * 1988-07-08 1990-02-05 Smithkline Beckman Corporation Retroviral protease binding peptides
AU4019289A (en) * 1988-08-24 1990-06-21 Merck & Co., Inc. Hiv protease inhibitors useful for the treatment of aids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3964489A (en) * 1988-07-08 1990-02-05 Smithkline Beckman Corporation Retroviral protease binding peptides
AU4019289A (en) * 1988-08-24 1990-06-21 Merck & Co., Inc. Hiv protease inhibitors useful for the treatment of aids

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DE3833764A1 (en) 1990-04-12
HU895215D0 (en) 1990-01-28
HU204709B (en) 1992-02-28
HUT51147A (en) 1990-04-28
AU4246189A (en) 1990-04-12
EP0369141A1 (en) 1990-05-23
ZA897549B (en) 1990-07-25

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